Midazolam for Continuous Sedation in Japanese ...

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Midazolam for Continuous Sedation in Japanese Patients in the Critical Care Setting: Phase II Study K Tsutsumi, N Aoyama, T Kitahara, M Endo, I Takahashi, M Kashiwa, Y Imai, K Soma and T Ohwada Journal of International Medical Research 2001 29: 335 DOI: 10.1177/147323000102900410 The online version of this article can be found at: http://imr.sagepub.com/content/29/4/335

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The Journal of International Medical Research 2001; 29: 335 – 341

Midazolam for Continuous Sedation in Japanese Patients in the Critical Care Setting: Phase II Study* K TSUTSUMI1, N AOYAMA1, T KITAHARA1, M ENDO1, I TAKAHASHI1, M KASHIWA2, Y IMAI2, K SOMA1 AND T OHWADA1 1

Department of Emergency and Critical Care Medicine, Kitasato University School of Medicine, Sagamihara, Japan; 2Clinical Development Division, Yamanouchi Pharmaceutical Co. Ltd, Tokyo, Japan

This prospective, phase II study was carried out to evaluate the efficacy and safety of midazolam as a sedative agent in nine critically ill Japanese patients without coma who had been admitted to an intensive care unit. An adequate level of sedation (sedative score [SS] 4 – 6) was induced by midazolam 0.14 – 0.39 mg/kg and maintained with a dose range of 0.08 – 0.24 mg/kg per h. One patient was excluded from the efficacy analysis since optimum sedation was not maintained by continuous infusion. The percentage of time during which SS 5 was achieved varied among the patients. The most

frequent adverse events were hypotension, partial pressure of carbon dioxide elevation and premature ventricular contraction. Population pharmacokinetic analysis suggested that lower drug clearance rates were correlated with the presence of complications. The 50% of effective concentration values of SS 5, estimated by logistic regression analysis, varied greatly (mean, 251 ng/ml). In conclusion, midazolam infusion achieved successful sedation in this critical care setting. The optimum dose differed among the patients, however, and was influenced by the presence of complications.

KEY WORDS: MIDAZOLAM; CONTINUOUS SEDATION; CRITICAL PHARMACODYNAMICS

Introduction Midazolam is a widely used sedative agent that may be given intravenously for the induction of the sedation (loading) and subsequent continuous infusion to patients in intensive care units to maintain sedation. Many reports have shown that the optimum *The Journal of International Medical Research recognizes that this paper reports the findings of the same investigation that was carried out by Kinoshita et al. (pages 342 – 348). As the studies were carried out independently, however, it was deemed appropriate to publish the reports separately.

CARE;

PHARMACOKINETICS;

dose of midazolam in patients in intensive care varies.1 – 5 In addition, the doses listed on the officially approved product labels differ considerably by country. For example, 0.03 – 0.3 mg/kg is the loading dose in the UK, whereas in the USA, it is 0.01 – 0.05 mg/kg. Information on the clinical use of midazolam in Japanese critical care patients is limited.1,6,7 Thus, a prospective study of midazolam, administered as a continuous infusion, in critically ill Japanese patients was undertaken to evaluate the efficacy and

335

K Tsutsumi, N Aoyama, T Kitahara et al. Midazolam sedation in critical care safety of the drug. This report describes the dosage range at which adequate sedation was achieved and the adverse events that occurred during the study. A pharmacokinetic and pharmacodynamic analysis of midazolam as a sedative agent in Japanese critical care patients is also presented.

Patients and methods PATIENTS Critically ill patients, excluding those with coma, who had been admitted to the Emergency Center of Kitasato University Hospital between February 1998 and January 1999 were evaluated. The study was conducted in accordance with the principles of the Declaration of Helsinki. The institutional review board approved this study project and written informed consent was obtained from all participating patients or their next of kin.

DRUG ADMINISTRATION To induce sedation, patients received an initial dose of 0.03 – 0.3 mg/kg midazolam intravenously and incremental doses were administered every 15 min thereafter, until optimum sedation was achieved. The level of sedation was classified using Ramsey’s sedative score (SS)8 and SS 5 was maintained by titrating the rate of continuous midazolam infusion (0.03 – 0.4 mg/kg per h). Concomitant use of benzodiazepines, general anaesthetics and the benzodiazepine antagonist, fulmazenil, were prohibited during the study. However, narcotic analgesics (morphine), muscle relaxants and local anaesthetics were used occasionally.

PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS Plasma samples were collected at least every 24 h and the midazolam concentrations of these samples were measured at SRL Teijin Bio Laboratories Inc. (Tokyo, Japan) using

high-performance liquid chromatography. Clearance (CL), total distribution volume and elimination half-life were estimated by population pharmacokinetic analysis. These parameters were investigated, using regression analysis, for correlation with the following characteristics: age; sex; SS before midazolam administration; and the presence of complications. Sedative scores were evaluated, every 4 h, against plasma midazolam concentrations in patients who were compatible with the infusion protocol and the estimated 50% of effective concentration (EC50) values were calculated using logistic regression analysis.

