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Systemic complications with intravenous diazepam
Systemic complications with intravenous diazepam David Donaldson, B.D.S., F.D.S.R.C.S., Vancouver, British Columbia, Canada UNIVERSITY
M,D.S., * and Gary Gibson, D.D.S., **
OF BRITISH COLUMBIA
There are few published reports of complications following intravenous diazepam administration. However, more than 200 cases were reported to the United States Department of Health, Education and Welfare during a 7-year period. The systemic complications have been categorized by the authors, and common contributing factors are emphasized. The information obtained from these reports provides further knowledge of both the avoidance and the treatment of such complications and emphasizes the importance of reporting the adverse effects of any drug to a central body.
ince its introduction in 1961,l diazepam has been S widely used as an intravenous sedative for minor surgery,’ outpatient dentistry,3 cardioversion,4 gastroendoscopy,5 bronchoscopy,6 and severe anxiety and agitation.’ Being a muscle relaxant, it has also been employed for the treatmentof severemuscle spasmand tetanus.* As an anticonvulsant, it has been used in the control of epileptic rigors9 and other seizure activity.‘O Reports in the literature of complications from intravenous diazepam, however, have been sparse, indicating its high therapeutic index. Among 173 hospitalized patients receiving intravenous diazepam, Greenblatt and Koch-Weser” discovered only six adverse reactions, three of which were life threatening. Other reports of respiratory, cardiac, and allergic complications also listed only a few actual cases.*2-14However, 220 cases of unpublished complications were reported to the United StatesDepartment of Health, Education and Welfare during the period from October, 1969, to October, 1976 (Table I). Approximately one third involved local complications, such as thrombophlebitis, intraarterial injection, and localized neuralgias, which could be associatedwith the irritant properties of the drug. RESULTS
Respiratory complications
Respiratory depressionin forty-seven patients proved to be the most frequent systemic problem. The most significant factor in adverse respiratory *Associate Professor, Department of Restorative Dentistry. **Assistant Professor, Department of Restorative Dentistry.
126
reactions was age (Fig. 1). The incidence of respiratory complications increasedwith age to a peak in the 70- to 80-year age group, while at the other end of the age scale there was also an increase in complications, including four neonates and four children between the agesof 2 and 30 months (Table II). Potentiation by other central nervous depressants was suggested in twenty-four cases in which the patients received other drugs before or during diazepam administration. Barbiturates were the most commonly used drugs (Table III), followed by the narcotic, meperidine hydrochloride, and the benzodiazepine, chlordiazepoxide. Other individual problems exhibited by patients suggestedthat the diazepamwas not solely responsible for the respiratory depression. Two patients were chronic alcoholics and one was a chronic drug abuser, suggesting that liver damage could have interfered with the metabolism of the drug. Two others were apneic before receiving the drug. In eight casesthere were signs of existing central nervous system damageprior to diazepam administration. One, a 33-month-infant, had a retinoblastoma with metastasisand venous sinus thrombosis. Three others were having convulsions at the time of injection, while three more had meningitis. In the eighth case, the patient was found to have had a subarrachnoid hemorrhage.An obeseelderly diabetic patient and a patient with atrioventricular fibrillation also demonstrated severe respiratory depression. The amount of diazepam given (from 2 mg. to 20 mg.) was within the normal sedative therapeutic range for adults with the exception of two patients who died. A 33-month-old convulsing child with glaucoma, ex0030-4220/80/020126+05$00.50/0
@ 1980 l-be C.
V. Mosby Co.
Systemic complications with intravenous diazepam
Volume 49 Number 2
127
Table 1.Complications with intravendus diazepam
I
No.
of cases 84 47 21 13 10 21 I 4 I 2 3 1
Local Respiratory Cardiovascular Allergies Comatose Hysteria Lack of effectiveness Neonataljaundice Muscle flaccidity Muscle spasm Headaches Visual disturbance
No. of cases
Age range
18 to 85 yr. 10 yr. 2 to 30 mo.
36 1 4 4
Table III. Other central nervous system depressants
involved in respiratory complications Drug
I
Barbiturates Meperidine Benzodiazepines Meprobomate Promethazine Morphine
60
60
100
AGE bears)
Fig. 1. Age and respiratory depression.
4s
1
Dosage
61 60 55
(mg.)
1
Other drugs
10
2 25
Barbiturate, ether
5
48 33 17 17 12 days
1.5 20 5
No data
No data
Barbiturate, narcotic
L
No. of cases
11 6 4 1 1 1
hibiting no reaction to pain or cornea1reflex, was given 10 mg. of diazepam intravenously. At the other extreme, a 79-year-old woman was given 15 mg. of diazepam for control of agitation. Three casesinvolved respiratory depression in neonates whose mothers had been administered intravenous diazepamduring labor. The most serious of these involved the administration of 10 mg. of diazepam in conjunction with narcotics. At delivery some 2 hours later the child gave an initial cry and then lapsed into secondary apnea with no heart beat. On resuscitation the child demonstratedhyporeflexes, had a weak cry, and was difficult to arouse for a period of 3 hours. Ten patients died of respiratory complications, but in none of these cases was the patient both healthy and receiving diazepam alone. Cardiovascular
46
Table IV. Hypotension
Tebie II. Respiratory depression Adults Adolescent Children Neonates
20
0
complications
Systemic cardiovascular problems accounted for twenty-seven of the reported cases. Of these, there were fifteen cases of cardiac arrest, ten cases of hypotension, and two casesof hypertension.
