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ANESTHETIC PHARMACOLOGY

Dexmedetomidine Sedation Leading to Refractory Cardiogenic Shock

From the St. Luke's-Roosevelt Hospital Center/Columbia University, New York City, New York.

Address correspondence and reprint requests to Tina C. Sichrovsky, MD, St. Luke's-Roosevelt Hospital Center/Columbia University, 1111, Amsterdam Ave., New York City, NY 10025. Address e-mail to Tina.sichrovsky{at}gmx.net.

	Abstract

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Dexmedetomidine is frequently used for deep sedation during electrophysiology procedures. We report a case where, presumably, the use of dexmedetomidine resulted in a patient's death. The patient developed unexplained and refractory cardiogenic shock and could not be resuscitated. Autopsy failed to demonstrate any abnormality or cause of death. We postulate that, in certain susceptible individuals, dexmedetomidine may lead to terminal complications. We therefore urge caution about using dexmedetomidine in the electrophysiology laboratory.

	Introduction

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Invasive cardiac interventions, such as electrophysiologic procedures that are prolonged or complex, often require the use of parenteral sedation, analgesia or anesthesia. A variety of medications are used for these purposes. Dexmedetomidine (Precedex^TM) is an ₂-adrenoreceptor agonist that possesses sedative, analgesic, and anxiolytic properties, but is not associated with significant respiratory depression.1 It can reduce the requirement for other sedative and narcotic drugs,1 and has been used by anesthesiologists during electrophysiologic procedures. We report on a patient who developed a severe adverse reaction, presumed to be due to dexmedetomidine, resulting in death.

	CASE REPORT

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A 50-yr-old man was referred for ablation of paroxysmal atrial fibrillation. He had no structural heart disease with a normal exercise stress echocardiogram performed 2 yr before admission; there was a history of mild polycythemia vera, not requiring treatment. He had been treated with diltiazem XL 240 mg and metoprolol XL 50 mg daily.

On arrival to the electrophysiology laboratory, his arterial blood pressure (BP) was 140/70 mm Hg and the heart rate 60 bpm. The cardiopulmonary examination was normal. He weighed 89 kg. At the beginning of the procedure, the patient was sedated with midazolam and fentanyl. A transseptal puncture was performed under intracardiac ultrasound guidance to access the left atrium for mapping and ablation. IV heparin was administered to a target activated clotting time of 300 s. The patient was very difficult to sedate throughout the procedure, and after he had received a total of 7 mg of midazolam and 125 µg of fentanyl over a 2-h period, the anesthesia service was called to assist with sedation. Dexmedetomidine was started at 200 µg/h. The package insert suggests dexmedetomidine to be dosed at 1 µg/kg given over 10 min, followed by continuous infusion of 0.2–0.7 µg · kg^–1 · h^–1.^*

Forty-five minutes later, the patient's systolic BP had slowly decreased from 140 to 100 mm Hg, and dexmedetomidine was reduced to 50 µg/h with return of systolic BP to 140 mm Hg. One hour and 45 min after dexmedetomidine had been started (after a total amount of 200 µg given), the patient became very agitated and tried to sit up. This was followed by the development of severe hypotension with a BP of 42/22 mm Hg and bradycardia at 30 bpm. Dexmedetomidine was stopped. A 20-s episode of asystole resolved with chest compressions, epinephrine, and atropine. Dopamine infusion was started. The development of cardiac tamponade was suspected by lack of movement of the cardiac silhouette on fluoroscopy. A bedside echocardiogram confirmed a moderately sized pericardial effusion and a normally contracting left ventricle. The patient was tracheally intubated, heparin was stopped (activated clotting time 267 s) and IV protamine was administered. Immediate pericardiocenthesis with drainage of 100 mL bloody fluid was performed, rapidly restoring the patient's vital signs to baseline.

However, a few minutes thereafter, hypotension developed again. A repeat echocardiogram revealed no residual pericardial fluid, but new severe global left ventricular hypokinesia with only minimal myocardial contraction and normal right ventricular function. This was followed by the development of recurrent episodes of ventricular fibrillation that were successfully terminated to sinus rhythm by external shocks, but followed by an electromechanical dissociated rhythm. The electrocardiogram revealed new 3 mm ST elevation in the precordial leads. Over the following 30 min epinephrine, atropine and vasopressin were given according to advanced cardiac life support protocol during continuous chest compressions without effect.

A bedside subxiphoid pericardial window was performed by the cardiothoracic surgeon, and a small amount of residual pericardial blood was drained without improvement. Under continuous cardiopulmonary resuscitation, he was brought to the operating room for exploration. After a short period of open cardiac massage and connection to extracorporal circulation, left ventricular function slowly and partially improved. No significant residual pericardial fluid or any other cardiac abnormality was found. The patient improved hemodynamically over the following hours, but had sustained severe anoxic injury leading to brain death.

An autopsy revealed myocardial hypertrophy, pinpoint perforation of the left atrium, 50% left anterior descending artery stenosis, and diffuse myocardial necrosis.

Examination of the brain demonstrated anoxic encephalopathy with transtentorial herniation. No other abnormalities were found.

