Acta Anaesthesiol Scand 1990: 34, Supplementum 92: 84-89
Anaesthesia techniques for midazolam and flumazenil - an overview P. M. LAUVEN and P. J. KULKA Institute for Anaesthesiology, University of Bonn, Bonn, Federal Republic of Germany
Midazolam, the latest henzodiazepine agonist, may be used in doses of 0.15 to 0.2 mg.kg-' for induction of anaesthesia. It provides good correlation between plasma concentration and anaesthetic effect with an interindividual variability of only 20-25%. On this basis, dosage recommendations for midazolam in total intravenous anaesthesia techniques are possible, aiming at hypnotic plasma concentrations of at least 250 ngml-'. Due to its biological half-life of 15&180 min and interindividual differences in drug susceptibility, prolonged recovery periods have been observed that can safely and reliably be antagonised by flumazenil, if necessary. It is recommended that flumazenil be administered carefully by titration in increments of 0.1 mgmin- ' to avoid emergence reactions by awakening too fast (tachycardia, hypertension). Usually a mean total dose of 0.4-0.5 mg will lead to prompt awakening.
Key words: Anesthesia; benzodiazepines; flumazenil; midazolam.
Anaesthesia can be defined as a drug-induced state combining amnesia or unconsciousness, analgesia, reflex depression and, to some degree, muscle relaxation. The action of muscle relaxants and of opioids can be safely antagonised by neostigmine and naloxone, respectively. However, unconsciousness and reflex depression due to the prolonged action of hypnotic drugs like barbiturates, non-barbiturate hypnotics like etomidate, or benzodiazepines administered during maintenance of anaesthesia could not be reliably reversed. Until the development of flumazenil they could only be reversed unspecifically by the functional antagonist physostigmine which increases the acetylcholine concentration in the central nervous system. However, physostigmine was not as reliably effective in counteracting the central depressant effects of hypnotics as, for example, the competitive opioid antagonist naloxone (1). Today, of all the hypnotic drugs used in anaesthesia, only the benzodiazepines offer the advantage that their action can be reversed at the end of anaesthesia. Intravenous anaesthesia techniques based on the administration of benzodiazepines, opioids and muscle relaxants make the control of all items of the anaesthesia tetrad accessible to the anaesthetist, thus providing for unique features in performing anaesthesia. However, even if the benzodiazepines can now be reversed at the end of anaesthesia, drugs with a clearance as high and a half-life as short as possible are of special value during anaesthesia. For years diazepam was the only available benzodiazepine. However, the onset of its action is slow, so
that it could not compete with the classical induction agents. Because of its extremely long half-life of about 40 h and more, which showed a large interindividual variability, the duration of drug action became unpredictable (2, 3). Plasma concentration and hypnotic effect were found not to correlate well (4).Therefore its use was limited, especially after high doses. A first improvement in benzodiazepine administration in anaesthesia was achieved when the partly water-soluble drug flunitrazepam and the much less used lormetazepam were introduced into clinical practice. But in spite of more appropriate pharmacodynamic properties, their use in anaesthesia was again limited, especially after high doses. Thus, the introduction of midazolam was a great step forward as it offered characteristics which were totally new compared to other benzodiazepines and more appropriate for use in anaesthesia. GENERAL PHARMACOLOGY OF MIDAZOLAM RELATED TO ANAESTHESIA First of all, midazolam hydrochloride is water-soluble and does not cause the irritation of veins or tissues reported for other hypnotic agents (5). Furthermore, it has a relatively short half-life of 2-3 h, which has been confirmed by many investigators (Table 1). Its plasma clearance of 400-500 mlamin-' is 15 times higher than that of diazepam, entirely due to its hepatic metabolism (9, 10). Its other pharmacokinetic parameters are similar to those of diazepam, including a comparable distribution half-life of about 15 min and
ANAESTHESIA TECHNIQUES - OVERVIEW Table 1 Mean pharmacokinetic parameters.
Lauven (6) Greenblatt (7) Nilsson (8)
8.6 18.6 18
152 126 185
84.2 92 89.8
472 533 483
a distribution period of 4 5 6 0 min, a similar large volume at steady state (1.1-1.8 1-kg-') and a high degree of protein binding (95%). In addition, interindividual variation of midazolam is relatively small as, for example, indicated by a variation coefficient of plasma concentrations after a single bolus dose in the range of 20% in almost all studies. The analysis of frequency distribution measured over predicted midazolam values demonstrated a normally distributed curve with a mean of 1.11 (i.e. the mean measured concentration differed only by 1 1yo from the predicted values). As is characteristic for almost all benzodiazepines used in anaesthesia, midazolam provides anterograde amnesia, anxiolytic, hypnotic, anticonvulsive and muscle relaxant effects, but is clinically 3-4 times as potent as diazepam (1 1). This potency is most probably due to its affinity to the benzodiazepine receptor which is at least twice as high as that of diazepam ( 12). Additionally, its hypnotic component is more pronounced ( 13). Besides, midazolam sufficiently attenuates the stress-related epinephrine response to surgery without suppressing adrenocorticosteroid synthesis ( 14, 15). It leads to venous pooling and decreases total peripheral resistance without significantly affecting inotropism or coronary circulation, so that it can safely be used in patients suffering from coronary artery disease or hypertension ( 16, 17). INDUCTION OF ANAESTHESIA WITH MIDAZOLAM The pharmacological properties led to the use of various anaesthesia techniques combining induction of anaesthesia with midazolam and maintaining unconsciousness and analgesia during surgery by administering inhalational agents or opioids. After induction, when the effects of volatile agents are not yet fully present, midazolam can guarantee unconsciousness and reflex depression by its relatively long distribution phase of 45-60 min. Thus, for procedures in the range of 30-60 min like short gynaecological or surgical interventions, induction of anaesthesia with 10-15 mg midazolam combined with repetitive bolus doses of alfentanil is quite a common anaesthesia technique combining smooth induction
85
and cardiovascular stability with a short recovery period. The patients are awake and cooperative but amnesic to their stay in the recovery room (18). However, in the first studies using induction doses of 0.15-0.2 mg.kg-' (15 mg/70 kg) midazolam was found not to be so reliable in inducing unconsciousness as thiopental, which was probably due to its slow onset of action (19-22). According to the dose-response relationship, Reves even recommended induction doses up to 0.4 mg-kg-' or, otherwise, to precede induction by heavy premedication to reduce the interpatient variability in response. But indeed, patients who had received thiopental on a previous occasion assessed the slow onset of action as pleasant (29).
