TITLE PAGE
MONITORING AND REVERSAL OF NEUROMUSCULAR
BLOCKADE: A COMPARISON OF CLINICAL VERSUS
QUALITATIVE ASSESSMENTS
BY
DR AYENI, Olajide O.
(M.B.B.S., BENIN)
A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT FOR THE AWARD OF THE FELLOWSHIP OF THE NATIONAL POSTGRADUATE MEDICAL COLLEGE OF NIGERIA, IN THE FACULTY OF ANAESTHESIA (FMCA).
NOVEMBER 2015
ATTESTATION
We hereby attest that this research titled “MONITORING AND REVERSAL OF NEUROMUSCULAR BLOCKADE: A COMPARISON OF CLINICAL VERSUS QUALITATIVE ASSESSMENTS” was carried out by Dr Olajide O. AYENI. We have reviewed and supervised the conduct of the study.
------PROF O.T KUSHIMO Supervisor Consultant Anaesthetist Lagos University Teaching Hospital (LUTH).
------DR A. MAFE DR. AKINTIMEHIN Supervisor Supervisor Consultant Anaesthetist Consultant Anaesthetist Lagos Island General Hospital GbagadaGeneraHospital Hospital Lagos. Lagos.
2
CERTIFICATION
I certify that this research titled “MONITORING AND REVERSAL OF
NEUROMUSCULAR BLOCKADE: A COMPARISON OF CLINICAL
VERSUS QUALITATIVE ASSESSMENTS” by Dr Olajide O. AYENI was conducted in the Department of Anaesthesia, LASUTH.
------DR A.A MAJEKODUNMI
Head of Department
Department of Anaesthesia, LASUTH.
3
DECLARATION
It is hereby declared that this work is original and done by me. I also acknowledge that the work has not been presented to any other College for a
Fellowship nor has it been submitted elsewhere for publication.
------DR. AYENI, Olajide Olabosipo
4
TABLE OF CONTENTS
Table of Contents TITLE PAGE...... 1 ATTESTATION...... 2 CERTIFICATION...... 3 DECLARATION...... 4 TABLE OF CONTENTS...... 5 DEDICATION...... 7 AKNOWLEDGEMENTS...... 8 LIST OF ABBREVIATIONS...... 9 LIST OF TABLES...... 10 LIST OF FIGURES...... 11 LIST OF APPENDICES...... 12 SUMMARY...... 13 CHAPTER ONE...... 15 INTRODUCTION...... 15 AIMS AND OBJECTIVES...... 19 SIGNIFICANCE OF THE STUDY...... 20 CHAPTER TWO...... 21 LITERATURE REVIEW...... 21 CHAPTER THREE...... 43 METHODOLOGY...... 43 STUDY DESIGN...... 43 STUDY SAMPLE...... 43 SAMPLE SIZE DETERMINATION...... 43 INCLUSION CRITERIA:...... 44 EXCLUSION CRITERIA:...... 45 TECHNIQUE...... 45 ANAESTHETIC PROCEDURE...... 46 ETHICAL CONSIDERATION...... 51 DATA ANALYSIS...... 51 CHAPTER FOUR...... 52 RESULTS...... 52 CHAPTER FIVE...... 63 DISCUSSION...... 63 CHAPTER SIX...... 78 CONCLUSION AND RECOMMENDATION...... 78 LIMITATIONS OF THE STUDY...... 79
5 RECOMMENDATIONS...... 80 REFERENCES...... 81 APPENDICES...... 91 APPENDIX I - PROFORMA: ...... 91 APPENDIX II - AUDIT QUESTIONAIRE ...... 94 APPENDIX III - INFORMED CONSENT ...... 95 APPENDIX IV - ETHICAL CONSIDERATIONS ...... 98 APPENDIX V - ETHICAL COMMITTEE APPROVAL...... 99 APPENDIX VI - NATIONAL POSTGRADUATE MEDICAL COLLEGE APPROVAL ...... 100
6
DEDICATION
This book is dedicated to God Almighty for the opportunity of a lifetime granted to me; my loving wife and wonderful children, Olanrewaju, Oluwanifemi and
Oluwatimilehin.
7
AKNOWLEDGEMENTS
I give God almighty the glory for the completion of the work He started in me. I wish to express my sincere appreciation and gratitude to Prof. O.T Kushimo, for her motherly love and patience as well as her encouragement in the writing of this book.
I also thank Dr A. A Majekodunmi , Dr A Mafe and Dr Akintimehin for their unrelenting support and input in supervising this book and making it good enough for submission. I equally express my sincere gratitude to all the
Residents in the Department of Anaesthesia, Lagos State University Teaching
Hospital (LASUTH) for their support.
8
LIST OF ABBREVIATIONS
ASA AMERICAN SOCIETY OF ANESTHESIOLOGISTS AMG ACCELEROMYOGRAPHY DBS DOUBLE-BURST-STIMULATION EMG ELECTROMYOGRAPHY LASUTH LAGOS STATE UNIVERSITY TEACHING HOSPITAL MMG MECHANOMYOGRAPHY NMBD NEUROMUSCULAR BLOCKING DRUGS NMJ NEUROMUSCULAR JUNCTION NSA NIGERIAN SOCIETY OF ANAESTHETIST PNS PERIPHERAL NERVE STIMULATOR PORC POSTOPERATIVE RESIDUAL PARALYSIS PTC POST-TETANIC-COUNT TOFC TRAIN OF FOUR COUNT TOFR TRAIN OF FOUR RATIO
9
LIST OF TABLES
Table I Demographic and clinical characteristics of patients.
Table II The TOF count and TOF ratio between the groups at 20
minutes and 30 minutes interval.
Table III The onset of intubation, extubation time interval and time
interval to achieve adequate neuromuscular block.
Table IV Complications and interventions
10
LIST OF FIGURES
Figure 1 Distribution of patients by surgical specialties
Figure 2 Distribution of complications and facemask interventions
Figure 3 Distribution of complications and Re-intubation
11
LIST OF APPENDICES
Appendix I Research pro-forma
Appendix II Audit form
Appendix III Informed consent
Appendix IV Ethical considerations
Appendix V Ethical Committee
Appendix VI College Approval
12 SUMMARY
Background: Inadequate recovery from neuromuscular blockade also referred to as residual paralysis has been strongly associated with the use of NMBD especially long-acting neuromuscular blocking drug (NMBD) when clinical test such as head-lift for 5 seconds were used for confirmation of adequate recovery of neuromuscular function. More recently subjective (visual/ tactile) monitoring of NMBD with the aid of peripheral nerve stimulator (PNS) in the peri-operative period has not been found to confer any added advantage in the reduction of residual paralysis when used intraoperatively for monitoring of NMBD.
Objectives: This study aimed to compare suitable method between clinical assessment and subjective assessment for monitoring and reversal of neuromuscular block in seventy American Society of Anaesthesiologists (ASA) I and II patients using safe extubation time interval, time to achieve adequate neuromuscular function and frequency of residual paralysis between the two groups.
Methods: This randomized controlled double-blinded study conducted at the Lagos State University Teaching Hospital (LASUTH) comprised of two groups of 35 surgical patients each (Control group - clinical test and Study group - nerve stimulator). Induction of anaesthesia was achieved with intravenous propofol 2.5mg/kg and intravenous fentanyl 1.5 μg/kg after pre-oxygenation for 5 minutes. Airway was secured with endotracheal tube after administration of intravenous pancuronium 0.1mg/kg and onset of intubation noted and compared between the two groups. Anaesthesia was maintained with halothane 0.75% in 100% oxygen and all patients were ventilated mechanically.
Results: The incidence of residual paralysis after 30 minutes in the recovery room was 30% in both groups. The incidence of residual in clinical assessment group was 43% while the incidence in peripheral nerve stimulator group was 17% (p = 0.001). The mean time interval in minutes for onset of intubation in the clinical assessment group was 2.46 ± 1.31 minutes, the mean time interval in minutes for onset of intubation in the PNS group was 3.49 ± 1.07 minutes (p = 0.001). The mean extubation time interval in minutes for the both control and study group was 11.36 ± 2.71 and 9.28 ± 2.57 minutes respectively (p = 0.01). Mean time interval to achieve adequate recovery of neuromuscular function in minutes for the control group was 41.36 ± 6.08 minutes while the mean time interval of 39.28 ± 3.61 minutes was recorded for the study group (p = 0.013).
13 Twenty (57.7%) patients in the control group and eight (22.9%) patients in the study group at a TOFC count of 4 had a TOF ratio of less than 0.7 (70%) at 20 minutes. Fifteen (42.9%) patients in the control group and six (17.1%) patients in the study group at a TOFC count of 4 had a TOF ratio of less than 0.7 (70%) at 30 minutes. This result shows a statistically significant difference between the two groups (p = 0.003).
A total number of twenty one patients (30%) had complications associated with residual paralysis in the two groups at TOFC of 4. Fifteen (43%) patients in the control group had hypoxia (oxygen saturation of < 92% on room air oxygen) and six (17%) of the patient in the study group (p = 0.001). Fourteen (66%) patients had hypoxia at SpO2 ≤ 92% on room air oxygen in both groups, nine (64%) in the control group and five (36%) in the study group (p > 0.05). Four patients (19%) had irregular shallow breathing in both groups, three patients in the control group and one patient in the study group, three patients with irregular breathing was resolved by supplemental facemask oxygen and one re-intubated and manually ventilated in the operating room. Three (14%) of the patients in the control group had hypoventilation at RR of less than 8 cycles/minutes that was resolved with re-intubation and manual ventilation in the operating room. None of the patients had aspiration pneumonitis from residual paralysis in the recovery room and there was no atelectasis recorded in the patients on the ward.
Conclusions: A high disparity in the incidence of residual paralysis was observed between the two groups in this study. The incidence of residual was more in the control group that was monitored with clinical test than in the study group monitored subjectively (tactile) assessment with PNS. The study group patients recorded faster recovery of neuromuscular function than the control group comparing the time interval to achieve adequate neuromuscular and extubation time interval. This study clearly demonstrated the advantages of PNS monitoring (subjectively) over clinical assessment in the reversal and monitoring of neuromuscular block. Surveys have shown lack of routine use of PNS monitors by Anaesthetist for monitoring of neuromuscular block due to complexity, fragility and time to set it up and in poor resource country “cost.” There is a need for careful re-examination and re-evaluation of the principles regarding monitoring and reversal of neuromuscular blockade in our sub-region when NMBD are administered.
14 CHAPTER ONE
INTRODUCTION Anaesthetists have historically been early adopters of new technologies such as capnography, end-tidal gas analysis, pulse-oximetry and even neurophysiologic monitors. These monitors, now found in virtually every modern operating room, provide the user with an objective real time value that is reasonably easy to interpret. The use of the peripheral nerve stimulator (PNS) for monitoring of neuromuscular blocking drugs (NMBD) was first demonstrated as far back in 1958 through the application of an electrical stimulus to a peripheral nerve and the evoked response observed correlate with the return of neuromuscular activity following the use of d-tubocurarine a long-acting NMBD1.
The use of PNS as a means of evaluating neuromuscular recovery was later demonstrated by Katz in the mid-60s.2 A breakthrough in neuromuscular monitoring occurred in the early 70s with the description of train-of-four (TOF) stimulus3,4. The ratio of the fourth twitch stimulus (T4) to the first twitch stimulus
(T1) is defined as the TOF ratio (T4/T1). The TOF stimulus has been found to give a reproducible measure of neuromuscular block and a correlation between the TOF fade ratio of 70% (0.70) and ability to perform head lift (HL) maneuver for 5 seconds demonstrated as adequate clinical recovery of neuromuscular function from neuromuscular blockade5. The ulnar nerve is usually selected as a reference
15 point for electrical stimulation and the evoked response at the adductor pollicis muscle shown by movement in the thumb assessed using the TOF 6,7,8.
