Failure of naloxone to reverse brimonidine-induced coma in an infant

Abstract

I read with interest the case reported by Berlin et al1Berlin RJ Lee UT Samples JR Rich LF Tang-Liu DD Sing KA et al.Opthalmic drops causing coma in an infant.J Pediatr. 2001; 138: 441-443Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar of brimonidine-induced coma reversed by naloxone in an infant. I would like to describe a 6-week-old girl in which a large naloxone dose failed to reverse similar effects induced by brimonidine. A previously healthy 50-day-old infant was admitted to the pediatric intensive care unit after an inadvertent accidental oral administration of 4 drops of 0.2% brimonidine tartrate ophthalmic solution (Alphagan; Allergan, Irvine, Calif).The solution was given by the child's grandmother, who mistook it for the antispasmodic the child had been taking. Twenty minutes after the administration, the infant became progressively more lethargic, floppy, and pale, and she was transported to the pediatric intensive care unit. Physical examination on admission revealed a well-nourished infant weighing 5450 g who was markedly hypotonic, hypothermic (35.5°C), and comatose. The heart rate was 120 beats/minute and blood pressure was 90/50 mm Hg. The breathing pattern was irregular with hypoventilation and deep sighing. Downward and binasal eye deviation was noted and the pupils were small but reactive to light stimulus. After toxicologic consultation, naloxone hydrochloride was given (intravenously) in 2 doses for a total of 0.8 mg (0.15 mg/kg) with no effect on pupil size, level of consciousness, or respiratory pattern. Because the blood gas analysis was normal, it was decided that intubation was unnecessary. Respiratory and hemodynamic conditions were closely monitored and the symptoms spontaneously resolved within 12 hours without further therapeutic interventions. During this period, the heart rate ranged between 120 and 140 beats/minute, and the blood pressure remained within the normal limits for the infant's age. She was discharged 20 hours after admission without any sequelae. The rationale for the use of naloxone to reverse the toxic effects of brimonidine is based on the structural similarity between this drug and clonidine, from which it is derived, and the existence of anecdotal reports of successful reversal of the toxic effects associated with the latter. To date, there are few reports of brimonidine intoxication in children and, in all of these cases, complete recovery was observed within several hours after administration of the drug, generally requiring no specific therapy beyond good supportive measures.2Korsch E Grote A Seybold M Soditt V Systemic adverse effects of topical treatment with brimonidine in an infant with secondary glaucoma.Eur J Pediatr. 1999; 158: 685Crossref PubMed Google Scholar, 3Carlsen JO Zabriskie NA Kwon YH Barbe ME Scott WE Apparent central nervous system depression in infants after the use of topical brimonidine.Am J Ophtalmol. 1999; 128: 255-256Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar The patient described by Berlin et al,1Berlin RJ Lee UT Samples JR Rich LF Tang-Liu DD Sing KA et al.Opthalmic drops causing coma in an infant.J Pediatr. 2001; 138: 441-443Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar in spite of the elevated brimonidine concentrations in plasma samples, completely awakened 3 to 9 hours after each coma episode, which suggests that it had been a mild intoxication. The well-described course of imidazoline toxicity typically has a cyclic nature and, in mild intoxications, even minimal stimulation of these infants could induce a dramatic improvement in vital signs and level of consciousness.4Banner W Lund ME Clawson L Failure of naloxone to reverse clonidine toxic effect.Arch Pediatr Adolesc Med. 1983; 137: 1170-1171Crossref Scopus (44) Google Scholar, 5Tenembeim M Naloxone in clonidine toxicicity.Arch Pediatr Adolesc Med. 1984; 138: 1084-1085Crossref Scopus (22) Google Scholar On this basis, the oscillatory level of consciousness described in this case could have been only the natural expected course of this intoxication in which a cause-and-effect relationship of therapy would be difficult to establish. Our patient received 2 large doses of naloxone and the mild alterations in vital signs she had during hospitalization were not associated with this therapy. The failure of naloxone to reverse the toxic effects associated with clonidine was previously reported by Banner et al,4Banner W Lund ME Clawson L Failure of naloxone to reverse clonidine toxic effect.Arch Pediatr Adolesc Med. 1983; 137: 1170-1171Crossref Scopus (44) Google Scholar, 5Tenembeim M Naloxone in clonidine toxicicity.Arch Pediatr Adolesc Med. 1984; 138: 1084-1085Crossref Scopus (22) Google Scholar who described 1 (of 5) continuously monitored patient who also had episodes of a raised level of consciousness associated with increased heart and respiratory rates. These were not associated with the naloxone infusion. In conclusion, I believe that the lack of convincing evidence of naloxone efficacy, in association with the usually benign course of brimonidine intoxication, should discourage its use until more compelling documentation becomes available.