RECOVERY AFTER MIDAZOLAM INDUCTION WI TH AND W I T H O U T FLUMAZENIL When emergence is evaluated after general anaesthesia, considerable variability exists. Some investigators found that awakening after midazolam ranged from 14 to 24 times as long as after thiopentone (19, 23-27). These results were confirmed by the pharmacological findings of Nilsson (28). To define the therapeutic concentration range of midazolam without the influence of other drugs, midazolam was administered to 10 female surgical patients given epidural anaesthesia. The results demonstrated that patients will be arousable at a mean midazolam concentration of 180 n g m - ' . Patients were sedated and amnesic until the concentration fell below 75 to 100 n g m - ' , while patients were assessed awake when concentration fell below 50 ng-ml-'. Interindividual variation in drug susceptibility is due to pharmacokinetic and pharmacodynamic influences. As demonstrated by Nilsson in the same study, alfentanil-supplemented midazolam leads to a more pronounced hypnotic effect as shown by a shift of the concentration-effect relationship to the left. Besides, when the opioid alfentanil was administered simultaneously, the interindividual variation was about 50%, which is considerably more than the 20% variation after midazolam alone. That there is considerable variation concerning dose-effect response when other hypnotic drugs are administered was confirmed by Tverskov et al. (29). The midazolam ED,, value for induction of anaesthesia proved to be 0.19 mgakg-' when midazolam was administered alone. It decreased to 0.05 mg.kg-' when thiopental (0.7 mg.kg-') was administered additionally. As this was a much smaller dose than the dose one would have expected in the case of additive
86
P. M. LAUVEN AND P. J. KULKA
drug action, it was concluded that the interaction between thiopental and midazolam was supra-additive. TOTAL INTRAVENOUS ANAESTHESIA TECHNIQUES WITH MIDAZOLAM Since droperidol in neurolept-anaesthesia has been substituted by benzodiazepines, midazolam has become the drug most frequently administered, due to its pharmacokinetic and pharmacodynamic properties. Various techniques have been described combining midazolam with fentanyl, alfentanil and ketamine where all techniques offer the advantage of rapid recovery and high postoperative vigilance after the administration of flumazenil (and naloxone) . When combined with fentanyl and controlled ventilation, satisfactory hypnotic effects and good cardiovascular stability were obtained when midazolam plasma levels of about 400 n g m - ’ were attained (30). As postoperative drowsiness and respiratory depression were often noted, which made naloxone administration necessary, fentanyl was later replaced by alfentanil (3 1). But especially after longer administration, prolonged recovery periods remained a frequent finding. Ataranalgesic combinations of benzodiazepines and ketamine have been reported to be advantageous alternatives to inhalational agents or high-dose opioids. As pharmacokinetic properties of midazolam and ketamine provide more similarities than diazepam or flunitrazepam, this combination was used for total intravenous anaesthesia in trauma patients, for peripheral and intra-abdominal surgery. In trauma patients no suppression of endocrine functions was found, but when the duration of surgical interventions exceeded 1 h a prolonged recovery period was observed (32, 33). There are other features that make midazolam unique in comparison to other benzodiazepines. It reveals a good and stable relationship between plasma concentration and effect as well as predictable plasma concentrations that make dosage recommendations on the basis of pharmacokinetic computer simulation and pharmacodynamic correlation possible (6). Without going too deeply into pharmacokinetic details and without reporting the various schemes used for total intravenous anaesthesia, simple administration schemes may be calculated on the basis of an open two-compartment model by biological half-life (150-180 min) and total clearance (500 ml.min-I). A repetitive dosage scheme of midazolam is demonstrated on the assumption of a desired hypnotic threshold concentration of about 250 ng-ml- ’. During the first 30 min, 28 mg of midazolam are necessary fol-
:
t3;
180 100 4 0 20
-f
0
60
90
120
40
40
40
t
t
t
150
180
210 m n
150
180
210
mg
peripheral amount
30
60
90
120
min
Fig. I . Midazolam plasma concentration according to computer simulation (upper curve) when a repetitive bolus scheme was applied. Doses and dosing intervals for a midazolam plasma concentration of 250 ngml-’ are listed under the time axis. The amount of midazolam in the peripheral compartment of an open two-compartment model (“body load”) is depicted in the bottom part.
lowed by incremental doses of 4 mg every 30 min (Fig. 1). Such intermittent injections of intravenous anaesthetics have been used for many years. The introduction of drugs with suitable pharmacokinetic profiles, e.g. high total clearance and short biological half-lives like midazolam led to the feasibility of continuous infusion techniques in total intravenous anaesthesia. Again, aiming at the hypnotic threshold concentration of 250 n g m - ’ , a fast initial loading infusion rate of 25 mg/lO min is followed subsequently by a slower maintenance infusion rate of 0.11 rngemin-l. Similar dosage regimens were administered in volunteer studies (Fig. 2) (34). The rigidity of fixed infusion schemes with specified loading and maintenance infusion rates has increased the demand for intelligent infusion pumps that can generate exactly those blood levels of intravenous anaesthetics and narcotics that are necessary for a particular patient and a particular procedure. By such dosage regimens it should be possible to avoid high initial plasma concentrations and subsequent potentially harmful side-effects like cardiovascular depression produced by the loading dose leading to high plasma concentrations at the very beginning. One possible way to approach this goal is offered by the so-called BET infusion scheme, a dosage regimen for constant blood levels from the very beginning onwards. It consists of three terms: a Bolus dose to fill the central compartment of a two-compartment model to the desired target concentration, a constant infusion equalling the Elimination rate at that concentration,
87
ANAESTHESIA TECHNIQUES - OVERVIEW
T
w/ml
BLOOD LEVEL
rnin 0
30
60
90
120
150
210
180
rn,"
0 0
\
0 11
I
I
I
I
1
20
40
80
80
100
I )
120
5 7 7 0 ~ INFUSION SCHEME
peripheral amount
rnin 0
30
60
90
120
150
210
180
rn,"0
Fig. 2. Midazolam plasma concentration according to computer simulation (upper curve) when a two-step infusion (or a bolus + infusion) scheme was administered. The dosage regimen aiming at a plasma concentration of 250 n g m - l consists ofan initial fast infusion followed by a maintenance infusion (middle part). The amount of midazolam in the peripheral compartment of an open two-compartment model ("body load") is shown in the bottom part.
0
'
FLUMAZENIL AFTER INTRAVENOUS ANAESTHESIA W ITH MIDAZOLAM The essentials of midazolam intravenous anaesthesia in terms of pharmacokinetic and pharmacodynamic correlation have now been well investigated and understood. But in single cases prolonged drug action may occur due to slow elimination even when sophisticated infusion schemes are used. In these patients, the half-life of midazolam may be prolonged due to decreased clearance (35, 36). In addition, high age, obesity, gender or high ASA-classes were found to influence pharmacokinetic properties, leading to pro-
I
I
I
I
40
60
80
100
I +
120
y-PERIPHERAL AMOUNT
1 0 7 rng
0 0
and an exponentially declining infusion rate substituting the Transfer of drug from blood to tissues, the socalled body load. To maintain a constant blood level of 250 ng-ml-l, an exponentially declining infusion is necessary starting at about 350 pgemin-' and decreasing within 60 min to about 200 pgamin-'. Such a BET dosage scheme, but aiming at a higher plasma concentration of about 400 ngeml-', was successfully demonstrated by Lauven et al. in 1982 (Fig. 3) (6). The dose necessary to establish a mean safe hypnotic midazolam concentration of 250 ngrnl- will be highest after repetitive dosing. A bolus + constant rate infusion, or a two-step infusion technique, requires a smaller dose of 30 mg within the first hour. The smallest dose will be necessary when a BET scheme is applied (Table 2) (computer simulated values).
