ACUPUNCTURE in ANAESTHESIA and SURGERY Studies in China and the Netherlands CIP-GEGEVENS KONINKLUKE BIBLIOTHEEK, DEN HAAG

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Studies in China and the Netherlands

H.G.KHO

ACUPUNCTURE IN ANAESTHESIA AND SURGERY Studies in China and the Netherlands CIP-GEGEVENS KONINKLUKE BIBLIOTHEEK, DEN HAAG

Kho, Hing Gwan

Acupuncture in anaesthesia and surgery: studies in China and the Netherlands/ Hing Gwan Kho. - (S.I.: s.n.). - 111. Proefschrift Nijmegen. - Met lit. opg. - Met samenvatting in het Chinees, Duits, Frans, Indonesisch en Nederlands. ISBN 90-9004082-X Trefw.: acupunctuur in de anesthesie / acupunctuur in de chirurgie.

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Dissertatie-Uitgeverij Mondiss, Kampen; Handboekbinderij Mathieu Geensen, Nijmegen. ACUPUNCTURE IN ANAESTHESIA AND SURGERY

Studies in China and the Netherlands

Een wetenschappelijke proeve op het gebied van de

MEDISCHE WETENSCHAPPEN in het bijzonder de GENEESKUNDE

PROEFSCHRIFT

ter verkrijging van de graad van doctor aan de Katholieke Universiteit van Nijmegen, volgens besluit van het College van Decanen in het openbaar te verdedigen op maandag 27 mei 1991 des namiddags om 3.30

door

HING GW AN KHO geboren te Surabaja Promotores Prof.Dr.P.W.C.Kloppenborg Prof.Dr.H.H.Beneken Kolmer

Co-promotor Dr.J.van Egmond ACUPUNCTURE IN ANAESTHESIA AND SURGERY

Studies in China and the Netherlands

THESIS

in the MEDICAL SCIENCES

to obtain the Ph.D. degree at the Catholic University of Nijmegen, by the decision of the College of Deans. The public defence will take place on Monday, May 27th, 1991 at 3.30 p.m.

HING GWAN KHO bom in Surabaja The studies reported in this thesis were performed in the Department of Anaesthetics of the First Affiliated Hospital of the Nanjing Medical College, China (head: Prof.Dr.G.L.Zhang) and the Institute for Anesthesiology, University Hospital Sint Radboud, Nijmegen (former head: Prof.Dr.J.F.Crul, present head: Prof.Dr.L.H.D.J. Booij). The Laboratory of Experimental and Chemical Endocrinology (head: Prof.Dr.T.J.Benraad), and the Laboratory of Paediatrics and Surgery (head: Prof.Dr.J.Trijbels) took the responsibility for the measurement of endocrine and immune variables. it χ CONTENTS

List of Abbreviations xi Prologue 1 Aim of the study 5

PART I

CHAPTER 1 Mechanisms of acupuncture analgesia 7

CHAPTER 2 Aspects of the response of the body to anaesthesia and surgery 29 CHAPTER 3 Techniques of blood sampling and methods of determination 45

PART II

CHAPTER 4 Acupuncture anaesthesia in China. History, development and clinical research

4.1 Development of medical services in China with particular reference to anaesthesia 53 4.2 Acupuncture anaesthesia revised. Observations on its use in thyroid surgery and influence on recovery and morbidity in a Chinese hospital. . . .61 Anaesthesia 1990;45:480-485. 4.3 The patterns of endocrine and immune responses in patients undergoing thyroid surgery under acupuncture anaesthesia in China 71 Acta Anaesthesiologica Scandinavica 1990;34:563-571.

CHAPTER 5 Acupuncture anaesthesia in the West. Clinical development and research.

5.1 Development of acupuncture anaesthesia in the West 87

viii 5.2 Acupuncture and transcutaneous stimulation analgesia in comparison with moderate-dose fentanyl anaesthesia in major abdominal surgery. Clinical efficacy and influence on recovery and morbidity 95 Anaesthesia 1991;46:129-135. 5.3 Effects of acupuncture and transcutaneous stimulation analgesia on plasma hormone levels during and after major abdominal surgery. Comparison of three anaesthetic techniques Ill Submitted. 5.4 Lack of effect of acupuncture and transcutaneous stimulation's analgesia on immunoglobulin levels and leucocyte counts following major abdominal surgery 123 Published, in part, European Journal of Anaesthesiology 1991;8:39-45.

CHAPTER 6 Final Comments 133

Summary 136 Gaiyao 141 Zusamenfassung 149 Resumé 155 Ringkasan 161 Samenvatting 167

Epilogue 173

Appendix 176

Publications 181

Curriculum vitae 185

ix Él *

* 3C * ΐ ft ft #, * * m A ί ш M* * ti 3È ¿S Ш И ΐ, Я Äfr « )S £ Ψ -Жо të Я * # f * fë, t * -У- Â H ί 4-c Ш Ü ^ # Ä - #, f m 4 ж * # и»

-ЛЗІ^

Self-Mockery

There's nothing you can do about a hostile fate: You bump your head before you even tum. When in the street I pull my old hat down; My leaky wine-boat drifts along the torrent. Coolly I face a thousand pointing fingers, Then bow to be an infant's willing ox. Hiding in our little house, sufficient to ourselves, I care not what the season is outside.

Lu Xun (1881-1936)

То Marie, Kuan Hua, Ay Lin, Kuan Kun and Pau Lin. ABBREVIATIONS

A adrenaline AA acupuncture analgesia ACAN acupuncture anaesthesia ACh acetylcholine ACTH adrenocorticotropic hormone Acu acupuncture Acupoint acupuncture point ADH antidiuretic hormone AN anaesthesia AN+S anaesthesia and surgery ANOVA analysis of variance AOAA aminooxyacetic ASA American Society of Anesthesiology BE beta-endorphin BSA bovine serum albumin CA catecholamine CATA combined acupuncture and transcutaneous stimulation analgesia CCK-8 cholecystokinin-octapeptide CBG corticosteroid binding globulin CNS central nervous system Con A concavanaline A COMT catechol-o-methyl-transferase CRH corticotrophin releasing hormone DA dopamine DAP diastolic arterial pressure DHT 5,6 (5,7) dihydroxytryptamine DNIC diffuse noxious inhibitory control DOPS dihydroxyphenilserine DPA D-phenylalanine EAC erythorcyte-amboreceptor complement EDTA ethylenediaminotetraacetate EGTA ethylene bis(oxyethylenenitrilo)tetraacetic acid FSH follicular stimulating hormone GABA gamma aminobutyric acid GH growth hormone GLM general linear model GSH glutathion GVG gamma-vinyl GABA HC-3 hemicholine 5HIAA 5-hydroxyindolacetic acid 5H1P 5-hydroxytiyptophan 5HT serotonin

XI LM. intramuscular IRMA immuno radio metric assay I.V. intravenous LEK leu-enkephalin LH luteinizing hormone MAO monoamine oxidase MAP mean arterial pressure MEK met-enkephalin MFA moderate-dose fentanyl anaesthesia MIT migration inhibition test 3-MP 3-mercapto-propionic acid MLC mixed lympholitic culture MN metanephrine NA, NE noradrenaline NKC natural killer cell NMN normetanephrine NRM nucleus raphe magnus N.S. not significant 60HDA 6-hydroxydopamine PAG periaqueductal grey matter PCPA parachlorphenylalanine PEG polyethylene glycol PHA phytohaemagglutinin PMN polymorphonuclear PRL prolactin PWM pokeweed mitogen RIA radio-immunoassay RR respiratory rate SAM S-adenosylmethionine SAP systolic arterial pressure SD standard deviation SEM standard error of mean SMD surgery for malignant disease SPA stimulation produced analgesia T3 3,5,3' triiodothyronine T4 3,5,3',5' tetraiodo-thyronine тем traditional Chinese medicine IF tail flick TPB tetraphenylborate TSH thyroid stimulating hormone VS versus WBC white blood cell WDRN wide dynamic range neurons ZWO zuiver wetenschappelijk onderzoek (Dutch organisation for academic research) PROLOGUE

The ancient Chinese method of inducing analgesia by acupuncture (acupuncture analgesia/AA) received little attention until its use as an anaesthetic (acupuncture anaesthesia/ACAN). It was introduced in 1958, and was reported in Western countries in the 1970's (1, 2). The scientific world was left with a dilemma, because such a phenomenon could not be explained by the current physiological knowledge. There was general disbelief and scepticism as to how needle stimulation of certain locations, the so called acupuncture loci, anatomically unrelated to the pain area, could produce analgesia. The assumption was made that the analgesia produced was based on a psychological effect or as a hypnotic manoeuvre (3). As is often the case, an answer became evident as the amount of scientific evidence increased. The technique was indeed reproducible in various clinics in the West 1.4-6). In addition, studies on animals not susceptible to suggestion demonstrated similar effects (7). In fact the use of ACAN had challenged the scientific community which in tum triggered and accelerated basic pain and analgesic research to the progress and achievements of the past decades. The gate control theory of pain has been adopted (8), although it could not support the observation that acupuncture suppressed selectively the nociceptive but not the non-nociceptive response. In addition, the delayed onset of analgesia and the fact that its optimal effect was reached after needle manipulation of at least 20 minutes duration did not fit with presynaptic inhibition, the main feature of the gate control theory. In 1960, an observation was made that the site of action of the analgesic effect of morphine was situated in the brain, particularly in the brain tissue along the wall of the third ventricle and the aqueduct (9). By 1972 and 1973 the presence of morphine receptors in the brain had been demonstrated (10, 11) and in 1975 enkephalins were discovered (12). A possible explanation of the mechanism of AA was suggested in 1979, when it was shown that the AA could be blocked by the opioid* antagonist naloxone (13). The result was confirmed in studies in healthy volunteers (14), in laboratory animals (15) and in patients with chronic pain (16). In addition, a controlled study has reported the positive influence of acupuncture on the experimental survival of ischaemic flaps (17). The interesting aspects of pain management by acupuncture, both acute and chronic and the fact that acupuncture, as a therapeutic modality, often achieved good results in cases where Western medicine offered no solution (18, 19) stimulated the author to study this branch of traditional Chinese medicine (TCM) further, especially its use within the operating theatre.

^Footnote: For convenience, the author in this thesis will not distinguish between opiates such as morphine and related alkaloid pharmacological agents, and opioids, a family of compounds that include the alkaloid opiates as well as a subclass of neuropeptides that have opiate-like activity and that are endogenously produced by the brain, pituitary gland and other peripheral tissues.

1 Conducting clinical studies

From the beginning it was clear that it would not be easy to carry out the studies described in the following chapters. In the first place, because of the "alternative" nature of the subject chosen for investigation and despite its increasing popularity with patients, there was a general lack of acceptance by Western physicians (20). Vanous meetings were therefore required to discuss the need for an investigation of acupuncture as a method of non-pharmacological analgesia. Secondly, in a time of retrenchment, it was a problem to find the support needed to carry out the study, as the laboratory measurement of the parameters used m the study protocol was costly. The "alternative" character of the subject might also have influenced the decision by the Z.W.O. (Dutch organisation for academic research) not to support the study. The research foundation of the Permanent Commission for Alternative Medicine of the Dutch Ministry of Welfare, Public Health and Culture, which was founded on the recommendations of the Commission of Muntendam in its final report in 1981, aims to stimulate and support scientific investigations within Alternative Medicine (21). Surprisingly, an application for support to this Authonty did not meet with a favourable response because of the "very specific character" of the subject to be studied. The third problem arose from the fact that it was author's firm belief that a part of the study had to be performed in the country of ongin of acupuncture. Chinese hospitals are not allowed to make direct arrangements for cooperation with Western hospitals without official permission from the provincial government. The preparation of two "important documents" proved very time consuming. A collaboration with a foreign hospital (see Appendix) had to be agreed at a provincial level and the same procedure had to be followed to get permission to take the samples out of China. With this documentation the teaching hospital was willing to cooperate. China's approach to the West in recent years has led to more exchanges with Western scientists. They are, however, pnmanly interested in exchanges in which they will have more profit than their Western counterparts. Scientific investigations of TCM do not receive such prionty. Moreover, the traditional Chinese fear of losing blood makes it extremely difficult to find enough blood donors, and even more so to persuade them of the need to draw blood samples for a scientific investigation. To illustrate this problem: Mrs. Xing Lixiang*, a senior official of the Beijing Blood Centre stated that for a donation of 200 ml of blood, an allowance ranging from US$ 8.00 to US$ 80.00 should be given (22). Some factories even promised their employees a week-long trip and three days off work for donating the same amount of blood. Several meetings were therefore

•Footnote This thesis uses the pinyin system for romanizing Chinese throughout The pmym was introduced by the Chinese in the 1950's and has replaced the older Wade-Giles system It is pronounced as it looks Three initial consonants, however, are not pronounced as they would be in English The pinyin "c" is pronounced "ts", the "q" is pronounced "ch", and the "x" is pronounced "sh" In some cases where the consonant break is unclear, an apostrophe is used to aid in pronounciation, such as the city Xi'an or Y an'an to distinguish them from xian or yanan.

2 needed to reach an agreement on the quantity of blood allowed to be withdrawn for each sample and the number of samples as well. Last but not least it was a rather complicated exercise in logistics to organize the collected samples, once frozen in dry ice, for transportation back to the laboratory in Nijmegen. As the rate of evaporation of dry ice is 150 g hour1, a delay in the air transportation might result in samples thawing Once the samples defrosted measurements would be worthless. It was very satisfying to see that the temperature inside the boxes containing samples remained far below 0oC on arrival at Schiphol, Amsterdam. Nevertheless, all the issues mentioned above have been overcome and have resulted in the data presented in the following chapters.

References

1 Majer EH, Bischko J Zur Akupunktur Analgesie bei tonsillenoperationen Arch klin exp Ohr-, Nas- u Kehlk -Heilk 1973,250 280-282 2 Bonica JJ Anesthesiology in the People's Republic of China Anesthesiology 1974,40 175- 186 3 Bowers JZ Reception of acupuncture by the scientific community from scom to a degree of interest Comp Med East West 1978,6 89-96 4 Benzer H, Bischko J, Pauser G, Zimmerman Ζ Die Akupunktur-Analgesie In Benzer H, Frey R, Hugin W, Maryrhofer O, eds Lehrbuch der Anasthesiologie Reanimation und Intensivtherapie Berlin/Heidelberg/New York Springer Verlag, 1977,403 408 5 Roccia L Klinische Bilanz von 500 Fallen der Akupunktur-Analgesie in der Allgemeinchirurgie, HNO, Gynäkologie und Zahnheilkunde In Bischko J, ed Kongressbencht der zweiten franzosisch-italiemsch-osterreichischen Tagung in Wien Vienna Verlag Η Egermann, 1976,15-20 6 Cahn AM, Carayon P, Hill C, Flamant R Acupuncture in gastroscopy Lancet 1978,i 182- 183 7 Han JS, Zhou ZF, Xuan YT Acupuncture has an analgesic effect in rabbits Pain 1983,15 83-91 8 Melzack R, Wall PD Pain mechanisms a new theory Sci 1965,150 971 979 9 Han JS Footsteps on the neurochemical study of acupuncture analgesia In Han JS, ed The neurochemical basis of pain relief by acupuncture, A Collection of papers 1973-1987 Beijing Med Umv Beijing Med Sci Press, 1987,3-18 10 Pert CB, Snyder SH Opiate receptor Demonstration in nervous tissue Sci 1973,179 1011- 1014 11 Terenius L Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex Acta Pharmacol Toxicol 1973,32 317-320 12 Hughes J, Smith TW, Kosterhtz HW, Fothergill LA, Morgan BA, Moms HR Identification of two related pentapeptides from the brain with potent opiate agonist activity Nature 1975,258 577-579 13 Mayer DJ, Pnce DD, Rafu A Antagonism of acupuncture analgesia in man by narcotic antagonist naloxone Brain Res 1977,121 368 372 14 Jiang ZY, Ye Q, Shen YT, Zhu FX, Tang SQ, Liang NJ, Zeng XC Effects of naloxone on expérimental acupuncture analgesia evaluated by sensory decision theory Acta Zool Sin 1978,24 1-8 15 Pomeranz B, Chiù D Naloxone blocks acupuncture analgesia and causes hyperalgesia endorphin is implicated Life Sci 1976,19 1757-1762 16 Sjolund B, Enkson M The influence of naloxone on analgesia produced by peripheral conditioning stimulation Brain Res 1979,173 295-301 17 Jansen G, Lundeberg Τ, Samuelson UE, Thomas M Increased survival of ischaemic musculocutaneous flaps in rats after acupuncture Acta Physiol Scand 1989,135 555-558

3 18 Philp Τ, Shah PJR, Worth PHL Acupuncture in the treatment of bladder instability Br J Urol 1988,61490-493 19 Fischi F, Riegler R, Biegelmayer С, Nasr F, Neumark J Die Beeinflußbarkeit der Samen Qualltat durch Akupunktur bei subfertilen Mannem Dtsch Ztschr Akup 1984,27 53 56 20 Kho HG Acupuncture as alternative medicine, facts and perspectives Ned Τ Geneesk 1987,131 1869-1902 21 Muntendam Ρ Alternatieve geneeswijzen in Nederland Rapport van de commissie alternatieve geneeswijzen Den Haag Staatsuitgeverij, 1981,255-262 22 Zhang TT Blood donors get new incentives Chma Daily 1987, April 20

4 AIM OF THE STUDY

Acupuncture for pain relief has been practised for many centuries in China, where it was also used to treat many other diseases and problems. In China since 1958, acupuncture is routinely used as a form of regional anaesthesia for certain surgical procedures, during which patients remain conscious. The interest in acupuncture from the Western scientific world was minimal until recently. Only a particular part of its broad indications, i.e. AA, has been the subject of numerous animal experiments and clinical studies. The evidence that acupuncture is capable of releasing natural pain-killing substances initiated its clinical application as a physiological method inducing analgesia in both acute and chronic pain in Western countries. The use of acupuncture in anaesthesia and surgery has increased the interest of scientists from various disciplines.

In modem anaesthetic practice the concept of balanced anaesthesia has gained more and more popularity. Specific drugs are applied to induce specific effects, i.e. unconsciousness, analgesia and muscle relaxation. In contrast to the Chinese concept of inducing ACAN during surgery in conscious patients, a modified ACAN technique has been developed in the West in which the analgesic component of balanced anaesthesia is obtained, as much as possible, by acupuncture instead of the administration of opioids. Depending on the type of surgery, this can result in the total or partial replacement of exogenous opioids. In this thesis, experimental results of two separate clinical studies are described. The first study was carried out in Nanjing, China, during classical ACAN in conscious patients. The second study was carried out in Nijmegen, The Netherlands, applying a modified ACAN technique.

This thesis is in two parts. Part I is divided into three chapters. Chapter 1 reviews the modem literature that focuses on the mechanisms of AA. Theories on these mechanisms are based on data of animal and clinical experiments performed at various laboratories inside and outside China. The afferent pathways transmitting acupuncture impulses have been identified and the involvement of neurochemical substances as mediators in AA have been demonstrated. Chapter 2 reviews the characteristics of the response of the body to surgery in terms of hormone and immune variables. The role of acupuncture and different anaesthetics, in particular the opioids, in the modulation of the body's response to surgery are also reviewed. Chapter 3 describes the techniques of blood sampling and the methods for determination of the different blood indices used in the clinical studies. Correct blood sampling and handling, in particular for the determination of hormones, is important for obtaining reliable quantitative results of plasma levels.

5 Part II consists of the chapters 4 and 5 describing the clinical studies in Nanjing and Nijmegen, respectively.

The first part of the chapter 4 (4.1.) gives an overview of the health system, especially the anaesthesia services, in China in the 1950's. Anaesthetic departments were upgraded to the same level as surgical departments, and priority was given to the integration of the TCM with Western medicine. This background is important for understanding the introduction of acupuncture as an anaesthetic. The other parts, 4.2 and 4.3, present the experimental data concerning the use of classical ACAN. This part of the study, conducted in Nanjing, aimed to observe whether or not classical ACAN has been revised since its introduction in 1958, to evaluate the clinical efficacy of classical ACAN and its influence on the recovery, convalescence and morbidity, and, to describe how and to what extent it influences the pattern of hormone and immune responses. This was accomplished during a standardized surgical procedure namely thyroid surgery.

The first part of chapter 5 (5.1) sketches the introduction of ACAN in Western countries. A search for an improvement of the classical ACAN has led to the development of the present technique, the modified ACAN. The rest of chapter 5 presents the data concerning the use of modified ACAN. This part of the study, conducted in Nijmegen, aimed to answer whether or not the reduction of opioids associated with the use of acupuncture implied a loss of stable haemodynamics during the course of surgery and/or led to a different demand for postoperative opioids. In addition, it was evaluated whether or not modified ACAN reduced perioperative blood loss and/or to what extent it affected the recovery, postoperative convalescence and morbidity. Another aspect that received careful attention was the evaluation of the body's response in terms of the sympatho adrenal, neuro-endocrine and immune variables, during the per- and postoperative periods. This was achieved using a standard major abdominal operation, i.e. retroperitoneal lymph node dissection, considered to be one of the most painful and stressful abdominal procedures.

6 CHAPTER 1

MECHANISMS OF ACUPUNCTURE ANALGESIA

The nociceptive response is a complex phenomenon that includes autonomic reflexes such as tachycardia, and somatic reflexes such as withdrawal and voluntary actions (fight or flight). Although these responses are activated through the same primary afferent neurones and can often be observed simultaneously, the neural substrates mediating these responses are not identical. The transmission of a nociceptive message, which involves peripheral and central substrates, has been reviewed extensively (1). Acupuncture is a physiological method of inducing an increase in the pain threshold, although it cannot produce total ablation of pain perception. This chapter reviews the possible underlying mechanisms of the antinociceptive effect produced by acupuncture (acupuncture analgesia/AA) in terms of neurophysiology and neurochemistry. Many studies have indicated that AA is mediated through the peripheral and central nervous systems (CNS) and detailed information about the neural circuitry involved has been elaborated. It has been thought that AA activates the pain modulatory systems of the body, thereby suppressing the transmission and perception of noxious stimuli at different levels of the CNS. Of particular interest are the nature of acupuncture points (acupoints), the neural pathways that are activated by stimuli from the needle insertion and stimulation, the role of neurotransmitters at the spinal and higher levels and the involvement of different endogenous opioids with corresponding different stimulation criteria.

Acupuncture points

Anatomical structure. Considerable effort has been expended in demonstrating the existence of acupoints and meridians. Anatomical and histological characteristics have been studied as well as electrophysiological responses and effects. Cadavers have been dissected in the attempt to identify anatomical features of acupoints. The acupoint has been described as a sharp cylindrical perforation of the superficial fascia of the body with a diameter of 2-8 mm, covered by a sheet of connective tissue in which a neurovascular bundle runs (2). Nearly all acupoints have been identified as having such characteristic structures. Moreover, they have been found to be intimately related to the distribution of nerve trunks, motor end plates and blood vessels (3-6). At the histological level, a study of large numbers of microtomed preparations originating from 34 skin areas, which included 11 acupoints and a number of 'neutral' skin areas, revealed two types of acupoint: receptor and effector (7). This was based on the difference in the distribution of the somatosensory receptors and a number of free nerve endings such as Meissner's corpuscles. Krause's end-bulbs, glomus-bodies and smooth muscle. More recently, the existence of acupuncture meridians has been subjected to two studies using Technetium 99m injected into a number of acupoints and non- acupoints. The first study (8) claimed to show that there was scintigraphic

7 evidence of specific radioactive paths which could be interpreted as acupuncture meridians. A second study (9) was unable to confirm this. Thus the controversy, as to whether acupuncture meridians exist or not, remains.

Biophysical properties. Various physical methods have been used to investigate the existence of acupoints. Most practitioners agree that acupoints possess a lower skin resistance (10). Based on this phenomenon, an acupoint detector device has been developed to identify the correct location of acupoints. Using electrodes designed to minimize contact pressure variations, a number of acupoints have been reported to have a significantly lower skin resistance when compared to adjacent areas (10). Other studies have reported significantly more positive potentials at acupoints, when compared to non-acupoints (11, 12). However, it is known that sweating or even light pressure on the epidermis, by an acupoint detector device, can lower skin impedance (4, 13). In addition, an electrode artifact might also influence the observed results. In view of these possibilities, studies showing differences in skin impedance should be interpreted with caution.

Studies of effects. The efficacy of needling at the correct acupoint and the analgesic effects of subsequent manual (classical) or electrical (modem) stimulation have been studied in animals and man. Most trials have compared real versus sham acupoints, with or without needling. Rabbits (14-17), cats (18-20), rats (14, 21, 22) and mice (23) have been used to study the phenomena of AA. Various noxious stimuli such as pinprick, clamping of the skin, radiant heat and electrical stimuli to the buccal skin and tooth pulp have been used. The AA in terms of behavioural signs such as vocalization, head jerk, tail flick (TF), escape response, jaw opening and reflex inhibition were evaluated. In man, changes in pain threshold after stimulation of tooth pulp (24-26), cold (27) or heat (28) stimuli and the corresponding effects including evoked potentials (29) and reflex inhibition (30, 31) have been studied. The evidence acquired in these controlled studies, involving induced acute pain, has shown that acupuncture produces significantly greater analgesia and reflex inhibition than placebo (needling non- acupoints or needling of no points at all). The validity of these studies has been questioned (32, 33). Unlike trials on drugs, acupuncture experiments in man have limitations since it is impossible to carry out a double blind study. This and the question as how to reduce the placebo effect, particularly in clinical studies, has received more attention recently (34, 35). The involvement of placebo should, therefore, be considered, although it is known that placebo has little effect (3%) in acute experimentally induced pain in contrast to a 30-35% response in chronic pain (36, 37). In Western medical practice, trigger points have been used for the diagnosis and treatment of pathological pain (38). Stimulation of trigger points often results in prolonged pain relief. Due to their similarity with acupoints in relieving pain, a study has been conducted to determine the correlation between acupoints and trigger points based on two criteria: spatial distribution and the associated pain pattern. A high degree of correlation (71%) was found (38). This indicates that both, though discovered independently but derived from the same kind of

8 empirical observations, represent the same phenomenon and could possibly be explained by the same neural mechanisms. Although acupoints and triggerpoints are used in practice for both diagnosis and treatment of pain conditions, their exact role remains to be clarified.

Neural pathways

Afferent impulses from puncture sites. The evidence that afferent pathways are involved in mediating AA has been documented by a study showing a correlation between the characteristic subjective needle sensations, dc qi, and the observed analgesic effect (39). De qi, which is thought to be a prerequisite for the analgesic effect of AA, is often described as a sudden feeling of numbness, soreness, distension or heaviness in the deep tissue experienced when the inserted needle has reached a certain depth. Numbness is usually experienced by direct stimulation of a nerve trunk or branch, whereas soreness will be felt when the needle-tip touches the periosteum, the aponeurosis, a tendon or a ligament. On the other hand, contraction or increased tension of muscles will result in sensations of heaviness or distension. Changes in pain threshold at different cutaneous points have been compared under four different conditions, i.e. conditions of rest, of acupuncture, of acupuncture following blockade of cutaneous nerves supplying the skin over the needling point and of acupuncture following blockade of the muscular nerves supplying the deep tissues underlying the needling point. Subcutaneous pretreatment with local anaesthetic did not, but intramuscular (i.m.) injection did abolish de qi and the corresponding analgesic effect (39). This suggests that the receptors in the deep tissue, particularly in muscles, are the origins of de qi. Neither de qi nor analgesia can be elicited when needling is performed below the levels of spinal cord damage. De qi and the corresponding analgesia are unaffected when needling is performed under experimental ischaemic condition, e.g. after the circulation of the upper arm has been occluded by a tourniquet (37, 39, 40). Further analysis, based on nerve block experiments and detailed measurements of the conduction velocity of activated individual fibres under different conditions in animals (cats, rats and monkeys) and in man, revealed that muscle pressure and stretch receptors are activated by needling stimulation and the afferent impulses from these receptors are mediated by large (group II or Aß) and medium (group III or Αδ) sized fibres (23, 40-43). Experiments in monkeys, with conditioning stimuli of mainly Aaß fibres of the tibial nerve, resulted in only a slight inhibition of the C-fibre evoked cell activities of the spinothalamic tract (44). However, when the stimulus strength was increased to a level that also activated Αδ fibres, a powerful inhibition was observed (44). The finest (group IV or C) fibres, conducting thermal, pain and mechanical noxious stimuli, were thought to be of less importance in carrying the input from the site of stimulation to the CNS. Supporting evidence has been demonstrated in studies using capsaicin, which selectively blocks C-fibre afférents (45, 46). Topical application of capsaicin on the sciatic nerves in rats did not affect AA (46). The stimulation criteria and the corresponding efficacy of antinociceptive

9 effect determine whether or not the C-fibres are involved (40, 47). It has been shown that stimuli strong enough to activate C-fibres will produce an antinociceptive effect via a diffuse noxious inhibitory control mechanism (DNIC). Such stimuli cannot be tolerated by the conscious patient and so cannot be used to explain clinical AA effects (46). The activation of lower excitation threshold, larger fibres (groups II and ΠΙ) powerfully suppresses the noxious stimuli transmitted by the higher excitation threshold fine C-fibres (18, 48). This principle concurs with clinical observations, in which dramatic relief of causalgia can be achieved by selective large fibre stimulation (49, 50).

Ascending pathways, higher centres and descending pathways. Upon entering the spinal cord, which is known to be the basic centre of nociceptive reflexes, primary afferent acupuncture impulses (Aß and Αδ) arrive at the medial and lateral portions of the dorsal horn. Aß fibres terminate in the nucleus propius and in more ventral regions of the dorsal grey matter, whereas Αδ fibres terminate in the marginal zones of the dorsal grey matter, the ventral portion of lamina II and thoughout lamina III (1, 18). Functionally, impulses from Aß and Αδ fibres, but also from C-fibres converge on the multi receptive (class 2) dorsal horn neurones (18). The ascending pathways carrying acupuncture impulses have been identified in rabbits by selective lesions of the well recognized ascending systems transmitting somatosensory information, viz. the lemniscal and the extralemniscal systems (51). Section of the contralateral anterolateral columns completely abolished the analgesic effect induced by needling of point Zusanli, whereas transection of the dorsal column or superficial lateral chordotomy at the level T^-L, did not affect AA significantly (51). Rostrally, AA impulses are believed to be transmitted through the extralemniscal system then to the thalamus and the sensory cortex. The thalamus is thought to be the most important component responsible for the processing of pain impulses and/or integration of pain sensation. During transmission of AA impulses, interactions and integrations occur with the incoming noxious stimuli at all levels of the CNS, from the reticular formation of the lower brain stem to the cerebral cortex. At different levels of the brain, afferent acupuncture impulses are thought to activate nociceptive inhibitory pathways. At the spinal level, the inhibitory effects of conditioning stimuli on the nociceptive discharges of dorsal hom neurones are characterized by prompt and effective onset and decay (18, 48). The evidence that higher centres are involved in the mechanisms of AA has come from the observation that the inhibitory effect of acupuncture develops much less promptly and decay is much more prolonged upon needle withdrawal when compared to conditioning stimuli (18). Focal brain stimulation, lesion or isolation of brain nuclei, evoked potentials and unit discharges have been used to investigate the role of some nuclei in AA. Considerable evidence suggests that the main centres involved are the centromedian nucleus (52) of the thalamus, the raphe magnus nucleus (NRM), and the arcuate nucleus (53-59). The NRM is thought to be the main supraspinal centre regulating the negative feedback mechanism for modulating pain. Acupuncture impulses activate the NRM, whose axons to the dorsal hom of the spinal cord are called the raphe-spinal neurones.

10 Once activated, the nociceptive response of these neurones in the dorsal hom can be inhibited (60). On the other hand, selective electrolytic lesions of these nuclei block AA and morphine analgesia (59). Generally, several criteria such as a long latency (about 200 ms), a prolonged after discharge, a lack of adaptation and a pronounced sensitivity to opioids have been adopted as typical discharge patterns of the thalamic neurones for nociceptive transmissions. It is reported that when an AA effect is observed, a similar firing pattern of those thalamic neurones is found when compared to the firing pattern elicited by innocuous peripheral stimulation (61). Activation of descending inhibitory pathways from the periaqueductal grey matter (PAG) through the medullary NRM to the spinal cord or trigeminal sensory complex has, therefore, been suggested as one of the important mechanisms involved in AA (58-62). The PAG has also been shown to activate the descending inhibitory pathways in morphine analgesia (59, 63). Additionally, the responses to noxious stimuli, e.g. viscero-somatic reflex discharges, are augmented and accelerated by about 40% after the descending pathways are interrupted by spinal cord transection at cervical or upper thoracic levels. A marked diminution of AA is also observed (64, 65). To determine which part of the cord is involved in transmission of the descending impulses leading to the AA effect, lesions were made in the spinal cord dorsolateral funiculi at the T13 levels. This resulted in the ablation of AA, an observation that was also seen after complete spinal transection (65). This indicates that a central control system, the output of which descends through the dorsolateral funiculus of the spinal cord, is activated by AA. Administration of opioids intravenously (i.V.), before section of the dorsolateral funiculi, completely abolishes viscero-somatic reflex discharges, but this does not occur if opioids are given after spinal cord transection (65).

Segmental relationship with the site of pain. Classically, substantia gelatinosa (corresponds to the Laminae II and HI) neurones, receiving most of the Αδ and C-fibres, have been postulated to modulate the transmission of information through the dorsal hom in a segmental manner (1). Studies on cats have demonstrated that nociceptive electrical discharges of the spinocervical tract, in the dorsolateral fasciculus at the lumbar region, can be inhibited by innocuous electrical stimulation of the same nerve or other sensory nerves. However, the inhibitory effect was found to be strongest and much greater when the innocuous stimulus was applied to the same nerve as opposed to the nerves belonging to adjacent spinal segments (1, 25, 66). It has been postulated that stimulation at any point of the body (non-specific) can increase the pain threshold, but the effect will be more pronounced if both the acupuncture point (specific) and the site of pain are innervated by nerves from the same or adjacent spinal segments. Acupuncture, however, does not produce a local analgesic effect (15, 67). Neuroanatomical and neurophysiological studies may explain the non-segmental distribution of A A (1, 68, 69). Spinal cord segments are not isolated from each other but have long ascending pathways which possess intersegmental links. The medial Lissauer's tract consists largely of collaterals of the unmyelinated and myelinated primary afferent fibres. Collaterals travel several segments rostrally and caudally prior to entering the dorsal hom grey matter (wide dynamic range

11 neurones/WDRN). Somatotopic convergent input is, however, the rule for WDRN and the activity of such neurones can be influenced by input from several adjacent spinal cord segments. In the intact animal, it has been shown that the size of the dermatome, as defined by the response to pin scratch, is influenced by roots as far away as five segments. Dorsal hom neurones, activated by afferent acupuncture impulses or by another stimulus create an electric field which activates neighbouring neurones (1, 68, 69). This is similar to the phenomenon of referred pain, where noxious stimuli in one area produces pain in a completely different area.

The involvement of neurochemical substances

Prior to the discovery of endorphins, the involvement of chemical substances in mediating AA was first suggested from experiments which demonstrated an increasing pain threshold in rats not given acupuncture but given blood from acupunctured rats (70). In another experiment, it was demonstrated that the pain threshold in recipient non-acupunctured rabbits could be increased when the CSF of donor acupunctured rabbits was infused into the cerebral ventricles of the former (71). In addition, although the degree of the increased pain threshold varied with needling at different acupoints, there was a similar slow onset time and exponential decline of the pain threshold after removing the needles. The half-life of AA is 15 to 17 minutes in man and 7.5-13 minutes in rabbits (15, 16, 71, 72). This cannot simply be explained by placebo. These phenomena are the typical characteristics of morphine analgesia and stimulation produced analgesia (SPA), such as PAG stimulation. Clinically, it has been demonstrated that anaesthetic requirements are reduced when the PAG is stimulated prior to surgery (73).

Neurotransmitters

The role of serotonin (5HT), noradrenaline (NA), dopamine (DA), acetylcholine (ACh) and gamma aminobutyric acid (GABA) has been extensively studied in relation to AA.

Serotonin. 5HT is putative neurotransmitter involved in the modulation of nociception (40, 74). In the CNS, the location of 5HT containing cells has been detected using fluororescence histochemical methods. Ascending 5HT fibres have been found running from the midline raphe nuclei in the midbrain and ventromedial reticular formation, with axons projecting through the ventral tegmentum and medial forebrain bundle to innervate forebrain structures (viz. amygdala, neocortex, hippocampus), and, descending 5HT fibres have been identified running from the NRM with axons projecting through the anterior and lateral funiculi to innervate the spinal cord, dorsal hom and sympathetic lateral column cells (74). Increases in serotonergic neurotransmission are associated with decreased pain

12 sensitivity and/or reactivity, and increased opioid drug potency. In contrast, manipulations that decrease serotonergic neurotransmission are associated with hyperalgesia and diminished opioid drug potency (74, 75). The effects of pharmacological and chemical manipulations on serotonergic neurones and fibres have been studied in laboratory animals (rats, rabbits) in relation to AA (76, 77). The influence of AA on the brain 5HT content has been explored and 5HT has been demonstrated to be an important mediator in AA. The i.v. administration of the 5HT synthesis blocker parachlorphenylalanine (PCPA), the 5HT receptor blockers cinancerin, methysergide or cyproheptadine (16, 64, 71, 77-79), the electrolytic lesions of the NRM or chemical denervation of serotonergic fibres using 5,6- or 5,7-dihydroxytryptamine (DHT) (16, 55, 57, 80) have all been studied. Depletion of the brain 5HT content significantly reduces but does not totally abolish AA. Thus, cerebral 5HT is not the only mediator for AA. Microinjection studies using cinancerin administered bilaterally into the PAG did not alter the pain threshold, but abolished AA and morphine analgesia (81). By contrast, when serotonergic transmission was elevated by direct stimulation of the raphe nucleus or when the brain 5HT content was raised by intrathecal administration of the 5HT precursor, 5-hydroxytryptophan (5HTP) or the monoamine oxidase (MAO) inhibitor pargyline, the effect of AA was enhanced markedly (82). It has been noted that the dose of 5HTP required to augment AA is only 1-2% if it is administered intraventricularly rather than intraperitoneally (82). This suggests a central site of action. The results of these experiments have been confirmed clinically using the 5HT uptake blocker, clomipramine, where AA was shown to be potentiated in a double blind study using this drug (83). Measurements of 5HT content and its metabolite 5-hydroxyindoleacetic acid (5HIAA) in various brain areas of rats, including the spinal cord, following stimulation of point Zusanli, revealed significant increases of both 5HT synthesis and utilization (84, 77, 85). The first was determined using pargyline and the latter using probenecid which blocked the transport of 5-HIAA from the brain. As the synthesis exceeded utilization, a net increase in cerebral 5HT ensued (Figure 1). Of interest is the observation, that the changes were only observed in those rats where acupuncture produced a significant antinociceptive effect.

Noradrenaline. Treatment of animals using i.v. dihydroxyphenylserine (DOPS), a precursor which raises the brain content of NA but not DA, depresses AA. Selective destruction of the ascending noradrenergic fibres using the chemical denervator 6-hydroxydopamine (60HDA), that reduces forebrain NA but not DA, augments AA (86). Stimulation of point Zusanli shows an increase in the synthesis and utilization of NA in the brain and spinal cord (77, 87). Measurements in various brain areas, however, including the spinal cord, using scintigraphic and autoradiographic methods reveals a significant decrease in NA content (77, 84). These changes mirror those of 5HT (Figure 1). This apparant contradiction may be explained by the possibility that the increased metabolism of NA exceeds the increased synthesis. Two different effects of NA on AA have been observed. In the brain, particularly in the habenula and PAG, NA has an antagonistic effect, whereas in

13 Telen Dien Brain Spinal captisi c«phal item cord Figure 1 Percent changes (mean and SEM) in 5HT and NA content in rat CNS after one hour low frequency acupuncture stimulation as compared with non-acupunctured group Monoamine contents were determined by spectro- fluorophotometric method *p<0 05, **p<0 01, ***p<0 001 By permission of the publisher the spinal cord, NA potentiates AA (86, 88, 89) These conclusions were derived from intracerebral and subarachnoidal microinjection studies. AA in the rabbit was potentiated after the intraventricular administration of the α-blocker phentolamine and attenuated after the intraventricular administration of α-agonist Clonidine No such changes were seen after treatment with the ß-blocker propanolol or the ß- agonist isoprenalme injected intraventncularly This indicates that the antagonistic effect of NA on AA in the brain is mediated via a-receptors. In rat experiments, an intraventricular injection of DOPS showed a dose- dependent increase in brain NA content and a corresponding dose-dependent decrease in AA (88) Stimulation of brain α-receptors by Clonidine has been shown to significantly attenuate AA, whereas phentolamine, injected intraventncularly, potentiates AA In contrast to rabbit expenments, intraventricular injection of propanolol in rats, produces a dose-dependent decrease in AA (88) This suggests the antagonizing effect of NA on AA in the brain is mediated via α-receptors, whereas the potentiating effect of NA in the brain is mediated via ß-reeeptors. In contrast to the complicated situation in the brain, NA content of the spinal cord in rabbits and rats has universally been reported to facilitate AA by activating a-receptors (77, 88-92)

Dopamine The systemic administration of the DA antagonists dropendol or spiropendol potentiate AA. The i.v. injection of the DA agonist apomorphine attenuates AA, but does not alter the pain threshold (86). This suggests that DA in the brain, like NA, might have an antagonistic effect on AA. No alteration of the total brain content of DA was reported after a single treatment of the acupoint Zusanh (84), although when the DA content in different brain regions was further analyzed, a clear decrease in the concentration of DA in the caudate nucleus was shown (87).

Acetylcholine Intracerebroventncular administration of the ACh synthesis blocker, hemicholine (HC-3), does not alter the pain threshold, but reduces AA significantly (93). The observed reduction m AA could be reversed by the ACh

14 precursor choline. Systemic treatment of rats with the muscarine cholinoreceptor blocker, atropine, reduces AA, whereas the Cholinesterase inhibitor, eserine, potentiates AA (93). These results suggest that central ACh may play a positive role in mediating AA.

Gamma aminobutyric acid. Two different effects of GABA on AA have been observed. In the brain, particularly in the PAG, GABA has an antagonistic effect (94, 95), whereas in the spinal cord, GABA potentiates AA (96, 97). These conclusions were derived from studies using a series of pharmacological tools. Systemic administration of the GABA synthesis inhibitor, 3-mercapto-propionic acid (3-MP), which reduces brain GABA content, significantly potentiated AA in a dose-dependent manner. The effect of 3-MP on AA was reversed by administration of the GABA transaminase inhibitor aminooxyacetic acid (AOAA). Systemic treatment of rats with AOAA and the GABA degrading enzyme inhibitor, gamma-vinyl GABA (GVG), which raises brain GABA content, produced a marked reduction of AA. Intraperitoneal diazepam, which facilitates the GABAergic transmission, suppresed AA (94, 95). The antagonistic effect of diazepam on AA could be reversed completely by the administration of the GABA receptor blocker picrotoxin (94, 97). Microinjection studies reveal that the PAG is one of the strategic sites of GABA action on AA. It is of interest that when the elevation of the pain threshold was achieved by morphine instead of stimulation of acupoints, the same results described above were demonstrated. Intrathecal administration of diazepam in anaesthetized rats, however, enhances AA and intrathecal picrotoxin blockes AA (96, 97).

Endogenous opioids

Endogenous opioids as mediators of pain relief by acupuncture. Several stringent criteria must be fulfilled if the involvement of endogenous opioids as a method for pain relief is to be proven. Generally, the analgesia produced should be naloxone-reversible (98). Naloxone may, however, have pharmacological actions unrelated to opiate receptor blockade (99, 100). Antagonism of analgesia by naloxone is necessary but is not sufficient as a sole proof for the involvement of endogenous opioids in the analgesia produced. Several other additional criteria are, therefore, needed (98, 99). These include: a. other opiate antagonists produce the same effect as naloxone, b. the demonstration of the stereospecificity of the opiate antagonists, с agents which prevent the degadration of endogenous opioids should potentiate, the naloxone-reversible response, d. the demonstration of a direct release of opioid peptides by the stimulus, e. the demonstration of tolerance and cross-tolerance with morphine. For AA, such supportive data have emerged in the past decade. The positive correlation between AA and morphine analgesia has been shown in many studies, where morphine has always been used as the experimental control (15, 59, 65, 76, 94, 95, 101-103). The blockade of AA by naloxone was first reported in clinical and animal studies (104, 105) shortly after the discovery of enkephalins in 1975

15 (106). These studies suggest a role for endogenous opioids in AA. In a clinical study, acute evoked tooth pulp pain was diminished using manual stimulation of the acupoint Hegu (104). There were five experimental groups in this study, i.e. control group (n=40) with only repeated measurements of pain threshold, naloxone baseline group (no treatment, n=30), acupuncture group (n=35), placebo control group (no treatment, n=31) and hypnosis group (n=14). Subjects in the acupuncture group, the naloxone baseline group and the hypnosis group received either i.v. naloxone or saline after a 30 minute treatment period. This was designed in a double blind fashion. Approximately one-half of each group received naloxone. Naloxone reduced the elevated pain threshold in the acupuncture group to the level of the no treatment groups, whereas the hypnosis group did not have a reduction in pain threshold after naloxone. An animal study (105) was carried out in awake mice, where AA was produced by low frequency electrical stimulation at the acupoint Hegu. In an attempt to untangle possible artifact seven experimental groups were used, viz. an acupuncture group, a group of sham acupuncture (needled at non-acupoint), a group of acupuncture plus saline, a group of acupuncture plus naloxone, a group of naloxone, a group of saline and a group of no treatment. Naloxone was shown to block completely the analgesia produced by AA. Since then, the partial or complete antagonism of AA by naloxone has been confirmed in many studies, in conscious and unconscious man as well as in monkeys, cats, rabbits, mice and rats (107-111), although one study has suggested that this is not the case (112). The relation between AA and endogenous opioids has been explored extensively and shown the almost certain involvement of endogenous opioids in AA. Some of these studies which demonstrate this involvement will be discussed briefly. A cross circulation study. The blood from acupunctured rabbits was cross connected, via the femoral vessels to non-acupunctured rabbits. The recipient rabbits had an increase in pain threshold which could be reversed using naloxone (113). This experiment confirmed previous studies carried out before the discovery of endorphins (70, 71). Stereospecificity. The laevo-isomer of naloxone was shown to reverse AA, whereas the dextro-isomer had no effect on AA in mice and rats (109). These studies provide more evidence that a stereospecific morphine receptor is involved in the production of AA. Other opiate antagonists e.g. naltrexone, diprenorphine and cyclazocine have also been shown to reverse AA (97, 110). It is therefore unlikely that the effect of naloxone on AA was due to an unkown side effects of naloxone, as has been suggested by Hayes, et al. (100). Studies preventing the degadration of endogenous opioids. A number of compounds which inhibit the degradation of met-enkephalin (MEK), e.g. D- phenylalanine (DPA), D-leucine and several other D-amino acids (bacitracin, puromycin, bestatin, Captopril) have been reported to produce naloxone reversible analgesia in mice (103, 114). A potentiation of AA has also been shown in mice treated with acupuncture combined with DPA when compared to acupuncture treatment alone (114, 115). The elicited AA was naloxone reversible. This suggested that the enhancement was endorphinergic. Further evidence has also been found in rat experiments.

16 The threshold and magnitude of the evoked potentials in the dorsal part of the PAG in non-responders became similar to that of responders after treatment with DPA (14, 116). These findings were consistent with studies from other laboratories using rabbits, rats and mice (95, 102). Injection of the peptidase inhibitor, bacitracin, into the lateral ventricle of the rabbit, prolonged AA, and this effect was reversed by naloxone. Rabbits were sacrificed 40 minutes after cessation of needling and the MEK and leu-enkephalin (LEK) contents in the hypothalamus and the corpus striatum were measured. The highest values were found in the bacitracin plus acupuncture group when compared to bacitracin alone or saline plus acupuncture groups (102). Another study used a combination of bestatin, thiorphan and DPA in an attempt to suppress completely the degradation of enkephalins released from nerve terminals (95). Treatment with these three enkephalinase inhibitors caused a slight increase in MEK and LEK levels in the hypothalamus and the corpus striatum of rats. AA alone caused a 40% increase, but as much as 120% increase was achieved with combined treatment of acupuncture and peptidase inhibitors (95). These data may suggest that AA accelerates both the production and release of enkephalins. Cycloheximide, a protein synthesis inhibitor, has been reported to interfere with the incorporation of (1H)tyrosine into enkephalin (117). Cycloheximide decreases the MEK content of the hypothalamus by 47% and the corpus striatum 20%. AA increases MEK in the hypothalamus by 113% and the corpus striatum 222%. A A in rats, pretreated with cycloheximide, increases the MEK content in the hypothalamus by only 28% and 123% in the corpus striatum. Thus, a number of compounds which inhibit the degradation of MEK can produce naloxone reversible analgesia and potentiate AA. MEK as a mediator of AA is, therefore, implicated. Clinically, DPA has been used successfully for the management of chronic intractable pain in man. The success rate of AA for dental surgery increased due to conversion of non-responders to responders after treatment with DPA. Longterm treatment of DPA both in animals and man, has shown no side effects, dependence or tolerance (114, 118). Studies using animals genetically deficient in opiate receptors. A poor AA effect has been found in mice known to be congenitally deficient in opiate receptors and shown previously to respond poorly to morphine (CXBK mice). A deficiency in the endorphin system has therefore been postulated in human non-responders (97, 119). Pharmacological studies to reduce pituitary endorphins. The importance of brain or pituitary endorphins in AA has been investigated in mice and rabbits. Chemical or surgical suppression of endorphin production leads to the abolition of AA (95, 120, 121). One study, however, failed to confirm the surgical suppression of AA (122). Dexamethasone, which suppressed adrenocorticotropic hormone (ACTH) production and therefore ß-endorphin (BE) production, has been shown to reduce AA significantly in man (123). Microinjection studies administering opioid antagonists into discrete brain areas. Suppression of AA has been demonstrated after microinjection of naloxone intrathecally in rats (124) or intracerebroventricularly into different brain areas such as the PAG, nucleus accumbens, amygdala and habenula in rabbits. Unilateral injection in rabbits had less effect than bilateral injection. The same

17 results were obtained if morphine was used instead of AA (95). Studies using a radioreceptor-assay technique. Increased opioid activity has been shown in rat brain and the caudate nucleus of rabbits following AA as measured by radioreceptor-assays (125-127). Dexamethasone lowered the pituitary endorphin content, whereas bilateral adrenalectomy increased both the pituitary endorphin content and the effectiveness of AA (125-127). Antibody microinjection studies using a specific antibody. Selective inactivation of enkephalin, BE and dynorphin in rabbits using microinjection of specific antibodies allowed the study of the role of the different peptides in AA. The functional changes elicited by antibody microinjection can be interpreted as the result of removal of the physiological effects of the inhibited peptide. It has been shown that AA utilizes MEK in the PAG and the spinal cord, BE in the PAG, and dynorphin A and В in the spinal cord (102, 128-132). In another study using a peptidase inhibitor combined with an antibody microinjection technique, the importance of MEK in mediating AA and morphine analgesia in the nucleus accumbens was demonstrated (103). Release of central opioid peptides. A rise in CSF of plasma BE has been measured in patients, with and without pain conditions, after acupuncture and (acupuncture like) transcutaneous stimulation (133-139). This has also been shown to occur in rats and horses (140, 141). Studies of tolerance and cross tolerance. Tolerance to AA, as measured by TF latency, occurs when repeated or prolonged AA is performed in rats and rabbits. This phenomenon mimics that of morphine tolerance. A diminution in the effectiveness of morphine analgesia has been found in rats made tolerant to AA. In rats receiving one session of AA, injection of moiphine 6 mg.kg ' produced a 110% increase in TF latency, but this effect decreased to 19% after five sessions of AA (142, 143). Similarly, a reduced effectiveness of AA in rats made tolerant to morphine has been shown (142, 143). These data indicate cross tolerance between AA and morphine analgesia. It has been suggested that prolonged morphine treatment may activate some neurochemical systems (an endogenous opioid antagonist) in the CNS leading to the suppression of its analgesic effect. Such an anti-opioid substance has been extracted from rat brains made tolerant to morphine. Its injection into naive rats caused the reversal of the effect of morphine or AA (144). Recently, it has been reported that cholecyctokinin-octapeptide (CCK-8) in the CNS is a potent antagonist of opioid-induced analgesia (145). Microinjection of 5-HTP either i.v. or into the nucleus accumbens bilaterally, has been shown to reverse the tolerance to AA or morphine (146). These findings suggest that at least two mechanisms can account for the development of AA and morphine tolerance. Firstly, prolonged AA stimulation leads to the production and release of CCK-8 in the CNS to counteract the opioid component of AA, and, secondly, a functional deficiency of brain 5HT may develop, especially in the nucleus accumbens.