Assessment of twitch response by visual or tactile means is termed qualitative or subjective assessment but when devices like sensors or transducers are attached to produce graphical interpretation it becomes quantitative or objective. Examples of quantitative monitors are acceleromyography (AMG), electromyography (EMG), mechanomyography (MMG), accelerometers (ACC). The administration of long- acting neuromuscular blocking agents such as pancuronium is associated with an unacceptable high incidence of postoperative residual paralysis (PORC).9 Potential solutions involve avoiding the use of pancuronium in cases planned for immediate tracheal extubation at the end of procedure or close monitoring of reversal of effects of neuromuscular blockade.
Anaesthetists in the past rely on routine empirical reversal with standard dose of anticholinesterase and anticholinergic in a ratio of 2:1 (neostigmine 0.05mg/kg body weight and atropine 0.02mg/kg body weight) at the end of surgical procedure. The acceptable bedside clinical criteria for adequate recovery of neuromuscular function for tracheal extubation at that time was based on the head lift maneuver (HL) for 5 seconds, hand grip strength by hand shake, eye opening and swallowing reflex.10 Alternative criteria used in the past involved subsequent administration of smaller doses of anti-cholinesterase until ventilatory effort is
16 improved for exchange11. The incidence of residual paralysis was documented in
30% of patients in recovery room after reversal with anticholinesterase 9, 12 ,13.
Complications such as difficulty in breathing, apnoea, aspiration pneumonitis, may occur from inadequate recovery from neuromuscular blockade 14, 15. Late detection of residual paralysis causes serious deleterious physiological consequences like hypoxia, respiratory distress that may necessitate tracheal re-intubation and ventilation; airway obstruction, atelectasis, patient discomfort as well as increased mortality14, 15, 16, hence residual paralysis is considered a public health problem.
Regulatory bodies such as the Association of Anaesthetist of Great Britain and
Ireland (AAGBI) stipulated monitoring of NMBD17 whenever they are administered. Train-of-four ratio of greater than or equal to 0.70 using qualitative assessment is considered safe threshold for adequate recovery from neuromuscular blockade and safe for extubation of tracheal5. Train-of-four ratio of greater than or equal to 0.90 when quantitative means of assessment is used 18.
Long-acting NMBD have been documented to have high risk of respiratory complications resulting from inadequate neuromuscular recovery at low T.O.F ratio of less than 0.70 when qualitative assessment is used and less than 0.90 using quantitative assessment9, 12. The incidence of residual paralysis in patients using quantitative assessment at a T.O.F ratio of 0.90 with accelerometers is 15% 19, 20.
The incidence of residual paralysis is 36% for qualitative assessment at a T.O.F ratio of 0.70 with long-acting NMBD 19, 20. The data on which this conclusion was
17 based are surprising and the correlation of adequate recovery of neuromuscular function from neuromuscular blockade with NMBD using T.O.F ratio of 0.70 as threshold warrants re-examination.
This prospective-comparative study was aimed primarily at determining effective method of monitoring and reversal of neuromuscular blockade and secondly, at evaluating the clinical relevance of peripheral nerve stimulator in monitoring and reversal of neuromuscular blockade by comparing with clinical assessment using the head-lift for 5 seconds, grip strength, swallowing reflex versus qualitative assessment (tactile). The study also evaluated the onset of time for tracheal intubation and time interval for safe tracheal extubation after reversal. The study also determined the time interval to achieve adequate neuromuscular recovery from neuromuscular blockade after empirical reversal with standard anticholinesterase (neostigmine 0.05mg/kg body weight) comparing clinical judgment versus qualitative assessment.
18
AIMS AND OBJECTIVES AIM
This study was designed to determine effective method of monitoring peri- operative neuromuscular blockade and to evaluate post-operative residual paralysis following reversal of blockade.
OBJECTIVES:
1. To evaluate time of onset for tracheal intubation and time interval for safe
tracheal extubation after empirical reversal by comparing qualitative
assessment with clinical assessment.
2. To evaluate the time interval to achieve adequate recovery from neuromuscular
blockade after empirical reversal comparing train of four count assessment
versus clinical assessment.
3. To evaluate complication related to residual paralysis during recovery at the
recovery room comparing qualitative versus clinical assessment.
19
SIGNIFICANCE OF THE STUDY In this sub-region, report of post-anaesthetic complications occurring in the recovery room as a result of residual paralysis had been anecdotal when empirical reversal and clinical criteria are used for monitoring and reversal of long-acting
NMBD. There are probabilities that most residual paralysis resolve spontaneously without clinical intervention by trained recovery room staff or respiratory complications in recovery room are secondary to other anaesthetic causatives apart from residual paralysis 21, 22. This study attempted to quantify the complication of residual paralysis in the recovery room comparing clinical criteria versus qualitative assessment following the use of a long-acting NMBD (pancuronium) in
Lagos State University Teaching Hospital (LASUTH) a tertiary institution located in the south-western region of Nigeria
The outcome of this study will aid in preventing the occurrence of complications of residual paralysis in the recovery room in our institutions in the sub-region. It would also improve sensitivity of anaesthetists to possible complications of residual paralysis in the recovery room and thereby reduce morbidity and mortality.
20
CHAPTER TWO
LITERATURE REVIEW The advent of neuromuscular blocking drugs (NMBD) has brought significant improvement to the practice of anaesthesia. Pioneer anesthetists depended on deep ether anaesthesia for muscle relaxation and analgesia before the advent of NMBD and patients breathe themselves out of anaesthesia spontaneously. Since the advent of NMBD anaesthesia has been redefined as a triad of narcosis, analgesia and muscle relaxation. The discovery of neuromuscular junction (NMJ), the elucidation that D-tubocurarine blocks that junction and introduction of curare into clinical anaesthesia were great events in modern medicine 23.
Neuromuscular blocking drugs were categorized into depolarizing and non- depolarizing agents based on their mechanism of action. The non-depolarizing agents act by binding to alpha sub-units of the post-synaptic nicotinic receptors at neuromuscular junction (NMJ) of skeletal muscles thereby competitively inhibiting the elicited excitatory stimulation of nicotinic receptors by acetylcholine. More than 75% of the receptors must be occupied before any blockade can be detected thereby conferring wide safety margin to NMBD.
The action of non-depolarizing agents can be antagonized at the nicotinic receptors by anticholinesterase whose mechanism of action is by increasing the concentration of acetylcholine at the neuromuscular junction (NMJ) and
21 potentiating excitatory stimulation of the 5 glycoprotein receptors to cause recovery of neuromuscular activity. The depolarizing agent for example suxamethionium (2 molecules of acetylcholine) acts by causing conformational change in the nicotinic receptors of the NMJ leading to changes in electrochemical gradient thereby causing excitatory stimulation that eventually lead to flaccidity(relaxation). The action of suxamethonium is not antagonized by anticholinesterase and characteristically there is no fade in twitch height to peripheral nerve stimulation 23.
D – tubocurarine, a long- acting agent was the first clinically relevant NMBD introduced in 1942 by Oscar Wintersteiner and James Ditcher but was associated with a high incidence of morbidity and mortality 24, 25. The introduction of d- tubocurarine to anaesthesia practice by Gray in 1948 led to the redefinition of balanced anaesthesia 26. The endpoint of d-tubocurarine was determined by obvious movement of a limb during surgery and the reversal of its effect was by prostigmine ( anticholinesterase) in an adequate dose of 3-5mg/kg IV and atropine
1/50 to counter the undesirable parasympathetic effects. Suxamethonium was introduced into clinical practice in 1951 by Foldes et al 27 as close to an “ideal agent” for muscle relaxation and a better replacement for D-tubocurarine because of its rapid onset and fast offset of neuromuscular effect. Reports following several decades of its acceptance revealed adverse effects such as myalgia, fasciculation, masseter and extraocular muscle spasm and malignant hyperthermia 28.
Suxamethonium was not only considered far from been “ideal” because of its
22 inferior safety profile, but also because it loses the fast offset of neuromuscular effect upon its continuous use by causing prolonged blockade (phase II block).
Phase II block occurs when depolarizing NMBD act as competitive antagonist of acetylcholine by blocking receptors at high doses or during continuous infusion.
Suggestion as to how clinical effects of NMBD should be monitored was scant and anecdotal, the best counsel at that era was expressed by Morris et al11, who suggested in 1953 that small doses of anti-cholinesterase (neostigmine) should be administered until ventilatory exchange improved and that additional doses of neostigmine should be given at 5 minutes interval until clinical signs like ability to perform a good head lift for 5 seconds, ability to obey command, grip strength and visible evidence of swallowing reflexes before endotracheal extubation11.
In 1958 Christie and Churchill-Davidson devised a means of monitoring neuromuscular blocking drugs when they are administered. They applied electrical stimulus to a peripheral nerve and observed the evoked response on the innervated muscle end-plate using d-tubocurarine as the neuromuscular blocker 1. This device was improved upon, and by 1965 the first commercially available peripheral nerve stimulator was manufactured as TOF watch device and subjective or qualitative assessment (visual and tactile) became the benchmark of neuromuscular monitoring using the TOF ratio 5.
TOF ratio is defined as the ratio of amplitude of the fourth twitch response to the first twitch response (T4 /T1) and expressing the ratio as a percentage when four
23 stimuli at 2 seconds each are delivered at a frequency of 2 hertz (Hz) and repeated at 12 seconds interval 3, 4. When there are less than four twitches the actual numbers of twitches are documented29, the fourth twitch of the TOF disappears at
75%-80% receptor occupancy, the third twitch disappears at 85% receptor occupancy and the second twitch disappears at 90%-95% occupancy. The absence of visible twitch signifies > 95% block and a TOF ratio of 0.25 30. Fade is a depression in twitch height on a TOF stimulation resulting from presynaptic receptor blockade by NMBD thus causing a reduction in the postsynaptic acetylcholine concentration.
A peripheral nerve stimulator is a portable battery operated device with a constant current range between 30-70mA delivered through a silver-silver chloride electrode of negative and positive charges placed distally and proximally not more than 6 cm apart respectively along the course of a peripheral nerve of a motor end- plate unit. For example the ulnar nerve which supplies the adductor pollicis muscle and other smaller muscles like lumbricoides causing twitches in the thumb with each stimulated contraction. Other neuromuscular units for assessment include the facial nerve using the orbicularis oris or orbicularis oculi muscles and posterior tibial nerve using the leg muscles but these other sites are not often accessible when patients are covered with drapes during certain surgical procedure, or in certain situations like abnormal positions or when cuffs are applied on that limb, there is need to utilize other sites. The facial nerve stimulation approximates the relaxation of the diaphragm better and so is much more reliable for assessment of
24 neuromuscular blockade of laryngeal muscle than adductor pollicis muscle of the
31 thumb .
The adductor pollicis muscle had a poor correlation with the effects of NMBD on the diaphragm and laryngeal muscle hence its selection as a reference point for neuromuscular monitoring is not full proof for complete recovery from neuromuscular blockade 29. The adductor pollicis muscle of the thumb is more accessible than others when patients are draped hence it is routinely utilized for assessment of neuromuscular blockade.
