Article, Cardiology

Severe reaction to inadvertent intravenous administration of a large dose of norepinephrine

Case Report

Severe reaction to inadvertent intravenous administration of a large dose of norepinephrine

Abstract

We report the first case ever published of norepinephrine overdose. A 43-year-old female patient admitted in the emergency department for abdominal pain inadvertently received an intravenous Bolus injection of 16 mg norepine- phrine instead of the scheduled antispasmodic drug phlor- oglucinol. She immediately experienced severe tachycardia, hypertensive crisis, peripheral vasoconstriction, and Acute cardiac ischemia. Although the initial symptoms subsided within a few minutes, the patient subsequently developed hypotension, severe pulmonary edema, and right cardiac failure. Symptomatic treatment resulted in complete recov- ery. The clinical pattern was similar to epinephrine overdose as previously described in the literature. Indeed, although norepinephrine and epinephrine exert different agonistic properties on ?– and ?-adrenergic receptors due to dissimilar receptor binding, these differences tend to diminish when high doses of either catecholamine are administered.

A 43-year-old white woman was admitted to the emergency unit on the night of May 20, 2008, for acute abdominal pain and vomiting. Her medical and surgical history included appendicectomy in childhood and intes- tinal functional disorders during the 10 last years approxi- mately. Her current drug treatment only consisted of laxatives (macrogol), veinotonics, and an oral estroproges- tative contraceptive.

Symptoms began in the afternoon with hypogastric pain, and then nausea and alimentary vomiting followed by shivering. Upon arrival at the emergency department, the clinical examination revealed a little defense on the painful abdominal area and no audible bowel sounds. However, she had had stools that very day. There was neither leukorrhea nor menometrorrhagia, and she had no fever. Biologically, ?-subunit of human chorionic gonadotropin (?-hCG) was negative. Hepatic and pancreatic enzyme levels were normal as well as C-reative protein (CRP). On the other hand, her blood cell count showed a moderate hyperleu- kocytosis (17 giga/L) primarily due to increased neutrophil granulocytes. Urinalysis was positive for leukocytes, without nitrites, and was sterile.

She was prescribed a symptomatic treatment with the antispasmodic agent phloroglucinol but was inadvertently injected an Intravenous bolus of 16 mg norepinephrine at 3:30 AM. Shortly thereafter, she developed supraventricular tachycardia up to 250 beats per minute, Arterial hypertension (160/100 mm Hg) associated with headaches, peripheral vasoconstriction (evidenced by cyanosis of the lips and fingers), and constrictive thoracic-abdominal pain. An electrocardiographic recording showed signs of myocardial ischemia including ST-segment depression in the inferior anterior lateral territory (D2, D3, aVF, V3, V4, and V5 leads) and ST-segment elevation in the septal apical lateral territory (aVL, aVR, V1, V2). Troponin levels were raised to 4.8 ug/L (normal b0.2). The clinical features died out within a few minutes and Repolarization abnormalities disappeared pro- gressively. Second, arterial pressure dropped transiently to 90/50 mm Hg, and the patient presented with acute dyspnea associated with congestion and hemoptysis. arterial blood gases showed moderate acidosis (pH 7.34) with hypoxemia (7.15 KPa) and moderate hypocapnia. Chest radiographs were in favor of a pulmonary edema with widespread bilateral alveolar opacities.

The patient was then admitted in the intensive care unit. She was presenting with clinical signs of right cardiac insufficiency including Ankle edema, jugular venous distention, and hepatojugular reflux. A transthoracic echo- cardiogram showed dilatation of the inferior vena cava and hepatic veins, raised ventricular pressures, but a correct left ejection fraction with only minimal septal hypokinesia. B-type natriuretic peptide blood test (548 pg/mL) was in favor of a moderate heart failure. The CT scan performed on the following day confirmed the bilateral alveolar con- densation. A diuretic treatment was started, and her clinical and biological status improved progressively. However, abdominal pain and vomiting recurred, and a CT scan revealed Small bowel obstruction due to adhesions. The patient underwent laparoscopic surgery on day 2. Immedi- ately after anesthesia induction, she presented with extreme bradycardia and Cardiovascular collapse. Cardiopulmonary resuscitation included Fluid replacement and 4 mg of epinephrine intravenously. Stable hemodynamics was recorded within 6 minutes and the surgical procedure was completed. The postoperative course was uneventful, and the patient was discharged from hospital in stable condition after 2 weeks.