Stimulation frequency determines the release of endogenous opioids. In classical acupuncture, stimulation is achieved by slow or rapid, mild or strong manipulations of the needle. The majority of the studies performed today, however, has been performed using electrical stimulation via the inserted needle

18 rather than mechanical needle manipulations, because the variability of the electrical stimuli could be defined more precisely. As a therapeutic modality, it has been claimed anecdotically that different manipulations at the same acupoint can produce different therapeutic effects and cure opposite symptoms, e.g. constipation and diarrhoea (147). As AA can be measured easily and precisely under experimental conditions, investigations focusing on the variability of the stimulation parameters have been carried out to evaluate whether or not they resulted in qualitatively different physiological effects. In rabbit experiments, it has been reported that naloxone could only block the analgesia resulting from low intensity (8 mA) but not a high intensity stimulation (15mA) (148). The failure of naloxone to block AA has also been demonstrated in mice (149) and in humans (150) if high frequency (200 Hz) rather than low frequency (4Hz) stimulation is applied. An hypothesis has been put forward that non-opioid mechanisms mediate high frequency, high intensity stimulation analgesia, whereas opioid mechanisms are activated by low frequency, low intensity stimulation analgesia. The involvement of multiple endogenous opiate and non-opiate analgesia systems has also been suggested for a number of related methods for pain relief such as SPA (151, 152) or when repeated acupuncture stimulations are given (153). Recently it has become clear that at least three families of endogenous opioids, viz. enkephalins, BE and dynorphins are known to be involved in pain control. Each class is derived from a different precursor and each has a distinct anatomical distribution within the brain and spinal cord (117, 154-157). In addition, each has a preference to act through a specific receptor type (mu, delta, kappa, and probably sigma and epsilon), although occupation of more than one receptor by each class is not unusual. While enkephalins act mainly at delta receptors, BE and dynorphins generate their analgesic effect by activating mainly mu and kappa receptors respectively. The susceptibility to naloxone differs widely among opioid receptors. Kappa receptors have a low affinity for naloxone (100). Naloxone 1 mg.kg"1 blocks 2 Hz AA completely, 15 Hz A A partially and has little effect on 100 Hz AA in experimental rats (148). Stimulation intensity below 3 mA did not affect these results. The doses of naloxone needed for 50% blockade of AA (IDs,,) were then estimated from experiments, in which different doses of naloxone were given in association with 2Hz, 15Hz and 100 Hz AA in rats. It was found that the ΙΟ,ο of naloxone was 0.5, 1.02 and 24 mg.kg'1 for 2 Hz, 15 Hz and 100 Hz AA respectively (158). These findings indicate two things. Firstly, low and high frequency AA are mediated by endogenous opioids. Secondly, dynorphin might be involved in high frequency AA, since a much higher dose of naloxone was needed to block this type of analgesia (159). Supporting evidence comes from receptor blocking studies as well as cross tolerance and antibody microinjection studies (128, 148). Intrathecal injection of the delta receptor blocker ICI 174,864 reverses, in a dose-dependent manner, 2 Hz but not 100 Hz AA, whereas the kappa receptor blocker Mr 2266 reverses 100 Hz but not 2 Hz AA. Intrathecal administration of the delta agonist, enkephalin, has no effect in rats made tolerant to 2 Hz, but produces significant analgesia in rats made tolerant to 100 Hz AA. Conversely, intrathecal injection of the kappa agonist, dynorphin A, has no effect in rats made tolerance to 100 Hz but produces significant analgesia in rats made tolerant to 2 Hz AA. In addition, no

19 significant cross tolerance has been found between 2 and 100 Hz AA. Studies applying five different antisera revealed that 2 Hz AA was only blocked by MEK antiserum, whereas 100 Hz AA was only blocked by dynorphin A antiserum. These data imply that MEK and dynorphin A mediate low and high frequency AA respectively.

Interactions of endogenous opioids and serotonin. The importance of brain 5HT in mediating AA has been implicated from the previous data: brain 5HT is an important but not the only mediator for AA. Also, the "key" role of the opioid peptides in AA has been established. Both substances were studied simultaneously to investigate their possible interactions with AA. Intravenous naloxone significantly increases the brain content of 5HT and 5H1AA in rats, whereas a lowering of 5HT brain content by PCPA or DHT is followed by a corresponding increase in the brain content of endogenous opioids (160, 161). The data suggest a physiological compensation mechanism between 5HT and the endogenous opioids. Evidence for the interrelationship of 5HT, endogenous opioids and AA has come from rat experiments. Excellent analgesia can be shown in rats with high CNS levels of both 5HT and endogenous opioids, moderate analgesia with a higher level of either 5HT or endogenous opioids, and poor analgesia with low levels of both 5HT and endogenous opioids. When the experiment is carried out in rats pretreated with PCPA (5HT synthesis blocker), acupunctured rats with excellent analgesia show a more pronounced increase of endogenous opioids than non-acupunctured rats. Correlative analysis revéales that the increase in the brain endogenous opioids compensates for the decrease in 5HT product. In acupunctured rats where no analgesia is produced (non-responder), the brain content of endogenous opioids does not change (160, 161).

Meso-limbic loop of analgesia

Previous data strongly suggest that AA is mediated not only by direct activation of opioid receptors, but also by some other neurotransmitters such as 5HT (59, 77, 81). The descending inhibitory pathways, involving 5HT, enkephalins and dynorphins, are activated to suppress nociceptive transmission at the spinal level. Activation of the descending 5HT pathway in mediating morphine analgesia in the spinal cord has also been documented (59, 162). The PAG plays a key role in controlling the descending inhibitory systems at the spinal level in AA and morphine analgesia. A cerebral neuronal circuit has been proposed to play an important role in mediating A A and morphine analgesia (163). This includes the PAG, nucleus accumbens and habenula. Experiments were designed to investigate whether or not these nuclei were connected in a closed loop. Morphine or 5HT was injected into one of the nuclei to induce analgesia, while a specific receptor blocker (naloxone, cinancerin or methysergide) was injected, to antagonize the produced analgesia, into another nucleus (assumed to be the next station within the neural loop). Specific antibodies have also been used to neutralize the opioid peptide which is

20 released into the synaptic cleft, thus preventing receptor activation, and, to differentiate the physiological functions of neuropeptides which act on the same receptor (MEK, LEK. delta receptor) Using this strategy, the existence of an ascending 5HT pathway from the PAG to the nucleus accumbens has been demostrated (164) In addition, a descending pathway from the nucleus accumbens to the PAG has also been identified with a relay station at the habenula (163, 165) This pathway uses MEK as a neurotransmitter to activate the opiate receptor in the PAG to produce analgesia Since the PAG belongs to the mesencephalon and the nucleus accumbens to the limbic system, the suggested neural loop is called the meso-hmbic loop of analgesia This, however, does not exclude the possibility that other pathways and/or opioid peptides may also be involved in mediating AA Such a role has been suggested for the amygdala (5HT, MEK) (95, 124) and the hypothalamo-pituitary system (BE) (95, 120-123)

References

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25 117 He LF Involvement of endogenous opioid peptides in acupuncture analgesia Pain 1987,3199-121 118 Hyodo M, Kitade T, Hosoka E Study on the enhanced effect induced by phenylalanine during acupuncture analgesia in humans In Bonica JJ, Lindblom U, Iggo A, eds Advances in Pain Research and Therapy New York Raven Press, 1983,577-582 119 Peets J, Pomeranz В CXBK mice deficient m opiate receptors show poor electroacupuncture analgesia Nature 1978,273 675-676 120 Cheng R, Pomeranz В Dexamethasone partially reduces and 2% saline-treatment abolished electro-acupuncture analgesia these findings implicate pituitary endorphins Life Sci 1979,24 1481-1486 121 Pomeran¿ В, Cheng R, Law Ρ Acupuncture reduces electrophysiological and behavioural responses to noxious stimuli pituitary is implicated Exp Neurol 1977 54 172-178 122 Fu TC, Halcnda SP, Dewey WL The effect of hypophysectomy on acupuncture analgesia in the mouse Brain Res 1980,202 33-39 123 Másala A, Satta G, Alagna S, Zolo TA, Rovasio PP, Rassu S Suppression of electroacupuncture(EA)-induced ß-Endorphin and ACTH release by hydrocortisone in man Absence of effects on EA-mduced anaesthesia Acta Endocrinol 1983,103 469-472 124 Peets JM, Pomeranz В Acupuncture-like transcutaneous electrical nerve stimulation analgesia is influenced by spinal cord endorphins but not serotonin An intrathecal pharmacological study In Fields HL, ed Advances in Pain Research and Therapy New York Raven Press, 1985,9 519 525 125 Tang J, Han JS Changes in opioid activity in brain and pituitary during electroacupuncture analgesia in rat In Han JS, ed The neurochemical basis of pain relief by acupuncture, A Collection of papers 1973-1987 Beijing Med Univ Beijing Med Sci Press, 1987,203 126 Tang J, Wang W, Yang XS, Han JS Pituitary opioids as related to electroacupuncture analgesia in the rat The effect of adrenalectomy and dexamethocin In Han JS, ed The neurochemical basis of pain relief by acupuncture, A Collection of papers 1973-1987 Beijing Med Univ Beijing Med Sci Press, 1987,204 127 He L, Lu R, Zhuang S, Zhang X, Pan X Possible involvement of opioid peptides of caudate nucleus in acupuncture analgesia Pain 1985,23 83 93 128 Han JS Antibody microinjection technique as a tool to clarify the role of opioid peptides in acupuncture analgesia Pain 1984,2(Suppl) 667 129 Han JS, Xie GX, Zhou ZF, Folkesson R, Teremus L Enkephalin and ß-Endorphin as mediators of electro-acupuncture analgesia in rabbits an antiserum microinjection study In Costa E, Trabucchi M, eds Regulatory Peptides From Molecular Biology to Function New York Raven Press, 1982,33 369-377 130 Xie GX, Han JS, Hollt V Flectroacupuncture analgesia blocked by microinjection of anli- beta-endorphin antiserum into periaqueductal grey of the rabbit Intern J Neurosci 1983,18 287-292 131 Han JS, Xie GX, Zhou ZF, Folkesson R, Teremus L Acupuncture mechanisms in rabbit studied with microinjection of antibodies against ß-endorphin, enkephalin and substance Ρ Neuropharmacol 1984,23 1-5 132 Han JS, Xie GX Dynorphin Important mediator for electroacupuncture analgesia in the spinal cord of the rabbit Pain 1984,18 367-376 133 Salar G, Job I, Mingnno S, Bosio A, Trabucchi M Effect of transcutaneous electrotherapy on CSF ß-endorphm content in patients without pain problems Pain 1981,10 169-172 134 Sjolund B, Teremus L, Enkson M Increased cerebrospinal fluid levels of endorphins after electroacupuncture Acta Physiol Scand 1977,100 382-384 135 Xu SL, Fu ZL, Xiang MJ, Lu ZS, Yang J, Zhao SL The effect of manual acupuncture analgesia and its relation to blood level of endorphins and histamine and the suggestibility in humans In Han JS, ed The neurochemical basis of pain relief by acupuncture, A Collection of papers 1973-1987 Beijing Med Univ Beijing Med Sci Press, 1987,232-233 136 Clement-Jones V, MacLoughin L, Tomhn S, Besser GM, Rees LH, Wen HL Increased ß- endorphin but not met enkephalin levels in human cerebrospinal fluid after acupuncture for recurrent pain Lancet 1980,ii 946-948

26 137 Panerei A E, Martini A, Abbate D, Villani R, De Benedittis G fl-Endorphin, met-enkephalin and B-hpotropin in chronic pain and electroacupuncture In Bonica JJ, Lindblom U, Iggo A, eds Advances in Pam Research and Therapy New York Raven Press, 1983,543-547 138 Zhang AZ Endorphin and acupuncture analgesia research in the People's Republic of China (1975-1979) Acupunct Electrother Res 1980,5 131-146 139 Chen GB, Li SC, Jiang CC Clinical study on neurophysiological and biochemical basis of acupuncture analgesia Am J Chin Med 1986,14 86-95 140 Pert A, Dionne R, Ng L, Bragin E, Moody TW, Pert CB Alterations in rat central nervous system endorphins following transauncular electroacupuncture Brain Res 1981,224 83-93 141 Lagerwey E, Nehs PC The twitch in horses A variant of acupuncture Sci 1984,225 1172- 1173 142 Han JS, Li SJ, Tang J Tolerance to electroacupuncture and its cross tolerance to morphine Neurophaimacol 1981,20 593-596 143 Zhou Z, Xuan Y, Wu W, Han J Tolerance to electroacupuncture and its cross tolerance to morphine in rabbits In Han JS, ed The neurochemical basis of pain relief by acupuncture, A Collection of papers 1973 1987 Beijing Med Umv Beijing Med Sci Press, 1987,360 144 Tang J, Hu CQ, Li SJ, Du MY, Haung BS, Zhang NH, Han JS Isolation and purification of the anti-opiate substances In Han JS, ed The neurochemical basis of pain relief by acupuncture, A Collection of papers 1973-1987 Beijing Med Umv Beijing Med Sci Press, 1987,380 145 Han JS, Ding XZ, Fan SG Cholecystokinin octapeptide (CCK-8) antagonism to electroacupuncture analgesia and a possible role in electroacupuncture tolerance Pain 1986,27 101-115 146 Xuan YT, Zhou ZF, Han JS Tolerance to electroacupuncture analgesia was reversed by microinjection of 5-hydroxytryptophan into nuclei accumbens in the rabbit Intern J Neurosa 1982,17 157-161 147 Kho HG Acupuncture as alternative medicine, facts and perspectives Ned Τ Geneesk 1987,131 1869-1902 148 Han JS, Sun SL Differential release of enkephalin and dynorphin by low and high frequency electroacupuncture in the central nervous system Acup Sci Intern J 1990,1 19-27 149 Cheng RS, Pomeranz В Electroacupuncture analgesia could be mediated by at least two pain relieving mechanisms endorphin and non-endorphin system Life Sci 1979,25 1957-1962 150 Sjolund BH, Enksson MBE The influence of naloxone on analgesia produced by peripheral conditioning stimulation Brain Res 1979,173 295-301 151 Mayer DJ, Watkins LR Multiple endogenous opiate and non-opiate analgesia systems In Kruger L, Liebeskind JC eds Advances in Pain Research and Therapy New York Raven Press, 1984,6 253-276 152 Watkins LR, Mayer DJ Organization of endogenous opiate and non-opiate pain control systems Sci 1982,216 1185-1192 153 Pomeranz B, Warma N Electroacupuncture suppression of a nociceptive reflex is potentiated by two repeated electroacupuncture treatments the first opioid effect potentiates a second non-opioid effect Brain Res 1988,452 232-236 154 Basbaum AI, Fields HL Endogenous pain control systems Brain stem spinal pathways and endorphin circuitry Ann Rev Neurosci 1984,7 309-338 155 Vacca-Galloway LL, Naftchi NE, Arakawa K, Guan XM, Ai MK Alterations of immunoreactive substance Ρ and enkephalins in rat spinal cord after electroacupuncture Peptides 1985,6(Suppl 1) 177-188 156 Conrath-Vemer M, Dietl M, Arluison, M, Cesselin F, Burgoin S, Hamon M Localization of met-enkephahn-like immunoreactivity within pain-related nuclei of cervical spinal cord, brainstem and midbrain m the cat Brain Res Bull 1983,11 587-604 157 Dirksen R Opioid receptors and pain Pharm Weekbl (Sci) 1990,12 41-45 158 Han JS, Xie GX, Ding SZ, Fan SG High and low frequency electroacupuncture analgesia are mediated by different opioid peptides Pain 1984,2(Suppl) 543 159 Han JS, Xie GX, Goldstein A Analgesia induced by intrathecal injection of dynorphin В in the rat Life Sci 1984,34 1573-1579

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28 CHAPTER 2

ASPECTS OF THE RESPONSE OF THE BODY TO ANAESTHESIA AND SURGERY

Much controversial data have been published on the body's response to anaesthesia and surgery. This chapter, however, reviews only those aspects of the body's response which can be related to the data presented in the second part of this thesis regarding AA. The purpose of the body's response to either exogenous or endogenous noxious stimuli is unknown but is thought to be part of an homeostatic mechanism. Surgery is one of the strongest noxious stimuli that the human body receives. In surgical patients, complex factors initiate and prolong the body's response (1-4). The pathology itself requiring surgical intervention acts as an endogenous noxious stimulus. Also, mental and emotional factors such as sleeplessness, fear, anxiety and pain prior to and after surgery; starvation and energy imbalance; the surgical procedure itself including tissue damage, blood and/or fluid loss and the possible associated hypotension; electrolyte disturbance and changes of body temperature, can all act as noxious stimuli inducing an hormonal and/or immune response.

The response of the body to surgery and the hypothalamus as a regulator

In surgical patients, noxious stimuli arise from damaged tissues. They are transmitted to the CNS not only by small myelinated (Αδ) and unmyelinated (C) sensory afferent fibres, but also by fast-conducting fibres (2, 5). The autonomic afferent pathways, particularly in abdominal surgery, have long been recognized as eliciting this response (3, 4). In addition, humoral pathways may also play an important role in initiating the response. Substances released from the wound areas such as prostaglandins, histamine, pyrogens, bacterial endotoxins and polypeptides produced by activated macrophages (e.g. interleukin-l) can all serve as mediators of the humoral pathways (2, 6-9). The hypothalamus is the target of all these neural and humoral stimuli from the surgical areas. It coordinates and mediates the adrenergic and pituitary responses.

Characteristics of the response of the body to surgery

In response to surgical trauma, the body reacts in a well-described pattern. This response can be divided into ebb and flow phases (4, 7, 10). The first phase is a hypodynamic state characterized by a reduction of the metabolic rate, i.e. a decreased oxygen consumption and lowered body temperature. This persists for a short time or can sometimes be absent (2, 7). Anaesthesia contributes to this phase by loss of tone in the capacitance vessels reducing venous return and so decreasing

29 cardiac output. The second phase is a hyperdynamic state characterized by an elevation of the metabolic rate, i.e. increased in oxygen consumption, carbon dioxide production and body temperature. There are also responses from the neuro-endocrine and immune systems. It is believed that the body's response to surgery is, in fact, a reflex response rather than a response because of an extra need for energy during the hyperdynamic state. This view is supported by studies in which preoperative administration of Cortisol or glucose in amounts comparable to or greater than their endogenous productions did not block the increase of plasma Cortisol or glucose during surgery (11, 12). Also, the hypermetabolic response, in terms of increased oxygen consumption, continues regardless of the intake of glucose (13).

Hormonal response to surgery

The neuroendocrine response plays a central role in the regulation of the hormonal stress response to surgery (1, 14). The magnitude of this response is directly related to the degree of injury. Minor surgery leads only to a slight and transient response and major surgery evokes a more pronounced response lasting for several days or weeks, even in the absence of complications (4, 14-16).

The sympatho-adrenal response. The equilibrium between the sympathetic and parasympathetic autonomic nervous systems is shifted towards the sympathetic system in nearly all 'stress conditions' including surgery (2, 17-19). It is a sensitive system that reacts even to slight changes of posture (3). Increased sympathetic activity results in the release of NA from presynaptic sympathetic fibres and/or catecholamines from the adrenal medulla. Adrenaline (A) and NA have a central role in the rapid regulation of the stress response (20). It is suggested that the adrenal response is a prerequisite to allow other hormones to produce effects (21). Sympathetic activity can be assessed directly by measurement of circulating NA and A. An indirect method of assessing sympathetic activity is the measurement of the haemodynamic parameters (heart rate and arterial pressure). Results of both direct and indirect assessments have been reported to correlate positively during stress (3, 17).

The pituitary response. Noxious stimuli reaching the hypothalamus lead to the secretion of the releasing hormones e.g. corticotrophin releasing hormone (CRH), thyrotrophin releasing hormone, luteinizing releasing hormone and growth hormone releasing hormone. These hormones stimulate the pituitary to produce the corresponding peptide hormones. Increased release of both posterior and anterior pituitary hormones has been reported as a response to surgery (4, 22-28). They stimulate the target organs to release peripheral hormones (e.g. adrenal cortex: Cortisol, aldosterone; thyroid: 3,5,3',5'tetraiodo-thyronine/thyroxine or T4, 3,5,3' triiodothyronine/TS; gonads: oestrogen). On the other hand, hormones released by the target organs influence the activity of the corresponding hypothalamic nuclei by

30 either positive or negative feedback mechanisms and so regulate pituitary function. The negative feedback mechanism of pituitary-adrenocortical secretion is thought to be altered during and after surgery, since both ACTH and Cortisol remain increased simultaneously. The administration of ACTH during surgery produces no greater increase in plasma Cortisol levels, and administration of adrenocortical hormone after surgery does not abolish the pituitary-adrenocortical response (29). While the levels of most peripherally circulating hormones increase in response to surgery, the concentrations of plasma testosterone and T3 have been reported to decrease (22, 30-33). In addition, enhanced secretion of glucagon and impaired secretion of insulin have been observed (8, 14). During major surgery, Cortisol appears to help the release and function of adrenomedullary catecholamines (7). Lack of Cortisol may result in circulatory collapse during surgery. Evidence exists that endogenous opioids, particularly BE must also be placed in the list of the 'stress' hormones. Its role in the stress response to surgery has been described (14, 34, 35).

Immune response to surgery

From the incidence of bacterial infections and the occasional rapid dissemination of cancer or an augmented tumour growth after surgical intervention, it seems that an impairment or suppression of the immune system occurs during and after surgery (36, 37). This is thought to be due to the greater activity of the sympatho-adrenal and pituitary-adrenocortical systems. The magnitude and duration of the altered immune system, lasting for several days or weeks, correlates with the severity of surgical trauma (38-41). The altered immune system involves both the humoral and cellular components as well as the corresponding effectors viz. bursa-dependent lymphocytes (B-cells) and thymus-dependent lymphocytes (T-cells) (42, 43).

Humoral immunity. Since B-cells synthesize immunoglobulins, the number of B- cells and the concentration of immunoglobulins reflect the status of humoral immunity. The number of B-cells decreases in response to surgery and they can be counted in two ways; firstly by demonstrating the presence of immunoglobulin molecules on the cell surface and secondly by using complement receptors on the cell surface which allow the formation of erythrocyte-amboreceptor-complement (EAC) rosette cells which can then be counted (36, 44, 45). Plasma immunoglobulins decrease in response to surgery (40, 46). The recovery to preoperative levels has been reported to take three days after minor surgery and seven to ten days after major surgery (38, 40, 46-49). A reduction or failure to produce specific antibodies in response to surgery has also been reported (50-52).

Cellular immunity. T-cells play an important role in cellular immunity. After contact with antigens, activated T-cells take part in the total immune response (45, 53). The number of T-cells decreases in response to surgery and the recovery to preoperative levels has been reported to take from one to ten days, depending on the type of

31 surgery (38, 44, 54). Leucocytosis occurs with an increase in the percentage of neutrophils and a decrease in the percentage of lymphocytes and eosinophils (40, 54, 55-57). The number of monocytes in the peripheral blood can be unchanged or increased after surgery, whereas that of basophils is, usually, unchanged (40, 44, 54, 55, 58). The duration of these changes is related to the extent of the operative trauma (9, 38, 44, 54, 55). Many other in-vitro and in-vivo tests are in use to demonstrate the effects of surgery on the function of cellular immunity (45, 53).

Interactions between the hormonal and immune responses

Until recently, it was believed that stress hormones influenced the immune system without any feedback. Cells of the immune system seem to possess receptors of peptide hormones. Binding affinities for ACTH have been demonstrated in mouse spleen cells and opioid receptors have been demonstrated in human lymphocytes (59-61). Also, glucocorticoid hormone receptors in leucocytes have been found (62). The influence of the stress hormones was described as an impairment of the immune response to surgery. For example, the immunosuppressive effects of catecholamines on lymphocyte function are well established (39, 40, 63, 64). Lymphopenia, monocytopenia, inhibition of the production of interleukin-2 and the impairment of antibody production are also well-documented effects of Cortisol (65, 66). Recent data, however, have suggested that there might be some feedback between the immune system and the stress hormones. For example, polypeptides produced by activated macrophages, such as interleukin-1, stimulate the hypothalamic-pituitary axis to secrete ACTH (65). This is thought to be a result of activation of CRH. It is not certain whether this is an effect on the hypothalamus or whether it is mediated by peripheral stress signals stimulating CRH secretion (65, 67). Interleukin-2 produced by T-cells in response to interleukin-1 is reported to play a role in the stress response. In patients receiving interleukin-2 infusions, the levels of ACTH, Cortisol and growth hormone (GH) in the blood have been shown to be elevated (50). Also, leucocytes are capable of synthesizing and secreting ACTH and BE. These levels appear to be controlled by an immunological challenge such as bacterial endotoxin (59, 65). It has also been shown that stress hormones do not always cause an impairment of the immune response. For example, overnight treatment with NA causes a dose- dependent development of antiviral activity in myocardial cells of mice (59). Another study showed a lymphocytosis and an augmentation of natural killer cells (NKC) activities after i.v. administration of A in healthy individuals (68). Plasma Cortisol levels after surgery do not correlate with the suppression of the cellular immunity as measured by in-vitro methods (69, 70). Enhancement of antibody formation and a rapid increase in the number of neutrophils are associated with an increase in circulation of Cortisol (65). BE and enkephalins enhance lymphocyte function in terms of the proliferative response, the generation of cytotoxic T-cells and the NKC activities in animal experiments and in man (71-75). The maintenance

32 of the T-cell response to antigenic stimulation in animal experiments has been shown to be dependent on the serum prolactin (PRL) level, i.e. a decrease of the PRL concentration leads to a decrease in T-cell response (76). It has been suggested that GH influences positively both the proliferation of T-cells and their terminal differentiation into effector cells (59, 77). From these and many other experiments, it does appear that stress hormones can have inhibitory and excitatory effects on the immune system.

Modulating effects of anaesthetics

It is beyond the scope of this thesis to review the effects of all anaesthetic agents that may be used during general anaesthesia on the hormone and immune systems. A general review of the effects of the drugs used in clinical studies presented in the second part of this thesis are, however, included.

On the hormonal response

Although general anaesthesia abolishes the perception of surgical stimuli by the patient, it does not interfere with the effect of noxious stimuli on the hypothalamus nor does it affect the reaction of the hypothalamus to the stimuli (2). The influence of anaesthesia itself on endocrine function is less than that of surgery (22, 78). Anaesthetic manipulations such as laryngoscopy and intubation can, however, induce a marked hormonal response (79).

Premedication. Diazepam 10 mg orally reduces preoperative emotional stress before induction of anaesthesia, as measured by a constant level of BE (80). Intramuscular diazepam 0.2 mg.kg"' correlates with a decrease in plasma Cortisol levels (22). Intravenous diazepam 20 mg does not increase the level of PRL in patients about to undergo gastroscopy (24). However, diazepam 10 mg or 15 mg orally does not prevent an increase in preoperative A levels (17). Since there is no correlation between the plasma A and a linear analogue score for anxiety, plasma A probably does not have value as a measure of anxiety in an individual patient before induction of anaesthesia (3). Diazepam has no influence on plasma concentrations of thyroid stimulating hormone (TSH), luteinizing hormone (LH), PRL or GH (20). Pethidine 2 mg.kg"1 i.m. does not inhibit the adrenocortical response nor influence the level of circulating antidiuretic hormone (ADH) caused by preoperative emotional stress (22, 81). Intramuscular pethidine 1 mg.kg'1 combined with promethazine 0.5 mg.kg"1 is more effective in lowering the levels of plasma A, NA, ADH, ACTH and Cortisol than i.m. diazepam 0.2 mg.kg"1 (82).

Induction and maintenance of balanced anaesthesia. The term balanced anaesthesia has been adopted for general anaesthesia induced and maintained by several drugs, each given for a specific purpose, i.e. unconsciousness, muscle relaxation and

33 analgesia. After i.v. thiopentone, plasma levels of A, NA and Cortisol show a slight decrease or remain unchanged (14, 83). Nitrous oxide leads to an increase in the plasma level of Cortisol (14, 83). The influence of muscle relaxants alone on stress hormones has not been studied clinically. However, in combination with different anaesthetics, conflicting observations have been reported for pancuronium bromide, ranging from a decreased level of circulating NA to an unchanged concentrations of Cortisol (3, 83, 84). The effect of vecuronium on the stress hormones is unkown. Since vecuronium has no haemodynamic effects, its influence is presumed to be minimal. Data on the effects of anticholinesterase drugs on circulating hormone levels are scarce. In one study, it was shown that galanthamine hydrobromide, a neostigmine- like drug, caused a significant increase in the levels of ACTH and Cortisol (85). The effect of pyridostigmine bromide on the circulating stress hormones is unknown. Phenothiazines, such as chlorpromazine and perchlorperazine, used to lower arterial pressure and as an antiemetic are reported to induce the release of PRL and ACTH (29, 86).

Opioids. Opioids are administered as a component of balanced anaesthesia. Their administration is always a compromise between the analgesic effect and side effects such as haemodynamic disturbances, nausea, vomiting and respiratory depression (87). Doses are based on the type and duration of surgery and the state of the patient. The concomitant use of other anaesthetic agents may potentiate the effect of opioids and reduce the doses needed. The presence of opioid receptors in the hypothalamus and the discovery of endorphins in the brain and pituitary (88) indicate that opioids (exogenous or endogenous) may be responsible for controlling the secretion of pituitary hormones (14). However, the mechanisms by which opioids modulate the endocrine response to surgery are not fully elucidated (89). Patients receiving anaesthesia by i.v. morphine 1 mg.kg"' combined with 50% nitrous oxide in oxygen without surgical intervention do not demonstrate a change in the level of ADH (90). A single i.v. dose of morphine 10 mg, however, did increase the level of circulating PRL, but not of GH, TSH or Cortisol (91). Intravenous pethidine 50 to 200 mg, in combination with nitrous oxide-oxygen anaesthesia, did not significantly influence adrenocortical function (92, 93). A dose- response study demonstrated that i.v. fentanyl 10 μg.kg"1 or 30 pg.kg'1 did not, but at a dose of 50 ug.kg', did prevent the initial increase of Cortisol during upper abdominal surgery, but had no influence on the hyperglycaemic response (94, 95). However, when the Cortisol response had already developed, i.v. fentanyl 50 μg.kg"1 could not reduce its concentration in lower abdominal surgery (96). In cardiac surgery, anaesthesia consisting of fentanyl (at doses more than 100 pg.kg'), oxygen and muscle relaxation attenuated greatly the responses of A, NA, ADH, Cortisol, aldosterone and renin to surgical stimuli during the pre-bypass period, but failed to do so during the period of cardiopulmonary bypass (89, 97). Moreover, the suppression effects of high-dose opioids on the stress hormones persisted only transiently during surgery, since the levels of these hormone increased significantly postoperatively (98). After premedication with i.m. morphine (0.15 mg.kg')

34 anaesthesia using fentanyl 100 pg.kg'1 in combination with nitrous oxide-oxygen, suppressed completely the peroperative response of A, Cortisol and GH in cholecystectomy. However, all patients in that study had to be admitted into intensive care unit (ICU) for prolonged postoperative ventilation (99, 100).

On the immune response

In-vitro studies have shown that anaesthetics interfere with the immune response and can suppress the function of a wide variety of cells (64, 101). These include inhibition of lymphocyte migration, cytotoxic activity and phagocytosis. However, the inhibitory effects on cell division did not occur when anaesthetics were administrated at normally used concentrations (63). The influence of general anaesthesia itself on the various immune parameters was of less importance when compared to surgically induced changes (40). Less immune depression is observed in surgery under regional anaesthesia. The postoperative immunological depression is, however, comparable to that seen after general anaesthesia (39, 102).

Premedication. Oral administration of diazepam 0.4 mg.kg"1 or atropine has no effect on the phytohaemagglutinin (PHA)-induced lympholytic response (103, 104). Atropine has no effect on the lymphocyte count or the number of the B- and T-cells (40). The influence of phenothiazines on cellular immunity is unclear, although their chronic use might decrease the PHA-induced lympholytic response (105). Pethidine decreases slightly the PHA-induced lympholytic response, but has no effect on the number of leucocytes and differential counts or on the number of T- and B-cells (40, 104).

Induction and maintenance of balanced anaesthesia. Leucocyte and differential counts fluctuate during general anaesthesia. Before surgical tissue trauma occurs, two factors influence the number of leucocytes (40). First, the effect of i.v. anaesthetics on the Chemotaxis of cells, leading to leucocytosis, can be observed shortly after induction. Secondly, the stimulation of humoral factors by i.v. anaesthetics, mediated by complement, kinins and prostaglandins, causes cell migration in terms of leucopenia and unchanged or slightly increased lymphocyte counts. Balanced anaesthesia consisting of thiopentone, nitrous oxide, oxygen, muscle relaxation and fentanyl has been shown to have no inhibitory effects on the PHA- or concavanaline (Con) A induced response of lymphocytes (106, 107). Another study, however, showed a clear lymphopenia, depressed NCK activity, PHA induced lymphocyte response and phagocytic activity (108, 109). The dual effects of thiopentone on the stimulated polymorphonuclear (PMN) leucocyte activities (i.e. aggregration, swelling and oxygen consumption) are reported in an in- vitro study: low concentrations of thiopentone (0.075-0.19 mmol.I"1) increased leucocyte activity, whereas high concentrations (1.9 mmol.!"1) depressed leucocyte activity (110). After prolonged exposure of animals to nitrous oxide for two days or thiopentone for 24-115 hours, a leucopenia is observed (36, 63).

35 Opioids. In the absence of surgery, fentanyl or pethidine in combination with general anaesthesia does not diminish the PHA- and Con A induced response of lymphocytes (40). No other investigations have been carried out regarding the influence of opioids on the immune response.

Modulating effects of acupuncture

On the hormonal response

After electrostimulation of body or ear acupoints, plasma BE and ACTH increase in animal experiments and man (111-114). Hydrocortisone pre-treatment abolishes this response (112). The level of BE, but not the level of MEK, increases in the CSF after electrostimulation in patients with pain conditions (115). The influence of the acupoint Hegu on plasma GH has been studied in healthy patients and patients with chronic musculoskeletal pain. The levels of circulating GH were unchanged in the first group, whereas the second group showed a clear increase in GH concentration (116). Needling of acupoints Hegu, Shanzhong and Shaoze in cases of inadequate lactation showed an increased concentration of PRL (117, 118), which in tum stimulates the production of milk. Electrostimulation at acupoints Hegu and Neiguan decreases the level of plasma Cortisol (119), whereas plasma Cortisol increases when acupoints Zusanli, Fengchi and Neiguan are manually stimulated in healthy volunteers (120). An increased concentration of Cortisol has also been reported after electro-acupuncture in horses (114, 121). The usual increase of ACTH following stress immobilization in rabbits (exposed to heat and/or cold) does not occur when the acupoint Zusanli is needled (122). Needling of the acupoint Zusanli enhances the adrenal production of corticosterone and Cortisol (123). Depending on the stimulation frequency, a decreasing or an increasing effect on the plasma Cortisol and NA levels has been shown by needling of acupoints Hegu and Waiguan in rabbits (124). The high level of serum aldosterone associated with essential hypertension decreases during acupuncture treatment, whereas the normal levels of the control group (healthy patients) are unchanged (125). Table 1 presents a view of the hormonal responses to acupuncture as well as anaesthesia and surgery.

On the immune response

After needling acupoints Zusanli and Hegu with and without electrostimulation, the number of leucocytes increases and phagocytosis is enhanced in animal experiments and in man (117, 126-129). In heart surgery, electrostimulation of acupoints to induce surgical analgesia has been reported to cause leucocytosis, but with a constant number of lymphocytes (130). A prolonged presence of circulating

36 Table 1 Hormonal response to acupuncture (Acu) and anaesthesia and surgery (AN+S) +, increased, 0, no effect, -, decreased = System/organ Hormone Acu AN+S

SNS NA + Antenor pituitary ACI'H + + BE + + TSH FSH 0 LH 0/+ PRL + + GH 0/+ + Postenor pituitary ADH + Oxytocin Thyroid T3 - T4 + Adrenal medulla A + NA -/+ + Adrenal cortex Cortisol -/+ + Aldosterone 0/- + Pancreas Insulin -/+ -/o Glucagon + Kidney Renin + Gonads Testosteron - Oestrogen 0

A, adrenaline, ACTH, adrenocorticotrophic hormone, ADH, antidiuretic hormone, BE, beta- endorphin, FSH, follicular stimulating hormone, GH, growth hormone, LH, luteinizing hormone, NA, noradrenaline, PRL, prolactin, SNS, sympathetic nervous system, TSH, thyroid stimulating hormone, T3, 3,5,3' tmodolhyronine, T4, 3,5,3 ,5' tetraiodo-thyronme antibody has been shown after electrostimulation of the acupoint Zusanli, while gamma-globulin increases after electroacupuncture of acupoints Zusanli and Hegu (131, 132). The T-lymphocyte transformation response increases after needling of the acupoint Jaiche in rabbits (133). This effect is thought to be mediated by the central catecholaminergic neurones and the endogenous opioids (133, 134). When T- cell activity of rosette formation in patients undergoing surgery under classical ACAN is compared to that under epidural anaesthesia, the activity of T-cells is more enhanced m the acupuncture group (135). Table 2 summarizes the changes of immune variables in response to acupuncture, anaesthesia, anaesthesia and surgery in general, and to surgery for malignant disease.

37 Table 2 Immune response to acupuncture (Acu), anaesthesia (AN), anaesthesia and surgery (AN+S) and surgery for malignant disease (SMD) +, increased, 0, no effect, -, decreased

Humoral immunity Acu AN AN+S SMD

B-cell count 0 ΟΖ Immunoglobulins Ο oz- 0 Antibody

Cellular immunity Acu AN AN+S SMD

T-cell count 0 oz- Leucocyte count + 0Z- + + Differential counts Neutrophil + + Lymphocyte oz- Eosinophil Monocyte 0Z+ Basophil 0 PPD οζ- ΟΖ PHA response Ο ΟΖ Con A response Ο oz- Cytotoxicity MIT MLC PWM

PPD, skin test, PHA, phytohaemagglutinm, Con A, concavanahne A, MIT, migration inhibition test, MLC, mixed lympholytic culture, PWM, pokeweed mitogen

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41 78 Oyama Τ, Wakayama S Effect of anesthetics on endocrine function ACTH, sex hormones, beta-endorphines, thyroid hormones In Roizen MF, ed Anesthesia for patients with endocrine disease Philadelphia/London Saundere WB, 1987,443^62 79 Derbyshire DR, Chmielewski A, Fell D, Vater M, Achola К, Smith G Plasma catecholamine responses to tracheal intubation Br J Anaesth 1983,55 855-859 80 Walsh J, Puig MM, Lovitz MA, Tumdorf H Premedication abolishes the increase in plasma beta-endorphin observed in the immediate preoperative penod Anesthesiology 1987,66 402- 405 81 Oyama Τ Influence of anaesthesia on the endocrine system In Stoeckel H, Oyama T, eds Anaesthesiology and Intensive Care Medicine 132 Endocrinology in anaesthesia and surgery Berlin/Heidelberg Springer Verlag, 1975,39 51 82 Adams HA, Russ W, Bomer U, Gips H, Hempelmnan G The influence of premedication and fentanyl-substitution on the endocrine stress repsonse during halothane anaesthesia Anasth Intensivther Notfallmed 1987,22 118-123 83 Takki S, Tammisto Τ Effects of anaesthesia and surgery on catecholamines In Stoeckel H, Oyama T, eds Anaesthesiology and Intensive Care Medicine 132 Endocrinology in anaesthesia and surgery Berlin/Heidelberg Springer Verlag, 1975,69-82 84 Muldon SM, Moss J, Freas W, Roizen MF The effects of anaesthetics on the sympathoadrenal system In Moss J, ed Clinics in Anaesthesiology Vasoactive Amines London Saunders WB, 1984:2 289-305 85 Cozamtis D, Dessypns A, Nuuttila К The effect of galanthamine hydrobromide on plasma ACTH in patients undergoing anaesthesia and surgery Acta Anaesth Scand 1980,24 166-168 86 Rees LH Prolactin In Alberti KOMM Proice CP, eds Recent advances in clinical biochemistry Edinburgh Churchill Livingstone, 1981,153-167 87 Hull CJ Uses and limitations of opioids m anaesthesia In Mimmo WS, Smith G, eds Opioid agonist/antagonist drugs in clinical practice Amsterdam Excerpta Medica, 1984,51-58 88 Terenius L Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex Acta Pharmacol 1973,32 317-320 89 Desborough JP, Hall GM Modification of the hormonal and metabolic response to surgery by narcotics and general anaesthesia In Brevan DR, ed Clinical Anaesthesiology Metabolic response to surgery London/Philadelphia Bailliére Tindall, 1989,317-334 90 Philbin DM Vasopressin and anesthesia In Oyama T, ed Monographs m Anaesthesiology, vol II Endocrinology and the Anaesthesist Amsterdam/New York Elsevier Sci Pub, 1983,81- 94 91 Tollis G, Hickey J, Guyda H Effect of morphine on serum growth hormone, Cortisol, prolactin and thyroid stimulating hormone in man J Clin Endocrinol Metabol 1975,41 797-800 92 Oyama T, Takiguchi M, Takazawa Τ Kimura К Effect of meperidine of adrenocortical function in man Canad Anaesth Soc J 1969,16 282-291 93 Han YH, Brown ES Pituitary blockade by meperidine in man Anesthesiology 1961,22 909- 914 94 Haxholdt OSt, Kehlet H, Dyrberg V Effect of fentanyl on the Cortisol and hyperglycaemic response to abdominal surgery Acta Anaesth Scand 1981,25 434-436 95 Cooper GM, Paterson JL, Ward ID, Hall GM Fentanyl and the metabolic response to gastric surgery Anaesthesia 1981,36 667-671 96 Bent JM, Paterson JL, Mashiter K, Hall GM Effects of high-dose fentanyl anaesthesia on the established metabolic and endocrine response to surgery Anaesthesia 1984,39 19-23 97 Stanley TH, Philbin DM, Coggins CH Fentanyl oxygen anaesthesia for coronary artery surgery Can Anaesth Soc J 1979,26 168-172 98 Walsh ES, Paterson JL, O'Riordan JBA, Hall GM Effect of high dose fentanyl anaesthesia on the metabolic and endocrine response to cardiac surgery Br J Anaesth 1981,53 1155-1165

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43 122. Liao Y Y, Sato К, Sailo H, Fujita M, Kawakami M. Effects of acupuncture on adrenocortical hormone production: II. Effect of acupuncture on the response of adrenocortical hormone production to stress. Am J Chin Med 1980;8:160-166. 123. Liao YY, Sato K, Saito H, Fujita M, Kawakami M. Effects of acupuncture on adrenocortical hormone production: I. Variation in the ability for adrenocortical hormone production in relation to the duration of acupuncture stimulation. Am J Chin Med 1980;7:362-371. 124. Cao XD, Xu SF, Lu WX. Inhibition of sympathetic nervous system by acupuncture. Acupunct Electrother Res 1983;8:25-35. 125. Anschelewitsch JW, Merson MA, Afanasseva SA. Dynamik des Aldosteronspiegels (Blutserum) bei Patienten mit essentieller Hypertonie unter Akupunktur-Behandlung. Dtsch Ztschr Akup 1986;29:74-76. 126. Brown ML, Ulett GA, Stern JA. The effects of acupuncture on white cell counts. Am J Chin Med 1974;4:383-398. 127. Chen GB. Role of the nervous system of the human body with regard to acupuncture analgesia. Acupunct Electrother Res 1981;6:7-17. 128. Kuan TK, Lee SP, Lin JG, Shen M. The effect of needle stimulation of acupuncture loci St-25 CV-12 on the immune response in sensitized mice against experimental cholera. Am J Chin Med 1986;14:73-85. 129. Zhou RX, Huang FL, Jiang SR, Jiang JC. The effect of acupuncture on the phagocytic activity of human leucocytes. J Trad Chin Med 1988;8:83-84. 130. Lackner J, Lackner F, Semsroth M. Observations on the course of leucocytes in cardiac surgery under acupuncture analgesia. Anaesthesist 1976;25:246-247. 131. Chu YM, Affronti LF. Preliminary observations on the effect of acupuncture on immune responses in sensitized rabbits and guinea pigs. Am J Chin Med 1975;3:151-163. 132. Rogora GA, Morelli R, Sacchetti, Frigoli D. Einige hämatochemische Veränderungen im verlauf von akupunktur: vorläufige Mitteilungen. In: Bischko J, ed. Akupunktur und Aurikulotherapie: Kongressbericht der zweiten französisch-italienisch-österreichischen Tagung in Wien. Wien: Verlag H.Egermann, 1976;] 11-115. 133. Zhao JC, Liu WQ. Relationship between acupuncture-induced immunity and the regulation of central neurotransmitters in rabbits: I. Effect of central catecholaminergic neurons in regulating acupuncture-induced immune function. Acupunct Electrother Res 1988;13:79-85. 134. Zhao J, Liu WQ. Relationship between acupuncture-induced immunity and the regulation of central neurotransmitters in rabbits: П. Effect of endogenous opioid peptides on the regulation of acupuncture-induced immune reaction. Acupunct Electrother Res 1989;14:1-7. 135. Wu JL, Zong AM, Chai ΧΜ, Cai DH, Luo HM, Као PW, Ren ZC, Hu ZF. Effects of electroacupuncture on cell-mediated immunity in human body. In: Zhang XT, ed. Research on acupuncture, moxibustion and acupuncture anaesthesia. Beijing/Berlin: Science Press and Springer Verlag, 1986;568-573.

44 CHAPTER 3

TECHNIQUES OF BLOOD SAMPLING AND METHODS OF DETERMINATION

The clinical studies described in the following chapters examine different bodily responses during and after surgery by the measurement of parameters such as blood gases, catecholamines, hormones and a number of immunological factors. It is known that the quantitative results of such measurements are influenced not only by sampling techniques but also by the method of determination. In order to minimize these influences, a standard sampling technique and assay method for each parameter was employed. These are described below. For the clinical study carried out in The Netherlands samples, on the operation day, were collected from a radial artery catheter, whereas venous samples were drawn on the following days. For the clinical study carried out in China however, all samples were collected from a venous catheter located on the back of the hand. Samples for the measurement of each parameter from each patient were analyzed at the same time to avoid intra-assay variation within one patient. To avoid decay, samples were analyzed within six months (1).

Catecholamines

Sampling technique. One ml of blood was drawn into an ice-cold tube containing 0.02 ml of 0.25 mol.l"1 EGTA (ethylene-bisoxyethylenenitrilotetraacetic acid and 0.2 mol.l ' GSH (glutathion), pH was adjusted to 7.40 by addition of NaOH. After gentle manual mixing, the blood sample was immediately placed in ice and centrifuged within 30 minutes at 1,500 g for 10 minutes at 4°C. After separation, the plasma was stored, frozen at -20°C, until the determinations which followed within six months. Method of determination. Plasma catecholamine (CA) concentration was determined by a COMT (catechol-O-methyl-transferase) based radio-enzymatic method with thin layer chromatography (2-4). It comprised the methylation of CA by COMT with radioactive S-adenosylmethionine (SAM) acting as the methyl donor, followed by purifying the reaction products metanephrine (MN) and normetanephrine (NMN) in several steps. Assay procedure. All steps preceding the enzyme reaction were carried out using ice-cold solutions and tubes were placed in melting ice. Into glass tubes the following solutions were pipetted in duplicate and mixed: blank: 0.05 ml oxidized plasma and 0.01 ml stabilizing solution (0.1 mol.l1 GSH in 0.01 mol.l ' HCl); samples: 0.05 ml plasma and 0.01 ml stabilizing solution; sample + internal standard: 0.05 ml plasma and 0.01 ml A and NA standard in plasma. To each tube 0.013 ml of Tris buffer, 0.003 ml of 3H-SAM (about 3 \iCi) in diluted H2S04 and 0.012 ml COMT were added and mixed. The tubes were placed in a waterbath at 37°C for one hour. Products of the reaction were

45 radioactive MN and NMN. The incubation was terminated by placing the tubes in melting ice and adding 0.05 ml of stop buffer (0.8 mol.l ' of bone acid, 80 mmol.l ' of EDTA, 5 mmol.l ' each of MN, NMN and 3-methoxytyramme, pH 8.0) to the tubes, followed by 0.088 ml 0.1 mol.l' TPB (tetraphenylborate) solution. The high concentration of non-radioactive NM and NMN m the stop buffer were used to identify the position of the small amounts of the radioactive NM and NMN later during chromatography. The MN and NMN were extracted into 2.0 ml water-saturated diethylether by vortexing for 30 s. The phases were separated by low-speed centnfugation and carefully freezing the plasma layer in an ethanol/C02 bath. The ether layer was decanted into an identical tube containing 0.04 ml 0.1 mol.l1 HCl. By vortexing for 10 s the A and NA were re- extracted into the acidic phase and after separation as described above, the ether layer was decanted and discarded. The HCl-phase was washed once with 2.0 ml diethylether as before and, after washing, it was quantitatively transferred to polyethylene conical tubes. The glass tubes were rinsed with 0.05 ml of a 4:1 mixture of ethanol and 0.01 mol.l ' HCl, which was also collected into the conical tubes. The volume of this acidic solution was reduced to approximately 0.03 ml in a heated vacuum centnfuge. The concentrated samples were spotted onto a silica gel thin layer chromatography plate, into which channels had been previously scraped with a home-made device. The tubes were nnsed with 0.01 ml of the ethanol/HCl mixture, which was also spotted. The plate was developed for about 60 minutes with freshly prepared developing solution, containing chloroform, ethanol and 40% aqueous methylamine (15-31, by vol ). The spots of MN, NMN and 3-methoxytyramine were localized and marked under UV light (mean Rf-values 0.29, 0.44 and 0.70, respectively). The silica gel containing the MN and NMN from each sample was scraped into a set of 6 ml plastic scintillation vials and eluted by adding 0.5 ml of 0.05 mol.l' NH4OH and vortexing. The MN and NMN were oxidized to vanillin by addition of 0.05 ml of 0.2 mol.l' NaI04 solution, exactly 5 minutes later followed by 0.05 ml of 1.5 mol.l ' glycerol solution, all at room temperature. After acidification with 0.5 ml 0.1 mol.l' HCl, the radioactive vanillin was extracted into 3.5 ml toluene, containing 4% (v/v) liquifluor. All vials were closed, vigorously shaken and vortexed. After phase separation, radioactivity was counted in a standard liquid scintillation counter. Precision The intra-assay coefficient of vanation for plasma A is 7.1% and the inter-assay coefficient of variation was 9%. For NA the intra-assay coefficient of vanation was 5.4% and the inter-assay coefficient of vanation was 7.5%. The normal range for A is 0.06-0.30 nmol.l ' and for NA 0.6-2.3 nmol.l '. Sensitivity. The lower limit of detection is 0.05 nmol.l ' for either A or NA.

