“Jansen et al. provide evidence that a new BK-channel blocker (i.e., ENA-001) […] may reverse the respiratory depressant effects of propofol, which may add to the utility of arousal-promoting agents and promises its own additional utility of ameliorating propofol’s respiratory depressant effects while permitting sedation.”

Respiratory depression during and after sedation and anesthesia is a recognized problem. We need look no further than the American Society of Anesthesiologists guidelines for anesthesia, sedation, and the postanesthesia care unit, which include continuous monitoring for oxygen saturation and capnography.  This level of surveillance is necessary because all hypnotic and opioid analgesic medications have the potential to produce life-threatening depression of ventilatory drive, and interventions need to be quickly and effectively instituted when respiratory depression is first detected. It stands to reason, then, that if a drug could partially or largely reverse the respiratory depressive effects of anesthetics, hypnotics, and opioids, they should be administered frequently as reversal agents for neuromuscular blockade. A recent review in Anesthesiology detailed the growing interest in developing safe and effective reversal agents that promote emergence from general anesthesia and deep sedation.  Encouraging preclinical results with orexin a hypothalamic neuropeptide involved in regulation of sleep and arousal states, and drugs that promote dopamine release targeting specific arousal-promoting pathways in the brain indicate that our practice may be moving in this direction. However, studies in this line of research largely examined measures of arousal and were not able to address reversal of respiratory depressant effects. In this issue of Anesthesiology, Jansen et al.  provide evidence that a new BK-channel blocker (i.e., ENA-001) that stimulates respiration by blocking calcium-activated potassium channels in the carotid bodies may reverse the respiratory depressant effects of propofol, which may add to the utility of arousal-promoting agents and promises its own additional utility of ameliorating propofol’s respiratory depressant effects while permitting sedation.

Early in a drug’s development and path toward regulatory approval, clinical trials that establish “proof of pharmacologic action” are needed. This reasoning informed the study design of Jansen et al. as they steered clear of trying to replicate any specific clinical situation, instead they designed a proof-of-concept study to examine the mechanism whereby ENA-001 exerts its effect. The conditions of this study design could not be replicated in any normal clinical setting because it requires a specialized respiratory circuit with mechanized, computer-controlled ability to set and maintain specific gas mixtures so that key ventilatory parameters could be measured and recorded under specified conditions. The authors quantitate an individual’s ventilatory drive at baseline and with two levels of propofol-induced respiratory depression, roughly corresponding to light sedation near the return of consciousness (plasma propofol concentration less than 1.0 µg/ml) and moderate sedation (plasma propofol concentration just less than 2.0 µg/ml). They show near and complete restoration of respiratory drive in the face of moderate hypoxia and hypoxia plus hypercapnia with low- and high-dose ENA-001, respectively. They demonstrated clear dose–effect relationships for the respiratory depressive effects of propofol and its reversal by ENA-001. Time and plasma drug concentration dependencies were accounted for by an elaborate pharmacokinetic–pharmacodynamic model that predicts that the hypoxic respiratory drive, depressed by escalating propofol effect-site concentrations, is completely reversed by ENA-001 at the higher dose tested.

Doxapram is another respiratory stimulant touted as being a useful reversal agent for anesthetic drugs because it possesses central nervous system stimulatory effects on both arousal and respiratory drive, as well as effects that enhance hypoxic respiratory drive via peripheral chemoreceptors.  However, doxapram was never widely accepted, and its use remains relatively niche. The reluctance to use doxapram on a routine basis perioperatively is likely related to its analeptic effects, making postoperative patients anxious, similar to the concern of counteracting the analgesic effects of opioids when naloxone is administered postoperatively to overcome μ-receptor agonist effects on respiratory drive. Clinical trials that more closely mimic clinical conditions and clinical outcomes such as sedation scores and processed electroencephalography parameters after administration of ENA-001 will be important next steps in the drug’s development if it is to see substantially more use than doxapram.

Even if a respiratory stimulant drug with minimal other effects or side effects were developed, there would remain challenges to get regulatory approval for meaningful clinical indications because benchmark routes to success are largely absent. First steps might entail carefully conducted proof-of-concept clinical trials.  Earlier studies addressed whether ENA-001 (previously known as GAL-021) could reverse a modest amount of opioid-induced depressive effects but not the full spectrum of central nervous system μ-opioid receptor agonist effects.  To explore whether ENA-001 would have better efficacy in reversal of respiratory depression caused by hypnotic agents, Jansen et al. have conducted an intricate crossover clinical trial in 14 healthy subjects to examine several key modulators of respiratory control under conditions of hypoxia, hypercapnia, and two clinical levels of propofol sedation. The crossover component was instituted on separate study days for each subject during which one of the three treatments was infused intravenously by random assignment: placebo, low-dose ENA-001, or high-dose ENA-001. Crossover study designs are efficient because each subject serves as their own control, and population pharmacokinetic–pharmacodynamic analysis allows an individual’s parameter estimates to be carried over to each study session, modified by potential interoccasion variability. The targeted effect-site propofol concentrations correspond to light and moderate sedation, with the latter administration rate averaging 49 µg · kg−1 · min−1 for greater than 70 min. It would be of great interest to determine whether ENA-001 at higher plasma concentrations could reverse more profound propofol-induced respiratory depression and/or airway obstruction.