At a reduced TOF ratio of 0.50 or less the diaphragm maintains a normal tidal volume and minute volume for quiet respiration because of its resistance to NMBD relatively compared with upper-airway muscles like geniohyoid, genioglossus and masseter that cannot maintain normal maximum inspiratory and expiratory pressures at TOF ratio 0.50 32. The implication is that the diaphragm plays a major role in maintaining normal quiet breathing and at profound blockade there is a reduction in ability to cough and vital capacity.
The safety of evaluating the adequacy of neuromuscular recovery between conventional PNS monitor using subjective tactile/visual assessment and clinical criteria had not been clearly reported. Meta-analytical reviews of past studies by
Naguib and coworkers 9 demonstrated no superior advantage of monitoring over clinical criteria in reducing risk of postoperative residual paralysis.
25 Perdersen et al 7 randomized 80 subjects to receive TOF monitoring intraoperatively at a count of 1-2 using tactile evaluation and no monitoring using clinical criteria after administration of vercuronium and pancuronium NMBD. The
TOF ratio were then determined in the recovery room after reversal at Train-of- four count of 2 (TOFC). TOFC is defined as the number of visible/tactile TOF twitches elicited peripherally at the thumb during peripheral nerve stimulation. The incidence of postoperative residual paralysis was the same in both groups, 20 out of 40 has a TOF ratio < 0.70.The incidence of PORC was not less in group with monitoring device. The reason for this result could be attributed to deep level of neuromuscular blockade at a TOFC of 1-2 preventing prompt and satisfactory antagonism by anticholinesterase thereby necessitating the use of intraoperative
TOF count to titrate the dose NMBD at the end of surgery.
Shorten et al 33 randomized 39 subjects using pancuronium a long acting NMBD into conventional PNS monitoring at TOF and clinical criteria. Intraoperative monitoring was done using TOF count of 1-2 and reversal by anticholinesterase at
TOFC count of 2. Both groups were monitored at TOF ratio of 0.70 in recovery room. The incidence of PORC was 15% in monitored group and 45% in clinical criteria group using a TOF ratio of 0.70. The outcome of this study may not be significant when considering the sample size.
A recent meta-analysis by Naguib and coworkers9 examined the effect of neuromuscular monitoring (qualitative and quantitative) on incidence of
26 postoperative residual paralysis comprising a total of 3375 patients between 1979 and 2005. They were unable to demonstrate that monitoring of neuromuscular blockade reduces the incidence of postoperative residual paralysis. These conclusions were limited by the quality of individual studies reviewed; they were poorly designed to detect the advantage of monitoring in reducing postoperative residual paralysis. Furthermore, large scale well designed randomized clinical trials are needed to assess the effect of qualitative monitoring on postoperative outcomes.
Ali et al 34 demonstrated a relationship between the TOF ratio and the head lift maneuver for 5 seconds. They reported that TOF of 0.60 guaranteed that subjects had ability to lift their heads for at least 3 seconds. A closer review of this study showed that a 3 second to 5 second head lift does not represent full recovery from neuromuscular blockade and that a head lift of 10 seconds required a TOF ratio of
0.70.
A follow up study by Brand et al 35 in 10 ASA III or IV patients demonstrated that a TOF ratio of 0.70 correlated well with clinical criteria used for tracheal extubation such as ability to sustain eye opening, hand grasp, head lift and tongue protrusion for at least 5 seconds. The validity of this data as a benchmark of adequate neuromuscular recovery remains questionable considering the small sample size of less than a dozen ill patients, the standard of the study was not criticized for 20 years for further reviews. The study was done in 1975, when early
27 patient discharge from hospital was uncommon. Ambulatory surgery was in its infancy and yet to gain popularity and also anaesthetic agents such as diethylether and methoxyflurane were widely used with residual effect on cognitive function affecting level of consciousness.
A follow up study conducted by Kopman et al 36 to investigate the signs and subjective symptoms that might accompany previously “acceptable” levels of neuromuscular block in correlation with TOF ratio of 0.70 with clinical criteria, studied 10 not sedated healthy volunteers using infusion of mivacurium titrated to
TOF ratio of 0.60 to 0.70. They discovered that none of the volunteers required intervention to maintain patent airway and oxygen saturation at room air was 96% at all times. Small decrements in the TOF ratio below 0.70 were accompanied by significant signs and symptoms of muscle weakness. At a TOF ratio of less than
0.70 all subjects were uncomfortable, speaking and swallowing required a great effort and sipping water through a straw became difficult. At a TOF ratio of 0.70, grip strength was decreased in all subjects to 57% of control, range of 44% to 77%.
Grip strength increased to 83%, range of 70% to 105% at TOF ratio of 0.90. This result strongly supports grip strength compared to head lift for 5 seconds as a more sensitive clinical criteria and that satisfactory neuromuscular recovery requires the return of TOF ratio to a value greater than 0.70.
TOF ratio of less than 0.90 have been associated with impaired respiratory hypoxic drive, functional impairment of the muscles of the pharynx and upper esophagus
28 making deglutition difficult37. Eriksson and coworkers in evidence based practice and neuromuscular monitoring suggested routine quantitative assessment at a TOF ratio of 0.90 as safe threshold for adequacy of neuromuscular recovery38.
Gatke et al 39 studied 120 patients randomized into groups using pancuronium.
Acceleromyography (AMG) was used for monitoring of 60 patients, the other group (control) of 60 patients clinical criteria was used. Postoperative TOF ratio for both groups was measured with mechanomyography (MMG). Train-of-four ratio of 0.80 as postoperative residual paralysis, at extubation 17% patients in clinical criteria group had postoperative residual paralysis compared with 3% patients in monitored group. This study showed that the residual paralysis in the control group was greater because the goal of the study was very clear and they may want to prevent postoperative residual paralysis in this group. The study justified quantitative (objective) monitoring in minimizing residual paralysis. The advantage of quantitative over qualitative monitoring had not been completely demonstrated but quantitative monitoring relatively reduces the risk and incidence of postoperative residual paralysis 9.
A prospective study by Baillard et al40 on incidence of postoperative residual paralysis for 3 months period in 1995 using a total of 568 patients documented postoperative residual paralysis to be 42% in recovery room using AMG at TOF ratio of less than 0.70 and 62% at TOF of less than 0.90. As a follow up and a means of reducing the incidence of postoperative residual paralysis the author
29 placed AMG monitors in all operating rooms and educational program about the use of neuromuscular monitoring and the indication for neostigmine reversal instituted. Nine years later the incidence of postoperative residual paralysis reduced drastically from 62% to less than 4%.
This result clearly shows that when NMBD are administered by knowledgeable clinicians and quantitative monitoring is used as adjunct combined with reversal by acetylcholinesterase antagonist (neostigmine), postoperative residual paralysis can be reduced to very low levels. Postoperative residual paralysis is the limitation of currently available NMBD and their antagonist and the incidence had been correlated with factors like the TOF ratio utilized, the type of NMBD, administration of reversal agent and the type of monitoring instituted.
The assumption of replacing long-acting NMBD with newer intermediate-acting
NMBD such as atracurium, cis-atracurium and rocuronium as a means of decreasing PORC was not totally acceptable. Dabaene et al showed that the incidence of residual paralysis with intermediate-acting NMBD range from a low value of 16% to as high as 70% 14.
Kopman et al 41 discovered that during cisatracurium – or rocuronium-induced blockade, pharmacologic reversal administration at a TOF count of 2 required at least 15 minutes, whereas some patients still had significant residual paralysis TOF less than 0.90 at greater than 30 minutes interval after reversal. Another factor responsible is quick administration of reversal agent even when complete recovery
30 from the action of NMBD is not guaranteed to reduce time between cases in day- case facilities. Lastly monitoring is considered as a tool and may not decrease the incidence of postoperative residual paralysis 17.The incidence of postoperative residual paralysis is 12% when intermediate-acting NMBD are used at a TOF ratio of 0.7 compared with 35% obtained in long-acting NMBD.9
Baillard et al 40 reported a high incidence of PORC (42%) using vercuronium an intermediate-acting NMBD without intra-operative neuromuscular monitoring and reversal with neostigmine. May be the incidence of postoperative residual paralysis could have been less if monitoring and reversal agent are instituted. A study done in 2008 by Murphy et al42 of 185 surgical patients randomized to intraoperative
AMG group and qualitative TOF monitoring group revealed that a lower frequency of residual paralysis in recovery room in AMG group (4.5%) at TOF ratio of ≤
0.90 compared with qualitative TOF group of 30.0% (p < 0.001) .
The study affirms that objective means of assessment is safer and more accurate than subjective means of assessment. Limitation to the study was that the TOF ratios derived from AMG are approximately 10% higher than MMG or EMG values thereby requiring normalization by referring to baseline control, for example if control TOF ratio is 1.20, a TOF ratio of 0.90 in recovery room corresponds to a normalized value of 0.75 (90 divided by 120) therefore a TOF ratio of 1.0 at completion of anaesthesia does not reliably exclude the possibility of incomplete neuromuscular recovery with AMG 42.
31 Subjective (qualitative) TOF monitoring do not detect fade at low TOF ratios especially with visual means of assessment and there is increased risk of residual paralysis at TOF ratio of 0.70 43, 44. Qualitative assessment means (subjective) visual or tactile assessment of response to peripheral nerve stimulation. The twitch elicited is dependent on the observer by visual or touch technique which makes it subjective to the observer’s opinion.
Tactile assessment means the movement of patients thumb against the observer’s finger during stimulation at the adductor pollicis muscle. The ratio of the fourth twitch to the first twitch height is the TOF ratio for the patient. The ratio of the fourth twitch height and first twitch height detected visually at the thumb during stimulation is the TOF ratio for visual means of assessment. Tactile evaluations are more sensitive in detecting residual blockade and fade more than visual assessments with influence on the experience of the anaesthetist.45 Viby-Mogensen et al 45 measured the ability of anaesthetist to detect fade using TOF stimulation at varying levels of neuromuscular blockade comparing tactile and visual assessment.
Anaesthetist that are not experienced in tactile fade detection were able to feel fade at TOF ratios < 0.3. The visual assessments were unable to detect fade in 80% of the time when TOF ratios were between 0.5 and 0.7. The results demonstrated the limitations of subjective evaluation of fade eluding majority of anaesthetist.
The most frequently used patterns of stimulation are TOF, DBS and tetanic stimulation. The ability of each mode of neurostimulation to diagnose residual
32 paralysis varies considerably. The DBS neurostimulation for subjective monitoring detects residual paralysis at TOF ratio of 0.6 to 0.7, whereas the threshold for detection of fade for TOF monitoring is 0.4 44.
Double burst stimulation (DBS) is done by application of current at frequency of
50Hz or 100Hz for 0.1 seconds and checking for elicited response. DBS is important in detecting profound block. The post-tetanic count is very reliable for detection of fade and residual paralysis. Elicited by applying 50Hz current for
5seconds and a pause of 2 seconds with a pause then followed by a stimulation of
1Hz.The appearance of the first twitch correlates inversely with the duration of action of NMBD for example intermediate-acting agents first visible twitch is 15-
20 minutes on PTC 42.
The 50-HZ tetanic stimulation pattern is the least sensitive qualitative method of monitoring. Fade can only be reliably detected at TOF ratios of less than or equal to 0.3 with tetanic stimulation 43. Probability analysis showed that when no fade was detected with either TOF or DBS there was still a 47% risk that the true TOF ratio measured by mechanomyography (MMG) was less than 0.7. This demonstrated the sensitivity of quantitative assessment over qualitative assessment in detection of residual paralysis.
TOF ratio of 0.90 was accepted as the safe threshold for residual paralysis after adequate reversal is administered using quantitative or objective monitoring 46.