Peptide hormones and Cortisol

Sampling technique. 15 ml of blood was drawn into three EDTA tubes of 5 ml each. After gently mixing manually, the samples were immediately placed in ice until centnfuged within 30 minutes at 1,500 g for 10 minutes at 4°C. The plasma was then divided between six plastic tubes. 250 U of Trasylol per ml of plasma

46 was added to tubes for the determination of ACTH, ADH and BE Samples for hormonal analysis were stored frozen at -20°C until determination, which followed within six months

Methods of determination

Adrenocorticotropic hormone The extraction and measurement of plasma ACTH were earned out using a specific radio-immunoassay (RIA) method (5) The entire extraction procedure was earned out at 4°C Extraction procedure A 0 5 ml sample of patient plasma and ACTH-free plasma samples with an ACTH standard curve (MRC 74/555) were extracted in duplicate by adding a suspension of 25 mg Vycor 325 Mesh glass powder in 0 25 ml H20 The mixture was inverted end over end for 30 minutes, then centnfuged at 5,000 g for 10 minutes The supernatant was aspirated and the pellet was washed with 2 ml H20 then 2 ml of 1 N HCl ACTH was eluted with 1 ml of acetone-H20 solution (50 50 v/v), centnfuged at 10,000 g for 10 minutes The eluate was dned overnight under a stream of air at 50°C The residue was dissolved in 0 25 ml of solution containing 0 9% NaCl and 0 25% Bovine Serum Albumin (BSA), the pH of which was adjusted to 3 5 by the addition of 1 N HCl The mixture was centnfuged for 60 minutes at 30,000 g The ACTH content of 01 ml of supernatant was estimated by a RIA technique RIA procedure 0 2 ml of Phosphate saline buffer pH 7 50 and 0 1 ml of rabbit ACTH antiserum (Wellcome, UK), titre 1 10,000, were added to 0 1 ml of the supernatant The mixture was incubated for three days, after which 0 1 ml of ACTH ,25I tracer (7,000 dpm, punfied by Sephadex G-50 fine column chromatography) was added to the mixture The incubation was continued for one day Bound and free hormones were separated by adding 1 ml of precipitating complex containing sheep anti rabbit IgG/PEG (Polyethylene Glycol) and incubated for 20 minutes at room temperature The mixture was centnfuged and the supernatant was aspirated The sediment containing the bound fraction of hormone was now ready to be counted in a gamma counter Precision The intra-assay and inter assay coefficients of variation were 6 3% and 12 3%, respectively The normal range at 8 am lies between 2 0-15 0 pmoll' Sensitivity The lowest detection level is 2 0 pmol 1 ' Specificity The specificity of the assay was tested by adding vanous ACTH peptides to the assay The antibody used recognized especially the amino acid sequence 17-24

Antidiuretic hormone The extraction and measurement of plasma ADH was earned out with a specific Buhlmann Laboratories AG Basel RIA Kit The whole procedure was earned out at 4°C Extraction procedure The extraction of ADH from plasma was earned out by mixing 1 0 ml of plasma with 5 ml of chilled (-20oC) 98% ethanol After vortexing for 3 minutes the mixture was centnfuged at 1,000 g for 20 minutes at 4°C The supernatant was evaporated with a stream of air at 37°C The sample was then reconstituted with 1 ml of buffer

47 Assay procedure. To 0.4 ml of this solution and standard curve, 0.1 ml of vasopressin antiserum was added. After 24 hours incubation, 0.1 ml of vasopressin l25I tracer was added and the mixture was incubated for a further two days. After addition of 0.1 ml of goat anti rabbit IgG precipitating complex, the mixture was incubated for one day and then centrifuged. The supernatant was aspirated and the sediment containing the bound fraction was measured in a gamma counter. Precision. The intra-assay and inter-assay coefficients of variation were 9.7% and 20%, respectively. The normal range lies between 4.2 and 11.8 pmol.l1. Specificity. The crossreaction with arginine vasopressin was 100%, with lysine vasopressin 0.85% and with oxytocin 0.0001%. Sensitivity. The lowest detectable level is 0.5 pmol.l '.

ß-Endorphin. The extraction and measurement of ßE were carried out with a specific plasma BE RIA Kit (INCSTAR, Stillwater, Minnesota, USA). The entire procedure was carried out at 4°C. Extraction procedure. Sepharose anti BE particles were added to columns containing standard and samples in duplicate. AH samples were assayed in duplicate to ensure confidence in values obtained. The columns were rotated for four hours and then placed in an upright position in a rack. The bottom and top caps were removed and the plasma drained through the column under pressure. The columns were washed with 3x1 ml aliquots of 0.85% saline. BE was then eluted into new tubes by rinsing the column surface with 0.25 ml of 0.025 N HCl twice. Assay procedure. Into 0.2 ml of the eluate 0.1 ml of neutralizing buffer and 0.1 ml of rabbit anti BE were added. The solution was incubated for 24 hours, after which 0.1 ml of '"I BE was added and the solution incubated for a further 24 hours. For the separation of bound and free hormones, 0.5 ml of goat anti rabbit PEG precipitating complex was added, incubated for 20 minutes and centrifuged. The supernatant was aspirated and the sediment containing the bound fraction was now ready for estimation in a gamma counter. Precision. The intra-assay variation was 7.8%, while the inter-assay variation was 12%. Normal values are 3-11 pmol.l1. Sensitivity. With this method of determination the minimum detectable amount is <3.0 pmol.l·'. Specificity. The cross reactivity with human BE is 100% and with B-lipotropin <5%.

Growth hormone. The measurement of plasma GH was carried out with a specific RIA method. Assay procedure. 0.05 ml of standard (MRC 66/217) or sample were mixed with 0.35 ml of Phosphate saline buffer, 0.05 ml anti serum (titre 1:40,000, gift from Tauber, Amsterdam) and 0.05 ml of GH 125I (7,000 dpm, purified by Sephadex G 75 column chromatography). The solution was then incubated for four days at 4°C. Into the mixture 1 ml of precipitating complex containing sheep anti rabbit PEG was added, incubated for 30 minutes at 40C and centrifuged for 20 minutes at 12°C. The supernatant was decanted and the sediment was measured in a

48 gamma counter. Precision. The intra-assay coefficient of variation was 5%, while the inter-assay coefficient of variation was 7%.The normal range is less than 20 тШ.Г1. Sensitivity. The lower detection level is 2 mIU.1 '.

Prolactin. The measurement of plasma PRL was carried out with IRMA (Immuno Radio Metric Assay) using a MAJA Clone Kit (Serono Diagnostics, Switzerland). Assay procedure. 0.05 ml of sample or standard (WHO 75/504) was added to 0.1 ml of a mixture of fluorescein labelled and 125I labelled monoclonal antibodies to PRL. After mixing, the solution was incubated at room temperature for one hour. Then 0.2 ml of a well-mixed solution of anti-fluorescein bound to magnetic panicles separation reagent was added to the solution and mixed. It was then incubated for a further 5 minutes at room temperature. The tubes were placed in a magnetic field, whereby the prolactin complex was sedimented. The supernatant was removed and the sediment was washed with a Tris buffer. The tubes were placed again in the magnetic field and again the supernatant removed. The sediment was then counted in a gamma counter. Precision. The intra-assay and inter-assay coefficients of variation were 3% and 4% respectively. The normal range lies between 140 and 360 тШ.Г'. Sensitivity. The detection limits of this assay method is 6.0 mIU.1 '. Specificity. The cross reactivity with PL, GH, LH, FSH, TSH within the scope of this experiment was negligible.

Cortisol. The plasma Cortisol concentration was measured by a specific RIA method (6). Assay procedure. After a 1:100 dilution of plasma with ethanol/water (1:20), corticosteroid binding globulin (CBG) was denatured by incubation at 70oC for one hour. Into the above diluted solution, 0.1 ml sample (= 0.001 ml plasma) or 0.1 ml of Cortisol standard curve, 0.25 ml tracer [3H] Cortisol and 0.25 ml antiserum were added. The antiserum was raised in rabbit against coTtisol-21- hemisuccinate coupled to bovine serum albumin. After incubation at 4°C for 18 hours, bound and free hormones were separated by dextran-coated charcoal. The bound fraction was measured in a liquid scintillation counter. Precision. The intra-assay and inter-assay coefficients of variation were 5% and 10%, respectively. The normal range at 8 a.m. lies between 0.19 and 0.55 μπιοΐ.ΐ '. Sensitivity. This measurement technique has a sensitivity of 0.02 μπτοϋ'.

Immunoglobulins and leucocyte and differential counts

Immunoglobulins

Sampling technique. Two ml of blood was drawn into a dry tube and centrifuged at 900 g for 10 minutes. The separated serum was frozen at -20°C until determination. The measurement was carried out within one month.

49 Method of determination. Concentration of IgA, IgG and IgM were estimated by an immunochemical method based on the precipitation of antigen-antibody complexes in agar gel (7, 8) using a Disc 120 Nephelometer (Hyland, Nivelles, Belgium). Assay procedure. Patient samples were prediluted 20 fold with isotonic saline. Depending on what was to be measured, 0.01 ml IgA, 0.005 ml IgG, 0.02 ml IgM or standard serum (Standard calibration for IgA, IgG and IgM was with WHO standard 67-86. Based on the results of an international collaborative assay examination (9), 67-86 has been established as the British research standard for human serum immunoglobulins IgA, IgG and IgM) and blanks were mixed with 1 ml of prediluted rabbit antisera against IgA, IgG and IgM or diluent (Polyethylene Glycol, Phosphate saline buffer) and incubated for exactly one hour. For concentrations of less than 15 lU.ml"1 (IgA, IgG and IgM) either the nephelometer was adjusted to a higher sensitivity setting or a larger sample volume, usually 0.1 ml of 20-fold prediluted sample, was taken. The relative light scatter was then measured from all samples nephelometrically. Precision. IgA, IgG and IgM in patients sera were determined in duplicate. The intra-assay coefficients of variation were less than 3% for IgA, IgG and IgM. Table 1 shows the between-run variation over more than one year for the normal serum pool and for the low-concentration control serum of IgA, IgG and IgM. The normal ranges are IgA:60-200 lU.ml1, IgG:70-170 IlLml"' and IgM:50-200 lU.ml1. Sensitivity. The lower limit of accurate detection of IgA, IgG and IgM was 3 lU.ml1.

Table 1. Between-шп variation of IgA, IgG and IgM (lU.ml·1) for control sera.

IgA IgG IgM Normal Low Normal Low Normal Low

N 66 66 66 66 66 64 Mean 122 31.1 117 32.1 120 28.8 SD 3.7 1.4 3.5 1.3 4.6 1.4 CV(%) 3.0 4.5 3.0 3.9 3.8 4.8

White blood cell and differential counts

Sampling technique. Two and half ml of blood was drawn into a heparinized tube and manually mixed to avoid clotting. The determination followed usually on the same day. Method of determination. The white blood cell (WBC) count was carried out in an electronic cell counter (Coulter counter. Model S,; Coulter Electronics Ltd., England). Assay procedure. All samples were assayed in duplicate to ensure confidence in values obtained. The counter was programmed to aspirate 1 ml of sample into the sampling valve and 0.447 ml of this was mixed with 10 ml of diluent (Isoton II). Nine millilitres of mixture was forced into the WBC Counting Bath and mixed

50 with 1 ml of Lyse S solution (Potassium cyanide) to lyse the red blood cells. A regulated vacuum in the isolating chamber drew diluted sample through the apertures of the two orifice tubes situated in each counting bath leading to changes of current flow. The WBC count was based on the current difference. Precision The intra-assay coefficient of variation was below 2%, while the inter- assay coefficient of variation was 3.5%. The normal range of WBC is 4.0- ll.OxlO'.r. Sensitivity The assay method has a lower detection limit of 0.5x10'.!'. Differentiation Blood smears were made in duplicate on object glasses and air dned. A solution of May-Griinwald was then used to fix the smears, which were stained with Giemsa solution. The differential counts were all carried out by the same person. The normal ranges of the differential cell count are: neutrophils:60- 70%, lymphocytes:20-30%, monocytes: 1-5%, eosinophils· 1-4% and basophils:0- 2%.

Blood gas and acid-base

Sampling technique One ml of arterial blood was drawn in a heparimzed synnge. Care was taken to remove all air from the synnge. The measurement followed within 15 minutes. Method of determination Blood gases were analyzed in an Automatic Gas Check

AVL 940 The P02 was measured electrochemically, the PC02 electrometncally and the pH potentiometncally. Assay procedure The analyzer was programmed to aspirate 0.04 ml of each sample. A peristaltic pump moved the sample from electrode to electrode in the measuring chamber, which was maintained at 370C.

Precision The coefficients of variation for P02 was 0.39% and for PC02 was 0.52%. The normal ranges of blood gas value are: PO,: 10.6 - 13.3 kPa; pH: 7.38 - 7.43; PC02: 4.5 - 6.0 kPa; НС03: 22 - 26 mmol.l ' and BE: -2 - +2 mmol.l ' Sensitivity The method of analysis has a measuring range of: 0 - 26.6 kPa for

P02; 0.53 - 26.6 kPa for PC02; 6.00 - 8.00 for pH; 1 - 100 mmol.l ' for HCO3 and -40 - +40 mmol.l ' for BE.

References

1 Falconer AD, Lake D, MacDonald IA The measurement of plasma adrenaline by high performance liquid chromatography with electrochemical detection an assessement of sample stability and assay reproducibility Int Neurosci Methods 1982,6-261 2 Peuler JD, Johnson GA Stimultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine Life Sci 1977,21 625-636 3 Hoffmann JJML, Willemsen JJ, Thien Th, Benraad ThJ Radioenzymatic assay of plasma adrenaline and noradrenaline evidence for a catechol-O-methyltransferase (COMT) inhibiting factor associated with essential hypertension Clin Chim Acta 1982,125 319-327 4 Hoffmann JJML, Willemsen JJ, Lenders JWM Benraad ThJ Reduced imprecision of the radioenzymatic assay of plasma catecholamines by improving the stability of the internal standards Clin Chim Acta 1986,156 221-226

51 5 Goverde HJM, Pesman J, Smais AGH The bioactivity of immunoreactive adrenocorticotrophin in human blood is dependent on the secretory state of the pituitary gland Clin Endocrinol 1989,31 25^-265 6 Smals AGH, Kloppenborg PWC, Goverde HJM, Benraad ThJ The effect of cyproterone acetate on the pituitary-adrenal axis in hirsute women Acta Endocrinol 1978,87 352 358 7 Mancini G, Carbonara АО, Heremans JF Immunochemical quantitations of antigens by single radial immumdiffusion Immunochem 1965;2 235 254 8 Renckens ALJM, Jansen MJH, van Munster PJJ, Weemaes CRM, Bakkeren JAJM Nephelometry of the kappa/lambda light-chain ratio in serum of normal and diseased children Clin Chem 1986,32 2147-2149 9 Rowe DS, Anderson SG, Grab В A research standard for human serum immunoglobulins IgG, IgA and IgM Bull Wld Hlth Org 1970 42 535 552

52 CHAPTER 4.1

DEVELOPMENT OF MEDICAL SERVICES IN CHINA WITH PARTICULAR REFERENCE TO ANAESTHESIA

Situation in 1949 and thereafter

Inadequate health care and chronic malnutrition contributed to the fact that China, for centuries, had one of the lowest life expectancies and highest death rates in the world (1-4) The war of resistance against Japan, followed by the civil war leading to the founding of the People's Republic in 1949, made the situation even worse The health system was virtually paralyzed, simply because of shortages of all medical facilities, from personnel to equipment and materials Since more than 90% of the population lived in rural areas and most Western trained physicians were concentrated in the cities, the care of the majority of the population was inadequate and was mainly provided by practitioners (around 500,000) of TCM (3-6) The ratio of physicians to population can be regarded as an index of the health condition and economic well being of a society (7) With a population ot around 520 million in 1949, the doctor-population ratio in China varied between 1 13,000 and 1 50,000 and the hospital bed-population ratio was estimated to be between 16,550 and 120,000 (8-11) This compared with a doctor-population ratio of 1 2,500 in Taiwan, Hongkong, Singapore, Brazil, Mexico and Peru and 1 750 in the United States (7, 9) The hospital bed-population ratios in the industrially developed countnes is 1 100 (6, 7) To equal this, more than 700 000 Western trained physicians and nearly five million hospital beds would need to ha\e been created in China (9) The earliest government ettorts in the health area consisted of developing its own capacity, pnmanly to provide preventative medicine and acute hospitalization needs (12) The first National Health Conference in Beijing in 1950 adopted tour principles for the development of health services health care must serve the common people, priority of pre\entive over the curative medicine, integration of TCM with Western medicine and coordination of mass health campaigns (3, 9) All these principles are still in effect This chapter, however, will deal only with

Table 1 Population and quantitative trends on the medical events in China until 1985 with the situation in 1949 as reference (2 6 7 9 Π 19)

1949 1955 1957 1966 1972 74 1980 1985

Population (10') 500 540 608 700 775 780 875 894 1045 Number of physician ( 10') 10 40 70 100 120 150 360 447 602 Number of TCM doctor (10') 276 500 337 321 250 262 336 Number of hospital (10') 0626 42 42 7 64 65 5 59 6 Number of hospital bed (103) 70 90 295 440 766 800 1 850 1,932 2,229 Number of barefoot doctor (io1) 1000 1600 Number of medical school 32 38 90 113 Number of TCM school 10 12 25

53 Table 2. Vital statistics in China (2, 3, 18, 19). 1949 1957 1965 1972 1980 1985

Life expectancy (years) 50 60-65 Birth rate (.103) 40-45 34 37.9 20-25 18-22 17.8 Death rate (•IO5) 20-25 10.8 9.5 7-15 8-11 6.6 Infant mortality (.IO3) 150-200 20-30 the third principle which was achieved by scientific analysis of TCM and joint TCM and Western diagnoses and treatment. Tables 1 and 2 give an impression of the quantitative trends and vital statistics in the reforms of the public health system from 1949 until 1985 in China.

Anaesthesia and the integration of traditional Chinese medicine and Western medicine

Manpower and hospitals. Before the civil war, anaesthesia was practised by surgeons and nurses. A one year training programme was set up in the early 1950's. This gradually increased to a three, four and eventually a five year programme in the late 1980's (personal communication). Activities in the field of research were included in the programmes. Physicians and nurses also received postgraduate training in anaesthesia for six to 12 months, after which they practised anaesthesia, on a part-time basis, in small peripheral hospitals. In the 1970's, the number of full-time anaesthetists was estimated to be between 5,000 and 8,000 and the number of part-time anaesthetists to be between 8,000-10,000 (20). The total number increased in the late 1970's by about 10% and thereafter by 10-15% annually. A survey by the Chinese Society of Anesthesiology, conducted in some provinces and cities in 1976 recorded the number of full- and part-time anaesthetists to be about 20,000 (21). Four kinds of new hospitals were built: teaching and specialist hospitals, provincial and municipal hospitals, district and county hospitals and community and neighbourhood hospitals (3, 9). Large hospitals have a 1,000 beds and small ones 40 beds (22). In practice, however, two kinds of hospitals exist; 'Western' hospitals practising mainly Western medicine and TCM hospitals practising mainly TCM (22). Anaesthetic departments were upgraded as much as surgical departments. TCM trained doctors were also accorded the same status as Western trained doctors.

Anaesthetic equipment and drugs. Ninety percent of the national demands for medical equipment and drugs, including those in anaesthesia, are met domestically. The most basic anaesthetic machine, equipped only with oxygen, is located in small neighbourhood hospitals, usually with only one operating room. Hospitals at the provincial level are provided with more modem anaesthetic machines similar to the Drager. Recently, Ohmeda Modulus II and Drager machines have been imported for use in teaching and specialist hospitals. Most drugs and local anaesthetics, currently used in The Netherlands, are available in

54 China, including pancuronium, fentanyl and bupivacaine (personal communication). Until 1987, monitoring devices were available in teaching and specialist hospitals only. In the last few years this situation has been gradually changing although the smallest hospitals still have virtually no monitoring equipment (personal communication). Inhalation anaesthetics such as halothane and methoxyflurane are used clinically. Nitrous oxide and ether are seldom used (20, 23, 24).

Anaesthetic practice. Various anaesthetic techniques are in use. General anaesthesia is induced and maintained using both inhalation and intravenous techniques. Inhalational anaesthesia tends to be performed using oxygen and halothane combined with muscle relaxants and analgesics. Intravenous anaesthesia is usually achieved using a combination of procaine, pethidine, tubocurarine or succinylcholine drip and sodium gamma-hydroxybutyrate (23, 25). This is perhaps one of the earliest demonstrations of the effectiveness of total intravenous anaesthesia. Although the use of general anaesthesia is increasing gradually, especially in the larger and better equipped hospitals, it is estimated to account for only 10-20% of all surgical operations (20, 24, 26). Local and regional anaesthesia, plexus and nerve blocks are widely used for different kinds of surgery in 60-90% of cases. Continuous epidural anaesthesia, inserted at levels varying from the sacral to cervical areas play an important role in regional anaesthesia. The technique is performed with a high degree of skill and dexterity. Its use, supplemented with sedation but without endotracheal intubation, is common for upper abdominal procedures and surgery for the neck and shoulder areas. The remaining 1-2% of surgical procedures are performed under ACAN (24, 26-28, personal communication).

Results of the integration of traditional Chinese medicine and Western medicine. The process of integration included the adaptation of the medical curricula (3, 9, 14). Students trained in Western medicine had to complete a training programme in TCM and TCM doctors had to be trained in Western medicine. Before 1964, government policy did not result in satisfactory primary medical care for the rural population. Due to the extremely uneven distribution of manpower, the peasant was still obtaining medical care from TCM doctors only or not at all (29). Although improved compared with pre-1964 (Table 1), the ratio of doctors to population was still 1:10,000 in the rural sector, compared to 1:600 in a city like Guangzhou (7). This led to the training of the so called "barefoot doctors" in 1965. Within a six month period, they had to study the theory of the 900 pages in "A barefoot doctor's manual" (30), followed by a three month practical training programme in a hospital. They were then sent back to the countryside to practise primary care in the rural community. Also, one-half of the medical and public health manpower was transferred, compulsorily, from city to rural areas to set up rural health centres. Large, modem hospitals began to add TCM doctors to their staff or to open special departments for TCM. TCM hospitals also accepted Western trained physicians on their staff. Research into TCM enjoyed considerable expansion and was intensified and accelerated. Within anaesthesia, this resulted in the use of acupuncture as an

55 anaesthetic and to the identification of the physico-chemical properties of a number of herbs, which had been in use in anaesthetic practice for a long time (20, 31, 32). For example, the key substance of mafusan, a well-known 'anaesthetic' used by Hua Tuo, a surgeon at the Han dynasty (206 B.C.-220 A.D.). appears to be scopolamine. Two kinds of muscle relaxants have been extracted from herbs, namely levocurine methyl chloride and cycleanine dimethobromide. Levocurine methyl chloride is a non-depolarizing neuromuscular blocking agent, which is 1.4 times more potent than D-tubocurarine chloride. The onset time is about 3 minutes and it lasts about 30 minutes. Cycleanine dimethobromide is an alkali extracted from tetrandra, having a chemical structure similar to that of D-tubocurarine and is often administered for controlled hypotension. An effective dose of 0.3 mg.kg"1 has been suggested (23).

Acupuncture in anaesthesia and surgery

Historical view. Zhenjiu* (Acupuncture) has been practised for many centuries in China as one of the most important branches of TCM (33, 34). The Huangdi Neijing or the Yellow Emperor's Classic of Internal Medicine (Neijing) is thought to be the oldest document about Chinese medicine. It is not certain when this document was written, but it is thought to come from the time of the Huangdi Emperor (2697-2598 B.C.) (34, 35). The content of the book is thought to be a report of a discussion held between the Emperor and his minister of health, Zhi Bo. It consists two parts, the Lingshu and the Suwen. Both describe the theoretical basis of TCM and the aetiology, diagnostic techniques and methods of treatment for various diseases and syndromes. The use of nine kinds of needles and their various clinical applications are also described (34). Stone needles, discovered recently, are similar to those described in the Neijing. These needles have been dated as far back as the Neolithic Age (about 10,000-4,000 years ago) (31). In the period of the Jin dynasty (265-420 A.D.) an important book was compiled on the subject of Acupuncture: A Classic of Acupuncture and Moxibustion (Zhenjiu Jiayijing). The first Faculty of Acupuncture and Moxibustion in the Imperial Medical College was founded during the period of the Tang dynasty (618-907 A.D.) (35). This was the beginning of the new era when TCM could be studied officially.

The use of acupuncture in anaesthesia and surgery. Acupuncture was first used as the sole anaesthetic agent in 1958 in Xi'an, during which tonsillectomy was performed (20). The technique developed after good results had been obtained in alleviating the postoperative pain of various surgical procedures. Although the term ACAN is used to describe its use in surgery, hypalgesia is probably more

*Footnote: The ancient Chinese art of healing using needles is called Zhenjiu. Acupuncture is derived from the Latin words Acus (needle) and punctura (piercing). It was introduced by the Dutch surgeon W. ten Rhijne in 1683, in which year his book on "Dissertano Arthrilide: Mantissa Schematica: de Acupunctura" was published in London (35, 36).

56 accurate, since only the sensation of pain is diminished by acupuncture. However, the term ACAN is used simply because of historical usage. From the beginning of its use, it has almost always been combined with analgesics, sedatives and local anaesthetics. However, in all cases, patients remain conscious during the entire procedure (20, 33, 37). In the last few years, its use in Chinese hospitals in general has been reduced, but it still undoubtedly plays an important role in the anaesthetic services in China. ACAN is now mainly reserved for certain surgical procedures in both Western and TCM hospitals. From the Chinese point of view, ACAN is considered to have the following characteristics (20, 23, 24, 27, 38): 1. safe and free from side effects, 2. causes less disturbance of physiological function than general anaesthesia. Rapid recovery of digestive function occurs and urine retention is prevented. Wounds are thought to heal more quickly and the incidence of postoperative infections is thought to be reduced, 3. allows active cooperation of the patient with the surgeon. This can reduce injury to the recurrent laryngeal nerve in thyroid surgery and to the facial nerve in surgery for acoustic neuromata. It also allows better surgical correction of strabismus, 4. economical and especially of value where a shortage of anaesthetic facilities exist, 5. incomplete analgesia, 6. lack of muscle relaxation.

Selection and presurgical preparation of patients. Patient selection is important. Patients who are anxious and fearful, those who are very muscular and those who are not cooperative are not suitable for ACAN (1, 23, 26-28, 31, 34, 38). There is a disagreement regarding the use of ACAN for children. Although, in the past, the use of ACAN during paediatric surgery had been reported, nowadays children are not generally accepted for ACAN (23, 39). During the preoperative assessment, or earlier, patients are informed about the advantages of ACAN over conventional general anaesthesia. They are also informed about the surgical procedure and are made aware of certain sensations they will feel during surgical manipulations. The patients' pain threshold is tested in order to determine the best stimulation technique. Premedication consists usually of a barbiturate the night before surgery.

Selection of surgery. In the late 1960's and in the 1970's, ACAN was performed for nearly all kind of surgical procedures, including thoracic and abdominal surgery. During the first and second National symposia in 1979 and 1984 in Beijing, the experiences of practitioners in the use of ACAN in all sorts of surgery were presented and discussed (40, 41). As a result of these meetings, the surgical indications for ACAN were adjusted and were more clearly defined. It was generally agreed that a number of operations were more suitable for ACAN such as dental surgery, tonsillectomy, thyroid surgery, neurosurgery and superficial surgery on the neck, arm and leg. Body cavity surgery was thought to be unsuitable for ACAN except for Caesarean Section. Surgical exploration without

57 pnor diagnosis and surgery where adhesions may be anticipated were also thought to be unsuitable for ACAN

Selection of acupoints There are 722 defined acupoints distributed throughout 14 channels (meridians) in the body. In contrast to its use as a method of treatment for diseases, only about 20 body and ten ear acupoints are regularly used during ACAN (23, 26) It is thought that the analgesic effect is dependent on the correct selection of acupoints, which vary with the type of surgery. There are several methods of choosing the acupoints to be stimulated (23, 37): 1 selection of body acupoints according to the 14 channels. Acupoints on the channels passing through or near the skin incision are selected 2. selection of body acupoints near the planned skin incision Needles are introduced parallel to the planned skin incision 3. selection of body acupoints according to the same spinal cord segments as the surgical area 4. selection of ear acupoints based on the assumption that the whole body image is projected onto the ear. Needling can be restricted to the organ involved m the surgical procedure 5. selection of specific ear acupoints (Jiaogan, Shenmen) which produce a general increase in pain threshold and sedation All these methods can be used alone to produce surgical analgesia. However, it is usual to use one of the first four methods and to combine it with method five Table 3 presents a few examples ot selected acupoints and the corresponding surgery.

Table 3 Body acupoints and ear acupoints frequently used to be stimulated for inducing surgical anaesthesia (18, 34, 40-42)

Operation Body acupoint Ear acupoint

Neurosurgery Taichoiig, Quanhao, Zulmqi, Xiangu Shen, Shenmen, Xin

Thyroid surgery Futu, Hegu, Neiguan Jiaogan, Jing, Neifenbi, Shenmen

PneumeUomy Sanyangluo towards Ximen Fe, Shenmen, Xin, Xiong

Caesarean section Jizhong, paraincision, Sanyinjiao Fu, Jiaogan, Shenmen, Zigong

Gastrectomy Shangjuxu, Zusanli Fe, Jiaogan, Shenmen, Wei

Methods of stimulation There are two methods of stimulating acupoints (23, 26, 33). Needles used to be manipulated manually They were not only rotated but also lift-thrusted at the same time. Later this was superseded by a battery powered (4 5-6 V) stimulation device Among the first generation of stimulators were the G-6805, 6-26, 71-1 and 71-3 devices (9, 45, 46) The waveforms (e.g. continuous wave, interrupted wave, dense-disperse wave, etc ) were biphasic with a positive pulse width of 0.5 ms. The stimulators consisted of three or four output channels, the intensity of which could be individually controlled through a potentiometer from 0-4 for the G-6805 and from 0-10 in the others The current

J8 frequency could be vaned between 0-50 Hz (9, 45, 46). Generally, acupoints located near surgical areas are stimulated with a higher frequency (>10 Hz) than those located away from the surgical areas (<10 Hz) The intensity of stimulation is adjusted to the limits of the patients' tolerance

Induction and maintainance of acupuncture anaesthesia Acupoints are stimulated for at least 20 minutes before surgery is allowed to commence and continued until the end of the procedure When inadequate analgesia is produced, the intensity of the stimuli is increased. During the course of surgery, if analgesia at some stage is insufficient, drugs may be administered ι ν Generally, three different drugs are used as adjuvants pethidine, chlorpromazine and procaine They are administered in such a way that the patient remains conscious and cooperative for the whole procedure

References

1 Murphy TM, Bonica JJ Acupuncture analgesia and anesthesia Arch Surg 1977,112 896-902 2 deHaas JH, deHaas-Posthuma JH Socio medical achievement in the People's Republic of China Int J Health Serv 1973,3 275 294 3 Chabot HTJ The Chinese system of health care Trop geogr Med 1976,28 S87-S134 4 Akhtar S Health care in the People's Republic of China A bibliography with abstracts Ottawa IDRC-038e, 1975 5 Spence JD The search for modem China New York/London WW Norton & Company, 1990 689 6 Sidel R, Sidel VW The health of China Currents conflicts in medical and human services for one billion people Boston Beacon Press, 1982 7 Cheng CY Health manpower growth and distribution In Wegman ME, Lin T, Purcell EF, eds Public health in the People s Republic China New York Josiah Macy, Jr Foundation, 1973,139-157 8 Penfield W Oriental renaissance in education and medicine Sci 1963,141 1153-1161 9 Sidel VW, Sidel R Serve the people Observations on medicine in the People's Republic of China New York Josiah Macy, Jr Foundation, 1973 10 Orleans LA Medical educations and manpower in communist China In Hu CT ed Aspects of Chinese education New York Columbia Univ Teachers College Press, 1969,20-42 11 Chen TH Science in communist China Washington Am Assoc Adv Sci, 1961,68 12 Gordon JB The organization and financing of health services In Quinn JR ed China medicine as we saw it US Public health service, DHEW Pub no (NIH)75 684, 1974,63 85 13 Fan FN China handbook Hongkong Kwong Yi Printing Press Ltd, 1980 14 Croizier RC Traditional medicine in modem China Cambridge/Massachusetts Harvard Univ Press, 1968 15 Wilenski Ρ The delivery of health services in the People's Republic of China Ottawa IDRC 056e, 1976 16 Huard P, Wong M La médecine des Chinois Verona Amoldo Mondadori Editore Officine Grafiche 1967 17 Hayes MV China Close up Life styles of the 800 Million New York Drake Pub, 1972,51- 57 18 State Statistical Bureau, People's Republic of China China a statistics survey in 1986 Beijing New World Press, 1986 19 Editorial Board of Encyclopedia of New China Encyclopedia of New China Beijing Foreign Languages Press, 1987 20 Bonica JJ Anesthesiology in the People's Republic of China Anesthesiology 1974 40 175- 186

59 21 Tan HY, Xie R The recent advances in anaesthesiology in China J Jpn Soc Clin Anesth 1989 9:369-170 22 Stuart Maddin W Integration ot traditional and modem medicine In Quinn JR ed China medicine as we saw it US Public health service, DHEW Pub no (NIH)75-684, 1974,13-34 23 I in GF Anesthesiology In Wu HG, Ran RT, eds Modem Chinese Medicine, volume 1 Chinese Surgery, A comprehensive review of surgery in the People's Republic of China, Lancaster/Beijmg MTP Press Limited and the People's Med Pub House, 1984,11 239-254 24 Hutschenreuter К Die Anästhesie im Geburtsland der Akupunktur, Impressionen aus China Dtsch Arztbl 1978,75(Suppl) 1933-1940 25 Gingras G, Geekie DA China report health care in the world's most populous country Can Med Ass J 1973,109 C-P 26 Pongratz W Akupunktur in der Anaesthesiologie In Lawin P, Loewenich von V, Scholmench P, Stoeckel H, Zumtobel V, eds Intensivmed Notfallmed Anasth Stuttgart/New York Georg Thieme Verlag, 1982,33 5 27 Baum J 20 Jahre Akupunktur-Analgesie in der Volksrepublik China, eine Bilanz der klinische Erfahrungen Dtsch Arztbl 1980,77(Suppl) 2223-2231 28 Bonica JJ Acupuncture anesthesia in the People's Republic of China, implications for American medicine JAMA 1974,229 1317 1325 29 Dimond EG More than herbs and acupuncture New York Norton & Company WW Ine, 1975,156 30 A barefoot doctor' manual Translated by Fogarty International Center for Advanced Study in the Health Science Philadelphia Running Press, 1977 31 Qian XZ Progress in Scientific Research on Acupuncture, Moxibustion and Acupuncture Anesthesia by Integrating Traditional Chinese and Western Medicine In Zhang XT, ed Research on Acupuncture, Moxibustion and Acupuncture Anesthesia Berlin/Beijing Science Press and Springer Verlag, 1986,1-18 32 Dimond EG Acupuncture Anesthesia, Western medicine and Chinese traditional medicine JAMA 1971,218 1558-1563 33 Cheng XN Chinese acupuncture and moxibustion Beijing Foreign Languages Press, 1987 34 Veith I The Yellow Emperor's classic ot internal medicine Berkeley/L A/London Univ Calif Press, 1973 35 Kho HG Acupunctuur, een overzicht van algemene ontwikkeling en basisbegrippen tot hedendaagse toepassing en huidige wetenschappelijke onderzoekingen Nijmegen B'Gottmer's uitgeversbedrijf 1975,9-13 36 Carrubba RW, Bowerz JZ The Western World s first detailed treatise on acupuncture Willem ten Rhyne's De Acupuntura J Hist Med 1974,29 371-398 37 Ho ST, Lu LK The principle and practical use of acupuncture anaesthesia Hongkong Med Health Pub Co 1981 38 Bischko J Observed uses of acupuncture In Quinn JR, ed China medicine as we saw it US Public health service, DHEW Pub no (NIH)75-684 1974,13-34 39 Anonymous A clinical analysis of 1474 operations under acupuncture anaesthesia among children Chin Med J 1973,1 369-374 40 Zhang XT, ed Research on Acupuncture, Moxibustion and Acupuncture Anesthesia Berlin/Beijing Science Press and Springer Verlag, 1986 41 All China Society of Acupuncture and Moxibustion, ed The second National Symposium on Acupuncture and Moxibustion and Acupuncture Anesthesia Beijing, 1984 42 Liu SZ, Ge CY, Fan PC, Sun SP Clinical evaluation of 1066 cases of thyroid operation under acupuncture anaesthesia 1st World Conference on Acupuncture and Moxibustion Beijing, November 22-26, 1987 43 Chen SD Summary of 9375 cases of Thyroidectomy under Acupuncture Anaesthesia In Zhang XT, ed Research on Acupuncture, Moxibustion and Acupuncture Anaesthesia Beijing/Berlin Science Press and Springer Verlag, 1986,993-999 44 He TH Observations of 158 cases of pneumectomy under acupuncture anaesthesia 1st World Conference on Acupuncture and Moxibustion Beijing, November 22-26, 1987 45 Baum J Characteristics of electrostimulations with the multi-purpose therapy apparatus 71-3 for electroacupuncture analgesia Anasth Prax 1979,14:14-22 46 Lowe WC Introduction to acupuncture anaesthesia Bem/Stuttgart Hans Huber Pub, 1973

60 CHAPTER 4.2

ACUPUNCTURE ANAESTHESIA REVISED Observations on its use in thyroid surgery and influence on recovery and morbidity in a Chinese hospital

Abstract. Acupuncture anaesthesia, supplemented by small doses of pethidine, was evaluated in 20 patients who had surgery for removal of a thyroid adenoma. There were significant increases in mean arterial pressure and respiratory rate during surgery, but no significant change in heart rate. The mean dose of pethidine given dunng surgery was 45.0 mg (SD 8.9). Postoperative recovery was rapid and complication free. Acupuncture anaesthesia did not provide complete analgesia, but was safe and preferable to general anaesthesia where there is a shortage of facilities.

ACAN was introduced in 1958 and became a commonly used technique in China The technique elevates the pam threshold sufficiently to allow surgery on conscious subjects (1) and many articles are published which describe its use dunng thoracotomy (2, 3), abdominal surgery (4, 5) and even paediatnc surgery (6). At a symposium in Beijing in 1984, experience with more than 2,000,000 cases was reported. Many Western scientists were invited to China to witness this technique, but their reports were limited to only a few cases (7) or based on a fleeting contact with the method (8-19). Until the late 1970's up to 80% of surgical procedures in China were performed under regional anaesthesia, acupuncture was used in 8-30% of these cases (8, 20). Nowadays, ACAN is only used routinely for procedures, for example operations on the head and neck, in neurosurgery and thyroid surgery. ACAN alone can be used in 95 4% of the latter procedure (21-23) and it was possible in recent years to evaluate the method more closely and to follow patients pre-, per- and postoperatively. This led to the present study on the evaluation of ACAN for removal of thyroid adenoma. The study protocol was designed after consultation between the Departments of anaesthesia of the University of Nijmegen, The Netherlands, and the First Affiliated Hospital of Nanjing Medical College, China. The study protocol was approved by the Ethics Committee of the latter hospital, which was visited from Apnl to June 1987.

Patients and methods

Twenty consecutive ASA 1 or 2 patients, scheduled for removal of thyroid adenoma were studied. Informed verbal consent was obtained at the preoperative visit. Psychological preparation and testing pain thresholds (23) were not earned out. Routine investigations for this type of surgery were obtained.

61 Table 1 Location of ear acupoints used at the First Affiliated Hospital of Nanjing Medical College, China for the surgical removal of ipsilaleral thyroid adenoma

Acupoint Auricle area Anatomical location

Jiaogan (sympathetic nerve) Infenor anti helix crus At junction of infenor antihelix crus and medial border of helix

Jing (neck) Antihelix At junction of antihelix and antitragus, near scapa

Neifenbi (adrenal) Tragus At lower tubercle on border of tragus

Shenmen Triangular fossa At bifurcation point of supenor antihelix cms and infenor antihelix crus

Figure 1 Ear acupoints used for surgery Arrows indicate the points chosen for removal of ipsilateral thyroid adenoma

62 Patients were premedicated with diazepam 10 mg orally 90 minutes before surgery, after fasting overnight. An intravenous infusion was set up and 10 minutes later a blood sample was taken from the other arm to exclude the presence of pethidine. The sample was frozen and the analysis was carried out in Nijmegen, using a HPLC assay method with a detection limit of 10 ng-ml"1 (24). Acupuncture was performed by the same anaesthetist in each case. Four ear acupoints on the same side as the thyroid adenoma were selected for puncture (Table 1, Figure 1). The needles were connected to a battery powered G-6805 acu-stimulator whose output could be varied from 0-4. Stimuli at a rate of 4 Hz were applied and the strength gradually increased to the limits of the patients' tolerance. The maximum amplitude reached was setting "3" in all cases, which resulted in a current up to 20 mA. Pethidine 30 mg was given i.v. 15 minutes after the start of stimulation. Surgery was allowed to commence 30 minutes after the start of stimulation and continued until the end of the procedure. Further small doses of pethidine together with a small dose of chlorpromazine were given i.v. if the arterial pressure (systolic arterial pressure/SAP, diastolic arterial pressure/DAP) and/or heart rate (HR) increased by more than 25% during surgery; in some cases procaine was infiltrated into the wound. The dose of pethidine did not exceed 1 mg.kg"'. SAP, DAP, HR and respiratory rate (RR) were recorded automatically before ACAN, after 15 minutes of stimulation, at the time of skin incision and at 10 minute intervals thereafter (HP 78354A). These variables were also recorded every 15 minutes during the immediate recovery period. The ECG was continously displayed (HP 78354A), and pain was measured on a verbal scale of 0-3 (0, no pain, 3 severe pain) at regular intervals. Pethidine was available for analgesia after operation and there was no restriction on mobility or oral fluid intake. The patient, surgeon and anaesthetist were asked to assess the quality of analgesia as good, satisfactory or unsatisfactory immediately after surgery. The patients were asked again to evaluate the anaesthetic on the first, second and third postoperative days. In addition, their daily activities such as getting out of bed, ability to go to the toilet were recorded and they were also asked to assess their fatigue level on a linear visual-analogue scale with extremities labelled 1, fit and 10 exhausted. The incidence of any complications was also noted. Data evaluation. Variables measured at admission or before induction were used as control. Data are means (SD). Mean arterial pressure (MAP) was calculated as 1/3 χ (SAP + 2xDAP). General Lineair Models (GLM) for repeated measures and Pearson correlation test were used. P<0.05 was the threshold of significance.

Results

Details of patients and duration of surgery and anaesthesia are shown in Table 2. All preoperative investigations were within normal limits. Pethidine was not found in any of the preoperative blood samples. The changes in MAP, HR and RR are shown in Figure 2. MAP was signifi cantly higher than control after 15 minutes of stimulation (point C, Figure 2) and

63 Table 2 Details of patients included in the study, surgical and anaesthetic time and preoperative values of haemoglobin and haematocnt Data represent mean (SD) values

Age (years) 38 8 (115) Weight (kg) 58 8 (9 5) Height (cm) 1613 (5 7) Sex M/F 2/18 ASA status Ш 16/4 Adenoma to be removed size (cm χ cm) 12(04 χ 2 3 (0 9) location L/R 9/11 Surgical time (mm) 88 8 (44 3) Anaesthetic time (mm) 127 7 (46 1) Haemoglobin (mmol 1 ') 6 61 (0 92) Haematocnt (%) 0 43 (0 06)

MAP Cmm Hg 130

P-D ог no ^ы р<0 Ol Ν ^ χ

90 ι 1 ' э с '-л^ Heat-t rate (beats min-1) . ^ Figure 2 Changes in p-O El mean arteria] pressure, \ Π^ heart rate, respiratory rate and pain scores

1 Figures are mean (SD) A, at hospital 1 p-O ВО ' admission, ' t 1) с: 1 " B, before acupuncture Resplr-аЪогц i-nto (breaths ij min stimulation, aa C, 15 minutes after stimulation, arrow, start of surgery p-O 73 34 The differences of / ч / І^ mean responses dunng Ν к and after surgery from го Υ reference are given by / ρ value и / ρ<0 Dl Ν э с Ι IR Ν

ηPai nΙ scoro CO-3}

Г N к I . . . . ι ^—I I . per-operatlve | | poat-op

64 remained elevated by up to 20% during the entire course of surgery (p<0.01). MAP was also significantly higher than preoperative values in the immediate recovery period. In contrast, HR remained stable throughout the study period with no significant changes from control. One hypertensive patient developed a bradycardia of 30 beats.min' immediately after skin incision and was given atropine. RR was significantly increased throughout surgery, but not in the immediate postoperative period. The increase in RR correlated with an increased pain score (p<0.05). No patient complained of pain at the time of surgical incision (Figure 2). The highest pain score (1.2, SD 0.8) was noted 10 minutes after incision, and the scores remained elevated throughout surgery. Sixty minutes after surgery, the mean pain score was 0.1 (SD 0.2). The supplementary drugs given are shown in Table 3. Only five patients required no further medication. The mean dose of pethidine given to the remaining 15 patients was 45.0 mg (SD 8.9). Chlorpromazine was given to reduce SAP and DAP in four patients. Infiltration with procaine was used in three patients; this was needed in two because surgery was extended to perform a lobectomy.

Table 3. Supplementary drugs during surgery.

Drug Number Dose Pethidine 14 20 mg 1 10 mg

Chlorpromazine 1 3 mg 3 2 mg

Atropine 1 0.5 mg

Local anaesthetic 1 5 ml (procaine 0.5%) 1 10 ml

The assessment of analgesia is shown in Table 4. Analgesia was judged unsatisfactory by the anaesthesist on only one occasion when a thyroid lobectomy had to be performed.

Table 4. Assessment of analgesia by surgeon, patient and anaesthetist in the immediate postoperative period.

Quality of analgesia Surgeon Patient Anaesthetist

Good 18 7 8 Satisfactory 2 13 11 Unsatisfactory 0 0 1

Surgery was completed in all patients without recourse to general anaesthesia. There were no complications relating to surgery, although one patient coughed repeatedly during mobilization of the gland. Twelve patients were noted to be

65 sweating dunng surgery, while one patient was nauseated One patient vomited in the recovery room The overall assessment of the anaesthetic technique by the patients is shown in Table 5.

Table 5 Overall assessment of the anaesthetic technique used as judged by patient, when questioned on days 1, 2 and 3 after operation Number of response Anaesthetic technique Day 1 Day 2 Day 3 Good 6 10 12 Satisfactory 12 8 8 Sufficient 2 2 0 Bad 0 0 0

The postoperative pain scores are shown in Figure 3 The majority of patients were pain free and none expenenced severe pain Pethidine was not used in any patient. INCIDENCE OF POSTOPERATIVE PAIN СО-ЭЗ in го h Z ω Ρ

DAY 1 DAY 3 Figure 3 Incidence of none (0), mild (1), moderate (2) and severe (3) pain on the first three days after operation

Postoperative recovery was rapid. Only one patient did not get out of bed on the first postoperative day (Figure 4). The fatigue score was 3 2 (SD 1.4) on the first day after surgery and had decreased to 1 4 (SD 0.6) by day 6 (Figure 5).

66 POSTOPERATIVE SELF RELIANCE . ЦП out of bed t=\ go to toilet I A QO for a walK

с л • I .

β a Tí 1U u Ы—ι J3 - 3ε =—І^ Ζ η = den 1 сіац Ξ day Э

Figure 4 Recovery after surgery recorded in the first three days Self Reliance

Po'sfcoperative Fatigue CI—lO)-

гіац day day

Figure 5 Recovery after surgery Fatigue score Return to the preoperative score was attained by day 6 Star indicates a significant difference (p<0 04) from the preoperative score

Discussion

The increases in arterial pressure found during ACAN and surgery in our patients were limited to 20%, this confirms the works of others (21, 25) We noted that more pronounced increases occured in two hypertensive patients, which is similar to that which occured during balanced anaesthesia (26) and indicates that preoperative treatment of hypertension is also necessary before ACAN No significant changes occured in HR during surgery, although one patient developed a marked bradycardia It has been suggested that HR is a reliable indicator of pain in conscious subjects during ACAN (27) There are so many factors that influence HR that changes cannot be reliably related to the amount of pain experienced A stable HR does not imply the absence of pain as shown in this study There was, however, a significant correlation between RR and pain scores No patient complained of pain at the time of incision, a feature that has been noted by others (8, 29) ACAN during surgery was unable to provide total analgesia, but all patients remained quiet and calm on the operating table and

67 Table 6 Pre and peroperative drugs used in thyroid surgery under local anaesthesia Studies by Ajao (3"!), Fernandez (36) and Saxe (37) compared with the present study F, fixed dose, M, mean dose

Kho Ajao Fernandez Saxe Drugs (mg) (n=20) (n=17) (n=433) (n=20)

Atropine F 0 5/n=l F 0 6/all - -

Valium F 10/all F 5/all F 10/all M 24 85/all

Pethidine M 45/all F lOO/all F 50-100 - (SD 8 9) /all

Fentanyl - - M 0 088/n=15

Ndbulphine - - F 25/n=l

Kctamme - - F 10/n=2

Propanolol - - - F 0 5/n=l

Phentolamine - - F 2/n=l

Chlorpronwine M 0 45/n=4 - - - (SD 0 9)

02/N20 30/70 - - n=3

Local anaesthetic Procaine Lidocaine Lidocaine Bupivacaine Concentration 0 5% \% 1% 0 25% Volume (ml) 5-10 10-10 25-30 46 5 Incidence (n) 2 17 433 20 Lidocaine 0 5% 10 20 surgery was completed in all cases. Such a state of affairs would not occur m western countries, although in selected patients ACAN has been used sucessfully for a number of different operations (29-34) Additional drugs were required in the present senes, but the amounts used were very small compared to other studies (Table 6) when thyroid surgery was performed under local anaesthesia (35-37) One of the commonest problems of performing thyroid surgery under local anaesthesia is laryngeal spasm associated with traction on the trachea (35-37) This was not seen in any of our patients, although one did cough during the procedure The overall incidence of minor complications was also low compared to other studies (Table 7) when thyroid surgery was performed under local anaesthesia (35-37), and the technique was generally acceptable to patient, anaesthetist and surgeon.

