MIDAZOLAM SEDATION FOLLOWING OPEN HEART SURGERY

Br. J. Anaesth. (1987), 59, 557-560

MIDAZOLAM SEDATION FOLLOWING OPEN HEART SURGERY H. M. L. MATHEWS, I. W. CARSON, P. S. COLLIER, J. W. DUNDEE, K. FITZPATRICK, P. J. HOWARD, S. M. LYONS AND I. A. ORR

H. M. L. MATHEWS, M.B., F.F.A.R.C.S.; J. W. DUNDEE, M.D.;

P. J. HOWARD, F.I.S.T; Department of Anaesthetics, The

Queen's University of Belfast. I. W. CARSON, M.D.; K. FITZPATRICK, M.B., F.F.A.R.C.S;

S. M. LYONS, M.D.; I. A. ORR,

M.D.; Department of Clinical Anaesthesia and the Cardiac Surgical Unit, Royal Victoria Hospital, Belfast. P. S. COLLIER, PH.D., Department of Pharmacy, The Queen's University of Belfast, Northern Ireland. Accepted for Publication: September 17, 1986.

SUMMARY Midazolam given as hourly intermittent injections was compared with the same dose given by infusion for postoperative sedation in patients after cardiopulmonary bypass. A stable concentration was rapidly attained with the infusion whereas 6-8 h was required to attain stable plasma {trough) concentrations in the intermittent injection group. Plasma concentrations decreased rapidly to low values within 6 h of discontinuation of therapy. High plasma concentrations and a long (16 h) half-life were noted in one patient who may be a slow metabo/izer of the drug.

PATIENTS AND METHODS

Twenty adult patients requiring ventilation following open heart surgery were studied. Those with hepatic dysfunction (noted on routine biochemical screening), receiving concurrent benzodiazepine therapy or with a history of hypersensitivity to benzodiazepines were excluded. Anaesthesia was induced with fentanyl 50 ug kg"1, and maintained with air-oxygen supplemented, if necessary, with halo thane. No benzodiazepines were given during the operative procedure. Neuromuscular blockade was produced with pancuronium 0.1 mg kg"1. Once in the cardiac recovery ward, all patients received a loading dose of midazolam 2 mg and they were then randomly allocated to receive either 2 mg at 1-h intervals or a continuous infusion of 2 mg h~l. Both therapies were delivered via the internal jugular vein. Both groups were given morphine 2 mg i.v., as required, when there was evidence (lachrymation, tachycardia) that the sedation was too light.

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Midazolam, a water-soluble benzodiazepine, with a short elimination half-life (1.5-3 h) and absence of clinically important hypnotically active metabolites, is a suitable agent with which to produce sedation in the intensive care unit. Short term ventilatory support is practised widely following open heart surgery (Peters, Bruin and Utley, 1979) and, because of its more favourable pharmacokinetic profile, midazolam has been shown to be preferable to diazepam when used in repeated intermittent doses in this situation (Lowry et al., 1985). Cumulation was less with midazolam, with little risk of a prolonged hypnotic effect following the discontinuation of its administration. However, because of the short elimination half-life, frequent small doses of midazolam are required to maintain a plasma concentration adequate for sedation while avoiding large swings in concentration after each administration. In spite of the low temperatures (25 °C) used during cardiac operations, the liver is well able to handle the midazolam presented to it, as clearance has been shown to be adequate in patients after cardiopulmonary bypass (Harper et al., 1985). Infusions of midazolam should, therefore, be a safe way of providing sedation during ventilatory support after open heart surgery. This paper presents the plasma concentrations obtained when midazolam 2.0 mg was administered hourly and compares these with the concentration obtained when the same dose was given as a continuous infusion.

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infusion rate concentration at steady state Terminal slopes in all patients were calculated by least squares regression using log concentration against time from 2 h after discontinuation of therapy. Half-lives were then calculated using the formula: Clearance =

terminal slope RESULTS

One patient receiving midazolam by infusion showed an atypical response with high plasma concentrations, a long elimination half-life and a very low morphine requirement (8 mg in 16 h).