Quantitative assessment methods for monitoring of neuromuscular blockade
33 include accelerometers (ACC), acceleromyography (AMG), electromyography
(EMG), mechanomyography (MMG), kinemyography (KMG), phonomyography
(PMG). They are modified response to nerve stimulation in form of contraction that is sensed by a transducer and converted to electrical signal which is proportional to the magnitude of muscular contraction and TOF ratio. The amplitude of the electrical signal is measured numerically or graphically and is easily reproducible 47. Mechanomyography (MMG) measures isometric contractions of peripheral muscles in response to ulnar nerve stimulation. MMG had been considered the gold standard until the mid-1990s because of relatively elaborate setup required and bulk of the equipment.
EMG measures the electrical activity of the stimulated muscle (action potential).
The EMG response can be calculated by measuring total area under the EMG curve and its limitation include abnormal signals during electrocautery. EMG responses are very consistent over time apart from this limitation considering the fact that the responses obtain are not subject to changes in the force of myofibril contractility, some experts opined that EMG should be considered the gold standard for neuromuscular monitoring 48. KMG measures the response caused by stimulation of the ulnar nerve at the wrist and the movement at the thumb is measured by the piezoelectric sensor placed between the thumb and index finger.
The movement at the thumb is converted to electrical signal proportionate to the force of contraction obtained by the sensor. KMG is similar to MMG but unlike
MMG is less reproducible because the response is affected by the position of the
34 sensor on the hand. Experts do not recommend KMG to be reliable in clinical settings 49. PMG measures and record the conversion of sound intensity made by isometric muscular contraction by high-fidelity microphone placed alongside the monitored muscle. Studies have documented a high degree of agreement among
PMG, MMG and KMG for determination of recovery from neuromuscular function in the clinical settings50, the use of this technology is not popular and its future development is uncertain. Acceleromyography (AMG) considered the best in clinical settings because of portability and relatively easy to use over MMG and
EMG.
The AMG calculates muscular activity using a miniature piezoelectric transducer attached to the stimulated muscle. The acceleration of the muscle generates a voltage in the piezoelectric crystal that is proportional to the force of contraction.
The precision is improved by application of an elastic preload to the thumb during
AMG monitoring. The use of AMG reduced incidence of postoperative residual neuromuscular blockade. Mortensen et al 51 randomized 40 patients to receive
AMG monitoring or no neuromuscular monitoring, clinical criteria were used to determine dosing and adequacy of reversal. Using TOF ratio of less 0.7 as threshold measured with MMG, the incidence of residual paralysis was significantly lower in the AMG group (5.3%) than in the group without monitoring
(50%). Also, the number of patients with clinical signs of muscle weakness after tracheal extubation was reduced by AMG monitoring.
35 The more commonly used reversal agents are acetylcholinesterase inhibitors for example neostigmine at 0.04-0.05 mg/kg body weight intravenous(I/V), pyridostigmine at 0.04-0.05 mg/kg body weight I/V and edrophonium at 0.5 mg/kg body weight I/V. The mechanism of action of this acetylcholinesterase inhibitors are similar but not identical 53. The catalytic site of acetylcholinerase is blocked and the enzyme is inhibited and as such cause a more prolonged effect of acetylcholine at the NMJ and other sites using acetylcholine transmitter including muscarinic receptors. The effect of acetylcholinesterase inhibitors at the muscarinic receptors should be antagonized with anticholinergic drugs (atropine- like drugs) to prevent cardiovascular (bradycardia), gastrointestinal (gastric motility, vomiting and excessive secretions) and bronchial effects (bronchospasm, bronchoria) and other deleterious effects. Edrophonium have prejunctional effects enhancing release of acetylcholine at the nerve terminal, a useful effect for reversal of deep neuromuscular blockade.
These 3 acetylcholinesterase inhibitors contain quaternary ammonium ions and do not have central nervous system (CNS) effect because they do not cross the blood- brain barrier, glycopyrolate (0.01mg/kg body weight I/V) a quaternary derivative of atropine is the suitable anticholinergic to limits their muscarinic effect. Other acetylcholinesterase inhibitors notably physostigmine and tacrine have profound
CNS effect are best antagonize with atropine (0.02 mg/kg body weight I/V). The use of acetylcholinesterase inhibitors precludes the administration of anti- cholinergic such as atropine (0.02mg/kg) or glycopyrolate (0.01mg/kg) to counter
36 the indirect vagal stimulatory effect of acetylcholinesterase inhibitors on the muscarinic receptors in a ratio of 1:2 proportion or based on body weight.
A high incidence of postoperative residual paralysis had been reported when reversal agents are not given as reported by a study conducted by Dabaene et al 15.
526 patients were given a single intubating dose of an intermediate-acting vercuronium 0.1mg/kg and no reversal administered. The TOF ratios of less than
0.70 in 16% and less than 0.90 in 45% was reported respectively in recovery room, 2 hours later 239 patients were tested, 10% had less than 0.70 and 37% less than 0.90 respectively.
Cadwell et al 54 studied 20 patients in recovery room for a period of 4 hours after an intubating dose of vercuronium 0.1mg/kg was given without reversal agent.
TOF ratios of less than 0.75 in 4 of 20 patients at 2 hours, 3 in 20 patients at 3 hours and 1 in 20 patients at 4 hours were recorded. These studies show a high risk of postoperative residual paralysis when NMBD are not reversed within the immediate postoperative period as also observed by Padmaja and Mantha 55.
A similar study randomized 150 surgical patients to groups where reversal was given and not given after an intubating dose of vercuronium 0.1mg/kg, sixty percent had a TOF ratio of less than 0.80 in group not reversed with acetylcholinesterase inhibitor and 49% in the reversed group in the recovery room
56. The result was not statistically significant as the p > 0.05, but routine administration of reversal of NMBD was recommended as a standard to reduce
37 postoperative residual paralysis as shown by the outcome of the study. Forty nine percent in the reversed group after an intubating dose is alarming and calls for review of this study properly.
A study randomized 120 surgical patients to group monitored by qualitative assessment and clinical criteria for full neuromuscular recovery before tracheal extubation after reversal with neostigmine. Eight minutes was reported as the average time of extubation after reversal at a TOF ratio of 0.67, at TOF ratio of >
0.9, 88% of patients does not fulfill the extubation criteria. At TOF ratio of > 0.7,
58% of patients failed to achieve the degree of recovery for tracheal extubation 57.
Kim et al 58 demonstrated that with neostigmine reversal of 0.07mg/kg at TOF count of 1,2,3,4 respectively after administration of rocuronium following the use of M.M.G-derived TOF ratios of 0.70, 0.80, 0.90, only 55% of the patients had a
TOF ratio of 0.90 within 10 minutes at TOF count of 4. The authors recommended a TOF count of 4 for adequate reversal from rocuronium for 15 minutes, because of significant individual variability of neuromuscular recovery noted among patients. This result supports the demonstrable presence of TOF count of 4 before giving neostigmine reversal. When reversal are given at 1 TOF count, all 4 twitches may be palpable at 10 minutes later with no detectable fade even though
TOF ratio is as low as 0.40. This may be followed by prolonged period of high risk of postoperative residual paralysis 59, 60.
38 Kopman et al 59 antagonize steady-state infusions of NMBD at a single twitch depression of 10% of control, twenty minutes after reversal with neostigmine,
EMG TOF ratios of 0.89 were observed in patients randomized to receive vercuronium. These studies illustrate an important limitation of acetylcholinesterase inhibitors regardless of the TOF count at the time of reversal, it is not always possible to achieve a TOF ratio of greater than 0.9 in all patients within 30 minutes of reversal with acetylcholinesterase inhibitors 61. The use of
NMBD (long-acting, intermediate and short-acting) requires the need for reversal with accholtylinesterase inhibitors because omitting NMBD antagonism introduces significant risk of residual paralysis even with short acting agents 62. Studies from pharmacodynamics suggest that reversal of intermediate-acting agents (cis- atracurium and atracurium ) may require much longer time intervals despite the fact that they both undergo auto-degradation known as Hoffman reaction which is dependent on the body pH and temperature. Payne et al60 reported depression of tetanic contraction and re-establishment of tetanic fade with administration of second dose of intravenous neostigmine for reversal within the interval of 2-5 minutes in patients who had received NMBD. Patients who received no NMBD in a similar study were given 2.5mg of neostigmine, depression of peak tetanic contraction and development of severe tetanic fade lasting longer than 20 minutes was reported. Goldhil et al 61 at TOF ratios of 0.5 and 0.9 administered neostigmine 5 minutes apart after spontaneous recovery from NMBD. The authors reported impaired neuromuscular function and acknowledged that such effects may
39 be short lived. These studies revealed the limitations that may be associated with the use of neostigmine for reversal when administered in successive repetition within a short interval. A ceiling (a higher dose has no benefit) effect had been reported with neostigmine at doses above 0.07mg/kg/iv 63. Efforts had been invested into development of short-acting NMBD with fast and rapid recovery profile that will not depend on acetylcholinesterase inhibitors for reversal of effect for example the chlorofumarate group like gantacurium.
The timely administration of reversal to antagonize the effect of NMBD confers greater advantage over not reversing42,54 and the recovery of neuromuscular function before administration of reversal is recommended at 4 visible twitches without fade or the presence of clinical signs( head lift for 4 seconds) at the end of procedure reduce the risk of developing postoperative residual paralysis 64,65.
Other factors that have been known to increase the risk of developing postoperative residual paralysis includes age of the patient with complications resulting from residual paralysis more common in the elderly and almost not existent in paediatric patients 66. The concomitant use of aminoglycoside antibiotics had been demonstrated to potentiate the effect of NMBD by reducing the acetylcholine release at the pre and post synaptic junction 67. Halogenated compounds (volatile anaesthetics ) for example halothane potentiate the effect of
NMBD by enhancing antagonistic action at the nicotinic receptors. Cardiovascular drugs such as calcium channel blocker (verapamil) had been demonstrated to have
40 sub-clinical effect or no interaction on the action of NMBD. Beta blocker
(esmolol) prolongs the effect of depolarizing neuromuscular blocker by reducing the amount of plasma cholinesterase available for metabolism leading to a potentiation of effect. Local anaesthetics for example, lidocaine, when given intravenously as antiarrhythmic agent potentiate the effect of non-depolarizing
NMBD. Small doses given through the intravenous route depress twitch height by inhibiting transmission at the pre-junctional receptors, large doses inhibit transmission at the post-junctional memebrane and act as a membrane stabilizer, post-operative administration of intravenous local anaesthetics can predispose to residual paralysis. The use of magnesium sulphate infusion in the treatment of conditions like preeclampsia and eclampsia also has potentiating effect on the depolarizing and non-depolarizing NMBD. Magnesium decreases the amount of acetylcholine release in the nerve terminal and the contraction of the muscle fiber and the amplitude of the end-plate potential.
Local disease conditions like muscular dystrophies, mysthenic syndrome and myasthenia gravis, cerebrovascular accidents with neurological deficit, spinal cord transection, hypothermia and hyperthermia, conditions of electrolyte imbalance, conditions of renal and hepatic impairment, and certain group of individuals categorized as slow acetylators. The categories of the afore-mentioned patients will benefit from peripheral nerve stimulator monitoring whether by qualitative or quantitative assessment during surgical procedure to determine degree of muscle relaxation desirable for enabling surgical conditions with safety margins.