I
20
20
40
80
80
100
120
Fig. 3. Midazolam plasma concentration according to computer simulation (upper curve) when a BET-infusion was applied (6). The dosage scheme for a midazolam plasma concentration of 250 n g m - l is demonstrated in the figure below. The amount of midazolam in the peripheral compartment of an open two-compartment model is shown in the bottom figure.
longed duration of midazolam action by slowed elimination (7). I n contrast to inhalational agents, recovery from total intravenous anaesthesia depends on distribution, hepatic metabolism and elimination by the kidney. Especially when high doses of midazolam are administered, for example as maintenance infusion during anaesthesia, distribution mechanisms become less effective as the tissues (peripheral compartment) are already filled. I n these cases termination of drug action relies mainly on the elimination half-life, thus potentially leading to prolonged recovery. Yet, it has to be considered that a reduced state of
Table 2 Dose of midazolam necessary to establish a mean hypnotic plasma midazolam concentration of 250 n g m - ' . Amount of midazolam administered after 30 min 60 rnin 90 rnin 120 min Repetitive boli Two-step-infusion BET-scheme
32 27.3 15.2
36 30.7 22.2
40 34.2 27.7
44 37.6 32.3
88
P. M. LAUVEN AND P. J. KULKA
awareness is a normal and may be a desired finding, independent of which anaesthetic technique is applied, and usually requires no intervention. But prolonged recovery periods may become a problem as soon as they are combined with vitally depressed organ functions or in special situations where a high degree of post-operative vigilance is required and beneficial for the patient, e.g. after laryngoscopy or bronchoscopy. In these cases the application of flumazenil may be desirable. Since its introduction, prompt recovery after benzodiazepine application can be obtained whenever it is required. This may lead to a less limited use of total intravenous techniques or induction procedures using midazolam, as the risk of a prolonged recovery period with depressed reflexes and vigilance at the end of surgery can be reduced. Up to now, flumazenil has been shown to be effective in reversing all effects of midazolam within minutes. Blood pressure and heart rate remained stable, and the stress response during the recovery period seemed not to be affected by the administration of the antagonist (37-39). As flumazenil has a half-life of about 60 min, which is relatively short, it can be expected that its antagonist action will be shorter than that of the agonist, thus leading to a recurrence of sedation. This applies especially to such cases where midazolam is also used for maintenance of anaesthesia in high doses. Recurrence of sedation stresses the point that close observation is mandatory after administration of the antagonist, even if the patient seems to be fully awake and oriented. Most probably antagonisation will not lead to an increased demand for analgesics in the post-operative period (40), but nevertheless there is evidence that anaesthesia is less accepted by some patients. In an examination by Raeder et al. (41), five of 25 patients were less content with an anaesthesia regime using midazolam, alfentanil and flumazenil compared with previous experiences. In the control groups where isoflurane or thiopentone was used, no complaints were mentioned. The authors explained their finding by different individual ideals concerning anaesthesia: some patients want to be fully awake and to recover rapidly after anaesthesia, while others want to be asleep without too much disturbance in a busy recovery room (41). We have to take into consideration that minor side-effects like nausea and vomiting may occur more frequently (42). Preliminary results were reported from a study where flumazenil was used after neurosurgical procedures with a mean duration of 5.5 h where anaesthesia was performed with midazolam and fentanyl. Patients improved rapidly after administration of the
antagonist according to the Glasgow coma scale, thus enabling the surgeon to perform accurate neurological assessment (43). Forster showed that flumazenil is effective in reversing the reduction of cerebral blood flow (CBF) due to midazolam application. The administration of flumazenil alone had no effect on CBF. Nevertheless, as this study was performed in healthy volunteers, further evaluation of its cerebrovascular effects is necessary before the use of flumazenil after neurosurgical procedures can be recommended (44). Anaesthesia for caesarian section implies the risk of aspiration during the induction and recovery period when reflexes are still partly depressed. In a study in gynaecological patients undergoing caesarian section, midazolam in a dose of 1 mg was injected prior to induction of anaesthesia for caesarian section in order to achieve amnesia. Rapid sequence induction was performed with 20 mg ketamine, 10 mg etomidate and 100 mg succinylcholine. After card clamp, anaesthesia was supplemented with alfentanil, vecuronium and 30 mg midazolam. After the end of the operation flumazenil was administered until the patients became cooperative or did not tolerate the endotracheal tube any longer. A mean dose of 0.48 & 0.12 mg was shown to be effective. Patients were cooperative but amnesic by this time. The authors concluded that this technique provides excellent anaesthesia recovery conditions with safe extubation (45). CONCLUSION Due to its pharmacokinetic and pharmacodynamic properties, midazolam can safely be used to induce and maintain anaesthesia. If unwanted prolonged recovery periods are observed, the benzodiazepine antagonist flumazenil can be administered to reverse, safely and reliably, the benzodiazepine action at the end of surgery. In general, the use of flumazenil (like the use of other antagonists) should be limited to special procedures and to those cases where patients will benefit, as judged by an experienced anaesthestist. REFERENCES 1. Stoeckel H, Lauven P. Das zentrale anticholinerge Syndrom:
Physostigmin in der Intensivemedizin, Anasthesiologie, Psychiatrie. INA 1985: 55. 2. Reves H G. Benzodiazepines, pharmacokinetics of anesthesia. Prys-Roberts C, Hug C C. Oxford: Blackwell Scientific Publications, 1984: 157-186. 3. Reves J G, Corssen G, Holcomb C. Comparison of two benzodiazepines for anaesthesia induction: midazolam and diazepam. Can Anaesth Soc J 1978: 25: 21 1. 4. Reidenber M, Levy M, Warner H. Relationship between diazepam dose, plasma level, age, and central nervous system depression. Clin Phannacol Thn 1978: 23: 371-374.