Even so, the context-sensitive pharmacokinetics of propofol can demonstrate the utility of treating the respiratory depressant effects of propofol by ENA-001 studied by Jansen et al. Figure 1 is a pharmacokinetic simulation using the very utilitarian, web-based, pharmacokinetic tool stanpumpR,12  which represents effect-site propofol concentrations that would result from a 200-mg induction dose and 100 μg · kg−1 · min−1 infusion for a total intravenous anesthesia lasting 12 h as may occur for a complex spinal surgery operation. Interposed with the stanpumpR propofol simulation are the data from Jansen et al.  highlighting the plasma propofol concentrations associated with their high-dose and low-dose propofol infusions, producing significant and minimal respiratory depression, respectively. Even after a long infusion, plasma and effect-site propofol concentrations fall rapidly out of the total intravenous anesthesia–target effect-site propofol concentration zone but then continue to fall, less rapidly, through the effect-site propofol concentration zones of deep, moderate, and light sedation tested by Jansen et al.  The simulation demonstrates that measurable, propofol-mediated, respiratory depression persists for at least 2.4 h after cessation of the propofol infusion that would be fully reversable by ENA-001.

Fig. 1.
Pharmacokinetic simulation, generated by stanpumpR,12 of a 200-mg propofol bolus and a 12-h 100 μg · kg−1 · min−1 infusion. The yellow line is the predicted effect-site propofol concentrations for the 12 h of infusion and the 4 h after the infusion is terminated. The yellow shaded area is the typical target zone for plasma/effect-site propofol concentrations during total intravenous anesthesia (TIVA) programed by stanpumpR. The dashed blue line is the approximate mean plasma propofol concentration produced by the high-dose infusion (Jansen et al.6), which resulted in “significant” respiratory depression. The dashed green line is the approximate mean plasma propofol concentration produced by the low-dose infusion (Jansen et al.6), which resulted in “relatively minor” respiratory depression. The blue arrow points to the “wake-up” effect-site concentration programed by stanpumpR. The red bracket indicates the time from termination of the propofol infusion until the effect-site propofol reaches the approximate concentration associated with the low-dose infusion.

Pharmacokinetic simulation, generated by stanpumpR of a 200-mg propofol bolus and a 12-h 100 μg · kg−1 · min−1 infusion. The yellow line is the predicted effect-site propofol concentrations for the 12 h of infusion and the 4 h after the infusion is terminated. The yellow shaded area is the typical target zone for plasma/effect-site propofol concentrations during total intravenous anesthesia (TIVA) programed by stanpumpR. The dashed blue line is the approximate mean plasma propofol concentration produced by the high-dose infusion (Jansen et al. ), which resulted in “significant” respiratory depression. The dashed green line is the approximate mean plasma propofol concentration produced by the low-dose infusion (Jansen et al.), which resulted in “relatively minor” respiratory depression. The blue arrow points to the “wake-up” effect-site concentration programed by stanpumpR. The red bracket indicates the time from termination of the propofol infusion until the effect-site propofol reaches the approximate concentration associated with the low-dose infusion.

Reversal of the effects of muscle relaxants by neostigmine and sugammadex, when demonstrated to be complete, permit a much less intensive level of monitoring for their potentially harmful effects. Thus, reversal agents for neuromuscular blockade are an accepted part of our therapeutic armamentarium and almost universally administered. For similar acceptance and employment of drugs that reverse respiratory depression, studies beyond those that clearly demonstrate proof-of-concept are needed. For instance, would clinically important outcomes improve if ENA-001 were administered to all patients in the early postoperative phase when propofol or sevoflurane have been used for anesthesia? Alternatively, perhaps simultaneous infusions of propofol and ENA-001 could provide safe and effective moderate to deep sedation without the need for the presence of an anesthesia provider. Additionally, propofol is usually administered under hyperoxic conditions and knowing the effects of ENA-001 on propofol-induced hypoventilation under such conditions would be useful. Demonstration of utility beyond definitive proof-of-concept studies, such as the one by Jansen et al. will require further clinical trials with equally imaginative hypotheses and study designs.