Table V. Lack of effect with diazepam Age
Dosage
(mg.)
25 22
10 20
30 55 55 61
30 50 50 120
Other drugs
-
100 mg. meperidine and 100 mg. pentobarbital -. -. -.
Cardiac arrests. Only four of the patients with cardiac arrest respondedto treatment, but there we= factors other than diazepam administration which may have attributed to thirteen of the complications. For the two exceptions no details were given other than the fact that two adult patients died of cardiac arrest after receiving intravenous diazepam. One third of the cardiac arrest patients in this series were over 60 years old. In two casesof fetal cardiac arrestreported, the heartsof the term fetusesstoppedas soon as the mothersreceived the intravenous diazqam. There may well have been an additive potentiating drug effect, as one mother had already received oral diazepam, pentazocine, and sodium pentobarbital and the other had already received a “minimal amount” of meperidine and oxycodone. In both casesdiazepamand n-desmethyl diazepam levels were found in the fetal circulatory systems,
128 Donaldson and Gibson
A 2-year-old child also died of cardiac arrest, but in that case the child already had congestive heart failure and was convulsing at the time of administration. Six of the cardiac arrest patients had received other central nervous systemdepressants,while another adult was given fentanyl with the diazepam despite a previous anaphylactic reaction to this drug. Medical conditions present which may have contributed to the arrests were severe liver disease, advanced diabetes with arteriosclerosis, severe renal diseaserequiring dialysis and one caseof multiple amniotic fluid emboli following a cesareansection, Hypotension. The ten reports of diazepam-induced hypotension occurred in patients ranging in age from 12 days to 61 years (Table IV). It took only 2 mg. of diazepamto causehypotension in both a neonateand a 60-year-old patient, In only two cases were other central nervous depressants involved, but chronic liver disease, severe brain damage following trauma, and encephalitis in a 12-day-old child complicated other fatal cases. Hypertension. In the two casesof hypertension, the condition occurred following injection, did not reach a serious level, and was transient. Allergic reaction
Unlike the respiratory and cardiovascular problems with intravenous diazepam, the thirteen allergic reactions reported showed no correlation to age. The most common reaction was an erythematous, urticarial rash, as found in ten cases. The rash was variously described as macular and pruritic, sometimes involving the arms but nearly always involving the head and neck. In one casethe rash was limited to the abdomen and trunk and was accompanied by convulsions. In another, the rash was preceded by sneezing and coughing with copious nasal discharge. Other drugs were not significant factors in this group of complications, as only three patients received barbiturates, one received meperidine, and two had received a local anesthetic. In most cases the described allergic reactions received only supportive treatment. In one case 100 mg. of intravenous cortisone reversed the rash, while 10 mg. of Chlor-Trimeton proved successful in another. Two patients showed signs of blood dyscrasias.One go-year-old man died of agranulocytosis some 5 weeks following the administration of diazepam,barbiturates, and nitrous oxide/oxygen with halothane for surgery. He was however, a terminally ill patient suffering from a pancreatic carcinoma. The other patient was a lomonth-old infant who was given 2 mg. of diazepam intravenously for meningitis-induced convulsions and later developed neutropenia. The child had also received penicillin and barbiturates during this period.
Oral Surg. February, 1980
One serious acute allergic reaction was reported. A 52-year-old man received both pentazocineand sodium barbiturate as premeditation the day before surgery and phenobarbital intramuscularly followed by 25 mg. diazepam intravenously as the induction agents prior to the surgical procedure. The patient lapsed into a prolonged coma accompanied by laryngeal edema and eventually died after 2 hours. Altered mental state
The purposeof administering diazepamis to produce an altered mental state, sedation. However, there are two groups in which the mental reaction is undesirable: comatosepatients and hysterical or agitated patients. Coma. Ten patients were reported to have become comatose upon receiving intravenous diazepam and, of those, one died and one suffered permanent brain damage. The fatality occurred in a 3-year-old child admitted with a temperatureof 107” F. and in a comatosestate. Intravenous diazepam, 7 mg., was administered and the child died without recovering consciousness. The brain damageoccurred in a 1-year-old child who received 400 mg. of diazepam over a l-hour period. Unfortunately, no other details of this case were recorded. In a similar case of apparent overdosing, a 15month-old girl in a semicomatosecondition with viral encephalitis received 160 mg. of diazepam in 5 mg. increments over 24 hours to control convulsions. The child remained comatosefor the following 10 days. After receiving 20 mg. of diazepam, a 2-year-old child remained comatose for 2 days and displayed muscle flaccidity throughout this period. The remaining two cases of diazepam-induced unconsciousnesswere both adults receiving treatment for alcoholism. In addition to 20 mg. of intravenous diazepam, one received chlorpromazine and hydroxyzine, while the other received 10 mg. of intravenous diazepam but also multiple doses of meperidine hydrochloride. Four other comatosepatients were elderly, between the agesof 69 and 89. In addition, their physical condition was poor; one had Parkinson’s disease, another had chronic asthma, and yet another was already on a respirator. The latter, given intravenous diazepam for treatment of agitation did not recover, while in two of the other cases 50 mg. of diazepam had been given intramuscularly prior to 5 mg. of intravenous diazepam. Hysteria. Twenty-one patients were reported to be either agitated or hallucinating following intravenous diazepam. They appearedto be in three distinct subgroups: hysterical, violent, and hallucinatory. Four casesof hysteria, with crying or sobbing im-
Volume 49 Number 2
mediately following the administration, were described. Significantly, two of these were young boys and the others were young women. In contrast to this submissivereaction, six caseswere reported in which the patients became,enraged, boisterous, and violent. This aggressiveattitude typically becameapparentfollowing the procedure, but in one case it was not until the next day that the symptoms expressedthemselves. The remaining twelve patients complained mainly of hallucinations with hysteria. In two casesthe hallucinations were auditory as well as visual, and in one case there was euphoria with erotic fantasies. In most instancesthe hallucinations lasted only for the remainder of the day, but one 51-year-old man hallucinated for 3 days, going without sleep for 2 nights before succumbing to three grand ma1seizures. Lack of effectiveness
