Total intravenous anaesthesia (TIVA) with ketamine-midazolam (KM) has been used for prolonged abdominal surgery , but clinical trials comparing KM with standard volatile anaesthetic agents have not been reported. For a judicious comparison of two anaesthetic techniques, one should report their ability to suppress surgical stress responses, to provide adequate operating conditions and an acceptable recovery profile. Haemodynamic changes, the main indirect indicators of stress, may be less reliable when intravenous agents are used , whereas circulating concentrations of cortisol and growth hormone might provide a more reliable marker of a stress response.
Whether KM anaesthesia provides better suppression of the surgical stress responses, adequate operating conditions and an acceptable recovery profile compared with halothane anaesthesia was the subject of this clinical trial. We compared KM anaesthesia with halothane anaesthesia in patients undergoing radical cystectomy. Patients were randomly allocated to receive either KM anaesthesia or halothane anaesthesia in nitrous oxide and oxygen. Haemodynamic and endocrine stress responses were the primary outcome variables while the adequacy of operating conditions and the recovery profile were secondary outcome variables. In addition, a computer simulation of the ketamine and midazolam infusion regimens of the KM technique calculated the expected plasma concentrations of ketamine and midazolam.
This controlled, randomized study was carried out with 50 patients undergoing radical cystectomy and bladder substitution. Exclusion criteria were mental disorders or a family history of mental troubles, cardiac (chronic congestive heart failure), hepatic (repeated serum bilirubin concentration >1.3 mg dL−1) or renal (repeated serum creatinine concentration >1.5 mg dL−1) insufficiency and endocrine disorders except type II diabetes mellitus. The study protocol was approved by the Hospital Research Ethics Committee and a written informed consent was obtained.
Memory span was selected as a suitable measure to assess the recovery of mental facilities after anaesthesia. This was assessed on the day before surgery by the digit forward and digit backward subset of the Wechsler-Bellevue adult intelligence scale . This test has been previously employed following KM anaesthesia . Patients were asked to repeat forwards and backwards an increasing long string of randomly arranged digits. The maximum number of digits the patient could recall was scored. Patients were pre-medicated with 5 mg diazepam orally two hours before transfer to the operation suite.
Patients were allocated by closed envelope randomisation to receive either TIVA with KM or halothane-nitrous oxide-oxygen anaesthesia (HAL). The technique of KM has been reported previously . Anaesthesia was induced in KM patients with midazolam 150 μg kg−1 i.v. followed by ketamine 2 mg kg−1. Tracheal intubation was facilitated with succinylcholine 1 mg kg−1 and the patients' lungs were ventilated with oxygen enriched air (FiO2 = 0.35). Anaesthesia was maintained by the infusion of ketamine and midazolam from separate infusion pumps in the doses shown in Table 1. If anaesthesia was longer than 5 h, the drug infusion rate during the sixth hour was the same as in the fourth, and the seventh was similar to the fifth hour. This sequence could be repeated further if necessary.
Anaesthesia was induced in HAL patients with fentanyl 100 μg and thiopental 500 mg i.v. Tracheal intubation was facilitated with succinylcholine 1 mg kg−1. The lungs were ventilated with N2O:O2 (FiO2 = 0.35) and halothane at an initial inspired concentration of 1%. Pipecuronium was used to maintain adequate surgical muscle relaxation. Heart rate and arterial pressure deviations of more than 20% were promptly restored. An increase of either during KM was treated with bolus doses of ketamine and midazolam (10 mg and 0.6 mg, respectively) and a 10% increase of the infusion rate. If this was not effective after 4 min the bolus doses were repeated and the infusion rates were increased by another 10%. Once arterial pressure and heart rate were within expected limits the drug infusion rates were reset to regimen rates. Cardiovascular responses during HAL were treated with a bolus dose of fentanyl (50 μg) and an increase of the inspired halothane concentration to 1.5%. This was reset to 1.2 or 1.0% according to the haemodynamic response. Hypotension was treated in the KM group by stopping the midazolam infusion and restarting it with a 10% lower infusion rate after arterial pressure was restored and by reducing the inspired halothane concentration in the HAL group. Size and motility of the intestinal loops as well as the degree of colon distension were recorded during surgery. Residual neuromuscular block was antagonised with neostigmine at the end of the operation.