ANAESTHESIA TECHNIQUES - OVERVIEW 5. Korttila K, Aromaa U.Venous complications after intravenous injection of diazepam, flunitrazepam, thiopentone and etomidate. Acta Anaesthesiol Scand 1980: 24: 227-230. 6. Lauven P M, Stoeckel H, Schwilden H. Ein pharmakokinetisch begriindetes Infusionsmodell fur Midazolam. Anaesthesist 1982: 31: 15-20. 7. Greenblatt D, Abernethy D, Locniskar A, Harmatz J, Limjucu R, Shader R. Effect of age, gender and obesity on midazolam kinetics. Anesthesiology 1984: 61: 27-35. 8. Persson P, Nilsson A, Hartvig P, Tamsen A. Pharmacokinetics of midazolam in total intravenous anaesthesia. Br 3Anaesth 1987: 59: 548-556. 9. Lauven P M, Stoeckel H, Ochs H, Greenblatt D J. Pharmakokinetische Untersuchungen mit dem neuen wasserloslichen Benzodiazepin Midazolam. Anaesthesist 1981: 30: 280-283. 10. Gerecke M. Chemical structure and properties of midazolam compared with other benzodiazepines. Br J Clin Pharmacol 1983: 16: 11-16. 11. Tallmann J F. Benzodiazepines: from receptor to function in sleep. Sleep 1982: 5: 12-17. 12. Mohler H, Okada T. Benzodiazepine receptor: demonstration in the central nervous system. Science 1977: 198: 849-851. 13. Pieri L, Schaffner R, Scherschlicht R. Pharmacology of midazolam. Arzneimitteljorschung 1981: 31: 2180-2201. 14. Lindahl S G E, Charlton AJ, Hatch D J, Norden N E. Endocrine response to surgery after premedication with midazolam or papavereturn. Eur 3 Anaesthesiol 1985: 2: 369-377. 15. Crozier T A, Beck P D, Schlaeger M, Wuttke W, Kettler D. Endocrinological changes following etomidate, midazolam or methohexital for minor surgery. Anesthesiology 1987: 66: 628-635. 16. Marty J, Nitenberg A, Blanchet F, Zouioueche S, Desmonts J M. Effects of midazolarn on the coronary circulation in patients with coronary artery disease. Anesthesiology 1986: 64: 206-2 10. 17. Miiller H, Schleusner E, Stoyanov M, Kling D, Hempelmann G. Hamodynamische Wirkungen und Charakteristika der Narkoseeinleitung mit Midazolam. Arzneitimitteljorschung 1981: 31: 2227-2232. 18. Saidman L J. Midazolam: pharmacology and uses. Anesthesiology 1985: 62: 310-324. 19. Jensen S, Schou-Olesen A, Hiittel S. Use of midazolam as induction agent: comparison with thiopentone. Br 3 Anaesth 1982: 54: 605407. 20. Kanto J, Sjovall S, Vuori A. Effect of different kinds of premedication on the induction properties of midazolarn. Br J Anaesth 1982: 54: 507-511. 2 1. Forster A, Gardaz J P, Suter P M, Gemperle M. I.V. midazolam as an induction agent for anaesthesia: a study in volunteers. Br 3 Anaesth 1980: 52: 907-91 1. 22. Gamble J A S, Dundee J W, Kawar P. Midazolam - an alternative to thiopentone? Br 3 Anaesth 1980: 52: 951-952. 23. Reves J G, Vinik R, Hirschfield A M, Holcom C, Strong S. Midazolam compared to thiopentone as hypnotic component in balanced anaesthesia: a randomized, double-blind study. Can Anaesth Soc J 1979: 26: 42549. 24. Pakkanen A, Kanto J. Midazolam compared with thiopentone as an induction agent. Acta Anaesthesiol Scand 1982: 26: 143-146. 25. Eisenkraft J B, Miller R. Induction dose of midazolam. Br 3 Anaesth 1981: 53: 318. 26. Berggren L, Eriksson I. Midazolarn for induction of anaesthesia in outpatients: a comparison with thiopentone. Acta Anaesthesiol Scand 1981: 25: 492496. 27. Nauta J, Stanley T H, De Lange S, Koopman D, Spierdijk J. Anaesthesia induction with alfentanil: comparison with thiopental, midazolam and etomidate. Can Anaesth Soc 3 1983: 30: 5 3 4 0 . 28. Persson M P, Nilsson A, Hartvig P. Relation of sedation and
29.
30.
31.
32.
33.
34. 35.
36.
37. 38.
39.
40.
41.
42. 43.
44.
45.
89
amnesia to plasma concentrations of midazolam in surgical patients. Clin Pharmacol Ther 1988: 3: 324-325. Tverskov M, Fleyshman G, Bradley E L, Kissin I. Midazolamthiopental anesthetic interaction in patients. Anesth Analg 1988: 67: 342-345. Nilsson A, Tansen A, Persson P. Midazolam-fentanyl anaesthesia for major surgery. Plasma levels of midazolam during prolonged total intravenous anaesthesia. Acta Anaesthesiol Scand 1986: 30: 66-69. Raeder J C, Nilsen G, Hole A. Pharmacokinetics of midazolam and alfentanil in outpatient general anaesthesia. Acta Anaesthesiol Scand 1988: 32: 467-472. Podlesch I, Dahn H, Engel M. Anaesthetic and side effects of midazolarn and ketamine in surgical patients. Anesthesiology 1985: 62: 68. Seitz W, Liibbe N, Hamkens A, Bornscheuer A. MidazolamKetamin-Kombinationsanaesthesiebei traumatologischen Eingriffen. Anaesthesist 1988: 37: 231-237. Lauven P M, Stoeckel H. Hypnotische wirksame Blutspiegel von Midazolarn. Anaesth Intensivther Notjallmed 1987: 22: 90-93. Dundee J W, Collier P S, Carlisle R J T, Harper K W. Prolonged midazolam elimination half-life. Br 3 Clin Pharmacol 1986: 21: 4255429. Klotz U, Mikus G, Zekorn C, Eichelbaum M. Pharmacokinetics of midazolam in relation to polymorphic sparteine oxidation. Br 3 Clin Pharmacol 1986: 22: 618419. Alon E, Baitella L, Hossli G. Ro 15-1788in reversing midazolam used for laparoscopy. Acta Anaesthesiol Scand 1985: 29: A 163. Klausen N 0, Sorensen J, Ferguson A H, Neumann P B, Larsen C, Juhl 0.Stress response during recovery after total intravenous anaesthesia with midazolam and fentanyl reversed by Ro 151788. In: Beitrage zur Anaesthesiologie und Intensivmedizin 16: VII. European Congress of Anaesthesiology, Abstract 11. 1986: A 133. Ritter J W, Flacke W E, Norel E, Gion H, Chen R, Hoskizaki G. Adrenergic and hemodynamic response to flumazenil (Ro 15-1788) reversal of midazolam sedation. Anesthesiology 1988: 69: A 109. Nilsson A, Persson M P, Hartvig P. Effects of the benzodiazepine antagonist flumazenil on postoperative performance following total intravenous anaesthesia with midazolam and alfentanil. Acta Anaesthesiol Scand 1988: 32: 441-446. Raeder J C, Hole A, Arnulf V, Hougens Grynne B. Total intravenous anaesthesia with midazolam and flumazenil. Acta Anaesthesiol Scand 1987: 31: 634-641. Wolff J. Flumazenil for postoperative recovery. Eur 3Anaesthesiol 1988: SUPPI2: 239-249. Uhiolero R, Ravussin P, Chassot P G, Neff R, Freeman J. Ro 15-1788 for rapid recovery after craniotomy. Anesthesiology 1986: 65: A 466. Forster A, Juge 0, Louis M, Nahory A. Effects of a specific benzodiazepine antagonist Ro 15-1788 on cerebral blood flow. Anesth Analg 1987: 66: 309-313. Waldvogel H H. A rational approach to the use of midazolam and flumazenil for caesarian section. Eur 3 Anaesthesiol 1988: SUPPI 2: 277-278.
