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TAJ June 2007; Volume 20 Number 1 ISSN 1019-8555 The Journal of Teachers Association RMC, Rajshahi

Original Article

Comparative Study Between Three Intravenous Drugs Thiopentone Sodium, and Midazolam : Study of 100 Cases and Critical Review

S K Mondol1, M A Rahim 2

Abstract

Intravenous became possible with drugs available since 1930 and the concept rapidly became popular with patients and anaesthetists. From the patient’s point of view it had the advantage of producing rapid loss of consciousness without excitement, distress, or the sensation of smothering often produced by a tightly pressed facemask. For the anesthetist, there was the predictable anaesthesia which was ideally rapid in onset and without coughing or movements. Thiopentone sodium, propofol and midazolam have been used in our comparative clinical study (About 100 cases) as an intravenous anaesthetic agent. Our clinical study was into three aged groups such as neonates & children (40 cases), middle aged (40 cases) and elderly (20 cases). 100 cases were divided into paediatric cases, in outpatient procedures, in neurosurgical cases, in geriatric anaesthesia, in obstetric cases. In our comparative study, we have seen when propofol used for induction of anaesthesia in briefer procedures, results in a significantly quicker recovery and an earlier return of psychomotor function as compared with thiopentone and midazolam irrespective of the agent used for maintenance of anaesthesia.

TAJ 2007; 20(1): 28-35

Introduction clinically. For that purpose 100 cases were assessed uring ASA grading. We have had no Intravenous anaesthesia became possible with anaesthetic . We have found propofol to be drugs available in 1930 and the concept rapidly a most valuable induction and maintenance agent became popular with patients and anaesthetists. for a great variety of cases. Intravenous anaesthetic agents are commonly used to induce anaesthesia, for maintenance, may be Patients and Methods administered as repeated doses and also used Our comparative clinical studies were performed for in the intensive therapy unit (ITU) and on 100 patients (Neonates & children 40 patients) treatment of . middle aged (male & female – 40 patients) and Among the current available intravenous elderly (20 patients) who had given their informed anaesthetic agents we have chosen three such as consent and were undergoing various out patients, thiopentone, propofol and midazolam for our paediatric cases, neurosurgical procedures, comprehensive comparative study between them obstetric cases& geriatric cases etc. at the Rajshahi

1 Assistant Professor, Department of Anaesthesiology, Rajshahi Medical College, Rajshahi. 2 Honorary Medical Officer, Department of Anaesthesiology, Rajshahi Medical College Hospital, Rajshahi. Medical College Hospital, Rajshahi from June anhydrous sodium emulsion should midazolam accounts 2005 to July 2006. The trial was conducted with carbonate is added not normally be for its stability in the whole supervision of Associate Professor Md. to the powder mixed with other solution & rapid Latifur Rahman of Rajshahi Medical College Hospital, Rajshahi. which is prepared drugs or infusion . The high in an atmosphere of fluids. lipophilicity accounts Results . It is for the rapid central largely non ionized nervous system The age of patients under study ranged from 2 yrs at body PH, a fact (CNS) effect as well to 70 yrs. Out of 100 cases 40% children, 20% male (18-40 yrs), 20% female (18-40 yrs) and which facilitates its as for their relatively 20% elderly patients diffusion through large volumes of membranes. distribution. Table -I : Age distribution of the patients Number of Table-III: of Thiopentone, Age group (years) Percentage patients Propofol & Midazolam 2-12 yrs 40 40

18-40 yrs (Male) 20 20 1 d 18-40 yrs (Female) 20 20 Cl e T Vc Vdss 2 Drug (ml/mi mate