41 Another altenative to the use of acetylcholinesterase inhibitor was the development of a modified gamma cyclodexterin agent tagged Organon 25969, an agent that form an inactive complex in a ratio 1:1 with aminosteroid containing NMBD thereby inhibiting their action 68. The agent later called ‘Sugammadex’ has more affinity for rocuronium and decreasing specificity for vercuronium and pancuronium respectively with a high association rate rather than dissociation and the guest-host complex is stable and in equilibrium. Other approaches include the use of aminoacids for example cystiene which facilitates the rapid conversion of chlorofumarate NMBD like gantacurium into inactive derivatives thereby limiting further action 69. However limitations encountered with qualitative monitoring led to the adoption of quantitative monitoring to reduce morbidity and mortality associated with residual paralysis but currently available quantitative monitoring devices are fragile, complex, requires time to set up in clinical practice 52, 70, 71.
Future directions in the monitoring and reversal of neuromuscular blockade include exploration of new NMBD whose neuromuscular action is not dependent on acetylcholinesterase inhibition alone for reversal combined with adequate quantitative monitoring with avoidance of total twitch suppression. However more studies to provide input into how NMBD should be monitored and reversed in the peri-operative period in our institutions are highly desirable.
42
CHAPTER THREE
METHODOLOGY
STUDY DESIGN This was a prospective randomized controlled double-blinded study conducted at the Lagos State University Teaching Hospital (LASUTH), a tertiary institution located in Lagos State, South-western region of Nigeria, between April and June,
2014.
STUDY SAMPLE Adult surgical patients undergoing procedures in Gynaecology, Urology,
Orthopaedics and General Surgery at the Lagos State University Teaching Hospital
(LASUTH) were recruited for the study within the 3-month duration.
SAMPLE SIZE DETERMINATION The minimum sample size for this study was calculated based on the data by
Shorten et al33 with 85% being coefficient of variation and power or accuracy of
80%. A power analysis72 was performed with the following assumptions: two groups (TOF monitoring and clinical assessment); unpaired t test (significant at p <
0.05); difference in prevalence of residual paralysis considered clinically important at TOF monitoring group of 15% and clinical test group of 45%.
2 2 n = [(Z + Zβ) (P1(1-P1) + (P2( 1-P2)] / ( P1-P2)
Where n = minimum sample size per group
43 Z = Standard normal deviate corresponding to 95% Confidence Interval = 1.96
Zβ = Percentage point of the normal distribution with power of 80% = 0.84
Previous studies comparing clinical judgment and qualitative monitoring put incidence of residual paralysis as 45% and 15% respectively33.
P1 = Incidence of residual paralysis control group = 45% = 0.45
P2 = Incidence of residual paralysis study group = 15% = 0.15
Thus,
n = (1.96 +0.84)2(0.45(1-0.45) + (0.15(1-0.15) / (0.45-0.15)2 n = 7.84 (0.375) / 0.09 n ≈ 32 minimum sample size
Attrition was corrected for by adding 10% of this minimum sample size to arrive at approximately 35 subjects per study group, making a total of 70 altogether.
INCLUSION CRITERIA: 1. Adult surgical patients aged 18 to 65 years
2. Patients with American Society of Anesthesiology (ASA) I and II physical
status
3. Patients undergoing surgical procedures that required muscle relaxation with
long-acting NMBD (Pancuronium Bromide) under general anaesthesia
expected to last for more than 40 minutes.
4. Patients with body mass index < 35 Kg/m2
44 EXCLUSION CRITERIA: 1. Patients aged less than 18 or greater than 65 years were excluded
2. Patients with hepatic, renal, neuromuscular disease, or electrolyte imbalance
3. Patients with body mass index > 35 Kg/m2,
4. Patients with anticipated difficult oro-tracheal intubation, greater than
mallampatil II or those undergoing procedures with less than 40 minutes
duration
5. Patients on medication known to interfere with NMBD
6. Patients with history of hypersensitivity to amino-steroid NMBD or any
medication used in the study were also excluded
7. Patients that refuse to give consent to the study.
TECHNIQUE All the patients were visited a day prior to surgery during which the study protocol was explained. This also included explanation on the use of peripheral nerve stimulator in the operating and in the recovery room. Patients were weighed and their weights recorded in kilograms (Kg). The heights of the patients were also measured in meters (m) with detailed documentation of individual body mass index (BMI) using the formula weight (Kg) / height (m).2 Preoperative data collected by the researcher with the help of the registrar anaesthetist were recorded using the pro-forma (Appendix I).
45 Patients were randomized into groups of 35 by systematic assignment of hospital numbers into columns and rows. Patients with even hospital numbers were assigned to the control group (P1) or clinical judgment group. They had no neuromuscular monitoring during surgery and were extubated based on clinical parameters: head lift for 5 seconds, hand grip strength, ability to obey command five minutes after reversal with neostigmine 0.05mg/Kg/IV. Patients with odd hospital numbers were assigned to the study group (P2) who had PNS monitoring during surgery at TOFC count of 2 at the adductor pollicis muscle (tactile) at a constant current of 70 mA on the ulnar nerve using PNS (Life Tech Ezstim II.
Model ES400).
ANAESTHETIC PROCEDURE All Patients in both groups had anaesthesia induced with propofol 1.5-2.5mg/kg body weight I/V after a pre-induction dose of fentanyl at 1.5µg/kg body weight
I/V. Endotracheal intubation was facilitated with a single dose of 0.1mg/kg I/V of pancuronium bromide as a standard protocol for the both groups and onset of intubation time interval for both groups recorded in the study pro-forma using disappearance of spontaneous respiration for clinical assessment group and absence of twitch on stimulation for the PNS group. Additional increments was administered using 1/5th of the loading dose by the senior registrar anaesthetist in the operating room as required by clinical assessment group when spontaneous respiratory efforts was noticed as indicated by visible curare cleft and PNS group when TOFC count was more than 2 counts.
46 The two groups had standard basic monitoring of blood pressure (Non-invasive blood pressure apparatus), oxygen saturation SPO2 and heart rate (pulse- oximeter), end tidal carbon-dioxide analysis (ETCO2), external temperature measurement (thermistor) during surgery. Anaesthesia was maintained with halothane at a minimum alveolar concentration (MAC) of 0.75% in 100% oxygen.
Additional analgesia was given as required by the patients using fentanyl at 1.5
µg/kg body weight I/V.
All subjects were given reversal with empirical standard dose of intravenous neostigmine at 0.05 mg/kg body weight and atropine at 0.02 mg/kg body weight after 1 hour from the last dose of pancuronium administered at the completion of the procedure. The duration of anaesthesia was recorded in minutes for both groups from induction time to extubation time. Time interval in minutes when extubation was completed five minutes after reversal using clinical parameters: head lift for 5 seconds, hand grip strength by hand shake, ability to obey command was documented in the clinical assessment group. The time interval for safe extubation after reversal in study group at TOFC Counts of 3 or 4 was noted. Patients with absent or delay in appearance of head lift for at least 5 seconds, grip strength and ability to obey command as clinical signs or patients with tactile TOFC count of ≤
2 after 5 minutes following reversal were considered to have prolonged extubation time interval.
47 The time to achieve adequate recovery of neuromuscular function using TOF ratio of ≥ 0.70 for both groups was recorded in the recovery room using the ratio of the fourth twitch height over the first twitch height extrapolated in the recovery room.
Patients with T.O.F ratio of < 0.70 after 30 minutes in the recovery room were considered for residual paralysis and the frequency was compared between the two groups. Patients that sustained complications from residual paralysis were given interventions such as administration of supplemental oxygen via facemask in the recovery room for mild hypoxia, severe respiratory complications was re-intubated and manually ventilated in the operating room till when spontaneous respiratory efforts were satisfactory for extubation as indicated by the endtidal capnograph, inspiratory pressure and expired tidal volume. The re-intubated patient was discharged from recovery room to high dependency unit (HDU) for close monitoring of vital signs (Blood pressure, SpO2, heart rate, respiratory rate) for 4 hours. Frequency and degree of complication resulting from residual paralysis were noted.
The following indices and variable were recorded in the pro-forma:
1. Duration of procedure (interval from induction of anaesthesia to extubation
2. Adequate neuromuscular recovery time interval
3. Extubation time interval after reversal
4. Total dose of pancuronium
5. Supplemental increments of pancuronium
48 6. Complications of resdidual paralysis in recovery room after 20 minutes and
30 minutes;hypoxia, tachypnoea,decrease respiratory rate <8cpm or apnoea,
7. Re-intubation or supplemental oxygen administration.
TOF Application Device:
TOF monitors applied a TOF stimulus through cutaneous self-adherent ECG electrodes affixed to the skin overlying the distal ulnar. Prior to application of
NMB, a supramaximal stimulus level was determined. The adductor twitch response was monitored and was assessed by feeling the patients thumb movement
(tactile) after ulnar stimulation. The TOF monitoring was continuous at supramaximal current of 70 mA intraoperatively for the monitored group at TOFC of 2.
49
Definitions of Terms:
1. Onset time for intubation: Time interval in minutes from administration of
pancuronium to when there is twitch disappearance for PNS group/ clinical
group when the spontaneous respiration disappears.
2. Safe extubation time: Time interval in minutes after empirical reversal when
endo-tracheal tube is removed safely.
3. Time to achieve adequate recovery of neuromuscular blockade: Time interval in
minutes when extubation is done to when patient attains a TOF ratio of 0.70 and
above or presence of good head lift for 5 seconds, ability to obey command,
good hand grip strength of 70% of control.
4. Respiratory Rate: The number of spontaneous breaths in one minute
(cycles/minutes).
i. normal value = 16-20 cycles/minutes
ii. -hypoventilation:< 8cycles/min
iii. -hyperventilation:>25cycles/min
5. Hypoxia: defines as oxygen saturation of less than 92% in room air oxygen
(SpO2 < 92%).
Complications of Residual Paralysis:
1. Hypoxia defined as an oxygen saturation of < 92% on room air oxygen
50 2. Hypoventilation defined as a respiratory rate of < 8cycles per minute
3. Aspiration pneumonitis (Mendelson’s syndrome) defined as chemical injury
to resulting from inhalation of sterile gastric contents.
4. Atelectasis defined as complete or partial collapse of a lung or lobe of a
lung.
5. Difficulty in swallowing
6. Double vision
ETHICAL CONSIDERATION A written approval for this study was obtained from the LASUTH Ethical
Committee. Individual informed consent was also obtained from the patients
(Appendices III and V). Patients enrolled were educated on the benefit of the study with respect to monitoring at no financial implication on the patients.
DATA ANALYSIS Data collected on the study pro-forma were entered into a personal computer and analyzed with the Statistical Package for Social Sciences (SPSS) version 16 (SPSS
Inc., Chicago, Illinois). The independent samples t test was used to compare means of continuous variables between the study and control groups while the chi-square test was used to determine differences in proportions as appropriate. Level of statistical significance was determined at p values less than 0.05. Results were presented in tables, pie and clustered bar charts.
51
CHAPTER FOUR
RESULTS
Seventy surgical patients belonging to ASA I or II classifications, aged 18-65 years were studied in the two groups. There were 35 patients in each of the two groups.
Table I displays the demographic data and the duration of anaesthesia and surgery between the two groups. Age range was 18-65 years with a mean of 38.5 ± 9.7 years in the control group which was similar to a mean of 39.2 ± 12.4 years in the study group. Both groups showed male preponderance of similar magnitude. There were more ASA I patients in both groups than ASA II patients. There was no significant difference in the duration of anaesthesia between the two groups. The average mean duration of anaesthesia was 86.1± 45 minutes.
Figure I shows the distribution of the four different surgical specialties studied.
