Article, Neurology

Cardiac conduction disturbances after an overdose of nefazodone and gabapentin

to Epstein-Barr virus, HSV-1, HSV-2, and other Viral etiologies [3-5]. There are multiple other etiologies to be considered for Aseptic meningitis, such as autoimmune disease and structural central nervous system abnormalities such as intracranial epidermoid tumors. However, most are accompanied by symptoms in other organs.

As of 2002, approximately 50 cases of recurrent HSV meningitis had been described in the United States and Europe, with most cases being caused by HSV-2 [6]. Women are more frequently affected compared with men with regards to the reported cases of HSV-2 Mollaret meningitis, and the attacks are not associated with a concurrent outbreak of genital herpes. Therefore, the etiology of the infection may escape detection.

Treatment for recurrent HSV-2 meningitis includes supportive care in addition to intravenous acyclovir [7]. With knowledge of this disease and proper screening of susceptible patients, emergency physicians will be able to more accurately diagnose and treat recurrent meningitis secondary to HSV-2.

Katrina Kardos MD Mara McErlean MD

conduction disturbances after an”>Department of Emergency Medicine

Albany Medical College Albany, NY 12208, USA

doi:10.1016/j.ajem.2006.03.010

References

  1. http://www.cdc.gov/std/Herpes/STDFact-Herpes.htm#common.
  2. Mollaret P. La meningite endothelio-leucocytaire multicurrente benigne: syndrome nouveau ou maladie nouvelle? Rev Neurol (Paris) 1944;76:57 – 76.
  3. Graman PS. Mollaret’s meningitis associated with acute Epstein Barr virus mononucleosis. Arch Neurol 1987;44:1204 – 5.
  4. Steel JG, Dix RD, Baringer JR. Isolation of herpes simplex virus type 1 in recurrent (Mollaret) meningitis. Ann Neurol 1982;11:17 – 21.
  5. Cohen BA, Rowley AH, Long CM. Herpes simplex type 2 in a patient with Mollaret’s meningitis: demonstration by polymerase chain reaction. Ann Neurol 1994;35:112 – 6.
  6. Kojima Y, Hashiguchi H, Hashimoto T, et al. Recurrent herpes simplex virus type 2 meningitis: a case report of Mollaret’s meningitis. Jpn J Infect Dis 2002;55:85 – 8.
  7. Tyler KL. Herpes simplex virus infections of the central nervous system: encephalitis, meningitis, including Mollaret’s. Herpes 2004;11 Suppl 2:57A- 64A.

Cardiac conduction disturbances after an overdose of nefazodone and gabapentin

Conduction disturbances, including QRS widening and QTc prolongation, can be an adverse event or a toxic complication of many antidepressant and antipsychotic medications [1,2]. This case report describes a self-induced poisoning in which a wide-complex tachycardia developed

after an overdose of nefazodone and gabapentin. The dysrhythmia quickly resolved after intravenous bicarbonate therapy. A literature search of PubMed, BioSYS, and Medline for gabapentin or nefazodone did not uncover reports of this pattern of cardiac conduction disturbances after exposure to these drugs; we therefore present this scenario to suggest novel clinical implications in the management of psychotropic drug toxicity.

A 44-year-old woman arrived at the ED approximately

50 minutes after a multiple drug overdose. Medications available to the patient included nefazodone, gabapentin, carvedilol, rabeprazole, digoxin, and quinapril. The patient eventually provided the history that all she ingested was gabapentin and nefazodone. Her prehospital blood pressure was 90/48 mm Hg but increased to 110/59 mm Hg after a bolus of 200 mL of normal saline solution. Her pulse rate was 80 beats/min, and her respiratory rate was 16 beats/min. Electrolytes and complete blood count were all within normal limits. The serum ethanol level was 231 mg/dL, and the digoxin level was 0.7 ng/mL. A urine drug screen by immunoassay was positive for ethanol and cannabinoids.

