Fatal diphenhydramine poisoning with increased vascular permeability including late pulmonary congestion refractory to percutaneous cardiovascular support

Abstract

Background. Fatal adult cases of acute diphenhydramine poisoning are extremely rare. Case Report. Transiently awakened by a roommate, a 39-year-old man admitted to massive ingestion of an over-the-counter drug containing diphenhydramine salicylate. On admission the patient was semicomatose and developed circulatory collapse with severe dehydration and metabolic acidosis, followed by status epilepticus. Despite extensive life support measures including percutaneous cardiopulmonary support, vascular permeability progressively increased, with pulmonary congestion as well as peripheral vasodilation evident as rubedo. The patient died without improvement of cardiac function. Subsequent diphenhydramine assays in serum specimens obtained at the time of delayed congestive symptoms indicated decreases in drug concentration to a sublethal amount. Discussion. We suspect that metabolites of diphenhydramine with histamine-agonist actions contributed to the development of fatal delayed symptoms.

Keywords:

• Diphenhydramine
• Pulmonary congestion
• Rubedo
• Percutaneous cardiopulmonary support

Background

Diphenhydramine is an ethanolamine derivative acting as a histamine H₁-receptor antagonist. As diphenhydramine also has sedative and anticholinergic properties, it is used widely in numerous over-the-counter preparations. Accordingly, diphenhydramine overdosage is rather common, although the drug is considered relatively nontoxic. While a few fatal pediatric cases of acute poisoning have occurred (1–3), fatal adult cases have been extremely rare (4,5). In the present report we describe an adult with lethal massive ingestion of diphenhydramine causing circulatory derangements refractory to intensive supportive care including percutaneous cardiopulmonary support (PCPS).

Case report

A 39-year-old man with no significant previous medical history was found in a lethargic state at 2:10 AM. Transiently awakened by a roommate, he admitted to massive ingestion of an over-the-counter product marketed as an antiemetic that was found to contain 40 mg of diphenhydramine salicylate per tablet. The number of tablets and time of ingestion were not given, and ingestion of other drugs was denied. He became unresponsive and was transported to the emergency center.

On arrival at 3:13 AM, the patient partially opened his eyes, groaned, rigidly retroflexed the neck, and slowly moved the extremities, but could not communicate. The skin was dry, and muscle tone was elevated in the extremities. The eyes were fixed in upward gaze, both pupils were 4.5 mm in diameter and sluggishly reactive to light. Body temperature was 36.5°C; blood pressure, 83/40 mm Hg; heart rate, 150 beats/min; and respiration rate, 30/min. Analysis of arterial blood gases (ABGs) sampled with the patient breathing room air showed pH, 7.310; PO₂, 54.1 Torr; PCO₂, 16.7 Torr; HCO₃^-, 8.2 mmol/L; and base deficit, 15.2 mmol/L. A complete blood count disclosed a white blood cell (WBC) count of 10,900/mm³; hemoglobin, 17.1 g/dL; and a platelet count of 285 000/mm³. Serum chemistry screening demonstrated a total protein of 8.8 g/dL; total bilirubin, 0.9 mg/dL; aspartate aminotransferase, 180 IU/L; alanine aminotransferase, 24 IU/L; lactate dehydrogenase, 419 IU/L; creatinine kinase, 12496 IU/L: blood urea nitrogen, 30 mg/dL; creatine, 1.0 mg/dL; Na, 145 mEq/L; K, 4.6 mEq/L; Cl, 101 mEq/L; and lactic acid, 186.9 mg/dL. The anion gap was calculated as 35.8 mEq/L. Roentgenograms of the chest and abdomen were unremarkable. The electrocardiogram demonstrated sinus tachycardia, and an echocardiogram showed diffusely and severely hypokinetic wall motion in the left ventricle as well as collapse of inferior vena cava. No gastric contents could be aspirated through an 18-Fr nasogastric tube before enteric administration of 1 g/kg of activated charcoal. A urine toxicology screen was negative (Triage DOA, Biosite Diagnostics, San Diego, CA).

