Opioids depress minute ventilation primarily by reducing respiratory rate. This results from direct effects on the preBotzinger Complex as well as from depression of the Parabrachial/Kolliker-Fuse Complex, which provides excitatory drive to preBotzinger Complex neurons mediating respiratory phase-switch. Opioids also depress awake drive from the forebrain and chemodrive.

Multi-Level Regulation of Opioid-Induced Respiratory Depression.

There is an urgent need to develop novel compounds that prevent the deleterious effects of opioids such as fentanyl on minute ventilation while, if possible, preserving the analgesic actions of the opioids. We report that L-glutathione ethyl ester (GSHee) may be such a novel compound. In this study, we measured tail flick latency (TFL), arterial blood gas (ABG) chemistry, Alveolar-arterial gradient, and ventilatory parameters by whole body plethysmography to determine the responses elicited by bolus injections of fentanyl (75 μg/kg, IV) in male adult Sprague–Dawley rats that had received a bolus injection of GSHee (100 μmol/kg, IV) 15 min previously. GSHee given alone had minimal effects on TFL, ABG chemistry and A-a gradient whereas it elicited changes in some ventilatory parameters such as an increase in breathing frequency. In vehicle-treated rats, fentanyl elicited (1) an increase in TFL, (2) decreases in pH, pO2 and sO2 and increases in pCO2 (all indicative of ventilatory depression), (3) an increase in Alveolar-arterial gradient (indicative of a mismatch in ventilation-perfusion in the lungs), and (4) changes in ventilatory parameters such as a reduction in tidal volume, that were indicative of pronounced ventilatory depression. In GSHee-pretreated rats, fentanyl elicited a more prolonged analgesia, relatively minor changes in ABG chemistry and Alveolar-arterial gradient, and a substantially milder depression of ventilation. GSHee may represent an effective member of a novel class of thiolester drugs that are able to prevent the ventilatory depressant effects elicited by powerful opioids such as fentanyl and their deleterious effects on gas-exchange in the lungs without compromising opioid analgesia.

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Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia.

Nitrosyl factors play a vital role in the ventilatory depressant effects of fentanyl in unanesthetized rats

Fentanyl causes naloxone-resistant vocal cord closure: A platform for testing opioid overdose treatments.

What is known and objective Food and Drug Administration (FDA) risk evaluation and mitigation strategies (REMs) encourage emergency responders, paramedics, law enforcement agents, and even laypeople to be trained in the administration of naloxone with the intent of rescuing individuals from a known or suspected opioid overdose. Comment Although naloxone is generally safe and effective at reversing respiratory depression caused by a conventional opioid such as morphine or heroin by competing with the opioid and displacing it from the μ-opioid receptor, questions increasingly are arising as to whether naloxone can adequately reverse opioid overdoses that may involve the potent opioids fentanyl and its analogues (F/FAs). In other words, as more and more opioid overdoses involve F/FAs, can naloxone keep up? What is new and conclusion As a competitive antagonist at μ-opioid receptors, naloxone is often a life-saving agent in cases of overdose caused by conventional opioids, but it may not be versatile or powerful enough to combat the rising tide of overdoses due to fentanyl and its illicit analogues, or in cases of overdose involving combinations of opioids and non-opioids.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcpt.13462

Overdoses due to fentanyl and its analogues (F/FAs) push naloxone to the limit.

Background As severe acute hypoxemia produces a rapid inhibition of the respiratory neuronal activity through a nonopioid mechanism, we have investigated in adult rats the effects of hypoxemia after fentanyl overdose-induced apnea on (1) autoresuscitation and (2) the antidotal effects of naloxone. Methods In nonsedated rats, the breath-by-breath ventilatory and pulmonary gas exchange response to fentanyl overdose (300 µg · kg · min iv in 1 min) was determined in an open flow plethysmograph. The effects of inhaling air (nine rats) or a hypoxic mixture (fractional inspired oxygen tension between 7.3 and 11.3%, eight 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 (4 rats). Data are expressed as median and range. Results In air-breathing nonsedated rats, fentanyl produced an apnea within 14 s (12 to 29 s). A spontaneous rhythmic activity always resumed after 85.4 s (33 to 141 s) consisting of a persistent low tidal volume and slow frequency rhythmic activity that rescued all animals. Naloxone, 10 min later, immediately restored the baseline level of ventilation. At fractional inspired oxygen tension less than 10%, fentanyl-induced apnea was irreversible despite a transient gasping pattern; the administration of naloxone had no effects. In sedated rats, when PaO2 reached 16 mmHg during fentanyl-induced apnea, no spontaneous recovery of breathing occurred and naloxone had no rescuing effect, despite circulation being maintained. Conclusions Hypoxia-induced ventilatory depression during fentanyl induced apnea (1) opposes the spontaneous emergence of a respiratory rhythm, which would have rescued the animals otherwise, and (2) prevents the effects of high dose naloxone.

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Severe Hypoxemia Prevents Spontaneous and Naloxone-induced Breathing Recovery after Fentanyl Overdose in Awake and Sedated Rats

Evidence for the emergence of an opioid‐resistant respiratory rhythm following fentanyl overdose

Introduction Diquat is an herbicide that can lead to rapid multiorgan system failure upon toxic ingestion. Although Diquat shares a similar chemical structure with paraquat, diquat is still readily available to the general population, and in contrast to paraquat, it is not regulated. We present a case of an intentional diquat poisoning which emphasizes the necessity of the early recognition due to atypical symptoms within the first 24 hours and certainly enhanced regulatory restrictions on this very toxic compound. Case A 60-year-old male with a history of severe depression presented to the emergency department after intentional ingestion of a commercial herbicide containing diquat dibromide 2.30%. The earliest manifestations of this acute diquat intoxication comprised a glomerulonephritis and proximal tubular dysfunction. Progressive multiorgan system failure then developed with a significant delay (24-38 hours) including acute renal, liver failure, and then respiratory failure with refractory hypoxemia. Despite maximal supportive care, the end organ failure was lethal. Discussion. Diquat intoxication should be suspected in patient presenting an acute glomerulonephritis with coma. Diquat should undergo the same regulatory restrictions as paraquat-containing compounds.

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Rapid Glomerulotubular Nephritis as an Initial Presentation of a Lethal Diquat Ingestion.

To the Editor: Sarcoidosis is a systemic granulomatous disease with unknown etiology with an estimated prevalence of 60 per 100,000. Previous studies report higher incidence of sarcoidosis in the Midwest and Northeast compared to the Southwest United States.1 It has been hypothesized that components of atmospheric particulate matter or infectious causes could serve as immunogenic triggers, causing a systemic granulomatous response.2 Further, prevalence rates for sarcoidosis are elevated among those with Scandinavian or Black/African American ancestry. 

https://doi.org/10.1016/j.jdin.2022.07.006

Daniel Guck

Papers

Severe Hypoxemia Prevents Spontaneous and Naloxone-induced Breathing Recovery after Fentanyl Overdose in Awake and Sedated Rats

Evidence for the emergence of an opioid‐resistant respiratory rhythm following fentanyl overdose

Rapid Glomerulotubular Nephritis as an Initial Presentation of a Lethal Diquat Ingestion.

The prevalence and geographic distribution of sarcoidosis in the United States

Image-Guided Bronchoscopy for Comprehensive Lymph Node Staging: A Phantom Study