0735-6757/$ – see front matter (C) 2010

113.e6 Case Report

Whereas several cases of epinephrine overdose have been reported in the literature [1-11], this is seemingly the first case report of norepinephrine overdose. As both drugs have limited therapeutic use outside emergency and resuscitation units, overdose is commonly linked to improper conditions of injection. Because epinephrine and norepinephrine are inactivated within a few minutes, they are mainly given as a dilute solution by slow intravenous infusion to maintain effective blood levels as required.

The usual Therapeutic dose of norepinephrine ranges from 0.1 to 10 ug/kg per minute. Our patient inadver- tently received 16 mg (320 ug/kg) instead of the scheduled antispasmodic drug. Inadvertent overdoses after intravenous injection of catecholamines manifest as acute clinical manifestations of Short duration, but these manifestations can result in Life-threatening complications. Epinephrine and norepinephrine are ?– and ?-adrenergic receptor agonists, and their effects differ mainly due to their variable ratio of binding to these receptors [12]. Both are potent ? receptor agonists, which accounts for increased peripheral vascular resistance, but norepinephr- ine is far less potent on ?2 receptors that are involved in decreased peripheral vascular resistance. Thus, blood pressure elevation is typically greater with norepinephrine than with epinephrine. The rapid elevation of systolic and diastolic blood pressure is associated with reflex vagal discharge, which counterbalances the ?-adrenergic cardiac tachycardia and results in heart rate slowing. At therapeutic doses, the effects of epinephrine and norepi- nephrine are somewhat different: the mean blood pressure is higher and the heart rate slower with norepinephrine that markedly increases peripheral resistance in most vascular beds (except coronary arteries). However, when epinephrine dose is increased up to a certain level, vasoconstriction occurs as well because epinephrine’s greater potency on ?2 receptors is overwhelmed. There- fore, epinephrine and norepinephrine overdoses bear clinical similarities.

The reported clinical manifestations of epinephrine over- dose include hypertensive crisis followed by a disastrous fall in blood pressure, tachycardia, chest pain, myocardial ischemia, cardiac arrhythmias, headache, cyanosis and coldness of extremities, and pulmonary edema [1-11]. The clinical manifestations in our patient after a norepinephrine overdose were very similar to those of an epinephrine overdose. This finding supports the view that both drugs exert nondifferential activation of adrenergic receptors in case of massive overdose. Thus, despite the low agonist potency of norepinephrine on ?2 receptors, hypotension after initial blood pressure increase may ensue in norepinephrine as well epinephrine overdose.

Both acute overdoses can lead to severe vasoconstric- tion including coronary and pulmonary vascular bed and thus results in myocardial infarction and acute pulmonary edema. Although direct pulmonary vasoconstriction occurs,

redistribution of blood flow from the systemic to the pulmonary circulation seems to play an important part in the increased pulmonary pressure [12]. Furthermore, elevation of pulmonary pressure is enhanced by the decrease in cardiac output linked to left ventricular afterload elevation, rapid tachycardia, and sometimes ischemic heart failure. The pathogenesis of pulmonary edema is not fully elucidated. Elevated local levels of the Proinflammatory cytokine interleukin 6 have been shown in rats [13-15]. Because our patient presented with right, but not left ventricular failure (her left ejection fraction remained normal), a generalized pulmonary vasoconstric- tion and elevated pulmonary pressure may have played a major role in her acute pulmonary edema.

Charlotte Girard MD Resuscitation Unit Fleyriat Hospital Center

01000 Bourg-en-Bresse, France

Christine Payen MD

Poison Center and Pharmacovigilance Department

69003 Lyon, France E-mail address: [email protected]

Xavier Tchenio MD Laurent Holzapfel MD Resuscitation Unit Fleyriat Hospital Center

01000 Bourg-en-Bresse, France

Jacques Descotes MD, PharmD, PhD

Poison Center and Pharmacovigilance Department

69003 Lyon, France

doi:10.1016/j.ajem.2009.02.029

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