Massively elevated creatine kinase levels in antihistamine-induced rhabdomyolysis

Abstract

Rhabdomyolysis is the destruction of skeletal muscle tissue with release of intracellular components into the circulation. Elevation of creatine kinase levels in serum is indicative of muscle damage and is associated with acute kidney injury. Antihistamines are a rare cause of nontraumatic rhabdomyolysis. Herein we describe a case of intentional ingestion of diphenhydramine resulting in rhabdomyolysis with subsequent elevation in creatine kinase levels exceeding 2 million IU/L. Aggressive intravenous volume expansion rapidly lowered creatine kinase levels and improved renal function.

Rhabdomyolysis is the destruction of skeletal muscle tissue characterized by the release of intracellular muscle constituents (proteins, electrolytes, myoglobin) into the circulation. It is characterized by myalgias and muscle weakness, dark urine (myoglobinuria), and elevated muscle enzymes, including creatine kinase (CK). Elevated CK levels are considered the most sensitive indicator of muscle injury in rhabdomyolysis.^1,2 Elevation of CK shows a moderate correlation with acute kidney injury (AKI) and serum creatinine values, but CK levels may not necessarily predict AKI.^3,4 Herein, we describe a case of antihistamine-induced rhabdomyolysis with massive elevation of CK levels.

CASE DESCRIPTION

A 43-year-old man was brought to the emergency department with acute alteration in mental status following intentional drug overdose. He was found in the presence of two empty bottles of diphenhydramine (each with a capacity of 30 tablets). On arrival, he was stuporous and confused. His temperature was 99.9°F; blood pressure, 140/112 mm Hg; heart rate, 140 beats/min; respiratory rate, 38 breaths/min; and oxygen saturation, 98% in ambient air. Examination disclosed bilateral mydriasis, dry mucus membranes, flushed skin, and decreased bowel sounds. A Foley catheter was placed and a minimal amount of dark brown urine was noted in the collecting bag. His initial laboratory studies were notable for a white blood cell count of 18,700 cells/mm³ and elevations in creatinine (1.5 mg/dL), aspartate aminotransferase (1287 IU/L), alanine aminotransferase (173 IU/L), lactic acid (2.3 mg/dL), and troponin T (0.41). A metabolic panel demonstrated a sodium level of 134 mmol/L, potassium of 5.1 mmol/L, bicarbonate level of 15 mmol/L, anion gap of 16, calcium level of 7.8 mg/dL, and uric acid level of 10.7 mg/dL. A urine dipstick was positive for blood, and supernatant was heme-negative after centrifugation, indicating myoglobinuria. Urinalysis was negative for red and white blood cells. The urine drug screen was negative for amphetamines, benzodiazepines, cocaine, cannabinoids, phencyclidine, and opioids. His serum CK level was significantly elevated at 2,000,760 IU/L.

Given the above clinical findings suggestive of acute anticholinergic toxicity, severe rhabdomyolysis, and AKI, the patient was admitted to the intensive care unit for further management. He was started on aggressive intravenous volume expansion and a safety companion was stationed in his room. Over the next 36 hours, he received 6 L of intravenous crystalloid (normal saline). His urine output improved from 30 cc/h at presentation to 100 cc/h after 24 hours. The CK levels showed a dramatic decrease over the next 24 hours, with an exponential fall to 215,318 IU/L (Figure 1). An accompanying improvement in his mental status was also noted, with return to baseline mentation within 24 hours of initiation of treatment. On day 4 of admission, his CK level had improved to 25,589 IU/L. Renal function also showed improvement with consistent robust urine output (100 cc/h) and improvement in azotemia and electrolyte abnormalities (Table 1). Clinical signs of anticholinergic toxicity had resolved. He did not undergo hemodialysis. He was subsequently transferred to the inpatient psychiatric unit for the management of his depression.

Figure 1.

Trend of creatine kinase levels during hospitalization.

Table 1.