51-60 yrs 10 10 i (L/kg) (L/kg) ratio n/kg) β (h) hepatic

61-70 yrs 10 10 Est extraction

Thiopenton 0.38 2.5 3.4 11.6 Table- II: Physico-chemical properties 0.15 e ± 0.10 ± 1.0 ± 0.5 ± 6 Thiopentone Propofol Midazolam 0.8L/kg sodium Propofol 2-10 20-30 4-7 - ± 0.5 This is sodium Propofol is an Midazolam belongs 0.40 Midazolam 1.1-1.7 6.4-11 1.7-2.6 - ethyl (1- methyl alkylphenol & is to the ± 0.10 butyl) virtually insoluble group. Midazolam Vc-Central volume of distribution, Vdss- Volume of thiobarbiturate. It is in water. Propofol solution contains 1 or distribution at steady state, Cle- Elimination clearance, the sulphur is normally a 1% 5mg/ ml of 1 T β - Elimination half-life. analogue of formulation in an midazolam with 0.8% 2 pentobarbitone, oil and water sodiumchloride and Introduced emulsion 0.01% disodium Table-IV: Important clinical properties of the commercially as containing 10% edetate with 1% thiopentone, propofol & midazolam pentothal sodium soybean oil, 1.2% benzyl as a in 1935. It is a egg phosphatide preservative. The PH yellow amorphous and 2.25% is adjusted to 3 with Drug powder, soluble in glycerol. The PH is HCL & NaOH. It is effects Induction Induction Recovery

water (and alcohol) 6-8.5. The the most lipid soluble Excitement Characteristics Characteristics Cardiovascular Cardiovascular Cerebral effects Predictability of of Predictability H & Pain Induction diluted to 2.5% preparation has a but because of its P effects Respiratory solution with PH similar viscosity to dependent solubility Thiopentone + 0 + - - + 10.8-11. To that of water. is water soluble as Propofol + - + - - ++ prevent formation Ampoules must formulated in a Midazolam 0 0 + 0 0 + of free acid by co2 not be frozen & buffered acidic ++ To - - a five point qualitative scale describing the relative from the should be shaken medium (PH 3.5) The positive (+,++),neutral (0) or negative (-, --) effect of each atmosphere, 6% before use. The ring of agent in each category. Table-V: . of 200- 300 scheme can to 1 µ g µ g/kg/min be utilized /kg/min with Cardiovasc Respirator Cerebral This consists ular y for the first 0.03 20 mins & of a loading to 0.06

dose of µ 2 30 to 70 g/kg/min Agent µ g/kg/min 1mg/kg over or alfentanyl 20 seconds HR ICP SVR CBF PVR PAO 0.5 to MBP MBP B'dil' B'dil' there after. VENT LVSWI

CMRO followed by 1.5 µ g/ 170 µ g/kg/min kg/min. ↑ ↓ 0 ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ Thiopentone ↑ ↓ ↓ ↓ ↓ ↓ (10mg/kg/hr ↓ ↓ ↓ ↓ for 10 mins, 0 ↓ ↓ ↓ ↓ 0 ↓ 0 ↓ ↓ ↓ then Propofol ↓ ↓ ↓ ↓ ↓ 130 µ g/kg ↓ ↓ ↓ ↓ ↓ /min ↑ ↓ ↓ ↓ 0 ↓ ↓ 0 ↓ ↓ ↓ Midazolam (8mg/kg/hr) ↓ ↓ ↓ ↓ ↓ for 10 mins HR- heart rate; MBP- mean blood pressure ; SVR- systemic and vascular resistance; LVSWI -Left Ventricular stroke work 100 µ g/kg/ index; PVR- Pulmonary vascular resistance; PAO – min Pulmonary artery occluded pressure; Vent – ventilatory drive; (6mg/kg/hr) B’dil – bronchodilation; CBF– cerebral blood flow; CMRO2 – there after. cerebral oxygen consumption, ICP – Intracranial pressure. 0 = No effect ↑ = increase (mild, moderate, marked) Administration of thiopentone, ↓ = decrease (mild, moderate, marked) propofol & midazolam by infusions.

Table-VI: Uses and Doses of Thiopentone, Administration of these drugs can be explained by Propofol and midazolam. looking at the context sensitive halftime (i.e. the Drug Thiopentone Propofol Midazolam time it takes for the plasma concentration in the Induction 4-5 mg/ kg 1.5-2.5 mg/ 0.05-0.15 central compartment to decrease by 50 percent) for I.V kg IV dose mg/kg thiopental relative to midazolam & propofol. In reduced with I.V this study it is believed that recovery after increasing age. reasonably long thiopental infusions is slow Maintenance 50- 0.05 mg/kg relative to that after propofol. Fig- I. shows this 150 µ g/kg / prn difference. min I.V 1 µ g/ kg/ combined min with N2O or an opiate Sedation An initial 25- 0.5-1 mg loading dose 75 µ g/kg/mi repeated 0.07 of 2 to 4 n IV mg/ kg IM mg/kg is followed by an infusion of 30 to 80 µ g/kg /min Infusion rate An initial To obtain a The infusion loading dose plasma level rate during of 2 to 4 of 3 to surgical mg/kg is 4 µ g/ml a anaesthesia followed by four stage is titrated an infusion infusion between 0.25 Fig: Context- sensitive half times as a function of infusion duration for each of the pharmacokinetics models simulated. Note the longer context sensitive halftime for thiopental as compared with propofol and midazolam as the infusion duration increases.