68 The present study has shown that it is possible to perform thyroid surgery under ACAN in Chinese patients However, it is important that patients are aware of, and accept, the fact that analgesia may not be complete throughout the entire procedure Also the anaesthetist must be prepared to give analgesics ι v. and the importance of gentle surgery is stressed upon the surgeon

Table 7 Complications of thyroid surgery under local anaesthesia Studies by Ajao (35), Fernandez (36) and Saxe (37) compared with the present study G A, general anaesthesia

Incidence

Kho Ajao Fernandez Saxe Complication (n=20) (n=17) (n=433) (n=20) Treatment

Respiratory distress 1 Intubation Laryngeal spasm 1 Tracheostomy Bradycardia 1 unknown unknown 1 Atropine (Kho) Intubation (Saxe) Transient hoarseness 8 some cases unknown none Excessive bleeding Hematoma some Surgery not completed 2 Recourse to G A

Total 1 (5%) 9 (53%) 27 (6 2%) 4 (20%)

References

1 Shanghai acupuncture anaesthesia co-ordinating group Acupuncture anaesthesia An anaesthetic method combining traditional chinese and western medicine Comp Med East West 1977,5 301-313 2 Anonymous Clinical studies on acupuncture anaesthesia in lung resection Chin Med J 1980,93 287-292 3 Wen W Acupuncture anaesthesia in China Comp Med East West 1977,5 185-188 4 Anonymous Abdominal hysterectomy under acupuncture anaesthesia using Jizhong point Chin Med J 1987,4 481-486 5 Anonymous Clinical analysis of 1000 cases of cesarean section under acupuncture anaesthesia Chin Med J 1980,93 231-238 6 Anonymous A clinical analysis of 1474 operations under acupuncture anaesthesia among children Chin Med J 1973,1 369-374 7 Thoma H, Benzer H, Mayrhofer O, Pauser G Telemetnsche EKG-Daten (Biorhythmen) bei Operationen in Akupunktur-Analgesie in der Volksrepublik China Anaesthesist 1975,24 32- 38 8 Hutschenreuter К Die Anästhesie im Geburtsland der Akupunktur, Impressionen aus China Dtsch Aerztbl 1978,75(Suppl) S1933-S1940 9 Baum J 20 Jahre Akupunktur Analgesie in der Volksrepublik China, eine Bilanz der klinische Erfahrungen Dtsch Aerztbl 1980,77(Suppl) S2223-S2231 10 Dimond EG Acupuncture anesthesia, Westem medicine and Chinese traditional medicine JAMA 1971,218 1558-1563 11 Bonica JJ Acupuncture anesthesia in the People's Republic of China, implications for amencan medicine JAMA 1974,229 1317-1325 12 Spoerel WE Acupuncture analgesia in China Am J Chin Med 1975,3 359-368 13 Alexander LL, Atkins NML Acupuncture in the People's Republic of China JAMA 1981,73 455-459

69 14. Kaada В, Hoel E, Leseth К, Nygaard-Ostby В, Setekleiv J, Stovner J. Acupuncture analgesia in the People's Republic of China. Τ Laege Forening 1974;94:417-442. 15. Ferguson NL. The use of acupuncture anaesthesia. Anaesth Intens Care 1973;1:325-327. 16. Jain KK. Glimpses of neurosurgery in People's Republic of China. Intern Surg 1972;57:155- 157. 17. Brown PE. Use of acupuncture in major surgery. Lancet 1972;i: 1328-1330. 18. Capperrauld I. Acupuncture anaesthesia and medicine in China today. Surg Gynaecol Obstetr 1972;135:440-445. 19. Cheng SB, Ding LK. Practical application of acupuncture analgesia. Nature 1973;242:559- 560. 20. Pongratz W. Akupunktur in der Anaesthesiologie. In: Lawin P, Loewenich von V, Scholmerich P, Stoeckel H, Zumtobel V, eds. Intensivmed Notfallmed Anästh. Stuttgart/New York: Georg Thieme Verlag, 1982;33:5. 21. Chen SD. Summary of 9375 cases of thyroidectomy under acupuncture anaesthesia. In: Zhang XT, ed. Research on Acupuncture, Moxibustion and Acupuncture Anaesthesia. Beijing/Berlin: Science Press and Springer Verlag, 1986;993-999. 22. Xin YL, Wang YL. A general survey on the developments in clinical acupuncture anaesthesia research in the past five years. J Trad Chin Med 1984;4:255-258. 23. Lin GF. Anaesthesiology. In: Wu HG, Ran RT, eds. Modem Chinese Medicine Vol 1. Chinese Surgery, A comprehensive review of surgery in the People's Republic of China, Lancaster/Beijing: MTP Press Limited and the People's Med Pub House, 1984;239-254. 24. Meatherall RC, Guay DRP, Chalmers JL. Analysis of Meperidine and normeperedine in serum and unne by high-performance liquid chromatography. J Chrom 1985;338:141-149. 25. Sawires R, Putz G. Klinische Erfahrungen bei Strumaoperationen in Sitzlage mit Elektrostimulationsanasthesie. Chir Prax 1984;33:407-412. 26. Takki S, Tammisto T. Effects of anaesthesia and surgery on catecholamines. In: Stoeckel H, Oyama T, eds. Anaesthesiology and intensive care medicine; endocrinology in anaesthesia and surgery. Berlin/Hcidclbcrg/New York· Springer Verlag, 1980;69-74. 27. Hynyncn KH, Ketovuon H, Mattila MAK, Mattila S, Nokso-Koivisto VM, Pontinen PJ. Heart-rate variation as a pain indicator in conscious subjects undergoing acupuncture analgesia. Acupunct Electrother Res 1981;647-55. 28. Wang Q. The operation of thyroid gland under acupuncture anaesthesia. In: China Association of Acupuncture and Moxibustion, ed. Selections from Article Abstracts on Acupuncture and Moxibustion. Beijing, 1987;299-300. 29. Bcnzcr H, Bisckho J, Kropej H, Pauser G, Baum M, Thoma H. Akupunktur-Analgesie. Anaesthesist 1972;21.252-455. 30. Benzer H. Mayrhofer О, Pauser G, Thoma H Klinische und experimentelle Erfahrungen mit der Akupunktur-Analgesie. Wien klin Wschr 1974;86:65-69. 31. Kao FF, Sechzer PH, Estnn J, Nguyen Van Nghi, Darras JC, Fang CF, Leung SJ. Acupuncture anesthesia in hcmiorraphy. Am J Chin Med 1973;1:327-328. 32. Mann F. Acupuncture analgesia, Report of 100 experiments. Br J Anaesth 1974;46:361-364. 33. Vallette С, Niboyet JEH, Imbert-Martelct M Roux JF. Acupuncture analgesia and cesarean section. J Reprod Med 1980,25:108-112. 34. Roccia L. Personal expenence with acupuncture in general Surgery. Am J Chin Med 1973;2:329-335. 35. Ajao OG. Thyroidectomy under local anaesthesia. Tropical Doctor 1979;9:73-75. 36. Fernandez FH. Cervical block anaesthesia in thyroidectomy. Intern Surg 1984;69:309-311. 37. Saxe AW, Brown E, Hamburger SW. Thyroid and parathyroid surgery performed with patient under regional anaesthesia. Surg 1988;103.415-420.

70 CHAPTER 4.3

THE PATTERNS OF ENDOCRINE AND IMMUNE RESPONSES IN PATIENTS UNDERGOING THYROID SURGERY UNDER ACUPUNCTURE ANAESTHESIA IN CHINA

Abstract. The patterns of catecholamines (adrenaline and noradrenaline), peptide hormones (adrenocorticotropic hormone, antidiuretic hormone, ß-endorphin, growth hormone and prolactin), hydrocortisone (Cortisol) and those of immunoglobulins (IgA, IgG and IgM) and total and differential leucocyte counts in the peripheral blood were investigated during, and for six days after, thyroid surgery in 20 patients (F/M:18/2) performed under acupuncture anaesthesia, supplemented by small doses of pethidine (mean:45.0 mg, SD 8.9). Throughout surgery the patients remained conscious. During surgery a significant increase in the level of catecholamines and the above-mentioned circulating hormones and a decrease of immunoglobulins were observed, whereas the leucocyte and differential counts demonstrated leucocytosis due to lymphocytosis, a decreased percentage of eosinophils and a remarkably reduced percentage of neutrophils. In the postoperative phase levels of noradrenaline and ß-endorphin remained elevated, whereas the other circulating hormones gradually returned to normal values. Immunoglobulin levels and eosinophil counts returned to the preinduction values within 24 hours, and those of neutrophil and lymphocyte counts within two days. Changes in number of monocytes and basophils could not be detected per- and postoperatively.

ACAN, supplemented by small doses of pethidine, is able to increase the pain threshold to such an extent, that surgery can proceed with patients fully conscious during the entire procedure (1, 2). Analgesia and the observed sedative effect induced by acupuncture is thought to be related to the release of endogenous opioids: the spinal release of mainly dynorphin and the supraspinal release of mainly ß-endorphin (3-6). In addition, the analgesia produced by acupuncture is naloxone-reversible (3, 7). Increasing evidence shows that the mechanisms of the analgesic effect of acupuncture differ from that in stress induced analgesia (8, 9). Data from animal and human studies indicate that the opioid system is involved in the biological response to surgical stress (10). The endorphin system stimulated by ACAN is thought to be responsible for modulating the response to noxious stimuli and hormonal secretion through the pituitary gland (11). Besides its apparent analgesic effect, ACAN is also thought to cause less disruption of a number of physiological parameters, e.g. arterial pressure, heart rate, respiratory rate, etc. (12). Moreover, it has been suggested that surgery performed under

71 ACAN is associated with a lower incidence of postoperative bacterial infections (13, 14). In animal and human studies acupuncture loci chosen as a therapeutic modality were reported to influence humoral and cellular immunity positively (IS IS). Although ACAN has been practised as a routine anaesthetic technique for various surgical procedures since 1958, little is known about how and to what extent it influences the endocrine and immune responses. The aim of the present study was to describe the endocrine and immune responses during and after surgery in a group of Chinese patients who, while fully conscious, underwent removal of thyroid nodules under classical ACAN, i.e. combined acupuncture and low-dose pethidine anaesthesia. The results are discussed against the background of literature data on endocrine and immune responses to surgery in unconscious patients.

Patients and methods

The protocol was approved by the hospital Ethics Committee. Twenty consecutive, otherwise healthy patients of ASA class 1 and 2 undergoing elective surgery for removal of thyroid nodules at the First Affiliated Hospital of Nanjing Medical College, China, were studied. No patients used current medication for endocrine disorders. Routine investigations for this type of surgery were carried out prior to surgery and informed verbal consent was obtained at the preoperative visit. After fasting overnight, 10 mg of diazepam was given orally to all patients 90 minutes before induction of ACAN. In all cases four ear acupoints (Jiaogan, Jing, Neifenbi and Shenmen) ipsilaterally to the thyroid nodules were selected for puncture (2). The needles were connected to a battery powered G-6805 stimulator whose output could be varied arbitrarily from 0-4. Stimuli at 4 Hz were applied and the strength gradually increased to the limits of the patients' tolerance. The amplitude reached was setting "3" in all cases, which resulted in a current up to 20 mA. Pethidine 30 mg was given i.v. just before skin incision. Surgery was performed between 9 and 12 a.m., in all cases 30 minutes after the start of ear acupoints stimulation, which was continued until the end of the procedure. Further small doses of pethidine (up to 1 mg.kg ') were given intravenously if arterial pressure and/or heart rate increased by more than 25% during surgery. Haemodynamics (systolic arterial pressure: SAP, diastolic arterial pressure:DAP, heart rate:HR) and respiratory rate (RR) were registered as a function of time during surgery and at recovery. Intravenous infusion during surgery was isotonic saline at a rate of 5-10 ml.kg'.hour'. At the end of recovery infusion was stopped and oral fluid intake encouraged. Postoperatively, pethidine was available for pain relief. The following blood variables were measured: adrenaline (A), noradrenaline (NA), adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), ß- endorphin (BE), growth hormone (GH), prolactin (PRL), Cortisol, immunoglobulins (IgA, IgG and IgM) and total and differential white blood cell (WBC) counts. Venous blood samples were drawn following a time schedule as presented in Table 1. Routinely, a venous blood sample was taken at hospital admission one day prior to surgery (T-l) for total and differential WBC counts.

72 Table 1 Time schedule for drawing blood samples Code Time Description Tl 10 mm after insertion of venous catheter but before induction T2 15 mm after the start of ear acupoints stimulation T3,4,5 5, 30, 60 mm after skin incision T6 end of surgery T7,8 1, 3 hours after surgery T9-14 1-6 days after surgery at 1 ρ m

Following immediate preparation after collection (i.e. centrifugation and separation), samples were frozen at -20°C until analysis, in which condition no decay of the concentrations of A, NA and other hormones in plasma have been reported for six months or even longer (19, T.J.Benraad: personal communication). At the end of the author's stay in Nanjing's First Affiliated Hospital, the frozen samples were taken back by him to The Netherlands, stored in dry ice. The measurements of catecholamines, other endoennes and immunoglobulins were carried out within six months in the Laboratory of Experimental and Chemical Endocrinology (head: Prof Dr.T.J.Benraad) and the Laboratory of Paediatrics (head: Prof.Dr.J.Trijbels) of the University Hospital, Nijmegen. Table 2 shows the characteristics of the assay methods for different vanables.

Table 2 The assay methods for determination of hormones and immunological vanables, their intra- and inter-assay coefficients of variation (%), sensitivity (=Sens), the resting range (=Rest) m non-stressed state, units and references (Ref) The ongm of the reagens kit or standard is mentioned under the method between parentheses Star represents values at 9 a m

Variable Method Intra Inter Sens Rest Unit Ref A COMT 71 90 0 05 0 06-0 30 nmol 1 ' 20 NA COMT 54 75 0 05 0 6-2 3 nmol 1 ' 20 ACTH RIA (own) 12 3 63 20 2 0-15 0* pmol 1 ' 21 BE RIA (Incstar) 79 12 0 <3 0 3-11 pmol 1 ' ADH RIA (Buhlmann) 97 20 0 05 4 2-118 pmol 1 ' GH RIA (own) 15 0 70 2 <20 mlUl' 22 PRL IRMA (Maja) 24 42 60 140-360 rnlUl' 22 Cortisol RIA (own) 50 100 0 02 0 19-0 55* μπιοί 1 ' 23 IgA NEPH (WHO 67-86) 3 0 40 30 60-200 lUml' 24 IgG NEPH 30 40 30 70-170 lUml' 24 IgM NEPH 30 40 30 50-200 lUml1 24 COMT, catechol-O-methyltransferase based radioenzymatic method, RIA, radioimmunoassay, IRMA, immuno radio metric assay, NEPH, nephelometry

The WBC count was determined with an electronic cell counter and the differential count (100 cells counted in duplicate) was estimated on blood smears fixed with May-Grunwald and stained with Giemsa solution, always by the same person at the Haematological Laboratory (head: Dr.Z.Y.Li) of the First Affiliated Hospital, Nanjing. The normal ranges referred to in this study are: WBC: 4.0- П.ОхЮ'.Г, neutrophils: 60-70%, lymphocytes: 20-30%, monocytes: 1-5, eosinophils: 1-4% and basophils: 0-2%.

73 Data evaluation. Variables before induction of anaesthesia were taken as reference. Unless otherwise stated, data are means (SD). Analysis of variance (ANOVA) including "repeated measures" routines and Pearson's correlation test were performed. In all tests p<0.05 was used as the threshold of significance.

Results

Table 3 presents the characteristics of patients included in the study, surgical and anaesthetic time and the preoperative values of haemoglobin and haematocrit.

Table 3. Characteristics of 20 patients, surgical and anaesthetic time and preoperative values of haemoglobin and haematocrit. Data represent means (SD) or incidence.

Age (years) 38.8 (11.5) Weight (kg) 58.8 (9.5) Height (cm) 161.3 (5.7) Sex M/F 2/18 ASA status ІДІ 16/4 Adenoma to be removed: size (cm χ cm) 1.2 (0.4)ι χ 2.3 (0.9) location L/R 9/11 Surgical time (min) 88.8 (44.3) Anaesthetic time (min) 127.7 (46.1) Haemoglobin (mmol.!-1) 6.61 (0.92) Haematocrit (%) 0.43 (0.06)

Preoperative investigations, including thyroid function and body temperature, were within normal limits in all. SAP, DAP and RR increased significantly after the start of surgery, whereas HR remained virtually unchanged. The pre- and peroperative total dose of pethidine administered was 45 mg (8.9). In four patients a 2-3 mg dose of chlorpromazine was given to decrease SAP. Total saline infusion during surgery was 530 ml (162.6) and total of blood loss 105.3 ml (62.1). At surgeon's request, two patients received 200 ml of whole blood: one during surgery and the other immediately thereafter. At recovery, haemodynamics and RR normalized, except SAP which remained elevated in the first 30 minutes. None required pethidine postoperatively. On day 7 all patients left the hospital uneventfully.

Responses of circulating hormones

Catecholamines (Figure 1). In each patient plasma A concentrations increased at T3 and throughout surgery from 0.2 nmol.l"1 (range:0.1-0.5) at Tl to 1.5 nmol.l"1 (range:0.3-6.6) at T4. The differences were significant from Tl values throughout surgery. Postoperative levels declined gradually, however, they remained higher than Tl until T9. Plasma NA levels rose in 16 of 20 patients at T3 and throughout surgery in 17 patients from 1.0 nmol.l1 (range:0.4-2.3) at Tl to 1.9 nmol.l ' (range:0.6-6.3) at T5. The differences were significant from Tl values throughout surgery. Postoperative values returned to the Tl level at T7, but

74 increased again (p<0.05) with a second peak concentration of 1.5 nmol.l' (range:0.3-2.9) at T9.

Figure 1 Plasma adrenaline and noradrenaline levels (mean with error bar equal to SEM) Arrow marks the incision time Letters and numbers on the horizontal axis reter to the samples taken at the different stages of anaesthesia and surgery according to Table 1 Star indicates a significant difference (p<0 05) from value at TI (ANOVA).

ACTH (Figure 2) Plasma ACTH levels were elevated in 18 of 20 patients at T3 and throughout surgery in all patients, rising from 2.9 pmol.l1 (range: 1.5-4.6) at Tl to 37.3 pmol.l' (range:6-235) at T6. Significant differences were found from Tl values throughout surgery. Postoperative values remained significantly elevated until T8, after which they returned to the Tl level.

75 40

го

τι тэ Т4 Т5 Т6 Т7 та тэ TÍO TU тіг Figure 2. Plasma ACTH levels. For the symbols see legend to Figure 1.

ßE (Figure 3). Plasma BE concentration was not elevated at T2 (3.6 pmol.l'; range:2.3-l 1). However, at T3 and throughout surgery it rose in each patient from 3.4 pmol.l' (range:2.1-5.5) at Tl to 47.2 pmol.l1 (range:8.5-266) at T6. Throughout surgery the differences were significant compared to values at Tl. Postoperative levels remained significantly elevated until T12, but the overall BE pattern mimicked that of ACTH. £-Endoirphir» Cpmol.l 1) BO

•ΊΟ ·

го

TI ТЗ T4 Т5 ТБ TV ТВ ТЭ TÍO Til Т12

Figure 3. Plasma ß-endorphin levels. For the symbols see legend to Figure 1.

76 ADH (Figure 4) At ТЗ an elevation of plasma ADH levels occurred in 18 of 20 patients but without significant difference compared to Tl values. Thereafter values increased in all patients throughout surgery from 5.7 pmol.l ' (range:3.4- 10 9) at Tl to 147 1 pmoll' (range 4.5-1260) at T4, which resulted m a significant difference from its value at Tl This peak value was, however, of short duration. Postoperative values returned to the Tl level, but they were still significantly elevated until T7.

Antidiuretic hormone Cpmol.l- О

BOO

lOO

Tl ТЭ T4 T5 ТВ TV ТВ ТЭ TÍO Til Τ1Ξ Figure 4 Plasma ADH levels hoi the symbols see legend to Figure 1 Growth hormone CmIU.l~^D 40

Tl T3 T4 T5 ТВ T7 ТВ ТЭ TÍO Til T12 Figure 5 Plasma growth hormone levels For the symbols see legend to Figure 1

GH (Figure 5) At T3 a rise in plasma GH levels occurred in only four of 20 patients without significant difference from Tl values. Thereafter values were elevated in 18 patients throughout surgery from 7.0 mlU.l1 (range:3-20) at Tl to 30 1 mlU 1 ' (range:5-115) at T5. This resulted in significant differences compared to Tl values. Postoperative levels remained significantly higher than Tl until T8.

77 PRL (Figure 6). Plasma PRL levels were elevated in 19 of 20 patients at T3 and throughout surgery in each patient from 400.4 тШ.Г' (range: 197-839) at Tl to 2540 mlU.l' (range:452-6000) at T4. Significant differences were found throughout surgery from Tl values. Postoperative values remained significantly higher until T9.

Prolactin CmIU.l_1i

aooo

1СШО

Tl ТЭ T4 T5 T7 Т T3 TÍO Til TIE

Figure 6. Plasma prolactin levels. For the symbols see legend to Figure 1.

Cortisol (Figure 7). At T3 an elevation of plasma Cortisol levels occurred in 12 of 20 patients without significant difference compared with values at Tl. Thereafter values rose in each patient throughout surgery from 0.3 цтоІ.Г' (range: 0.2-1.0) at Tl to 0.7 μηιοΐ.1 ' (range:0.5-1.5) at T6. This resulted in significant differences from Tl values throughout surgery. Postoperative levels remained significantly elevated until T9, after which they dropped below the Tl level.

Cortisol Cumol.l *J

О.Б

G.4

Ο.Ξ "1 T3 T4 T5 T6 T7 ΤΘ ТЭ TÍO Til ТІЭ

Figure 7. Plasma Cortisol levels. For the symbols see legend to Figure 1.

78 The relationships between the preinduction value of each hormone and the corresponding surgery induced maximum plasma level for the individual patients were studied. The only hormone for which a significant correlation was found was A.

Responses of immunoglobulins and WBC and differential counts

Immunoglobulins (Figure 8). In one patient, with the highest Tl value, the T4 sample for Ig A determination was lost. Plasma Ig A decreased slightly in 16 of 19 patients from 148.8 Ш.тГ' (range:? 1-262) at Tl to 143.6 Ш.тГ (range:73-253) at T6, at which time the difference was significant from values at Tl. Postoperative values remained significantly higher until T14. Plasma IgG decreased in 13 of 20 patients from 154.2 Ш.тГ (range:! 16-218) at Tl to 148.4 lU.ml ' (range:99-206) at T6, at which time a significant difference was found from Tl values. Postoperative values had already returned to the Tl level at T9.

IB« (lU.ml-1!

-1·. IBS 1\r

155 . / _ Figure 8. Plasma ^Л ^^_. immunoglobulin levels. \ / \ In one patient value of N: ^-j IgA was missed at T4. к" For the symbols see 144 legend to Figure 1.

TÍO Til

Plasma IgM fell in 11 of 20 patients from 185.7 Ш.тГ (range: 100-381) at Tl to 177.9 lU.ml' (range:91-394) at T6, at which time there was a significant

79 difference from values at Tl. Postoperative values had already returned to the Tl level at T9.

WBC and differential counts (Figure 9). WBC counts increased in 17 of 20 patients from S^xlOM"1 (range:3-10.1) at Tl to 6.9χ109.Γ (range:4-11.5) at T6, at which time there was a significant difference from Tl values. Postoperative values rose further and remained significantly higher until Til; thereafter a return to Tl took place.

NeufcropKil· fE>

Figure 9. Responses of leucocyte and differential counts. For the symbols see legend to Figure 1.

80 Percentages of neutrophils decreased in 17 of 20 patients, from 71.6 (range:58- 84) at Tl to 65.5 (range:49-77) at T4, which resulted in a significant difference compared with Tl values. They had already normalized at T6. Postoperative values, after a significant increase at T9, returned to the Tl level at T10. Percentages of lymphocytes increased in 16 of 20 patients from 25.7 (range: 13- 38) at Tl to 32 (range:20-48) at T4, which resulted in a significant difference from Tl values. They had already normalized at T6. Postoperative values, after a significant fall at T9, returned to the Tl level at T10. Percentages of eosinophils dropped from 0.8 (range:0-3) at Tl to 0.2 (range:0- 1) at T6, at which time the difference was significant from Tl values. Postoperative values normalized at T9. Percentages of monocytes and basophils did not show any change during or after surgery compared to values at Tl.

Discussion

Study design. Although in China different anaesthetic techniques are in use for thyroid surgery, in the First Affiliated Hospital of Nanjing ACAN is regularly performed. The possibility for comparing with regional anaesthesia such as cervical blockade or cervical epidural anaesthesia, practised in other Chinese hospitals was not considered because of the local problems with preparation of samples and the obvious difficulties expected in randomization with other techniques. In the light of a planned, controlled study in Nijmegen, The Netherlands, in which modified ACAN would be compared with balanced anaesthesia in major surgery the present study was carried out, to the satisfaction of both parties, as an open one.

Circulating hormones

Effect of ear acupoints stimulation in ACAN. The expected rise of circulating BE at T2, i.e. after 15 minutes of ear acupoints stimulation, was not observed. This does not exclude, however, alterations in hypothalamic or pituitary BE content, which has been reported to be elevated following acupuncture stimulation (6). Three main reasons can be considered for the lack of BE response at T2. First, ear acupoints stimulation does not influence BE secretion at all. Secondly, there is a persisting effect of diazepam, which has been known to abolish the rise of BE due to emotional stress (25, 26). Thirdly, the circumstances under which the stimulation was performed. The current intensity was adjusted to the toleration of patients and therefore might not be sufficient to allow the increase of BE.

Effect of ACAN (ear acupoints stimulation plus pethidine) and surgery. Our finding that surgical stress activated two major pathways in the body, i.e. the sympatho- adrenomedullary and pituitary-adrenocortical systems as demonstrated by an increase of A, NA on the one hand and ACTH, BE, ADH, GH, PRL and Cortisol on the other, is consistent with previous studies of stress responses during surgery

81 under general anaesthesia (27-29). The significant correlation between the individual preinduction values of A and the maximum plasma responses, together with the well-known modulatory effect of the catecholamine on the secretion of the measured peptide hormones (30), suggest that A may act as a trigger for inducing the response of other circulating hormones. The increase of plasma catecholamines was associated with a corresponding increase of SAP and DAP but not HR, which, in fact, did not change. Similar observations have also been reported in surgery performed under general anaesthesia (31). As expected, since ACTH and BE share the same molecular precursor and are concomitantly secreted by the pituitary gland either during acupuncture stimulation or surgery (32, 33), the patterns of response are almost identical. As a function of time, two types of responses can be distinguished. Early responses were shown by A, NA, ACTH, BE and PRL, levels of which had already elevated at T3, and responses in ADH, GH and Cortisol, levels of which did not rise until later (T4). The insignificant increase of ADH at T3 can be explained by the great inter-individual variability of the data at this time point. It has been documented that circulating Cortisol increases secondary to ACTH (27). The delay of GH rise, with respect to that of PRL, agrees also with data of previous studies (34, 35). Pethidine evokes release of PRL but not GH (36). It is therefore not surprising that the combination of pethidine administered just before incision and stress of incision itself led to an earlier PRL response. The short but marked peak of ADH levels observed has not been reported earlier, except during cardiopulmonary bypass (37).

The postoperative state. Postoperative values decreased gradually to (A, ACTH, ADH, PRL and GH) or below the Tl levels (Cortisol). In contrast to ACTH, BE values remained above the Tl levels until Τ12. The second peak of circulating NA on the first postoperative day may be associated with the patients' early mobilization, as physical activity also induces release of NA. The data do not conflict with results of other studies (28, 38, 39).

Immunoglobulins and WBC and differential counts

The fall of plasma immunoglobulins during surgery was in agreement with earlier investigations (40, 41). However, the accelerated recovery, i.e. return to preinduction values on the first postoperative day, has not been reported earlier. In a study of thyroid surgery under general anaesthesia, levels of immunoglobulin had not return to normal three days after surgery (42, 43). Since IgG plays an important role in bacterial defence, its early recovery may be of value in preventing postoperative infections. The observed early occurring lower percentage of neutrophils and lymphocytosis at T4 is noteworthy and has not been reported in patients undergoing surgery with other types of anaesthesia. This lymphocytosis was responsible for the observed increase in the number of leucocytes rather than the classical neutrophilia by surgical stress (41, 42, 44). Moreover, the lower postoperative percentage of eosinophils lasted only 24 hours and postoperative neutrophilia and lymphopenia two days. In a study of less invasive surgery under

82 general anaesthesia, including thyroidectomy, a persistent lymphopenia until the sixth postoperative day has been reported (42). The rapid recovery of the number of lymphocytes may be beneficial, since lymphopenia has been associated with impaired lymphocytic response to bacterial antigens and impaired T-cell activity (45). The patterns of monocytes and basophils were in accordance with the findings of others (40, 45, 46). Several factors are thought to influence the results of the present study. First, the lack of a possible inhibitory effect of major anaesthetic agents, i.e. sodium pentothal, nitrous oxide and other inhalation agents on the immune system in general, although their depressant effect is thought to be minimal (47). Secondly, the possible effect of peroperative saline haemodilution (fluid balance: plus 425 ml) and redistribution, since the biological half-life of immunoglobulins is several days. To what extent the patient's fluid status following overnight fasting contributed to a haemoconcentration, thus neutralizing the effect of saline dilution cannot be answered here, since no measurements of haematocrit and serum protein were carried out. Thirdly, thyroid surgery is less invasive than thoracic or abdominal surgery. The extent of surgical trauma is said to be the most important factor in the postoperative alteration of the immune system (40). It is therefore not unexpected, that rapid recovery of immunoglobulins occurred. The recovery of immunoglobulins after invasive surgery is not expected within seven to ten days (41, 42, 46, 48). Fourthly, a great number of hormones modulate immune responses. Cortisol and catecholamines may be, in part, responsible for the inhibition of the synthesis of immunoglobulins postoperatively (40). On the other hand, ACTH and its related opioids, exemplified by BE in this study, might play a role in the observed changes in the cellular elements of the immune response (neutrophils, lymphocytes and eosinophils), whereas the GH response may cause proliferation of T-lymphocytes and their terminal differentiation (49-51). From the present data it is not possible to link exactly the many changes in the endocrine and the immune responses during thyroid surgery under ACAN. Further studies are needed to unravel possible interrelations.

In summary. Surgery of thyroid nodularity performed in conscious patients under ACAN is followed by a significant increase in the level of a number of circulating hormones and a decrease of immunoglobulins, whereas the leucocyte and differential counts showed leucocytosis due to lymphocytosis, decreased percentage of eosinophils and a remarkably reduced percentage of neutrophils. Except for the prolonged elevated levels of NA and BE, the postoperative phase was characterized by a rapid recovery in the levels of circulating hormones and the measured immune variables. The observed changes in a number of endocrine and immune variables during ACAN in a limited number of patients in China do not essentially differ from those reported in Western literature on general anaesthesia with the use of much higher doses of opioids. The data therefore strongly suggest that ACAN mimics the activity of opioids in their endocrine and immune effects.

83 References

1 Xin YL, Wang YL A general survey on the developments in clinical acupuncture anaesthesia research in the past five years J Trad Chin Med 1984,4 255-258 2 Kho HG, Zhuang CF, Egmond J van, Zhang GL, Lin GF Acupuncture anaesthesia Observation on its use in removal of thyroid adenomata and influence on recovery and morbidity in a Chinese hospital Anaesthesia 1990,45 480-485 3 Cheng RS, Pomeranz BH Electroacupuncture analgesia is mediated by stereospecific opiate receptors and is reversed by antagonists of type I receptors Life Sci 1980,26 631-638 4 Han JS, Xie GX Dynorphin important mediator for electroacupuncture analgesia in the spinal cord of the rabbit Pain 1984,18 367-376 5 Pert A, Diorme R, Ng L, Bragin E, Moody TW, Pert CB Alterations in rat central nervous system endorphins following transauncular electroacupuncture Brain Res 1981,224 83-93 6 Sjolund B, Terenius L, Enkson M Increased cerebrospinal fluid levels of endorphins after electroacupuncture Acta Physiol Scand 1977,100:382-384 7 Mayer DJ, Pnce DD, Rafii A Antagonism of acupuncture analgesia in man by narcotic antagonist naloxone Brain Res 1979,121 368 372 8 Millan MJ, Przewlocki R, Herz A A non-ß-endorphmergic adenohypophyseal mechanism is essential for an analgetic response to stress Pain 1980,8 343-353 9 Pomeranz В Relation of stress-induced analgesia to acupuncture analgesia Ann NY Acad Sci 1986,467 444 447 10 Dubois M, Pickar D, Cohen MR, Roth YF, MacNamara Th, Bunney WE Surgical stress in humans is accompanied by an increase in plasma ß-endorphin immunoreactivity Life Sci 1981,29 1249-1254 11 Anand KJS The Stress Response to Surgical Trauma From physiological basis to therapeutic implications Prog Food Nutr Sci 1986,10 67 132 12 Lin GF Anaesthesiology In Wu HG, Ran RT, eds Modem Chinese Medicine, vol 1 Chinese Surgery, A comprehensive review of surgery in the People's Republic of China Lancaster/Beijing MTP Press Limited and the People's Med Pub House, 1984,239-254 13 Wu JL, Zong AM, Chai ΧΜ, Cai DH, Luo HM, Kao PW, Ren ZC, Hu ZF Effects of electroacupuncture on cell-mediated immunity in human body In Zhang XT, ed Research on acupuncture, moxibustion and acupuncture anesthesia Beijing/Berlin Science Press and Spnnger Verlag, 1986,568-573 14 Chen GB Role of the nervous system of the human body with regard to acupuncture analgesia Acupunct Electrother Res 1981,6 7 17 15 Chu YM, Affronti LF Preliminary observations on the effect of acupuncture on immune responses in sensitized rabbits and guinea pigs Am J Chin Med 1975,3 151-163 16 O'Connor J, Bensky D A summary of research concerning the effects of acupuncture Am J Chin Med 1975,3 377-394 17 Zhao J, Liu W Relationship between acupuncture-induced immunity and the regulation of central neurotransmitters in the rabbit I Effect of central catecholaminergic neurons in regulating acupuncture-induced immune function Acupunct Electrother Res 1988,13 79-85 18 Sabolovic D, Michon С Effect of acupuncture on human peripheral Τ and В lymphocytes Acupunct Electrother Res 1978,3 97-107 19 Falconer AD, Lake D, MacDonald IA The measurement of plasma adrenaline by high performance liquid chromatography with electrochemical detection an assessement of sample stability and assay reproducibility Inter Neurosa Methods 1982,6 261-271 20 Hoffmann JJML, Willemsen JJ, Lenders JWM, Benraad TJ Reduced imprecision of the radioenzymatic assay of plasma catecholamines by improving the stability of the internal standards Clin Chim Acta 1986,156 221-226 21 Goverde HJM, Pesman J, Smals AGH The bioactivity of immunoreactive adrenocorticotrophin in human blood is dependent on the secretory state of the pituitary gland Clin Endocnnol 1989,31 255-265

84 22 Smals AEM, Pieters GFFM, Smals AGH, Benraad TJ, Laarhoven J, Kloppenborg PWC Sex difference in human growth hormone (GH) response to intravenous human pancreatic GH- releasing hormone administration in young adults J Clin Endocrino) Metabol 1986,62 336- 341 23 Smals AGH, Kloppenborg PWC, Goverde HJM, Benraad TJ The effect of cyproterone acetate on the pituitary-adrenal axis in hirsute women Acta Endocrinol 1978,87 352-358 24 Renckens AUM, Jansen MJH, van Munster PJJ, Weemaes CRM, Bakkeren JAJM Nephelometry of the Kappa/Lambda Light-Chain Ratio in Serum of Normal and Diseased Children Clin Chem 1986,32 2147-2149 25 Walsh J, Puig MM, Lovitz MA, Tumdorf H Premedication abolishes the increase in plasma beta-endorphin observed in the immediate preoperative period Anesthesiology 1987,66 402- 405 26 Miralles FS, Olaso MJ, Fuentes Τ, Lopez F, Laorden ML, Puig MM Presurgical stress and plasma endorphin levels Anesthesiology 1983,59 366-367 27 Oyama Τ Endocrine response to general anesthesia and surgery In Oyama T, ed Monographs in Anaesthesiology Endocrinology and the anaesthetist Amsterdam/New York Elsevier Sci Pub, 1983,11 1 21 28 Derbyshire DR, Smith G Sympathoadrenal responses to anaesthesia and surgery Br J Anaesth 1984,56 725-737 29 Wilmore DW, Long JM, Mason AD, Pruitt BA Stress in surgical patients as a neurophysiologic reflex response Surg Gyn Obstet 1976,142 257-269 30 Berkenbosch F, Vermes I, Binnenkade R, Tilders FJH Beta-adrenergic stimulation induces an increase of the plasma levels of immunoreactive a-MSH, ß-endorphin, ACTH and of corticosterone Life Sci 1981,29 2249-2256 31 Balogh D, Hammerle AF, Hortnagel H, Brücke Th, Stadler-Wolffersgrun R A comparative study on the effect of halolhane-N,0-anaesthesia and neuroleptanalgesia on plasma catecholamines during the intra- and postoperative period Anaesthesist 1979,28 517-522 32 Guillemin R, Vargo Th, Rossier J, Mimck S, Ling N, Rivier С, Vale W, Bloom F ß- endorphin and adrenocorticotropin are secreted concomitantly by the pituitary gland Sci 1977,197 1367-1369 33 Malizia E, Andreucci G, Paolucci D, Crescenzi F, Fabbri A, Fraioli F Electroacupunclure and peripheral ß-endorphin and ACTH levels Lancet 1979,ii 535-536 34 Bellmann O, Criveanu T, Stockel H, Walter W, Lauven Ρ Das Verhallen glandulärer Stresshormone bei Strumektomie in kombinierter Elektroakupunktur-ancsthesie In Haid B, Mitterschnfthaler G, eds Anesthesiologie und Intensivmedizin 140 Zentraleuropaischer Anasthesiekongress Berlin Springer Verlag, 1981,149 35 Dehtala G, Tornasi Ρ, Virdis R Proloactin, growth hormone and thyrotropin thyroid hormone secretnon during stress states In Grossman C, ed Bailliere's Clinical Endocrinology and Metabolism Neuroendocnnology of stress London Bailhere, 1987,391-414 36 Tollis G, Hickcy J, Guyda Η Effect of morphine on serum growth hormone, Cortisol, prolactin and thyroid stimulating hormone in man J Clin Endocnnol Metab 1975,41 797-800 37 Philbm DM, Coggins CH The effects of anaesthesia on antidiuretic hormone levels In Stoeckel H, Oyama T, eds Endocrinology in anaesthesia and surgery Berlin, Heidelberg Spnnger Verlag, 1980,76-82 38 Moore RA, McQuay HJ Neuroendocnnology of the postoperative state In Smit G, Covino BG, eds Acute pain London/Boston Butterworths, 1985,133-154 39 Mclntosch TK, Bush HL, Palter M, Hay JR, Aun F, Yeston NS, Egdahl RH Prolonged disruption of plasma ß-endorphin dynamics following surgery J Surg Res 1985,38 210-215 40 Salo M Effects of anaesthesia and surgery on the immune response In Watkins J, Salo M, eds Trauma, Stress and Immunity in anesthesia and surgery London/Boston Butterworth Scientific, 1982,211-253 41 Gierhake FW, Johannsen R, Stocker R, Rickmeyer L, Eben KP, Meyer-Hoepfel W, Meyer- Hoepfel I Immunosuppressive Wirkungen bei Operationen und Möglichkeiten ihrer Begrenzung Immun Infekt 1975,3 116-124 42 Ryhanen Ρ Effects of anesthesia and operative surgery on the immune response of patients of different ages Thesis Oulu University, Finland 1977

85 43 Cohnen G Changes m immunoglobulin levels after surgical trauma J Trauma 1972,12:249- 253 44 Cullen BF, Belle G van Lymphocyte transformation and changes in leukocyte count effects of anesthesia and operation Anesthesiology 1975,43 563-568 45 Everson NW, Neoptolemos JP, Scott DJA, Wood RFM, Bell PRF The effect of surgical operation upon monocytes Br J Surg 1981,68 257-260 46 Rem J, Saxtrup Nielsen O, Brandt MR, Kehlet H Release mechanisms of postoperative changes in various acute phase proteins and immunoglobulins Acta Chir Scand 1980,502 SI SÓ 47 Kehlet H, Wandall JH Hjortso NCh Influence of anesthesia and surgery on immunocompetence Reg Anesth 1982,7(Suppl) S68-S74 48 Wemer M, Cohnen G Changes in serum proteins in the immediate postoperative period Clin Sci 1969,36 173-184 49 Weigent D, Blalock JE Interactions between the Neuroendocrine and Immune systems Common hormones and receptors Immunol Rev 1987,100 79-108 50 Gilman SC, Schwartz JM, Milner RJ, Bloom FE, Feldman JD ß-endorphin enhances lymphocyte proliferative responses Proc Natl Acad Sci USA 1982,79 4226-4230 51 Mathew PM, Froehch CJ, Sibbitt Jr WL, Bankhurst AD Enhancement of natural cytotoxicity by ß-endorphin J Immunol 1983,130 1658-1662

86 CHAPTER 5.1

DEVELOPMENT OF ACUPUNCTURE ANAESTHESIA IN THE WEST

The use of classical acupuncture anaesthesia

In the early 1970's, the West was informed about the use of acupuncture as an anaesthetic for various types of surgery in China (1, 2). This new use of acupuncture aroused great interest in the West. Although many aspects associated with its use could not be explained in the light of our medical knowledge at that time, the West was stimulated to study the technique clinically and in animals. In March 1972, classical ACAN was performed for tonsillectomy in Vienna, and for appendicectomy in Turin, in their respective University hospitals (1, 3). In the USA, it was first used for tonsillectomy at the St.Louis Memorial Hospital Chicago in 1972, for the removal of a salivary calculus in Wharton's duct, and for tonsillectomy at the South Bay Community Hospital in Redondo Beach California in 1972, and for hemiorraphy at the Down State Medical Centre, New York, in 1973 (4-6). In 1973 and 1974, clinical experiences with 100 tonsillectomies and 64 other selected operations under ACAN were reported from the University hospital of Vienna (1, 7). In 1975, after experiences with around 600 cases of minor and major surgery, the research workers in Vienna and Turin evaluated the results together during the second symposium on Acupuncture and Auriculotherapy in Vienna (7-9). Based on clinical criteria, the overall success rate, i.e. excellent pain relief, was achieved in only 64% of cases. The data proved that classical ACAN was applicable in the West. However, the major objection to its routine use was that a great deal of time was involved in selecting and preparing patients for surgery. It was suggested that ACAN be reserved for a small number of patients, for whom local or general anaesthesia was thought to be unsuitable (7, 10).

Combined technique with general anaesthesia

Since the meeting in Vienna in 1975, the classical ACAN has been modified and developed to try to reduce the disadvantages of ACAN without losing the advantages. The first and most important step in this direction was the integration of ACAN with balanced anaesthesia (6, 8). Using i.v. drugs, anaesthesia is induced, patients intubated, and, depending on the surgery to be performed, ventilation may be spontaneous or controlled. Acupuncture is used only for its analgesic effect. By so doing, the indications for its use can be widened, avoiding the need to apply extensive exclusion criteria prior to surgery. In addition, abdominal surgery is no longer contraindicated since muscle relaxants can be administered when necessary. This method was first called two phase acupuncture anaesthesia. Since then, many phrases have been used to describe this technique (combined acupuncture anaesthesia, electro acupuncture anaesthesia, electrostimulation

87 anaesthesia and electroanalgesia). Between 1975 and 1977, experiences of more than 6,000 cases with modified ACAN, ranging from hemiorraphy to heart surgery have been reported (11-20). Patients were thought to recover more quickly than those receiving conventional anaesthesia. There was also the clinical impression that less conventional anaesthetics were needed to produce adequate anaesthesia and that there were fewer minor side effects (e.g. nausea, vomiting, etc) compared to conventional general anaesthesia. In animal and clinical studies, electrostimulation of acupoints, skin or certain brain areas has been shown to significantly decrease anaesthetic requirements (21-23).

Selection of points; a rational approach. The second step in the development of two phase ACAN was the standardization of the selected body acupoints. Classical theory suggested that only certain body acupoints could be used for certain operations (24). This was modified by Western workers who found that good analgesia could be produced using only segmental, paravertebral stimulation of the surgical field (25). These paravertebral stimuli are, in fact, situated on the classical Foot-Taiyang meridian (Figure 1) (26). Usually three or four bilateral paravertebral acupoints are used in this modified ACAN.

Figure 1. Acupoints located at the Foot-Taiyang meridian which can be selected according to the same spinal cord segments as the surgical field.

88 The third step in the modification of classical ACAN was that needles were replaced by skin electrodes* (25, 27-30). This change reduced the invasiveness and awkwardness of needling without reducing the efficacy of ACAN. Besides its use during surgery, modified ACAN has also been reported to be useful for postoperative pain relief (31-35). Despite these modifications, the use of ear acupoints has remained unchanged from the classical Chinese teaching, probably due to the ease of access for the anaesthetist. The ear acupoints alone can be chosen or can be combined with paravertebral acupoints (36-39). Table 1 summarizes a number of commonly used ear acupoints for puncture and stimulation.

Table 1 Location of a number of ear acupoints usually selected for inducing surgical anaesthesia.

Acupoint Auricle area Anatomical location

Jiaogan Infenor anti helix cms At junction of infenor antihehx crus and medial border of helix

Jing Antihehx At junction of antihehx and antitragus near scapa

Neifenbi Tragus At lower tubercle on border of tragus

Shenmen Triangular fossa At bifurcation point of superior anti helix crus and inferior antihehx crus

Fe Cavum concha A U-shaped area supenor, infenor and posterior to the heart point

Xin Cavum concha In the central depression of cavum concha

Qiguan Cavum concha In the area of lung, between mouth and heart points

Stimulation devices

Since the introduction of the Chinese made stimulator devices G-6805, 6-26, 71- 1 and 71-3, many versions have been developed and introduced in the West. They operate on the same principles and can be used either for therapy or to produce surgical analgesia (40-42). In the clinical studies performed in Nijmegen, two devices were used. One was a battery powered, Chinese made, portable device WQ-6F and the other the mains powered, Swiss made Doltron ESA 400. The device WQ-6F was used for percutaneous stimulation of ear acupoints through inserted needles, whereas the Doltron ESA 400 was used for transcutaneous

•Footnote: A method of electrostimulation through surface electrodes is defined as transcutaneous stimulation, whether or not the electrodes are placed at classical acupoints. Transcutaneous nerve stimulation (TNS) or transcutaneous electncal nerve stimulation (TENS) is reserved as a method of stimulation through surface electrodes located at the skin area where nerves run superficially.

89 Table 2. Characteristics of the devices used in clinical studies in Nijmegen.

WQ-6F Doltron ESA 400 (Chinese made) (Swiss made)

Power source battery 4.5 V 220 V, 50 Hz, 0.5 A Number of output 7 4 Pulse bipolar bipolar Frequency 0-2,000 Hz 4-120 Hz* Pulse shapes asymmetrical:pos.square symmetrical and with neg.overswing rectangle Pulse width positive: 0.06-0.8 ms 0-4% negative: 0.42-10 ms Output voltage 0-18 V 0-40 V* Output current 0-50 mA 0-55 mA Weight 1200 g 4000 g *, can be digitally displayed. stimulation of paravertebral acupoints through skin surface electrodes. Table 2 presents the characteristics of both devices.

Device WQ-6F. All controls are situated on the front panel (Figure 2). The apparatus consists of two independent sections (A and B); the A section has four output channels and the В section three. Each output is able to deliver eight different waveforms of pulse series, the intensity of which can be individually controlled through a potentiometer that can be adjusted, as required, from 0-10. The device generates an asymmetrical biphasic pulse with a positive pulse of 0.7 ms at a frequency of 10 Hz.

«'«T«^ | #ф*

Figure 2. The front panel of the device WQ-6F. Seven output channels are located on the top.

Mil The output charactensctics of this device were measured oscillographicaliy (Tektronix T912) before clinical use. The resistance between the two needles inserted at symmetrical ear acupoints was 600 Ω (SD 211), but was constant during the course of surgery (40). Therefore, the measurements in the laboratory were set up across a variable resistance between 300-800 Ω. All output channels showed pulse currents of between 0-50 mA and a voltage of between 0-18 V. Potentiometer readings (1-9) were found to be directly proportional to the current (0-50 mA) over the resistance range from 300-800 Ω (Figure 3).

Figure 3. Current delivery (mean with error bar equal to SD) of the device WQ-6F in relation to the setting of output channels. Measurements were carried out through a resistance of 300 Ω and 800 Ω. Numbers on the horizontal axis refer to the setting of the potentiometer, adjustable from 0-10. The maximum setting used was "7".

Doltron ESA 400. The Doltron ESA 400 is a constant current apparatus, which fulfils the international standards for safe clinical use. All controls are situated on the front panel (Figure 4). For the adjusted current (0-55 mA), the corresponding voltage of every output channel can be displayed (0-40 V).

Figure 4. The front panel of the Doltron ESA 400

91 Safety aspects

Application of electrical current to the body requires some considerations, since there are some possible hazardous effects. For example, 1. Electrolysis of needles can occur (41, 43). This can be avoided by the use of an alternating (AC) current rather than a direct current (DC). This is in fact used in both the above mentioned devices. 2. Needles can break or can introduce infection, so great care must be taken during insertion, removal, during surgery and sterilization. 3. Burning of the skin may occur. Heat production per unit of time at silver nitrate surface electrodes or needles can be calculated from the formula: W = VxIxFx PW, where voltage (V), current (I), pulse frequency (F) and pulse width (PW) are important factors (44). The maximum heat production at the skin electrodes (1=50 mA, V=45 V) or needles (1=35 mA, V=14 V, Figure 3, output setting 7) will be: 45x50x1 Ox 103=22.5 mW or 35x14x10x10 *=4.9 mW, respectively. Assuming that all of the heat production is absorbed by the skin when using surface electrodes, the heat production is distributed over two electrodes each of 2 cm2 surface area: 22.5/(2x2)=8 mW.cm2. In contrast to surface electrodes, needle electrodes do not produce all the heat at the contact area, since much of the needle is subcutaneous. Even in the case that all heat production takes place at the skin surface, one can calculate for the surface of two needles of 0.3 mm diameter and inserted 3 mm into the tissues, a total contact area of 0.06 cm2, resulting in a heat production of 4.9/0.06=82 mW.cm2. In both cases this heat production is not hazardous, since skin (tissue) damage has not been observed under 100-150 mW.cm2 (45). 4. Arrythmias. The pulse frequency should not be equal, or even nearly equal, to the heart rate, as it may induce arrythmias. In addition, placement of needles or electrodes near the heart or crossing the body such as left-right arm should be avoided and a current of 100 m A should not be exceeded. During open heart surgery, measurements taken between two points two cm apart on the surface of the heart, demonstrated that simultaneous stimulation of the needles, inserted in the acupoint Sanyangluo in both arms, with a current of 100 mA, resulted in a voltage of 0.025-0.03 V.cm ' in the heart. This amounts to an eighth or a tenth of the voltage necessary to cause ventricle fibrillation (44, 46). It would appear, then, that electrolysis of needles, burning of skin or arrythmias are more theoretical problems than actual practical problems during normal Western ACAN. Since needles are not actually used, the danger of needles breaking or infection does not exist. ACAN is, therefore, safe and virtually free from side effects.