Monitoring and fluid replacement
Patients were monitored by continuous 5-lead electrocardiography, pulse oximetry, capnography, and invasive haemodynamic measurements using an arterial cannula and a pulmonary artery flotation catheter. Appropriate fluids were infused on the basis of fasting hours, surgical trauma and fluid losses. Blood loss was calculated empirically from the amount of blood collected in the graduated, reservoir of the suction unit and from the number of blood soaked towels, and was replaced with homologous blood at the end of dissection of the urinary bladder.
During their stay in the recovery room, the patients were observed and their physiological signs were assessed. Postoperative pain was qualified by the patient as absent, slight and bearable, or severe and requiring analgesics. Abnormal behaviour in the form of spontaneous verbalisation, hallucinations or other psychomimetic reactions were recorded. The digit forward and digit backward test was performed every 30 min. On the second morning, the patients returned to the ward and routinely observed. Bowel sounds were auscultated by members of the surgical team on the morning of each postoperative day.
Plasma hormone assays
Cortisol and growth hormone concentrations were quantified by immunoassay. Venous blood samples were drawn on the morning of surgery, 5 min after arrival in the operation suite, 5 min after induction of anaesthesia, 30 min after incision, after bladder dissection, at the end of surgery and 2 h after conclusion of surgery. The blood samples were collected into plain tubes, centrifuged and stored at −20°C in aliquots until hormonal quantification was carried out. Commercially available kits for hormonal assay were obtained from Medix Biotech for cortisol and from Medgenix for growth hormone.
Computer simulation of ketamine and midazolam plasma concentrations
The expected plasma concentrations of ketamine and midazolam during the entire procedure were calculated with commercial pharmacokinetic and pharmacodynamic software  using the available pharmacokinetic data of ketamine  and midazolam  as input parameters for the computer program.
Power of the study
The power of this study was calculated using GPower analysis program . Using a post hoc power analysis with accuracy mode calculation and assuming type 1 error protection of 0.05 and effect size convention of 0.5, a total sample size of 50 patients yields a power of 0.94.
Data were analysed by repeated measures of analysis of variance (ANOVA) and by the Mann-Whitney U-test as appropriate. P < 0.05 was considered statistically significant.
This randomized trial was conducted on 50 patients of either gender undergoing radical cystectomy and urinary diversion. Closed envelope randomization assured equal numbers of patients in each group. Patient characteristics and duration of anaesthesia were homogeneous in both groups (Table 2).
Intraoperative features are shown in Table 3. There was no significant difference between the two groups in either the need for interventions to control the depth of anaesthesia or the dose of muscle relaxant. During KM, the intestinal loops were collapsed and spontaneous and touch-inducible intestinal motility was observed. The peritoneal cavity became more 'roomy' allowing surgery with minimal assistance. Significantly fewer units of blood were transfused in the KM group than in the HAL group (P < 0.05). The measured and calculated haemodynamic and oxygenation variables are shown in Figure 1 and Table 4. Cardiac index and systemic and pulmonary vascular resistances were similar in both groups with minimal fluctuations (Fig. 1). Mixed venous oxygen saturation was reasonably steady in both groups and always above 70% indicating that global oxygenation was adequate. The oxygen extraction ratio, a function of oxygen delivery and oxygen consumption, was within safe limits (<0.30) for both anaesthetic techniques. The profiles of the shunt fraction for both techniques were comparable (Table 4).
The patterns of hormone concentration changes during the procedure were identical and parallel in both groups. The maximum increase in serum concentrations occurred at the end of dissection of the urinary bladder. Serum cortisol concentrations remained elevated (twice the baseline value) during recovery. Growth hormone concentrations increased after the start of surgery then declined to reach baseline values towards the end of surgery (Fig. 2).
Postoperative features are shown in Table 5. All patients in the HAL group required postoperative analgesics while only seven KM patients needed analgesics. The incidence of postoperative shivering was significantly lower after KM than after HAL. There was no significant difference between the two anaesthetic techniques with regard to patient orientation and return of the memory span score to preanaesthetic values. Audible bowel sounds returned earlier in patients with KM than with HAL (P < 0.05). The respective mean total doses of ketamine and midazolam were 1051 ± 231 mg and 36 ± 7 mg.
