Midazolam use in the emergency department

Printed in the USA * Copyright

The Journal of Emergency Medione. Vol. 9, pp. 247-251, 1991

0

1991 Pergamon Press plc

Toxkology

MIDAZOLAM USE IN THE EMERGENCY DEPARTMENT Edward A. Ramoska,

MD, FACEP,*+

Robert Linkenheimer,

DO,*

and Cheri Glasgow,

RN, CEN+

*Thomas Jefferson University Hospital, +Methodist Hospital, and *Frankford Hospital, Philadelphia, Pennsylvania Reprint address: Edward A. Ramoska, MD, Director, Emergency Services, Methodist Hospital, 2301 South Broad Street, Philadelphia, PA 19148

0 Abstract - Midaxolam is a new imidaxobenxodiaxepine derivative that is two to three times as potent as diaxepam, is water-soluble, has a rapid onset and short duration of action, and produces a profound amnestic effect. These properties maice it an extremely useful drug for outpatient sedation. We performed retrospective review of midaxolam use in a general emergency department over a oneyear period. Midazolam was used in 120 patients, 71 men and 49 women, with an average age of 46 years. The average dose given was 3.4 mg, with a range of 1 to 10 mg. In 69 of the cases (57%) other drugs were administered, most commonly an opiate. There were only four adverse reactions. One patient developed urinary retention, one patient vomited, and two patients were somnolent for a prolonged period of time. There were no serious cardiovascular or respiratory problems. We conclude that midaxolam is a safe drug to use in the emergency department. Close monitoring of the patient and the availability of airway support equipment are mandatory.

tic of benzodiazepines (4). In addition, it has several other useful properties including a rapid onset, short elimination half-life, and lack of bioactive metabolites (2,4). These features, combined with its ability to produce an intense antegrade amnesia (5), make it an ideal agent to use for outpatient sedation. The purpose of our study was to examine the use of midazolam in a general emergency department (ED). METHODS

Patients were identified by examining the ED narcotics log for the use of midazolam during a one-year period (1988). The ED charts were then reviewed. Data were collected on name, age, indication for use, dosage employed, other drugs used, adverse effects and complications, disposition, and observation time after the use of midazolam until exit from the department. Follow-up consisted of a review of the hospital record for the admitted patients and of the ED’s daily call-back log for the discharged patients. There was no official ED policy governing the use of midazolam during the study period. The indications for use, dose of midazolam, and administration of other drugs was at the discretion of the treating physician.

0 Keywords - midaxoiam; benxodiaxpines; sedation

INTRODUCTION

Midazolam (Versed/Roche) is a water-soluble imidazobenzodiazepine derivative that is finding broad use as an agent for outpatient sedation. It has been used during endoscopy (l), ambulatory surgery (2), and dental procedures (3). Midazolam has the anxiolytic, hypnotic, anticonvulsant, and muscle relaxant effects characteris-

RESULTS

Midazolam was used in 120 patients. The average age was 46 years with a range of 3 to 93 years. There were

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Toxicology-one of the most critical and challenging areas confronting the emergency department staff-is

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by Kenneth Ku&,

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MD,

February 1990; October 1990

coordinated

of the Rocky Mountain Poison Center.

FINAL SUBMISSION RECEIVED:19 September

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1990;

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+ .OO

Edward A. Ramoska, Robert Linkenheimer, Cheri Glasgow

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Table 2. Other Drugs Employed

Table 1. Indications for Use Number

Indication Sedation for Procedure Reduction of fracture/dislocation lntubation Chest tube insertion Sedation for CT scan Wound care Incision and drainage of abscess Cardioversion Miscellaneous procedures General Sedation Sedation for agitation Drug intoxication Sedation while on ventilator Other Uses Seizure Muscle spasm Total

36 19 10 7 4 3 2 5 9 9 8

Drug morphine meperidine ibuprofen diazepam pancuronium hydroxyzine haloperidol succinylcholine thiopental butorphanol lorazepam acetaminophen diflunisal Total

Number 34 17 6 4 3 3 2 1 1 1 1 1 1 75

5 3 120

71 men and 49 women. The indications for use are

shown in Table 1. Midazolam was not effective in achieving adequate sedation in only two patients (that is, efficacy > 98%). In one of the two failures, 2 mg of midazolam failed to adequately sedate an agitated patient and diazepam was then used successfully. In the other case, a total of 9 mg of midazolam failed to calm a patient who was intubated and on a ventilator and again diazepam was subsequently used with success. The average total dose of midazolam was 3.4 mg with a range of 1 to 10 mg. All doses were administered intravenously (IV). In 69 (57%) of the cases, other drugs were administered in addition to midazolam. The most common second drug was an opiate, either morphine, meperidine, or butorphanol. Table 2 lists the other drugs that were administered. Note that the total adds up to more than 69, since several patients received more than one drug. Forty-eight of the patients (40%) were eventually discharged from the ED, while the remaining 72 were admitted. In 17 cases, no follow-up was available. Patients were observed for an average of 160 min (range: 15 to 630 min) after the use of midazolam but before being either admitted or discharged. There were 4 adverse reactions (3.3%). These were a single case of urinary retention, two cases of excessive somnolence, and a case of vomiting in a head-injured patient. None of the patients was admitted because of a complication, although the head-injured patient was admitted for observation . DISCUSSION Midazolam is a unique benzodiazepine that was introduced into clinical medicine in 1986. It has a fused