In contrast to those cases of patients showing increased sensitivity to diazepam, seven reports were received describing little or no reaction to the drug (Table V). In the case of a normal healthy adult who demonstratedno effect with 10 mg. of intravenous diazepam, this could be accepted as being within the bounds of normality. However, where 20 mg. were given of both meperidine and pentobarbital, the lack of effectiveness demonstratesthe variation in individual reaction to this drug. Even more remarkable is the case of the 61-year-old man who received the 120 mg. of diazepamin 20 mg. incrementswith no apparenteffect. Neonatal jaundice
Four casesin which the mothers had been given intravenous diazepam prior to delivery resulted in jaundiced neonates. One mother who received 10 mg. of diazepam intravenously and oxytocin delivered a pale, jaundiced child, while another who received 30 mg. of diazepam in addition to morphine and meperidine becamejaundiced herself and delivered a jaundiced child who respondedto intubation. Two caseswere reported of increasedblood levels of bilirubin in the children of mothers who had received only 5 mg. of intravenous diazepam together with 50 mg. of meperidine. Muscular complications
Despite diazepam being used as a muscle relaxant, only one case of muscle flaccidity was reported. That case involved a 3-year-old child who received 20 mg. of intravenous diazepam to control convulsions. The child remained comatose for 2 days and showed marked muscle flaccidity. Two other muscular complications were in the form of muscle spasms. One patient was a 26-year-old woman who received only 6 mg. of intravenous diaze-
Systemic complications
with intrar,enorrs din:cptrm
129
pam and, on recovery, displayed generalized muscle contractions, especially in the arms. One hour after receiving 5 mg. of intravenous diazepam with 50 mg. of meperidine, a 57-year-old man developed muscle tremors, which w,ere controiled with additional meperidine Headaches
Three young adult male outpatients who received 10 mg. of intravenous diazepam together with atropine developed headachessoon afterward. Two of the cases were otherwise uneventful, but in the third there was a history of hypertension and 1 week later the patient died of a subarrachnoid hemorrhage. Visual abnormalities
Only one case of visual disturbancesother than hallucinations was reported. In that case a 19-year-old male patient, on receiving 10 mg. of intravenous diazepam, claimed to have bright green visions. The sensation began after 4 minutes and lasted for 20 minutes. The patient had been studying for examinations and had drunk a great deal of coffee and had little sleep for several days before the appointment. DISCUSSION
There are conflicting reports of the effects of diazepam on respiration, probably because of differing methodsof administration and evaluation. lJ-” Respiratory depressionwith diazepamhas been likened to that produced during sleep and would not, therefore, endanger a healthy patient.‘” However, in patients with medical conditions which cause carbon dioxide retention, this depressioncan be significant since these patients have reduced sensitivity to pC0, and their respiratory drive has become dependent on a low pO,?O Features which contribute to this pattern are chronic pulmonary disease, other central nervous system depressan&and extremesof age. In this review, twentyfour of forty-seven patients with respiratory depression had received other central nervous system depressants, eight patients had existing central nervous systemdamage, and three patients were already apneic. The effect of age is also demonstratedin Fig. 1 and is confirmed by other reports of respiratory depression.“. Ir. ‘I. 22 Cardiovascular complications were rare and probably related to respiratory depression and central nervous system depressants.Cardiac arrest reported by others following both oral and intravenous administration also indicated accompanying respiratory depreSsion.“. 1,~.2B
A further complicating factor was liver disease, as five patients in the investigation with respiratoryicardiovascular problems were either chronic alcoholics or drug abusersor had liver disease.The mechanismmay
130 Donaldson and Gibson
be due to failure to metabolize the drug effectively or to increased CO, retention from pulmonary shunts often found in cirrhotic persons.l l* I3324 Eleven cases of allergic reaction are well documented, although none reported the allergic conjunctivitis seenby Lutz.14The two casesof blood dyscrasias cannot be consideredas definite allergic responses.The reversal of the allergic responseby physostigmine supports the findings of others,‘*’ 25*26 while Bellz7 reported successwith naloxone. Comas induced by diazepam were accompanied by respiratory and cardiovascular complications, age, central nervous system depressantdrugs, and existing brain damage, although at least two caseswere due to obvious overdosage. The hysterical reactions to diazepam were not dose related, however. Sobbing following diazepam administration is not uncommon in adolescents, but the violent hysteria reported in six of the caseshas not been reported before. Neonatal jaundice in children born to mothers who received intravenous diazepam was reported in only four cases and may have been unrelated to the drug. The three neonates exhibiting respiratory depression, however, demonstratethe need for caution in administering intravenous diazepam prior to delivery. Complications involving muscle spasm and flaccidity, headaches,and visual abnormalities would appear to be rare or of such little significance to clinicians that reports are limited. CONCLUSIONS
Diazepam has a high therapeutic index and, therefore, reports in the literature of complications are rare. The elderly and very young are obviously most sensitive to diazepam, while central nervous system depressants,existing brain damage,and liver diseasewill also render patients more responsive to the drug’s effect. The delayed onset of hysterical reactions and hallucinations mandatesthat outpatients receiving intravenous diazepamshould be escortedfor the remainder of the day. Care must be exercised in administering intravenous diazepam to the expectant mother, as adverse effects on the fetus have been clearly shown. We should like to thank the United States Department of Health, Education and Welfare for furnishing the edited reports of the cases described here. REFERENCES 1. Stembach, L. H., and Reeder, E. J.: Quinazolines and I,4 BenzodiazepinesI. V. Transformationsof 7-chloro-2-methylamino5-phenyl-3H-1,4benzodiazepine 4-oxide, J. Org. Chem. 26: 49364960, 1961. 2. Brown, S. S., and Dundee, J. W.: Clinical Studiesof Induction Agents, Br. J. Anaesth. 40: 108112, 1968.
