As clinicians, we often question why some patients respond to naloxone and others do not when opioid-induced ventilatory impairment is suspected. This inexplicability is disconcerting, given the toll of opioid-induced ventilatory impairment–related deaths. Our search for greater understanding, as recently provided in this Journal by van Lemmen et paramount.

As minute ventilation falls under the influence of an opioid, the Pao2 will decline, and the Paco2 will rise.  This relationship may be estimated in a perfect circumstance (without any contribution from shunt, for example) by the alveolar gas equation.  A patient affected by opioid-induced ventilatory impairment breathing room air may present with an arterial oxygen saturation of 60% and a Paco2 100 mmHg estimated by the alveolar gas equation.  Observational studies in human respiratory failure patients note aberrations of consciousness at Paco2 90 mmHg and above and a loss of consciousness at 120 to 130 mmHg.  Central to hypercarbia-induced sedation or loss of consciousness seems to be the presence of a resulting acidosis of the cerebrospinal fluid (CSF). The lowering of CSF pH from a rise in Paco2 was shown to have a time constant (63% of change) of 12 min. Thus, Paco2 must likely be consistently elevated before the CSF pH lowers and consciousness is depressed.  Paco2 likely needs to be consistently normalized on the corollary for consciousness to return. 

Depression of consciousness from sustained hypercarbia may explain the failure of response to naloxone in some patients. Naloxone perhaps is antagonizing the direct sedative effects of the opioid without correcting the depression of consciousness from hypercarbia. Research to date on opioid-induced ventilatory impairment does not seem to adequately clarify the role of direct opioid-induced sedation versus the consciousness-depressant effect of hypercarbia. Many clinicians have cared for patients who did not respond to naloxone as predicted. Two examples are known opioid use disorder presenting late to the emergency department unconscious or the postoperative ward patient administered opioids who was similarly detected to be unconscious after a time delay. Typically, these patients regain consciousness after several hours in intensive care with sustained invasive positive pressure (hyper)ventilation. This normalizes the Paco2 for an extended period; we can suspect CSF pH with it. Often nonresponse to naloxone is initially ascribed to the coadministration of other sedative medications. Later, on further enquiry or rational thinking, it transpires that the only substance exposed to excessively was an opioid.

The learned opinion of van Lemmen et al. on the possible role of hypercarbia would aid our understanding of the pathogenesis of naloxone nonresponders.