A diagnosis of circulatory collapse with severe dehydration and metabolic acidosis induced by diphenhydramine toxicity was made. In response to initial intravenous infusion of lactated Ringer's solution (1000 mL) and 60 mEq (1 mEq/kg) of sodium bicarbonate over the first 10 min, blood pressure rose to 124/72 mm Hg. However, metabolic acidosis worsened. ABGs at 3:30 AM sampled with the patient breathing 5 L/min of oxygen by face mask showed pH, 7.214; PO₂, 134.3 Torr; PCO₂, 14.5 Torr; HCO₃^-, 5.7 mmol/L; and base deficit, 19.4 mmol/L. Repeated intravenous administration of 60-mEq doses of sodium bicarbonate was necessary to maintain pH above 7.20. At 4:20 AM the patient was admitted to the intensive care unit.

At 4:50 AM the patient developed status epilepticus; 10 mg of diazepam was injected intravenously followed by continuous infusion of midazolam at the rate of 3 to 8 mg/h. At 5:20 AM systolic blood pressure fell below 60 mm Hg. Mechanical ventilatory assistance was given after endotracheal intubation. Intravenous infusion of catecholamines was initiated in addition to volume rescucitation. At 6:50 AM, systolic blood pressure decreased further to less than 40 mm Hg despite intravenous infusion of dopamine (20 μg/kg/min) and norepinephrine (1 μg/kg/min). ABG values with an inspired oxygen fraction (FIO₂) of 1.0 were pH, 7.148; PO₂, 411.7 Torr; PCO₂, 22.9 Torr; HCO₃^-, 7.8 mmol/L; and base deficit, 19.3 mmol/L. At 7:00 AM PCPS was initiated with a blood flow of 3.0 L/min. Immediately after initiation of PCPS, tachycardia with widened QRS complex was noted on the electrocardiogram. Soon afterward, the QRS complex gradually narrowed as metabolic acidosis decreased without additional administration of sodium bicarbonate. ABG values at 7:25 AM were pH, 7.326; PCO₂, 39.2 Torr; HCO₃^-, 20.0 mmol/L; and base deficit, 5.5 mmol/L.

After 9 AM, blood flow in PCPS became difficult to maintain, presumably because of hypovolemia despite massive infusion of fluids and albumin as well as transfusions. At this time, rubedo, which transiently blanched upon finger compression, was conspicuous over the upper half of the body. The patient gradually became edematous, and foamy sputum began to appear. A chest roentgenogram showed a diffuse infiltrate. Metabolic acidosis worsened again. ABG analysis at 9:23 AM showed pH, 7.197; PCO₂, 52.6 Torr; HCO₃^-, 17.6 mmol/L; and base deficit, 8.2 mmol/L. At 9:30 AM continuous hemodiafiltration (CHDF) was initiated, primarily for renal support including maintenance of acid-base balance. A repeat echocardiogram at 2:00 PM demonstrated no improvement of left ventricular wall motion. Chest roentgenogram showed diffuse, severe pulmonary edema, and ABG values were pH, 6.982; PCO₂, 63.1 Torr; HCO₃^-, 11.6 mmol/L; and base deficit, 16.3 mmol/L. The patient died at 5: 20 PM.

Toxicologic analysis

Concentrations of diphenhydramine in sera stored at –40°C later were determined by high-performance liquid chromatography. Serum diphenhydramine concentrations on admission, at initiation of PCPS, and at initiation of CHDF were 0.652 μg/mL, 0.148 μg/mL, and 0.092 μg/mL, respectively. The limit of detectability by this method was 0.001 μg/mL. Concentrations of salicylate in the same sera also were determined by high-performance liquid chromatography. All serum salicylate concentrations were less than the detectability limit with this method (0.5 μg/mL).

Autopsy findings in the respiratory tract

An autopsy was performed 16 hr postmortem. Tracheal and bronchial lumina contained serosanguinous liquid. The lungs demonstrated extraordinarily severe vascular congestion, associated with increased weight (right, 1525 g; left, 1435 g). Other organs demonstrated no remarkable findings except for mild to moderate congestion.

