Antihistamine-induced rhabdomyolysis.

Abstract: Antihistamines, which are readily available over the counter in sleeping aids, are commonly found in intentional overdoses. We report three new cases of severe rhabdomyolysis related to ingestion of these agents. This is a rarely reported but potentially overlooked complication among patients who present to the emergency center after intentional overdoses. We also describe the potential mechanism of muscle injury in antihistamine overdoses and comment on the potential for cross-reactivity of antihistamines with the urine screen for phencyclidine.

Key Words: diphenhydramine, doxylamine, histamine [H.sub.1] antagonists, rhabdomyolysis

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Antihistamines, including diphenhydramine and doxylamine, which are common components of over-the counter sleeping medicines, are often ingested in large quantities by patients attempting suicide. We present three cases in which ingestion of large amounts of diphenhydramine or doxylamine was associated with impressive rhabdomyolysis.

Discussion

Rhabdomyolysis occurs in a variety of clinical settings including direct muscle injury (crush, burns, electrical shock, freezing, prolonged immobility), muscle overuse (excessive exercise, seizures), ischemia (vascular occlusion), infection (especially viral illnesses), metabolic disorders (hypophosphatemia, hypokalemia, profound hypophosphatemia), inflammatory myopathies, toxins, and drugs (ethanol, opiates, cocaine, amphetamines, PCP, neuroleptics, barbiturates, antibiotics, azathioprine, amphotericin B). In general, any drug that increases energy requirements beyond the production of adenosine triphosphate (ATP) or impairs the production or use of ATP can potentially cause rhabdomyolysis. (1)

Doxylamine has been associated with rhabdomyolysis in 11 reported cases in the literature. (2-7) Admission CPK values in these cases have ranged from 597 to 78,750 IU/L, with a mean of 22,300 IU/L. Acute renal failure requiring hemodialysis occurred in only one of these patients. (8) Diphenhydramine overdose has been associated with rhabdomyolysis in two reported cases in the literature. (3,4)

The mechanism for rhabdomyolysis in antihistamine overdose is uncertain. Antihistamine may exert a direct toxic effect on muscle, including possibly through injury to the sarcolemma. (1) Injury to the sarcolemma would lead to leakage of intracellular contents as well as to an increase of sodium into the cell. A higher intracellular sodium concentration causes activation of the energy-dependent N[a.sup.+]/[K.sup.+] ATPase, thus depleting the cell of cellular ATP. Moreover, an increase in intracellular sodium will lead to an increase in intracellular calcium as well, thereby enhancing the activity of intracellular proteolytic enzymes. It has been suggested that by depleting the cell of ATP required for energy-dependent processes, and by activating intracellular proteolytic enzymes, the cell will undergo progressive injury. (1) The role of antihistamines in this suggested mechanism is uncertain. However, animal studies suggest that histamine can decrease the activity of intracellular sodium by directly stimulating a Na-K pump. These studies suggested that histamine can stimulate a sarcolemmal Na-K pump through the activation of both [H.sub.1] and [H.sub.2] receptors. In these experiments, the effect of histamine on intracellular sodium concentration was at least partially blocked by a combination of antihistamines (cimetidine and chlorpheniramine). (9) More studies would be required to delineate the pathophysiology of rhabdomyolysis caused by antihistamines.

Medications impairing the central nervous system, including antihistamines, can cause rhabdomyolysis by pressure-induced ischemia due to prolonged immobilization. (1) However, none of these patients had a history that suggested prolonged immobilization. Although seizures may have contributed to muscle breakdown in some of the previously reported cases, there was no history to suggest seizure activity in any of these patients.

The urine toxicology screen in one of our patients was positive for PCP, which may have contributed to the rhabdomyolysis. However, current immunoassays (immunoassays are used in drug screens at our hospital) may show false positive PCP results in the presence of diphenhydramine. At the National Institute for Drug Abuse, two specimens that screened positive for PCP by immunoassay subsequently tested negative by the more sensitive assays. (10) Interestingly, a more comprehensive screen of these samples revealed large concentrations of diphenhydramine. Experiments indicated a cross-reactivity of diphenhydramine with the immunoassays.(10 The National Academy of Clinical Biochemistry Laboratory Medicine also indicated that existing immunoassays may exhibit significant cross-reactivity toward other drugs, including diphenhydramine for PCP. (11) These findings suggest that we may be missing other cases of antihistamine induced rhabdomyolysis by erroneously identifying them as PCP-induced rhabdomyolysis.

Treatment of antihistamine-induced rhabdomyolysis initially requires recognizing the appropriate toxidrome associated with antihistamines, terminating further exposure, and reducing the further absorption of the medication. (1) The subsequent treatment for antihistamine-induced rhabdomyolysis is the same as that used for any other type of rhabdomyolysis, including aggressive volume replacement, careful monitoring of electrolytes and renal function, and hemodialysis if these conservative measures fail. The use of physostigmine, an acetylcholinesterase inhibitor, is reserved for cases of pronounced delirium unresponsive to conservative therapy, intractable/ resistant seizures, and hemodynamically compromising arrhythmias. (12) The use of this medication for the treatment of antihistamine-induced rhabdomyolysis has not been studied.