imidazole ring that distinguishes it from the other benzodiazepines and accounts for its stability in aqueous solutions and rapid metabolism (4). Because of midazolam’s water solubility it causes minimal local irritation after parenteral administration and is rapidly and nearly completely absorbed after intramuscular (IM) injection (6). Midazolam is highly lipophilic at physiologic pH and has a very rapid onset of action (4). This lipophilicity coupled with its rapid metabolism by the liver account for its short duration of action (4). Midazolam demonstrates all the effects characteristic of the benzodiazepines. It has an anxiolytic effect that is less than that of diazepam but has a hypnotic effect that is at least two times that of diazepam (4). Midazolam produces antegrade amnesia that is more intense than diazepam, but shorter lasting than lorazepam (4,7). The degree of amnesia often parallels the degree of drowsiness (5) but the drowsiness seems to outlast the amnesia (8). Midazolam may be a more effective anticonvulsant than either diazepam or lorazepam (9). It exhibits muscle relaxant effects similar to the other benzodiazepines (4). Because of midazolam’s pharmacology and pharmacokinetics, it is an ideal agent for outpatient sedation. Midazolam has been used extensively during gastrointestinal endoscopic procedures (l,lO-13). It has also been found to be useful for ambulatory surgery (2,14), dental procedures(3,15),bronchoscopy(4,16),cystoscopy(l7), and cardiac catheterization (4). Midazolam should find wide use in the emergency department; however, only one study has documented its use there (18). In our study, the most common use of midazolam was to provide sedation for a variety of painful, uncomfortable, or unpleasant procedures (see Table 1). The total dose employed for this indication varied from 1 to 10 mg, but averaged 3.4 mg. In most cases, incremental doses of 1 to 3 mg IV were titrated until adequate

Midazolam Use in the ED

sedation was achieved. Total doses in excess of 5 mg were usually not required. To obtain sedation for the majority of our procedures, midazolam was combined with an analgesic agent, most commonly morphine or meperidine. Although it has been shown that opiates facilitate the induction of anesthesia with midazolam (19,20), it is not clear whether it is necessary or desirable to combine midazolam with another agent to obtain adequate sedation. Sury and Cole report that during bronchoscopy the combination of nalbuphine and midazolam improves the quality of sedation when compared with midazolam alone; however, the combination also prolonged the recovery time and increased the incidence of side effects (16). If a second drug is to be used, a better choice than nalbuphine might be fentanyl since, like midazolam, fentanyl has a rapid onset and short duration of action. Midazolam can be used to calm patients who are agitated or severely anxious. We used small doses (1 to 2 mg) to sedate patients who were agitated or anxious from a variety of causes. We have also found midazolam useful to sedate patients who are agitated after being intubated and placed on a ventilator. In these cases larger doses (4 to 10 mg) administered as a bolus were generally employed. However, because of midazolam’s short half-life, repeated boluses may be required. Alternatively, a constant midazolam infusion has been used for long-term sedation of patients on ventilators in the intensive care unit (21,22). In addition, we frequently used midazolam as a “chemical restraint” to quiet patients who were violent or psychotic after ingesting hallucinogenic drugs. In these cases, 2 to 3 mg every 5 to 10 minutes to a total dose of 10 mg usually suffices to control the symptoms. While we did not use midazolam in any patients with acute functional psychosis, Mendoza et al have used it to sedate psychiatric patients with aggressive and violent behavior (23). Whether midazolam is more efficacious than haloperidol for the rapid tranquilization of agitated patients has not been examined, although we did encounter two patients who were agitated and combative after recreational drug overdoses and who were still unmanageable after 5 and 10 mg of haloperidol. Both patients were quieted after receiving 8 and 6 mg of midazolam, respectively. In an animal model, midazolam is a more effective anticonvulsant than either diazepam or lorazepam (9). We used from 1 to 4 mg of IV midazolam to terminate repetitive seizures in five of our patients. In all cases the convulsions were rapidly controlled without any difficulty. Jawad et al have shown that IM midazolam is more effective than TM diazepam and just as effective as IV diazepam in abolishing interictal spikes on the electroencephalograms (EEGs) of adult epileptics (24).