The predicted plasma concentrations of ketamine were 2120 ng mL−1 following induction of anaesthesia, 900 ng mL−1 at the end of the fifth hour and 390 ng mL−1 1 h after stopping infusion. The respective predicted plasma concentrations of midazolam were 440, 93 and 50 ng mL−1.
The results of this study show that KM is comparable to halothane-nitrous oxide-oxygen (HAL) in their effects on the stress responses to surgery with the advantage of providing better operating conditions and a more acceptable recovery profile.
Our knowledge of the neuropharmacology of ketamine is expanding. Ketamine is a non-competitive agonist at the N-methyl-D-aspartate (NMDA) subset of glutamate receptors . It binds to the phencyclidine receptor and inhibits glutamate activation of the channel in a non-competitive manner . A similar inhibitory activity has been reported in non-NMDA glutamate receptors . Ketamine interacts with the opioid system  and muscarinic acetylcholine receptor function  playing a minor role in its central inhibitory activity. Of great importance is the effect of ketamine on the GABAA receptor-channel complex, which is suggested by in vitro findings [13,14] as well as from the results in convulsive and anaesthetic behavioural models in mice . These indicate that ketamine-induced anaesthesia is mediated, at least in part, by the GABAA receptor-channel complex.
Benzodiazepines are specific agonists at the benzodiazepine receptors that are part of the GABAA receptor-channel complex . They enhance the binding of GABA to the very-low affinity GABA receptor-channel complex , while GABA enhances the binding of midazolam to the GABA receptor-channel complex .
The role of the GABAA receptor-chloride channel complex in anaesthesia has been excellently reviewed .
The plasma hormone concentrations are useful as direct markers of a stressful state: increased activity of the adrenal cortex is an essential part of the body's response to stress and cortisol may be enormously increased in stress . Growth hormone, is not always released in less complex and traumatic procedures, but situations reflecting a demand for oxidisable substances are probably the principal stimuli for its release . In this study, the pattern of changes in serum levels of these stress hormones was identical during both anaesthetic techniques. Serum cortisol concentrations remained elevated during recovery despite the good analgesia in KM group and parenteral opioids in HAL. High cortisol concentrations in the postoperative period were also reported following midazolam-alfentanil TIVA as well as thiopental-nitrous oxide-alfentanil anaesthesia . However, the plasma cortisol concentrations did not exceed the physiological range (137-630 nmol L−1). Similarly, the serum concentrations of growth hormone also did not exceed the physiological range (0.2-30 nmol L−1). The same hormones were previously measured in patients undergoing radical cystectomy and anaesthetized by a combination of extradural lidocaine-bupivacaine-morphine analgesia and general halothane anaesthesia . At the end of surgery, the mean plasma cortisol concentrations increased by 40% while growth hormone concentrations had doubled. This reflects the efficacy of extradural analgesia combined with general anaesthesia in suppressing the surgical stress response.
Haemodynamic activation, an indirect stress indicator, which can be inferred from the intraoperative analgesic and hypnotic requirements, was similar in the two anaesthetic techniques. The haemodynamic and oxygenation variables did not differ between the two groups. It seems that midazolam attenuated the sympathomimetic activity of ketamine on the cardiovascular system to a degree that mimicked the effects of halothane. The mean dose of neuromuscular blocking agents was similar in both groups.
The intestines were collapsed in the KM group giving better operating conditions. This might be because nitrous oxide was not used. This TIVA technique produced acceptable postoperative analgesia and reduced the need for analgesics. Ketamine has been reported previously to reduce postoperative pain and wound hyperalgesia beyond the end of anaesthesia . The incidence of shivering following KM was lower than either that observed in our HAL group or reported by others following general anaesthesia . A central protective effect attributable to ketamine or midazolam is a feasible explanation . Audible bowel sounds returned earlier in the patients of the KM group than in those of HAL and enteral alimentation was likely to be earlier. Freye and Knufermann reported that KM anaesthesia had no inhibitory effects on gastrointestinal motility compared with enflurane or fentanyl-midazolam anaesthesia .
