HYPOXEMIA PREVENTS RECOVERY FOLLOWING FENTANYL OVERDOSE IN AWAKE AND SEDATED RATS

Abstract

BackgroundAs severe acute hypoxemia produces a rapid inhibition of the respiratory neuronal activity through a non‐opioid mechanism, we have investigated in adult rats the effects of hypoxemia following fentanyl overdose‐induced apnea on 1‐ auto‐resuscitation and 2‐ the antidotal effects of naloxone.MethodsIn unsedated rats, the breath‐by‐breath ventilatory and pulmonary gas exchange response to fentanyl overdose (300 mg.kg−1.min−1 iv in one minute) was determined in an open flow plethysmograph. The effects of inhaling air (9 rats) or a hypoxic mixture (FIO2 between 7.3 amd 11.3%, 8 rats) on the ability to recover a spontaneous breathing rhythm and on the effects of naloxone (2 mg/kg) were investigated. In addition, arterial blood gases, arterial blood pressure, ventilation and pulmonary gas exchange were determined in spontaneously breathing tracheostomized urethane‐anesthetized rats in response to 1‐ fentanyl induced hypoventilation (7 rats), 2‐ fentanyl induced apnea (10 rats) in air and hyperoxia, and 3‐ isolated anoxic exposure (6 rats).ResultsData are expressed as median and range. In the unsedated rat model, bolus fentanyl injection in air breathing produced an apnea within 14 seconds (12 – 29 seconds). A spontaneous rhythmic activity resumed after 85.4 s (33–141 seconds) consisting in a persistent low tidal volume and slow frequency rhythmic activity that rescued all animals. Naloxone at 10 minutes immediately restored the baseline level of ventilation. At FIO2 below 10%, fentanyl induced apnea was irreversible despite a transient gasping pattern, the administration of naloxone had no effects. In sedated rats, no spontaneous recovery of breathing occurred following fentanyl‐induced apnea, when PaO2 was lower than 16 mmHg, akin to the effects of hypoxemia alone. Naloxone had no rescuing effect on fentanyl‐induced apnea despite circulation being maintained.ConclusionHypoxia‐induced ventilatory depression during fentanyl induced apnea 1) opposes the spontaneous emergence of a respiratory rhythm, which would have rescued the animals otherwise, 2) prevents the effects of high dose naloxone.Support or Funding InformationNone