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While the more rapid onset of action of midazolam may be useful, the shorter duration of action may not be beneficial in seizure control. There have been no controlled studies comparing midazolam and diazepam or lorazepam for initial seizure control in humans. There were 4 adverse reactions (3.3%) encountered during our study, but none of them was serious. The first was a 34-year-old man who had his shoulder reduced after 5 mg morphine and 5 mg midazolam IV. He returned to the ED 8 hours later in urinary retention and required catheterization; there were no long-term sequelae. Urinary retention is not a reported complication of midazolam administration. It is, however, a recognized complication of opiate use, and it is likely that the urinary retention seen in this patient was due to the morphine rather than the midazolam. The second adverse reaction involved a lCyear-old boy who fell, hit his head, and was knocked unconscious for 2 to 3 minutes. He presented with headache and nausea and received 2 mg of midazolam IV to calm him during a CT scan of the head. One and one-half hours later he developed vomiting that was controlled with metoclopramide. He was admitted for observation and was discharged the next day without any other problems. It is unclear in this case whether the vomiting was due to the midazolam or the closed head injury. While vomiting is a frequent symptom following head trauma in children, nausea and vomiting are also reported complications of IV midazolam and occur in 2% to 3% of patients (25). Finally, there were two cases of excessive somnolence. One involved a 70-year-old woman who received 50 mg meperidine and 3 mg midazolam to reduce a shoulder dislocation. The other was a 21-year-old man, also with a shoulder dislocation, who was initially given 50 mg meperidine and 50 mg hydroyzine IM for pain relief. He later received 6 mg morphine and 2 midazolam IV to reduce his shoulder. In both of these cases, the patients remained drowsy for prolonged periods of time, 4 and 5.5 hours, respectively, and that delayed their discharge from the ED. In neither case was there any cardiovascular or respiratory compromise noted. Excessive sedation and prolonged drowsiness are reported in 1% to 2% of patients following parenteral administration of midazolam and may be related to excessive dosage of the drug (25). However, the use of an opiate with midazolam is also known to prolong recovery time (16)) and this synergistic effect may have contributed to the extended ED stay in these cases. None of our patients was admitted because of a complication, although the head-injured patient was admitted for observation. Local venous complications after IV use, including pain upon injection, erythema and induration, and phle-

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Edward A. Ramoska, Robert Linkenheimer, Cheri Glasgow

bitis, were not noted in our study. The incidence of these problems has varied from 0% to 10% (26-29) and may be influenced by other variables such as the technique of IV cannulation, type of catheter used, duration of cannulation, and differences of interpretation among observers (4). In any case, the incidence of local venous problems with midazolam appears to be less than that seen with diazepam (4). While midazolam is remarkably free of side effects (4), there have been serious problems associated with its use. As of June 30, 1989, Roche Laboratories has received reports of 74 deaths associated with the use of midazolam (30). Of these deaths, 47 (64%) involved the use of midazolam for IV sedation or as an adjunctive agent for sedation during a procedure. In the majority of these cases, it appears that death was due to respiratory arrest related to iatrogenic overdosage based on age, debilitation, or the concomitant use of other central nervous system depressants. The recommended dose for sedation was 0.1 to 0.2 mg/kg; but because of these cases, drug labeling was revised to recommend a lower dosage for sedation and to stress the need for close monitoring during administration. We suggest an initial dose of 0.03 mg/kg, with a maximum dose of 0.15 mg/kg. Clinically, this means using an initial IV bolus of 2 to 3 mg administered slowly over 1 to 2 min. It is important to remember that apnea is not only dose-related, but also a function of the speed of injection (4). Further increments of 1 to 2 mg can then be administered every 2 min and titrated to effect. The customary end-point is when the patient becomes drowsy, develops slurred speech, or loses the blink reflex. Total doses in excess of 5 mg are usually not required. The use of adjunctive agents such as opiates may increase the quality of midazolam-induced sedation, but they must be used cautiously since their synergistic effects will also increase the risk of respiratory embarrassment and prolong recovery time. The use of the narcotic antagonist naloxone and, when it is released in this country, the benzodiazepine antagonist

flumazenil should be considered in patients who are oversedated or when it is desirable to reverse the sedation rapidly. Other important factors to consider are the setting in which midazolam is used, the type of monitoring available, and the ability of the staff to respond to emergencies. In all of our patients, IV access was secured prior to the use of midazolam. The patients were placed in the acute care area of the ED where they were constantly watched by the nursing staff and where oxygen and airway management equipment were always close at hand. Monitoring included at least pulse oximetry and frequently continuous electrocardiographic (ECG) recording and the use of automatic blood pressure monitors.

CONCLUSION Midazolam is a unique benzodiazepine that, because of its rapid onset, short duration of action, and watersolubility, has the potential to become an extremely useful emergency department drug. It possesses all the characteristics of the other benzodiazepines, including anxiolytic and hypnotic effects, profound antegrade amnesia, anticonvulsant activity, and muscle-relaxing properties. It can be employed as a general sedative or for producing sedation, either as the sole agent or combined with other drugs. It has a low incidence of side effects; however, it must be used cautiously and in the proper setting to avoid cardiorespiratory compromise. The suggested dose for IV sedation is initially 2 to 3 mg over 1 to 2 min. Subsequent l- to 2-mg doses may be given at 2-min intervals; usually more than 5 mg is not needed. The use of adjunctive agents such as opiates may increase the quality of sedation, but they must be used cautiously as their concomitant use with midazolam will increase the risk of respiratory embarrassment. Close monitoring of the patient and the availability of airway support equipment is mandatory.

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