Oral Surg. February, 1980 3. Brown, P. R. H., Main, D. M. G., and Lawson, J. 1. M.: Diazepam in dentistry, Br. Dent. J. 125: 498-504, 1968. 4. Kahler, R. L., and Burrow, Cl. N.: Diazepam-inducedamnesia for cardioversion, J.A.M.A. 200: 189-190, 1967. 5. Dundee, J. W., and Haslett, W. H. K.: The Benzodiozepines:A Review of Their Actions and Uses Relative to AnaestheticPractice, Br. J. Anaesth. 42: 217-234, 1970. 6. Ecker, R. R., Sugg, W. L., and Rea, J.: Diazepam as an Adjunct to Bronchoscopy, Chest 62: 259-262, 1972. 7. Dundee, J. W., and Kielty, S. R.: Diazepam, Int. Anaesthesiol. Clin. 7: 91-121, 1964. 8. Femi-Pearse, D.: Experience With Diazepam in Tetanus, Br. Med. J. 2: 862-865, 1966. 9. Bell, D. S.: Dangers of Treatment of Status Epileptics With Diazepam, Br. Med. J. 1: 159-161, 1969. 10. Smith, B. T., and Masotti, R. E.: Intravenous Diazepam in the Treatment of Prolonged Seizure Activity in Neonates and Infants, Dcv. Med. Child. Neurol. 13: 630-634, 1971. 11. Greenblatt, D. J., and Koch-Weser, 1.: Adverse Reactions to Intravenous Diampam, Am. J. Med. Sci. 266: 261-266, 1973. 12. Braunstein, M. C.: Apnea With Maintenance of Consciousness Following Intravenous Diazcpam, Anesth. Analg. 58: 52-53, 1979. 13. Sherman, P. M.: Cardiac Arrest With Diazepam, I. Oral Surg. 32: 567, 1974. 14. Lutz, E. G.: Allergic Conjunctivitis Due to Diazepam, Am. J. Psychiatry 132: 548, 1975. 15. Cohen, R., Finn, H., and Steen, S. H.: Effect of Diazepam and Meperidine Alone and in Combination on Respiratory Response to Carbon Dioxide, Anesth. Analg. 48: 353-355, 1969. 16. Steen, S. H., Weitzner, S. W., and Amaha, K.: The Effect of Diazepam on the Respiratory Responseto Carbon Dioxide, Can. Anaesth. Sot. J. 13: 324-377, 1966. 17. Dalen, J. E., Evans, G. L., and Banas, J. S.: The Hemodynamics and Respiratory Effects of Diazepam (Valium), Anesthesiology 30: 259-263, 1969. 18. Lakshmimarayan, S., Sahn, S. A., Hudson, D. L., and Weil. J. V.: Effect of Diazepam on Ventilatory Responses, Clin. Phannacol. Ther. 20: 178-183, 1976. 19. Rao, S., Sherbaniuk, R. W., Prasad, K., Lee, S. J. K., and Sproule, B. J.: Cardiopulmonary effects of diazepam, Clin. Pharmacol. Ther. 14: 182-189, 1973. 20. Stewart, R. C.: Respiratory DepressionWith Diazepam: Potential Complications and Contraindications, Anesth. Progr. 25: 117-l 18, 1978. 21. Brauminger, G., and Ravin, M.: Respiratory Arrest Following Intravenous Diazepam, Ann. Ophthalmol. 6: 805-806, 1974. 22. Hall, S. C., and Ovassauian,A.: Annea After IntravenousDiazepam Therapy, J.A.M. A. 2&h 1052, 1977. 23. Berger, R., Green, G., and Melnick, A.: Cardiac Arrest Caused by Oml Diazepam Intoxication, Clin. Pediatr. 14: 842-844, 1975. 24. Flemming, D. C.: Cardiac Arrest With Diazepam, J. Oral Surg. 32: 807, 1974. 25. Larson, G. F., Hurlben, B. J., and Wingard, D. W.: Physostigmine Reversal of Diazepam induced Depression, Anesth. Analg. 56: 348-350, 1977. 26. DiLiberti, J., O’Brien, M. L., and Turner, T.: The Use of Physostigmineas an Antidote in Accidental Diazepam Intoxication, J. Pediatr. 86: 106-107, 1975. 27. Bell, E. F.: The Use of Naloxone in the Treatment of Diazepam Poisoning, J. Pediatr. 87: 803-804, 1975. Reprint requests to: Dr. David Donaldson Department of Restorative Dentistry School of Dentistry University of British Columbia Vancouver, British Columbia, Canada
M,D.S., * and Gary Gibson, D.D.S., **
OF BRITISH COLUMBIA
There are few published reports of complications following intravenous diazepam administration. However, more than 200 cases were reported to the United States Department of Health, Education and Welfare during a 7-year period. The systemic complications have been categorized by the authors, and common contributing factors are emphasized. The information obtained from these reports provides further knowledge of both the avoidance and the treatment of such complications and emphasizes the importance of reporting the adverse effects of any drug to a central body.