Address: Prof. Dr. II M. Lauuen Institut fur Anasthesiologie der Universitat Bonn Sigmund-Freud-Strasse 25 D-5300 Bonn 1 Federal Republic of Germany
Anaesthesia techniques for midazolam and flumazenil - an overview P. M. LAUVEN and P. J. KULKA Institute for Anaesthesiology, University of Bonn, Bonn, Federal Republic of Germany
Midazolam, the latest henzodiazepine agonist, may be used in doses of 0.15 to 0.2 mg.kg-' for induction of anaesthesia. It provides good correlation between plasma concentration and anaesthetic effect with an interindividual variability of only 20-25%. On this basis, dosage recommendations for midazolam in total intravenous anaesthesia techniques are possible, aiming at hypnotic plasma concentrations of at least 250 ngml-'. Due to its biological half-life of 15&180 min and interindividual differences in drug susceptibility, prolonged recovery periods have been observed that can safely and reliably be antagonised by flumazenil, if necessary. It is recommended that flumazenil be administered carefully by titration in increments of 0.1 mgmin- ' to avoid emergence reactions by awakening too fast (tachycardia, hypertension). Usually a mean total dose of 0.4-0.5 mg will lead to prompt awakening.
Key words: Anesthesia; benzodiazepines; flumazenil; midazolam.
Anaesthesia can be defined as a drug-induced state combining amnesia or unconsciousness, analgesia, reflex depression and, to some degree, muscle relaxation. The action of muscle relaxants and of opioids can be safely antagonised by neostigmine and naloxone, respectively. However, unconsciousness and reflex depression due to the prolonged action of hypnotic drugs like barbiturates, non-barbiturate hypnotics like etomidate, or benzodiazepines administered during maintenance of anaesthesia could not be reliably reversed. Until the development of flumazenil they could only be reversed unspecifically by the functional antagonist physostigmine which increases the acetylcholine concentration in the central nervous system. However, physostigmine was not as reliably effective in counteracting the central depressant effects of hypnotics as, for example, the competitive opioid antagonist naloxone (1). Today, of all the hypnotic drugs used in anaesthesia, only the benzodiazepines offer the advantage that their action can be reversed at the end of anaesthesia. Intravenous anaesthesia techniques based on the administration of benzodiazepines, opioids and muscle relaxants make the control of all items of the anaesthesia tetrad accessible to the anaesthetist, thus providing for unique features in performing anaesthesia. However, even if the benzodiazepines can now be reversed at the end of anaesthesia, drugs with a clearance as high and a half-life as short as possible are of special value during anaesthesia. For years diazepam was the only available benzodiazepine. However, the onset of its action is slow, so
that it could not compete with the classical induction agents. Because of its extremely long half-life of about 40 h and more, which showed a large interindividual variability, the duration of drug action became unpredictable (2, 3). Plasma concentration and hypnotic effect were found not to correlate well (4).Therefore its use was limited, especially after high doses. A first improvement in benzodiazepine administration in anaesthesia was achieved when the partly water-soluble drug flunitrazepam and the much less used lormetazepam were introduced into clinical practice. But in spite of more appropriate pharmacodynamic properties, their use in anaesthesia was again limited, especially after high doses. Thus, the introduction of midazolam was a great step forward as it offered characteristics which were totally new compared to other benzodiazepines and more appropriate for use in anaesthesia. GENERAL PHARMACOLOGY OF MIDAZOLAM RELATED TO ANAESTHESIA First of all, midazolam hydrochloride is water-soluble and does not cause the irritation of veins or tissues reported for other hypnotic agents (5). Furthermore, it has a relatively short half-life of 2-3 h, which has been confirmed by many investigators (Table 1). Its plasma clearance of 400-500 mlamin-' is 15 times higher than that of diazepam, entirely due to its hepatic metabolism (9, 10). Its other pharmacokinetic parameters are similar to those of diazepam, including a comparable distribution half-life of about 15 min and
ANAESTHESIA TECHNIQUES - OVERVIEW Table 1 Mean pharmacokinetic parameters.
Lauven (6) Greenblatt (7) Nilsson (8)
8.6 18.6 18
152 126 185
84.2 92 89.8
472 533 483
a distribution period of 4 5 6 0 min, a similar large volume at steady state (1.1-1.8 1-kg-') and a high degree of protein binding (95%). In addition, interindividual variation of midazolam is relatively small as, for example, indicated by a variation coefficient of plasma concentrations after a single bolus dose in the range of 20% in almost all studies. The analysis of frequency distribution measured over predicted midazolam values demonstrated a normally distributed curve with a mean of 1.11 (i.e. the mean measured concentration differed only by 1 1yo from the predicted values). As is characteristic for almost all benzodiazepines used in anaesthesia, midazolam provides anterograde amnesia, anxiolytic, hypnotic, anticonvulsive and muscle relaxant effects, but is clinically 3-4 times as potent as diazepam (1 1). This potency is most probably due to its affinity to the benzodiazepine receptor which is at least twice as high as that of diazepam ( 12). Additionally, its hypnotic component is more pronounced ( 13). Besides, midazolam sufficiently attenuates the stress-related epinephrine response to surgery without suppressing adrenocorticosteroid synthesis ( 14, 15). It leads to venous pooling and decreases total peripheral resistance without significantly affecting inotropism or coronary circulation, so that it can safely be used in patients suffering from coronary artery disease or hypertension ( 16, 17). INDUCTION OF ANAESTHESIA WITH MIDAZOLAM The pharmacological properties led to the use of various anaesthesia techniques combining induction of anaesthesia with midazolam and maintaining unconsciousness and analgesia during surgery by administering inhalational agents or opioids. After induction, when the effects of volatile agents are not yet fully present, midazolam can guarantee unconsciousness and reflex depression by its relatively long distribution phase of 45-60 min. Thus, for procedures in the range of 30-60 min like short gynaecological or surgical interventions, induction of anaesthesia with 10-15 mg midazolam combined with repetitive bolus doses of alfentanil is quite a common anaesthesia technique combining smooth induction
85
and cardiovascular stability with a short recovery period. The patients are awake and cooperative but amnesic to their stay in the recovery room (18). However, in the first studies using induction doses of 0.15-0.2 mg.kg-' (15 mg/70 kg) midazolam was found not to be so reliable in inducing unconsciousness as thiopental, which was probably due to its slow onset of action (19-22). According to the dose-response relationship, Reves even recommended induction doses up to 0.4 mg-kg-' or, otherwise, to precede induction by heavy premedication to reduce the interpatient variability in response. But indeed, patients who had received thiopental on a previous occasion assessed the slow onset of action as pleasant (29).