This patient was excluded from all calculations and is discussed later. Table I shows that the two groups of patients were broadly comparable with respect to age, gender, weight and duration of bypass. The average duration of midazolam therapy was 16 h in both groups and the mean dose of midazolam was 34 mg in both groups. All patients were successfully weaned from mechanical ventilation in an average of 2.75 h in the infusion group and 2.5 h in the intermittent injection group, after the withdrawal of the midazolam. Blood loss (approximately 500 ml) and volume of blood products administered (approximately 1600 ml) during the period of midazolam therapy were similar in both groups. The mean morphine requirements were 62 mg (range 38-93 mg) in the intermittent injection group and 52 mg (18-71 mg) in the infusion group. These did not differ significantly. Two patients having intermittent injections required morphine 93 mg during the period of therapy, whereas the maximum individual morphine requirement in the infusion group was 71 mg. Figure 1 shows the decay in plasma concentrations following the initial midazolam 2.0 mg, the trough plasma concentrations in the intermittent injection group and the plasma concentrations obtained during the infusion. A steady plasma concentration was rapidly attained with the infusion and maintained during the period of study. Estimation of trough concentrations showed a delay of 6-8 h in attaining a steady state with intermittent injection. The near-peak plasma concentrations (ngml->±SEM) averaged 92 ±9.5 at 4 h, 107±9.4 at 8 h and 102± 12.7 at 12 h. Figure 2 shows similar decays in mean plasma concentrations in both groups following the discontinuation of therapy. Concentrations decreased to very low values within 6 h, and by 24 h midazolam could not be detected in the plasma. The clearance averaged 335 ±31.9 ml kg"1 h"1 in the infusion group. Individual elimination half-lives averaged 5.1 h (range 3.3-7.1) with

TABLE I. Physical characteristics and time on bypass in both groups (mean ± SEAT) Mode of administration Infusion (n = 9) Intermittent (n = 10)

Age (yr)

Sex

Weight (kg)

Pump time (min)

58 ±2.7 5O±3.7

6M 6F

70 ±3.9 65 ±3.0

85 ± 9.8 78 ±10.0

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Samples of arterial blood (5 ml) were drawn before midazolam was administered and at 7.5,15, 30,60,120 min and 4,6,8,10,12 h after the initial dose. In the intermittent injection group the blood was drawn immediately before a supplementary dose, thus reflecting the minimum (trough) concentration. At 4, 8 and 12 h further samples were drawn 10 min after administration, reflecting near-peak concentrations. Another sample was taken before the discontinuation of the infusion at approximately 06.00 h the following morning, and also before and 10 min after the last intermittent injection. Further blood was drawn at 2, 4, 6, 12 and 24 h following the discontinuation of the administration of the midazolam. Blood was kept at 4 °C and centrifuged within 24 h, the plasma being stored at — 20 °C until analysed for total plasma midazolam concentration using gas-liquid chromatography (Howard, McClean and Dundee, 1985). The coefficient of variation of the method of analysis was 4 % over the range of concentrations obtained in this study. As far as possible blood volume, arterial pressure, temperature and acid-base state were kept constant, and within their normal physiological ranges during the period of study. Individual clearances from each patient in the infusion group were obtained using the formula:

559

SEDATION WITH MIDAZOLAM 120TOO-

I 80

,--T v

§ 60oo

1 40 Q.

20

6

10

12

Time (h) FIG. 1. Mean plasma concentrations ( ± S E M ) over 12 h associated with the intermittent injections (trough) (A A ) or infusion ( # • ) of midazolam.

an infusion. In contrast to the findings in the other patients, midazolam was present in the 24-h sample and 7jP was 15.6 h in this patient. Clearance was 236 ml kg"1 h"1.

