Intravenous administration of benzodiazepines is rare in U.S. psychiatric emergency services. Algorithms of sedation in the United States and Europe focus primarily on intramuscular injection of lorazepam with or without haloperidol or droperidol (1,2).
However this approach is not appropriate for all extremely agitated psychotic patients, because some have complicating medical problems. This column discusses a rational approach to emergency pharmacological management of seriously agitated and psychotic patients.
A prospective study conducted in a psychiatric intensive care unit in Japan in 1996 showed that of 554 patients admitted during a one-year period, 132 patients (24 percent) had comorbid physical diseases or conditions (3). Forty-four of these patients (8 percent) required treatment by specialists. Eight patients (1 percent) had severe physical disorders because their psychotic symptoms resulted from intracranial hemorrhage or encephalitis. These complications were not recognized until a few hours after the patients were admitted to the unit, primarily through observation of fluctuations in the patients' level of consciousness.
Another study in the same intensive care unit showed that of 259 male patients with acute schizophrenia, 7 percent were dehydrated, a third had hypokalemia and leukocytosis, and two-thirds of these patients showed elevated serum muscle enzymes (4). A quarter of the patients required medical management.
Hypokalemia is associated with agitation (5), and the mean QTc interval of patients in an emergency psychiatry setting has been found to be mildly prolonged (6). As sedation decreases agitation and reduces sympathetic activity, it tends to improve QT prolongation and reduces adrenergic stimulation of the myocardium, which can trigger automatic ventricular activity and facilitate the onset of reentry arrhythmias.
The dose of a benzodiazepine administered intramuscularly is typically higher than that administered by intravenous injection. Thus, if an intramuscular injection is given when patients are admitted, the higher dose may mask the patients' physical complications. Furthermore, the effects of intravenous benzodiazepines can be easily reversed by using flumazenil. Therefore, the intravenous route may be superior when severe complications cannot be ruled out.
Because agitated and psychotic patients often do not cooperate with medical personnel, information from history taking and physical examination, including initial vital signs, may not be sufficient for clinicians to detect comorbid medical conditions. Frequent laboratory screening and monitoring of urine output is essential.
The most important objective during psychiatric emergencies is to control patients' aggression toward themselves or others. During this period, several problems may arise, including difficulty in quickly making a differential diagnosis about the cause of aggression, the detection of physical complications not noted at admission, and the appearance of serious adverse effects of medication. Therefore, an important factor in sedating these patients is the clinician's ability to respond immediately to unpredictable changes in patients' physical and mental condition and to modify the methods of sedation. This flexibility and reversibility, which help ensure patients' safety, are as important as the choice of an effective sedating medication.
The choice of medication depends not only on the severity of the target symptoms but also on the level of medical management at the facility—for example, the availability of monitoring devices and staff skills. Exceeding the highest recommended dose of a drug is justified in some cases, because reducing the risk of self-harm or assaultive behavior is of paramount importance. In emergency situations, knowing how to manage patients who receive high doses is more important than avoiding high doses (7).
Another approach is recommended when monitoring devices are not available. When the target symptoms are moderate or mild, intramuscular haloperidol is the usual choice. Diazepam can be used to augment the effects of haloperidol (lorazepam is unavailable in Japan). However, severe aggression cannot be controlled by this augmentation. In such cases, intramuscular levomepromazine—the most potent sedative phenothiazine—is recommended. Use of intramuscular sedatives is indicated when a patient is unlikely to have severe physical complications and physiological abnormalities seem to be slight.
When deep sedation is required, intravenous benzodiazepines are recommended. A pulse oximeter should be used to monitor the patient's status. When a patient cannot be sedated with intravenous benzodiazepines, intravenous barbiturates are indicated. Benzodiazepines are safer than barbiturates, because they are less likely to cause respiratory depression. Even though the sedative effects of benzodiazepines are less reliable than those of barbiturates, the effects of intravenous benzodiazepines can be reversed by using flumazenil. Prolonged respiratory depression is rare with benzodiazepines, regardless of whether parenteral haloperidol is also used (8). However, abnormal airway structures, including micrognathia, macroglossia, tonsilar or adenoidal hypertrophy, and obesity, raise the risk of upper airway obstruction. In addition, staff should be alert to the possibility of sleep apnea syndrome.
The parenteral use of a benzodiazepine with levomepromazine has been reported to be associated with prolonged upper airway instability (8,9). Thus close observation or pulse oximetry may be required, preferably for 150 minutes or longer (9). Although levomepromazine generally does not affect respiration, its use may enhance the slight effects of a benzodiazepine on respiration. Respiratory problems do not appear to be caused by a decrease in metabolism, by clearance due to competition for a common metabolic enzyme, or by individual variations in metabolism.
In our experience, an initial injection of haloperidol may decrease the dose of benzodiazepine or barbiturate needed, which would lower the risks of respiratory depression.
Use of a telemetry system and maintenance of a venous line may be indicated. Benzodiazepines are used for initial sedation, and haloperidol is used to maintain sedation. For the initial sedation, intravenous flunitrazepam is administered slowly, up to 8 mg as needed. If this is inadequate, intravenous thiopental is given.
For 47 patients in a recent cross-sectional cohort study, the change in QTc over a two-month period was moderately correlated with the dose of intravenous haloperidol; however, no ventricular tachyarrhythmia was detected among 307 patients over a one-year period (10). Therefore, when patients are monitored, intravenous haloperidol can be safely used when alcoholism or serious hypokalemia are present, when ion channel disorders that clinicians cannot exclude in emergency situations become manifest, and when the dose of intravenous haloperidol is greater than 35 mg per day (11).
Maintenance of a venous line has three advantages. First, it enables fluid therapy, which will improve abnormal physiological conditions. Such improvement may take from half a day to several days. It lowers the risk of adverse effects, including pneumonia, consciousness disturbance, arrhythmia, rhabdomyolysis, renal failure, malignant syndrome, and sudden death. Second, maintaining a venous line helps in crisis management when unpredictable events occur, such as cardiopulmonary arrest. Third, it enables rapid and adequate sedation when patients become aggressive on awakening after the initial injection. Thus, for uncooperative and aggressive patients, the use of a telemetry system and maintenance of a venous line is superior to other methods. It enhances safety, the adequacy and promptness of response, and reversibility of pharmacological effects.
Recently, untoward events have occurred after sedation of agitated psychotic patients in Japan, which has prompted judges to suggest that use of monitoring devices such as he pulse oximeter is essential during sedation. As a result, mobile pulse oximeters are becoming increasingly popular in Japan. Furthermore, hospitals that are important psychiatric emergency settings in the Japanese health care system have begun to use telemetry, which enables continuous and remote monitoring of pulse oximetry, respiration rate, electrocardiography, and heart rate. However, the Japanese government has not established incentives for hospitals to provide such monitoring during sedation. The cost of acquiring telemetry systems is high: more than 6 million yen, or about $50,000. The Japanese Association of Emergency Psychiatry is working with government representatives to rectify this situation.
Dr. Hatta is affiliated with the department of psychiatry at Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyoku, Tokyo 113-8421, Japan (e-mail: email@example.com). Douglas H. Hughes, M.D., is editor of this column.