Discussion

In our clinical comparative study we selected patients in paediatric cases, outpatient procedures neurosurgical cases, obstetric cases and elderly patients (61-70yr) in various cases. Here discussion should be based on case basis which as follows: Propofol In paediatric cases Propofol is highly lipophilic and rapidly Intravenous anaesthetics: distributes into & out of the vessel rich organs, its rapid redistribution, hepatic glucoronidation and Thiopentone high renal clearance account for the rapid termination of its effects. As with thiopentone, the Thiopentone remains the standard intravenous induction dose is higher in younger patients induction agent (2.5% sol 5 to 6 mg/kg) for (2.9mg/kg) for (2yr) than in older patients children. Intravenous injection is painless and (2.2 mg/kg) for patients 6-12yr. This may be produces smooth induction of anaesthesia in one related in part to a longer central, volume and arm brain circulation time. Recovery occurs in5- greater clearance in the younger patients. 10 mins by redistribution of the drug. There are no significant differences in distribution kinetics or Midazolam apparent recovery times between children and Midazolam is water soluble and therefore is not adults. painful on intravenous administration. The dose of thiopentone varies with age. In Midazolam is the only benzodiazepine approved neonates the ED sleep dose is only 3.5mg/kg but by the food and drug administration for use in 50 neonates. It should be noted that because of its increases rapidly to around 7mg/kg in infants aged water solubility, midazolam takes three times as 1-6 months, thereafter declining gradually long to reach a peak electroencephalograph effect. throughout infancy and childhood. Thus it appears that neonates require 4-5mg/kg, infants 7-8mg/kg The clinical importance of this finding is that one and children 5-6mg/kg of thiopentone for fast should wait at least 3 minutes between intravenous reliable induction of anaesthesia. These doses may doses in order to avoid a `stacking’ of effect. The be reduced by up to 50 percent with short elimination half-life (2h) offers an advantage for use as a in children. Our study medication. The reduced requirements in neonates has shown it is rapidly absorbed after 1.m (0.1- compared with older infants can be explained by a 0.15mg/ kg), oral 0.5 -0.75mg/kg, rectal (0.75- decrease in . The increased 1mg/kg) administration. requirements in infants and children compared with adults (usual adult doze 4mg/kg) may be due Out Patients Surgery to their increased cardiac out-put as this would be Patient selection expected to reduce the first parts concentration of The selection of patients must take account of two thiopentone arriving at the brain separate aspects: firstly the patients state of health and secondly his social circumstances. Patients patients to detect common medical problems should normally be ASA i or ii i.e. normal healthy which are shown in Table - (2). people or those with minor systemic disease not • Have you had anything to eat or drink in the interfering with normal activities the latter last 4 hrs? including medical conditions that are well controlled with therapy e.g. . An • Have you had any previous operations? upper age limit of 65-70 years should be judged on • Will you go home alone? biological rather than chronological age. In our • Do you have a cough or a cold? study age is not contraindication of out patient • Do you suffer with heart disease or high blood surgery with the following exceptions. pressure? • Premature infants • Do you get breathless or have chest pain on • Infants with a history of bronchopulmonary exercise or at night? dysplasia or apnoeic episodes who have been Do you have asthma or bronchitis? symptomatic within the last 6 months. • • Do you smoke? • Siblings of infants who have died of sudden syndrome. • Do you have diabetes? • Do you suffer form anemia, bruise easily or Table-1: A selection of surgical procedures bleed excessively? commonly under taken as day cases. • Are you pregnant? (In case of female) a) Gynaecology - Dilatation & curettage, When considering children for day case laparoscopy, vaginal termination of procedures they should be healthy normally falling , colposcopy. into ASA I or II groups. Premature babies who b) Plastic surgery: Dupytren’s contracture have not reached 34 wks conceptual age should release, removal of small skin lesions, nerve not be considered for day case surgery & special decompression. consideration should be given to bodies that have c) Ophthalmology: Strabismus correction, been on ventilatory support. lacrimal duct probing, examination under anaesthesia. Our purpose of study of these three drugs is to b) ENT: Myringotomy, removal of foreign delivery of safe and effective bodies, polyp removal. with nominal side effects and a rapid recovery in e) Urology: Cystoscopy, circumcision, outpatient, surgical procedures. Thiopentone (3- vasectomy. 6mg/kg) is usually associated with a rapid f) Orthopaedics: Arthroscopy, Carpal tunnel induction of anaesthesia without psychomotor release, ganglion removal. recovery and subjective feelings of tiredness and g) General Surgery: Breast lumps, hernia, drowsiness limit its usefulness in day case varicose veins, and endoscopy. patients. Midazolam (0.2-0.4mg/kg) alone is also h) Circumcision, orchidopexy, dental extractions. an adequate intravenous induction agent. However its is slower and recovery is The selection of patients for day case surgery is prolonged compared with the thiopentone and made at the time of out patient consultation where propofol. a specific benzodiazepine routine measurement of pulse, B.P. and urine antagonist, given at the end of surgery, speeds analysis and other relevant investigations (e.g. recovery following midazolam induction but its Sickle cell tasting) are performed. Studies have duration of reversal is limited in 60 minutes. demonstrated that a simple preparation However, compared with propofol recovery after questionnaire can be very effective in screening flumazenil antagonism of midazolam anaesthesia was still significantly slower. On the other hand Thiopentone the authors consider propofol (1.5-2.5mg/kg) to he Thiopentone has played a valuable part in neuro- the best intravenous induction agent of choice for anaesthesia. It lowers the CMRO2 and the CBF outpatient anaesthesia. Although induction of falls in parallel. The effects are dose dependent, anaesthesia with propofol is associated with a when enough thiopentone has been given to greater decrease in blood pressure and heart rate produce an iso-electric electroencephalogram, the that with thiopentone or midazolam but this is CMRO2 is about 50 percent of awake values. No offset by a more rapid recovery and fewer further fall in CMRO2 occurs if more thiopentone postoperative side effects. Propofol may be used in in given. The decrease in CBF is associated with a the elderly out patient but the dose should be lowering of ICP and the use of thiopentone during reduced by 25 percent. Pain on injection may be induction of anaesthesia in patients with reduced by the addition of lignocaine or cooling intracranial space occupation is particularly the propofol to 40C. The direct anti-emetic action valuable as it may prevent increases in ICP of propofol may offer a further advantage. The remitting from laryngoscopy & tracheal following figure shows the comparison of mean intubation. changes in choice reaction time in patients - Propofol The effects of propofol on CMRO2 and CBF are similar to those produced by thiopentone: Propofol 1.5mg/kg produced a 32 percent fall in CSF Pressure 2 minutes after induction of anaesthesia. The reduction in MAP may be greater with