Majority of the cases were general surgical (GS) procedures, 40 (58.2%) patients,
14 (20%) from gynaecology, 9 (12.5%) from urology and 7 (10%) from
Orthopaedic surgery.
The time interval in minutes for onset of intubation and safe extubation time as well as the interval to achieve adequate recovery from neuromuscular blockade are shown in Table II. The mean time interval in minutes for onset of intubation in the control group was 2.46 ± 1.31 minutes, the mean time interval in minutes for onset
52 of intubation in the study group was 3.49 ± 1.07 minutes. This result was statistically significant between the two groups (p = 0.001).
The mean extubation time interval in minutes for the both control and study group was 11.36 ± 2.71 and 9.28 ± 2.57 minutes respectively. (p = 0.01).This result was significant statistically. Mean time interval to achieve adequate recovery of neuromuscular function in minutes for the control group was 41.36 ± 6.08 minutes while the mean time interval of 39.28 ± 3.61 minutes was recorded for the study group. This result was also statistically significant. (p = 0.013).
Table III: shows the TOF ratio in the recovery room at 20 minutes and 30 minutes.
Twenty (57.7%) patients in the control group and eight (22.9%) patients in the study group at a TOFC count of 4 had a TOF ratio of less than 0.7 (70%) at 20 minutes. Fifteen (42.9%) patients in the control group and six (17.1%) patients in the study group at a TOFC count of 4 had a TOF ratio of less than 0.7 (70%) at 30 minutes. This result shows a statistically significant difference between the two groups (p = 0.003).
Table IV shows complications in the recovery room after 30 minutes. A total number of twenty one patients (30%) had complications associated with residual paralysis in the two groups at TOF ratio < 0.7. Fifteen (43%) patients in the control group and six (17%) of the patient in the study group had complications of residual paralysis. This result shows a statistically significant difference between the two groups (p = 0.001). A total of 14 (66%) patients in both groups had hypoxia with
53 SpO2 ≤ 92% on room air oxygen, nine (64%) in the control group and five (36%) in the study group that was resolved by supplemental facemask oxygen (Figure 2).
Table V shows intervention instituted for the complications. Four (19%) had abnormal breathing pattern, three in the control group and one in the study group, three was resolved by supplemental facemask oxygen and one re-intubated and manually ventilated in the operating room. Three (14%) of the patients in control group had hypoventilation at RR of less than 8 cycles/minutes that was resolved with re-intubation and manual ventilation in the operating room (Figure 3). None of the patients had aspiration pneumonitis from residual paralysis in the recovery room and no patient recorded atelectasis on the ward.
54
TABLES AND FIGURES
TABLE I: DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF PATIENTS
Variables Control group Study group P value (n = 35) (n = 35) Age (years) Mean± SD 38.5 ± 9.7 39.2 ± 12.4 0.220 Gender (M:F) ratio 20:15 22:13 0.626 ASA I:II 20:15 20:15 1.000 BMI (Kg/m2) 28.7 ± 2.9 28.7 ± 2.7 0.410 Duration of anaesthesia (min) 98.4 ± 57.0 74.6 ± 34.0 0.080 Duration of surgery (min) 85.4 ± 57.0 65.3 ± 31.0 0.130 Dose of Pancuronium 5.76 ± 0.52 6.00 ± 0.00 0.030 Incremental Dose 2.71 ± 1.25 1.86 ± 0.90 0.170
55
FIGURE 1: DISTRIBUTION OF PATIENTS BY SURGICAL SPECIALTIES
56 TABLE II: SHOWING TIME INTERVAL IN MINUTES FOR INTUBATION ONSET, EXTUBATION TIME AND ADEQUATE RECOVERY OF NEUROMUSCULAR FUNCTION TIME.
Variables Control group Study group P value (n = 35) (n = 35) Onset of intubation 2.46 ± 1.31 3.40 ± 1.07 0.001 Extubation time interval 11.36 ± 2.71 9.28 ± 2.57 0.010 Adequate recovery 41.36 ± 6.08 39.28 ± 3.61 0.013
57
TABLE III: SHOWS THE TOFC COUNT AND THE TOF RATIO BETWEEN THE TWO GROUPS AT 20 MINUTES AND 30 MINUTES Control group Study P value group n(%) n(%)
TOFC At 20 min TOF Ratio At 20 min
≤ 0.7 20(57.1) 8(22.9) 0.003
4 ≥ 0.7 15(42.9) 27(77.1)
TOFC At 30 min TOF Ratio At 30 min
≤ 0.7 15(42.9) 6(17.1) 0.140
4 ≥ 0.7 20(57.1) 29 (82.9)
TOFC - The number twitches at the thumb during stimulation with PNS measured by tactile evaluation.
TOF Ratio (T4/T1) - Ratio of the fourth twitch height to the first twitch height.
58
59
TABLE IV: SHOWING COMPLICATIONS BY CONTROL AND STUDY GROUP IN RECOVERY ROOM AFTER 30 MINUTES. Complications Control Study Total (n=21) P-value group group n(%) n(%) n(%) 9(64%) 5(36%) 14(100.0%) 0.230 Hypoxia 3(75%) 1(25%) 4(100.0%) Irregular / shallow breathing Hypoventilation 3(100%) 0 (0%) 3(100.0%)
60
FIGURE 2: DISTRIBUTION OF COMPLICATION BY CONTROL AND STUDY GROUP.
61
TABLE V: SHOWING COMPLICATIONS AND INTERVENTION IN RECOVERY ROOM AFTER 30 MINUTES.
Complications Intervention Intervention Total (n=21) Facemask Intubation n(%) n(%) n(%)
Hypoxia 14(100%) 0 (0%) 14(100%) 3(75%) 1(25%) 4(100%) Irregular shallow breathing 3(100%) 0 (0%) 3(100%) Hypoventilation
62
FIGURE 3: DISTRIBUTION OF COMPLICATION AND FACEMARK / RE-INTUBATION INTERVENTION
CHAPTER FIVE
DISCUSSION
Inadequate recovery from neuromuscular blockade called residual paralysis causes adverse postoperative respiratory complications that are potentially lethal to patients in recovery room, when severe and undiscovered 9. Residual paralysis is considered a serious health problem because morbidity resulting from hypoxia, acute respiratory failure, pulmonary collapse and aspiration of gastric content may lead to prolonged hospital stay, unnecessary cost implication, permanent brain damage or death 14,15,16.
63 The long-acting NMBD “Pancuronium” used in this study is readily available and affordable for day to day practice of anaesthesia. Pancuronium had been associated with three-fold higher risk of residual paralysis9, but on the contrary various studies reported low incidence of postoperative respiration complications in the recovery room. A Study done by Murphy et al 42 showed disparity between a high incidence of residual block at 35% and low incidence of respiratory events at 0.8% in the recovery room. The high disparity showed that critical respiratory events from residual paralysis may have been overstated otherwise residual paralysis in the recovery room are often overcome by the patients without intervention when neuromuscular block monitors are not utilized, especially when transient. Abdy 21 in an audit of respiratory complications in the recovery room, reported that respiratory complications were due to other anaesthetic causatives rather than residual paralysis. Abdulahi 22, who conducted a study on post-operative anaesthetic complications in the recovery room at University College Hospital
(Ibadan) reported that a large proportion of respiratory complications in the recovery room were due to other anaesthetic causes other than residual paralysis from NMBD. The findings of these studies are different from those of the present study which obtained a high incidence of residual paralysis at 30% associated with an increase frequency of postoperative respiratory complications in the recovery room. This present study clearly demonstrated the importance of the continuous present of anaesthetist in the recovery room to detect residual paralysis in its transient form and the sensitivity of neuromuscular block monitoring. The finding
64 of this present study also differentiate between the high “awareness” and “false positive” result that may be created by the presence of sophisticated neuromuscular monitor over the long time reliable clinical assessment 73.
Monitoring of neuromuscular blockade through clinical assessment or by peripheral nerve stimulator in the peri- operative period as compared by the present study had shown statistically significant difference in the time interval safe for extubation between the two groups (p< 0.05). The control group had a mean time interval of 11.36 ± 2.71 post reversal while the study group had a mean time interval of 9.28 ± 2.57 post reversals. This finding showed that the study group patients recovered from neuromuscular blockade faster than the control group. The logical explanation for this finding is linked to the TOFC guided incremental dose of NMBD administered in the study group. This demonstrated the benefit of qualitative monitoring (tactile TOFC) over the clinical assessment in reducing the risk of residual paralysis and pharmacoeconomic advantage of using lower doses of NMBD. The finding by this present study is similar to the findings of studies done by Rudis et al74 and Zarowits et al75 that demonstrated faster recovery and reduction in dose requirements of the NMBD monitored group. Prielipp et al 76 and
Strange et al 77 in their studies obtained contrary reports that showed no demonstrable beneficial advantage of monitoring qualitatively with a peripheral nerve stimulator over clinical assessment. The discrepancy noticed between these studies had a direct link on the NMBD utilized for the studies. Rudis et al74 and
Zarowits et al75 used vercuronium whose elimination pathway is dependent on
65 renal and liver function for clearance as opposed to atracurium and Cis-atracurium cleared independent of end-organ function indicating their less association with residual paralysis used by the latter studies.
The present study also reported a statistically significant difference in the onset of intubation time interval between the two groups. The control group using the time interval the swallowing reflex disappears had onset of intubation at a mean time interval of 2.46 ± 1.31 minutes and study group using the time interval for total twitch disappearance was recorded at a mean time interval of 3.49 ± 1.07 minutes.
This study showed a faster onset of intubation time interval when clinical test of disappearance of swallowing reflex was utilized for monitoring as compared with when subjective (tactile) monitoring was used. The onset of intubation time after intravenous administration of NMBD is a reflection of the time by which about
90% to95% of the neuromuscular junction (NMJ) receptors had been blocked30.
The difference in the onset time of intubation between the two groups is due to variation of individual skeletal muscle groups to the effect of NMBD 29, 31.The adductor pollicis muscle responsible for thumb movement during tactile evaluation of neuromuscular stimulation has a slower onset of block being a slow twitch muscle as compared with the laryngeal and pharyngeal muscles that are fast twitch muscle responsible for swallowing. The finding by this present study is similar to the findings by Yusuf et al 77 that reported the onset of intubation at 2.3 ± 0.8 minutes (135.8 ± 46.23s) though the NMBD utilized for their study was atracurium
66 and the best intubating response was obtained using suppression of swallowing reflex.
The time interval to achieve adequate neuromuscular recovery was discovered by this present study to be statistically significant between the two groups. The control group achieved adequate neuromuscular function at a mean time interval of 41.36
± 6.08 while a mean time interval of 39.28 ± 3.61 was recorded for the study group. This study showed that at 20 minutes after reversal at TOFC of four, 77.1% of patients in study group at 39.28 and 42.3% in control group at 41.36 ± 6.08 respectively had adequate neuromuscular recovery at TOF ratio > 0.7 (70%).