Laboratory results by day of hospitalization

Variable	Day 0	Day 1	Day 2	Day 3	Day 4	Day 5
Sodium (mmol/L)	140	143	141	139	138	142
Potassium (mmol/L)	4.7	5.0	4.7	4.3	3.8	3.4
Bicarbonate (mmol/L)	21	15	17	19	18	20
Calcium (mg/dL)	7.8	6.8	7.3	7.9	7.8	7.9
Phosphorus (mg/dL)	4.5	4.3	3.5	3.8	2.9	3.3
Magnesium (mg/dL)	2.9	2.7	2.2	1.9	1.7	1.6
Creatinine (mg/dL)	1.50	1.67	1.89	1.74	1.56	1.45
Blood urea nitrogen (mg/dL)	20	22	26	27	24	21

DISCUSSION

The etiology of rhabdomyolysis can be broadly categorized into traumatic and nontraumatic causes (Table 2). Drugs and toxins are a significant contributor to the incidence of nontraumatic rhabdomyolysis.² Diphenhydramine and other antihistamines are among the most commonly available over-the-counter sleep aids in the United States. A number of cases of rhabdomyolysis induced by antihistamines have been reported.^5–10 Both doxylamine^5,6 and diphenhydramine^7–9 have been implicated in these cases. It is postulated that antihistamines alter sarcolemmal permeability, causing leakage of intracellular contents and impairment of Na-K ATPase pumps and ATP-dependent calcium channels, causing intracellular calcium accumulation. These mechanisms result in excessive myofibril contraction and impairment of energy-dependent processes leading to myocyte injury and death.^1,7

Table 2.

Differential diagnosis of rhabdomyolysis

Category	Diagnosis
Trauma	Compartment syndrome, crush injury
Muscle ischemia	Arterial thrombosis/embolism, intraoperative clamping of feeding vessel, shock states
Drugs and toxins	Alcohol, statins, heroin, cocaine, phencyclidine, antipsychotics, antihistamines, antidepressants, corticosteroids, antibiotics, chemotherapy, snake venom, heavy metals
Electrolyte abnormalities	Hypokalemia, hypophosphatemia, hypocalcemia
Infection	Coxsackie virus, Clostridium sp., Staphylococcus aureus, Streptococcus pyogenes, influenza
Temperature  dysregulation	Heatstroke, malignant hyperthermia, malignant neuroleptic syndrome
Metabolic	Carnitine deficiency, McArdle disease, phosphofructokinase deficiency, mitochondrial respiratory chain enzyme deficiency
Autoimmune	Polymyositis, dermatomyositis

Although dramatic rises in CK levels were noted in many reported cases, none were above 100,000 IU/L in adults. We were able to find only one other reported case of rhabdomyolysis in which CK levels were in the seven figures—a case of pediatric viral myositis with a documented CK level of 1.7 million U/L.¹⁰ In the case described above, the CK level at presentation was approximately 2 million IU/L. It is important to note that this level was obtained after serial dilution of the original specimen in order to get the analyte (i.e., CK) within range of the laboratory assay, which is then used to recalculate the original concentration. This provides quantitation at very high serum levels of analyte, but it does introduce an error if there are small inaccuracies in the dilution process. Despite this, it is unlikely that calculation error alone could have resulted in a CK level that high. The patient did not have any other risk factors that could have contributed to the development of rhabdomyolysis, such as consumption of alcohol or drugs, trauma or muscle injury, or seizures. With aggressive intravenous volume expansion and concomitant improvement in renal function and urine output, there was a dramatic decline in serum CK level.

This case illustrates findings that suggest the serum CK level does have loose correlation with AKI, but is not necessarily a strong predictor for the incidence or severity of AKI. Our patient showed significant improvement in renal function within 4 days and did not require dialysis. Clinicians must maintain a low threshold to suspect rhabdomyolysis in any case of AKI in the setting of antihistamine toxicity or overdose. Aggressive and early intravenous volume expansion is an essential component of treatment and can improve clinical (especially renal) outcomes.