An electrocardiogram recorded approximately 85 minutes postingestion demonstrated normal sinus rhythm with normal intervals. One hour later, the QRS duration was

148 milliseconds and the QTc interval was 490 milli- seconds, having increased from 86 and 405 milliseconds, respectively. The patient was treated with one 50-mEq ampoule of sodium bicarbonate, intravenously, followed by continuous intravenous infusion of D5W containing 3 ampoules of sodium bicarbonate and 40 mEq of KCl per liter. Another electrocardiogram was obtained 40 minutes later, which, apart from a sinus tachycardia of 105 beats/ min, was again normal with a QRS duration of 94 milli- seconds and a QTc interval of 436 milliseconds.

Despite a period of lethargy and depressed mental status that followed the said events, lasting from approximately

4 to 13 hours after the ingestion, the patient never lost consciousness and recovered with no other symptom or sequela. Serial electrocardiograms showed no further abnormality, with one obtained 15 hours postingestion yielding a QRS duration of 90 milliseconds and a QTc of 399 milliseconds. Upon questioning, the patient claimed to have taken large but uncertain quantities of both nefazodone and gabapentin. She denied ingesting any of the other medications believed to be available to her. Repeated digo- xin levels never exceeded 0.8 ng/mL. High performance liquid chromatography (HPLC) analysis of the patient’s urine revealed ethanol and trace benzodiazepines but no cannabinoid. A rigorous comprehensive drug screen of both serum and urine with confirmation by gas chromatography– mass spectrometry was positive only for ethanol, nicotine, and trace benzodiazepines. Quantitative assays were per- formed for the presence of nefazodone and gabapentin; tests were not available for quantitation of carvedilol, rabepra- zole, and quinapril serum levels, but qualitative testing did

not detect the presence of these compounds. Specific assays performed on samples obtained 2 hours postingestion revealed therapeutic serum levels of both nefazodone (0.1 lg/mL; therapeutic range = 0.08-3.9 lg/mL) and gabapentin (7 lg/mL; peak range after therapeutic dosing = 2.7-8.5 lg/mL). It was 30 minutes after the blood collections corresponding to these results that the patient’s cardiac conduction disturbances were appreciated on electrocardio- gram. Therefore, it is possible that the levels of either or both agents increased in the interim as a consequence of continued drug absorption.

Although we cannot be entirely certain that the patient did not ingest other medications besides the nefazodone and gabapentin, we believe that her electrocardiographic changes may have resulted from toxic effects of one or both of these drugs on the myocardium. Their interaction with digoxin or carvedilol is a possibility as well. However, we found no report in the literature to suggest adverse Cardiac effects occurring when either of these drugs is taken concomitantly with nefazodone and gabapentin. Overdose of b-adrenergic receptor antagonists alone is associated with widening of the QRS complex [3], although the QTc is generally shortened, if affected at all, not prolonged as it was in this case [4-6]. A study on the pharmacodynamics of interaction between nefazodone and digoxin revealed no impact on the QRS or QTc interval by either drug alone or in combination [7]. However, a case report suggesting QTc prolongation resulting from therapeutic dosing of nefazo- done was recently published [8]. Although in that instance, details of the patient’s baseline Cardiac electrophysiology before initiation of nefazodone treatment and the timing of drug initiation in relation to the emergence of Torsade de pointes were not reported, the authors uncovered no other likely etiology for the observed Repolarization abnormalities. No widening of the QRS complex was noted, in contrast to our case, which raises the possibility of more profound cardiotoxicity as a result of one or both of the Psychotropic medications ingested.

The patient’s clinical course is consistent with an overdose of nefazodone and gabapentin. Her symptoms of drowsiness, tachycardia, and hypotension are well- recognized manifestations of gabapentin toxicity [9]. Dizziness and ataxia are also common side effects [10] that the patient experienced before emergency medical services intervened and transported her to the hospital. Drowsiness, dizziness, and the potentially more serious problem of hypotension are also consistent with a toxic ingestion of nefazodone [11,12]. The a-adrenergic block- ade induced by nefazodone can produce a fall in blood pressure, which, as in this case, is usually responsive to resuscitation with intravenous fluids without the need for more aggressive management [12]. Based on this patient’s ingestion history, clinical presentation, and laboratory data, we believe that overdoses of nefazodone and gabapentin were primarily responsible for the patho- physiologic course described. Therefore, despite the