During inhalational anaesthesia, it is easy to measure the end-tidal concentrations of the agent on breath-by-breath basis and assess adequate plasma concentrations. This is not feasible with TIVA since the measurement of blood concentrations is still time consuming. The manual drug infusion regimen in the KM group gave a similar, although only approximate, adjustment of drug concentrations during anaesthesia. This was suggested both by the comparable haemodynamics and by the results of the computer simulation. The calculated plasma concentrations of ketamine during surgery were between 2120 and 700 ng mL−1 (mean 1500 ng mL−1). Similar values were achieved by two independent studies [27,28]. One hour after cessation of infusion, the predicted plasma concentration of ketamine was still higher than that required to produce analgesia in human beings . Similarly, the predicted plasma concentration of midazolam coincided with the results of other studies [30,31]. The predicted plasma concentration of midazolam at the end of the fifth hour (93 ng mL−1) was slightly lower than the previously reported 100 ng mL−1 minimal hypnotic concentration of midazolam [30,32]. However, during KM, ketamine and midazolam act synergistically to create the anaesthetic state. The minimal hypnotic plasma concentration of midazolam in combination with ketamine is hitherto unknown, but concomitant administration of alfentanil shifted the midazolam concentration-effect curve for sedation to the left . Furthermore, by the end of the fifth hour, either surgery was either coming to an end or the drug infusion rate had been increased. Computer simulation showed that the plasma concentrations of ketamine and midazolam achieved by this pragmatically designed, manually controlled regimen were sufficient to meet the patients' requirements during the perioperative period.
For prolonged non-ambulatory surgery, like total cystectomy, midazolam is used as the sedative hypnotic agent. Its low cost is 'attractive' and the slow recovery is not an issue when very early return of consciousness and ambulation are not essential. The high cost of propofol in this setting might not be advisable when cost effectiveness is a priority. Halothane, a low cost volatile anaesthetic agent, was used for comparison since it is still commonly used around the globe. KM represents a comprehensive pharmaco-economic approach to prolonged abdominal surgery.
We hold that KM is a simple, effective and promising anaesthetic technique. Intraoperatively, the intestinal loops look normal, never 'spastic' and with occasional peristaltic activity and the colon was not distended. The peritoneal cavity was more 'roomy' facilitating surgical intervention with minimal surgical assistance. The adequacy of postoperative analgesia and early return of bowel sounds indicate a satisfactory recovery profile in which early enteral feeding is possible.
In conclusion, TIVA with KM for prolonged abdominal surgery has a similar effect on the surgical stress responses as halothane-nitrous oxide-oxygen anaesthesia (HAL) with the advantages of providing satisfactory operative conditions and an acceptable recovery profile.
Dr. Ahmed A. Shorrab spent one year (1997) at Guy's Hospital in the Division of Anaesthetics of the United Medical & Dental Schools of Guy's and St. Thomas' Hospitals (University of London), London UK, under a co-supervision program financed by the Egyptian Government. During his stay, Dr. J. Károvits helped as supervisor and provided the computer simulation program. All the experimental work was conducted at the Urology and Nephrology Center, Mansoura, Egypt.
1. Atallah MM, el-Mohayman HA, el-Metwally RE. Ketamine-midazolam total intravenous anaesthesia for prolonged abdominal surgery. Eur J Anaesthesiol
2. White PF. Clinical uses of intravenous anesthetic and analgesic infusions. Anesth Analg
3. Meleika LK, Ismail ME, Wechsler-Bellevue Intelligence Scale for Adults and Adolescents, Arabic version.
Cairo, Egypt: Al-Nahda, 1991: 19-21.
4. Minto C, Schnider T. PKPD tools for Excel with XLMEM. Version: 1.02;
Palo Alto, June 1995.
5. Domino EF, Domino SE, Smith RE, et al.
Ketamine kinetics in unmedicated and diazepam-premedicated subjects. Clin Pharmacol Ther
6. Avram MJ, Fragen RJ, Caldwell NJ. Midazolam kinetics in women of two age groups. Clin Pharmacol Ther
7. Buchner A, Erdfelder E, Paul F. How to use GPower [wwwdocument
] URL. http://www.psycho.uni-duesseldorf.de/aap/projects/gpower/index.html
(last accessed December 3, 2002).