RECOVERY AFTER MIDAZOLAM INDUCTION WI TH AND W I T H O U T FLUMAZENIL When emergence is evaluated after general anaesthesia, considerable variability exists. Some investigators found that awakening after midazolam ranged from 14 to 24 times as long as after thiopentone (19, 23-27). These results were confirmed by the pharmacological findings of Nilsson (28). To define the therapeutic concentration range of midazolam without the influence of other drugs, midazolam was administered to 10 female surgical patients given epidural anaesthesia. The results demonstrated that patients will be arousable at a mean midazolam concentration of 180 n g m - ' . Patients were sedated and amnesic until the concentration fell below 75 to 100 n g m - ' , while patients were assessed awake when concentration fell below 50 ng-ml-'. Interindividual variation in drug susceptibility is due to pharmacokinetic and pharmacodynamic influences. As demonstrated by Nilsson in the same study, alfentanil-supplemented midazolam leads to a more pronounced hypnotic effect as shown by a shift of the concentration-effect relationship to the left. Besides, when the opioid alfentanil was administered simultaneously, the interindividual variation was about 50%, which is considerably more than the 20% variation after midazolam alone. That there is considerable variation concerning dose-effect response when other hypnotic drugs are administered was confirmed by Tverskov et al. (29). The midazolam ED,, value for induction of anaesthesia proved to be 0.19 mgakg-' when midazolam was administered alone. It decreased to 0.05 mg.kg-' when thiopental (0.7 mg.kg-') was administered additionally. As this was a much smaller dose than the dose one would have expected in the case of additive
86
P. M. LAUVEN AND P. J. KULKA
drug action, it was concluded that the interaction between thiopental and midazolam was supra-additive. TOTAL INTRAVENOUS ANAESTHESIA TECHNIQUES WITH MIDAZOLAM Since droperidol in neurolept-anaesthesia has been substituted by benzodiazepines, midazolam has become the drug most frequently administered, due to its pharmacokinetic and pharmacodynamic properties. Various techniques have been described combining midazolam with fentanyl, alfentanil and ketamine where all techniques offer the advantage of rapid recovery and high postoperative vigilance after the administration of flumazenil (and naloxone) . When combined with fentanyl and controlled ventilation, satisfactory hypnotic effects and good cardiovascular stability were obtained when midazolam plasma levels of about 400 n g m - ’ were attained (30). As postoperative drowsiness and respiratory depression were often noted, which made naloxone administration necessary, fentanyl was later replaced by alfentanil (3 1). But especially after longer administration, prolonged recovery periods remained a frequent finding. Ataranalgesic combinations of benzodiazepines and ketamine have been reported to be advantageous alternatives to inhalational agents or high-dose opioids. As pharmacokinetic properties of midazolam and ketamine provide more similarities than diazepam or flunitrazepam, this combination was used for total intravenous anaesthesia in trauma patients, for peripheral and intra-abdominal surgery. In trauma patients no suppression of endocrine functions was found, but when the duration of surgical interventions exceeded 1 h a prolonged recovery period was observed (32, 33). There are other features that make midazolam unique in comparison to other benzodiazepines. It reveals a good and stable relationship between plasma concentration and effect as well as predictable plasma concentrations that make dosage recommendations on the basis of pharmacokinetic computer simulation and pharmacodynamic correlation possible (6). Without going too deeply into pharmacokinetic details and without reporting the various schemes used for total intravenous anaesthesia, simple administration schemes may be calculated on the basis of an open two-compartment model by biological half-life (150-180 min) and total clearance (500 ml.min-I). A repetitive dosage scheme of midazolam is demonstrated on the assumption of a desired hypnotic threshold concentration of about 250 ng-ml- ’. During the first 30 min, 28 mg of midazolam are necessary fol-
:
t3;
180 100 4 0 20
-f
0
60
90
120
40
40
40
t
t
t
150
180
210 m n
150
180
210
mg
peripheral amount
30
60
90
120
min
Fig. I . Midazolam plasma concentration according to computer simulation (upper curve) when a repetitive bolus scheme was applied. Doses and dosing intervals for a midazolam plasma concentration of 250 ngml-’ are listed under the time axis. The amount of midazolam in the peripheral compartment of an open two-compartment model (“body load”) is depicted in the bottom part.
lowed by incremental doses of 4 mg every 30 min (Fig. 1). Such intermittent injections of intravenous anaesthetics have been used for many years. The introduction of drugs with suitable pharmacokinetic profiles, e.g. high total clearance and short biological half-lives like midazolam led to the feasibility of continuous infusion techniques in total intravenous anaesthesia. Again, aiming at the hypnotic threshold concentration of 250 n g m - ’ , a fast initial loading infusion rate of 25 mg/lO min is followed subsequently by a slower maintenance infusion rate of 0.11 rngemin-l. Similar dosage regimens were administered in volunteer studies (Fig. 2) (34). The rigidity of fixed infusion schemes with specified loading and maintenance infusion rates has increased the demand for intelligent infusion pumps that can generate exactly those blood levels of intravenous anaesthetics and narcotics that are necessary for a particular patient and a particular procedure. By such dosage regimens it should be possible to avoid high initial plasma concentrations and subsequent potentially harmful side-effects like cardiovascular depression produced by the loading dose leading to high plasma concentrations at the very beginning. One possible way to approach this goal is offered by the so-called BET infusion scheme, a dosage regimen for constant blood levels from the very beginning onwards. It consists of three terms: a Bolus dose to fill the central compartment of a two-compartment model to the desired target concentration, a constant infusion equalling the Elimination rate at that concentration,
87
ANAESTHESIA TECHNIQUES - OVERVIEW
T
w/ml
BLOOD LEVEL
rnin 0
30
60
90
120
150
210
180
rn,"
0 0
\
0 11
I
I
I
I
1
20
40
80
80
100
I )
120
5 7 7 0 ~ INFUSION SCHEME
peripheral amount
rnin 0
30
60
90
120
150
210
180
rn,"0
Fig. 2. Midazolam plasma concentration according to computer simulation (upper curve) when a two-step infusion (or a bolus + infusion) scheme was administered. The dosage regimen aiming at a plasma concentration of 250 n g m - l consists ofan initial fast infusion followed by a maintenance infusion (middle part). The amount of midazolam in the peripheral compartment of an open two-compartment model ("body load") is shown in the bottom part.
0
'
FLUMAZENIL AFTER INTRAVENOUS ANAESTHESIA W ITH MIDAZOLAM The essentials of midazolam intravenous anaesthesia in terms of pharmacokinetic and pharmacodynamic correlation have now been well investigated and understood. But in single cases prolonged drug action may occur due to slow elimination even when sophisticated infusion schemes are used. In these patients, the half-life of midazolam may be prolonged due to decreased clearance (35, 36). In addition, high age, obesity, gender or high ASA-classes were found to influence pharmacokinetic properties, leading to pro-
I
I
I
I
40
60
80
100
I +
120
y-PERIPHERAL AMOUNT
1 0 7 rng
0 0
and an exponentially declining infusion rate substituting the Transfer of drug from blood to tissues, the socalled body load. To maintain a constant blood level of 250 ng-ml-l, an exponentially declining infusion is necessary starting at about 350 pgemin-' and decreasing within 60 min to about 200 pgamin-'. Such a BET dosage scheme, but aiming at a higher plasma concentration of about 400 ngeml-', was successfully demonstrated by Lauven et al. in 1982 (Fig. 3) (6). The dose necessary to establish a mean safe hypnotic midazolam concentration of 250 ngrnl- will be highest after repetitive dosing. A bolus + constant rate infusion, or a two-step infusion technique, requires a smaller dose of 30 mg within the first hour. The smallest dose will be necessary when a BET scheme is applied (Table 2) (computer simulated values).