SAFETY ASSESSMENTS Routine patient monitoring involved electrocardiography, pulse oximetry, body temperature, respiration rate, arterial pressure and blood gases. The safety of midazolam was also evaluated in routine laboratory testing, including blood count (white blood cells, red blood cells and platelets), haemoglobin, haematocrit, total bilirubin, serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), blood urea nitrogen, creatinine, total protein, sodium, potassium, chloride, lactic acid dehydrogenase, uric acid, urinary protein, urinary sugar and occult blood. Any adverse events were recorded and the investigators judged whether adverse events or abnormal laboratory value causality were drug-related.

STATISTICAL ANALYSIS The correlation between CL and presence of complications was estimated by the approximate likelihood ratio test (at the degrees of freedom [df] = 1) for the exponential error models of individual CL between the presence and absence of complications as a fixed effect in the non-linear, mixed-effect model analyses.

336

K Tsutsumi, N Aoyama, T Kitahara et al. Midazolam sedation in critical care

Results PATIENTS Nine critically ill patients admitted to the Emergency Centre of Kitasato University Hospital from February 1998 to January 1999 were evaluated. Patients’ disease, complications, Ramsey’s SS and rating on the Glasgow Coma Scale before midazolam injection are listed in Table 1. One patient (0001), who had a thoracic burn, was excluded from the efficacy analysis since midazolam was administered as a bolus three times during the infusion because optimum sedation was not maintained by continuous infusion.

SEDATION SCORING Sedative scores of the eight efficacy evaluable patients prior to midazolam injection were SS 1 in three patients and SS 2 in five. A deeper level of sedation (SS 4 – 6) was induced by 0.14 – 0.39 mg/kg midazolam (total dose of each increment), and was followed by a maintenance dose (0.08 – 0.24 mg/kg per h midazolam), and was infused continuously for 3 – 58 h until sedation was no longer necessary. The percentage of time during which SS 5 was achieved during the infusion varied among the patients. In five patients with subarachnoid haemorrhage or suspected subarachnoid haemorrhage (0002, 0003, 0004, 0005 and 0007), it was achieved 13 – 97% of the time during which the patients received the midazolam infusion and in the other three (0006, 0008, 0010), 81 – 98% of the time. In two patients (0005 and 0007) with subarachnoid haemorrhage, SS 6 predominated.

PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS The logistic regression correlation between SS

analysis for and plasma

midazolam in the infusion-protocolcompatible patients is shown in Fig. 1. Two patients (0001 and 0006) were excluded from this analysis because there was an operative violation of midazolam titration at the loading phase that was considered to interfere with the maintenance phase. The individual effective concentration achieving SS 5 varied widely (as shown in Fig. 1) and the average EC50 value was estimated to be 251 ng/ml midazolam using the logistic regression pharmacokinetic/pharmacodynamic model. Values for CL, total distribution volume and elimination half-life are shown in Table 2. There was a wide variation in these parameters among the patients, and the presence of complications was the only patient characteristic that correlated significantly with CL (P = 0.0020). No clear correlation was found between the estimated plasma concentration and systolic blood pressure (r = 0.128; Fig. 2).

SAFETY All nine patients recovered from sedation after the discontinuation of midazolam infusion, or after the continuous administration of surgical anaesthetic during aneurysm repair ceased following sedation with midazolam. The most frequent adverse event was hypotension (four cases) and partial pressure of carbon dioxide (PaCO2) elevation (four cases) followed by premature ventricular contraction(s) (two cases). Among these adverse events, four cases of hypotension, one case of PaCO2 elevation, and one case of premature ventricular contraction were considered by the investigators to be either possibly or probably related to midazolam. Clinically significant variations in laboratory test values were observed in all nine patients. Most variations appeared to

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TABLE 1: Characteristics of critically ill patients included in a prospective study of midazolam continuous infusion and dose administered

Patient Age Sex no. (years) (M/F)

Primary condition

Complication

Baseline GCS SS pre-loading

Loading dose (mg/kg)

Maintenance Time taken dose to recover (mg/kg per h) from sedation (h)

25

M

Thoracic burn

–

2

15

0.17

0.17 – 0.28

0a

0002

53

M

Subarachnoid haemorrhage

–

2

15

0.22

0.12 – 0.24

–b

0003

49

F

Suspected subarachnoid haemorrhage

–

2

15

0.31

0.12

0a

0004

63

M


Hypertension, diabetes

1

14

0.23

0.09 – 0.15

–b

0005

70

F


Hypertension, diabetes

2

15

0.26

0.11 – 0.23

–b

0006

50

F

Cardiac failure

Hyperthyroidism, acute pulmonary oedema, hyperuricaemia

2

15

0.17

0.13

0.5

0007

66

F


Hypertension

1

15

0.14

0.14 – 0.16

–b

0008

68

M

Ischaemic heart disease

Acute pulmonary oedema, hypertension, chronic renal failure

2

15

0.16

0.14

38

0010

69

F

Bronchial asthma

Hyperthyroidism, diabetes

1

15

0.39

0.08 – 0.15

aSedative

17.75

score (SS) was SS 2 when midazolam infusion was terminated. were not collected because these patients with subarachnoid haemorrhage were anaesthetized for craniotomy before the recovery from midazolam sedation. GCS, Glasgow Coma Scale. bData