	DISCUSSION

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Dexmedetomidine is an agonist of pre- and postsynaptic ₂-adrenoreceptors, located in the central and peripheral nervous system and causes sedation, analgesia, and sympatholysis. Via effects on post- and extra-synaptic receptors in target organs including smooth muscle cells and endothelial cells, it can produce both, vasoconstriction and vasodilatation.2–5 The most common observed side effects are hypotension, hypertension, and bradycardia.1,6,7

Animal studies have also demonstrated a dose-dependent decrease in cardiac output and an augmented bradycardic response in the presence of certain narcotic drugs like fentanyl, which then can be resistant to atropine.8

Two cases of prolonged asystole after administration of dexmedetomidine have been reported.9,10

Ingersoll-Weng et al. reported on a 56-yr-old patient with myasthenia gravis who underwent a thymectomy via median sternotomy. Upon sternal retraction, severe bradycardia developed, followed by asystole after atropine was given. Open cardiac massage and the administration of epinephrine restored a normal rhythm and BP within <2 min. The concomitant use of vasoactive and negative inotropic and chronotropic drugs, as well as a vasovagal response from surgical stimulation, were postulated as aggravating factors leading to asystole.9

Videira and Ferreira reported on a patient who developed asystole after insufflation of the peritoneal cavity for a laparoscopic gynecological procedure. Dexmedetomidine had been given, in addition to sevoflurane and fentanyl anesthesia plus cisatracurium for neuromuscular blockade. The episode lasted <2 min, and responded to abdominal deflation, IV atropine, and a brief period of thoracic compressions.10

Another report describes a case of cardiac arrest in a 76-yr-old patient awaiting surgery for abandoned pacemaker leads. Shortly after dexmedetomidine infusion had been started, the patient developed refractory cardiogenic shock unresponsive to resuscitation efforts. This occurred before the procedure was started and no other medication had been administered, in a patient with a functioning pacemaker, a history of normal systolic left ventricular function and nonobstructive coronary artery disease.11 The explanation that dexmedetomidine caused an acute elevation of pacing threshold is inconsistent with expected physiologic responses; instead this case was much more likely due to severe myocardial depression, as was ours.

In our patient, myocardial failure was persistent and refractory to pharmacologic interventions. Our patient had normal left ventricular function without clinical manifestations of coronary artery disease before the procedure.

In addition, our patient had been taking metoprolol and diltiazem, each night before the procedure; fentanyl and midazolam were administered at the beginning of the procedure. The initial hemodynamic deterioration could be explained by the development of cardiac tamponade, which was rapidly and successfully treated, made obvious by the return of the patient's vital signs to baseline and absence of pericardial fluid on postpericardiocenthesis echo. However, recurrent refractory hypotension and new profound myocardial dysfunction overwhelmed the patient's course, producing refractory cardiogenic shock. The presence of ST-segment elevation raised the concern of diffuse myocardial ischemia.

Our patient had moderate nonobstructive coronary artery disease demonstrated by autopsy. Alpha2-adrenoreceptors-mediated vasoconstriction can involve the coronary circulation, especially in the presence of atherosclerosis and endothelial dysfunction and high sympathetic tone.12,13

Additionally, there is evidence that the response to ₂-adrenoreceptor activation has genetic determinants. A polymorphism of the ₂-B adrenoreceptor subtype was associated with an increased incidence of fatal nonthrombotic acute myocardial infarction and sudden cardiac death, possibly mediated by coronary vasospasm.12,14,15 It is possible that in certain genetically predisposed individuals, stimulation of ₂-adrenoreceptors by dexmedetomidine may lead to augmented coronary vasoconstriction causing profound myocardial ischemia and myocardial dysfunction. Furthermore, certain clinical scenarios: combination of dexmedetomidine with other cardiodepressant drugs that reduce cardiac output (i.e., fentanyl), high sympathetic stimulation or a fixed stroke volume (i.e., tamponade), or subclinical coronary artery disease and endothelial dysfunction, could all augment the adverse effects of dexmedetomidine and make them resistant to pharmacologic interventions.

	CONCLUSIONS

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Dexmedetomidine has complex and counteracting cardiovascular effects, but is usually well tolerated.

Adverse effects such as bradycardia and hypotension are observed in up to 30% of patients, but are generally easily managed with IV fluids and atropine. It appears that dexmedetomidine may rarely cause profound left ventricular dysfunction and refractory shock. The concomitant use of negative chronotropic and inotropic drugs, and, in certain individuals, an idiosyncratic reaction, possibly mediated by a genetic predisposition, could be responsible for these effects, perhaps due to diffuse coronary vasoconstriction. We raise caution about use of dexmedetomidine in patients with underlying cardiac disease or at risk for cardiac complications during procedures.

	Footnotes

 
*Available at: www.http://precedex.hospira.com/_docs/PrecedexPI.pdf. Accessed June 28, 2007.

Accepted for publication February 13, 2008.

	REFERENCES

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sichrovsky, T. C. Articles by Steinberg, J. S. Search for Related Content PubMed PubMed Citation Articles by Sichrovsky, T. C. Articles by Steinberg, J. S.