The finding by this study demonstrated the advantage of neuromuscular blockade monitoring over the clinical assessment. This present study showed a total of thirty six (51.4%) patients in the two groups were not adequately recovered at 20 minutes after reversal at a TOFC of 4 using TOF ratio of 0.7 as cut off point. Twenty eight patients (57.7%) in the control group and eight (22.9%) in the study group had
TOF ratio < 0.7 after reversal at a TOFC count of 4 at 20 minutes. Also, at 30 minutes after reversal at TOFC count of 4, fifteen patients (42.9%) in the control group and six (17.1%) in the study group had a TOF ratio of < 0.7 in the recovery room. This study demonstrated a delayed extubation time in the clinical assessment group and a tendency to prolong recovery of neuromuscular function. The findings of this study correlate with the findings of the studies by Perdersen et al7 and
Kopman et al36 that reported clinical test as inadequate for safe threshold of
67 adequate neuromuscular recovery. These two studies reported a correlation between the clinical test (head-lift for 5 seconds) and average TOF ratio of 0.62 ±
0.09. Similar finding was also obtained in the studies done by El Mikatti et al78 and
Engbaek et al79 that reported a high incidence of residual paralysis and delayed extubation time when most patient could perform headlift at 5 seconds at TOF ratio of 0.6. These studies corroborate with the finding of the present study proving clinical test (head-lift of 5 seconds) inadequate and does not clinically correlate with TOF ratio of 0.7 (70%). Band et al35 showed that good correlation exist between response to TOF stimulation and clinical recovery of neuromuscular function and they confirmed a TOF ratio of ≥ 0.7 safe for adequate neuromuscular recovery. The major limitation to their study which supports the finding of the present study that shows clinical test not to be a good correlation with response to
TOF ratio is that, a true TOF ratio of > 0.7 may be difficult to determine subjectively and lastly a high percentage of failure to detect fade at TOF ratio of
0.4-0.7 when tactile evaluation is used for assessment.
The hand grip strength used as the other clinical test apart from head-lift for 5 seconds had also been shown by studies reviewed in the literature to be an insensitive indicator of residual paralysis. Russell et al 80 found out in their study that voluntary hand grip force can be quantified and use as a measure of postoperative residual paralysis. The major disadvantage of handgrip strength is that it is dependent on all the factors that govern patient’s co-operation and it is reduced to 77% of control value by inhalational agents.
68 Gal et al 81 documented in their study that the hand-grip strength is reduced to 6% of its control value when maximum inspiratory pressure (MIP) and vital capacity
(VC) are decreased to 40% and 30% of control values respectively. Pavlin et al 82 noted a complete absence of hand-grip strength at MIP of 20 cm H2O. O’Connor et al 83 discovered in their study that hand-grip strength is a very sensitive test but substantially decreased when a five seconds head-lift can be sustained corresponding to a degree of skeletal muscle weakness. This present study reported similar findings to O’Connor et al 83 that a satisfactory head-lift of 5 seconds does not correlate well with a hand-grip strength measured by hand-shake which is too subjective. Patients reported signs of inadequate neuromuscular function such as double vision, difficulty in swallowing at TOF ratio of 0.6 because the time course for skeletal muscles controlling these actions to recover from neuromuscular blockade is markedly longer than that of peripheral skeletal muscle groups such as larynx, diaphragm, hand and face. The result of TOF response obtained at the adductor pollicis depends on the functional relationship between the airway muscles and the peripheral skeletal muscle groups 37. Hutton et al 84 in their study discovered that clinical tests are insensitive test of complete antagonism of residual block and not reliable for assessment of adequate recovery of neuromuscular function.
Grayling et al 85 showed in their survey that some anaesthetists depend primarily on clinical test to determine suitability for tracheal extubation and the head-lift for
5 seconds was the highest test used. The finding by this present study clearly
69 revealed the risk and potential hazards patients are exposed to whenever neuromuscular block recovery is totally dependent on clinical assessment for tracheal extubation.
The result obtained at 30 minutes after reversal showed that 57.1% of the control group and 82.9% of the study group had TOF ratios of > 0.7 was not statistically significant. This result at 30 minutes after reversal demonstrated that as the time elapsed more NMBD were diffused and more receptors were available for neuromuscular transmission and this help the return of normal neuromuscular function in the peripheral muscles and as such patients were more awake to perform hand grip, eye opening test. The clinical tests requires awake and cooperative patients which may not be possible in the immediate postoperative period, this explains the reason why more patients 14.1% in the control group and
5.8% in the study group were ready for extubation after waiting for additional 10 minutes interval after reversal.
This current study also discovered that the depth of neuromuscular blockade at the time of administration of reversal play a vital role in the rate and degree of adequate recovery from neuromuscular blockade. At TOFC count of four (57%) of control group and (22.9%) of study group had a TOF ratio of less than 0.7 at 20 minutes and these patients were not ready for extubation. This result showed that
77% patients were ready for extubation at 20 minutes after reversal in the study group than the 42% in the control group therefore more patients had tracheal
70 extubation prolonged in the control group. At TOFC count of 4 (57%) and (82.9%) in the control and study group respectively were ready for extubation at 30 minutes.
A similar study by Kim et al 58 as reviewed in the literature reported a shorter duration of time to achieve adequate recovery of neuromuscular function when reversal is given at TOFC count of 4 with exclusion of fade than when giving at
TOFC counts of 1,2,3 respectively. Kopman et al 59 in their study discovered a shorter duration of reversal for neuromuscular blockade at 10% depression of twitch height from control than reversal at TOFC count of 2. These studies illustrate an important limitation of anticholinesterase drugs showing that regardless of TOFC count at reversal, it is not always possible to achieve a complete recovery of neuromuscular function in 30 minutes. The current study reflect that at 30 minutes after reversal in the recovery room 15 patients (43%) in the control group and 3 patients (7%) in the study group had not recovered completely from neuromuscular blockade.
This present study reported statistically significant findings at TOF ratio of 0.7 between the two groups after 30 minutes in the recovery room. After 30 minutes in the recovery room this study reported a total of twenty one patients (30%) had not recovered completely from neuromuscular blockade (residual paralysis) in the two groups. Fifteen (43%) in the control group and six (17%) in the study group when reversal was done at TOFC of 4 sustained residual paralysis. (p=0.003). The
71 finding by this present study is similar to that observed by Shorten et al 33 who reported a statistically significant difference in incidence of residual paralysis between the two groups. They showed that 15% of the study group patients monitored by tactile assessment and 45% of patients in the control group with clinical test had residual paralysis respectively. Baillard et al 40 as reviewed in the literature reported a reduction in the incidence of residual paralysis in their patients in the recovery room between1995 to 2004 when intra-operative monitoring PNS was utilized. The incidence of residual paralysis was observed to have decreased from 60% to 2% and reversal increase from 6% to 42% respectively (p = 0.001).
The findings by these studies are similar to those of this present study which clearly demonstrated a reduction in the occurrence of complications secondary to residual paralysis in the group monitored with a peripheral nerve stimulator.
Most studies reviewed in the literature found a higher incidence of residual paralysis in the clinical assessment group than the TOF monitored group.
However, Gatke et al 39 reported the incidence of 17% residual paralysis in the non-monitored group and just 3% in the monitored group at TOF ratio of 0.8. This is similar to the findings from the present study.
The report of those studies showed that subjective monitoring reduce the incidence of residual paralysis relatively when compared with bed side test of clinical recovery, the 5 seconds head lift. The reason for the higher incidence of residual paralysis obtained in the clinical assessment group as supported by most of the
72 studies reviewed in the literature could be attributed to the facts that, the simple clinical tests must be interpreted in the light of the well-recognized differential sensitivities of different skeletal muscles to the effects of NMBD. Since the most important neuromuscular functions are pulmonary ventilation, airway protection and maintenance of airway patency, “ideally recovery in these muscles should be measured directly.” A reasonable and practicable alternative is to assess muscle groups in which recovery is consistently preceded by that in the diaphragm and muscles of the upper airway.
Miller and coworker 86 discovered in their study the logic of using the response to peripheral nerve stimulator to estimate residual paralysis” the diaphragm recovers from the effects of NMBD more rapidly than does the adductor pollicis and, at a
TOF ratio of 0.7, vital capacity returns to normal (15-20ml/kg) and maximum inspiratory and expiratory force are slightly depressed (-20 to -25 cm H2O).” A train-of-four ratio of ≥ 0.7 is commonly accepted to indicate adequate recovery from neuromuscular blockade. The upper airway muscles (masseter, genioglossus, geniohyoid) are considered to be more sensitive than adductor pollicis of the thumb in response to NMBD and the recovery rate faster than that of the diaphragm. A study by Band et al 35 reported similar findings but recent studies by
Isono et al 87 reported that muscles involved in upper airway function and protection may be more sensitive to the effects of small degree of residual paralysis.
73 Murphy et al 42 demonstrated in their study a statistically significant difference between qualitative (subjective) and quantitative (objective) monitoring in reducing residual paralysis. The incidence of residual paralysis was (4.5%) in the quantitative group at a TOF ratio of 0.9 as compared to (30%) in qualitative group.
(p=0.001) .This current study had demonstrated a reduction in the incidence of residual paralysis when neuromuscular monitoring using peripheral nerve stimulator (subjective) is utilized.
A clear policy statement on practice and guidelines to proper management of neuromuscular block had been elusive, regulatory bodies and various authors suggests from professional organizations on management of neuromuscular blockade.88
Association of Anaesthetis of Great Britain and Ireland (AAGBI) stipulated neuromuscular monitoring with PNS for NMBD17, Australian and New Zealand college of Anaesthetists has a professional standard on recommendations on monitoring during anaesthesia. American Society of Anaesthesiology (ASA) does not recommend routine neuromuscular monitoring. The recent report of the ASA task force on post anaesthetic care 89 stated that” assessment of neuromuscular function primarily includes physical examination and on occasion may include neuromuscular monitoring.”
Views on monitoring and reversal of neuromuscular blockade during administration of NMBD differ among anaesthetists globally. A Survey conducted
74 online by Naguib et al 90 on the routine use of neuromuscular monitors showed that
70.2% of European anaesthetist out of 52.2% and 22.7% of American anaesthetist out of 64.1% that responded have neuromuscular monitors. However, 19.3% of
European and 9.4% of Americans never use neuromuscular monitor respectively.
The conclusion was that the use of neuromuscular monitors was far from routine despite the high frequency and problematic sequelae of residual neuromuscular block. This survey was not accurate because the respondents were authors interested in neuromuscular blocking drugs monitoring. The anaesthetists that had never used neuromuscular monitor stated reasons such as “the device is fragile and complex to interpret and takes time to set up.” The cost of the device was not stated among the reasons why some practitioners are not using the neuromuscular monitors during the administration of NMBD because one of such devices, T.O.F watch, costs about $500 (USD). Poor-resource countries may present cost as a constraint to the routine use of neuromuscular stimulators.
Preliminary audit conducted at Lagos State University Teaching Hospital Lagos,
Nigeria among all grades of anaesthetists by the author using audit form Appendix
II showed poor knowledge on the use of neuromuscular monitors for monitoring of
NMBD. The audit showed that twenty-five (83%) that responded included consultant and residents (junior and senior), sixteen (65%) have heard about peripheral nerve stimulators for neuromuscular block monitoring. About 20% of the consultant who had seen one know how to use the device, 85% of residents had seen it before but had no experience with the device while 2% of the consultant
75 claimed to have actually utilized P.N.S but not routinely for neuromuscular monitoring perioperatively. The poor knowledge of anaesthetist on neuromuscular monitors does not account to large incidence of residual paralysis in this institution hence the background for this current study. The concern is that majority of these patients has shown in the study sustained residual when they are not monitored but as time elapses the effect is subdued especially when it is transient. Severe residual paralysis manifest with serious respiratory complications as demonstrated in this study leading to prolonged hospital stay and unnecessary cost implication on the patients. When these severe respiratory problems are not identified on time it may lead to death. Hence, residual paralysis is a serious health problem that needs to be eradicated from our recovery room and recommended guidelines is long overdue from regulatory professional organization on monitoring and reversal of NMBD.