338

0001


6

Sedation score

5 4 3 2 1

0.10

1.00

10.00

Estimated plasma concentration (µg/ml)

FIGURE 1: Correlation of sedation score (SS) and plasma concentration of midazolam in six critically ill patients receiving continuous infusion of midazolam. The horizontal axis shows the estimated plasma midazolam concentration when the scores were evaluated. Logistic regression analysis showed a wide variation in the individual 50% of effective concentration values of patients achieving SS 5 (mean, 251 ng/ml midazolam)

be related to the patient’s primary disease or condition, except for total bilirubin (two cases), white blood cell count (one case), platelet count (one case), AST (one case), uric acid (one case) and occult blood (one case), which were considered as ‘undeniably’ related to midazolam administration by the investigators.

Discussion Our results suggest that continuous midazolam infusions were successful in the sedation of the critically ill patients in this prospective study. In two of the patients with subarachnoid haemorrhage, a deeper level of sedation was achieved, i.e. predominantly SS 6. It is generally believed that patients with

TABLE 2: Summary of pharmacokinetic parameters in eight critically ill patients receiving continuous infusion of midazolama Parameter

Mean ± SD

Range

Clearance (ml/min)

164 ± 189

49 – 609

Vss (l)

99.6 ± 35.2

51.0 – 145.2

t1/2,α (h)

0.122 ± 0.039

0.066 – 0.179

t1/2,β (h)

13.99 ± 10.01

4.25 – 36.56

Vss, total distribution volume; t1/2, half-life. aSedation was induced by 0.14 – 0.39 mg/kg midazolam and maintained with a dose range of 0.08 – 0.24 mg/kg per h.

339

Systolic blood pressure (mmHg)


200 180 160 140 120 100

0.10

1.00

10.00

Estimated plasma concentration (µg/ml)

FIGURE 2: Correlation of systolic blood pressure and plasma concentration of midazolam in eight critically ill patients (r = 0.128). Horizontal axis shows estimated plasma midazolam concentrations at the points when systolic blood pressure was evaluated brain haemorrhage require deeper sedation to prevent re-rupture of their aneurysm. It is hypothesized that antagonism by 1-hydroxy metabolites,9 decreased renal/ hepatic blood flow10 or albumin loss11 may contribute to the lower CL rate. Our pharmacokinetic results support the findings of these reports that the optimum

midazolam dose differs from one patient to another and is influenced by the functional status of organs such as the liver and kidney.

Acknowledgement We thank research associates and physicians who supported this study.

• Received for publication 13 March 2001 • Accepted 23 March 2001 ©2001 Cambridge Medical Publications References 1 Kawamata M, Ujike Y, Miyabe M, Kobayashi I, Arakawa J, Namiki A, et al: Continuous infusion of ketamine and midazolam for prolonged sedation in the intensive care unit (in Japanese). Masui 1991; 40: 1793 – 1798. 2 Barrientos-Vega R, Mar Sanchez-Soria M, Morales-Garcia C, Robas-Gomez A, Cuena-Boy R, Ayensa-Rincon A: Prolonged sedation of critically ill patients with midazolam or propofol: impact on weaning and costs. Crit Care Med 1997; 25: 33 – 40. 3 Kress JP, O’Connor MF, Pohlman AS, Olson D, Lavoie A, Toledano A, et al: Sedation of critically ill patients during mechanical ventilation. A comparison of propofol and

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of midazolam and ketamine on respiratory pattern (in Japanese). Kokyu To Junkan (Respiration and Circulation) 1993; 41: 1181 – 1184. 7 Nishiyama T, Furuya C, Hanaoka K: Clinical use of midazolam (in Japanese). Masui 1997; 46: 1172 – 1178. 8 Ramsey MA, Savege TM, Simpson BR, Goodwin R: Controlled sedation with alphaxalonealphadolone. BMJ 1974; 2: 656 – 659. 9 Shelly MP, Mendel L, Park GR: Failure of

critically ill patients to metabolize midazolam. Anaesthesia 1987; 42: 619 – 626. 10 Shafer A, Doze VA, White PF: Pharmacokinetic variability of midazolam infusions in critically ill patients. Crit Care Med 1990; 18: 1039 – 1041. 11 Vree TB, Shimoda M, Driessen JJ, Guelen PJ, Janssen TJ, Termond EF, et al: Decreased plasma albumin concentration results in increased volume of distribution and decreased elimination of midazolam in intensive care patients. Clin Pharmacol Ther 1989; 46: 537 – 544.

Address for correspondence Dr M Kashiwa Clinical Development Division, Yamanouchi Pharmaceutical Co. Ltd, 3-17-1 Hasune, Itabashi, Tokyo 174-8612, Japan. E-mail: [email protected]

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