120 100 80

DISCUSSION

60 40200

4

6 8 Timed)

10

12

FIG. 2. Mean plasma concentrations ( ± S E M ) following discontinuation of midazolam. A A = Intermittent injections; • • = infusion.

intermittent injection and 4.5 h (range 2.0-7.1) with infusions. The patient previously mentioned with an abnormal elimination half-life was female, aged 55 yr and weighed 54 kg. Her urine output was satisfactory during the period of study and liver function was normal. This patient was weaned from mechanical ventilation 3 h after discontinuing the infusion, but remained very drowsy for the next 24 h. Figure 3 compares the plasma concentrations of midazolam obtained in this patient with the mean of the other nine patients receiving

The clearance and elimination half-lives found in this study are similar to previously reported values obtained following cardiopulmonary bypass (Harper et al., 1985). Despite the severe physiological upset of cardiopulmonary bypass, the elimination half-life of midazolam was only slightly longer than that obtained in association with other forms of surgery. The concentrations of midazolam necessary for adequate sedation (80-10C ng ml"1) were attained rapidly and remained relatively stable in patients receiving midazolam by infusion when compared with the 6-8 h delay associated with intermittent injection. With the latter, trough concentrations were very low during the first 4-6 h and there was a considerable difference between the peak and trough values indicating, possibly, a swing from adequate to light sedation. This agreed with the clinical impressions of the nursing and medical staff that sedation was better with the infusion— particuarly during the first few hours. The plasma concentrations on weaning from the ventilator were less than 40 ng ml"1, the value considered necessary to achieve any sedative effect (Allonen, Ziegler and Klotz, 1981).

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560 20Ch

150-

§

100

a.

50-

4

6 8 10 12 Time (h) FIG. 3. Mean plasma concentrations ( ± SEM) (infusion) ( • • ) compared with those obtained in a patient with an abnormal half-life for midazolam metabolism ((

The one patient with a long elimination half-life would appear to be a slow metabolizer of the drug. Dundee and colleagues (1986) found this in about 6 % of over 200 patients and a 1:20 occurrence in this study is a similar frequency. Midazolam administered by a bolus dose of 2 mg followed immediately by an infusion at 2 mg h"1 is a safe and simple method of providing sedation during short-term ventilatory support after open-heart surgery. On account of its simplicity, this dosage regimen is preferred to more complicated regimens in which the drug is given on a weight basis, or in decreasing concentration. In patients who are normal metabolizers of the drug there is no risk of cumulation with this method of administration, and midazolam concentrations decrease rapidly following the discontinuation of the infusion. However, in about one patient in 20 there is a risk of a slow metabolism of the midazolam leading to cumulation with prolonged hypnotic effect after discontinuation.

ACKNOWLEDGEMENTS The authors wish to thank Mr Hugh O'Kane and Mr Jack Cleland, Consultant Cardiac Surgeons, junior medical and nursing staff of Cardiac Surgical Intensive Care Unit, Royal Victoria Hospital, Belfast. Throughout the study Dr Mathews was supported by a grant from Roche Products Ltd. REFERENCES Allonen, N., Ziegler, G., and Klotz, U. (1981). Midazolam kinetics. Clin. Pharmacol. Ther., 30, 653. Dundee, J. W., Collier, P. S., Carlisle, R. J. T., and Harper, K. W. (1986). Prolonged midazolam elimination half-life. Br. J. Clin. Pharmacol., 21, 425. Harper, K. W., Collier, P. S., Dundee, J. W., Elliott, P., Halliday, N. J., and Lowry, K. G. (1985). Age and nature of operation influence the phannacokinetics of midazolam. Br. J. Anaesth., 57, 866. Howard, P. J., McClean, E., and Dundee, J. W. (1985). The estimation of midazolam, a water soluble benzodiazepine by gas liquid chromatography. Anaesthesia, 40, 664. Lowry, K. G., Dundee, J. W., McClean, E., Lyons, S. M., Carson, I. W., and Orr, I. A. (1985). Phannacokinetics of diazepam and midazolam when used for sedation following cardiopulmonary bypass. Br. J. Anaesth., 57, 883. Peters, R. M., Bruin, T. E., and Utley, J. R. (1979). Predicting the need for prolonged ventilatory support in adult cardiac patients. J. Thorac. Cardiovasc. Surg., 77, 175.

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