I
20
20
40
80
80
100
120
Fig. 3. Midazolam plasma concentration according to computer simulation (upper curve) when a BET-infusion was applied (6). The dosage scheme for a midazolam plasma concentration of 250 n g m - l is demonstrated in the figure below. The amount of midazolam in the peripheral compartment of an open two-compartment model is shown in the bottom figure.
longed duration of midazolam action by slowed elimination (7). I n contrast to inhalational agents, recovery from total intravenous anaesthesia depends on distribution, hepatic metabolism and elimination by the kidney. Especially when high doses of midazolam are administered, for example as maintenance infusion during anaesthesia, distribution mechanisms become less effective as the tissues (peripheral compartment) are already filled. I n these cases termination of drug action relies mainly on the elimination half-life, thus potentially leading to prolonged recovery. Yet, it has to be considered that a reduced state of
Table 2 Dose of midazolam necessary to establish a mean hypnotic plasma midazolam concentration of 250 n g m - ' . Amount of midazolam administered after 30 min 60 rnin 90 rnin 120 min Repetitive boli Two-step-infusion BET-scheme
32 27.3 15.2
36 30.7 22.2
40 34.2 27.7
44 37.6 32.3
88
P. M. LAUVEN AND P. J. KULKA
awareness is a normal and may be a desired finding, independent of which anaesthetic technique is applied, and usually requires no intervention. But prolonged recovery periods may become a problem as soon as they are combined with vitally depressed organ functions or in special situations where a high degree of post-operative vigilance is required and beneficial for the patient, e.g. after laryngoscopy or bronchoscopy. In these cases the application of flumazenil may be desirable. Since its introduction, prompt recovery after benzodiazepine application can be obtained whenever it is required. This may lead to a less limited use of total intravenous techniques or induction procedures using midazolam, as the risk of a prolonged recovery period with depressed reflexes and vigilance at the end of surgery can be reduced. Up to now, flumazenil has been shown to be effective in reversing all effects of midazolam within minutes. Blood pressure and heart rate remained stable, and the stress response during the recovery period seemed not to be affected by the administration of the antagonist (37-39). As flumazenil has a half-life of about 60 min, which is relatively short, it can be expected that its antagonist action will be shorter than that of the agonist, thus leading to a recurrence of sedation. This applies especially to such cases where midazolam is also used for maintenance of anaesthesia in high doses. Recurrence of sedation stresses the point that close observation is mandatory after administration of the antagonist, even if the patient seems to be fully awake and oriented. Most probably antagonisation will not lead to an increased demand for analgesics in the post-operative period (40), but nevertheless there is evidence that anaesthesia is less accepted by some patients. In an examination by Raeder et al. (41), five of 25 patients were less content with an anaesthesia regime using midazolam, alfentanil and flumazenil compared with previous experiences. In the control groups where isoflurane or thiopentone was used, no complaints were mentioned. The authors explained their finding by different individual ideals concerning anaesthesia: some patients want to be fully awake and to recover rapidly after anaesthesia, while others want to be asleep without too much disturbance in a busy recovery room (41). We have to take into consideration that minor side-effects like nausea and vomiting may occur more frequently (42). Preliminary results were reported from a study where flumazenil was used after neurosurgical procedures with a mean duration of 5.5 h where anaesthesia was performed with midazolam and fentanyl. Patients improved rapidly after administration of the
antagonist according to the Glasgow coma scale, thus enabling the surgeon to perform accurate neurological assessment (43). Forster showed that flumazenil is effective in reversing the reduction of cerebral blood flow (CBF) due to midazolam application. The administration of flumazenil alone had no effect on CBF. Nevertheless, as this study was performed in healthy volunteers, further evaluation of its cerebrovascular effects is necessary before the use of flumazenil after neurosurgical procedures can be recommended (44). Anaesthesia for caesarian section implies the risk of aspiration during the induction and recovery period when reflexes are still partly depressed. In a study in gynaecological patients undergoing caesarian section, midazolam in a dose of 1 mg was injected prior to induction of anaesthesia for caesarian section in order to achieve amnesia. Rapid sequence induction was performed with 20 mg ketamine, 10 mg etomidate and 100 mg succinylcholine. After card clamp, anaesthesia was supplemented with alfentanil, vecuronium and 30 mg midazolam. After the end of the operation flumazenil was administered until the patients became cooperative or did not tolerate the endotracheal tube any longer. A mean dose of 0.48 & 0.12 mg was shown to be effective. Patients were cooperative but amnesic by this time. The authors concluded that this technique provides excellent anaesthesia recovery conditions with safe extubation (45). CONCLUSION Due to its pharmacokinetic and pharmacodynamic properties, midazolam can safely be used to induce and maintain anaesthesia. If unwanted prolonged recovery periods are observed, the benzodiazepine antagonist flumazenil can be administered to reverse, safely and reliably, the benzodiazepine action at the end of surgery. In general, the use of flumazenil (like the use of other antagonists) should be limited to special procedures and to those cases where patients will benefit, as judged by an experienced anaesthestist. REFERENCES 1. Stoeckel H, Lauven P. Das zentrale anticholinerge Syndrom:
Physostigmin in der Intensivemedizin, Anasthesiologie, Psychiatrie. INA 1985: 55. 2. Reves H G. Benzodiazepines, pharmacokinetics of anesthesia. Prys-Roberts C, Hug C C. Oxford: Blackwell Scientific Publications, 1984: 157-186. 3. Reves J G, Corssen G, Holcomb C. Comparison of two benzodiazepines for anaesthesia induction: midazolam and diazepam. Can Anaesth Soc J 1978: 25: 21 1. 4. Reidenber M, Levy M, Warner H. Relationship between diazepam dose, plasma level, age, and central nervous system depression. Clin Phannacol Thn 1978: 23: 371-374.