92 1 Majer EH, Bischko J Zur Akupunktur Analgesie bei tonsillenoperationen Arch klin exp Ohr-, Nas- u Kehlk -Heilk 1973,250 280-282 2 Kho HG Akupunktuur Een overzicht van algemene ontwikkeling en basisbegrippen tot hedendaagse toepassing en huidige wetenschappelijke ontwikkeling Nijmegen В Gottmer's uitgeversbedrijf, 1975 3 Roccia L Personal expenence with acupuncture in general surgery Am J Chin Med 1973,1 329-335 4 Kao FF, Sechzer PH, Estrin J, Nguyen VN, Darras JC, Fang CF, Leung SJ Acupuncture anesthesia in hemiorraphy Am J Chin Med 1973,1 327-328 5 Ho WYH, Chen JYP Acupuncture anaesthesia Am J Chin Med 1973,1 151-154 6 Benzer H, Bischko J, Pauser G, Zimmerman Ζ Die Akupunktur-Analgesie In Benzer H, Frey R, Hugin W, Maryrhofer O, eds Lehrbuch der Anaesthesiologie, Reanimation und Intensivtherapie Berlm/Heidelberg/New York Springer Verlag, 1977,403-408 7 Benzer H, Mayrhofer O, Pauser G, Thoma Η Klinische und experimentelle Erfahrungen mit der Akupunktur Analgesie Wien klin Wschr 1974,86 65-69 8 Pauser G, Benzer H, Thoma Η Akupunktur analgesie klinische und experimentelle Ergebnisse der wiener Schule In In Bischko J, ed Kongressbencht der zweiten franzosisch- italiemsch-osterreichischen Tagung in Wien Vienna Verlag Η Egermann, 1976,39-48 9 Roccia L Klinische Bilanz von 500 Fallen der Akupunktur-Analgesie in der Allgemeinchirurgie, HNO, Gynäkologie und Zahnheilkunde In Bischko J, ed Kongressbericht der zweiten franzosisch-italiemsch-osterreichischen Tagung in Wien Vienna Verlag Η Egermann, 1976,15 20 10 Gerschman JA, Wikstrom PO The use of acupuncture as an alternative dental analgesic in an individual with multiple allergies Swed Den J 1984,8 225-230 11 Pauser G, Benzer H, Bischko J, Ganglberger J, Haider M, Mayrhofcr O, Schmid Η, Semsroth S, Thoma H Clinical and experimental results with acupuncture analgesia Anaesthesist 1976,25 215-222 12 Mane D Elektroakupunktur-anasthesie Heidelberg Haug Verlag, 1979 13 Hollinger I, Richter JA, Pongratz W, Baum M Acupuncture anaesthesia for open heart surgery a report of 800 cases Am J Chm Med 1979,7 77 90 14 Kramer M, Kramer J, Herget HF, Walter P, Patschke D Electrostimulation-analgesia and neurolept analgesia during aorto-coronary bypass operation A comparative haemodynamic study Anaesthesist 1981,30 229-236 15 Grabow L, Cnveanu Τ Combined acupuncture-analgesia as a method in general anaesthesia Anaesthesist 1976,25 231-234 16 Sawires R, Putz G Klinische Erfahrungen bei Struma-operationen in Sitzlage mit Elektrostimulationsanasthesie Chir Prax 1984,33 407-412 17 Herget HF, L'Alleman H, Kaiweit K, Walter P, Hehrlem FW, Schlepper M Combined acupuncture analgesia and controlled respiration A new modified method of anaesthesia in open heart surgery Anaesthesist 1976,25 223-230 18 Doenicke A, Kampik G, Praetonus B, Pitterling P, Gob E, Matusczyk U Electrical stimulation anaesthesia in abdominal surgery in special consideration of selective proximal vagotomy Anaesthesist 1976,25 248-256 19 Gloeckner RJ, Lahrtz H Erfahrungen mit der kombinierten Elektro-Stimulationsanasthesie (Akupunktur-Analgesie) in der Bauchchinirgie Anasth Prax 1977,14 53-59 20 Grabow L, Lemer L Electrohypalgesia Prakt Anasth 1977,12:511-522 21 Tseng CK, Tay AA, Pace NL, Westenskow R, Wong КС Electro-acupuncture modification of halothane anaesthesia in dog Can Anaesth Soc J 1981,28 125-128 22 Bourke DL, Barry AC, Smith AC, Enckson J, Gwartz B, Lessard L TENS reduces halothane requirements during hand surgery Anesthesiology 1984,61 769-772 23 Roizen MF, Newfield P, Eger E, Hosobuchi Y, Adams JE, Lamb S Reduced anaesthetic requirement after electrical stimulation of periaqueductal grey matter Anesthesiology 1985,62 120-123

93 24 Lin GF Anaesthesiology In Wu HG, Ran RT, eds Modem Chinese Medicine, volume 1 Chinese Surgery, A comprehensive review of surgery in the People's Republic of China, Lancaster/Beijing MTP Press Limited and the People's Medical Publishing House, 1984,11 239-254 25 Fischer M, Just OH Clinical uses of electrostimulation anaesthesie Anasth Prax 1979,14 1-8 26 Cheng XN Chinese acupuncture and moxibustion Beijing Foreign Languages Press, 1987 27 Fischer M, Just OH, Mane D Electrostimulation anaesthesia for surgery of the limbs Anasth Prax 1979,14 8-13 28 Abdulla W, Sostegno С, Frey R, Gartner J The circulatory system in patients under electrostimulation anaesthesia during opthalmological operations Anaesthesist 1979,28 221- 236 29 Fntsche К Electrostimulation anaesthesia compared with enflurane-mtrous oxide in gynaecological operations 1 Clinical observations Anaesth Intensivther Notfallmed 1984 19 49-52 30 Fischer MV, Raab Ρ, Reumont ν J Circulatory conditions in electrostimulation-anacsthesia Anaesthesist 1983,32 591-596 31 Chnstensen PA, Noreng M, Anderseb PE, Nielsen JW Electroacupuncture and postoperative pain Br J Anaesth 1989,62 258-262 32 Martclete M, Fiori AMC Comparative study of the analgesic effect of transcutaneous nerve stimulation (TNS), electroacupuncture (EA) and meperidine in the treatment of postoperative pain Acupuncl Electrother Res 1985,10 181-193 33 Ah J, Yaffe C, Serrette С The effect of transcutaneous electric nerve stimulation on postoperative pain and pulmonary function Surg 1981,89 507-512 34 Vanderark GD, McGralh KA Trancutaneous electncal stimulation in treatment of postoperative pain Am J Surg 1975,130 338-340 35 Grabow L, Thiel W, Hendnkx B, Hem A, Schilling E Alternativen fur die postoperative Schmerzbehandlung Dtsch Aerztbl 1986,83 1361-П66 36 Kho HG, Maas Ρ, Kerkkamp Η Drent M Kippersluis E, Egmond van J Haemodynamische Wirkungen der kombinierten Akupunkturanasthesie bei abdomineller urologischer Chirurgie Dtsch Ztschr Akup 1987,30 60-64 37 Baum J, Schilling A Combined electrostimulation-hypalgesia in surgery of the lumbar vertebral column A tentative evaluation of this method Anaesthesist 1979,28 227 236 38 Martin E, Ott E Effects of high doses of fentanyl in companson with electrostimulation In Wood C, ed Stress-free anaesthesia Analgesia and the supression of stress responses Intem Congress and Symposium Senes, London/New York Royal Society of Medicine, Academic Press and Grune & Stratton, 1978,3 61-63 39 Lein DH, Clelland JA, Knowles CJ, Jackson JR Companson of effects of transcutaneous electrical stimulation of auricular, somatic and the combination of auricular and somatic acupuncture points on expenmental pain threshold Phys Ther 1989,69 671 678 40 Baum J Charactcnstics of electrostimulations with the multi-purpose therapy apparatus 71-3 for electroacupuncture analgesia Anasth Prax 1979,14 14-22 41 Omura Y Electncal parameters for save and effective electro-acupuncture and transcutaneous electncal stimulation threshold potentials for tingling, muscle contarction and pain, and how to prevent adverse effects of electro-therapy Acupunct Electrother Res 1985,10 335-337 42 Schaer H, Mariella Ρ Doltron ESA 1000 A new apparatus for electrostimulation-anaesthesia Anaesthesist 1979,28 97-100 43 Ho ST, Lu LK The principle and practical use of acupuncture anaesthesia Hongkong Med Health Pub Co, 1981 44 Thoma H, Benzer H, Fitzal S, Losert U On the application of electnc stimulation currents in operations Concept of a clinically applicable device Anaesthesist 1976,25 239-245 45 Lehmann JF, de Lateur J Ultrasound, shortwave, microwave, superficial heat and cold in the treatment of pain In Wall PD, Melzack R, eds Textbook of Pain London Churchill Livingstone, 1984,717-724 46 Pongratz W Akupunktur in der Anaesthesiologie In Lawin P, Loewenich von V, Scholmench P, Stoeckel H, Zumtobel V, eds Intensivmed Notfallmed Anasth Stuttgart-New York Georg Thieme Verlag, 1982,33 5

94 CHAPTER 5.2

ACUPUNCTURE AND TRANSCUTANEOUS STIMULATION ANALGESIA IN COMPARISON WITH MODERATE-DOSE FENTANYL ANAESTHESIA IN MAJOR ABDOMINAL SURGERY Clinical efficacy and influence on recovery and morbidity

Abstract. The efficacy of acupuncture and transcutaneous stimulation analgesia, supplemented by small doses of fentanyl (mean 1.2 μ£.1^1, SD 1.7) was compared with moderate-dose fentanyl anaesthesia (mean 22.9 μg.kg'1, SD 2.8) in 29 patients who underwent surgery for retroperitoneal lymph node dissection. The present study describes the anaesthetic techniques and a comparison of haemodynamics, demand for analgesics after surgery, recovery, blood gases, restoration of urinary and bowel functions, convalescence in terms of self- reliance and the postoperative course in respect of fatigue and morbidity. A more rapid return of consciousness, an absence of hypercapnia and a smaller decrease in pH were observed in patients who received acupuncture and transcutaneous stimulation (p<0.05). No clinically relevant disadvantages attributable to the acupuncture and transcutaneous stimulation were demonstrated.

The use of acupuncture as an anaesthetic in China has led to its investigation and application in the West. Incomplete analgesia is the main disadvantage of the technique and limits its use (1). It has therefore been modified and combined with chemical anaesthetics: conventional drugs are administered to induce sleep, unconsciousness and muscle relaxation, and percutaneous and/or transcutaneous stimulation is used for pain relieve. The technique has been used by anaesthetists for a wide range of indications (2-4) and its ability to obviate or reduce the need of opioids has been demonstrated intra-operatively and in the early postoperative period (5-7). However, a more intensive investigation to evaluate the clinical efficacy of the technique and its influence on recovery and morbidity after a standardized surgical procedure has not been performed previously. The present study was designed to discover whether the reduction in the dose of opioids associated with the use of the technique would result in stable perioperative haemodynamics or increased demand for postoperative analgesics. In addition, an evaluation was made of perioperative blood loss and postoperative convalescence and morbidity.

Patients and methods

Study Design. The study was approved by the hospital Ethics Committee. A total

95 of 29 patients (ASA 1 or 2) scheduled for retroperitoneal lymph node dissection due to a non-seminomatous testicular tumour, were studied. Informed consent was obtained at the preoperative visit. Those who required prolonged postoperative artificial ventilation were excluded. Patients and the investigators who acquired postoperative data were not aware of the used anaesthetic technique. Patients were premedicated with diazepam 10 mg orally 90 minutes before induction of anaesthesia. Anaesthetic procedure. After arrival in the anaesthetic room, an i.v. infusion and a radial artery catheter were inserted. Four electrocardiograph (ECG) electrodes

(3M) were placed paravertebrally (8) and symmetrically between T4 and Ц (Table 1 and Figure 1) corresponding to the dermatomes of the surgical site, i.e. xyphoid to upper part of pubic bone, and connected to a Swiss made Doltron ESA 400 stimulator. ECG and the arterial pressure were monitored continuously (HP 78353 BU).

Table 1. Location of paravertebral (1-4) and ear (5-7) acupoints used in surgery for the retroperitoneal lymph node dissection. Acupoint Anatomical location

1. Jueyinshu 3 cm lateral to the lower border of the spinous process of T4 2. Geshu 3 cm lateral to the lower border of the spinous process of T,

3. Danshu 3 cm lateral to the lower border of the spinous process of Tm 4. Shensu 3 cm lateral to the lower border of the spinous process of L2 5. Fe Cavum concha: a U-shaped area superior, inferior and posterior to the point Heart 6. Shenmen Triangular fossa: at bifurcation of superior antihelix crus and inferior antihelix crus 7. Jiaogan Inferior anti helix crus: at junction of inferior antihelix crus and medial border of helix induction Protocol. Anaesthesia was induced with thiopentone 5 mg.kg"' and vecuronium 0.1 mg.kg' was administered. Manual mask ventilation was given

(N20:02=6:3). Patients were then allocated randomly to one of two groups viz., combined acupuncture and transcutaneous stimulation anaesthesia (CATA) and moderate-dose fentanyl anaesthesia (MFA). The Doltron ESA 400 was switched on (10 Hz, 40 mA and 0.5% pulse width) if the patient was in the CATA group. Three symmetrical ear acupoints were then selected for puncture (Table 1 and Figure 2), and the needles were connected to a Chinese-made stimulator WQ-6F. Stimuli at 10 Hz with a pulse width of 0.7 ms were applied, and the maximum output was setting "7" in all cases. Tracheal intubation was delayed until paravertebral and ear acupoints stimulation had been applied for 15 minutes, or until 15 minutes after induction. A catheter was then inserted into the right internal jugular vein. Surgery was started 30 minutes after the start of induction or stimulation. Stimulation was continued until the end of the procedure.

Maintenance Protocol. Ventilation was controlled (N20:02=2:l) to maintain end expiratory Pco2 at 5.1-5.3 kPa without the use of inhalational anaesthetics (Servo 900 B, HP 47210 A). Muscle relaxation was provided by a continuous infusion of vecuronium until the peritoneum was closed. The rate (2-6 mg.hour') was

96 determined by the number of twitches (one to two) of the train of four of the adductor pollicis muscle after supramaximal stimulation at the left wrist of the ulnar nerve through the surface electrodes using a Myotest nerve stimulator continuously.

Figure 1. Paravertebral acupoints used for surgery. Arrows indicate the points chosen І for retroperitoneal lymph node dissection.

The Doltron ESA 400 was not switched on, nor the ear acupoints punctured, if the patient was in the MFA group. Patient in this group received fentanyl 10 μg.k:g ' as an i.v. bolus 5 minutes before incision and as a continuous infusion at a rate of 5 μg.kg1.hour1 for the first hour and 4 μg.kg,.hourl thereafter until the surgeon began to suture the skin. Fentanyl 50 μg was given i.v. to patients in either group if analgesia at any time was considered to be insufficient, as indicated by either an increase of arterial pressure (SAP, DAP) and/or heart rate (HR) by more than 25% of baseline values, or the presence of tears, sweating or salivation. Peroperative colloid and crystalloid were infused (10-15 ml.kg'.hour') to maintain the central venous pressure within normal limits. Blood and fluid loss were assessed, and if necessary, packed red cells were given. Postoperatively, patients received a glucose-saline (3.3%/0.25%) infusion (100 ml.hour') until oral fluid was allowed. No parenteral nutrition was given.

97 Recovery Procedure. Residual curarisation was determined by nerve stimulation (Myotest) and, if indicated, pyridostigmine 5-10 mg mixed with atropine 0.25-0.5 mg were given. Apnoeic patients in whom end expiratory Pco2 was above 10.7 kPa received increments of i.v. naloxone 0.04 mg. Patients were kept in the recovery room for careful observation for at least 90 minutes after extubation.

Figure 2. Ear acupoints used for surgery. Arrows indicate the points or area chosen for retropentoneal lymph node dissection.

Operative technique. A bladder catheter was inserted. A midline skin incision from xyphoid to the upper part of pubic bone was made. Abdominal organs and retroperitoneal lymph nodes were explored. After mobilization, the dissection of lymph nodes was started from bilateral renal supra-, traditional- and infrahilar zones. All lumbar arteries and veins were divided and nodal and connective tissue was rotated under these and dissected off the posterior body wall in a continuous package. The lateral border of dissection was either ureter or psoas muscle, the inferior extent was two to three cm beyond each hypogastric artery and the superior borders were the coeliac axis, aortic crura, superior medial borders of both adrenals and retrohepatic inferior vena cava. Appendicectomy was performed before the abdominal wall was closed.

98 Data acquisition

Peroperative. SAP, DAP and HR were recorded at admission, before and after induction, after 15 minutes of stimulation, one minute after intubation, at incision and then at 10-minute intervals in the first hour and at 15-minute thereafter. SAP, DAP, HR and respiratory rate (RR) were recorded on arrival in the recovery room and then at 30-minute intervals until discharge.

Postoperative. The degree of consciousness (confused, respond to command or fully awake) was assessed on arrival in the recovery room, after one hour and just before returning to the ward. Arterial blood gases were analyzed in duplicate at one, three and five hours after surgery, while the patient was breathing room air. The duration of the recovery room stay was recorded. The haemoglobin concentration (Hb), the haematocrit (Hct) and the patient's feeling of pain using a mixed verbal-visual analogue pain scale of 0-3 (0, no pain, 3 severe pain) were assessed preoperatively, one hour after surgery and again daily at 1 p.m. until day 6. The incidence of nausea and vomiting was recorded. Nicomorphine 0.1 mg.kg"' i.m. and prochlorperazine 25 mg as a suppository were available for analgesia and antiemesis respectively as required. The patients' opinion on their anaesthetic experience was evaluated as: bad, sufficient, satisfactory or good on days 1, 2 and 3. Patients were questioned on each of those days about awareness during surgery or pain in the peroperative period. Awareness was defined as remembering conversations which occurred during anaesthesia and/or having experienced unpleasant dreams.

Follow up. The time between the end of surgery and the removal of the bladder catheter was noted. The return of colonic motility (assessed by bowel sounds), the first passage of flatus and the time when fluid and/or food was first consumed orally were recorded. In addition, daily activities such as getting out of bed, ability to go to the toilet, wash and go for a walk, were noted and patients were asked to assess their fatigue level on a linear visual analogue scale with extremities numbered 1, fit to 10, exhausted. The incidence of complications and the length of hospitalization were recorded. A standard 12-lead ECG was recorded daily at 1 p.m. until day 6 by the same personnel. ECG abnormalities analyzed were: prolonged PR interval (>0.20 sec), horizontal ST-segment depression (>1 mm from the isoelectric line), flattened Τ wave (

Data evaluation

Values measured on admission or before induction of anaesthesia served as controls. Data are presented as mean (SD) unless otherwise stated. Mean arterial pressure (MAP) was calculated as 1/3 χ (SAP + 2xDAP). GLM for "repeated measures" and Fisher exact test were applied; p<0.05 was the level of statistical significance.

99 Results

Twenty nine patients entered the study. One patient in the CATA group and three in the MFA group were withdrawn because of peroperative excessive blood loss of more than five litres. This led to a violation of the protocol since postoperative artificial ventilation was needed. The data of one CATA patient who did not respond to the stimulation and required a dose of fentanyl which equalled 76% of the mean dose required by MFA patients, although completely assessed, was excluded from analysis. Table 2 shows details of the remaining 24 patients. The two groups of 12 patients each were comparable with respect to sex, age, weight, height and duration of anaesthesia, surgery and recovery room stay.

Table 2. Means (SD) values of demographic data, duration of anaesthesia, surgery and the stay in the recovery room (recovery time).

CATA MFA

Sex ratio (M/F) 12/0 12/0 Age (year) 24.8 (6.3) 30.0 (9.6) Weight (kg) 70.2 (5.6) 78.0(15.5) Height (cm) 181.7 (3.6) 180.3 (8.2) Anaesthetic time (h) 4.1 (0.6) 3.8 (0.3) Surgical time (h) 3.4 (0.6) 3.1 (0.4) Recovery time (h) 2.2 (0.3) 2.4 (1.3) There was no significant difference between the groups (ANOVA). Table 3 shows the peroperative drug administration and the postoperative requirement of nicomorphine. No differences were found between the groups except for the dose of fentanyl. Four of 12 patients in the CATA group tolerated surgery without fentanyl, whereas seven of 12 patients in the MFA group did not need any supplement of fentanyl above the doses required by the protocol. The fentanyl requirement in the CATA group was 4.7% (SEM 1.8; range 0-19.9%) of the mean doses in the MFA group. Naloxone 0.08 mg was given to one MFA patient.

Table 3. Mean (SD) values of peroperative anaesthetic drug administration and postoperative demand of nicomorphine.

Drug CATA MFA

Thiopentone (mg.kg1) 5.0 (0.3) 5.4 (1.6) Vecuronium (mg.kg-.h') 0.1 (0.04) 0.1 (0.02) Vecuronium (mg.kg1) 0.4 (0.1) 0.3 (0.1) Fentanyl ^g.kg'.h-') 0.3* (0.4) 6.3 (1.3) Fentanyl ^g.kg-1) 1.2* (1.7) 22.9 (2.8) Nicomorphine (mg.kg') 0.9 (0.5) 0.8 (0.4)

*p<0.05.

Peroperative. Comparable MAP and HR were found in the two groups before surgery (after 15 minutes of stimulation or 15 minutes after induction and after

100 tracheal intubation) and peroperatively in both groups (Figure 3). There were significant increases of both MAP and HR by 21% and 35% (CATA) respectively 19.4% and 32% (MFA) after tracheal intubation. Both MAP and HR at incision were lower than baseline (p<0.05) in the MFA group, whereas there was no such decrease in the CATA group: This difference was significant. Both MAP and HR in the MFA group increased shortly after incision to values similar to or greater than those observed in the CATA group. Tachycardia and arrythmias were not observed in either group.

MAP filini Hcj)-

D С . 1

P-O.40 ^Ч*^1- ν P-O.; О Q С D Пil _ Μ tí «il t rane ( hn nt s. in t n"1 J

•u ι

Ri'sp rata < br e a t h s. ni ι ιΓ1 ) ρ'Ο.ΟΎ

U'-i

Figure 3. Mean arterial pressure (MAP), heart rate (HR) and respiratory rate (RR) with error bars equal to SEM. 1, CATA; 2, MFA. Arrow indicates the incision time. A, admission; B, 5 minutes after insertion of arterial line; C, after 15 minutes of stimulation; D, 1 minute after intubation. The significance of the differences of mean responses during and after surgery from the reference are given by ρ values.

Postoperative. MAP in the CATA group was consistently but not significantly lower than that observed in the MFA group (p=0.22) at awakening and during the recovery room stay; HR was similar in both groups. The CATA group had a consistently but insignificantly higher RR compared with MFA group (Figure 3). All CATA patients were fully awake (Table 4) on arrival in the recovery room as opposed to seven in the MFA group (p<0.05). No patient in the CATA group

101 was confused at TI, compared to two in the MFA group

Table 4 Degree of consciousness (number of patients) on amval at the recovery room (Tl), 1 hour later (T2) and at the end of the recovery penod (T3)

Tl T2 T3 Consciousness CATA MFA CATA MFA CATA MFA

Confused (Y/N) 0/12 2/10 0/12 0/12 0/12 0/12 Respond to command (Y/N) 12/0 9/3 12/0 12/0 12/0 12/0 Fully awake (Y/N) 12/0 7/5* 12/0 11/1 12/0 12/0

* P<0 05 (Fisher's exact test)

Лгьап»! pOa CKPeï —

Figure 4 Arterial blood gases in the early

Art-rial рСО CkPa> recovery penod For groups and symbols г see Figure 3 Star indicates statistically significant difference between the groups at vanous sampling points

HCO3 {mmol I lì

Ваяа deficit Cintnal I-1

Tim· thî poatopsi-afcivelti

102 Blood gas results are shown in Figure 4. Both groups had a lower Pa02 than the baseline value throughout the assessment period (p<0.01), but without differences between the groups. Patients in the CATA group had a normal mean PaC02 (range: 3.2-5.8 kPa), whereas in the MFA group PaC02 (range: 4.2-9.0 kPa) was without exception higher than baseline (p<0.01); between the groups, differences existed at one and three hours (p<0.05). Both groups had a lower pH (p<0.01) than baseline (CATA range: 7.29-7.45); MFA range: 7.19-7.36); differences between the groups existed at one and three hours (p<0.O5). Values of standard bicarbonate and base deficit were comparable. The fluid balance during operation and in the early postoperative period was comparable between the groups (Table 5). One CATA patient received two units and one MFA patient one unit, of packed red cells during surgery.

Table 5 Fluid balance dunng (per-op) and after surgery (post-op) as recorded in the recovery room Mean (SD) values are given

Fluid balance (ml) CATA MFA

Fluid and blood loss per-op 1115 (962) 843 (337) Fluid and blood loss post-op 68 (46) 85 (50) Unne output per-op 335 (210) 324 (159) Urine output post-op 219 (112) 189 (113) Colloid infusion per-op 1154 (335) 1125 (311) Colloid infusion post-op 17 (58) 25 (87) Crystalloid infusion per-op 3171(1074) 3475 (893) Crystalloid infusion post-op 586 (261) 445 (271)

No difference between the groups (ANOVA) The values of Hb and Hct one hour after surgery were comparable and significantly lower than baseline in both groups: 8 1 mmol.l ' (0.7) and 0.39% (0.03) respectively in the CATA group and 8.6 mmol.l ' (0.9) and 0.41 % (0.05) in the MFA group. The incidence of postoperative nausea and vomiting in the recovery room and the first three days was comparable in both groups. Prochlorperazine was given to one CATA patient and five MFA patients on day 1; but the difference failed to reach significance (Fisher's exact test, p=0 06). The mean total dose of prochlorperazine required was 10.4 mg (16.7) in the CATA group and 19.2 mg (26.1) in the MFA group. No patient complained of recall of pain during operation, but one CATA patient and two MFA patients had awareness of other intraoperative events. These patients judged the anaesthetic technique as sufficient, one of the two patients in the MFA group described the technique as bad and the other as satisfactory on day 3 (Table 6). The rest of the patients were generally satisfied with their anaesthetic expenence.

103 Table 6 An overall assessment of the anaesthetic technique used as judged by patient on days 1, 2 and 3 after surgery

Anaesthetic Day 1 Day 2 Day 3 technique CATA MFA CATA MFA CATA MFA

Bad 0 0 0 0 0 1 Sufficient 1 1 1 2 1 0 Satisfactory 4 5 3 4 3 4 Good 7 6 8 6 8 7

The postoperative pain scores and the daily requirements of nicomorphine (Figure 5) did not differ significantly (p=0.47) between the groups. The highest score was recorded one hour after surgery and the highest requirement of nicomorphine was on day 1. None of patients in the CATA group consumed nicomorphine on days 5 and 6.

Pain score CO-3J

D. 1

Figure 5 Postoperative pain score and the demand for nicomorphine For groups and symbols see Figure 3 Follow up The bladder catheter was removed after 17.8 (12.9) hours in the CATA group and after 26.3 (10.7) hours in the MFA group (Table 7): this was

104 not significantly different (p=0.06). Comparable data were found in the two groups concerning the resumption of colonic peristalsis, the delay in passing flatus, the time to resumption of oral fluid, the time to restarting food intake and the length of hospitalization. Also, the convalescence in terms of self-reliance was comparable in both groups (Table 8).

Table 7. Recovery of urinary and bowel functions and postoperative hospital stay. Mean values (SD) are given.

Delay (hours or days) CATA MFA ANOVA

Bladder catheter out (h) 17.8(12.9) 26.3 (10.7) p=0.06 Colon peristalsis (h) 39.4 (9.5) 42.1 (19.1) ns Flatus (h) 51.2(23.1) 51.3 (14.0) ns Oral fluid intake (d) 2.8 (0.7) 2.6 (0.4) ns Oral food intake (d) 4.4 (1.5) 4.4 (1.9) ns Hospitalization (d) 9.3 (2.2) 10.0 (2.5) ns

Fatigue scores (Figure 6) did not differ between the groups (p=0.26). It increased after surgery (p<0.05) and normalized by day 10 in both groups.

Postoperative Fatigue CI—ІОЭ

pme day day day day day day day op 1 Ξ 3 5 ID 15 ΞΟ Figure 6. Postoperative Fatigue. For groups and symbols see Figure 3.

Morbidity. There were no major complication in either group. In both groups, temporary ECG signs of myocardial ischaemia were observed as judged by Τ wave flattening (Table 9). The highest incidence was recorded on days 2 and 3 (11 and 8 CATA patients; 8 and 8 MFA patients; a statistically significant difference between the groups existed on day 5. ST depression was found in one MFA patient on days 1 and 2. Other ECG abnormalities were not recorded.

105 Table 8 Recovery after surgery Self Reliance in the first six days

Self-reliance Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 CATA MFA CATA MFA CATA MFA CATA MFA CATA MFA CATA MFA

Out of bed 4 1 8 10 11 11 12 12 12 12 12 12 Go to toilet 0 0 0 0 4 3 8 8 12 11 12 12 Have a wash 0 0 2 0 8 4 11 10 12 12 12 12 Go for a walk 0 0 1 0 6 3 10 9 12 12 12 12

No significant difference between the groups exists (Fisher's exact test)

Table 9 The postoperative changes of electrocardiogram Note the occurance of the Τ wave flattening in both groups and its recovery

ECG PRE-OP DAY 1 DAY 2 DAY 3 DAY 4 DAY 5 DAY 6 characteristics CATA MFA CATA MFA CATA MFA CATA MFA CATA MFA CATA MFA CATA MFA

Sinus rhythm 7 9 8 9 5 7 11 9 12 12 12 12 11 12 Sinus bradycardia 5 3 0 0 0 0 0 0 0 0 0 0 0 0 Sinus tachycardia 0 0 4 3 7 5 1 3 0 0 0 0 1 0 Prolonged PR 0 0 0 0 0 0 1 0 0 0 0 0 0 0 ST depression 0 0 0 1 0 1 0 1 0 0 0 0 0 0 Flattened Τ wave 0 0 6 8 11 8 8 8 6 5 0 5* 1 3 Inverted Τ wave 0 0 0 1 2 5 2 3 I 2 0 0 0 0 U wave 1 0 1 3 2 3 3 3 1 2 0 0 0 0

*P<0 05 (Fisher's exact test) Discussion

Study design. By means of a rigid protocol the efficacy of CATA and the associated recovery, convalescence and morbidity were compared with those of MFA, in a standardized major abdominal operation. This is mainly based on the expected difference in the use of peroperative opioids between the two groups. It was decided to exclude the data of one non-responder CATA patient, who consumed fentanyl to an extent about equal to those in the MFA group, since this patient may behave as the latter. From the practical point of view and unlike trials on drugs, it was impossible to carry out the present study in a double-blind fashion, even for a short period until incision. First, the stimulation of ear acupoints is quickly followed by erythematous changes of the ears which can be observed readily. Secondly, stimulation causes a small artifact on the ECG monitor which may be recognized easily. Bias was minimised by ensuring that the study was randomized, that it was performed as single-blind and that the evaluators outside the operating theatre were blinded.

Cardiovascular response, fentanyl and vecuronium requirement. To allow time for body- and ear acupoints stimulation to take effect, intubation of the trachea was delayed for 15 minutes. Nevertheless, CATA did not prevent the cardiovascular response. The same phenomenon was found in MFA group and it was clear that neither 70% nitrous oxide nor its combination with acupuncture and transcutaneous stimulation were sufficient to prevent the pressor response to intubation. Many methods to modulate this response have failed to gain widespread acceptance as a result of either a lack of efficacy, inapplicablility for routine anaesthetic practice or complexity and problems inherent in the technique (9-12). Frequent traction of the peritoneum, exploration and mobilization of abdominal organs and lymph nodes near the vessels and sympathetic ganglia, were reflected by the patterns of MAP and HR in the MFA group; even the bolus of fentanyl given 5 minutes before incision, which caused decreases of MAP and HR, did not prevent the continuous increase of MAP and HR in the first 30 minutes after incision. However, patients in the CATA group had a relatively stable MAP and HR over the same period. This stability may have been achieved by a combination of at least two factors; analgesia produced by acupuncture and transcutaneous stimulation and a vagal effect due to stimulation of ear areas innervated by the vagal nerve. The overall patterns of haemodynamics in both groups were, however, stable. Earlier data from a controlled study comparing four narcotic drugs in balanced anaesthesia revealed that a potent inhalational agent was required in 23% of patients to maintain stable haemodynamics (13). The CATA group required a considerably lesser amount of fentanyl to an average total dose of 1.2 (SD 1.7) μg.kg1 than the MFA group 22.9 (SD 2.8) μg.kg '. It could be suggested that excessive fentanyl was given, particularly since naloxone had to be administered in one patient to restore respiration. However, we do not believe that the fentanyl dose was excessive because of the changes in haemodynamics during the first 30 minutes after incision and because the maintenance dose of fentanyl given as a continuous infusion was derived from the usual and average requirements of fentanyl for this type of surgery performed

107 under balanced anaesthesia without the use of neuroleptic, benzodiazepine or inhalational anaesthetics. This was calculated to be 100 to 150 μg every 10 minutes. In addition, five of the 12 patients required another supplementation of fentanyl in excess of the doses given according to the protocol. The incidence of non-responders in the CATA group is in accordance with previous data (4). The requirement for muscle relaxants in the CATA group did not increase, a finding which agrees with an earlier study (5).

Follow up. As the demand for fentanyl in the CATA group was less, this may account for the rapid awakening and the absence of hypercapnia. The hypercapnia led, in part, to the lowering of pH in the MFA group. Although arterial P02 decreased, hypoxaemia was not observed in either group in contrast to other studies of upper abdominal surgery (15-17). Acupuncture has been reported to reduce postoperative nausea (18). This might contribute to the lower need of prochlorperazine on day 1 in the CATA group, the requirement of postoperative analgesics being comparable in the two groups. Several factors may have contributed to the high incidence of awareness (CATA:1/12; MFA:2/12). CATA patients received opioids only on clinical signs of insufficient analgesia, although all denied remembering feeling peroperative pain, and the use of a nitrous oxide-oxygen anaesthesia and opioids in combination with neuromuscular blockade is known to be associated with a high incidence of awareness (19). The occurance of awareness in the MFA group indicates that total unconciousness cannot be assured even when this commonly employed technique is used. Awareness is reported to occur in one to four percent of the cases (19). A much higher incidence, e.g. 14 from 20 cases, has recently been reported with the use of a routinely applied anaesthetic technique (20). This major variation of reported incidences of awareness might be related to the definitions used. Following laparotomy, normal colon motility is resumed after at least 48 hours. Increased sympathetic activity and the use of opiods are the major cause in prolonging the postoperative alteration of colonic motility (21). The CATA group may have failed to show a more rapid recovery of bowel function because of the normal postoperative consumption of opioids, although the peroperative need was low. The small number of patients may account for the failure of the difference in recovery of urinary function to reach a level of statistical significance (p=0.06). The recovery of fatigue score in both groups, while similar, was obviously shorter than that reported in another study (22). Reversible ECG signs of myocardial ischaemia developed postoperatively; similar findings have been reported after cholecystectomy (23). The recovery might possibly be more rapid in the CATA group, although the significance of this phenomenon is doubtful considering the time course and the great number of comparisons made. It is not clear whether the reported improvement of microcirculation and coronary blood flow due to a reduction of blood viscosity by acupuncture (24) contributed to the observed ECG recovery.

In conclusion, the use of acupuncture and transcutaneous stimulation in major abdominal surgery, although not preventing the pressor response of intubation,

108 maintained stable haemodynamics per- and postoperatively with a rapid recovery without hypercapma. Any other clinically relevant disadvantages attributable to the method, though carefully searched for, were not demonstrated.

References

1 Kho HG, Van Egmond J, Zhuang CF, Zhang GL, Lm GF Acupuncture anaesthesia Observations on its use in removal of thyroid adenomata and influence on recovery and morbidity in a Chinese hospital Anaesthesia 1990,45 480-485 2 Pauser G, Benzer H, Bisthko J, Ganglberger J, Haider M, Mayrhofer O, Schmid H, Semsroth S, Thoma H Clinical and experimental results with acupuncture analgesia Anaesthesist 1976,25 215-222 3 Fischer M, Just OH Clinical uses of electrostimulation anaesthesie Anasth Ртах 1979,14 1-8 4 Fischer M, Just OH, Muller С Indikationen und klinische anwendung der Elektrostimulationsanalgcsie (ESA) In Haid B, Herschi ffthaler G, eds Anaesthesiologie und Intensivmedizin 140, Zentraleuropaischcr Anaesthesie Kongress, band 2, Berlin Springer Verlag, 1981,145-147 5 Grabow L, Cnveanu Τ Combined acupuncture-analgesia as a method in general anaesthesia Anaesthesist 1976,25 231-234 6 Kho HG, Maas Ρ, Kerkkamp Η, Drent M, Kippersluis E, Egmond van J Haemodynamische Wirkungen der kombinierten Akupunkturanasthesie bei abdomineller urologischer Chirurgie Dtsch Ztschr Akup 1987,30 60-64 7 Chnstensen PA, Noreng M, Andersen PE, Nielsen JW Electroacupuncture and postoperative pain Br J Anaesth 1989,62 258-262 8 Cheng XN Chinese acupuncture and moxibustion Beijing Foreign Languages Press, 1987,167-170 9 Prys Roberts C, Foex P, Biro GP, Roberts JG Studies of anaesthesia in relation to hypertension V Adrenergic betareceptor blockers Br J Anaesth 1973,45 671-679 10 Tolksdorf W, Schäfer E, Pfeiffer J, Mittelstaedt ν G Behaviour of adrenaline, noradrenaline, blood pressure and heart rate during intubation, depending on different fentanyl dose Anasth Intensivther Notfallmed 1987,22 171 176 11 Dohi S, Nishikawa T, Ujike Y, Mayumi Τ Circulatory responses to airway stimulation and cervical epidural blockade Anesthesiology 1982,57 359 363 12 Stoelting RK Circulatory changes during direct laryngoscopy and tracheal intubation Influence of duration of laryngoscopy with and without prior lidocame Anesthesiology 1977,47 381-384 13 Racke JW, Bloor ВС, Kripke BJ, Flacke W, Wameck ChM, Van Etten AP, Wong DH, Katz RL Companson of morphine meperidine, fentanyl and sufentanyl in balanced anaesthesia A double-blind study Ancsth Analg 1985,64 897-910 14 Fischer MV, Raab Ρ, ν Reumont J Consumption of muscle relaxants in electrostimulation- anaesthesia Anaesthesist 1983,32 597 600 15 Craig DB Postoperative recovery of pulmonary function Anesth and Analg 1981,60:46-52 16 Campbell IT, Willatt DJ, Childs D, Stell PM Arterial oxygenation after major head and neck surgery involving tracheotomy Br J Anaesth 1987,59 1121-1126 17 Simonneau G, Vivien A, Sartene R, Kunstlmger F, Samn K, Noviant Y, Duroux Ρ Diaphragm dysfunction induced by upper abdominal surgery Role of postoperative pain Am Rev Resp Dis 1985,128 899-903 18 Dundee JW, Chestnut! WN, Ghaly RG, Lynas AGA Traditional Chinese acupuncture a potentially usefull antiemetic'' Br Med J 1986,293 583-584 19 Gareth Jones J Awareness under anaesthesia ICI Pharmaceut Anaesth Round 1988,21 1-28 20 Baraka A, Louis F, Noueihid R, Diab M, Dabbous A, Sibai A Awareness following different techniques of general anaesthesia for caesarean section Br J Anaesth 1989,62 645-648 21 Twecdle D, Nogthingale Ρ Anaesthesia and gastrointestinal motility Acta Chir Scand 1988,550(Suppl) 131-139

109 22 Chnstensen Τ, Bendix Τ, Kehlet H Fatigue and cardiorespiratory function following abdominal surgery Br J Surg 1982,69 417 419 23 Jacobsson J, Rehnqvist N, Davidson S Computerised evaluation of the electrocardiogram during and for a short period after gall bladder surgery Acta Anaesth Scand 1989,33 474- 477 24 Zhu BJ, Bi LG, Liang SY, Pang L, Wang SL, et al Effect of acupuncture on left ventncular function, microcirculation, blood rheology and cyclicnucleotides m patients with acute myocardial infarction J Trad Chin Med 1989,9 63-68

110 CHAPTER 5.3

EFFECTS OF ACUPUNCTURE AND TRANSCUTANEOUS STIMULATION ANALGESIA ON PLASMA HORMONE LEVELS DURING AND AFTER MAJOR ABDOMINAL SURGERY Comparison of three anesthetic techniques

Abstract. The effects of acupuncture and transcutaneous stimulation analgesia on plasma catecholamines A and NA, peptide hormones adrenocorticotropic hormone (ACTH), ß- endorphin (BE), anti-diuretic hormone (ADH) and hydrocortisone (Cortisol) were evaluated during and for four days after surgery in 42 male patients submitted to a standardized major abdominal operation performed under three different anaesthetic techniques Group 1 received acupuncture and transcutaneous stimulation as the main and non- pharmacological analgesic during surgery, supplemented by small doses of fentanyl (1 2 μg kg1, SD 1 7), Group 2 received moderate-dose fentanyl (22 9 μg kg ', SD 2 8) and Group 1 received acupuncture and transcutaneous stimulation combined with moderate-dose fentanyl (23 6 μg kg ', SD 3 3) All were induced with thiopentone 5 mg kg ', intubated after vecuronium

0 1 mg kg ' and normocapmcally ventilated (N20 02=2 1) without the use of an inhalation agent The use ot acupuncture and transcutaneous stimulation in Group 1 induced an early hyperendorphinemia and showed a peroperative response of circulating NA and Cortisol similar to that in Groups 2 and 3, whereas the responses of the circulating A, ACTH, BE and ADH in Group 1 were more pronounced (p<0 01) Post operatively no differences in the hormonal profiles could be discerned between the groups with and without electrostimulation (Group 2 vs Group 3) nor between those with or without moderate-dose fentanyl anaesthesia (Group 1 vs Group 3)

Vanous stimuli in surgical patients initiate changes in endocrine functions. Acting as a neurophysiologic reflex, the response is believed to be important for survival (1) Evidence has accumulated that the body's response is mediated through the peripheral and central nervous systems by the release of catecholamines, pituitary and pituitary dependent hormones (1-2) Studies on regional anaesthesia in lower abdominal surgery resulted in the inhibition of these responses, suggesting that afferent neurogenic pathways arising from surgical areas are the main releasing mechanisms of the responses (1,3) In contrast, no feasible anaesthetic technique can ablate the body's stress response in upper abdominal surgery (3) The use of ACAN with general anaesthesia has gained increasing popularity While reduction

111 of peroperative analgesic requirements with this technique has been reported during various types of surgery (4, 5), corresponding information concerning stress responses are sparse and conflicting (6-8). The purpose of the present study was to evaluate the sympatho-adrenomedullary and pituitary-adrenocortical effects of ACAN during and after major abdominal surgery. This was accomplished by the use of only one type of surgical procedure.

Patients and methods

Approval of the hospital Ethics Committee was obtained. Forty-two male patients of ASA class 1 and 2, undergoing elective major abdominal surgery for extended retroperitoneal lymph node dissection because of non-seminomatous testis tumour were studied. Those who required prolonged postoperative ventilation were excluded. Informed consent was obtained from every patient. All were free of cardiovascular or endocrine disorders and none had received steroid treatment. After fasting overnight, patients were premedicated with diazepam 10 mg orally 90 minutes prior to induction of anaesthesia. On arrival in the anaesthetic room, a 20-gauge cannule was inserted in the non-dominant radial artery under local anaesthesia, an i.v. infusion was set up and four electrocardiograph (ECG) electrodes (3M) were placed paravertebrally and symmetrically between T4 and L2 (i.e. at the levels of T4, T7, Tl0 and L2), corresponding to the dermatomes of the surgical incision, i.e. xyphoid to upper part of pubic bone. The electrodes were connected to a Doltron ESA 400 stimulator. ECG and the arterial pressure were continuously monitored (HP 78353 BU). Anaesthesia was induced with i.v. thiopentone 5 mg.kg"1 and vecuronium

0.1 mg.kg' was administered, after which manual mask ventilation (N20:02=6:3) was given. Patients were then allocated to one of the three anaesthetic groups. The Doltron ESA 400 was switched on (10 Hz, 40 m A and a 0.5% pulse width) if the patient was in the Groups 1 and 3. In addition, three symmetrical ear acupoints, Fe, Jiaogan and Shenmen, were selected for puncture, the needles were connected to a Chinese made WQ-6F stimulator and the stimuli applied (10 Hz, output amplitude at setting "7" and a 0.7 ms pulse width) until the end of surgery. Tracheal intubation was delayed till after 15 minutes of stimulation (Groups 1 and 3) or after 15 minutes of induction (Group 2). Ventilation was controlled (N20:02=2:l, Servo 900 B) to maintain end expiratory PC02 at 38-40 mm Hg (HP capnometer 47210A). Inhalation anaesthesia was not used in any patient. The Doltron ESA 400 was not switched on nor the ear acupoints punctured, if the patient was in the Group 2. Patients in this group but also those who were in Group 3 received fentanyl 10 μg.kg"' as an i.v. bolus 5 minutes before incision and as a continuous infusion at a rate of 5 μg.kg1.houг' in the first hour and 4 Ц£^1.Ііоиг'1 thereafter until the surgeon began to suture the skin. Surgery was performed between 9 a.m. and 2 p.m., in all cases after 30 minutes of stimulation (Groups 1 and 3) or induction (Group 2). Fentanyl 50 μg i.v. was given to the patient in all groups at any time during

112 surgery if analgesia was considered to be insufficient, as indicated by either an increase of arterial pressure (SAP, DAP) and/or heart rate (HR) by more than 25% of baseline values, or the presence of tears, sweating or salivation. Muscle relaxation was maintained by a continuous infusion of vecuronium until the peritoneum was closed. The rate (2-6 mg.hour ') was determined by the number of twitches (one to two) of the train of four of the adductor pollicis muscle after supramaximal stimulation at the left wrist of the ulnar nerve through the surface electrodes using a Myotest nerve stimulator continuously. Peroperative colloid and crystalloid solutions 10-15 ml.kg'.hour' were infused to maintain central venous pressure, monitored through a catheter inserted in the right internal jugular vein, within normal limits. When needed, packed red cells were given. At the end of surgery, residual curarisation was determined by nerve stimulation and, if indicated, pyridostigmine 5-10 mg i.v. mixed with atropine 0.25-0.5 mg were given. Postoperatively, all patients received glucose-saline (3.3%/0.25%) infusion 100 ml.hour1. No parenteral nutrition was given in the entire postoperative phase. Intramuscular nicomorphine 0.1 mg.kg' was available for analgesia postoperatively. Blood samples were taken following the schedule presented in Table 1; arterial blood samples from the radial artery catheter at T1-T12 and venous blood samples from the right internal jugular vein catheter thereafter. Plasma adrenaline (A) and noradrenaline (NA), adrenocorticotropic hormone (ACTH), ß-endorphin (BE), antidiuretic hormone (ADH) and Cortisol were measured. Samples were coded after collection in order to prevent bias by personnel performing the determination. Following immediate preparation (i.e. centrifugation and separation), samples were frozen and stored at -20oC until analysis. The measurements of catecholamines and other endocrines variables were carried out within six months in the Laboratory of Experimental and Chemical Endocrinology (head: Prof.Dr.T.J.Benraad) of the University Hospital, Nijmegen. Table 2 shows the characteristics of the assay methods for different variables.

Table 1. Time schedule for drawing blood samples.

Code Time Description

TI 10 min After insertion of radial artery catheter but before induction T2 15 min After induction and the start of paravertebral and ear acupoints stimulation T3 5 min After intubation T4-8 5, 20, 40, 60, 120 min After skin incision T9 End of surgery Τ10-12 1, 3, 5 hours After the end of surgery T13-16 1, 2, 3, 4 days After the end of surgery at 1 p.m. T17-20 1, 2, 3, 4 days After the end of surgery at 8 a.m.

Data evaluation. Variables measured before the induction of anaesthesia were taken as reference. Unless otherwise stated all values given below are means and standard deviation in parentheses: Mean (SD). Statistical analysis was performed using the SAS-procedures (SAS Ine, Cary, NC, USA) on a VAX/785 computer.

113 Table 2 The assay methods for determination of hormones and immunological vanables, their intra- and inter-assay coefficients of variation (%), sensitivity (=Sens), the resting range (=Rest) in non-stressed state, units and references (Ref) The origin of the reagens kit or standard is mentioned under the method between parentheses Star represents values at 9 am

Variable Method Intra Inter Sens Rest Unit

A COMT 71 90 005 0 06-0 30 nmol 1 ' NA COMT 54 75 005 0 6-2 3 nmol 1-1 ACTH RIA (own) 12 3 63 20 2 0-15 0* pmoll-1 BE RIA (Incstar) 79 120 <3 0 3-11 pmol 1 ' ADH RIA (Buhlmann) 97 20 0 05 42-118 pmol 1 ' Cortisol RIA (own) 50 100 0 02 0 19-0 55* μπιοΐΐ-ΐ

COMT, catechol-O methyltransfera.se based radioenzymatic method, RIA, radioimmunoassay

In an ANOVA procedure, in which the peroperative (postoperative) values incontrasi to the preoperative value were treated as "repeated measures" of the effect on a variable, the significance of homogeneity of effects was analyzed In another procedure to evaluate the effects of surgery on a variable the "mean response" of a vanable during a period (peroperative, T4-T9 or postoperative, T10 and later times) was defined as the mean difference from this preoperative reference value These mean responses were calculated for each individual and used in a one-way analysis of vanance (ANOVA) with subsequent Scheffé procedure Also the preoperative values of all vanables were checked for their homogeneity between groups in a one-way ANOVA procedure Because of the great inter- and intra-individual variability during the course of surgery, no attempt was made to exactly indicate at what time intra- or postoperative differences are statistically significant and when not, restriction is made to an overall difference of behaviour during the total penod. In all tests p<0 05 was used as the threshold of significance

Results

Forty two patients entered the study In five patients (Group l- one, Group 2· three and Group 3 one) the study could not be finished because of excessive bleeding of more than five litres during the course of surgery, which made postoperative prolonged ventilation necessary, thereby violating the protocol One patient from Group 1, in which acupuncture did not result in analgesia as proven by hemodynamic changes as indicated in the method section, consumed therefore fentanyl in doses comparable to the patients in Groups 2 and 3 In the final analysis his data were excluded. Table 3 shows a number of clinical data of the 36 patients included in this study, whereas m Table 4 the amount of anaesthetic drugs that had to be given are tabulated The tables illustrated nicely that no statistical differences between the three groups were found except for the amount of fentanyl which was in Group 1 about 5% of the amount used in Groups 2 and 3. One patient in Group 1 received two units and one patient in Groups 2 and 3 one unit of packed red cells during surgery. The postoperative study penod was clinically uneventful.

114 Table 3 Patient data, fluid balance and total postoperative demand of nicomorphine Group 1, acupuncture and transcutaneous stimulation with supplementation of small-dose fentanyl. Group 2, moderate-dose fentanyl, Group 3, acupuncture and transcutaneous stimulation plus moderate-dose fentanyl Data represent mean (SD)

Group 1 Group 2 Group 3

Number 12 12 12 Age (year) 24 8 (6 3) 30 0 (9 6) 319 (144) Weight (kg) 70 2 (5 6) 78 0 (15 5) 72 4 (9 4) Height (cm) 1817 (3 6) 180 3 (8 2) 1810 (9 4) Anaesthetic time (h) 4 1 (06) 3 8 (0 3) 3 6 (0 7) Surgical time (h) 34 (06) 3 1 (0 4) 2 9 (0 7) Fluid + blood loss (ml) 1185 (962) 843 (336) 1181 (737) Colloid infusion (ml) 1154 (335) 1125 (310) 1083 (221) Cnstalloid infusion (ml) 3171 (1074) 3475 (893) 3000 (533) Unne output (ml) 335 (210) 324 (159) 278 (264) Nicomorphine (mg kg ') 0 9 (0 5) 0 8 (0 4) 0 8 (0 6)

No significant differences between the groups existed (ANOVA)

Table 4 Peroperative anaesthetic drugs For groups see legend to Table 3 Data represent mean (SD)

Drug Group 1 Group 2 Group 3

Thiopentone (mg kg ') 50 (0 3) 5 4 (16) 49 (0 2) Vecuronium (mg kg " 04 (0 1) 0 3 (0 1) 04 (0 1) Fentanyl ^g kg ') 12* (17) 22 9 (2 8) 23 6 (3 3)

Star indicates a significant difference (p<0 05) between the groups

Haemodynamic changes The preoperative (at Tl, T2 and T3) mean MAP and HR did not differ significantly between the three groups (Table 5) Electrostimulation did not cause changes in mean MAP and HR in Groups 1 and 3 (at T2), whereas values at T3 rose (p<0 05) about equal in either group There were no obvious differences between the three groups per- and postoperatively.