potential complexity of this patient’s pharmacologic pic- ture, we present this case so that other physicians would also monitor patients for electrocardiographic changes after nefazodone and/or gabapentin ingestion. Furthermore, this potentially toxic interaction in overdose may be worthy of consideration in the psychiatric management of patients with a propensity for self-harm. Both medications have heretofore been deemed relatively safe in even large ingestions, with case reports and reviews suggesting that they are quite benign [13,14]. In fact, one retrospective study on antidepressant overdoses indicated that nefazo- done has a more favorable safety profile than the Selective serotonin reuptake inhibitors with no comparatively signif- icant difference in QRS or QTc interval [15]. The cardiotoxicity seen in this case and in the case described by Siddiqui and Khan [8] may therefore indicate the presence of uncommon but potentially serious underlying physiologic diatheses. It may be reasonable to consider screening electrocardiography in the management of patients taking nefazodone, either alone or in combination with gabapentin, even at Therapeutic doses.

Joseph J. Rasimas MD, PhD

Department of Psychiatry and Psychology

Mayo Clinic Rochester, MN 55905, USA

E-mail address: [email protected]

Keith K. Burkhart MD, FACEP

Penn State College of Medicine

Hershey, PA, USA

doi:10.1016/j.ajem.2006.03.011

References

  1. Crane GE. Cardiac toxicity and psychotropic drugs. Dis Nerv Syst 1970;31(8):534 – 9.
  2. Lathers CM, Lipka LJ. Cardiac arrhythmia, sudden death, and psychoactive agents. J Clin Pharmacol 1987;27(1):1 – 14.
  3. Joye F. Beta-blocker intoxication. Presse Med 2000;29(18):1027 – 33.
  4. Yildirir A, Sade E, Tokgozoglu L, et al. The effects of chronic carvedilol therapy on QT dispersion in patients with congestive heart failure. Eur J Heart Fail 2001;3(6):717 – 21.
  5. Fesmire SI, Marcoux LG, Lyyski DS, et al. Effect of selective versus nonselective beta blockade on QT dispersion in patients with non- ischemic dilated cardiomyopathy. Am J Cardiol 1999;84(3):350 – 4.
  6. Senior R, Muller-Beckmann B, DasGupta P, et al. Effects of carvedilol on ventricular arrhythmias. J Cardiovasc Pharmacol 1992; 19:S117 – 21.
  7. Dockens RC, Greene DS, Barbhaiya RH. Assessment of pharmacoki- netic and pharmacodynamic Drug interactions between nefazodone and digoxin in healthy male volunteers. J Clin Pharmacol 1996;36(2):160 – 7.
  8. Siddiqui MA, Khan IA. Nefazodone-associated torsade de pointes. Int J Cardiol 2004;93(1):85 – 6.
  9. Klein-Schwartz W, Shepherd JG, Gorman S, et al. Characterization of gabapentin overdose using a poison center case series. J Toxicol Clin Toxicol 2003;41(1):11 – 5.
  10. Marson AG, Kadir ZA, Hutton JL, et al. The new Antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 1997;38(8):859 – 80.

Table 1 Results of laboratory tests

PT, prothrombin time; PTT, partial thromboplastin time; CPK,

Creatine phosphokinase; HCO3, bicarbonate level in arterial gas.

Day 1

Day 2

Hematologic values

Hemoglobin (g/dL)

18.4

13.1

White cells (per mm3)

10.8 x 103

7.8 x 103

Neutrophils (%)

Platelets (per mm3)

45

48 x 103

19 x 103

PT (s)

33.8

PTT (s)

82.9

Fibrinogen (mg/dL)

150

Sodium (mmol/L)

154

151

Potassium (mmol/L)

2.5

7.9

Magnesium (mg/dL)

1.3

1.0

Calcium (mg/dL)

5.5

Phosphorous (mg/dL)

0.5

Blood urea nitrogen (mg/dL)

55

Creatinine (mg/dL)

2.2

2.3

Total bilirubin (mg/dL)

0.8

Lactate dehydrogenase (U/L)

474

1733

Amylase (U/L)

174

Lactic acid (mg/dL)

39.8

Glucose (mg/dL)

86

Aspartate aminotransferase (U/L)

96

2283

Alanine aminotransferase (U/L)