ANAESTHESIA TECHNIQUES - OVERVIEW 5. Korttila K, Aromaa U.Venous complications after intravenous injection of diazepam, flunitrazepam, thiopentone and etomidate. Acta Anaesthesiol Scand 1980: 24: 227-230. 6. Lauven P M, Stoeckel H, Schwilden H. Ein pharmakokinetisch begriindetes Infusionsmodell fur Midazolam. Anaesthesist 1982: 31: 15-20. 7. Greenblatt D, Abernethy D, Locniskar A, Harmatz J, Limjucu R, Shader R. Effect of age, gender and obesity on midazolam kinetics. Anesthesiology 1984: 61: 27-35. 8. Persson P, Nilsson A, Hartvig P, Tamsen A. Pharmacokinetics of midazolam in total intravenous anaesthesia. Br 3Anaesth 1987: 59: 548-556. 9. Lauven P M, Stoeckel H, Ochs H, Greenblatt D J. Pharmakokinetische Untersuchungen mit dem neuen wasserloslichen Benzodiazepin Midazolam. Anaesthesist 1981: 30: 280-283. 10. Gerecke M. Chemical structure and properties of midazolam compared with other benzodiazepines. Br J Clin Pharmacol 1983: 16: 11-16. 11. Tallmann J F. Benzodiazepines: from receptor to function in sleep. Sleep 1982: 5: 12-17. 12. Mohler H, Okada T. Benzodiazepine receptor: demonstration in the central nervous system. Science 1977: 198: 849-851. 13. Pieri L, Schaffner R, Scherschlicht R. Pharmacology of midazolam. Arzneimitteljorschung 1981: 31: 2180-2201. 14. Lindahl S G E, Charlton AJ, Hatch D J, Norden N E. Endocrine response to surgery after premedication with midazolam or papavereturn. Eur 3 Anaesthesiol 1985: 2: 369-377. 15. Crozier T A, Beck P D, Schlaeger M, Wuttke W, Kettler D. Endocrinological changes following etomidate, midazolam or methohexital for minor surgery. Anesthesiology 1987: 66: 628-635. 16. Marty J, Nitenberg A, Blanchet F, Zouioueche S, Desmonts J M. Effects of midazolarn on the coronary circulation in patients with coronary artery disease. Anesthesiology 1986: 64: 206-2 10. 17. Miiller H, Schleusner E, Stoyanov M, Kling D, Hempelmann G. Hamodynamische Wirkungen und Charakteristika der Narkoseeinleitung mit Midazolam. Arzneitimitteljorschung 1981: 31: 2227-2232. 18. Saidman L J. Midazolam: pharmacology and uses. Anesthesiology 1985: 62: 310-324. 19. Jensen S, Schou-Olesen A, Hiittel S. Use of midazolam as induction agent: comparison with thiopentone. Br 3 Anaesth 1982: 54: 605407. 20. Kanto J, Sjovall S, Vuori A. Effect of different kinds of premedication on the induction properties of midazolarn. Br J Anaesth 1982: 54: 507-511. 2 1. Forster A, Gardaz J P, Suter P M, Gemperle M. I.V. midazolam as an induction agent for anaesthesia: a study in volunteers. Br 3 Anaesth 1980: 52: 907-91 1. 22. Gamble J A S, Dundee J W, Kawar P. Midazolam - an alternative to thiopentone? Br 3 Anaesth 1980: 52: 951-952. 23. Reves J G, Vinik R, Hirschfield A M, Holcom C, Strong S. Midazolam compared to thiopentone as hypnotic component in balanced anaesthesia: a randomized, double-blind study. Can Anaesth Soc J 1979: 26: 42549. 24. Pakkanen A, Kanto J. Midazolam compared with thiopentone as an induction agent. Acta Anaesthesiol Scand 1982: 26: 143-146. 25. Eisenkraft J B, Miller R. Induction dose of midazolam. Br 3 Anaesth 1981: 53: 318. 26. Berggren L, Eriksson I. Midazolarn for induction of anaesthesia in outpatients: a comparison with thiopentone. Acta Anaesthesiol Scand 1981: 25: 492496. 27. Nauta J, Stanley T H, De Lange S, Koopman D, Spierdijk J. Anaesthesia induction with alfentanil: comparison with thiopental, midazolam and etomidate. Can Anaesth Soc 3 1983: 30: 5 3 4 0 . 28. Persson M P, Nilsson A, Hartvig P. Relation of sedation and
29.
30.
31.
32.
33.
34. 35.
36.
37. 38.
39.
40.
41.
42. 43.
44.
45.
89
amnesia to plasma concentrations of midazolam in surgical patients. Clin Pharmacol Ther 1988: 3: 324-325. Tverskov M, Fleyshman G, Bradley E L, Kissin I. Midazolamthiopental anesthetic interaction in patients. Anesth Analg 1988: 67: 342-345. Nilsson A, Tansen A, Persson P. Midazolam-fentanyl anaesthesia for major surgery. Plasma levels of midazolam during prolonged total intravenous anaesthesia. Acta Anaesthesiol Scand 1986: 30: 66-69. Raeder J C, Nilsen G, Hole A. Pharmacokinetics of midazolam and alfentanil in outpatient general anaesthesia. Acta Anaesthesiol Scand 1988: 32: 467-472. Podlesch I, Dahn H, Engel M. Anaesthetic and side effects of midazolarn and ketamine in surgical patients. Anesthesiology 1985: 62: 68. Seitz W, Liibbe N, Hamkens A, Bornscheuer A. MidazolamKetamin-Kombinationsanaesthesiebei traumatologischen Eingriffen. Anaesthesist 1988: 37: 231-237. Lauven P M, Stoeckel H. Hypnotische wirksame Blutspiegel von Midazolarn. Anaesth Intensivther Notjallmed 1987: 22: 90-93. Dundee J W, Collier P S, Carlisle R J T, Harper K W. Prolonged midazolam elimination half-life. Br 3 Clin Pharmacol 1986: 21: 4255429. Klotz U, Mikus G, Zekorn C, Eichelbaum M. Pharmacokinetics of midazolam in relation to polymorphic sparteine oxidation. Br 3 Clin Pharmacol 1986: 22: 618419. Alon E, Baitella L, Hossli G. Ro 15-1788in reversing midazolam used for laparoscopy. Acta Anaesthesiol Scand 1985: 29: A 163. Klausen N 0, Sorensen J, Ferguson A H, Neumann P B, Larsen C, Juhl 0.Stress response during recovery after total intravenous anaesthesia with midazolam and fentanyl reversed by Ro 151788. In: Beitrage zur Anaesthesiologie und Intensivmedizin 16: VII. European Congress of Anaesthesiology, Abstract 11. 1986: A 133. Ritter J W, Flacke W E, Norel E, Gion H, Chen R, Hoskizaki G. Adrenergic and hemodynamic response to flumazenil (Ro 15-1788) reversal of midazolam sedation. Anesthesiology 1988: 69: A 109. Nilsson A, Persson M P, Hartvig P. Effects of the benzodiazepine antagonist flumazenil on postoperative performance following total intravenous anaesthesia with midazolam and alfentanil. Acta Anaesthesiol Scand 1988: 32: 441-446. Raeder J C, Hole A, Arnulf V, Hougens Grynne B. Total intravenous anaesthesia with midazolam and flumazenil. Acta Anaesthesiol Scand 1987: 31: 634-641. Wolff J. Flumazenil for postoperative recovery. Eur 3Anaesthesiol 1988: SUPPI2: 239-249. Uhiolero R, Ravussin P, Chassot P G, Neff R, Freeman J. Ro 15-1788 for rapid recovery after craniotomy. Anesthesiology 1986: 65: A 466. Forster A, Juge 0, Louis M, Nahory A. Effects of a specific benzodiazepine antagonist Ro 15-1788 on cerebral blood flow. Anesth Analg 1987: 66: 309-313. Waldvogel H H. A rational approach to the use of midazolam and flumazenil for caesarian section. Eur 3 Anaesthesiol 1988: SUPPI 2: 277-278.
Address: Prof. Dr. II M. Lauuen Institut fur Anasthesiologie der Universitat Bonn Sigmund-Freud-Strasse 25 D-5300 Bonn 1 Federal Republic of Germany