Table 5 Preoperative haemodynamic data For groups see legend to Table 3 TO, admission, Tl, 5 minutes after insertion of radial artenal catheter, T2, 15 minutes after stimulation, T3, 1 minute after intubation

Time Group Group 1 2 3 1 2 3 MAP (mm Hg) HR (beats ιmm' )

TO 93 (10) 93 (10) 94 (11) 68 (9) 73 (8) 76 (19) Tl 94 (11) 94 (9) 98 (13) 73 (12) 76 (16) 78 (16) T2 94 (15) 84 (14) 110 (15) 73 (14) 67 (9) 75 (16) T3 112* (12) 110* (19) 127* (13) 94* (18) 96* (14) 103* (23)

Star indicates differences (p<0 05) within the groups as compared to previous measurement

115 ENDOCRINE PROFILES

Pre- and postoperative values (Figure 1-6, Table 6) Preoperative concentration of the circulating hormones (at Tl) were homogeneous in all the three groups. Their patterns in the postoperative phase were also similar in the three groups. In stimulated patients (Groups 1 and 3) plasma BE at T2 was, in contrast to that in Group 2, higher (p<0.01) than at Tl (Group 1: 29.6 pmol.l1, SEM 5.2 vs 7.8 pmol.r, SEM 0.9; Group 2: 8.7 pmol.l1, SEM 2.6 vs 11.1 pmol.l1, SEM 2.9; Group 3: 22.9 pmol.l', SEM 3.4 vs 8.4 pmol.l', SEM 2.2). After intubation (at T3) values increased in Group 2 (p<0.05) when compared to T2 values; this led to disappearance of differences between the three groups at T3.

Peroperative changes

Adrenaline (Figure 1) Plasma A rose significantly in all groups dunng surgery when compared to the Tl values but with the highest level observed in Group 1 (Group 1 vs Group 2, p<0 01. Group 1 vs Group 3, p<0.01. Group 2 vs Group 3, not sigmficant/n.s.).

1 • L-. . . 1 1 '—TV-' ' ' ' ' ' ' Tl T3 T4 T5 T6 T7 ΤΘ T9 TÍO Til ΤΙΞ Т1Э T14 T15 TIB

Figure 1 Plasma adrenaline levels (mean with error bar equal to SEM) Arrow marks the incision time For groups see legend to Table 3 Letters and numbers on the horizontal axis refer to the samples taken at the different stages of anaesthesia and surgery according to Table 1 The per- and postoperative differences of mean responses from the preinduction levels at Tl are given by ρ values Star indicates a significant difference (p<0 05) between the groups

Noradrenaline (Figure 2) Plasma NA rose significantly dunng surgery in all groups when compared to the Tl values, however, significant differences in the profiles of the groups did not exist.

116 ЪЛ -* ,Л — шт. W-_ϋ„ _ f 1 ι-h ο α : 1 5 η . > : Ξ Í + : \ ,-,-Π Ρ? ι ^ \ : 3 \ ι· \ τ \ \ 3 τ / ^Ч ' χ ' ^^^^ч, /i*—ΤΡ^ν τ y У 1 ^^^5?! //•-// ' -*-ι ' 1i^fe rSt-L^ τ/'χ /^Τ 4 ί \_^

. L , , , , ^ye-. Tl ТЭ Т4 Т5 ТБ Т7 Т ТЭ TÍO TU TIS T13 T14 T15 Т1Б Figure 2. Plasma noradrenaline levels. For the symbols see legend to Figure 1.

ACTH (Figure 3). During surgery plasma ACTH rose in all groups (p<0.01) when compared to the Tl values but with the highest levels observed in Group 1 (Group 1 vs Group 2, p<0.01, Group 1 vs Group 3, p<0.01, Group 2 vs Group 3, n.s.). ACTH Cpmol.l-1)-

ΞΟ

т -1- Tl T3 T4 T5 T6 T7 Т T9 TÍO Til TIE Т1Э T14 T15 T16

Figure 3. Plasma ACTH levels. For the symbols see legend to Figure 1.

ß-Endorphin (Figure 4). During surgery plasma BE increased in all groups (p<0.01) when compared to the Tl values but with the highest level observed in Group 1 (Group 1 vs Group 2, p<0.01) Group 1 vs Group 3, p<0.01, Group 2 vs Group 3, n.s.).

117 β—Endomphin Cpmol.l ^)-

БО

го

Tl T3 -Г4 T5 ТБ T7 TB T3 TÍO Til TIE T13 T14 T15 T16

Figure 4. Plasma BE levels. For the symbols see legend to Figure 1.

ADH (Figure 5). During surgery plasma ADH increased in either group (p<0.01) when compared to the Tl values but with the highest level was observed in Group 1 (Group 1 vs Group 2, p<0.01, Group 1 vs Group 3, p<0.01. Group 2 vs Group 3, n.s.).

Antidiui-etic hormone Cpmol.l *) BOO

4QQ

BOO

Tl T3 T4 T5 ТБ T7 Т ТЭ TÍO Til TIS Т1Э T14 T15 T16

Cortisol (Figure 6). During surgery plasma Cortisol rose without exception in all groups (p<0.01) when compared to the Tl values, however, significant differences in the profiles of the groups did not exist.

118 о.э

D.7

0.5

О.З TI ТЭ Т4 Т5 TG Т7 ТВ ТЭ TÍO Til ΤΙΞ Т1Э Т14 Т15 TIG

Figure 6 Plasma Cortisol levels For the symbols see legend to Figure 1

Table 6 Postoperalive hormone levels of ACTH (pmol 1 ') and Cortisol (μιτιοί 1 ') at 8am For Groups see legend to Table 3

Sampling Value Group Group code 1 2 3 1 2 3 ACTH Cortisol

T17 mean 33 59 34 0 48 0 52 051 sem 06 33 14 0 06 0 03 0 07 mm 20 20 01 0 20 0 23 0 18 max 93 31 8 17 6 0 85 0 66 0 92

Τ 18 mean 30 27 29 041 0 48 0 55 sem 05 03 06 004 0 05 0 06 mm 20 20 10 0 26 0 26 0 22 max 77 48 7 1 0 82 081 0 87

Τ 19 mean 24 22 28 041 0 46 0 52 sem 02 02 09 0 03 0 03 0 05 mm 20 20 10 0 30 0 20 0 15 max 41 34 10 5 0 59 0 61 0 76

Τ 20 mean 3 1 24 21 0 45 040 0 53 sem 04 02 05 0 03 0 03 004 mm 20 20 10 031 0 21 031 max 55 33 72 0 65 051 0 75

No differences between the groups existed

119 Discussion

From the practical point of view and in contrast to the most trials on drugs, it was impossible to carry out the present study in a double-blind fashion, even for a short period until incision. First, the stimulation of ear acupoints is quickly followed by erythematous changes of the ears which can be observed readily. Secondly, stimulation causes a small artifact on the ECG monitor which may easily be recognized also. Bias was minimized by ensuring that the study was randomized and was performed as single-blind. The patients, the surgeons, the personnel within the operating theater as well as the laboratory personnel were not aware as to which anaesthetic group the patients belonged. Also, the anesthetists were blinded as to the results of the laboratory work until all measurements were finished and decoded. It was decided to exclude the data of one non-responder patient in the Group 1, who consumed fentanyl to an extent about equal to those in Groups 2 or 3, since this patient may behave as the latter Groups. Electrostimulation percutaneously (by acupuncture) and transcutaneously (via skin surface electrodes) lowers the analgesic requirement in major abdominal surgery. In two earlier studies (4, 5) the analgesic requirement in surgery with balanced anaesthesia or acupuncture stimulation was compared. In open heart surgery Hollinger, et al. (4) reported an impressive lowering of the amount of fentanyl needed. Schaer (5) estimated that the amount of fentanyl needed in various gynaecological surgical procedures with the use of electrostimulation of ear acupoints decreased substantially. In none of these and other studies (12-15), however, randomization of the patients and standardization of the surgical procedures were properly used. The surgical procedure goes along with periods of frequent traction on the peritoneum, mobilization of large masses of abdominal viscera and exploration and excision of lymph nodes along the larger abdominal vessels and the sympathetic ganglia. These rather painful, nociceptive procedures clearly activated the endocrine adrenomedullary and the pituitary-adrenocortical systems as illustrated by significant rises in the circulating levels of A on the one hand, and those of BE, ACTH and ADH on the other. These signs of surgical stress unequivocally occurred in all the three groups of patients, two of whom underwent electrostimulation. Although the circulating levels of NA and Cortisol rose significantly in all groups throughout surgery, no differences between the groups existed. Literature data have indicated that small doses of diazepam in combination with fentanyl to induce analgesia, as practised in all our patients, suppress the catecholamine response (16). In the presurgical period (Tl until T4) we observed after 15 minutes of stimulation (in Groups 1 and 3) a brisk rise in the levels of circulating BE, but not however in Group 2 without electrostimulation. After intubation (at T3) this difference had disappeared by the rise of the endorphins' levels in Group 2. Thus, electrostimulation has to be considered responsible for the early hyperendorphinaemia in the Groups 1 and 3. It is of interest that these increases left the mean MAP and HR unchanged in these groups. We wonder whether electrostimulation with the thereby induced early hyperendorphinaemia is somehow

120 related to this haemodynamic stability By comparing the data obtained during the surgical procedure (T4-T9) in the three groups, one can discern the effect of moderate-dose of fentanyl, administered to the Groups 2 and 3 on the endocrine stress response. The profiles of A, BE, ACTH and ADH were in these groups significantly lower than in Group 1, in which more than 90% less fentanyl was used It is well-known that high-dose opiate anaesthesia inhibits the endocrine response to surgery (16, 17) Our data illustrate that moderate-dose fentanyl anaesthesia (5 μg kg ' hour ' and 4 μg kg'hour' respectively infused continuously after a bolus of 10 μgkg1) also modifies this response In the postoperative period no significant differences between the profiles of any of the measured circulating hormones were found in the three groups After awakening (at T10) the circulating levels of both catecholamines temporarily rose, while those of the peptide hormones decreased slowly to the levels about equal to those before the induction of anaesthesia (at Tl) None of the changes observed, however, differed significantly between the groups, nor the changes in the late recovery period until four days after Tl.

In conclusion, the use of electrostimulation (via acupuncture needles and skin surface electrodes) as an effective non-pharmacological analgesic procedures in major abdominal surgery appeared to go along with a significantly more pronounced endocrine response, in terms of nsing levels of circulating A, ACTH, ADH and BE, than moderate-dose fentanyl anaesthesia either with (Group 3) or without (Group 2) electrostimulation Postoperatively, no differences in the hormonal profiles could be discerned between the groups with and without electrostimulation (Group 2 vs Group 3) nor between those with or without moderate-dose fentanyl anaesthesia (Group 1 vs Group 3) Thus, electrostimulation can replace moderate-dose fentanyl anaesthesia in major abdominal surgery under the proviso of a more enchanced neuroendoenne stress response to surgery These studies do not provide an intelligible explanation for the analgesic efficacy of the combined electrostimulation via ear needles and skin surface electrodes as practised in these patients The brisk early hyperendorphinaemia observed in the two electrostimulated groups can hardly be considered responsible for the peroperative analgesic effect The differences between the observed peroperative endocrine profiles most probably due to the lack of moderate-dose fentanyl administration in Group 1 does not appear to have any significant effect on the endoenne profiles after stopping electrostimulation and/or fentanyl infusion and awakening the patients.

References

1 Wilmore DW, Long HM, Mason AD, Fruiti BA Stress in surgical patients as a neurophysiologic reflex response Surg Gynaecol Obstr 1976,142 257-269 2 Barton RN The neuroendocnnology of physical injury In Grossman A, ed Bailliere's Clinical Endocrinology and Metabolism Neuroendocnnology of stress London Saunders WB, 1987,1 355-374

121 3 Kehlet H The stress response to anaesthesia and surgery Release mechanism and modifying factors In Moss J, ed Clinics in Anaesthesiology Vasoactive Amines London Saunders WB, 1984,2 315-339 4 Hollmger I, Richter JA, Pongratz W, Baum M Acupuncture anaesthesia for open heart surgery a report of 800 cases Am J Chin Med 1979,1 77-90 5 Schaer H On the quantification of the analgesic-anaesthetic effect of electrostimulation Anaesthesist 1979,28 12-49 6 Hammerle AF, Brücke Τ, Balogh D, Hortnag Η, Leitner E Plasma cathccolamines in open heart surgery and abdominal operations uding a combined electrical stimulation analgesia Anaesthesist 1979,28 523-529 7 Bellmann O, Fntsche K, Hengstmann J, Stoeckel Η Anaesthesia by electrostimulation compared with enflurance-nitrous oxide inhalation anaesthesia on gynaecological operations 2 Endocrinological observations Anasth Intensivther Notfallmed 1984,19 53 56 8 Abdulld W, Cordes U, Sostegno С, Beyer J Frey R, Gartner J Plasma catecholamines under electrostimulation and neuroloept anaesthesia for retina and vitreous body operations Anaesthesist 1979,28 237-242 9 Hoffmann JJML, Willemsen JJ, Lenders JWM Benraad ThJ Reduced imprecision of the radioenzymatic assay of plasma catecholamines by improving the stability of the internal standards Clin Chim Acta 1986 156 221 226 10 Goverde HJM, Pesman J, Smals AGH The bioactivity of immunoreactive ddrenocorticotrophin in human blood is dependent on the secretory state of the pituitary gland Clin Endocrinol 1989 31 255-265 11 Smals AGH, Kloppenborg PWC, Goverde HJM, Benraad ThJ The effect of cyproteronc acétate on the pituitary adrenal axis in hirsute women Acta Endocrinol 1978 87 352-358 12 Grabow L, Cnveanu Τ Combined acupuncture-analgesia as a method in general anaesthesia Anaesthesist 1976,25 231-234 13 Doemcke A, Kampik G, Praetonus В Pitterlmg P, Gob E, Matusczyk U Electrical stimulation anaesthesia in abdominal surgery in special consideration of selective proximal vagotomy Anaesthesist 1976,25 248-256 14 Fischer M, Just OH, Mane D Electrostimulation anaesthesia for surgery of the limbs Anaslh Prax 1979,14 8-13 15 Sawires R, Putz G Klinische Erfahrungen bei Struma-operationen in Sitzlage mit Elektrostimulationsanasthesie Chir Prax 1984 33 407 412 16 Muldoon SM, Moss J, Freas W, Rouen MF The effects of anaesthetics on the sympathoadrenal system In Moss J, ed Clinics in Anaesthesiology Vasoactive Amines London Saunders WB, 1984,2 289-305 17 Giesecke K, Hamberger В, Jamberg PO, Klingstedt С, Persson В High- and low dose fentanyl anaesthesia Hormonal and metabolic responses during cholecystectomy Br J Anaesth 1988,61 575 582

122 CHAPTER 5.4

LACK OF EFFECT OF ACUPUNCTURE AND TRANSCUTANEOUS STIMULATION'S ANALGESIA ON IMMUNOGLOBULIN LEVELS AND LEUCOCYTE COUNTS FOLLOWING MAJOR ABDOMINAL SURGERY

Abstract To determine whether acupuncture analgesia influences the surgically induced suppression of the body's immune system, the changes of immunoglobulins (IgA, IgG and IgM) and total and differential leucocyte counts in the peripheral blood dunng and for six days after surgery were investigated in 42 male patients submitted to a standardized major abdominal operation performed under three different anaesthetic techniques Group 1 received acupuncture and transcutaneous stimulation as the main (non-pharmacological) analgesic during surgery, supplemented by small doses of fentanyl (mean 12 μgkg-l, range 0 0-5 7), Group 2 received moderate-dose fentanyl (22 9 Hg kg ', range 17 5-29 8) and Group 3 received acupuncture and moderate-dose fentanyl (23 6 μgkg1, range 16 5-29 6) All were induced with thiopentone (5 mg kg '), intubated after vecuronium (0 1 mg kg '), and ventilated with 67% nitrous oxide in oxygen Inhalation anaesthesia was not used Surgery was followed by a similar fall of immunoglobulins, lymphocyte and eosinophil counts and a rise in leucocyte and neutrophil counts in the three groups of patients (p<0 01) No recovery was observed until the last assessment on day 6 after surgery for IgA, IgG, leucocyte, neutrophil and lymphocyte counts in all groups, whereas IgM and eosinophil counts recovered by day 4 Monocyte and basophil counts remained unchanged in all groups Acupuncture and transcutaneous stimulation analgesia did not influence the body's immune system either dunng or after surgery as measured by the concentrations of immunoglobulins and total and differential leucocyte counts

Postoperative morbidity, such as delay in wound healing, (pulmonary) infections and occasional rapid dissemination of cancer, has been associated with the alteration in the body's immune system following surgery and anaesthesia (1-3). Despite continued advances in surgical skills and anaesthetic techniques this problem remains unsolved Although it cannot be completely neglected, the influence of general anaesthesia per se on the various immune parameters is thought to be short-lived, reversible and small compared to the surgically induced changes both of the cell-mediated and humoral immunity (2-4) Less immune depression is observed in surgery under regional anaesthesia However, postoperative immunological depression is ultimately comparable to that seen with

123 general anaesthesia (5). Efforts are still being made to determine the anaesthetic technique which will minimize the suppression of the immune system following surgery and anaesthesia and/or speed its return to normal in the postoperative phase. ACAN, introduced in China in 1958, is nowadays also being performed in the West (6, 7). It has been suggested that surgery under ACAN is followed by a lower incidence of postoperative bacterial infections (8). In animal and human studies stimulation of certain acupuncture loci have been reported to modulate both humoral and cellular immunity (9-11). The present study attempted to evaluate the possible influences of acupuncture and transcutaneous stimulation analgesia on immunoglobulins and total and differential WBC counts in the peripheral blood in a standardized major abdominal operation.

Patients and methods

The study was approved by the Ethics Committee of the University Hospital of Nijmegen. Forty two otherwise healthy male patients of ASA class 1 and 2, scheduled for elective major abdominal surgery (i.e. extended retroperitoneal lymph node dissection because of a non-seminomatous testicular tumour) were studied. Patients who required prolonged postoperative artificial ventilation were excluded. Evidence of infection was not observed at the preoperative physical examination, during which informed verbal consent was obtained. Body temperature was normal in all. After fasting overnight, patients were premedicated with diazepam 10 mg orally 90 minutes before induction. After arrival in the anaesthetic room, an i.v. infusion was set up and a radial artery catheter was inserted under local anaesthetic. Four electrocardiograph (ECG) electrodes (3M) were placed paravertebrally and symmetrically between T4 and L2 (i.e. at the levels of T,, T7,

T,0 and L2) corresponding to the dermatomes of the surgical incision (i.e. xyphoid to upper part of pubic bone). They were connected to a Swiss made Doltron ESA 400 stimulator. ECG was monitored continuously (HP 78353 BU). All patients were induced with thiopentone 5 mg.kg ' i.v., intubated after vecuronium 0.1 mg.kg'1, and ventilated artificially (nitrous oxide:oxygen=2:l) to maintain normocapnia. Patients were then allocated to one of three anaesthetic techniques. The Doltron ESA 400 was switched on (10 Hz, 40 mA and 0.5% pulse width) if the patient was in the Groups 1 and 3. In addition, three symmetrical ear acupoints, Fe, Jiaogan and Shenmen were selected for puncture, and the needles were connected to a Chinese-made stimulator WQ-6F. Stimuli at 10 Hz with a pulse width of 0.7 ms were applied, and the maximum output was setting "7" in all cases. Stimulation was continued until the end of the surgical procedure. The Doltron ESA 400 was not switched on nor the ear acupoints punctured, if the patient was in Group 2. Patients in this group but also those who were in Group 3 received fentanyl 10 μg.kg ' as an i.v. bolus 5 minutes before incision and as a continuous infusion at a rate of 5 μg.kg1.hour'' in the first hour and 4 μg.kg''.houг"' thereafter until the surgeon began to suture the skin. Surgery was allowed to commence 30 minutes after the start of stimulation in Groups 1 and 3

124 or 30 minutes after induction in Group 2. Fentanyl 50 \ig i.v. was given to patients in any group at any time during surgery if analgesia was thought to be insufficient as judged by clinical signs, i.e. increase of systolic (SAP) or diastolic pressure (DAP), monitored continuously from an indwelling radial artery catheter and/or heart rate (HR) of more than 25% or the presence of lacrimation, sweating and salivation. No inhalation anaesthesia was used. Muscle relaxation was maintained by a continuous infusion of vecuronium. The rate (2-6 mg.hour"1) was determined by the number of twitches (one to two) of the train of four of the adductor pollicis muscle after supramaximal stimulation at the left wrist of the ulnar nerve through the surface electrodes using a Myotest nerve stimulator continuously. Peroperative colloid and crystalloid solutions 10-15 ml.kg'.hour1 were infused to maintain central venous pressure, monitored through a catheter inserted in the right internal jugular vein, within normal limits. When needed, packed red cells were given. At the end of surgery residual curarisation was reversed by pyridostigmine 5-10 mg i.v. mixed with atropine 0.25-0.5 mg. Postoperative glucose-saline (3.3%/2.5%) solution was infused at a rate of 100 ml.hour"1 in all patients until oral fluid and/or food intake were allowed, which was determined after colon peristalsis had resumed. No parenteral nutrition was given in the entire postoperative phase. Postoperative analgesia was achieved by nicomorphine 0.1 mg.kg' i.m. Arterial blood Vvas drawn on the day of surgery following defined time schedules as presented in Table 1, whereas venous blood samples were collected afterwards through the right internal jugular vein catheter to analyse haemoglobin (Hb) and haematocrit (Hct), immunoglobulins (IgA, IgG and IgM) and total and differential WBC counts. Samples were coded after collection in order to prevent

Table 1. Time schedule for collecting blood samples. Code Time Description

Tl 10 min Preinduction, after insertion of radial artery catheter T2,3 40, 120 min After skin incision T4 End of surgery T5 60 min After the end of surgery T6-11 1-6 days After the end of surgery at 1 p.m. bias by personnel performing the test. Following immediate preparation, i.e. centrifugation and separation, samples were frozen and stored at -20CC until analysis. The concentrations of immunoglobulins were analyzed using the nephelometry method (13), with a sensitivity of 3 lU.ml1 and intra- and inter- assay coefficients of variation less than 3% and 4% respectively. The normal ranges referred to in this study were: IgA:60-200 lU.ml1, IgG:70-170 lU.ml' and for IgM:50-200 lU.ml '. The WBC count was determined with an electronic cell counter and the differential count (100 cells counted in duplicate) was estimated on blood smears fixed with May-Griinwald and stained with Giemsa solution, always by the same person. The normal ranges referred to in this study were: WBGA.O-ll.OxlO'.l1, neutrophils:60-70%, lymphocytes:20-30%, monocytes: 1-5%, eosinophils: 1-4% and basophils:0-2%.

125 Data évaluation Unless otherwise stated all concentrations given below are means and SD Statistical analysis was performed using the SAS-procedures (SAS Ine, Сагу, NC, USA) on a VAX/785 computer. One way analysis of vanance (ANOVA) was used, with subsequent Scheffé multicompansons procedure as appropriate, to test the preoperative homogeneity of the groups and the hypotheses of no effect and no difference between the groups during and after surgery respectively. In all tests p<0 05 was used as the threshold of significance

Results

Forty two patients entered the study; five patients (Group 1· one, Group 2- three and Group 3: one) were withdrawn because of excessive bleeding of more than five litres during the course of surgery, which made postoperative prolonged artificial ventilation necessary, thereby violating the protocol One patient from Group 1, in which aupuncture did not result in analgesia as suggested by haemodynamic changes as indicated in the method section, consumed therefore fentanyl in doses comparable to the patients in Groups 2 and 3. In the final analysis his data were excluded Table 2 shows details of 36 patients included in this study. Except for the dose of fentanyl, the three groups of 12 patients each were comparable. Haemodynamic changes during surgery were also comparable in the three groups.

Tabic 2 Patients demograhic data, peroperative anaesthetic drugs and fluid balance and post operative demand of nicomorphme Group 1, acupuncture and transcutaneous stimulation + low- dose fentanyl, Group 2, moderate-dose fentanyl, Group 3, acupuncture and transcutaneous stimulation + moderate dose fentanyl Mean (SD) values are given Group 1 Group 2 Group 3

Number of patients 12 12 12 Age (year) 24 8 (6 3) 30 0 (9 6) 319 (14 4) Weight (kg) 70 2 (5 6) 78 0 (15 5) 72 4 (9 4) Height (cm) 1817 (3 6) 180 3 (8 2) 181 0 (9 4) Anaesthetic time (h) 4 1 (0 6) 3 8 (0 3) 3 6 (0 7) Surgical time (h) 3 4 (06) 3 1 (04) 2 9 (0 7) Thiopentone (mg kg ') 5 0 (0 3) 5 4 (16) 4 9 (0 2) Vecuronium (mg kg ·> 04 (0 1) 0 3 (0 1) 04 (0 1) Fentanyl ^gkg') 12* (17) 22 9 (2 8) 23 6 (3 3) Fluid + blood loss (ml) 1185 (962) 843 (336) 1181 (737) Colloid infusion (ml) 1154 (335) 1125 (310) 1083 (221) Cnstalloid infusion (ml) 3171 (1074) 3475 (893) 3000 (533) Unne output (ml) 335 (210) 324 (159) 278 (264) Nicomorphme (mg kg1) 09 (05) 0 8 (04) 0 8 (0 6)

Star indicates a significant difference between the groups (p<0 05) One patient in Group 1 received two units and one patient in Groups 2 and 3 one unit of packed cells during surgery respectively. Postoperative values of Hb were similarly lower in all groups (p<0.05), but without signs of anaemia. A minor degree of intravascular haemodilution occurred as indicated by the lower values of

126 Het at T5 and later postoperatively (Table 3) in all patients (p<0.01), but with no significant differences between the groups. Clinical follow up showed that all patients had a satisfactory postoperative course without infection or secondary wound healing.

Table 3 Mean (SD) haematocnt values For groups, see legend to Table 2

Sampling Haematocnt (%) code Group 1 Group 2 Group 3

Tl 0 42 (0 03) 044 (0 05) 0 42 (0 06) T5 0 39* (0 03) 0 41* (0 05) 0 40* (0 06) T6 0 39 (0 04) 0 38 (0 05) 0 37 (0 06) T7 0 38 (0 05) 0 37 (0 03) 0 36 (0 07) T8 0 37 (0 04) 0 36 (0 05) 0 36 (0 06) T10 0 36 (0 03) 0 34 (0 04) 0 33 (0 04) Til 0 36 (0 03) 0 35 (0 04) 0 35 (0 05)

*P<0 05 at T5 compared with TI (ANOVA), but without differences between the groups

Responses of immunoglobulins (Figure I). At Tl IgA and IgG values were comparable in all groups, whereas that of IgM was higher in Group 1 (Group 1 vs Group 2, p<0.05; Group 1 vs Group 3, p<0.05). During surgery immunoglobulins fell similarly in all groups (p<0.01), but without differences between the groups Postoperative values remained below the Tl levels until Tl 1

ia" CIU ml-1)- О—О 1 г ' 1 э 1GO

Figure 1 Mean (with ISO error bar equal to SEM) levels of IgA, IgG and 4 \ .i- t' ' tJ ^ i IgM. Letters and eo numbers on the '— У/*- horizontal axis refer to the samples taken at the different stages of anaesthesia and surgery according to Table 1 At TI a significant difference of means existed between the groups (Group 1 vs Group 2, p<0 05. Group 1 vs Group 3, p<0 05) for IgM

Tl та ТЭ ТЧ ТБ Т7 ТЭ TÍO Til 127 for Ig A and IgG. IgM returned to the Τ1 levels by day 4 and rose above the Tl levels in all groups on days 5 and 6 (p<0.01). Differences between the groups existed neither during nor after surgery.

Responses of WBC and differential counts (Figure 2). At Tl WBC counts were comparable in all groups. Values increased similarly following surgery in all groups and without differences between the groups. Postoperative values, though decreased, remained above the Tl levels until Til. The differential counts in

Figure 2. Levels of total and differential WBC counts For the symbols see legend to Figure 1. Significant differences between the groups did not exist.

, -l·J ,

ι. • ¿,• 4 Ь ' w¿ ^ ^ ^M ¿г M в..« wt..

UW^JOJ τι те та Т4 т? те т· TÍO ти peripheral blood showed similar and comparable response patterns in the three groups during and after surgery. In contrast to the eosinophil counts, which had recovered by day 4, the alteration of neutrophil and lymphocyte counts persisted until Til in the three groups. Monocyte and basophil counts remained unchanged in all groups.

128 Discussion

The present study was conducted to determine the effect of acupuncture and transcutaneous stimulation analgesia on the surgically induced alterations of the immunoglobulins and WBC and differential counts in a standardized elective major abdominal operation (i.e. extended retroperitoneal lymph node dissection for a non-seminomatous testicular tumour). No explanation can be given other than a statistical one as to why control values of IgM (at Tl) differed significantly between the groups. The results show clearly that although the use of acupuncture and transcutaneous stimulation was associated with a considerably lesser dose required of fentanyl, the data failed to reject the hypothesis that no difference existed between the groups with respect to the immune variables during and after surgery. Literature data suggested that the higher the endocrine stress response the more suppressed the immune system during surgery and the longer the period of recovery of immune surveillance after surgery (14). In an earlier study it was shown that the use of lesser exogenous opioids in Group 1 leads to a more pronounced endocrine stress response (chapter 5.3, 15). Nevertheless differences in the immune responses between the three studied groups were not detected. It is therefore concluded that the admittedly limited study of immune variables do not support the above mentioned hypothesis. In non-surgical conditions prolonged presence of antibody in circulation has been shown after needling point Zusanli and gamma-globulin has been reported to increase after needling points Zusanli and Hegu (9, 10, 16). The T-cells' activity of rosette formation in patients operated under classical ACAN with the use of only analgesic loci was reported to be more enhanced compared with that under epidural anaesthesia (8). Moreover, a more rapid recovery of the surgically induced suppression of immunoglobulins and differential WBC counts in the peripheral blood has been observed in patients undergoing thyroid surgery performed under classical ACAN, i.e. patients remaining fully conscious during surgery (chapter 4.3, 17). The use of i.v. anaesthetics and the extended surgical trauma in the present study may have overruled the reported modulating effects of acupuncture. Besides, the present study was a part of a clinical study which aimed at broad evaluation of the use of peroperative non-pharmacological analgesia, its possible beneficial influence on the recovery and morbidity (chapter 5.2, 18) and the patterns of hormonal response (chapter 5.3, 15). Within that study design the acupuncture loci used were selected primarily because of the described analgesic but not the surmised immunological effects. The suggested beneficial effects of regional anaesthesia on the immune system required its extension to the postoperative period. It is tempting to speculate that similar results might be obtained when the use of acupuncture and stimulation analgesia was prolonged postoperatively rather than limited into the peroperative phase. This view is supported by the well- known endorphins' release by acupuncture (19-22) and the fact that endorphins have been reported to have an immunostimulatory effect (23-25). This aspect merits further study. Despite the evidence of malignancy, preoperative values of immunoglobulins

129 and those of total and differential WBC counts in the three groups were within the normal range for healthy subjects. In accordance with earlier investigators (3, 26-28), an initial but significant decrease of immunoglobulin levels, leucocytosis due to neutrophilia, lymphopenia, eosinopenia and unchanged monocyte and basophil counts during surgery was found, thus rejecting the hypothesis of no effect. Although protein concentrations were not available, it is libely that the disruption of the intravascular equilibrium due to blood and fluid loss, as well as the concomitant infusion of crystalloid and colloid, resulted in haemodilution and increase in plasma volume which contributed to the demonstrated lower levels of immunoglobulins. The fall of Hct at T5 supports this view. The postoperative reduction of immunoglobulin levels from preoperative values agreed with previously published data (3, 27). The present study was, however, unable to confirm the reported further postoperative decrease in immunoglobulin levels (27). Two factors are suggested to have affected the results. First, postoperative alterations in the vascular permeability of injured tissues would be expected to develop as seen in severe burned patients (3, 26). If this is true, this mechanism could be responsible for the protein loss into the interstitial space, thus lowering the postoperative immunoglobulin levels. Secondly, a disturbance in postoperative immunoglobulin synthesis due to the suggested inhibitory effects of stress hormones, catecholamines and Cortisol in particular, which levels are elevated during surgery, should be considered (3). However, since the biological half-life of immunoglobulins is several days, the contribution of the mentioned mechanism to the observed lower levels was minor, especially early in the postoperative phase. The recovery of IgM on day 4 and its elevated values on days 5 and 6 (p<0.01) were in accordance with an earlier study in surgery for non-malignant pathology (27). The severity of trauma is said to be the most important factor causing postoperative changes of leucocyte and differential counts (3) resulting in the redistribution of lymphocytes due to the neurohumoral responses induced by surgery. So far humoral stress responses have been assumed to be responsible for the mentioned changes. Specifically, suppression of the number of lymphocytes and the corresponding B- and T-cells as well as neutrophilia are well-known effects of glucocorticoids, the levels of which increased during surgery. Although lymphopenia developed, its function as host defence has been reported to improve under the influence of other stress hormones such as BE, PRL and GH both in animals and humans (23, 29). Evidence has accumulated that this is the case for T-cell rosette formations, NKC activity and mononuclear Chemotaxis (23, 25, 28, 30). Thus, lymphopenia would concur with qualitative improvement of immune functions. The complexity of the interactions between pituitary hormones and the immune system and their clinical implications need, however, to be further clarified.

In conclusion; Acupuncture and transcutaneous stimulation analgesia performed for major abdominal surgery did not discemibly influence the body's immune system as measured by the concentrations of immunoglobulin and total and differential WBC counts.

130 References

1 Watkins J How important are post-operative changes in immunological parameter'' Clin Res Rev 1984,4 133-137 2 Moudgil GC Update on anaesthesia and the immune response Can Anaesth Soc J 1986,33(Suppl) S54-S60 3 Salo M Effects of anaesthesia and surgery on the immune response In Watkins J, Salo M, eds Trauma, Stress and Immunity in Anaesthesia and Surgery London/Boston Buttenvorth Scientific, 1982,211-253 4 Meakins JL Host defense mechanisms in surgical patients Effect of surgery and trauma Acta Chir Scand 1988,550(Suppl) 43-53 5 Kehlet H, Wandall JH Hjortso NCh Influence of anesthesia and surgery on immunocompetence Reg Anesth 1982,7(Suppl) S68-S74 6 Kho HG, Maas Ρ, Kerkkamp Η, Drent M, Kippersluis E, Egmond van J Haemodynamische Wirkungen der kombinierten Akupunkturanasthesie bei abdomineller urologischer Chinirgie Dtsch Ztschr Akup 1987,30 60-64 7 Fntsche К Electrostimulation anaesthesia compared with enflurane-nitrous oxide in gynaecological operations 1 Clinical observations Anaesth Intensther Notfallmed 1984,19 49-52 8 Wu JL, Zong AM, Chai ΧΜ, Cai DH, Luo HM, et al Effects of electroacupuncture on cell- mediated immunity in human body In Zhang XT, ed Research on Acupuncture, Moxibustion and Acupuncture Anesthesia Beijing/Berlm Science Press and Springer Verlag, 1986,568-573 9 Chu YM, Affronti LF Preliminary observations on the effect of acupuncture on immune responses in sensitized rabbits and guinea pigs Am J Chin Med 1975,3 151-163 10 О Connor J, Bensky D A summary of research concerning the effects of acupuncture Am J Chin Med 1975,3 377-394 11 Zhao J, Liu W Relationship between acupuncture-induced immunity and the regulation of central neurotransmitters in the rabbit I Effect of central catecholaminergic neurons in regulating acupuncture-induced immune function Acupunct Electrother Res 1988,13 79-85 12 Lin GF Anaesthesiology In Wu HG, Ran RT eds Modem Chinese Medicine, vol 1 Chinese Surgery, A comprehensive review of surgery in the People's Republic of China Lancaster/Beijing MTP Press Ltd and the People's Med Pub House, 1984,239-254 13 Renckens ALJM, Jansen MJH, van Munster PJJ, Weemaes CRM, Bakkeren JAJM Nephelometry of the kappa/lambda light-chain ratio in serum of normal and diseased children Clin Chem 1986,32 2147 2149 14 Lecky JH Anesthesia and the immune system Surg Clin N Am 1975 55 795-799 15 Kho HG, Kloppenborg PWC, J van Egmond Effects of acupuncture and transcutaneous stimulation analgesia on plasma hormone levels during and after major abdominal surgery Companson of three anaesthetic techniques Submitted 16 Rogora GA, Morelli R, Sacchetti E, Fngoli D Einige hamatochemische Veränderungen im verlauf von akupunktur vorlaufige Mitteilungen In Bischko J, ed Akupunktur und Aunkulotherapie Kongressbencht der zweiten ftanzosisch-italiemsch-osterreichischen Tagung in Wien Wien Verlag H Egermann, 1976,111-115 17 Kho HG, van Egmond J, Zhuang CF, Zhang GL, Lm GF The patterns of stress response in patients undergoing thyroid surgery under acupuncture anaesthesia in China Acta Anaesthesiol Scand 1990,34 563-571 18 Kho HG, Egmond van J, Eijk RJR, Kapteyns WMMJ Acupuncture and transcutaneous stimulation analgesia in companson with moderate-dose fentanyl anaesthesia in major surgery Clinical efficacy and influence on recovery and morbidity Anaesthesia 1991 (in press) 19 Cheng RS, Pomeranz BH Electroacupuncture analgesia is mediated by stereospecific opiate receptors and is reversed by antagonists of type I receptors Life Sci 1980,26 631-638 20 Han JS, Xie GX Dynorphin Important mediator for electroacupuncture analgesia m the spinal cord of the Rabbit Pain 1984,18 367-376 21 Pert A, Dionne R, Ng L, Bragin E, Moody TW, Pert CB Alterations in rat central nervous system endorphins following transauncular electroacupuncture Bram Res 1981,224 83-93

131 22 Sjolund В, Teremus L, Enkson M Increased cerebrospinal fluid levels of endorphins after electroacupuncture Acta Physiol Scand 1977,100 382-384 23 Bateman A, Singh A, Krai T, Solomon S The immune-hypothalamic-pituitary-adrenal axis Endocr Rev 1989,10 92-112 24 Faith RE, Liang HJ, Murgo AJ, Plotmkoff NP Neuroimmunomodulation with enkephalins Enhancement of human natural killer (NK) cell activity in vitro Clin Immunol Immunopath 1984,31 412-418 25 Froehch CJ, Bankhurst AD The effect of ß-endorphin on natural cytotoxicity and antibody dependent cellular cytotoxicity Life Sci 1984,35 261-265 26 Rem J, Saxtrup Nielsen O, Brandt MR, Kehlet H Release mechanisms of postoperative changes in various acute phase proteins and immunoglobulins Acta Chir Scand 1980,502 SI SÓ 27 Ryhanen Ρ Effects of anesthesia and operative surgery on the immune response of patients of different ages Ann Clin Res 1977,9(Suppl 19) 1-75 28 Tonnesen E, Bnnklov MM, Chnstensen NJ, Olesen AS, Madsen Τ Natural killer cell activity and lymphocyte function during and after coronary bypass grafting in relation to the endocrine stress response Anesthesiology 1987,67 526-553 29 Hiestand PC, Mekler P, Nordmann, R, Gneder A, Permongkol С Prolactin as a modulator of lymphocyte responsiveness provides a possible mechanism of action for cyclosponn Proc Natl Acad Sci USA 1987,83 2599-2603 30 Gilman SC, Schwartz JM, Milner RJ, Bloom FE, Feldman ГО ß-Endorphin enhances lymphocyte proliferative responses Proc Natl Acad Sci USA 1982,79 4226-4330

132 CHAPTER 6

FINAL COMMENTS

The use of classical acupuncture anaesthesia (ACAN) in Nanjing, China, allowed effective thyroid surgery on conscious patients with stable haemodynamics, per- and postoperatively, and rapid convalescence without significant postoperative morbidity ACAN, as the main analgesic component of balanced anaesthesia in Nijmegen, the Netherlands, allowed the performance of one of the most painful major abdominal procedures, retroperitoneal lymph node dissection This led to rapid recovery without hypercapnia, and without any discernible effect on convalescence and postoperative morbidity There is frequent traction on the peritoneum during this procedure with mobilization of large masses of abdominal viscera and exploration and excision of lymph nodes along the larger abdominal vessels and the sympathetic ganglia It has been shown that ACAN decreased the amount of the exogenous opioid (fentanyl) needed to less than 10% of that necessary in balanced anaesthesia without acupuncture and transcutaneous stimulation No per- or postoperative haemodynamic differences between the three groups of patients studied were observed despite the large differences in the amounts of exogenous opioids used In the preoperative phase, before laryngoscopy and intubation, electrostimulation of paravertebral and ear acupoints did not give nse to changes in haemodynamics, whereas the levels of the circulating ß-endorphin (BE) rose

P-Endor-phin Cpmol.l -l1Ji

» p<0.05 ЭО

ΞΟ

τι та тэ τι ΤΞ тз τι та тэ Figure 1 Preoperative plasma ß-endorphin levels (mean with error bar equal to SEM) 1, acupuncture and transcutaneous stimulation with supplementation of small-dose fentanyl, 2, moderate dose fentanyl, 3, acupuncture and transcutaneous stimulation plus moderate-dose fentanyl, Tl, before induction of anaesthesia, T2, 15 minutes after induction and the start of electrostimulation of paravertebral and ear acupoints, T3, 5 minutes after intubation Star indicates differences (p<0 05) between and within the groups

133 briskly (Figure 1). Laryngoscopy and intubation led to similar increases in arterial pressure and heart rate in all three groups. Thus, endogenous opioids as released in these studies had no effect on the cardiovascular response to laryngoscopy and intubation. The data of these studies obtained in healthy and relatively young women and men (Nanjing: mean age, 38.8 year, SD 11.5; sex ratio, F/M: 18/2; Nijmegen: mean age, 28.9 year, SD 10.7; sex ratio, F/M: 0/36) illustrates that arterial pressure and heart rate remains virtually unchanged either during thyroid surgery under classical ACAN (in China) or in major abdominal surgery under balanced anaesthesia with or without electrostimulation, and, with or without regular doses of exogenous opioids (in the Netherlands). Thus, neither exogenous fentanyl nor endogenous opioids as used or released in these studies had any effect on the cardiovascular response. Thyroid surgery under classical ACAN in China, with patients remaining conscious, led to an endocrine stress response qualitatively similar to that in major abdominal surgery in the Netherlands under balanced anaesthesia in combination with ACAN with patients being unconscious during surgery. These observations suggest that it is surgery itself rather than pain that elicits the stress responses. The use of electrostimulation as an analgesic in major abdominal surgery led to a significantly more pronounced endocrine stress response in terms of rising levels of adrenaline (A), ACTH, ADH and BE than moderate-dose fentanyl anaesthesia either with or without electrostimulation, whereas the responses of noradrenaline (NA) and Cortisol were similar. This enhanced endocrine stress response is probably due to much lower exogenous opioid levels in the patients in whom electrostimulation served as the main (non-pharmacological) analgesic. Morphine- like opiates such as fentanyl are known to dampen the hypothalamo-pituitary as well as the sympatho-adrenomedullary stress axes in vivo (1). In thyroid surgery under classical ACAN in China, a decrease of the number of circulating neutrophils coincided with a rise in the number of lymphocytes within the first 30 minutes of surgery. These, not previously reported, changes were followed by a neutrophilia and lymphopenia. In the surgical procedure in the Netherlands, this early neutropenia and lymphocytosis was not observed. Neutrophilia and lymphopenia occurred as usual in situations of a powerful endocrine stress response. The changes in the levels of the circulating immunoglobulins were essentially similar in China and the Netherlands. Decreases in their concentrations during surgery were followed by recovery thereafter; in the conscious Chinese patients who underwent less invasive surgery, within one day, and in the Netherlands, after more invasive surgery in unconscious patients restoration of normal levels of immunoglobulins took place four or more days after surgery. Literature data suggests that a "deep" anaesthetic, most probably due to lesser response of the endocrine stress hormones, results in less immune depression than does "light" anaesthesia (2). The use of less exogenous opioids, in these studies, led to a more pronounced endocrine stress response intraoperatively. Nevertheless, differences in the immune responses between the three studied groups were not detected per- and postoperatively. It is therefore concluded that the results of these studies do not support the hypothesis that a greater stress response to surgery leads to greater immune depression.

134 In the literature there is much debate over the value or harm of the stress response to surgery. Endocrine (and immune) stress responses are considered to be physiological reactions of the body to injury, e.g., surgery. The data seem to indicate that the use of regular doses of exogenous opioids, as used in balanced anaesthesia, partially dampens the endocrine stress responses. The hypothesis has been put forward that inhibition of these surgically induced stress responses may reduce postoperative morbidity (3). The data of this thesis do not support this hypothesis. The present studies indicate that acupuncture and electrostimulation can almost completely replace the use of exogenous opioids in balanced anaesthesia for even major abdominal surgery. It is doubtful whether the brisk hyperendorphinaemia observed shortly after starting electrostimulation in the Dutch patients before laryngoscopy and intubation is responsible for this phenomenon, since in the Chinese patients a similar hyperendorphinaemia was not observed. The results do not allow further speculation on the mechanisms by which acupuncture and electrostimulation led to analgesia. One might suggest that measurements of simple haemodynamic functions, circulating levels of hormone levels and simple immune parameters are unable to monitor or clarify the subtle changes in the complicated, and for the greater part, unknown nervous systems involved in nociception and its translation into reactions which supposedly help to keep body and mental integrity. A Western cynic, who still intends to repudiate the potential of acupuncture and elecrostimulation in to-day's and to-morrow's anaesthesia (and medicine in general), might comment on the present studies by arguing that the results could simply be explained by the assumption that the use of exogenous opiates in Western medicine by anaesthetists is based on rather poor - albeit practical - indicators of the degree of analgesia needed. This would suggest that the amounts of exogenous opiates regularly in use in anaesthetic practice are far greater than necessary to fulfil analgesic requirements. There does not seem to be any evidence for this in these studies. Acupuncture and electrostimulation in these studies clearly reduced intraoperative opiate requirements and had no harmful effect on the postoperative morbidity when compared to a standard anaesthetic technique. Indeed, the patients who received electrostimulation and acupuncture wakened more quickly and had less C02 retention than the patients who received moderate-dose fentanyl. Further work clearly needs to be done to see if any other beneficial effects of acupuncture can be elicited.

References

1. Bolloux PG. Cardiovascular responses to stress: the role of opioid peptides. In: Grossman A, ed. Clinical endocrinology and metabolism. Neuroendocrinology of Stress. London: Bailliere Tindall, 1987;1:439-465. 2. Lecky JH. Anesthesia and the immune system. Surg Clin N Am 1975:55:795-799. 3. Kehlet H. The stress response to surgery: releasing mechanisms and the modifying effect of pain relief. Acta Chir Scand 1988;550(Suppl):22-28.

135 SUMMARY

The Prologue starts with a discussion of the number of problems that had to be overcome before the clinical studies presented in this thesis could be carried out. These were mainly to do with the "alternative" nature of the subject to be studied and the fact that a part of the study had to be carried out in China.

The aim of the present study is summarized as follows: 1. to observe whether or not classical acupuncture anaesthesia had been revised since its introduction in 1958, 2. to observe and analyse the clinical efficacy of classical acupuncture anaesthesia and its influence on the recovery, convalescence and morbidity in thyroid surgery, 3. to describe how, and to what extent classical acupuncture anaesthesia may influence the surgically induced patterns of hormonal and immunological variables during and after thyroid surgery, 4. to answer whether or not the reduction of opioids associated with the use of modified acupuncture anaesthesia implied the loss of stable haemodynamics during major abdominal surgery and whether it led to a different demand for postoperative opioids, 5. to evaluate whether or not modified acupuncture anaesthesia in major abdominal surgery reduces perioperative blood loss and/or to what extent it affected the recovery, convalescence and morbidity, 6. to evaluate the influence of modified acupuncture anaesthesia on the surgically induced pattern of the hormonal and immunological responses during and after major abdominal surgery.

Chapter 1 represents a review of the literature on the mechanisms of acupuncture analgesia. Although evidence for the morphological structure of acupoints and meridians is still controversial, much data exists that supports the involvement of the peripheral and various parts of the central nervous system in mediating acupuncture analgesia. The mechanisms of acupuncture analgesia are brought about by changes in neuronal activity at different levels of the central nervous system following certain types of afferent discharges. This is a very complicated phenomenon with many transmitters and modulators likely to be involved. Segmental and non-segmental pain inhibitory systems can be selectively activated depending on the stimulation variables and the location of the chosen points. Both opioid and non-opioid analgesia systems are involved in mediating acupuncture analgesia. Following needle insertion and stimulation, the peripheral afferent pathways carrying acupuncture impulses, viz. group II nerve fibres (or Aß) and group III nerve fibres (or Αδ), are activated. The impulses are transmitted via the spinal cord anterolateral tract to reach the hypothalamo-pituitary system, which releases ß-endorphin into blood and cerebrospinal fluid, and the periaqueductal grey matter, which then develops two actions; viz. it releases met-enkephalin and ß- endorphin to suppress the transmission of nociceptive information and to activate

136 the raphe nuclei, leading to the activation of the descending inhibitory system. This system runs from the raphe nuclei to the spinal cord dorsal hom neurones through the dorsolateral tract. This results in an inhibition of the dorsal hom cells receiving the nociceptive impulses using the neurotransmitters serotonin and noradrenaline and the neuropeptides met-enkephalin and dynorphin. Also, a meso- limbic loop of analgesia, releasing met-enkephalin and serotonin, is brought into play at the supraspinal level. Thus, analgesia elicited by acupuncture occurs as a result of activation of the spinal cord, the periaqueductal grey matter and the hypothalamo-pituitary system leading to an inhibition of incoming nociception.

Chapter 2 describes the characteristics of the response of the body to anaesthesia and surgery. Noxious and other stimuli from damaged tissues activate the sympathetic system and the hypothalamus to secrete releasing hormones and thus stress hormones. This is thought to be a physiological reaction of the body to injury. The immune response of the body involving the humoral and cellular components, is also altered. The magnitude of neuroendocrine and immune responses is proportional to the degree of trauma. The interactions of the stress hormones and immune system are complex, and much remains to be clarified. Stress hormones have probably a regulatory function on the immune system, on which they can exert an inhibitory and an excitatory effect. Activated leucocytes and their products can secrete adrenocorticotropic hormone and ß-endorphin either directly or via the hypothalamo-pituitary axis by activating corticotrophin releasing hormone. The role played by different anaesthetics and acupuncture in modifying the responses of stress hormones and immune variables is reviewed.

Chapter 3 describes the technique of blood sampling and methods of determination for each of the blood indices. To avoid incorrect interpretation of the results, a number of procedures were employed, such as standardization of the sampling procedure and analyzing of samples for each parameter from each patient, at the same time.