ince its introduction in 1961,l diazepam has been S widely used as an intravenous sedative for minor surgery,’ outpatient dentistry,3 cardioversion,4 gastroendoscopy,5 bronchoscopy,6 and severe anxiety and agitation.’ Being a muscle relaxant, it has also been employed for the treatmentof severemuscle spasmand tetanus.* As an anticonvulsant, it has been used in the control of epileptic rigors9 and other seizure activity.‘O Reports in the literature of complications from intravenous diazepam, however, have been sparse, indicating its high therapeutic index. Among 173 hospitalized patients receiving intravenous diazepam, Greenblatt and Koch-Weser” discovered only six adverse reactions, three of which were life threatening. Other reports of respiratory, cardiac, and allergic complications also listed only a few actual cases.*2-14However, 220 cases of unpublished complications were reported to the United StatesDepartment of Health, Education and Welfare during the period from October, 1969, to October, 1976 (Table I). Approximately one third involved local complications, such as thrombophlebitis, intraarterial injection, and localized neuralgias, which could be associatedwith the irritant properties of the drug. RESULTS
Respiratory complications
Respiratory depressionin forty-seven patients proved to be the most frequent systemic problem. The most significant factor in adverse respiratory *Associate Professor, Department of Restorative Dentistry. **Assistant Professor, Department of Restorative Dentistry.
126
reactions was age (Fig. 1). The incidence of respiratory complications increasedwith age to a peak in the 70- to 80-year age group, while at the other end of the age scale there was also an increase in complications, including four neonates and four children between the agesof 2 and 30 months (Table II). Potentiation by other central nervous depressants was suggested in twenty-four cases in which the patients received other drugs before or during diazepam administration. Barbiturates were the most commonly used drugs (Table III), followed by the narcotic, meperidine hydrochloride, and the benzodiazepine, chlordiazepoxide. Other individual problems exhibited by patients suggestedthat the diazepamwas not solely responsible for the respiratory depression. Two patients were chronic alcoholics and one was a chronic drug abuser, suggesting that liver damage could have interfered with the metabolism of the drug. Two others were apneic before receiving the drug. In eight casesthere were signs of existing central nervous system damageprior to diazepam administration. One, a 33-month-infant, had a retinoblastoma with metastasisand venous sinus thrombosis. Three others were having convulsions at the time of injection, while three more had meningitis. In the eighth case, the patient was found to have had a subarrachnoid hemorrhage.An obeseelderly diabetic patient and a patient with atrioventricular fibrillation also demonstrated severe respiratory depression. The amount of diazepam given (from 2 mg. to 20 mg.) was within the normal sedative therapeutic range for adults with the exception of two patients who died. A 33-month-old convulsing child with glaucoma, ex0030-4220/80/020126+05$00.50/0
@ 1980 l-be C.
V. Mosby Co.
Systemic complications with intravenous diazepam
Volume 49 Number 2
127
Table 1.Complications with intravendus diazepam
I
No.
of cases 84 47 21 13 10 21 I 4 I 2 3 1
Local Respiratory Cardiovascular Allergies Comatose Hysteria Lack of effectiveness Neonataljaundice Muscle flaccidity Muscle spasm Headaches Visual disturbance
No. of cases
Age range
18 to 85 yr. 10 yr. 2 to 30 mo.
36 1 4 4
Table III. Other central nervous system depressants
involved in respiratory complications Drug
I
Barbiturates Meperidine Benzodiazepines Meprobomate Promethazine Morphine
60
60
100
AGE bears)
Fig. 1. Age and respiratory depression.
4s
1
Dosage
61 60 55
(mg.)
1
Other drugs
10
2 25
Barbiturate, ether
5
48 33 17 17 12 days
1.5 20 5
No data
No data
Barbiturate, narcotic
L
No. of cases
11 6 4 1 1 1
hibiting no reaction to pain or cornea1reflex, was given 10 mg. of diazepam intravenously. At the other extreme, a 79-year-old woman was given 15 mg. of diazepam for control of agitation. Three casesinvolved respiratory depression in neonates whose mothers had been administered intravenous diazepamduring labor. The most serious of these involved the administration of 10 mg. of diazepam in conjunction with narcotics. At delivery some 2 hours later the child gave an initial cry and then lapsed into secondary apnea with no heart beat. On resuscitation the child demonstratedhyporeflexes, had a weak cry, and was difficult to arouse for a period of 3 hours. Ten patients died of respiratory complications, but in none of these cases was the patient both healthy and receiving diazepam alone. Cardiovascular
46
Table IV. Hypotension
Tebie II. Respiratory depression Adults Adolescent Children Neonates
20
0
complications
Systemic cardiovascular problems accounted for twenty-seven of the reported cases. Of these, there were fifteen cases of cardiac arrest, ten cases of hypotension, and two casesof hypertension.
Table V. Lack of effect with diazepam Age
Dosage
(mg.)