Control propofol and there is evidence that propofol protects more effectively against the presser Midazolam response to intubation. Propofol Midazolam Thiopentone

(0.15mg/kg) has been shown to reduce CMRO2 by 21-30 percent and CBF by 26 percent in patients with space occupation. One study showed that induction of anaesthesia with midazolam (0.32 mg/kg) was associated with no change in ICP.

In Obstetric Cases Fig. Comparison of mean changes in choice Thiopentone - Thiopentone neither depresses nor reaction time (CRT) in patients following increases the tone of the gravid uterus. induction of anaesthesia with thiopentone, Thiopentone is not harmful induction for cesarean midazolam and propofol (P<0.05). section in doses up to 6mg/kg but 8mg/kg does

depress the foetus. Placental circulatory factors Neuro Surgery anaesthesia and re-distribution of thiopentone in the mother Anaesthetic drugs have major effects on cerebral and foetus protect the foetal brain and spinal cord function and much work has been done to identify from high concentrations of thiopentone and these effects and to evaluate their clinical explain why the umbilical cord blood significance. The induction agents (Thiopentone, concentration of thiopentone at delivery is one half propofol and Midazolam) have been given in that in maternal blood. The neonatal condition is patients undergoing neuro surgery which is stated letter after thiopentone induction than after below: midazolam induction. Propofol Other problems Propofol is suitable for both the induction of and Physically frail with impaired temperature control maintenance of anaesthesia and has also been increased likelihood of gastro-oesophageal reflux, approved for use in neurological, obstetric and cervical spondylosis & arthritis with limitation of cardiac anaesthesia. Because of its movement, thin vulnerable skin & diabetes. pharmacokinetics, Propofol provides a rapid recovery is thus superior to thiopentone for Debilitated & sickly older patients are particular prone to preoperative complications but healthy maintenance of anaesthesia. order surgical patients should do well. Whether the

