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.