Life-threatening fentanyl overdose beyond medullary depression in breathing.

We sought to determine how the balance between O₂ delivery (Do₂) and O₂ consumption is altered by fentanyl during the initial and the most critical period following a bolus intravenous injection of high-dose fentanyl. We determined the acute changes in ventilation, gas exchange, and hemodynamic-including cardiac function-along with the acid-base and arterial blood gas status-in 27 unsedated rats, following an intravenous bolus injection of 150 µg/kg fentanyl. This injection produced an immediate coma and central apnea, followed by the emergence of a regular and sustained, yet very depressed, breathing pattern ∼2.5 min later. All rats displayed an instantaneous and profound decrease in Q̇c (from 295.7 ± 42.62 to 140.74 ± 74.96 mL/kg/min; P < 0.0001) resulting from abrupt bradycardia (from 333.3 ± 20.8 to 112.2 ± 36.4 beats/min; P < 0.05) with a transient decreased cardiac contractility, associated with very severe hypoxemia that persisted throughout the ensuing period of hypoventilation, for example, [Formula: see text] = 39.0 ± 18.4 mmHg; [Formula: see text] = 50.1 ± 26.2%, at 5 min. Do₂ was therefore immediately decreased by several folds; and the abrupt decrease in Q̇c was even more severe than the drop in oxygenation. Twenty-four rats survived; the three remaining animals presented a rapid cardiac arrest by pulseless electrical activity. Fentanyl overdose induces an instant decrease in Do₂, with a very early and predominant drop in Q̇c, out of proportion with the decrease in V̇o₂, a protective mechanism produced by hypoxemia. The relevance and translation of these findings to human hypoxic cardiac arrest are discussed.NEW & NOTEWORTHY Fentanyl overdose induces an instant decrease in arterial transport of O₂, with a very early drop in cardiac output, out of proportion of O₂ requirement. These results point to the prominent role of the cardiac (through bradycardia) and circulatory effects of fentanyl as major contributors to the lethality of a fentanyl overdose when apnea and hypoventilation-induced hypoxemia develop.