A recent panel on monitoring of neuromuscular block discovered that at TOF of approximately 0.7 patients demonstrated residual paralysis by reporting double vision, inability to drink from straw, and absent of head-lift for 5 seconds. Even at
TOF of 0.9 there were measurable differences in grip strength. This panel also reported that function of the laryngeal musculature and the diaphragm returns faster than the pharyngeal and adductor pollicis (thumb) muscles and as such there is a greater risk of aspiration at low TOF ratio particularly in the elderly patients who have impaired pharyngeal function at baseline. This panel discovered more residual paralysis been associated with long-acting NMBD than intermediate and short acting-NMBD and a lower incidence of residual paralysis and mild
76 respiratory events when quantitative (objective) assessment is used as compared with qualitative (subjective) assessment. Finally the panel agreed that clinical test and subjective assessment using tactile/visual means are dependent on individual ability to see and to touch the thumb which is often not accessible and that longer duration of head-lift or handgrip for 10 seconds is more accurate, while quantitative assessment is superior and more accurate than qualitative assessment.
The report of this panel was similar to the findings of this study therefore careful monitoring of neuromuscular block with a peripheral nerve stimulator is essential and should be used routinely when NMBD are administered.
77
CHAPTER SIX
CONCLUSION AND RECOMMENDATION
In view of the findings from this study, it is concluded that
1. The readiness for extubation and recovery profile from neuromuscular
blockade using extubation time interval and time to achieve adequate
neuromuscular recovery was faster when subjective monitoring was used at a
mean of 9.28 ± 2.57 minutes and 13.76 ± 3.61 minutes respectively compared
to the clinical tests with means 11.36 ± 2.71 and 17.40 ± 6.08 minutes
respectively.
2. The incidence of residual paralysis in adult ventilated patients aged 18-65
years at the Lagos State University Teaching Hospital following the use of
long-acting NMBD (pancuronium) when clinical test was used for tracheal
extubation was 43% and 17% when subjective (tactile) assessment was used.
3. The incidence of hypoxia (SpO2 ≤ 92%) was 66% in both groups with 64%
occurring in the clinical test group and 36% in the subjective assessment
group. The incidence of irregular shallow respiration was 19% in both groups
with 75% occurring in clinical test and 25% in the subjective assessment
group. The incidence of hypoventilation (RR < 8) was 14% with all occurring
in the clinical test group and none in the subjective group.
78 4. Only one patient had shallow irregular respiration in the subjective
assessment group and three patients in the clinical test group had
hypoventilation. They received supplemental oxygen at 6 liters/min flow rate
with facemask for the hypoxia in the recovery room and re-intubation of the
tracheal with manual ventilation after a repeated reversal in the operating
room.
LIMITATIONS OF THE STUDY 1. Regular replacement of battery of PNS to achieve adequate current delivery to
the patients.
2. Using tactile response to interpret ratio of fourth twitch to the first twitch
(T4/T1) per patient was subjective and prone to error from the assessor.
3. Achieving steady current delivery with the PNS device used for the study was
not possible.
4. Awake patients in the recovery room experience painful nerve stimulation at
30 mA and some of the patients were not cooperative.
79
RECOMMENDATIONS 1. Subjective neuromuscular block monitors should be used routinely in the
operating room when NMBD are utilized.
2. Reversal should be given at TOFC of greater than 2 counts.
3. Reversal of neuromuscular block should be routine in the absence of
monitoring the degree of neuromuscular blockade with a peripheral nerve
stimulator.
4. Clinical test; Head-lift and leg-lift before tracheal extubation should not be
less than 10 seconds.
5. Training of anaesthetists on the use of peripheral nerve stimulator is
recommended in our institutions in the sub-region.
80
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67 Hasfurther DL & Bailey PL. Failure of neuromuscular blockade reversal after rocuronium in a patient who received oral neomycin. Canadian journal of anaesthesia 1996; 43(6): 617-620.
68 De Boer HD, Van Egmond J, Von de Pol F, Bom A, Booij LH. Sugammadex: A new reversal agent for neuromuscular block induced by rocuronium in the anaesthesized Rhesus monkey.Br J Anaesth 2006;96:473-9
69 Lien CA, Savard P, Belmont M, Sunaga H, Savarese JJ. Fumarates: Unique non-depolarizing neuromuscular blocking agents that are antagonized by cysteine. J Crit Care 2009;24:50-7
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72 Cohen J.Statistical power analysis for the behavioural sciences. Second edition. Hilsdale, NJ: Lawrence Erlbaun Associates 1998.
73 Strange C, Vaughan L, Franklin C et al. Comparison of train-of-four and best clinical assessment during continuous paralysis. Am J Respir Crit Care Med 1997;156:1556-1561
88 74 Rudis MI, Sikora CA, Angus E, et al. A prospective, randomized, controlled evaluation of peripheral nerve stimulation versus standard clinical dosing of neuromuscular blocking agents in critically ill patients.Crit Care Med 1997; 25:575-583
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90
APPENDICES
APPENDIX I - PROFORMA: MONITORING AND REVERSAL OF NEUROMUSCULAR BLOCKADE-
CLINCAL VERSUS QUALITATIVE ASSESSMENT
DEPARTMENT OF ANAESTHESIA
LAGOS STATE UNIVERSITY TEACHING HOSPITAL (L.A.S.U.T.H)
A.BIODATA;
Serial number………….
Marital status…………
Age………………………..
A.S.A Status:…………
Sex:……………………
Surgical Procedure: …………………..
Weight:…………….KG
Height:………………m
91
B. Method of Assessment of neuromuscular function: Pre-test T.O.F.C
1. Clinical judgment ……………………………… ………………..
2. Peripheral nerve stimulator……………………..
C. ANAESTHETICS/DURATION OF ANAESTHESIA: i. Duration of Anaesthesia……………mins ii. Dose of pancuronium……………mg Additional Doses…..mg iii. Dose of neostigmine……………..mg Atropine Dose………mg iv. Dose of fentanyl………………µg Paracetamol…………mg v. Onset of intubation…………..mins vi. Time interval before extubation after reversal ……..mins
D.VITAL SIGNS: B/P H.R R.R SPO2 TOFC TOFR
Pre-operative: …… ………. …… ……. …… ………
Post-operative (after- extubation):
20 minutes ……….. ……… …….. ………. ………….. …….
30 minutes . ………. ………. …….. ………. …………. …… vi. Presence of clinical signs:
Swallowing reflex: YES/NO
Hand grip: YES/NO
Obeys command: YES/NO
92 Good headlift for 5 seconds: YES/NO
E.COMPLICATIONS IN RECOVERY ROOM:
Hypoxia; YES/NO Re-intubation: YES/NO
Hypoventilation; YES/NO Facemask oxygen: YES/NO
93
APPENDIX II - AUDIT QUESTIONAIRE CLINICAL RELEVANCE OF PERIPHERAL NERVE STIMULATOR
DEPARTMENT OF ANAESTHESIA
LAGOS STATE UNIVERSITY TEACHING HOSPITAL
L.A.S.U.T.H, IKEJA
CONSULTANT…………….
RESIDENT……………..Senior/Junior
1. Years of experience in Anaesthesia……… <1yr <5yrs >5yrs others………
2. Have you heard about peripheral nerve stimulator?……..YES/NO
3. Have you seen it being used?...... YES/NO
4. Have you used it before?………YES/NO
5. If the answer to question(3) is YES.
6. What is your opinion?…………………………….
7. If your answer to question (4) is YES
8. What is your opinion?......
9. Do you think it is simple to use ?……………YES/NO
10. Do you think it is complex to use ?……….YES/NO
11. If you have it, will you use it?...... YES/NO
12. If your answer to (11) is yes give reasons………………
13. If your answer to (11) is no give reasons……………….
Thank you
94 APPENDIX III - INFORMED CONSENT
FOR PARTICIPATION IN MEDICAL RESEARCH ACTIVITIES
[LAGOS STATE UNIVERSITY TEACHING HOSPITAL] DEPARTMENT OF ANAESTHESIA E-Mail [email protected], Phone number 08037150189
Participant: ______
Principal Investigator: Dr Ayeni Olajide Olabosipo
Title of Project: Monitoring and reversal of neuromuscular blockade-
clinical versus qualitative assessment.
1. I,………………………………agree to participate in the research study under
the direction of Drs. ………………… and…………………………
I understand that while the study will be under the supervision of Drs
………………………………, other personnel who work with them may be
designated to assist or act in their behalf.
2. The overall purpose of this research is to improve on the effectiveness of
monitoringPerioperatively and to aid surgical outcome of patient undergoing
operative procedures in Lagos University State Teaching Hospital
(L.A.S.U.T.H)
3. My participation would involve allowing a particular monitor peripheral nerve
stimulator (P.N.S) to be applied on me during my procedure in the operating
theatre.
95 4. My participation in the study would only be as long as the procedure lasts in
the operating theatre of L.A.S.U.T.H
5. I understand that the overall purpose of the study is to improve on the way and
manner patients are being cared for perioperatively
6. I understand that there are possible risks in the form of discomfort associated
with the study of which medical treatment shall be instituted at the expense of
health care provider.
7. I understand that my estimated expected recovery time after the experiment will
be immediately and there is no indication for follow up for evaluation.
8. I understand that I may choose not to participate in this research.
9. I understand that my participation is voluntary and that I may refuse to
participate and/or withdraw my consent and discontinue participation in the
project or activity at any time without penalty or loss of benefits to which I am
otherwise entitled.
10. I understand that the investigator(s) will take all reasonable measures to protect
the confidentiality of my records and my identity will not be revealed in any
publication that may result from this project. The confidentiality of my records
will be maintained in accordance with applicable rules of the hospital ethics and
scientific committee. If I participate in a sponsored research project, a
representative of the sponsor may inspect my research records.
11. I understand that the investigator is willing to answer any inquiries I may have
concerning the research herein described. I understand that I may contact Lagos
96 State University teaching Hospital ethics and committee chairperson if I have
other questions or concerns about this research. If I have questions about my
rights as a research participant, I understand that I can contact authorities of
Lagos state university teaching hospital (L.A.S.U.T.H).
12. I will be informed of any significant new findings developed during the course
of my participation in this research which may have a bearing on my
willingness to continue in the study.
13. I understand to my satisfaction the information regarding participation in the
research project. All my questions have been answered to my satisfaction. I
have received a copy of this informed consent form which I have read and
understand. I hereby consent to participate in the research described above.
14. Interpreters shall be consulted for patients that do not understand English
language when necessary.
…………………………………. ………………………………… Participant’s Signature & Date Witness Signature & Date
I have explained and defined in detail the research procedure in which the subject has consented to participate. Having explained this and answered any questions, I am cosigning this form and accepting this person’s consent.
………………………………………. Principal Investigator signature & Date
97
APPENDIX IV - ETHICAL CONSIDERATIONS I have explained to the patient that the information obtained from the research shall be kept confidential and under no circumstances will it be divulged to any individual or organization. The Financial implication of the study will not have any effects on the patient and the drugs and materials used will not interfere negatively with the treatment and outcome of the primary procedure of the patient.
The confidentiality of the records will be maintained in accordance with guidelines and rules of hospital ethics and scientific committee of L.A.S.U.T.H.
Patients privacy and confidentiality shall be completely respected and that the
Study will not in any form cause physical/mental injury to the patients but rather improve the standard of care given in the perioperative period.
98
APPENDIX V - ETHICAL COMMITTEE APPROVAL.
99
APPENDIX VI - NATIONAL POSTGRADUATE MEDICAL COLLEGE APPROVAL
100