Survey of Opioid-Induced Respiratory Depression in Critically Ill Patients Without Mechanical Ventilation and Construction of a Risk Nomogram

Objectives To investigate the current status of opioid-induced respiratory depression (OIRD) and potential risk factors in critically ill patients without mechanical ventilation in the intensive care unit (ICU) and to construct a risk nomogram to predict OIRD. Methods A total of 103 patients without (or who were weaned from) mechanical ventilation who had stayed for more than 24 h in the ICU between June 1, 2021 and September 31, 2021, were included. Patient data, including respiratory depression events, were recorded. The least absolute shrinkage and selection operator regression model were used to select features that were then used to construct a prediction model by multivariate logistic regression analysis. A nomogram was established for the risk of respiratory depression events in patients without mechanical ventilation. The discriminatory performance and calibration of the nomogram were assessed with Harrell’s concordance index and a calibration plot, respectively, and a bootstrap procedure was used for internal validation. Results Respiratory depression was diagnosed in 49/103 (47.6%) patients. Factors included in the nomogram were cardiopulmonary disease (odds ratio [OR]=5.569, 95% confidence interval [CI]=0.751–118.083), respiratory disease (OR=32.833, 95% CI=4.189–725.164), sepsis (OR=6.898, 95% CI=1.756–33.000), duration of mechanical ventilation (OR=3.019, 95% CI=0.862–11.322), lack of mechanical ventilation (OR=20.757, 95% CI=2.409–502.222), and oxygenation index (OR=7.350, 95% CI=2.483–24.286). The nomogram showed good performance for predicting respiratory depression events in critically ill patients without mechanical ventilation. Conclusion The nomogram can be used to identify ICU patients without mechanical ventilation who are at risk of opioid-induced respiratory depression and may therefore benefit from early intervention.

Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity

Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since there is an increasing number of conditions where the administration of the opioid receptor antagonist naloxone is inadequate or undesired, there is an increased interest in the development of novel reversal and prevention strategies aimed at providing efficacy close to that of the opioid receptor antagonist naloxone but with fewer of its drawbacks such as its short duration of action and lesser ability to reverse high-affinity opioids, such as carfentanil, or drug combinations. To give an overview of this highly relevant topic, the authors systematically discuss predominantly experimental pharmacotherapies, published in the last 5 yr, aimed at reversal of opioid-induced respiratory depression as alternatives to naloxone. The respiratory stimulants are discussed based on their characteristics and mechanism of action: nonopioid controlled substances (e.g., amphetamine, cannabinoids, ketamine), hormones (thyrotropin releasing hormone, oxytocin), nicotinic acetylcholine receptor agonists, ampakines, serotonin receptor agonists, antioxidants, miscellaneous peptides, potassium channel blockers acting at the carotid bodies (doxapram, ENA001), sequestration techniques (scrubber molecules, immunopharmacotherapy), and opioids (partial agonists/antagonists). The authors argue that none of these often still experimental therapies are sufficiently tested with respect to efficacy and safety, and many of the agents presented have a lesser efficacy at deeper levels of respiratory depression, i.e., inability to overcome apnea, or have ample side effects. The authors suggest development of reversal strategies that combine respiratory stimulants with naloxone. Furthermore, they encourage collaborations between research groups to expedite development of viable reversal strategies of potent synthetic opioid-induced respiratory depression.

Non-Opioid Peptides Targeting Opioid Effects

Opioids are the most potent widely used analgesics, primarily, but not exclusively, in palliative care. However, they are associated with numerous side effects, such as tolerance, addiction, respiratory depression, and cardiovascular events. This, in turn, can result in their overuse in cases of addiction, the need for dose escalation in cases of developing tolerance, and the emergence of dose-related opioid toxicity, resulting in respiratory depression or cardiovascular problems that can even lead to unintentional death. Therefore, a very important challenge for researchers is to look for ways to counteract the side effects of opioids. The use of peptides and their related compounds, which have been shown to modulate the effects of opioids, may provide such an opportunity. This short review is a compendium of knowledge about the most important and recent findings regarding selected peptides and their modulatory effects on various opioid actions, including cardiovascular and respiratory responses. In addition to the peptides more commonly reported in the literature in the context of their pro- and/or anti-opioid activity—such as neuropeptide FF (NPFF), cholecystokinin (CCK), and melanocyte inhibiting factor (MIF)—we also included in the review nociceptin/orphanin (N/OFQ), ghrelin, oxytocin, endothelin, and venom peptides.

Improving Newborn Resuscitation by Making Every Birth a Learning Event

One third of all neonatal deaths are caused by intrapartum-related events, resulting in neonatal respiratory depression (i.e., failure to breathe at birth). Evidence-based resuscitation with stimulation, airway clearance, and positive pressure ventilation reduces mortality from respiratory depression. Improving adherence to evidence-based resuscitation is vital to preventing neonatal deaths caused by respiratory depression. Standard resuscitation training programs, combined with frequent simulation practice, have not reached their life-saving potential due to ongoing gaps in bedside performance. Complex neonatal resuscitations, such as those involving positive pressure ventilation, are relatively uncommon for any given resuscitation provider, making consistent clinical practice an unrealistic solution for improving performance. This review discusses strategies to allow every birth to act as a learning event within the context of both high- and low-resource settings. We review strategies that involve clinical-decision support during newborn resuscitation, including the visual display of a resuscitation algorithm, peer-to-peer support, expert coaching, and automated guidance. We also review strategies that involve post-event reflection after newborn resuscitation, including delivery room checklists, audits, and debriefing. Strategies that make every birth a learning event have the potential to close performance gaps in newborn resuscitation that remain after training and frequent simulation practice, and they should be prioritized for further development and evaluation.

Structural insights into distinct signaling profiles of the μOR activated by diverse agonists

Drugs targeting the G protein-coupled μ-opioid receptor (μOR) are the most effective analgesics available but are also associated with fatal respiratory depression. While some partial opioid agonists appear to be safer than full agonists, the signaling pathways responsible for respiratory depression have yet to be elucidated. Here we investigated the structural and mechanistic basis of action of lofentanil (LFT) and mitragynine pseudoindoxyl (MP), two μOR agonists with different safety profiles. LFT, one of the most potent and lethal opioids, and MP, a derivative from the kratom plant with reduced respiratory depression in animal studies at equianalgesic doses, exhibited markedly different signaling efficacy profiles for G protein subtype activation and recruitment of β-arrestins. Cryo-EM structures of the μOR-Gi1 complex with MP (2.5Å) and LFT (3.2Å) revealed that the two ligands engage distinct sub-pockets, and molecular dynamics (MD) simulations showed additional differences in the binding site that propagate to the intracellular side of the receptor where G proteins and β-arrestins bind. While MP favors the precise G protein-bound active state observed in the cryo-EM structures, LFT favors a distinct active state. These results highlight how drugs engaging different parts of the μOR orthosteric pocket can lead to distinct signaling outcomes.