25 22
10 20
30 55 55 61
30 50 50 120
Other drugs
-
100 mg. meperidine and 100 mg. pentobarbital -. -. -.
Cardiac arrests. Only four of the patients with cardiac arrest respondedto treatment, but there we= factors other than diazepam administration which may have attributed to thirteen of the complications. For the two exceptions no details were given other than the fact that two adult patients died of cardiac arrest after receiving intravenous diazepam. One third of the cardiac arrest patients in this series were over 60 years old. In two casesof fetal cardiac arrestreported, the heartsof the term fetusesstoppedas soon as the mothersreceived the intravenous diazqam. There may well have been an additive potentiating drug effect, as one mother had already received oral diazepam, pentazocine, and sodium pentobarbital and the other had already received a “minimal amount” of meperidine and oxycodone. In both casesdiazepamand n-desmethyl diazepam levels were found in the fetal circulatory systems,
128 Donaldson and Gibson
A 2-year-old child also died of cardiac arrest, but in that case the child already had congestive heart failure and was convulsing at the time of administration. Six of the cardiac arrest patients had received other central nervous systemdepressants,while another adult was given fentanyl with the diazepam despite a previous anaphylactic reaction to this drug. Medical conditions present which may have contributed to the arrests were severe liver disease, advanced diabetes with arteriosclerosis, severe renal diseaserequiring dialysis and one caseof multiple amniotic fluid emboli following a cesareansection, Hypotension. The ten reports of diazepam-induced hypotension occurred in patients ranging in age from 12 days to 61 years (Table IV). It took only 2 mg. of diazepamto causehypotension in both a neonateand a 60-year-old patient, In only two cases were other central nervous depressants involved, but chronic liver disease, severe brain damage following trauma, and encephalitis in a 12-day-old child complicated other fatal cases. Hypertension. In the two casesof hypertension, the condition occurred following injection, did not reach a serious level, and was transient. Allergic reaction
Unlike the respiratory and cardiovascular problems with intravenous diazepam, the thirteen allergic reactions reported showed no correlation to age. The most common reaction was an erythematous, urticarial rash, as found in ten cases. The rash was variously described as macular and pruritic, sometimes involving the arms but nearly always involving the head and neck. In one casethe rash was limited to the abdomen and trunk and was accompanied by convulsions. In another, the rash was preceded by sneezing and coughing with copious nasal discharge. Other drugs were not significant factors in this group of complications, as only three patients received barbiturates, one received meperidine, and two had received a local anesthetic. In most cases the described allergic reactions received only supportive treatment. In one case 100 mg. of intravenous cortisone reversed the rash, while 10 mg. of Chlor-Trimeton proved successful in another. Two patients showed signs of blood dyscrasias.One go-year-old man died of agranulocytosis some 5 weeks following the administration of diazepam,barbiturates, and nitrous oxide/oxygen with halothane for surgery. He was however, a terminally ill patient suffering from a pancreatic carcinoma. The other patient was a lomonth-old infant who was given 2 mg. of diazepam intravenously for meningitis-induced convulsions and later developed neutropenia. The child had also received penicillin and barbiturates during this period.
Oral Surg. February, 1980
One serious acute allergic reaction was reported. A 52-year-old man received both pentazocineand sodium barbiturate as premeditation the day before surgery and phenobarbital intramuscularly followed by 25 mg. diazepam intravenously as the induction agents prior to the surgical procedure. The patient lapsed into a prolonged coma accompanied by laryngeal edema and eventually died after 2 hours. Altered mental state
The purposeof administering diazepamis to produce an altered mental state, sedation. However, there are two groups in which the mental reaction is undesirable: comatosepatients and hysterical or agitated patients. Coma. Ten patients were reported to have become comatose upon receiving intravenous diazepam and, of those, one died and one suffered permanent brain damage. The fatality occurred in a 3-year-old child admitted with a temperatureof 107” F. and in a comatosestate. Intravenous diazepam, 7 mg., was administered and the child died without recovering consciousness. The brain damageoccurred in a 1-year-old child who received 400 mg. of diazepam over a l-hour period. Unfortunately, no other details of this case were recorded. In a similar case of apparent overdosing, a 15month-old girl in a semicomatosecondition with viral encephalitis received 160 mg. of diazepam in 5 mg. increments over 24 hours to control convulsions. The child remained comatosefor the following 10 days. After receiving 20 mg. of diazepam, a 2-year-old child remained comatose for 2 days and displayed muscle flaccidity throughout this period. The remaining two cases of diazepam-induced unconsciousnesswere both adults receiving treatment for alcoholism. In addition to 20 mg. of intravenous diazepam, one received chlorpromazine and hydroxyzine, while the other received 10 mg. of intravenous diazepam but also multiple doses of meperidine hydrochloride. Four other comatosepatients were elderly, between the agesof 69 and 89. In addition, their physical condition was poor; one had Parkinson’s disease, another had chronic asthma, and yet another was already on a respirator. The latter, given intravenous diazepam for treatment of agitation did not recover, while in two of the other cases 50 mg. of diazepam had been given intramuscularly prior to 5 mg. of intravenous diazepam. Hysteria. Twenty-one patients were reported to be either agitated or hallucinating following intravenous diazepam. They appearedto be in three distinct subgroups: hysterical, violent, and hallucinatory. Four casesof hysteria, with crying or sobbing im-
Volume 49 Number 2
mediately following the administration, were described. Significantly, two of these were young boys and the others were young women. In contrast to this submissivereaction, six caseswere reported in which the patients became,enraged, boisterous, and violent. This aggressiveattitude typically becameapparentfollowing the procedure, but in one case it was not until the next day that the symptoms expressedthemselves. The remaining twelve patients complained mainly of hallucinations with hysteria. In two casesthe hallucinations were auditory as well as visual, and in one case there was euphoria with erotic fantasies. In most instancesthe hallucinations lasted only for the remainder of the day, but one 51-year-old man hallucinated for 3 days, going without sleep for 2 nights before succumbing to three grand ma1seizures. Lack of effectiveness