Discussion

Diphenhydramine, first described pharmacologically in 1945, is an antihistaminic drug with additional anticholinergic and sedative effects. In Japan, diphenhydramine-containing preparations are marketed without prescription as hypnotics and antiemetics. Both absorption and tissue distribution of diphenhydramine are rapid, so diphenhydramine is cleared rapidly from serum after peak serum concentrations occur 2 hr from ingestion (6). Half-life, distribution volume, and protein binding of diphenhydramine in adults are 3 to 14 hr, 3 to 4 L/kg, and 98%, respectively. Diphenhydramine is believed to undergo extensive oxidative metabolic transformation in the liver to nor- and dinordiphenhydramine, and to diphenylmethoxyacetic acid (Fig. 1). The latter metabolite is a product of deamination and most likely is excreted as a glycine or glutamine conjugate (7).

Fig 1.  Chemical structures of histamine and metabolites of diphenhydramine.

In overdosage, anticholinergic and sedative effects of diphenhydramine often are prominent. Central nervous system symptoms depend on age. Children and young adults, who are remarkably susceptible to the anticholinergic effect, often present with central nervous system stimulation manifested by excitement, tremors, hyperactivity, hallucinations, hyperpyrexia, and tonic-clonic seizures. On the other hand, adults, who are usually more susceptible to the sedative effect, often present with central nervous system depression leading to coma, and rarely have seizures. Cardiovascular derangements including hypertension, hypotension, tachycardia, ventricular arrhythmia, and metabolic acidosis also have been reported.

Fatal clinical cases of acute diphenhydramine poisoning including the present one are summarized in Table 1. A few have involved children and teenagers. Krenzelok et al. (1) reported a 14-year-old girl in whom partial cardiopulmonary bypass was initiated because hemodynamics could not be maintained by conventional methods. Finally blood pressure could be maintained with dopamine alone, but the patient was declared brain dead. Goetz et al. (2) reported a 15-month-old boy in whom generalized seizures continued despite conventional therapy, and a chest roentgenogram showed pulmonary edema, and a serosanguinous discharge was obtained from the endotracheal tube. Although seizure activity finally was controlled by a continuous thiopental infusion, this patient also eventually was declared brain dead. Lindsay et al. (3) reported a 34-month-old girl whose generalized seizures were controlled by diazepam, lorazepam, and phenobarbital, but diffuse infiltrates in the chest roentgenogram as well as generalized edema gradually progressed to acute respiratory distress syndrome, resulting in death. On the other hand, reports of fatal cases in adults have been extremely rare. Hausmann et al. (4) reported a 28-year-old man who died from sudden cardiac arrest. In this patient hemorrhagic pulmonary edema developed 2 days after ingestion. On postmortem examination the main finding was hemorrhagic pulmonary edema, and the highest concentrations of diphenhydramine were found in lung and kidney. Koppel et al. (5) reported a 30-year-old woman found with a rectal temperature of 16^oC less than 24 hr after ingestion of an unknown quantity of diphenhydramine; she died without responding to any conventional support, showing massive interstitial and intraalveolar pulmonary edema.

Table 1.  Fatal clinical cases of acute diphenhydramine poisoning

Age	Gender	Concentration (Time from intake)	Main symptoms	Treatments	Reference
14 yr.	F		cardiogenic shock, generalizdseizure, metabolic acidosis	partial cardiopulmonarybypass	Krenzelok et al.
15 mo.	M	10 μg/mL (3 hr)	generalized seizure, pulmonryedema	continuous thiopentalinfusion	Goetz et al.
34 mo.	F	12.8 μg/mL (1–2 hr)	generalized seizure, metabolicacidosis, cardiogenic shock, ARDS		Lindsay et al.
28 yr.	F	5 μg/mL (?)	hyperpyrexia, tachycardia,pulmonary edema		Hausmann et al.
30 yr.	F	4.7 μg/mL (?)	hypothermia, pulmonary edema	hemodialysis,hemoperfusion	Koppel et al.
39 yr.	M	0.7 μg/mL (?)	cardiogenic shock, metabolicacidosis, pulmonary edema	partial cardiopulmonarybypass	Present case

yr., years old; mo., months old; F, female; M, male; ARDS, acute respiratory distress syndrome.