8. Brockmeyer DM, Kendig JJ. Selective effects of ketamine on amino acid-mediated pathways in neonatal rat spinal cord. Br J Anaesth
9. Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg
10. Gonzales JM, Loeb AL, Reichard PS, Irvine S. Ketamine inhibits glutamate-N-methyl-D-aspartate- and quisqualate-stimulated cGMP production in cultured cerebral neurons. Anesthesiology
11. Sarton E, Teppema LJ, Olievier C, et al.
The involvement of the mu-opioid receptor in ketamine-induced respiratory depression and antinociception. Anesth Analg
12. Durieux ME. Inhibition by ketamine of muscarinic acetylcholine receptor function. Anesth Analg
13. Gage PW, Robertson B. Prolongation of inhibitory post-synaptic currents by pentobarbitone, halothane and ketamine in CAI pyramidal cells in rat hippocampus. Br J Pharmacol
14. Lin LH, Chen LL, Zirrolli JA, Harris RA. General anesthetics potentiate γ-aminobutyric acid actions on γ-aminobutyric acidA
receptors expressed by Xenopus oocytes: lack of involvement of intracellular calcium. J Pharmacol Exp Ther
15. Irifune M, Sato T, Kamata Y, Nishikawa T, Dohi T, Kawahara M. Evidence for GABAA
receptor agonistic properties of ketamine: convulsive and anesthetic behavioral models in mice. Anesth Analg
16. Guidotti A, Toffano G, Costa E. An endogenous protein modulates the affinity of GABA and benzodiazepine receptors in rat brain. Nature
17. Tallman JF, Thomas JW, Gallager DW. GABAergic modulation of benzodiazepine binding site sensitivity. Nature
18. Tanelian DL, Kosek P, Mody I, MacIver MB. The role of GABAA
receptor/chloride channel complex in anesthesia. Anesthesiology
19. Hodges JR. The hypothalamo-pituitary-adrenocortical system. Br J Anaesth
20. Noel GI, Suh HK, Stone JG, Frantz AG. Human prolactin and growth hormone release during surgery and other conditions of stress. J Clin Endocrinol Metab
21. Nilsson A, Person MP, Hartvig P, Wide L. Effect of total intravenous anaesthesia with midazolam/alfentanil on the adrenocortical and hyperglycaemic response to abdominal surgery. Acta Anaesthesiol Scand
22. Atallah MM, Abdelbaky SM, Saied MM. Does timing of hemodilution influence the stress response and overall outcome? Anesth Analg
23. Tverskoy M, Oz Y, Isakson A, Finger J, Bradley EL Jr, Kissin I. Effect of fentanyl and ketamine on postoperative pain and wound hyperalgesia. Anesth Analg
24. Crossley AW. Peri-operative shivering. Anaesthesia
25. Kurz A, Sessler DI, Annadata R, Dechert M, Christensen R, Bjorksten AR. Midazolam minimally impairs thermoregulatory control. Anesth Analg
26. Freye E, Knufermann V. No inhibition of intestinal motility following ketamine-midazolam anaesthesia. A comparison of anaesthesia with enflurane and fentanyl/midazolam. Anaesthesist
27. Idvall J, Ahlgren I, Aronsen KR, Stenberg P. Ketamine infusions: pharmacokinetics and clinical effects. Br J Anaesth
28. White PF, Dworsky WA, Horai Y, Trevor AJ. Comparison of continuous infusion of fentanyl or ketamine versus thiopental - determining the mean effective serum concentrations for outpatient surgery. Anesthesiology
29. Grant IS, Nimmo WS, Clements JA. Pharmacokinetics and analgesic effects of i.m. and oral ketamine. Br J Anaesth
30. Nilsson A, Tamsen A, Persson P. Midazolam-fentanyl anaesthesia for major surgery. Plasma levels of midazolam during prolonged total intravenous anaesthesia. Acta Anaesthesiol Scand
31. Persson P, Nilsson A, Hartvig P, Tamsen A. Pharmacokinetics of midazolam in total intravenous anaesthesia. Br J Anaesth
32. Persson P, Nilsson A, Hartvig P. Relation of sedation and amnesia to plasma concentrations of midazolam in surgical patients. Clin Pharmacol Ther