Chapter 4 begins with the description of the situation of the medical services in China in the fifties, shortly after the end of the civil war (chapter 4.1). Shortage of manpower, hospitals and equipment led to a policy that was based on self sufficiency. The importance of integration of traditional Chinese medicine with Western medicine was stressed, since the overwhelming majority of the population were obtaining medical care from traditional Chinese medicine doctors. Priority was given to a more equal distribution of health resources. Within anaesthesia, the outlined policy resulted in an increasing number of qualified anaesthetists, a domestic supply of most of the equipment, an identification of some herbal anaesthetics and the introduction of acupuncture as an anaesthetic. A prospective observational study is described in 20 consecutive patients scheduled for thyroid surgery under classical acupuncture anaesthesia. Patients were followed pre-, per- and postoperatively until their discharge from hospital. Premedication consisted of 10 mg diazepam orally. Peroperative analgesia was obtained by electrostimulation of four ear acupoints on the same side as the

137 adenoma or thyroid lobe to be removed. Based on clinical signs (arterial pressure respiratory rate and heart rate) and the pain scores, small doses of pethidine up to 1 mg.kg ' were given intravenously. Patients remained conscious during the entire operation. In chapter 4.2, the clinical results are described: acupuncture anaesthesia did not provide complete analgesia. However, stable haemodynamics were shown per- and postoperatively with the minimum use of adjuvant drugs, when compared to the literature data on the use of anaesthetics in thyroid surgery performed under local anaesthesia. The recovery was rapid and complication free. The technique was acceptable to the patients, anaesthetists and surgeons. In chapter 4.3, data of pre-, per-, and for six days postoperative hormone and immune measurements are described. Plasma levels of stress-hormones increased significantly during surgery, whereas a decrease of immunoglobulins was noted. A leucocytosis occured but its composition was different when compared to data of thyroid surgery under general anaesthesia. During classical acupuncture anaesthesia, a decreased percentage of neutrophils and an increased percentage of lymphocytes were noted, whereas during general anaesthesia an increased percentage of neutrophils and a decreased percentage of lymphocytes were observed. The reason for this difference is not known. Also, the recovery to preoperative levels of leucocyte and differential counts as well as those of immunoglobulins were more rapid in this study when compared to data of thyroid surgery under general anaesthesia.

Chapter 5 describes first the development of modified acupuncture anaesthesia in the West (chapter 5.1). In selected patients, classical acupuncture anaesthesia was initially performed. However, some major objections to its routine use led to a modification of classical acupuncture anaesthesia; it was introduced for its pain relieving effect in balanced anaesthesia. A prospective study is described in 42 patients scheduled for retroperitoneal lymph node dissection. Patients were followed pre-, per- and postoperatively until their discharge from hospital. Premedication consisted of 10 mg diazepam orally. Patients were allocated to one of the three balanced anaesthetic groups. In Group 1, percutaneous electrostimulation of three symmetrical ear acupoints and transcutaneous electrostimulation of four symmetrical paravertebral acupoints were used as the peroperative main non-pharmacological analgesic. Group 2 received moderate-dose fentanyl (intravenous bolus of 10 μg.kg"' given 5 minutes before surgical incision, followed by a continuous infusion at a rate of 5 μg.kg"' in the first hour and 4 μg.kg ' thereafter until the surgeon began to suture the skin). Group 3 received a combination of the methods used in the Groups 1 and 2. Thus, analgesia in Group 3 was obtained by percutaneous electrostimulation of three symmetrical ear acupoints and transcutaneous electrostimulation of four symmetrical paravertebral acupoints as well as moderate-dose fentanyl. In all groups, small doses of fentanyl 50 μg were given intraveneously, based on clinical signs of insufficient analgesia. Intramuscular nicomorphine 0.1 mg.kg' was available for analgesia postoperatively in all patients. The study was carried out in a single-blind fashion. The patients, the surgeons, the personnel within the operating theatre, the evaluators outside the operating theatre as well as the

138 laboratory personnel were not aware as to which anaesthetic group the patients belonged. Also, the anaesthetists were blinded as to the results of the laboratory work until all measurements were finished and decoded. In chapter 5.2, the clinical results of Groups 1 and 2 are compared. The clinical results of Group 3, which were not described in the published article, did not differ from those of Group 2. With a minimal use of fentanyl (Group 1: 1.2 μg.kg1, SD 1.7; Group 2: 22.9 μg.kg1, SD 2.8; Group 3: 23.6 μg.kg-' SD 3.3) haemodynamic functions were kept stable during and after surgery in Group 1 and a more rapid recovery without hypercapnia in the first three hours was demonstrated in Group 1 when compared to Groups 2 and 3. There were no other differences in the postoperative course in all groups. In chapter 5.3, data of pre-, per- and for four days postoperative hormone measurements are described. Samples were coded after collection. The effect of laryngoscopy and intubation on the plasma ß-endorphin level and haemodynamic functions was investigated. Electrostimulation of ear and paravertebral acupoints releases, within 15 minutes, ß-endorphin without concomitant changes in arterial pressure and heart rate. Laryngoscopy and intubation also leads to a rise in ß- endorphin levels by about the same amount as electrostimulation alone. This increase, however, is accompanied by an increase in arterial pressure and heart rate. The use of electrostimulation as an effective non-pharmacological analgesic in major abdominal surgery allows a significantly more pronounced endocrine response, in terms of rising levels of circulating adrenaline, adrenocorticotropic hormone, antidiuretic hormone and ß-endorphin, than moderate-dose fentanyl anaesthesia either with or without electrostimulation, whereas the responses of noradrenaline and Cortisol were similar. Thus, the similarity in the profiles of noradrenaline and Cortisol on the one hand and the difference in the profiles of adrenaline, adrenocorticotropic hormone, ß-endorphin and antidiuretic hormone on the other do not justify the statement that the more pronounced stress response during modified acupuncture anaesthesia (Group 1) is due to insufficient analgesia or inadequate anaesthesia. Postoperatively, no differences in the hormonal profiles could be discerned between the groups with and without electrostimulation or between those with and without moderate-dose fentanyl anaesthesia. The differences between the observed peroperative endocrine profiles, most probably due to the lack of moderate-dose fentanyl administration, does not appear to have any significant effect on the endocrine profiles after stopping electrostimulation and/or fentanyl infusion and wakening the patients. In chapter 5.4, data of pre-, per-, and for six days postoperative immune variables are described. Samples were coded after collection. Similar and typical response patterns of immunoglobulins and leucocyte and differential counts per- and postoperatively were demonstrated in the three anaesthetic groups. Significant differences between the groups with and without electrostimulation or between those with and without moderate-dose fentanyl were not detected.

139 To conclude: 1. Classical acupuncture anaesthesia, as routinely used nowadays in China, has undergone some revision. Preoperative psychological preparation and/or testing whether or not the pain threshold is sufficiently elevated by acupuncture are no longer necessary.

2. Thyroid surgery under classical acupuncture anaesthesia, which does not provide complete analgesia, is acceptable to patients, anaesthetists and surgeons in China. The technique is safe and can be used when no general or local anaesthetic facilities are available.

3. The observed changes in a number of endocrine and immune variables during and after thyroid surgery in China under classical acupuncture anaesthesia are generally similar to those reported in the literature under general anaesthesia in the West where much higher doses of opioids were used. These results strongly suggest that acupuncture anaesthesia mimics the activity of opioids in their endocrine and immune effects in thyroid surgery.

4. The use of modified acupuncture anaesthesia in retroperitoneal lymph node dissection is capable of maintaining stable per- and postoperative haemodynamics with rapid recovery without hypercapnia. Postoperative demand for opioids is unchanged. Any other clinically relevant disadvantages attributable to the method, although carefully searched for, were not demonstrated.

5. Modified acupuncture anaesthesia does not abolish the cardiovascular response to laryngoscopy and intubation. ß-Endorphins have no effect on the heart rate or arterial pressure and do not diminish the cardiovascular response to laryngoscopy and intubation.

6. The use of modified acupuncture anaesthesia in retroperitoneal lymph node dissection lowers the intraoperative need of analgesic opioids dramatically and is accompanied by a more pronounced increase in adrenaline, adreno corticotropic hormone, ß-endorphin and antidiuretic hormone levels, but with a comparable response of noradrenaline and Cortisol. Postoperatively, no differences in the hormonal profiles could be discerned between the groups with and without electrostimulation or between those with and without moderate-dose fentanyl.

7. The use of modified acupuncture anaesthesia in retroperitoneal lymph node dissection does not influence the body's immune system during or after surgery as measured by the concentrations of immunoglobulins and total and differential white blood cell counts. Thus, the intraoperative, more pronounced, increase in stress hormones seen in the modified acupuncture anaesthetic group did not lead to any difference in the immune response per- or postoperatively when compared to the moderate-dose fentanyl anaesthetic groups with and without electrostimulation.

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[ âR^ *j ZUSAMMENFASSUNG

In der Einfuhrung werden einige der Probleme erläutert, die bereits in der Vorbereitungsphase dieser Promotionsarbeit zur Durchfuhrung der klinischen Untersuchungen überwunden werden mußten Sie hingen mehrheitlich mit dem "alternativen" Charakter des Untersuchungsobjektes, und der Tatsache, daß die Studie teilweise in China durchgeführt werden mußte, zusammen.

Die Ziele der vorliegenden Arbeit können wie folgt zusammengefaßt werden 1 Die Beobachtung, inwieweit die klassische Akupunkturanasthesie seit ihrer Einführung 1958 einer Veränderung unterzogen wurde, 2. Die Beobachtung und Analyse der kimischen Wirksamkeit der klassischen Akupunkturanasthesie und ihr Einfluß auf die Rekonvaleszens und Morbidität bei Schilddrusenoperationen, 3 Die Beschreibung des Einflusses der klassischen Akupunkturanasthesie auf den Umfang hormoneller und immunologischer Veränderungen wahrend und nach Schilddrusenoperationen, 4. Die Beantwortung der Frage, ob wahrend großer bauchchirurgischer Eingriffe unter einer modifizierten Akupunkturanasthesie reduzierte Opiatdosen zu einem Verlust der hamodynamischen Stabilität und zu einer Veränderung des postoperativen Opiatbedarfs fuhren, 5. Die Beurteilung, inwieweit die modifizierte Akupunkturanasthesie bei großen bauchchirurgischen Eingriffen den penoperativen Blutverlust vermindert und die Aufwach- und Wiederherstellungsphase sowie die Morbidität beeinflußt, 6 Die Beurteilung des Einflusses der modifizierten Akupunkturanasthesie auf das Muster hormonaler und immunologischer Reaktionen wahrend und nach großen abdominalchirurgischen Eingriffen

Kapitel 1 gibt eine Literaturubersicht über die Mechanismen der Akupunkturanalgesie Obwohl die Existenz eines morphologischen Substrats der Akupunkturpunkte und -meridiane kontrovers bleibt, steht eine große Anzahl von Daten zur Verfugung, die die Involvierung des penpheren und unterschiedlicher Anteile des zentralen Nervensystems bei der Vermittlung der Akupunkturanalgesie nahelegt Der Wirkungsmechanismus der Akupunkturanalgesie wird auf Veränderungen der Neuronenaktivitat in unterschiedlichen Ebenen des Zentralnervensystems nach bestimmten Formen afferenter Entladungen zurückgeführt. Viele Transmitter und Modulatoren sind an diesem äußerst komplizierten Phänomen beteiligt Das segmentale und nichtsegmentale Schmerzunterdruckungssystem kann abhangig von den Stimulationsvanablen und den gewählten Punkten selektiv aktiviert werden Sowohl das Opiat-, als auch das Nichtopiat-Analgesiesystem sind bei der Vermittlung der Akupunkturanalgesie beteiligt. Nach Nadelung und Stimulation werden penphere afferente, die Akupunktunmpulse weitertragende Bahnen, namheh Nervenfasern der Gruppe II (oder Aß) und III (oder Αδ), aktiviert Diese Impulse werden über die antero-lateralen Bahnen des Ruckenmarks zum Hypothalamus-Hypophysensystem,

149 wo ß-Endorphin in das Blut und die Zerebrospinalflüssigkeit freigesetzt wird, sowie zur periaquaeduktalen grauen Substanz geleitet. In der letzteren kommt es zu zwei unterschiedlichen Reaktionen. Zum ersten werden Metenkphalin und ß-Endorphin sezemiert. Hierdurch wird die Übertragung von nociceptiven Informationen unterdrückt und die Raphekeme und damit das absteigende inhibitorische System aktiviert. Dessen Bahnen verlaufen von den Raphekemen über den tractus dorsolateralis zu den Hinterhomzellen des Rückenmarks. Hier treten normalerweise die nociceptiven Impulsen ein, wobei die Neurotransmitter Serotonin, Noradrenalin und die Neuropeptide Metenkephalin und Dynorphin involviert sind. Die Hinterhomzellen werden durch das inhibitorische System hemmend beeinflußt. Zum zweiten spielt auf supraspinalem Niveau eine mesolimbische Schleife, in der Metenkephalin und Serotonin wirksam sind, eine Rolle. Die durch die Akupunktur bewirkte Analgesie resultiert demnach aus einer durch die Aktivierung spinaler Zentren, der periaquaeductalen grauen Substanz und des Hypothalamus-Hypophysen-Systems bedingten Unterdrückung nociceptiver Afferenzen.

Kapitel 2 beschreibt die charakteristischen Antworten des Körpers auf chirurgische Reize. Noxen und andere, durch die Gewebszerstörung hervorgerufene Reize aktivieren das sympathische System und den Hypothalamus. Es kommt zu einer Freisetzung von (Stress-)Hormonen. Dieses kann als physiologische Reaktion des Körpers auf ein Trauma betrachtet werden. Ferner kommt es zu humoralen und zellulären Immunantworten des Körpers. Die Stärke der neuroendokrinen und immunologischen Antwort ist direkt proportional zum Ausmaß des Traumas. Die Interaktionen zwischen Stresshormonen und Immunsystem sind komplex und zum großen Teil noch unklar. Die Stresshormone üben möglicherweise einen regulatorischen Einfluß auf das Immunsystem aus, welcher sowohl inhibierend als auch stimulierend sein kann. Aktivierte Leukozyten und deren Produkte sind in der Lage, adrenokortikotropes Hormon und ß-Endorphin sowohl direkt als auch über die hypothalamische-hypophysäre Axe mittels Corticotropin releasing factor zu sezemieren. Die Rolle verschiedener Anästhetika und der Akupunktur bei der Modifikation der humoralen Stressantwort und der immunologischen Reaktionen wird dargestellt.

Kapitel 3 beschreibt die Blutentnahmetechnik und die Bestimmungsmethoden für die verschiedenen Parameter. Um falsche Interpretationen der Ergebnisse zu vermeiden, wurden eine ganze Anzahl von Maßnahmen ergriffen, wie z.B. die Standardisierung der Entnahmetechnik und die gleichzeitige Analyse der Parameter aus derselben Patientenprobe.

Kapitel 4 beginnt mit einer Darstellung der chinesischen Gesundheitsversorgung in den fünfziger Jahren, kurz nach Beendigung des Bürgerkriegs (Kapitel 4.1). Mangel an Personal, Krankenhäusern und Ausstattung führte zu einer Politik der Selbstbesinnung. Die Bedeutung der Integration traditioneller chinesischer Heilkunde in die westliche Medizin wurde hervorgehoben, zumal die traditionellen chinesischen Ärzte die überwiegende Mehrzahl der Bevölkerung medizinisch

150 versorgten Die gleichmaßige Verteilung der medizinischen Betreuung erhielt eine Priorität In der Anasthesiologie führte diese Politik zu einer zunehmenden Zahl qualifizierter Anästhesisten, einer eigenen Produktion der meisten medizinisch- technischen Apparate, der Entdeckung einiger pflanzlicher Anasthetika, sowie zur Einfuhrung der Akupunktur als anasthesiologisches Verfahren Danach wird eine prospektive Studie an 20 konsekutiven Patienten, die sich einer Schilddrusenoperation in klassischer Akupunkturanasthesie unterzogen, vorgestellt Die Patienten wurden pra-, intra- und postoperativ bis zur Klinikentlassung beobachtet Die Pramedikation bestand aus 10 mg Diazepam per os Eine intraoperative Analgesie wurde mit der Elektrostimulation von 4 Ohr-Akupunkturpunkten ipsilateral zum betroffenen Schilddrusenlappen oder -adenom durchgeführt Abhangig von klinischen Zeichen (arterieller Druck, Atem- und Herzfrequenz) und Schmerzintensitat wurden kleine Dosen Pcthidin bis zu 1 mg kg ' verabfolgt Die Patienten blieben wahrend der Operation wach Im Kapitel 4.2 werden die Ergebnisse wiedergegeben Die Akupunkturanasthesie konnte keine vollständige Analgesie gewährleisten Trot/dem bestanden intra- und postoperativ stabile hamodynamische Verhaltnisse Zusatzliche Medikamente waren im Gegensatz zu dem in der Literatur angegebenen Anasthetikabedarf bei Schilddrusenoperationen unter Lokalanästhesie nur minimal notig. Die Wiederherstcllungsphase verlief zugig und unkompliziert Die Technik akzeptieren sowohl Patienten, als auch Anästhesisten und Chirurgen Im Kapitel 4.3 werden die Ergebnisse der praoperativen, intra- und bis zum 6 postoperativen Tag durchgeführten hormonellen und immunologischen Untersuchungen vorgestellt Wahrend des chirurgischen Eingriffs stiegen die Plasmaspiegel der Stresshoimone signifikant an, die der Immunoglobuline nahmen hingegen ab Es trat zwar eine Leukozytose auf, doch war deren Zusamensetzung unterschiedlich zu der, die bei Schilddrusenoperationen unter Allgemeinanasthesie beobachtet wird Unter klassischer Akupunkturanasthesie nahm der prozentuale Anteil der Neutrophilen ab, der von Lymphozyten jedoch zu Unter Allgemeinanasthesie wird ein umgekehrtes Verhalten beobachtet Die Ursache dieses Unterschiedes ist unbekannt Das wiedererreichen praoperativer Werte von Leukozytenzahl und Differentialblutbild sowie der Immunoglobuline vorlief in der vorliegenden Untersuchung verglichen mit Daten bei Allgemeinanasthesie schneller

Kapitel 5 beschreibt einleitend (Kapitel 5.1) die Entwicklung der modifizierten Akupunktur im Westen Zunächst wurde bei selektierten Patienten die klassische Form der Akupunkturanasthesie angewandt. Allerdings führten stärkere Bedenken gegen deren routinemäßigen Einsatz zu ihrer Modifikation Diese fand wegen ihres analgetischen Effekts Eingang in die balancierte Anästhesie Eine prospektive Untersuchung an 42 Patienten die sich einer retropentonealen Lymphknotendissektion unterzogen, wird wiedergegeben Die Patienten wurden pra-, intra- und postoperativ bis zu ihrer Klinikentlassung beobachtet Zur Pramedikation erhielten sie 10 mg Diazepam per os Die Patienten wurden einer der drei Gruppen mit balancierter Anästhesie zugeordnet Die Gruppe 1 erhielt zur intraoperativen nicht-pharmakologischen Analgesie eine perkutane Elektrostimulation von drei symmetrischen Ohr- und eine transkutane

151 Elektrostimulation von vier symmetrischen paravertebralen Akupunkturpunkten. Patienten der Gruppe 2 wurden moderate Fentanyldosen (Bolus von 10 μg.kg ' i.v. vor Hautinzision, gefolgt von einer kontinuierlichen Infusion von 5 μg.kg ' in der ersten Stunde und danach von 4 μg.kg' bis zum Beginn des Hautverschlusses) verabfolgt. Die Gruppe 3 erhielt eine Kombination der in Gruppe 1 und 2 verwendeten Methoden, d.h. eine Analgesie wurde mit der perkutanen Elektrostimulation von drei symmetrischen Ohr- und der transkutanen Elektrostimulation vier symmetrischen paravertebralen Akupunktur-punkten sowie mit moderaten Fentanyldosen erreicht. In allen Gruppen wurden bei klinischen Zeichen einer unzureichenden Analgesie kleine Dosen von 50 μg. i.v. Fentanyl gegeben. Zur postoperativen Analgesie stand allen Patienten Nicomorphin 0.1 mg.kg-1 intramuskulär zur Verfügung. Die Studie war einfach blind konzipiert. Weder den Patienten, noch den Chirurgen, dem Operationssaalpersonal, den Untersuchen! außerhalb des OP's und den Laboranten war die Gruppenzugehörigkeit der Patienten bekannt. Ebensowenig erfuhren die Anästhesisten die Laborergebnisse vor Abschluß aller Analysen und der Decodierung. Im Kapitel 5.2 werden die Ergebnisse in den Gruppen 1 und 2 verglichen. Die klinischen Ergebnisse der Gruppe 3, die in der Publikation nicht wiedergegeben werden, unterschieden sich nicht von denen der Gruppe 2. Bei einem Minimalbedarf an Fentanyl (Gruppe 1: 1.2 ц§.к§'1, SD 1.7; Gruppe 2: 22.9 μg.kg ', SD 2.8, Gruppe 3: 23.6 μg.kg ', SD 3.3) konnten die hämodynamischen Parameter während des Eingriffs in Gruppe 1 stabil gehalten werden. In Gruppe 1 war die Auchwachphase kürzer und wurde in den ersten drei postoperativen Stunden keine Hyperkapnie verglichen mit Gruppe 2 und 3 beobachtet. Die postoperativen Verläufe aller Gruppen unterschieden sich nicht. Das Kapitel 5.3 gibt die Ergebnisse der präoperativen, intra- und bis zum 4. postoperativen Tag durchgeführten Hormon-Analysen wieder. Nach ihrer Entnahme wurden die Proben codiert. Der Einfluß der Laryngoskopie und Intubation auf den Plasma-ß-Endorphinspiegel und die Hämodynamik wurde untersucht. Die Elektrostimulation von Ohr- und paravertebralen Akupunkturpunkten führt ohne begleitende Veränderungen von Herzfrequenz und arteriellem Blutdruck zur einer Erhöhung des ß-Endorphin-Plasmaspiegels. Andererseits führen Laryngoskopie und Intubation zu einem Anstieg des Plasma-ß-Endorphinspiegels, der dem nach peripherer Elektrostimulation entspricht; in diesem Falle ist allerdings ein Anstieg von Blutdruck und Herzfrequenz zu verzeichnen. Die Elektrostimulation als eine effektive, nicht-pharmakologische Analgesiemethode bei großen chirurgischen Eingriffen zeigte eine signifikant prononciertere endokrine Reaktion als die Anästhesie mit moderaten Fentanyldosen in oder ohne Kombination mit einer Elektrostimulation: die Plasmaspiegel von zirkulierendem Adrenalin, adrenokortikotropem Hormon (ACTH), antidiuretischem Hormon (ADH) und ß-Endorphin stiegen stärker an; Noradrenalin und Cortisol zeigten keine Verlaufsunterschiede. Es kann an der Ähnlichkeit der Verlaufsprofile von Noradrenalin und Cortisol einerseits und der Unterschiedlichkeit der Reaktionsmunster von Adrenalin, ACTH, ADH und ß-Endorphin anderseits nicht abgeleitet werden, daß die prononciertere Stressantwordt während der modifizierten Akupunkturanästhesie einer mangelhaften Analgesie oder einer unzureichenden

152 Anästhesie zuzuschreiben ist. In der postoperativen Phase wurden keine Verlaufsdifferenzen zwischen den Hormonspiegeln wahrgenommen, weder in den Gruppen mit oder ohne Elektrostimulation, noch in den mit oder ohne moderater Fentanyldosis. Die unterschiedlichen intraoperativen Verläufe der Hormonspiegel, vor allem dem Fehlen von Fentanyl in moderaten Dosierungen zuzuschreiben waren, scheinen keinen Einnuß auf die honnonellen Reaktionen nach Beendigung der Elektrostimulation und/oder Fentanylinfusion und dem Erwachen der Patienten zu haben. Das Kapitel 5.4 beschreibt die präoperativen, intra- und bis zum 6. postoperativen Tag erhobenen immunologischen Befunde. Nach ihrer Entnahme wurden die Proben codiert. Gleiche und charakteristische Reaktionsmuster der Immunglobuline, Leukozyten und des Differentialblutbildes traten per- und postoperativ in allen drei Gruppen auf. Signifikante Unterschiede bestanden nicht.

Schlußfolgerungen:

1. Die klassische Akupunkturanästhesie in ihrer heutigen Form erfuhr einige Revisionen. Eine präoperative psychologische Vorbereitung und/oder ein Austesten, der Schmerzschwellenerhöhung durch Akupunktur erscheinen nicht mehr notwendig.

2. Schilddrüsenoperationen unter klassischer Akupunkturanästhesie werden in China von Patienten, Anästhesisten und Chirurgen akzeptiert, obwohl keine vollständige Analgesie erreicht wird.

3. Die während oder nach Schilddrüsenoperationen unter klassischer Akupunkturanästhesie in China beobachteten Veränderungen endokriner und immunologischer Variablen sind denen in der Literatur wiedergegebenen, im Westen unter Allgemeinanästhesie mit wesentlich höheren Opiatdosen ermittelten Daten ähnlich. Diese Ergebnisse legen den Schluß nahe, daß die Akupunkturanästhesie in ihren endokrinen und immunologischen Wirkungen der balancierten Opiatanästhesie ähnelt.

4. Bei der retroperitonealen Lymphknotenausräumung kann die modifizierte Akupunkturanästhesie stabile peri- und postoperative Kreislaufverhältnisse aufrechterhalten. Die Aufwachphase ist kurz und nicht mit einer Hyperkapnie verbunden. Der postoperative Opiatbedarf wird nicht verändert. Trotz sorfältiger Analyse konnten keine methodologisch bedingten, klinisch relevanten Nachteile beobachtet werden.

5. Die modifizierte Akupunkturanästhesie verhindert nicht die kardiovaskulären Reaktionen auf Laryngoskopie und Intubation. ß-Endorphine üben keinen Einfluß auf die Herzfrequenz und den arteriellen Blutdruck aus und dämpfen nicht die kardiovaskulären Reaktionen von Laryngoskopie und Intubation.

153 Die modifizierte Akupunkturanästhesie verringert bei der retroperitonealen Lymphknotendissektion den Opiatbedarf dramatisch. Sie bedingt jedoch einen prononcierteren Anstieg der Plasmaspiegel von Adrenalin, adrenokortiktropem Hormon, ß-Endorphin und antidiuretischem Hormon. Noradrenalin und Cortisol zeigen keine unterschiedlichen Reaktionen. Postoperativ konnten keine Unterschiede in den Hormonprofilen zwischen den Gruppen mit oder ohne Elektrostimulation, bzw. mit oder ohne moderaten Fentanyldosen herausgearbeitet werden.

Die modifizierte Akupunkturanästhesie beeinflußt bei der retroperitonealen Lymphknotendissektion das Immunsystem während oder nach der Operation nicht, wie die Messungen der Immunglobulinspiegel, der Leukozytenzahl und des Differentialblutbildes ergaben. Der intraoperative, prononciertere Anstieg der Stresshormone bei der modifizierten Akupunkturanästhesie führt folglich verglichen mit der moderaten Fentanylanästhesie mit oder ohne Elektrostimulation zu keinerlei Unterschied in der peri- oder postoperativen Immunantwort. RESUMÉ

Le prologue débute par une discussion des nombreux problèmes à surmonter avant que les études cliniques exposées dans cette thèse ne soient mises à exécution Ils sont essentiellement à rapprocher de la nature "alternative" du sujet à explorer et du fait qu'une partie de cette étude a dû être effectuée en Chine

Le but de la présente étude peut être résumé ainsi' 1 regarder si l'anesthésie acupuncturale classique a subi ou non des modifications depuis son introduction en 1958, 2 observer et analyser l'eficauté clinique de l'anesthésie acupuncturale et son influence sur le réveil, les suites et la morbidité dans la chirurgie de la thyroïde, 3 décnre comment, et dans quelle mesure, l'anesthésie acupuncturale classique peut influencer les changements hormonaux et immunologiques induits par la chirurgie pendant et au décours de la chirurgie de la thyroidie, 4 affirmer ou infirmer que la diminution d'administration de morphiniques pendant l'anesthésie acupuncturale modifiée se traduit par une perte de la stabilité hémodynamique lors de la chirurgie abdominale majeure et si elle entraîne une consommation différente de morphiniques dans la pénode post opératoire, 5 évaluer si l'anesthésie acupuncturale modifiée entraîne ou non une diminution des pertes sanguines pén-opératoires lors de la chirurgie abdominale majeure et/ou dans quelle mesure elle influence le réveil, la convalescence et la morbidité, 6 évaluer l'influence de l'anesthésie acupuncturale modifiée sur les réactions hormonales et immunologiques provoquées pendant et au décours de la chirurgie abdominale majeure

Le chapitre 1 rapporte une revue de la littérature concernant les méchanismes de Γ analgésie acupuncturale Bien que la preuve de la structure morphologique des points d'acupuncture et des méndiens soit toujours mise en doute, il existe de nombreux arguments en faveur d'un rôle du système nerveux périphérique et de certaines régions du système nerveux central dans l'analgésie acupuncturale. Les méchanismes de l'analgésie acupuncturale passent par des modifications de l'activité neuronale à des niveaux variables du système nerveux central après certains types de décharges afferentes II s'agit d'un système tres complexe mettant en jeu de nombreux neurotransmetteurs et modulateurs Les systèmes inhibiteurs segmcntaires et non segmentaires peuvent être activés de façon sélective en fonction de l'importance des stimulations et de la situation des points choisis Les systèmes Opioides et non Opioides sont tous deux sollicités dans l'analgésie acupuncturale Apres la mise en place des aiguilles et stimulation, les voies afférentes périphériques véhiculent les influx acupuncturaux, à savoir les fibres du groupe II (ou fibres Aß) et du groupe III (ou Αδ) qui sont activées Les influx sont transmis par le cordon antéro-lateral de la moelle vers le système hypothalamo-

155 hypophysaire où il y a libération de ß-endorphine dans le sang et dans le liquide céphalo-rachidien, et vers la substance grise périacqueducale où deux phénomènes peuvent se produire; la libération de met-enképhaline et de ß-endorphine intenromp la transmission du message nociceptif et active le noyau du raphe, permettant ainsi Γ activation du système inhibiteur descendant. Ce système va du noyau du raphé au neurones de la corne dorsale de la moelle par le faisceau dorso-latéral. Ceci entraîne une inhibition des cellules de la come dorsale qui reçoivent les influx nociceptifs par l'intermédiaire de la serotonine, la noradrenaline et des neuropeptides comme la met-enképhaline et la dynorphine. De même, un circuit mésolimbique d'analgésie est déclenché au niveau supra spinal avec libération de met-enképhaline et de serotonine. Ainsi l'analgésie induite par l'acupuncture apparaît comme le résultat d'une activation de la moelle, de la substance grise périacqueducale et du système hypothalamo-hypophysaire permettant une inhibition de l'arrivée des stimuli nociceptifs.

Le chapitre 2 décrit les caractéristiques de la réponse de l'organisme à l'anesthésie et à la chirurgie. Les stimuli nociceptifs et ceux issus des tissus endommagés activent le système sympathique et l'hypothalamus à sécréter des "releasing" hormones et donc des hormones du stress. Ceci semble être une réponse physiologique de l'organisme à une blessure. La réponse immunitaire de l'organisme mettant en jeu les composantes humorales et cellulaires est également altérée. L'importance de la réponse neuroendocrinienne et immunitaire est proportionnelle à l'importance du traumatisme. Les interactions entre les hormones du stress et le système immunitaire sont complexes, et de nombreux points sont à clarifier. Les hormones du stress ont probablement une fonction de régulation sur le système immunitaire et ont sur lui un effet inhibiteur et excitateur. Les leucocytes activés et leurs produits peuvent sécréter l'hormone adrénocorticotrophique et la ß-endorphine directement ou par l'axe hypothalamo- hypophysaire en activant la "corticotrophin releasing hormone". Le rôle que jouent les différents agents anesthésiqucs et l'acupuncture dans la modification de la réponse immunitaire et des hormones du stress sont analysés.

Le chapitre 3 décrit les techniques de prélèvement sanguin et les différentes méthodes permettant de déterminer les taux plasmatiques de chaque index. Pour éviter les interprétations erronnées des résultats, un certain nombre de précautions ont été employées, comme l'uniformisation des méthodes de prélèvement et d'analyse de chaque paramètre chez tous les malades, au même moment.

Le chapitre 4 commence par la description de la situation des services de medicine en Chine dans les années cinquante, juste après le guerre civile (chapitre 4.1). Le manque de personnel, d'hôpitaux et d' équipement a été responsable d'une politique d'autarcie. L'importance de l'intégration de la médecine traditionnelle chinoise dans la médecine occidentale a été soulignée, car l'immense majorité de la population recevait ses soins de la part de médecins formés à la médecine traditionnelle chinoise. Une priorité a été donnée a une répartition plus égale des ressources de santé. En ce qui concerne l'anesthésie, la

156 politique définie a abouti à la formation d'un nombre de plus en plus important d'anesthésistes qualifiés, une production intérieure de la plupart des équipements, l'identification de produits anesthésiants à base d'herbes et l'introduction de l'acupuncture comme technique d'anesthésie. Une étude prospective est rapportée sur 20 malades successifs programmés pour subir une intervention sur la thyroïde avec une méthode d'anesthésie acupuncturale classique. Les malades ont été suivis avant, pendant et après l'intervention jusqu' à leur sortie de l'hôpital. La prémédication consistait en la prise de 10 mg de diazepam par voie orale. L'analgésie peropératoire était obtenue par la stimulation électrique de 4 points d'acupuncture au niveau de l'oreille du même côté que l'adénome ou du lobe de la thyroïde à retirer. Sur l'observation des signes cliniques (pression artérielle, fréquence respiratoire et fréquence cardiaque) et à partir de scores de la douleur, de petites doses de pethidine pouvant aller jusqu' à 1 mg.kg'1 étaient administrées par voie intraveineuse. Les malades restaient conscients durant toute l'intervention. Dans le chapitre 4.2, les résultats cliniques sont analysés. L'anesthésie acupuncturale n'entraîne pas une analgésie totale. Cependant, les paramètres hémodynamiques ont été stables durant les périodes per et postopératoires, en n'utilisant que de faibles doses de médicaments adjuvants, si on les compare aux données de la littérature concernant les consommations de produits anesthésiques lors de la chirurgie de la thyroïde pratiquée sous anesthésie locale. Le réveil était rapide et il n'y a pas eu de complications. La technique était acceptable pour les malades, les anesthésistes et par les chirurgiens. Le chapitre 4.3 décrit les données concernant les hormones et les mesures sur l'immunité pendant la période pré, per et les 6 jours postopératoires. Les taux plasmatiques des hormones stress s'élevaient significativement pendant la chirurgie, en même temps que les immunoglobulines s'abaissaient. La leucocytose apparaissait, mais sa composition était différente en comparée aux données de la chirurgie de la thyroïde sous anesthésie générale. Pendant l'anesthésie acupuncturale classique, une diminution du pourcentage des neutrophiles et une augmentation du pourcentage des lymphocytes ont été observées alors que sous anesthésie générale une augmentation du pourcentage des neutrophils et une diminution du pourcentage des lymphocytes ont été signalées. La raison de cette différence n'est pas connue. La restitution de la leucocytose aux niveaux préopératoires et celle des immunoglobulines étaient plus rapides en comparaison avec les données de la chirurgie de la thyroïde sous anesthésie générale aussi. Le chapitre 5 décrit d'abord l'essor de l'anesthésie acupuncturale modifiée en Occident (chapitre 5.1). Chez les patients sélectionnés, l'anesthésie acupuncturale classique était réalisée au début. Cependant, d'importantes objections à son utilisation en routine vont faire modifier l'anesthésie acupuncturale classique: elle était utilisée pour son effet analgésique dans l'anesthésie balancée pour permettre une diminution de la consommation des autres analgésiques. Une étude prospective est rapportée sur 42 malades programmés pour une chirurgie sur les ganglions lymphatiques rétropéritoneaux. Ces patients ont été suivis en pré, per et postopératoire jusqu' à leur sortie de l'hôpital. La prémédication a consisté en 10 mg de diazepam par voie orale. Les malades étaient répartis au hasard en trois groupes. Dans le premier groupe: il était

157 pratiqué une anesthésie balancée avec une electrostimulation percutanée de trois points d'acupuncture symétriques au niveau de l'oreille et une électrostimulation de quatre points d'acupuncture symétriques au niveau paravertebral (analgésique majeur non pharmacologique peropératoire). Dans le second groupe, il était pratiqué une anesthésie balancée utilisant de faible dose de fentanyl (la dose initiale intraveineuse de 10 μg kg ' 5 minutes avant l'incision suivie par l'infusion continue de 5 Hgkg-l pendant la première heure, remplacée par 4 μgkg, après et jusqu'à la suture de la peau Le 3ème groupe recevait un mélange de méthodes utilisées dans le groupe 1 et 2 Ainsi, l'analgésie dans le groupe 3 était obtenue par Γ electrostimulation percutanée de trois points d'acupuncture symétriques au niveau de l'oreille et l'électrostimulation transcutanée de quatre points d'acupuncture symétriques au niveau paravertebral ainsi que des doses modérées de fentanyl Dans les trois groupes, de petites doses de fentanyl (50 μg) étaient données, si nécessaire, quand des signes d'analgésie insuffisante étaient remarqués. Les malades pouvaient recevoir de la mcomorphine 0 1 mg kg ' intramusculaire en postopératoire s'ils le nécessitaient -ceci dans les trois groupes. Toute l'étude était effectuée "single blind" Les malades, les chirurgiens, tout le personnel de la salle d'opération, ainsi que des laboratories étaient ignorants des groupes anesthétiques prédisposés Même les anesthésistes n'étaient pas mis au courant avant que les résultats du laboratoire aient été décodés Le chapitre 5.2 compare les résultats cliniques obtenus dans les groupes 1 et 2 Les résultats du groupe 3 qui n'étaient pas décrits dans l'article publié, ne diffèrent pas de ceux du groupe 2 Avec un besoin minime en fentanyl (groupe 1· 1.2 μgkgl, SD 1.7; groupe 2. 22 9 μgkg1, SD 2 8, groupe 3: 23.6 μgkgl, SD 3 3) les paramètres hémodynamiques sont restés stables pendant la chirurgie et un réveil rapide sans hypercapnie a pu être observé dans le groupe 1 par comparaison au groupes 2 et 3. Aucune différence dans l'évolution de la pénode postopératoire n'a été notée entre les trois groupes. Dans le capitre 5.3, les valuers pré, per et des 4 premiers jours postopératoires concernant les hormones sont analysées Les échantillons prélevés étaient codés. L'effet de la mise en place du laryngoscope et de l'intubation sur les taux de ß- endorphine et les paramètres hémodynamiques a été étudié L'électrostimulation des points d'acupuncture au niveau de l'oreille et de la région paravertébrale entraîne une libération de ß-endorphine sans modification concomitante de la pression artérielle et de la fréquence cardiaque La mise en place du laryngoscope et l'intubation se traduisent également par une augmentation de ß-endorphine à peu près identique à celle obtrenue après stimulation électrique seule. Cette augmentation va de pair, cependant, avec une augmentation de la pression artérielle et de la fréquence cardiaque. L'utilisation de l'électrostimulation comme analgésique non pharmacologique dans la chirurgie majeure permet une réponse endocrinienne significativement plus prononcée en terme d'augmentation des taux circulants d'adrénaline, d'hormone adrénocorticotrope, d'hormone antidiurétique et de ß-endorphine que celle obtenue avec une anesthésie utilisant de faible dose de fentanyl avec ou sans stimulations, alors que les réponses de noradrenaline et de Cortisol étaient identiques. Ainsi, la similarité des profiles de noradrenaline et de Cortisol d'un côté et la différence des profiles d'adrénaline, d'hormone adrénocorticotrope, d'hormone antidiurétique

158 et de ß-endorphine de l'autre, ne justifient pas la thèse que la réponse stress plus prononcée pendant l'anesthésie acupuncturale modifiée (groupe 1) est un résultat d'analgésie insuffisante et d'anesthésie inadequate. En postopératoire il n'y avait pas de différence dans les profils hormonaux entre les groupes avec et sans électrostimulation ni entre celles avec ou sans anesthésie utilisant des doses modérées de fentanyl. Les différences observées entre les profils endocriniens peropératoires, dues très probablement à un manque d'administration de doses modérées de fentanyl, ne semblent pas avoir d'effet significatif sur les profils endocriniens à l'arrêt de l'électrostimulation et/ou de l'administration de fentanyl, et le réveil des malades. Dans les chapitre 5.4, des informations concernant les paramètres immunologiques pendant la periode pré, per et les 6 jours postopératoires sont décrites. Les échantillons étaient codés après prélèvement. 11 a été montré, un aspect similaire et des réponses typiques concernant les immunoglobulines et les leucocytes ainsi que les comptes différentiels en per et postopératoire dans les 3 groupes. Des différences significatives entre les groupes n'ont pu être montrées.

Conclusion

1. L'anesthésie acupuncturale classique, comme elle est utilisée aujourd'hui a été modifiée. Une préparation psychologique préopératoire et/ou un test d'exploration du seuil de tolérance à la douleur n'est plus nécessaire.

2. La chirurgie de la thyroïde sous l'anesthésie acupuncturale classique, qui ne donne pas une analgésie complete, convient aux patients, aux anesthésistes et aux chirurgiens en Chine. Cette technique est sans danger et peut être utilisée si l'on ne dispose pas d'un équipement pour pratiquer une anesthésie générale ou locale.

3. Les modifications qui étaient notées dans quelques données endocrinienne et immunologique pendant et après la chirurgie thyroïdienne sous anesthésie acupuncturale classique en Chine sont en gros similaire à celles qui étaient observées dans la littérature occidentale ou des doses beaucoup plus importantes de morphiniques sont utilisées. Pourtant les résultats font penser fortement que l'anesthésie acupuncturale ressemble à l'action des opoides dans leur effets endocrinologiques et immunologiques en chirurgie thyroïdienne.

4. L'anesthésie acupuncturale modifiée dans la chirurgie des ganglions lymphatiques rétropéritoneaux est capable de maintenir les paramètres hémodynamiques stables dans les périodes per et postopératoires, avec un réveil précoce et sans hypercapnie. La demande d'analgesie en postopératoire reste la même quand on arrête l'analgésie acupuncturale à la fin de l'intervention chirurgicale. Tous les autres désavantages cliniques qui peuvent être attribués à cette méthode n'ont pas été démontrés malgré une recherche soigneuse.

159 L'anesthésie acupuncturale modifiée ne supprime pas les réponses cardiovasculaires à la laryngoscopie et l'intubation trachéale. Les ß- endorphines n'ont pas d'effets sur la fréquence cardiaque ni la pression artérielle et elles ne diminuent pas la réponse cardiovasculaire à la laryngoscopie et l'intubation.

L'anesthésie acupuncturale modifiée dans la chirurgie des ganglions lymphatiques rétropéritoneaux réduit d'une façon très importante les besoins peropératoires d'analgésie en morphiniques et elle est accompagnée par une forte augmentation du taux plasmatique d'adrénaline, d'hormone adrénocorticotrope, ß-endorphine et d'hormone antidiurétique mais avec une réponse similaire de noradrenaline et Cortisol. Dans la période postopératoire aucune différence dans les profils hormonaux n'a été montrée entre les groupes avec et sans l'électrostimulation, ni entre les groupes avec et sans doses intermédiaires de fentanyl.

L'anesthésie acupuncturale modifiée dans la chirurgie des ganglions lymphatiques rétropéritoneaux n'a pas d'effet sur le système immunologique pendant ou après la chirurgie comme il a été montré par les taux des immunoglobulines et le taux total et différentiel des leucocytes. Ainsi, l'augmentation des hormones de stress qui a été observée dans la période peropératoire n'a pas produit de différence dans les réponses immunologiques per et postopératoire par rapport au group« qui a reçu des doses intermédiaires de fentanyl. «3 RINGKASAN

Dalam bagian Pendahuluan dibicarakan beberapa masalah yang hams ditanggulangi sebelum penelitian klinis yang dibahas dalam tesis ini dapat dilaksanakan. Masalah-masalah tersebut terutama berkaitan dengan ciri khusus subjek yang akan diselidiki, dan kenyataan bahwa sebagian dari penelitian tersebut harus dilaksanakan di Tiongkok.

Tujuan penelitian klinis ini dapat diringkaskan sebagai berikut: 1. mempelajari apakah penggunaan anestesi akupunktur klasik mengalami perubahan sejak cara ini diperkenalkan pada tahun 1958, 2. mengamati dan mempelajari penggunaan anestesi akupunktur klasik dan pengaruhnya terhadap masa pemulihan, penyembuhan dan kemungkinan timbulnya komplikasi setelah pembedahan kelenjar gondok, 3. mempelajari pcngaruh anestesi akupunktur klasik terhadap perubahan gambaran sistem endokrin dan sistem kekebalan tubuh sciama dan sesudah pembedahan kelenjar gondok, 4. menjawab apakah pengurangan pemakaian opioid dengan penggunaan anestesi akupunktur modifikasi akan menyebabkan hilangnya kestabilan hemodinamik selama pembedahan dan akan menyebabkan perbedaan kebutuhan opioid setelah pembedahan besar abdominal, 5. menilai apakah penggunaan anestesi akupunktur modifikasi akan mengurangi perdarahan selama dan setelah pembedahan, mempengamhi masa pemulihan dan penyembuhan serta kemungkinan timbulnya komplikasi setelah pembedahan besar abdominal, 6. menilai pengaruh anestesi akupunktur modifikasi terhadap perubahan gambaran sistem endokrin dan sistem kekebalan tubuh selama dan sesudah pembedahan besar abdominal.

Bab 1 membicarakan ulasan kepustakaan tata kerja analgcsi akupunktur. Walaupun masih terdapat perbedaan pendapat tentang struktur morfologis titik-titik akupunktur dan meridiannya, fakta risalah ilmiah menunjukkan bahwa saraf perifer dan sejumlah sistem saraf pusat mempunyai kaitan dengan pengurangan rasa sakit yang disebabkan oleh akupunktur. Bekerjanya analgesi akupunktur ini disebabkan adanya kepacuan neron dibcrbagai tingkat sistem saraf pusat setelah memperoleh jenis rangsang tertentu dari saraf aferen. Hai ini merupakan proses yang rumit, dimana banyak transmiter dan modulator ikut berperan. Sistem endogen hambatan rasa sakit, segmental maupun non-segmental, dapat dipacu secara selektif dengan penusukan titik-titik tertentu dan atau dengan pemberian rangsang tertentu pada titik-titik tersebut. Disamping itu, sistem analgesi opioid dan non-opioid ikut berperan sebagai mediator analgesi akupunktur. Serabut saraf aferen perifer pembawa rangsang akupunktur, yaitu serabut saraf kelompok II (Aß) dan kelompok III (Αδ) dapat dipacukan karena penusukan dan rangsang jarum. Rangsang tersebut akan diteruskan ke sistem hipotalamus- hipofise melalui bagian anterolateral dari traktus spinotalamus dan ke jaringan abu-abu peri-akwaduktus. Sistem hipotalamus-hipofise melepaskan ß-endorpin ke

161 peredaran darah dan ke cairan serebrospinalis, sedangkan jaringan abu-abu peri- akwaduktus membentuk dua kegiatan. Pertama, ia melepaskan met-enkepalin dan ß-endorpin untuk menghambat pengiriman nosisepsi dan perifer ke pusat dan memacukan sistem hambatan yang menurun dan pusat ke perifer. Sistem ini menghubungkan inti raphe dengan neron dikomu dorsal sungsum tulang punggung melalui traktus dorsolateral. Kegiatan tersebut, dengan memakai neurotransmiter serotonin dan noradrenalin disatu pihak dan neuropeptid met-enkepalin dan dynorpin dilain pihak akan menimbulkan hambatan sel-sel dikomu dorsal yang meneríma rangsang nosisepsi. Kedua, lingkaran analgesi meso-limbis ditingkat supraspinal dipacukan dimana met-enkephalin dan serotonin dilepaskan. Disimpulkan bahwa analgesi yang terjadi karena akupunktur disebabkan oleh kepacuan sungsum tulang punggung, jaringan abu-abu peri-akwaduktus dan sistem hipotalamus-hipofise. Kepacuan tiga sistem tersebut dapat memadamkan rangsang nosisepsi yang masuk ke sistem saraf pusat.

Bab 2 menjelaskan mengenai jawaban tubuh terhadap anestesi dan pembedahan. Rangsang nosisepsi dan rangsang lain dari jaringan rusak akan memacukan sistem simpatis dan hipotalamus, yang akan melepaskan hormon pengantar dan hormon stres. Hal ini dipandang sebagai reaksi fisiologis tubuh terhadap luka. Reaksi sistem kekebalan tubuh, terdiri dari bagian humoral maupun selular, pada umumnya dipengaruhi secara négatif oleh pembedahan. Reaksi nero-endokrin dan reaksi sistem kekebalan tubuh tergantung dari derajat luka. Interaksi antara hormon stres dan sistem kekebalan tubuh masih memerlukan penyelidikan lebih lanjut. Hormon stres mungkin bertugas mengatur sistem kekebalan tubuh, dalam arti penghambatan atau pemacuan. Sei sistem kekebalan tubuh dapat membentuk peptid secara langsung atau melalui sistem hipotalamus-hipofise yang menghasilkan ß-endorfm dan melepaskannya ke cairan darah. Peranan akupunktur dan obat anestesi yang dapat mempengaruhi jawaban kekebalan tubuh dan hormon stres juga dibicarakan.

Bab 3 menguraikan cara pengambilan contoh darah, pengolahannya dan cara pemeriksaan tiap parameter. Untuk mencegah penafsiran yang salah dari hasil pemeriksaan, dilakukan beberapa cara baku, antara lain dalam pengambilan contoh darah, cara penelitian dan melakukan pemeriksaan tiap parameter dari setiap penderita dalam waktu yang sama. Karyawan laboratorium tidak mengetahui cara anestesi yang diberikan ke tiap penderita. Setelah semua pemeriksaan contoh darah selesai baru diungkapkan tanda yang tercantum pada tiap tabung contoh darah.

Bab 4 menggambarkan keadaan pelayanan kesehatan di Tiongkok pada tahun lima puluhan tidak lama setelah perang saudara berakhir (bab 4.1). Terbatasnya karyawan kesehatan, jumlah rumah sakit dan peralatan yang ada disatu pihak, dan sikap negara Barat terhadap Tiongkok dilain pihak, mendesak pemerintah Tiongkok untuk mewujudkan suatu kebijaksanaan yang bersifat mandiri. Disini ditekankan pentingnya perpaduan antara pengobatan secara tradisionil dan pengobatan secara Barat, guna pembaharuan sistem pelayanan kesehatan yang sampai saat itu sebagian besar masih berada ditangan dokter tradisionil. Pendistribusian yang seimbang dari sumber-sumber kesehatan juga diutamakan.