In the forensic medical literature, Baker et al. (8) reported postmortem findings in five diphenhydramine-related deaths in children (6, 8, 9, 12, and 12 weeks old). Serum concentrations of diphenhydramine were 1.6, 1.5, 1.6, 1.1, and 1.1 μg/mL, respectively. However, anatomic findings in each case were normal. Karch (9) reported postmortem findings of four diphenhydramine-related deaths in adults 18, 35, 49, and 57 years old. Serum concentrations of diphenhydramine were 14.7 to 35.0 35.0 μg/mL, while significant pulmonary edema and visceral congestion were observed in all four cases. Backer et al. (10) reported autopsy findings after suicidal diphenhydramine ingestion by a 37-year-old man; the serum concentration of diphenhydramine was 31.0 μg/mL, and lungs weighed 1600 mg, showing marked congestion.

In the present case, ingestion of a diphenhydramine-containing drug was confirmed by toxicologic analysis. In addition, clinical manifestations including coma, status epilepticus, cardiogenic shock, metabolic acidosis, and pulmonary edema were compatible to those reported in the fatal cases of acute diphenhydramine poisoning. However, the serum diphenhydramine concentration on admission was lower than in other fatal cases. Koppel et al. (5) evaluated a total of 136 cases of diphenhydramine poisoning, reporting that plasma diphenhydramine concentrations showed a wide range (0.1 to 4.7 μg/mL) and did not correlate with symptom severity. They explained the lack of association in terms of differences in time between ingestion and hospital admission as well as ingested dose. In the present case, time and dose of ingestion were not known. Considering the rapidly decreasing serum diphenhydramine concentrations after admission, the patient may have arrived at the hospital many hours after ingestion of the drug, after experiencing undocumented plasma diphenhydramine excesses far higher than those on admission.

Most reported fatal cases had pulmonary edema (2–5). Marked pulmonary congestion was a shared finding in all adult subjects in forensic case reports (9,10), but was not prominent in pediatric subjects in a forensic report (8). Pulmonary congestion appears to be among the most important causes of death in adults, with status epilepticus being the more important cause of death in children. The mechanism of development of pulmonary edema in these cases is not clear, although it may be related to the peak tissue diphenhydramine concentration attained in the lung (4). In the present case, pulmonary edema and rubedo developed simultaneously, showing a time lag behind other serious symptoms including cardiogenic shock and metabolic acidosis; further, plasma diphenhydramine concentrations already had decreased below the lethal level. These delayed events suggest increased vascular permeability and vasodilation, which would appear to contradict the known action of diphenhydramine as a histamine H₁-receptor antagonist; rather, they are similar to the actions of histamine itself. Lindsay et al. (3) postulated that massive blockade of histamine H₁- receptors would leave H₂-receptors free for stimulation by massively released histamine, resulting in increased vascular permeability as well as vasodilation unopposed by the H₁ antagonist effect. However, this hypothesis cannot adequately explain the delay in appearance of congestive pulmonary symptoms in the present case, which also was prominent in other reports of fatal cases. Pulmonary edema developed 2 days after ingestion in the case reported by Lindsay et al. (3), and decompensated on day 2 in the case reported by Hausmann et al. (4). As shown in Figure 1, dinordiphenhydramine, one of the metabolites of diphenhydramine, is chemically similar to histamine. We suspect that metabolites of diphenhydramine with the action of histamine agonist may contribute to the delayed development of the symptoms.

Travelmin (Eisai, Tokyo, Japan), the over-the-counter product massively ingested by the patient, contains 40 mg of diphenhydramine salicylate per tablet. The product is very popular as an antiemetic in Japan, although there as elsewhere diphenhydramine hydrochloride is the most commonly used form of diphenhydramine. Calculating from the ratio of molecular weights of diphenhydramine and salicylate, the product contains about 14 mg of salicylate per tablet. In contrast, over-the-counter products marketed in Japan with salicylate as the main ingredient usually contain 81 to 600 mg of salicylate per tablet. All serum salicylate concentrations were less than the limit of detectability (0.5 μg/mL). The result is consistent with concentrations of diphenhydramine found in the same sera (0.652 to 0.092 μg/mL). Considering that clinically significant serum concentrations of salicylate are over 10 μg/mL, salicylate appears unlikely to have contributed to the symptoms of the patient.

Rhabdomyolysis with highly elevated creatine kinase concentrations also developed in the present case. Rhabdomyolysis has been reported previously following diphenhydramine overdose (11,12). Although a direct toxic effect of diphenhydramine on myocytes has been proposed, the exact mechanism remains unclear.