20

2330

CPK (U/L)

220

5000

venous blood gas

Paco2 (mm Hg)

26

pH

7.02

HCO3 (mmol/L)

10

Arterial blood gas analysis

Paco2 (mm Hg)

22

pH

7.10

HCO3 (mm Hg)

13

Urinary fractional excretion

FeNa (%)

3

FeMg (%)

4.3

FeK (%)

13.2

FeP (%)

27.2

  1. Catalano G, Catalano MC, Tumarkin NB. Nefazodone overdose: a case report. Clin Neuropharmacol 1999;22(1):63 – 5.
  2. Benson BE, Mathiason M, Dahl B, et al. Toxicities and outcomes associated with nefazodone poisoning: an analysis of 1,338 exposures. Am J Emerg Med 2000;18(5):587 – 92.
  3. Gaffney PN, Schuckman HA, Beeson MS. Nefazodone overdose. Ann Pharmacother 1998;32(11):1249 – 50.
  4. Verma A, St. Clair EW, Radtke RA. A case of sustained massive gabapentin overdose without serious side effects. Ther Drug Monit 1999;21(6):615 – 7.
  5. Kelly CA, Dhaun N, Laing WA, et al. Comparative toxicity of citalopram and the newer antidepressants after overdose. J Toxicol Clin Toxicol 2004;42(1):67 – 71.

Hypoelectrolytemia accompanied by acute renal failure in Exertional heatstroke

A 27-year-old male marathon runner was admitted to the hospital under suspicion of dehydration. The physical examination revealed petechial rash. Meningococcal disease was suspected, and antibiotic therapy (ceftriaxone) was initiated. He was then transported to the ED of the Em’ilio Ribas Institute of Infectious Diseases.

The marathon was held on a day when the ambient temperature was 318C, and the relative humidity was 35%. During the marathon, the patient began to bwobbleQ and later collapsed. His daily medications included dietary supplements consisting of salicylates, ephedrine alkaloids, and guarana derivatives. In addition, he was taking creatine and Protein Supplements. On initial presentation, we observed a limited petechial rash. His skin was warm and dry, and his axillary temperature was 418C. The rectal temperature of the patient was not measured. Heart rate was

160 beats/min, respiratory rate was 40 breaths/min, and blood pressure was 140/70 mm Hg. The lungs were clear to auscultation. His Glasgow Coma Scale score was 10, and his pupils were equal and reactive to light. A computed tomography scan of the brain was normal, and a lumbar puncture was performed. The cerebrospinal fluid (CSF) contained 3 cells/mm3, total protein was 25 mg/dL, and total glucose was 120 mg/dL. The Gram stain was negative. Immunological tests, including counterimmunoelectropho- resis and latex agglutination test of CSF and serum, were negative for Neisseria meningitidis. Blood and CSF samples were collected for culture. Laboratory findings are shown in Table 1 and were remarkable for various hypoElectrolyte disorders. Based on a preliminary diagnosis of meningo- coccemia without meningitis, antibiotic treatment with ceftriaxone was continued. In addition, supportive measures to maintain homeostasis, including Electrolyte replacement and fluid therapy, were adopted. However, the rectal temperature of the patient was not measured, and appropri- ate cooling procedures were not carried out.

Over a 4-hour period, 4000 mL of 0.9% normal saline solution was administered. Two hours later, widespread

petechial hemorrhages were evident. The patient became cyanotic, lapsed into unconsciousness, and presented signs consistent with frank pulmonary edema. In response, an airway tube was inserted, and the patient was placed on mechanical ventilation. Evidence of disseminated intravascular coagulation became apparent (diffuse petechiae and splinter hemorrhages), and infusion of fresh frozen plasma was started.

By the second day, the platelet count had fallen, and the patient developed rhabdomyolysis. Despite intravenous infusion of saline, urine volume was minimal. The patient developed hemodynamic instability and received cardio- vascular support, including norepinephrine. He also devel- oped Fulminant hepatic failure. Sustained low-efficiency dialysis therapy, using bicarbonate-based dialysate solution, was started.

Despite all of the supportive measures taken, the patient died approximately 60 hours after his initial collapse. Cultures obtained at the time of admission demonstrated no growth.