In contrast to those cases of patients showing increased sensitivity to diazepam, seven reports were received describing little or no reaction to the drug (Table V). In the case of a normal healthy adult who demonstratedno effect with 10 mg. of intravenous diazepam, this could be accepted as being within the bounds of normality. However, where 20 mg. were given of both meperidine and pentobarbital, the lack of effectiveness demonstratesthe variation in individual reaction to this drug. Even more remarkable is the case of the 61-year-old man who received the 120 mg. of diazepamin 20 mg. incrementswith no apparenteffect. Neonatal jaundice
Four casesin which the mothers had been given intravenous diazepam prior to delivery resulted in jaundiced neonates. One mother who received 10 mg. of diazepam intravenously and oxytocin delivered a pale, jaundiced child, while another who received 30 mg. of diazepam in addition to morphine and meperidine becamejaundiced herself and delivered a jaundiced child who respondedto intubation. Two caseswere reported of increasedblood levels of bilirubin in the children of mothers who had received only 5 mg. of intravenous diazepam together with 50 mg. of meperidine. Muscular complications
Despite diazepam being used as a muscle relaxant, only one case of muscle flaccidity was reported. That case involved a 3-year-old child who received 20 mg. of intravenous diazepam to control convulsions. The child remained comatose for 2 days and showed marked muscle flaccidity. Two other muscular complications were in the form of muscle spasms. One patient was a 26-year-old woman who received only 6 mg. of intravenous diaze-
Systemic complications
with intrar,enorrs din:cptrm
129
pam and, on recovery, displayed generalized muscle contractions, especially in the arms. One hour after receiving 5 mg. of intravenous diazepam with 50 mg. of meperidine, a 57-year-old man developed muscle tremors, which w,ere controiled with additional meperidine Headaches
Three young adult male outpatients who received 10 mg. of intravenous diazepam together with atropine developed headachessoon afterward. Two of the cases were otherwise uneventful, but in the third there was a history of hypertension and 1 week later the patient died of a subarrachnoid hemorrhage. Visual abnormalities
Only one case of visual disturbancesother than hallucinations was reported. In that case a 19-year-old male patient, on receiving 10 mg. of intravenous diazepam, claimed to have bright green visions. The sensation began after 4 minutes and lasted for 20 minutes. The patient had been studying for examinations and had drunk a great deal of coffee and had little sleep for several days before the appointment. DISCUSSION
There are conflicting reports of the effects of diazepam on respiration, probably because of differing methodsof administration and evaluation. lJ-” Respiratory depressionwith diazepamhas been likened to that produced during sleep and would not, therefore, endanger a healthy patient.‘” However, in patients with medical conditions which cause carbon dioxide retention, this depressioncan be significant since these patients have reduced sensitivity to pC0, and their respiratory drive has become dependent on a low pO,?O Features which contribute to this pattern are chronic pulmonary disease, other central nervous system depressan&and extremesof age. In this review, twentyfour of forty-seven patients with respiratory depression had received other central nervous system depressants, eight patients had existing central nervous systemdamage, and three patients were already apneic. The effect of age is also demonstratedin Fig. 1 and is confirmed by other reports of respiratory depression.“. Ir. ‘I. 22 Cardiovascular complications were rare and probably related to respiratory depression and central nervous system depressants.Cardiac arrest reported by others following both oral and intravenous administration also indicated accompanying respiratory depreSsion.“. 1,~.2B
A further complicating factor was liver disease, as five patients in the investigation with respiratoryicardiovascular problems were either chronic alcoholics or drug abusersor had liver disease.The mechanismmay
130 Donaldson and Gibson
be due to failure to metabolize the drug effectively or to increased CO, retention from pulmonary shunts often found in cirrhotic persons.l l* I3324 Eleven cases of allergic reaction are well documented, although none reported the allergic conjunctivitis seenby Lutz.14The two casesof blood dyscrasias cannot be consideredas definite allergic responses.The reversal of the allergic responseby physostigmine supports the findings of others,‘*’ 25*26 while Bellz7 reported successwith naloxone. Comas induced by diazepam were accompanied by respiratory and cardiovascular complications, age, central nervous system depressantdrugs, and existing brain damage, although at least two caseswere due to obvious overdosage. The hysterical reactions to diazepam were not dose related, however. Sobbing following diazepam administration is not uncommon in adolescents, but the violent hysteria reported in six of the caseshas not been reported before. Neonatal jaundice in children born to mothers who received intravenous diazepam was reported in only four cases and may have been unrelated to the drug. The three neonates exhibiting respiratory depression, however, demonstratethe need for caution in administering intravenous diazepam prior to delivery. Complications involving muscle spasm and flaccidity, headaches,and visual abnormalities would appear to be rare or of such little significance to clinicians that reports are limited. CONCLUSIONS
Diazepam has a high therapeutic index and, therefore, reports in the literature of complications are rare. The elderly and very young are obviously most sensitive to diazepam, while central nervous system depressants,existing brain damage,and liver diseasewill also render patients more responsive to the drug’s effect. The delayed onset of hysterical reactions and hallucinations mandatesthat outpatients receiving intravenous diazepamshould be escortedfor the remainder of the day. Care must be exercised in administering intravenous diazepam to the expectant mother, as adverse effects on the fetus have been clearly shown. We should like to thank the United States Department of Health, Education and Welfare for furnishing the edited reports of the cases described here. REFERENCES 1. Stembach, L. H., and Reeder, E. J.: Quinazolines and I,4 BenzodiazepinesI. V. Transformationsof 7-chloro-2-methylamino5-phenyl-3H-1,4benzodiazepine 4-oxide, J. Org. Chem. 26: 49364960, 1961. 2. Brown, S. S., and Dundee, J. W.: Clinical Studiesof Induction Agents, Br. J. Anaesth. 40: 108112, 1968.