Conclusion

These three cases are reminders that antihistamines, components of readily available over-the-counter sleeping medicines, may result in dramatic rhabdomyolysis when ingested in intentional overdoses. The specific pathophysiology of antihistamine-induced rhabdomyolysis remains unclear. Cross-reactivity of diphenhydramine with illicit substances such as phencyclidine may cloud the diagnosis; however, the treatment is the same as for other causes of rhabdomyolysis. This rare but impressive potential complication should be actively investigated and vigorously treated.

Jealousy never allows reason to judge things as they really are.

Jealous people see things through an inverted looking glass

Which turns small things large, dwarves into giants, and suspicions into truths.

--Cervantes

From the Department of Internal Medicine, Baylor College of Medicine, Houston, and the Department of Family Medicine, CentroMed. San Antonio, TX.

Reprint requests to Daniel P. Hunt, MD, Section of General Internal Medicine, Ben Taub General Hospital, 1504 Taub Loop, 2RM81-001. Houston, TX 77030. Email: [e-mail]

Accepted March 24, 2003.

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9610-1023

References

1. Larbi EB. Drug-induced rhabdomyolysis. Ann Saudi Med 1998;18:525-530.

2. Frankel D, Dolgin J, Murray BM. Non-traumatic rhabdomyolysis complicating antihistamine overdose. J Toxicol Clin Toxicol 1993;31:493-496.

3. Koppel C, Ibe K, Oberdisse U. Rhabdomyolysis in doxylamine overdose. Lancet 1987;1:442-443 (letter).

4. Mendoza FS, Atiba JO, Krensky AM, et al. Rhabdomyolysis complicating doxylamine overdose. Clin Pediatr (Phila) 1987;26:595-597.

5. Soto LF, Miller CH. Ognibere AJ. Severe rhabdomyolysis after doxylamine overdose. Postgrad Med 1993;93:227-229,232.

6. Leybishkis B, Fasseas P, Ryan KF. Doxylamine overdose as a potential cause of rhabdomyolysis. Am J Med Sci 2001;322:48-49.

7. Hampel G, Horstkotte H. Rumpf KW. Myoglobinuric renal failure due to drug-induced rhabdomyolysis. Hum Toxicol 1983;2:197-203.

8. Emadian SM, Caravati EM, Herr RD. Rhabdomyolysis: A rare adverse effect of diphenhydramine overdose. Am J Emerg Med 1996;14:574-576.

9. Yang JM, Chu CH, Yang SN, et al. Effects of histamine on intracellular Na+ activity and twitch tension in guinea pig papillary muscles. Jpn J Physiol 1993;43:207-220.

10. Levine BS, Smith ML. Effects of diphenhydramine on immunoassays of phencyclidine in urine. Clin Chem 1990;36:1258 (letter).

11. Wu AH, McKay C, Broussard LA, et al. National Academy of Clinical Biochemistry Laboratory Medicine practice guidelines; Recommendations for the use of laboratory tests to support poisoned patients who present to the emergency department. Clin Chem 2003;49:357-379.

12. Roth B. Toxicity, antihistamine, eMed J 2002 Jan 18;3 (1). Available at: http://www.emedicine.com/emerg/topic38.htm. Accessed May 5, 2003.

RELATED ARTICLE: Case Reports

Patient 1

A 37-year-old man in excellent health began experiencing difficulties in his relationship with his fiancee several months before his admission to the hospital. Because of his despondency over the deteriorating relationship, he ingested 48 Unisom (doxylamine) tablets in a suicide attempt as evidenced by a suicide note. He was found by his sister later that day and was brought to the hospital by ambulance.

The patient's medical history was remarkable only for orthopedic problems sustained several years previously in athletic activity. He took no medications. He drank one glass of wine per week, and did not use tobacco or illicit drugs. There was no history of heavy exercise, muscle trauma, preceding illness, or seizure activity.

Physical examination at admission showed an alert, well-developed, muscular man in no distress. Vital signs showed a temperature of 36.2[degrees]C, a blood pressure of 134/64 mm Hg, a pulse of 88 beats/min, and a respiratory rate of 22 breaths/min. Physical examination was normal.

Laboratory evaluation showed a normal complete blood count; his sodium was 145 mEq/L, his potassium was 4.7 mEq/L, his chloride was 116 mEq/L, his carbon dioxide was 27 mEq/L, his blood urea nitrogen was 8 mg/dl, and his creatinine was 1.4 mg/dl. Liver function tests showed an aspartate aminotransferase of 145 and a lactate dehydrogenase of 898 IU/L (upper limit of normal, 172 IU/L). His creatine phosphokinase (CPK) at admission was 28,040 IU/L (upper limit of normal, 224 IU/L). Urinalysis showed trace blood but no red blood cells (RBCs) by microscopic examination. Urine drug screen was negative for cocaine, cannabis, barbiturates, phencyclidine (PCP), amphetamines, and benzodiazepines.