age of the patients a satisfactory and Midazolam uncomplicated anaesthetic course requires (1) an When Midazolam is used in appropriate doses anaesthetic plan compatible with the patients induction occurs less rapidly than with thiopentone physical status and the type of surgery (2) but the anesthesia is more reliable. Numerous consistent and (3) careful attention to factors such as dose, Speed of injection, degree of detail. In our clinical study the dose as of premedication, age influence the rapidity of action. thiopentone, propofol & midazolam were reduced In obstetric cases the neonatal condition is less to 20-40% in elderly patients. No additional or good than after thiopentone induction. unique major principles need to be observed when caring for the elderly patient. In geriatric Cases Anaesthetic problems of the elderly. Conclusion The present study tried to bridge the gap of Cardiovascular system knowledge of information about the currently Ischaemic heart disease, poor cardiac function and available intravenous anaesthetic drugs to the perfusion of vital organs, atherosclerosis and patients as well as for the anaesthetists. It was hypertension. found in various types of cases that the propofol as compared with thiopentone and midazolam results Respiratory System in a significantly quicker recovery and an earlier In creased closing capacity with airway collapse & return of psychomotor function and very much hypoxia; poor respiratory response to hypoxia, valuable in maintenance of anaesthesia. Because increased incidence of atelectasis, pulmonary of its pharmacokinetics profile, propofol provides embolus and postoperative chest infection. a rapid recovery and is thus superior to thiopentone and midazolam. Nervous System Cerebrovascular impairment, hearing & sensory Acknowledgement impairment, confusion. We acknowledge the help rendered by M.A. Rahim (Honourary - Anaesthesiology) and also by Pharmacology Director, Rajshahi Medical College in collecting Increased sensitivity to CNS and other data. We are very much thankful for their kind co- drugs, impaired drug distribution metabolism and operation in preparing this study work. elimination, altered plasma protein and drug finding. References 1. Ronald D. Miller 2000 5th edition Anaesthesia. Metabolism 2. WYLIE AND CHURCHILL DAVIDSONS: A practice Slower metabolic rate; Impaired renal blood flow of anaesthesia 6th edition. and function; Impaired fluid balance and 3. G. Edward Morgan Ir. M.D Mageds. Mikhail MD- malnutrition. Clinical Anaesthesiology (3rd edition) 4. R.S. Atkinson G.B. Rushman, J Alfred Lee (1986) pain. British Journal of Anaesthesia 1982; 54 Lee’s Synopsis of Anaesthesia (Pharmacology of 307-11. thiopentone and propofol) 10. Dundee JW, Robinson FP, McCollum JSC, 5. Goodman and Gillman. Pharmacology of Patterson CC, Sensitivity to propofol in the elderly. thiopentone. Anaesthesia 1986; 41: 482-5. 6. Morgan DJ. Blackman GL, Paull JD, Wolf LJ, 11. McCollum JSC, Dundee JW, Comparison of Pharmacokinetics and plasma binding of induction characteristics of four intravenous thiopentone. Studies at caesarean section. anaesthetic agents. Anaesthesia 1986:41: 995- Anaesthesiology 1981 54:474-80. 1000. 7. Christensen JH, Andreaser F, Janssen JA, 12. Lippmann M, Paicius R, Gingerich S, etal, A effects Increased thiopental sensitivity in cardiac patients. of propofol versus thiopental during anaesthesia Acta Anaesthesiologica Scandinavia 1985; 29: 702- induction. Anaesthesia and Analgesia 1986; 65; 5. 589. 8. Cockshott ID, Propofol (Diprivan) pharmacokinetics 13. Reves JG, Fragen RJ, Vinik HR et al : Midazolam and metabolism -an overview. Postgraduate Pharmacology and uses. Anaesthesiology 62:310 medical Journal 1985:61 45 - 50. 1985. 9. Briggs L.P, Dundec JW, Baha M, Clarke RSJ. 14. Persson MP Nilsson A. Hartvig P: Relation of Comparison of the effect of di-isopropyl (ICL sedation and to plasma concentrations of 35868) and thiopentone on response to somatic midazolam in surgical patients, clin pharmacol Ther 43:324 1988.

All correspondence to: Swapon Kumar Mondol Department of Anaesthesiology Rajshahi Medical College, Rajshahi.