Oral Surg. February, 1980 3. Brown, P. R. H., Main, D. M. G., and Lawson, J. 1. M.: Diazepam in dentistry, Br. Dent. J. 125: 498-504, 1968. 4. Kahler, R. L., and Burrow, Cl. N.: Diazepam-inducedamnesia for cardioversion, J.A.M.A. 200: 189-190, 1967. 5. Dundee, J. W., and Haslett, W. H. K.: The Benzodiozepines:A Review of Their Actions and Uses Relative to AnaestheticPractice, Br. J. Anaesth. 42: 217-234, 1970. 6. Ecker, R. R., Sugg, W. L., and Rea, J.: Diazepam as an Adjunct to Bronchoscopy, Chest 62: 259-262, 1972. 7. Dundee, J. W., and Kielty, S. R.: Diazepam, Int. Anaesthesiol. Clin. 7: 91-121, 1964. 8. Femi-Pearse, D.: Experience With Diazepam in Tetanus, Br. Med. J. 2: 862-865, 1966. 9. Bell, D. S.: Dangers of Treatment of Status Epileptics With Diazepam, Br. Med. J. 1: 159-161, 1969. 10. Smith, B. T., and Masotti, R. E.: Intravenous Diazepam in the Treatment of Prolonged Seizure Activity in Neonates and Infants, Dcv. Med. Child. Neurol. 13: 630-634, 1971. 11. Greenblatt, D. J., and Koch-Weser, 1.: Adverse Reactions to Intravenous Diampam, Am. J. Med. Sci. 266: 261-266, 1973. 12. Braunstein, M. C.: Apnea With Maintenance of Consciousness Following Intravenous Diazcpam, Anesth. Analg. 58: 52-53, 1979. 13. Sherman, P. M.: Cardiac Arrest With Diazepam, I. Oral Surg. 32: 567, 1974. 14. Lutz, E. G.: Allergic Conjunctivitis Due to Diazepam, Am. J. Psychiatry 132: 548, 1975. 15. Cohen, R., Finn, H., and Steen, S. H.: Effect of Diazepam and Meperidine Alone and in Combination on Respiratory Response to Carbon Dioxide, Anesth. Analg. 48: 353-355, 1969. 16. Steen, S. H., Weitzner, S. W., and Amaha, K.: The Effect of Diazepam on the Respiratory Responseto Carbon Dioxide, Can. Anaesth. Sot. J. 13: 324-377, 1966. 17. Dalen, J. E., Evans, G. L., and Banas, J. S.: The Hemodynamics and Respiratory Effects of Diazepam (Valium), Anesthesiology 30: 259-263, 1969. 18. Lakshmimarayan, S., Sahn, S. A., Hudson, D. L., and Weil. J. V.: Effect of Diazepam on Ventilatory Responses, Clin. Phannacol. Ther. 20: 178-183, 1976. 19. Rao, S., Sherbaniuk, R. W., Prasad, K., Lee, S. J. K., and Sproule, B. J.: Cardiopulmonary effects of diazepam, Clin. Pharmacol. Ther. 14: 182-189, 1973. 20. Stewart, R. C.: Respiratory DepressionWith Diazepam: Potential Complications and Contraindications, Anesth. Progr. 25: 117-l 18, 1978. 21. Brauminger, G., and Ravin, M.: Respiratory Arrest Following Intravenous Diazepam, Ann. Ophthalmol. 6: 805-806, 1974. 22. Hall, S. C., and Ovassauian,A.: Annea After IntravenousDiazepam Therapy, J.A.M. A. 2&h 1052, 1977. 23. Berger, R., Green, G., and Melnick, A.: Cardiac Arrest Caused by Oml Diazepam Intoxication, Clin. Pediatr. 14: 842-844, 1975. 24. Flemming, D. C.: Cardiac Arrest With Diazepam, J. Oral Surg. 32: 807, 1974. 25. Larson, G. F., Hurlben, B. J., and Wingard, D. W.: Physostigmine Reversal of Diazepam induced Depression, Anesth. Analg. 56: 348-350, 1977. 26. DiLiberti, J., O’Brien, M. L., and Turner, T.: The Use of Physostigmineas an Antidote in Accidental Diazepam Intoxication, J. Pediatr. 86: 106-107, 1975. 27. Bell, E. F.: The Use of Naloxone in the Treatment of Diazepam Poisoning, J. Pediatr. 87: 803-804, 1975. Reprint requests to: Dr. David Donaldson Department of Restorative Dentistry School of Dentistry University of British Columbia Vancouver, British Columbia, Canada