162 Dilingkungan anestesi kebijaksanaan tersebut temyata berhasil untuk: meningkatkan jumlah ahli anestesi yang trampil, memenuhi peralatan dan obat buatan dalam negeri dibidang anestesi, meng-identifikasikan beberapa obat anestesi tradisionil dan memperkenalkan penggunaan akupunktur untuk anestesi dan pembedahan. Secara prospektif dipelajari kasus 20 penderita, yang menjalani pembedahan kelenjar gondok dengan anestesi akupunktur klasik di Tiongkok. Penderita diamati sebelum, selama dan sesudah pembedahan sampai keluar dari rumah sakit. Untuk premedikasi diberikan 10 mg diazepam secara oral. Analgesi selama pembedahan dilakukan dengan penusukan dan perangsangan pada empat titik akupunktur ditelinga, disisi yang sama dengan kelenjar gondok yang akan dibedah. Berdasarkan parameter klinik yang terdiri dari tekanan darah, frekwensi pernapasan dan denyut jantung, serta derajat rasa sakit, petidin disuntikkan sewaktu-waktu secara intravena, tetapi jumlah dosisnya tidak melampaui 1 mg.kg'1. Penderita tetap sadar selama pembedahan. Bab 4.2 menguraikan tentang hasil klinis. Anestesi akupunktur klasik tidak menghilangkan seluruh rasa sakit. Akan tetapi sistem hemodinamik tetap stabil selama dan sesudah pembedahan dengan pemakaian obat tambaban yang minimal, jika dibandingkan dengan angka kepustakaan pembedahan kelenjar gondok dengan anestesi lokal. Waktu pemulihan berjalan cepat tanpa komplikasi. Penderita, ahli anestesi dan ahli bedah menerima cara anestesi ini. Bab 4.3 menguraikan tentang hasil pemeriksaan sistem endokrin dan kekebalan tubuh sebelum, selama dan sampai enam hari setelah pembedahan. Terdapat peningkatan bermakna sejumlah kadar hormon stres selama pembedahan, sedangkan kadar imunoglobulin menurun. Terdapat lekositosis selama pembedahan, tetapi dengan komposisi yang berbeda jika dibandingkan dengan lekositosis yang terjadi pada pembedahan kelenjar gondok dengan anestesi umum. Selama anestesi akupunktur klasik, persentase netrofil menurun, sedangkan persentase limfosit meningkat. Sebaliknya, selama anestesi umum terjadi peningkatan persentase netrofil dan penurunan persentase limfosit. Sebab perbedaan ini tidak diketahui. Sesudah pembedahan, perubahan yang terjadi selama pembedahan itu cepat menghilang.

Bab 5 menguraikan tentang perkembangan anestesi akupunktur modifikasi di negara Barat (bab 5.1). Walaupun pada penderita tertentu anestesi akupunktur klasik temyata juga dapat dipergunakan untuk berbagai macam pembedahan, ditemukan kesukaran untuk pemakaiannya secara rutin. Cara tersebut kemudian disesuaikan, dan kini hanya dipergunakan untuk menghilangkan rasa sakit dalam rangka apa yang dinamakan "anestesi berimbang". Secara prospektif dipelajari kasus dari 42 penderita, yang menjalani pangangkatan kelenjar getah bening retroperitoneal yang disebabkan karena penyakit kanker testis. Penderita tersebut diamati sebelum, selama dan sesudah pembedahan sampai keluar dari rumah sakit. Untuk premedikasi diberikan 10 mg diazepam secara oral. Penderita dibagi ke salah satu dari tiga kelompok anestesi umum secara acak. Dikelompok pertama, analgesi selama pembedahan dilakukan dengan penusukan dan perangsangan pada tiga titik akupunktur di kedua telinga dan perangsangan melalui elektroda yang diletakkan pada empat titik akupunktur

163 di kedua sisi tulang belakang. Kelompok kedua menerima dosis sedang fentanyl (intravena 10 (ig.kg1 5 menit sebelum pembedahan dimulai, dilanjutkan dengan tetesan sebanyak 5 μg.kg ' dalam jam pertama dan 4 \lg.kg~l selanjutnya sampai ahli bedah mulai menjahit kulit). Kelompok ketiga mendapat gabungan cara yang digunakan dikelompok pertama dan kedua. Jadi, analgesi dikelompok ketiga diwujudkan dengan perangsangan pada tiga titik akupunktur dikedua telinga maupun pada empat titik akupunktur dikedua sisi tulang belakang, disertai dengan dosis sedang fentanyl. Disamping i tu, pada semua penderíta diberikan tambaban fentanyl 50 pg intravena sewaktu-waktu, apabila berdasarkan parameter klinik menurut apa yang ditetapkan sebelumnya disimpulkan bahwa analgesi tidak memadai. Pada tiap pendeñta disiapkan nicomorfin 1 mg.kg ' secara intramuskuler untuk menghilangkan rasa sakit setelah pembedahan. Penderita, ahli bedah dan karyawan diruang bedah tidak mengetahui cara anestesi yang dipergunakan pada tiap penderita. Juga mereka yang mengamati penderita setelah pembedahan dan karyawan laboratorium tidak mengetahui tentang pembagian kelompok anestesi. Ahli anestesi mengetahui cara anestesi sehingga penyelidikan secara pembutaan rangkap tidak dimungkinkan. Akan te tapi, ahli anestesi tidak mengetahui tentang hasil pemeriksaan contoh darah sampai seluruh pemeriksaan tersebut selesai dan tanda yang tercantum pada tiap tabung contoh darah diungkapkan. Bab 5.2 membicarakan tentang perbedaan hasil klinis dari kelompok pertama dan kedua. Hasil klinis kelompok ketiga yang tidak dicantumkan dalam karya ilmiah ini temyata tidak berbeda dengan hasil kelompok kedua. Dengan dosis minimal fentanyl (kelompok pertama: 1,2 μg.kg"1 SD 1,7; kelompok kedua: 22,9 μg.kg ' SD 2,8 dan kelompok ketiga: 23,6 μg.kg"1 SD 3,3) sistem hemodinamik tetap stabil sciama dan setelah pembedahan pada kelompok pertama. Kesadaran penderita pulih lebih cepat tanpa disertai kadar zat asam arang yang tinggi pada tiga jam pertama setelah pembedahan, jika dibandingkan dengan kelompok kedua atau ketiga. Perbedaan lain antara kelompok pertama, kedua dan ketiga setelah pembedahan tidak ditemukan. Bab 5.3 menguraikan hasil pemeriksaan sistem endokrin sebelum, sciama dan sampai empat hari setelah pembedahan. Tanda dicantumkan pada setiap tabung yang bensì contoh darah. Diteliti pengaruh laringoskopi dan intubasi pada kadar ß-endorpin. Perangsangan titik-titik akupunktur pada kedua telinga dan pada kedua sisi dari tulang belakang dalam waktu 15 menit temyata dapat meningkatkan kadar ß-endorpin tanpa diikuti oleh perubahan tekanan darah dan denyut jantung. Laringoskopi dan intubasi juga sanggup meningkatkan kadar ß-endorpin yang serupa jika dibandingkan dengan perangsangan pada titik-titik akupunktur saja. Akan tetapi peningkatan tersebut disertai dengan kenaikan tekanan darah dan denyut jantung. Perangsangan titik-titik akupunktur sebagai cara non-farmakologis yang efektif untuk menghambat rasa sakit selama pembedahan besar abdominal menimbulkan peningkatan bermakna sistem endokrin, yaitu kadar adrenalin, hormon adrenokortikotropis, hormon antidiuretis dan ß-endorpin jika dibandingkan dengan anestesi dosis sedang fentanyl dengan (kelompok ketiga) atau tanpa perangsangan titik-titik akupunktur (kelompok kedua), akan tetapi reaksi dari noradrenalin dan kortisol tidak berbeda. Wajar jika disimpulkan bahwa dosis fentanyl yang jauh lebih banyak itu dapat lebih menekan jawaban sistem endokrin. Gambaran kadar

164 kortisol dan noradrenalin yang serupa disatu pihak dan gambaran kadar adrenalin, hormon adrenokortikotropis, hormon antidiuretis dan ß-endorpin yang berbeda dilain pihak diantara ketiga kelompok anestesi tersebut tidak dapat membenarkan begitu saja pemyataan bahwasanya reaksi stres yang lebih tinggi selama akupunktur anestesi modifikasi (kelompok pertama) disebabkan oleh analgesi atau anestesi yang tidak memadai. Setelah rangsangan titik-titik akupunktur dan atau pemberian fentanyl dihentikan serta penderita pulih kesadarannya, gambaran sistem endokrin antara ketiga kelompok tersebut tidak dapat dibedakan lagi. Bab 5.4 menguraikan hasil pemeriksaan sistem kekebalan tubuh sebelum, selama dan sampai enam hari setelah pembedahan. Tanda dicantumkan pada setiap tabung contoh darah. Hasil pemeriksaan imunoglobulin maupun lekosit dan hitung jenis memperlihatkan reaksi tubuh yang berciri khusus dan serupa selama dan setelah pembedahan. Tidak ditemukan perbedaan yang bermakna antara kelompok dengan atau tanpa perangsangan titik-titik akupunktur maupun antara kelompok dengan atau tanpa dosis sedang fentanyl.

KESIMPULAN

1. Anestesi akupunktur klasik yang digunakan secara rutin pada saat ini di Tiongkok telah mengalami beberapa perubahan. Persiapan psikologis dan atau pemeriksaan penderita sebelum pembedahan apakah akupunktur dapat menaikkan ambang rasa sakit yang memadai tidak diperlukan lagi.

2. Anestesi akupunktur klasik pada pembedahan kelenjar gondok, yang tidak menghilangkan rasa sakit secara menyeluruh, temyata dapat diterima oleh penderita, ahli anestesi dan ahli bedah di Tiongkok. Cara ini cukup aman dan dapat dipergunakan jika perlengkapan untuk anestesi lokal dan atau anestesi umum tidak memadai.

3. Perubahan sistem endokrin dan sistem kekebalan tubuh selama dan sesudah pembedahan kelenjar gondok dengan anestesi akupunktur klasik di Tiongkok pada umumnya tidak berbeda dengan apa yang dilaporkan dikepustakaan Barat dengan penggunaan anestesi umum yang memakai dosis opioid yang jauh lebih besar. Hasil tersebut menyokong pendapat bahwa anestesi akupunktur klasik mencerminkan kegiatan opioid dalam pengaruhnya terhadap sistem endokrin dan sistem kekebalah tubuh pada pembedahan kelenjar gondok.

4. Penggunaan anestesi akupunktur modifikasi untuk pengangkatan kelenjar getah bening retroperitoneal temyata dapat menjaga kestabilan sistem hemodinamik selama dan setelah pembedahan. Pemulihan kesadaran berjalan lebih cepat tanpa diawali oleh kadar zat asam arang yang tinggi. Kebutuhan opioid setelah pembedahan temyata tidak berubah. Ditinjau dari segi klinis setelah dilakukan pengamatan secara saksama, cara anestesi ini temyata tidak memperlihatkan suatu kerugian.

165 Anestesi akupunktur modifikasi tidak menghambat reaksi sistem kardiovaskuler pada waktu laringoskopi dan intubasi. ß-Endorpin tidak mempengaruhi denyut jantung atau tekanan darah dan tidak mengurangi reaksi sistem kardiovaskuler pada saat laringoskopi dan intubasi.

Anestesi akupunktur modifikasi untuk pengangkatan kelenjar getah bening retroperitoneal yang hanya memerlukan dosis opioid tambaban yang tidak berarti selama pembedahan, disertai dengan kenaikan yang lebih tinggi dari kadar adrenalin, hormon adrenokortikotropis, ß-endotpin dan hormon antidiuretis, sedangkan reaksi dari kadar noradrenalin dan kortisol tidak berbeda. Setelah pembedahan tidak ada perbedaan gambaran sistem hormon antara kelompok dengan atau tanpa perangsangan titik-titik akupunktur maupun antara kelompok yang memakai atau tidak memakai dosis sedang fentanyl.

Anestesi akupunktur modifikasi untuk pengangkatan kelenjar getah bening retroperitoneal tidak berpengaruh pada sistem kekebalan tubuh selama dan sesudah pembedahan, seperti terlihat dari hasil pemeriksaan kadar imunoglobulin dan lekosit serta hitung jenis. Ini berarti bahwa kadar hormon stres yang lebih tinggi selama pembedahan di kelompok anestesi akupunktur modifikasi temyata tidak mengakibatkan perbedaan apapun terhadap jawaban sistem kekebalah tubuh selama maupun setelah pembedahan, jika dibandingkan dengan kelompok yang memakai dosis sedang fentanyl dengan atau tanpa perangsangan titik-titik akupunktur. SAMENVATTING

In de proloog wordt een aantal problemen besproken, die moesten worden opgelost om de in dit proefschrift beschreven studies te kunnen uitvoeren Zij kwamen vooral voort uit het "alternatieve" karakter van het te bestuderen onderwerp en uit het feit dat een deel van de studies in China /ou worden uitgevoerd

De doelstellingen van het in dit proefschrift beschreven onderzoek worden als volgt samengevat- 1 het waarnemen van de veranderingen die de klassieke acupunctuur-anesthesie, sinds de invoering ervan tegen het einde van de zestiger jaren, heeft ondergaan 2. het observeren en analyseren van het gebruik van de klassieke acupunctuur- anesthesie bij struma-chirurgie in China, met name ten aanzien van haar klinische effectiviteit en de invloed ervan op het postoperatieve herstel en eventuele complicaties 3 bestudering van de invloed van de klassieke acupunctuur-anesthesie bij struma-chirurgie op de patronen van een aantal endoencne en immunologische variabelen tijdens en na de ingreep 4 nagaan of toepassing van een zogenoemde gemodificeerde acupunctuur- anesthesie bij grote buikchirurgie in Nederland ook zou leiden tot een belangrijke reductie in de behoefte aan opiaten ter bestrijding van pijn en daarbij speciaal de vraag te beantwoorden of dergelijke anesthesie mogelijk zou zijn met stabiele hemodynamica tijdens de ingreep en tot een bevredigend beloop na de ingreep 5 nagaan of toepassing van deze wijze van anesthesie bij grote buikchirurgie in Nederland invloed zou hebben op het penoperatieve bloedverlies en evalueren in hoeverre deze techniek van anesthesie het postoperatieve herstel en het optreden van eventuele complicaties na de operatie beïnvloedt 6 de invloed bestuderen van gemodificeerde acupunctuur-anesthesie op de patronen van endocriene en immunologische vanabelen bij grote buikchirurgie in Nederland

In Hoofdstuk 1 wordt een overzicht gegeven van de veronderstelde of mogelijke werkingsmechanismen van de acupunctuur-analgesie Hoewel de morfologische structuur van acupunctuurpunten, laat staan van meridianen, uiterst omstreden of een produkt van fantasie zijn, tonen experimentele bevindingen aan dat het perifere en centrale zenuwstelsel betrokken zijn bij door acupunctuur geïnduceerde analgesie Door acupunctuur worden de transmissie en perceptie van nociccptieve informatie op verschillende niveau's van het centrale zenuwstelsel onderdrukt Afhankelijk van de gekozen acupunctuurpunten en de wijze, waarop de/e punten worden gestimuleerd, kunnen segmentale en met-segmentale systemen van endogene pijnremming worden geactiveerd Zowel Opioide als met-opioide, analgetische systemen zijn betrokken bij het tot stand komen van deze vorm van analgesie Intacte afferente banen zijn vereist om het insteken en manipuleren van

167 een naald in analgesie te doen resulteren. Dikke (groep II/Aß) en middelgrote (groep ΙΠ/Αδ) afferente zenuwvezels kunnen de acupunctuur impulsen naar het ruggemerg geleiden, die dan ter plaatse een aantal neurotransmitters zouden activeren. Via de antero-lateraal gelegen tractus spinothalamicus in het ruggemerg bereiken deze impulsen onder andere het hypothalamus-hypofyse systeem, dat ß- endorfinen produceert, die aan het bloed en de liquor worden afgegeven. Via de peri-aquaductale grijze stof wordt met behulp van met-enkefaline en ß-endorfinen als neurotransmitters de nucleus raphe geactiveerd en daarmee ook het descenderende neurale systeem, dat vanuit deze kem via de tractus dorsolateralis naar de achterhoomen van het ruggemerg remmende impulsen afgeeft. Op deze wijzen zou blokkade van nociceptieve transmissie kunnen optreden, zowel op spinaal als op supraspinaal niveau. Andere neurotransmitters zoals serotonine, noradrenaline en neuropeptiden zouden bij deze neural mechanismen ook een rol spelen. Analgesie door acupunctuur zou, naar thans wordt verondersteld, ontstaan als resultaat van activering van het raggemerg, op het niveau van de peri-aquaductale grijze stof en het hypothalamus-hypofyse systeem, die tezamen in het centrale zenuwstelsel binnenkomende nociceptieve impulsen kunnen doven.

Hoofdstuk 2 beschrijft de reactie van het lichaam op anesthesie en chirurgie. Nociceptieve en andere prikkels afkomstig uit de beschadigde weefsels activeren het sympatische zenuwstelsel en de hypothalamus. Zij produceren en scheiden releasing- en stress-hormonen af. Dit wordt als een fysiologische reactie van het lichaam op de door chirurgie geïnduceerde verwondingen beschouwd. De immunologische afweer van het lichaam, bestaande uit humorale en cellulaire componenten, wordt door chirurgie in het algemeen negatief beïnvloed. De mate van neuro-endocrien en immunologisch antwoord is gerelateerd aan de ernst van het chirurgische trauma. De interactie tussen, enerzijds de endocriene stress-me chanismen en anderzijds de immunologische afweer behoeft nog nader onderzoek. Stress-hormonen hebben een regulerende functie op het immunologische systeem op een nog niet geheel opgehelderde wijze. Cellen behorende tot het im munologische apparaat kunnen peptiden produceren, die rechtstreeks of via het hypothalamus-hypofyse systeem ß-endorfinen produceren en in het bloed afscheiden. Een aantal anesthetica en acupunctuur kunnen op verscheidene wijzen deze mechanismen beïnvloeden.

In Hoofdstuk 3 wordt de techniek en het schema van afnamen van bloed alsmede de methode ter bepaling van de verschillende hormonen en een aantal immunologische variabelen beschreven. Een aantal strikte procedures werd gehanteerd om de spreiding van de resultaten, die bij dit soort onderzoek doorgaans groot is, zo veel mogelijk te beperken. Het laboratoriumpersoneel was niet op de hoogte van de bij elke individuele patiënt gevolgde anesthesiologische procedure. Eerst nadat alle bepalingen waren uitgevoerd, werden de gegevens van elke individuele patiënt gedecodeerd.

Hoofdstuk 4 schetst eerst de situatie van de gezondheidszorg in China in de jaren vijftig, kort na het einde van de burgeroorlog (Hoofdstuk 4.1). Gebrek aan

168 medisch personeel, ziekenhuizen en medische uitrusting aan de ene kant en de houding van de Westerse wereld ten aanzien van de Volksrepubliek aan de andere, leidden tot een beleid gebaseerd op vertrouwen in eigen kracht. Het belang van integratie van de traditionele Chinese en de Westerse geneeskunde wordt benadrukt. Zulks was en is immers nodig bij de modernisering van een geneeskunde die tot dan toe geheel in handen is van de traditionele artsen. In de loop der jaren wordt gestreefd naar een meer evenwichtige spreiding van de gezondheidsdiensten. Binnen de anesthesiologie heeft dit geresulteerd in een stijgend aantal opgeleide anesthesiologen, de beschikbaarheid van binnenlandse productie van apparaturen en medicamenten, de identificatie en productie van een aantal plantaardige anesthetica zoals mafusan en niet-depolariserende spierverslappers en de introductie van acupunctuur als goedkope methode voor chirurgische analgesie. Een prospectieve studie bij 20 patiënten, die struma-chirurgie onder de klassieke acupunctuur-anesthesie in Nanjing, China, ondergingen wordt beschreven. De patiënten werden vanaf de dag van opname tot die van ontslag uit het ziekenhuis vervolgd. Bij de operatie werd als premedicatie 10 mg diazepam per os gegeven. Analgesie werd nagestreefd door electrosimulatie van een viertal acupunctuurpunten in het oor aan de zijde van de schildklierkwab, die chirurgisch werd benaderd. Aan de hand van klinische parameters als bloeddruk, adem- en hartfrekwentie aangevuld door pijnscores, werden kleine hoeveelheden pethidine tot een maximum van 1 mg.kg ' intraveneus toegediend. Patiënten bleven tijdens de ingreep bij bewustzijn. In Hoofdstuk 4.2 worden de klinische resultaten beschreven. De klassieke acupunctuur-anesthesie resulteerde niet in complete analgesic. Niettegenstaande minimaal gebruik van anesthetica werd gedurende en na de chirurgische ingreep een stabiele hemodynamiek geregistreerd. Een vergelijking wordt getrokken met literatuurgegevens over het gebruik van anesthetica bij struma-chirurgie onder locale anesthesie. Het postoperatieve beloop was voorspoedig en zonder complicaties. De techniek werd als voldoende beschouwd door patiënten, anesthesiologen en chirurgen. In Hoofdstuk 4.3 worden de gegevens van metingen van hormonale en immunologische variabelen vóór, tijdens en tot zes dagen na de ingreep beschreven. De spiegels van een aantal stress-hormonen stegen significant gedurende de ingreep terwijl die van een aantal immuunglobulinen daalden. Het totale aantal leucocyten nam toe. Onder klassieke acupunctuur-anesthesie daalde het percentage circulerende neutrofielen, terwijl dat van lymfocyten steeg. Tijdens de ingreep onder algehele anesthesie steeg het percentage circulerende neutrofielen, terwijl dat van lymfocyten daalde. Deze veranderingen bij patiënten in China onder acupunctuur-anesthesie verschillen dus van soortgelijke waarnemingen bij struma-chirurgie elders in de wereld onder algehele anesthesie. De reden van dit verschil is vooralsnog onbekend. In de postoperatieve fase verdwenen de tijdens de ingreep opgetreden veranderingen snel.

Hoofdstuk 5 beschrijft allereerst de ontwikkeling van de "gemodificeerde acupunctuur-anesthesie" in de Westerse wereld (Hoofdstuk 5.1). Hoewel de klassieke acupunctuur-anesthesie bij geselecteerde patiënten voor verschillende

169 ingrepen kan worden toegepast, is zij voor routine-gebruik toch bezwaarlijk De techniek is daarom aangepast en zij wordt thans nagenoeg uitsluitend als middel voor analgesie in het kader van "gebalanceerde anesthesie" toegepast. Een prospectieve studie bij in totaal 42 mannen, bij wie wegens testis- carcinoom electieve retropentoneale lymfklierdissectie werd uitgevoerd, wordt beschreven. Deze patiënten waren ten tijde van de ingreep in goede gezondheid, zij het op de hoogte van de ingnjpendheid van de uit te voeren chirurgie en in bezorgdheid over de konsekwenües van het vinden van uitzaaiingen in de lymfkherstations Zij werden uiteraard geïnformeerd over het uit te voeren onderzoek. Zij werden willekeurig in dne groepen van anesthesie-techniek ingedeeld De premedicatie was voor allen dezelfde, 10 mg diazepam per os In groep 1 werd analgesie in het kader van "gebalanceerde anesthesie" voornamelijk nagestreefd door percutané electrostimulatie van een dnctal symmetrische acupunctuurpunten in het oor en transcutane electrostimulatie van vier sym metrische paravertebrale acupunctuurpunten (acupunctuur-groep) In groep 2 werd analgesie zonder electrostimulatie van acupunctuurpunten bereikt via "gebalanceerde anesthesie" met middelmatige doses fentanyl (intraveneus bolusinjectie van 10 μgkg1 5 minuten voor de incisie gevolgd door een continu infuus van 5 μg kg ' gedurende het eerste uur en 4 μg kg ' ema tot het begin van de huidhechting aan het emde van de ingreep). In groep 3 bestond de pijnbestrijding uit de combinatie van de analgetische procedures van de groepen 1 en 2. Aan elke patient werden tijdens de chirurgische ingreep kleine hoeveelheden van 50 μg fentanyl intraveneus extra toegediend, wanneer op grond van tevoren protocollair vastgestelde klinische parameters tot onvoldoende anesthesie werd geconcludeerd Patienten, chirurgen en het overige operatie- en anesthesiepersoneel werden met geïnformeerd over de individuele procedure bij elke ingreep Ook zij die de patient па de ingreep vervolgden en het laboratonumpersoneel waren niet op de hoogte van de groepsindeling De onderzoeker, die de anesthesie verzorgde, was uiteraard wel bekend met de anesthesie-procedure. Zo was een "dubbelblinde" onderzoekssituatie niet mogelijk. De anesthesist was met op de hoogte van de uitslagen van het laboratoriumonderzoek tot dat dit geheel was uitgevoerd, waarna eerst de onderzoeksresultaten werden gedecodeerd In Hoofdstuk 5.2 zijn de klinische resultaten bij de groepen 1 en 2 vergeleken De resultaten in groep 3, die in de inmiddels verschenen publicatie met zijn opgenomen, verschilden met van die in groep 2. Hemodynamisch waren de groepen gelijkelijk stabiel, terwijl de behoefte aan fentanyl in de acupunctuur- groep tijdens de chirurgische ingreep (met een gemiddelde duur van 4,1 uur) meer dan 90 procent gennger was (groep 1 1,2 μgkg' SD 1.7, groep 2: 22,9 μgkg1 SD 2.8, groep 3· 23,6 μg kg ' SD 3,3) De patiënten uit de acupunctuur-groep ontwaakten sneller en vertoonden geen hypercapme in de eerste dne uur na beëindiging van de ingreep Verschillen in het penoperatieve bloedverlies, in de opioid behoefte na de operatie, in de aard en de kwaliteit van de reconvalescentie noch in de postoperatieve morbiditeit konden worden vastgesteld. In Hoofdstuk 5.3 zijn de gegevens over verandenngen in de patronen van een aantal hormonen vóór, tijdens en tot vier dagen na de operatieve ingreep in de dne groepen patiënten, bij wie retropentoneale lymfklierdissectie werd uitgevoerd, bijeen gezet. Electrostimulatie bleek binnen 15 minuten, vóór

170 laryngoscopie en intubatie, de concentratie van circulerende ß-endorfinen met een factor drie te doen stijgen. Daarbij werden geen veranderingen in bloeddruk en polsfrekwentie geregistreerd. Vijf minuten na laryngoscopie en intubatie bleken de spiegels van de ß-endorfinen ook in de groep zonder electrostimulatie (groep 2) gestegen tot waarden zoals na electrostimulatie vóór intubatie (in de groepen 1 en 3). Intubatie deed zowel de bloeddruk als de hartfrekwentie significant stijgen. Acupunctuur en hyperendorfmemie zijn dus niet in staat deze verandering in hemodynamiek door laryngoscopie en intubatie te voorkomen. Het gebruik van electrostimulatie in combinatie met een minimale hoeveelheid fentanyl leidt gedurende de chirurgische ingreep tot ongeveer dezelfde stijgingen in de spiegels van circulerend noradrenaline en Cortisol als bij de groepen 2 en 3, die ongeveer tien maal zoveel fentanyl kregen toegediend (zie boven). Tegen deze achtergrond viel het op dat de spiegels van circulerend adrenaline, ACTH, ß- endorfine en van anti-diuretisch hormoon in groep 1 duidelijk meer stegen dan in de groepen 2 en 3, die beide de veel hogere doses fentanyl toegediend kregen. Het ligt dan ook voor de hand te overwegen dat deze veel hogere doses Opioiden de endocriene "stress response" afremmen. Ter verklaring van het verschillende gedrag van noradrenaline en adrenaline tussen enerzijds groep 1 en anderzijds de groepen 2 en 3 is nader experimenteel onderzoek gewenst. De overeenkomsten in de patronen van Cortisol en noradrenaline enerzijds en de verschillen in de patronen van adrenaline, ACTH, ß-endorfinen en anti-diuretisch hormoon anderzijds maken de verklaring, dat de sterkere endocriene "stress response" tijdens gemodificeerde acupunctuur-anesthesie (groep 1) simpelweg het gevolg zou zijn van een geringere mate van analgesie tijdens de ingreep in die groep uiterst onwaarschijnlijk. Postoperatief zijn geen significante verschillen gevonden in de profielen van de gemeten hormonen. Nadat acupunctuur en fentanyl-toediening gestaakt zijn en de patiënt weer bij kennis is, zijn de drie groepen dus niet meer van elkaar te onderscheiden. In Hoofdstuk 5.4 zijn de veranderingen in een aantal immunologische variabelen vóór, tijdens en tot zes dagen na de operatieve ingreep bij de 3 groepen patiënten, bij wie retroperitoneale lymfeklierdissectie werd uitgevoerd, vergeleken. Bij alle drie groepen trad een ongeveer gelijk grote daling op in de concentraties van de immuunglobulinen en in de percentages circulerende lymfocyten en eosinofiele witte bloedcellen, terwijl het totale aantal leucocyten en de neutrofiele component daarin bij elk van de drie groepen gelijkelijk toenam. De percentages monocyten en basofiele leucocyten bleven tijdens de ingreep onveranderd. Postoperatief waren de spiegels van circulerende immuunglobulinen van het M- type evenals het percentage eosinofielen op de vierde dag weer normaal, terwijl de concentraties van immuunglobulinen van de typen A en G evenals de tallen leucocyten en de percentages van neutrofielen en lymfocyten zich op de zesde postoperatieve dag nog niet hadden hersteld. In dit onderzoek kon dus geen specifiek effect van acupunctuur op enige gemeten immunologische variabele worden vastgesteld. De relatie tussen de endocriene "stress response" en het immunologische antwoord op een chirurgische ingreep onder de omstandigheden van algehele anesthesie is dus niet simpel

171 evenredig. Slechts grofweg kan gesteld worden dat de als gevolg van anesthesie en chirurgie optredende endocriene "stress response" vergezeld gaat van veranderingen in immunologische variabelen, die in het algemeen worden geïn terpreteerd als vermindering van immunologische afweer. Eerder in deze studie kon worden vastgesteld dat verschillen in klinisch herstel en postoperatieve morbiditeit tussen de drie groepen patiënten niet werden gevonden.

172 EPILOGUE

In 1985 the Institute for Anesthesiology Nijmegen allocated no. 538501 to a project, which deals with scientific aspects of the effects of non-pharmacological methods on pain and pain treatment. In the period 1985-1988, the project has given the opportunity to five students, Mr.R. van Wanroy, Mrs.M. Drent, Mrs.D.E. Kippersluis, Mr.F. Huitema and Mr.C.H. de Koning, for a three months' fellowship ("wetenschappelijke keuze-stage"). This is a Faculty regulation before MD exams can be taken. In 1988 the project was registered at the Faculty of Medicine Nijmegen under no. 538809. The author firmly believes that this project should be continued and perhaps even widened since this thesis presents only part of the initial project. Also, this is the first such study in the Netherlands. "Alternative" medicine will - perhaps - increase in importance to society in general as more of the disadvantages of conventional medicine become clearer.

Anyhow, the studies finished and presented in the previous chapters are the result of support from many people. Among those who made this study possible and without whose continual support this thesis could not have been finished in this form are: all participating patients; Mr.G.H. Tjan, former head of the Department for Pesticide and Contaminants of the Food Inspection Service Nijmegen and Mr.S.I. Kho, businessman, from Balwyn, Victoria, Australia, who introduced me to the colleagues at the First Affiliated Hospital of Nanjing Medical College; Mrs.B. Han-Etty, secretary of the Coordination Commission for Scientific and Education Contacts with China of the Dutch Ministry of Education and Science, Leiden, for assistance in getting financial support for the study in Nanjing; Mrs.L. Tang and Mrs.D. Ku, former co-workers of the Hongkong Branch of Janssen Pharmaceutica, for their assistance in clearing the research materials from an air cargo building in Hongkong, making them ready for further air transport to Nanjing and finding the only supplier of the dry ice in Hongkong, needed for the transportation of frozen samples back to the Netherlands; Mr.P. Synaeve BA., former director of the Scientific Department of Xian Janssen, China, and Mr.H. Noorduin MD., from Janssen Pharmaceutica, Belgium, for information and generous support during the preparation of the study in Nanjing; Mr.E. Наг, head of Hongkong Branch of KLM air cargo Department, for his assistance in informing the author of the location of the research materials after their arrivals in Hongkong; Mr.H. Jansen and Mr.S.K. Yeung, sales engineers of Nederlands and Shanghai Branches of Hewlitt Packard, for making a combined ECG and non invasive arterial pressure/respiratory monitor, needed for the clinical study, available; Mr.J.C. Zhu, former co-worker of the Shanghai Branch of Develing Far East, for his assistance in finding the only supplier of dry ice in Shanghai and Nanjing, needed for the transportation of frozen samples

173 to Hongkong; Miss T. van Huet en Miss A. Paauwen, from the University Hospital Nijmegen, for their assistance during the data acquisition in Nanjing; Mrs.H. Jacobs and Mr.H. Jacobs, former director of the Hongkong Branch of DMV Campina Far East, for their hospitality and assistance in providing a freezer for the samples during the transit in Hongkong on the way back to the Netherlands from Nanjing; colleagues and co-workers, from the Department of Endocrine Surgery of the Nanjing First Affiliated Hospital, China, for their generous cooperation; the Nanjing's Wujing chemical factory, China, for delivering dry ice to a private customer; colleagues and co-workers from the Clinic of Urology, University Hospital Nijmegen for their cooperation; Mr.W. Hoekstra MD. PhD., Mr.A.P.M. van der Meyden MD. PhD., Mr.M.A. Drost MD., and Mr. H.G. van Middelkoop MD., from the Willem Alexander Hospital 's-Hertogenbosch, as well as Mr. J.W.M. Lenders, PhD., from the Department of Medicine, University of Nijmegen, for their friendly cooperation; Mr.G. Pesman, Mr.J. Willems PhD. and Mr.J. Willemsen and other co-workers, from the Laboratory for Experimental and Chemical Endocrinology as well as from the Laboratory for Paediatrics and Surgery, University Hospital Nijmegen, for the advice and generous cooperation; Prof.J.S. Han MD., from the Department of Physiology of Beijing Medical University, China, for spending time in reading critically the chapter on the mechanisms of acupuncture analgesia and correcting the Chinese summary; Mr.H.A. Ross PhD., from the Department of Medicine, Division of Endocrinology, University Hospital Nijmegen, for statistical advice; Mr.P. Allen FFARCSI, from the Department of Anaesthesia, Royal Brisbane Hospital, Australia, and Mr.E.N. Robertson FFARCS, from the Institute for Anesthesiology Nijmegen, for correcting the English manuscript; Mrs.B. O'Kelly FFARCSI, from the Assistance Publique Hôpitaux de Paris, France, for translating the summary into French; Prof.L.Y. Zhuang, from the Beijing Teacher's College, China, for translating the summary into Chinese; Mrs.M. Sanioso MD., from the Hasan Sadikin Hospital Bandung, Mr.R. Umbas MD., from the University of Indonesia, Jakarta and Mr. Wahyudi MD., from the Atma Jaja University, Jakarta, Indonesian, for correcting the Indonesian summary; Mr.B. Arnold MD. PhD., from the Institute for Anesthesiology Nijmegen, for translating the summary into German, to all of whom the author is delighted to express his gratitude.

I would like to especially thank my parents for their confidence in me and for their continuous support. Last, but not least, I thank my wife Leng Nio, for her patience, encouragement, support and for taking care of the children, Kuan Hua, Ay Lin, Kuan Kun and Pau Lin, during the preparation of this thesis.

174 Climbing the Peak of Shangshan Mountain

The peak I have climbed is so high that looking down I see but mists and clouds; down there lies a great road used by those going south or west in the hope of gaining honour; some move fast, with profit their aim; yet among them are two kinds of people; those who ride in carts and those who carry burdens on their backs; with so much coming and going, there are great crowds; I myself am among them, for I cannot leave society; I have passed over this road three times; how can I laugh at others?

Bai Juyi (772-846)

175 ^^—^ APPENDIX

' y. -THE AGREEMENT ON SCIENTIFIC RESEARCH COOPERATION BETWEEN CATHOLIC UNIVERSITY OF NIJMEGEN, THE

NETHERLANDS, ANP FIRST AFÜ'ILIATED HOSPITAL OF NANJING MEDICAL COLLEGE ( PEOPLE'S HOSPITAL OF JIANGSU PROVINCE ), CHINA

On the principle of exchange, promotion, mutual benefits, and contribution to human health, the Catholic Universi ty of Nijmegen,· the Netherlands, and the First Affilia ted Hospital of Nanjing Medical College, China, initial this agreement on cooperation of scientific research as follows: Ί. The research title is " On the stress parameters of patients undergoing thyroid surgery under acupuncture •anesthesia (А.А,) и. The aim of the study is: —-Firstly, to objectivate the stress response before, during, and after surgery; comparing them to the well known technique, namely the neurolept anesthesia.

Secondly, to monitor the postoperative period carefully to see whether there is any ¿ifference in the morbidity frequency; this again in comporison with neurolept anesthesia^ Thirdly, to objectivate some parameters of the immu ne system to see whether the suppression of this sys tem, due mainly to the surgery,.can be prevented by A.A.

176 2. The study will be performed on the measurement of stress pcirameters and clinical aspects. China-side will do the clinical work, including selection of patients, anesthesia, operation according to the protocol, etc. The Netherlands-side will undertake the measurement tasks, including measurement of catecholamines, -endorphines, ADH, and related immunological parameters. All of these experiments will be performed in the Netherland . 3. We are planning on finishing all clinical aspects within one and half months after signature, and measure ment aspects in three months after the samples arrive at Holland. 4. Each side will have one of the same copy of all the final information and data from the study, and can not perform any other research based on or around this study until both sides have come to an agreement. 5. China-side will pay for all clinical aspacts. The all experimental expenses, including drugs, neccessary г зеат eh fee, and some compensation for patients' blood ( 40l each patient ), will be paid by Catholic University of Nijmegen. The travelling and aj.1 accoinmodation expenses which the two Netherlandish investigators will spend mus· also be paid by the Netherlands-side. 6. According to the agreement, the benefit will be aharei as soon as the result of Ihe study is acquired. 7. In the First Affiliated Hospital of Nanjing Medical

177 College, Chinai, A.A. haa been used for different kinda of operationa since years and haa reached a higher level in clinical practice. In Catholic Univeraity of Nijmegen, the lletherlanda, the laboratory facilitiea are good. Both aides hope that this cooperation Ъесошеэ a good beginning ao that they can extend their research cooperation, make much pro gress, benefit each other, and even extend this friendly cooperation to other acientific fields in future. Θ. The signatures both in English and in Chinese on thii> agreement will have the same effect, SIGNATURE:

DEPARTMENT OF ANESTHESIOLOGY INSTITUTE FOR ANESTHESIOIOGY PEOPIE'S HSOPITAL OF JIANGSU CATHOLIC UNIVERSITY OF PROVINCE NIJMEGEN CHINA THE NETHERLANDS

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180 PUBLICATIONS

Explanation of letters between parentheses: A, abstract; B, book; Ch, chapter; CR, case report; FP, full paper; IA, invited abstract; IP, invited paper; LTE, letter to the editor; P, proceedings.

1. Kho HG. Acupunctuur. Een overzicht van algemene ontwikkeling en basisbegrippen tot hedendaagse toepassing en huidige wetenschappelijke onderzoekingen. Nijmegen: B'Gottmers uitgeverbedrijf, 1975. (B) 2. Kho HG. Acupunctuur, de tijd dringt om konkreet onderzoek te verrichten. Aarde & Kosmos 1975;6:248-250. (FP) 3. Kho HG. Acupuncture for hearing impairment: a useful treatment? Ned Τ Geneesk 1977;121:1568-1569. (LTE) 4. Kho HG. Treatment of cluster headache by acupuncture. Am J of Chin Med 1977;5:91-94. (CR) 5. Kho HG. Acupuncture treatment of cervical syndrome. Am J Acup 1981;9:227-234. (FP) 6. Kho HG. Acupuncture, from traditional to modem treatment In: Galen K, ed. Acupuncture. Amsterdam: De Driehoek, 1983;9-30. (Ch) 7. Kho HG. Acupuncture analgesia has a solid scientific background. Med Contact 1984;39:233. (LTE) 8. Kho HG. Modification of classical acupuncture anesthesia in abdominal surgery. 2nd. World Congres of Sci Acup. London, 1986. (A) 9. Drent M, Kho HG, van Egmond J. Stress and Immunity: the importance of multidisciplinary investigation. Ned Τ Geneesk 1986;130:1665-1666. (LTE) 10. Kho HG. Combined acupuncture anesthesia: Preliminary results of a clinical study on haemodynamic, hormonal and metabolic responses in upper abdominal surgery. In: Nijhuis GMM, ed. Intern. Symposium of Anesth: Feedback and feedforward. Nijmegen: Institute for Anaesthesiology, 1987; 165- 176. (P) 11. Kho HG. A clinical study on stress responses of patients operated with combined acupuncture anesthesia. Acupunct Electrother Res 1987:12:263- 264. (P) 12. Kho HG. Acupuncture as alternative medicine, facts and perspectives. Ned Τ Geneesk 1987;131:1869-1902. (IP) 13. Kho HG. A clinical study of patients operated with combined acupuncture anesthesia. 1st. World Conference on Acupuncture and Moxibustion, Beijing: November, 1987. (A) 14. Kho HG, Maas Ρ, Kerkkamp Η, Drent M, Kippersluis E, Egmond van J. Haemodynamische Wirkungen der kombinierten Akupunkturanästhesie bei abdomineller urologischer Chirurgie. Dtsch Ztschr Akup 1987;30:60-64. (FP) 15. Kho HG. Acupuncture as alternative medicine, facts and perspectives. Ned Τ Geneesk 1988;132:125-126. (LTE) 16. Kho HG. Acupuncture as alternative medicine, facts and perspectives. Ned Τ Geneesk 1988;132:319-320. (LTE)

181 17. Kho HG. Spinal anaesthesia without post spinal headache. Reg Anaesth 1988;11:119. (A) 18. Kho HG, Egmond van J, Crul J F. The Stress responses of patients undergoing upper abdominal surgery Comparative study balanced anaesthesia versus combined acupuncture anaesthesia. 3th World Congress Sci Acup, Prague: May, 1988. (A) 19. Kho HG. Headache after lumbar puncture. Ned Τ Geneesk 1988,132 179 (LTE) 20. Zwarts SJ, Hasenbos MAWM, Gielen MJM, Kho HG. The effect of continuous epidural analgesia with sufentanyl and bupivacaine during and after thoracic surgery on the plasma Cortisol concentration and pain relief. Reg Anesth 1989;14:183-189. (FP) 21 Kho HG, van Egmond J. Acupuncture reduces the use of fentanyl in retropentoneal lymph node dissection. Eur Urol 1990;18(Suppl)-246. (A) 22. Kho HG. Does acupuncture anaesthesia prevent the alteration of immunoglobulins and leucocyte counts following thyroid surgery? 8th. European Congress of Anaesthesiology Warsaw: September, 1990. (P) 23. Kho HG, Eijk RJR, Kapteyns WMMJ, Egmond van J. Acupuncture does not influence the morbidity after major abdominal surgery. 8th. Asian and Australasian Congress Anaesth, Seoul. September, 1990. (A) 24. Kho HG. Pain treatment by alternative medicine. In: Michiels JJM, ed. Cancer pain. Almere. Versluys Uitgeverij, 1990;91-95. (Ch) 25 Kho HG, Zhuang CF, J van Egmond, Zhang GL, Lin GF. Acupuncture anaesthesia. Observations on its use for removal of thyroid adenomas and influence on recovery and morbidity in a Chinese hospital Anaesthesia 1990:45:480-485. (FP) 26. Kho HG, Zhuang CF, J van Egmond, Zhang GL, Lin GF. The patterns of stress response in patients undergoing thyroid surgery under acupuncture anaesthesia in China. Acta Anaesth Scand 1990,34:563-571. (FP) 27. Kho HG, van Egmond J, Zhuang CF, Zhang GL, Lin GF. The patterns of catecholamine and hormone changes in patients undergoing surgery for thyroid adenoma under acupuncture anaesthesia. In: Matsuki A, Ishihara H, Oyama T, eds. Endocrine response to anesthesia and intensive care. Amsterdam/New York: Excerpta Medica, 1990;49-55. (Ρ) 28. Kho HG, J van Egmond. A double needle technique for spinal anaesthesia to prevent post spinal headache. Eur J Anaesth 1990;7:403-410. (FP) 29. Allen PW, Slappendel R, Kho HG. Life treatening post-operative stridor. Eur J Anaesth 1990,7 429-432. (CR) 30. Kho HG, Eijk RJR, Egmond van J, Kapteyns WMMJ. Lack of acupuncture and transcutaneous stimulation's influence on the altered immunoglobulins and leucocyte counts following upper abdominal surgery. Eur J Anaesth 1991;8:39-45. (FP) 31. Kho HG, Egmond van J, Eijk RJR, Kapteyns WMMJ. Acupuncture and transcutaneous stimulation analgesia in companson with moderate-dose fentanyl anaesthesia in major surgery Clinical efficacy and influence on recovery and morbidity. Anaesthesia 1991;46:129-135. (РФ)

182 32. Kho HG. The patterns of stress response in patients undergoing thyroid surgery under acupuncture anaesthesia in China. Anesth Digest 1991 (in press). (IA) 33. Kho HG, Kloppenborg PWC, J van Egmond. Effects of acupuncture and transcutaneous stimulation analgesia on plasma hormone levels during and after major abdominal surgery. Comparisons of three anaesthetic techniques. Submitted. (FP) 34. Kho HG, Roberston EN, Han JS. Mechanisms of acupuncture analgesia. An overview and update. Submitted. (FP) 35. Kho HG, J van Egmond. Metabolic effects of acupuncture and transcutaneous stimulation analgesia during and after major abdominal surgery. Submitted. (FP)

183

CURRICULUM VITAE

The author of this thesis was bom in Surabaja on January 20, 1948. He attended primary and secondary school at "Mater Dei", Probolinggo (1954-1960) and at Canisius College, Jakarta (1960-1966) respectively. In 1967 he began his medical study at the Medical School of the University of Nijmegen. Having finished the first part of his studies in 1970, at the written recommendation of Prof.Dr.F.Kreuzer, former head of the Department of Physiology, he had the opportunity for research on the topic of Glycoprotein in lung connective tissue at the O'Donnell Memorial Research Laboratories, Saranac Lake, N.Y. (head: Prof.Dr.V.Hospelhom). On returning to Nijmegen, he became involved in a research project of the Division of Rheumatology, Department of Medicine of the University Hospital of Nijmegen (head:Dr.J.K.van der Korst), studying Age related biochemical changes of bone cartilage. In the summer of 1971 he worked as a clinical assistant in the clinic of obstetric of the "Dr.Zdravke Kucic" Hospital, Rijeka, Jugoslavia (head: Prof.Dr.D. Perovic). Graduating as a physician in 1974 he first practised in Volendam and Utrecht as a family practitioner. Shortly after graduating and in the two subsequent years he received training in acupuncture at the Ludwig Bolzmann Institute for Acupuncture in Vienna (head: Prof.Dr.J. Bischko). The interest in anaesthesia began during his surgical residency in the Clinic of General Surgery of the "Evangelisches Krankenhaus", Wesel, FRG (head: Dr.med.H. Höffken) in the period 1978-1979. He trained in Anaesthesia between 1979-1982 at the Institute for Anesthesiology Nijmegen (head: Prof.Dr.J.F. Crul). In November 1982 he was registered as an anaesthetist. In 1983 he joined the Institute as a regular staff member and was appointed as Anaesthetic Consultant to the Clinic of Urology. Outside anaesthesia in all its aspects, he is especially interested in public health in developing countries and traditional Chinese medicine. A cooperation with the Chinese medical institution resulted in a visiting research physicianship at Nanjing Teaching Hospital in 1987, during which period a part of the study of the thesis was carried out. He became a member of the Austrian Society of Acupuncture and Auriculotherapy in 1977, the Dutch Society of Anesthesiology in 1983, the American Society of Regional Anesthesia in 1988 and the European Society of Regional Anaesthesia in 1989. Since 1987 he is one of the reviewers of the Dutch Journal of Medicine (Nederlands Tijdschrift voor Geneeskunde) for books on the topic of Alternative Medicine. In 1989 he became a member of the Editorial boards of Acupuncture: the Scientific International Journal. The author is married and has four children.

185 The contributions of the following trades for the publication of this thesis is greatly acknowledged.

Janssen Pharmaceutica Drager Nederland Homeoropa Dr. Loges & Co Holland L'Univers, Dedemsvaart Serva-Synthex Nederland

STELLINGEN

behorende bij het proefschrift

ACUPUNCTURE IN ANAESTHESIA AND SURGERY Studies in China and The Netherlands

Nijmegen, 27 mei 1991

H.G. Kho 1. Bij struma-chirurgie is klassieke acupunctuur-anesthesie even veilig als doelmatig. Kho HG, et al. (1990). Anaesthesia 45:480-485.

2. De door acupunctuur geïnduceerde analgesie als component van "gebalanceerde anesthesie" maakt uitgebreide buikchirurgie mogelijk bij gebruik van uiterst geringe hoeveelheden opiaten met behoud van stabiele hemodynamiek zonder nadelige invloed op het herstel na de operatie. Kho HG, et al. (1991). Anaesthesia 46:129-135.

3. Het profiel van de hormonale veranderingen bij patiënten, die struma- chirurgie onder acupunctuur-anesthesie ondergaan, vertoont sterke gelijkenis met dat bij gebruik van algehele anesthesie. Kho HG, et al. (1990). Acta Anaesthesiologica Scandinavica 34:563-571.

4. "Gebalanceerde" anesthesie is aan vier voorwaarden gebonden: bewusteloosheid, endogene of exogene analgesie, spierrelaxatie en een beperkte endocriene en immunologische "stress"-reaktie.

5. Endorphinen en serotonine zijn nauw betrokken bij de mechanismen ter verhoging van de pijndrempel door acupunctuur. Han JS, et al. (1982). Annual Review of Pharmacology and Toxicology 22:193-220. Lagerweij, E, et al. (1984). Science 225: 1172-1173. Mayer DJ, et al. (1976). In: Bonica JJ, Albe-Fessard D, eds. Advances in Pain Research and Therapy. New York: Raven Press, 1:751-754. Pomeranz B, et al. (1976). Life Sciences 19:1757-1762.

6. Zowel technische als klinische aspecten van regionale anesthesie kunnen assistenten in opleiding tot anesthesioloog zich snel en efficiënt eigen maken via een stage in één der grote Chinese opleidingsziekenhuizen. Dit proefschrift.

7. Als één van de wetenschappelijk meest onderbouwde "alternatieve" geneeswijzen, is acupunctuur als behandelingsmethode niet weg te denken uit de gezondheidszorg, zowel intra- als extramuraal. Kho HG (1987). Nederlands Tijdschrift voor Geneeskunde 131:1896-1902.

8. Ten behoeve van wetenschappelijk onderzoek is "placebo"-acupunctuur om meer dan één reden even onuitvoerbaar als "placebo"-chirurgie. Kubiena G (1989). Wiener klinische Wochenschrift 101:362-367.

9. Kwantitatieve verschillen in de mate van endocriene "stress response" beïnvloeden de immunologische afweer noch het herstel na grote buikchirurgie. Eigen waarneming. 10. Goed uitgevoerde acupunctuur-anesthesie kan de doorgaans toegediende hoeveelheid opiaten ook bij grote buikchirurgie vrijwel volledig vervangen. Kho HG, et al. (1987). Deutsche Zeitschrift für Akupunktur 30:60-65. Dit proefschrift.

11. Spinale anesthesie via een "30-gauge" naald is één van de voorkeurs technieken bij "day care surgery". Kho HG, et al. (1990). European Journal of Anaesthesiology 7:403-410.

12. Bij de registratie van een nieuw geneesmiddel dient de farmaceutische industrie zich te verplichten een budget te reserveren voor onderzoek naar de bijwerkingen van het geneesmiddel bij grootschalig gebruik.

13. De "stress response" balanceert gezond leven in de zin van Yin en Yang: overmatige en vooral langdurige stress (Yang) kan gezondheid schaden, onvoldoende "stress response" (Yin) kan onder bepaalde omstandigheden de dood tot gevolg hebben.

14. Het (verplicht) aannemen van een autochtone naam als middel om assimilatie van leden van derde en latere generaties van een minderheidsgroep te bevorderen, is uiterst bedenkelijk en mist het beoogde doel.

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