He was treated with IV normal saline at a rapid rate of infusion. Renal function remained stable and CPK rapidly decreased (to 9,030 IU/L 2 days after admission). He felt well throughout his hospital course. The consulting psychiatry service felt he was not an ongoing suicide risk. He was referred to a community family services unit. The second and third cases include rhabdomyolysis occurring in an intentional overdose of diphenhydramine, an even more unusual presentation.

Patient 2

The police brought to the emergency center a 29-year old man who had been arrested for public intoxication. Initially, the patient was agitated; was mumbling rapid, incoherent phrases; and was noted to have a frightened stare. He could obey some commands but did not respond appropriately to questions.

Examination revealed an agitated man. His axillary temperature was 37.6[degrees]C, his blood pressure was 144/76 mm Hg, his pulse was 131 beats/min, his respiratory rate was 20 breaths/min, and pulse oximetry showed an oxygen saturation of 96% on room air. His pupils were mydriatic (5 mm) and poorly responsive to light. He would not allow a funduscopic examination. His oral mucosa was extremely dry. Cardiac examination was remarkable only for tachycardia. His lungs were clear and his abdomen was soft and nontender, but the bowel sounds were diminished. The patient moved all extremities voluntarily and was without rigidity.

Laboratory data revealed normal hemoglobin of 15.5, but the white blood cell (WBC) count was elevated at 20,700 cells/mm[m.sup.3]. Blood chemistries revealed the following: sodium, 141 mmol/L; potassium, 3.7 mmol/L; bicarbonate, 22 mmol/L; blood urea nitrogen, 15 mg/dl; creatinine, 1.7 mg/dl; glucose, 105 mg/dl; albumin, 5.1 g/dl; total bilirubin, 0.6 mg/dl; alkaline phosphatase, 74 U/L; alanine aminotransferase, 26 IU/L; aspartate aminotransferase, 67 IU/L; and lactate dehydrogenase, 412 IU/L. His CPK was 6,690 IU/L. Urinalysis showed dark red urine with a specific gravity of 1.016, 1+protein, trace ketones, and large blood; microscopy showed 14 RBCs/high power field (HPF), 2 WBCs/HPF, few bacteria, and no casts. Serum toxicology was negative for acetaminophen and salicylates. Urine toxicology was negative for amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, PCP, and opiates.

Because of the anticholinergic findings on examination (mydriasis, dry oropharyngeal mucosa, tachycardia, and intestinal hypomotility), he was given physostigmine. A dramatic improvement in mental status occurred minutes after the administration of this agent. He responded to questions at that time and admitted that he had attempted suicide with Benadryl (diphenhydramine).

The patient's hospital course was one of gradual improvement. He was treated with vigorous IV fluid replacement and careful observation. He continued to be agitated during the first 48 hours, although this improved on the third hospital day. His CPK increased from 6,690 IU/L to 133,300 IU/L during the first day, but then steadily declined to a value of 422 IU/L by hospital Day 8. On the basis of the recommendations of the consulting psychiatry team, he was transferred to an inpatient psychiatry unit for further treatment on Day 8 of his hospital stay.

Patient 3

A 32-year-old man was found unresponsive in a hotel room with a suicide note stating that he was "tired of living," with detailed instructions for his burial. Empty Nytol (diphenhydramine) bottles were found in the room as well. On arrival in the emergency room, the patient was noted to be uncooperative and possibly hallucinating. He was not combative. He denied using any other illicit substances.

Physical examination showed a temperature 37.1[degrees]C, a blood pressure of 131/78 mm Hg, a pulse of 146 beats/min, a respiratory rate of 14 breaths/min, and oxygen saturation of 98%. There was no evidence of trauma. Pupils were dilated but reactive. The patient's lungs were clear, and cardiac examination was remarkable for regular tachycardia but no murmurs. Abdominal examination revealed hypoactive bowel sounds but was otherwise normal. Neurologic examination revealed an alert man who was poorly cooperative. Strength was judged to be equal and normal. He was mildly hyperreflexic.

Laboratory data showed the following: WBC count, 13, 900 cells/m[m.sup.3]; hemoglobin, 17.1 g/dl; and hematocrit, 50.8. Chemistries included the following: sodium, 137; potassium, 4.0; chloride, 100; bicarbonate, 21; blood urea nitrogen, 21; creatinine, 2.3; and glucose, 159. Liver function tests were normal. Urinalysis revealed a specific gravity of 1.008 and 1+ blood; microscopy showed 3 RBCs/HPF and no casts. Urine toxicology was positive for PCP and his CPK was 16,050.

With aggressive IV fluids, the patient's CPK decreased rapidly. He was transferred to an impatient psychiatric facility 3 days later.

RELATED ARTICLE: Key Points

* This report describes three cases in which intentional overdoses of doxylamine or diphenhydramine led to dramatic rhabdomyolysis, one of which also illustrates the important finding of a false-positive urine toxicology screen for phencyclidine, which may be seen in these types of overdoses.

* Antihistamines are found in a number of readily available sleeping aids sold over the counter.

* This unusual complication should be identified and aggressively treated in patients with suicide attempts using over-the-counter sleeping medicines.

Uday Khosla, MD, Kelly S. Ruel, MD, and Daniel P. Hunt, MD