Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia: A Randomized Clinical Trial.

Importance: Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects. Objective: To study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia. Design, Setting, and Participants: Randomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021. Interventions: Oxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo. Main Outcomes and Measures: Ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary). Results: Among 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], -4.9 L/min [1-sided 97.5% CI, -∞ to -0.6]; P = .01) and day 5 (25.1 vs 35.3 L/min; MD, -10.2 L/min [1-sided 97.5% CI, -∞ to -6.3]; P < .001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, -1.2 L/min [1-sided 97.5% CI, -∞ to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, -0.6 L/min [1-sided 97.5% CI, -∞ to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, -9.3 L/min [1-sided 97.5% CI, -∞ to -3.9]; P < .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, -∞ to 6.4]; P = .67). No drug-related serious adverse events were reported. Conclusions and Relevance: In this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04310579.

Sex differences in pulmonary function parameters among Indigenous Australians with and without chronic airway disease.

BACKGROUND: Studies assessing normative values and sex differences in pulmonary function test parameters (PFTPs) among Indigenous populations are sparse. METHODS: PFTPs were compared between male and female Indigenous Australian adults with and without chest radiologically proven chronic airway diseases (CADs). RESULTS: 485 adults (56% were female) with no significant difference in age, body mass index or smoking status between sexes were included. Females displayed a higher prevalence of radiology without CADs compared to males (66 vs. 52%, respectively). Among patients without CADs, after adjustment for age, stature and smoking, males displayed significantly higher absolute values of Forced Vital Capacity (FVC) (mean difference, 0.41L (0.21,0.62), p<0.001) and Forced Expiratory Volume in one second (FEV1) (mean difference 0.27L (0.07,0.47), p<0.001), with no significant difference in FEV1/FVC ratio (mean difference -0.02 (-0.06, 0.02), p = 0.174). Male and female patients with radiologically proven CADs demonstrated lower FEV1/FVC values. However, compared to females, males showed significantly greater reductions in pre- [-0.53 (-0.74, -0.32) vs. -0.29 (-0.42, -0.16), p = 0.045] and post- [-0.51 (-0.72, -0.3) vs. -0.27 (-0.39, -0.14), p = 0.049] bronchodilator FEV1. CONCLUSIONS: There are significant sex differences in the PFTPs among Indigenous Australians. Recognising these differences may be of value in the accurate diagnosis, management, monitoring and prognostication of CADs in this population.

Comparison of propofol-nalbuphine and propofol-fentanyl sedation for patients undergoing endoscopic retrograde cholangiopancreatography: a double-blind, randomized controlled trial.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) has been increasingly used to treat patients with biliary/pancreatic duct obstruction or stricture outside the operating room. Effective and safe sedation techniques are needed because of painful stimuli and the long duration of the ERCP procedure.Nalbuphine has been shown to cause less respiratory depression during sedation than similar cases without nalbuphine. This study compared the effects of propofol-nalbuphine (PN) and propofol-fentanyl (PF) sedation in patients undergoing ERCP. METHODS: Four hundred patients scheduled for ERCP procedures were divided into two groups: the PF group (receiving PF sedation,n = 199) and the PN group (receiving PN sedation,n = 201). Vital signs, adverse events during surgery, patient movement scores, pain scores, and adverse events one day post-ERCP were recorded. RESULTS: Stable haemodynamics were observed in both groups.Compared to the PF group, the PN group showed significantly decreased respiratory depression (P < 0.0001) and surgical interruptions (P = 0.048).Nalbuphine decreased patient movement by reducing pain from ERCP. CONCLUSION: Nalbuphine, instead of fentanyl, precipitated less respiratory depression while permitting adequate/equivalent sedation for ERCP and therefore provides more efficient and safer sedation. Trial registration ChiCTR, ChiCTR1800016018, Registered 7 May 2018, http://www.chictr.org.cn/showproj.aspx?proj=27085.

Mechanisms of the Effects of Short-Term Inhalations of Xe and O2 Gas Mixture in the Rehabilitation of Post-COVID Ventilation Failure.

The article presents a theoretical rationale and a clinical case of relief of post-COVID ventilation failure by inhalation of Xe and O2 gas mixture. Pneumonitis of coronavirus etiology transforms saturated phospholipids of surfactant into a solid-ordered phase, which disrupts surface tension, alveolar pneumatization, and alveolar-capillary gas exchange. Using molecular modeling (B3LYP/lanl2dz; GAUSSIAN09), we demonstrated that Xe atom due to the van der Waals dispersion interaction increases the distance between the phospholipid acyl chains providing a phase transition from the solid-ordered to liquid phase and restored the surface-active monolayer surfactant film. A clinical case confirmed that short-term inhalations of the Xe and O2 gas mixture relieved manifestations of ventilation insufficiency and increased SpO2 and pneumatization of the terminal parts of the lungs.

Effect of dexmedetomidine on cardiorespiratory regulation in spontaneously breathing adult rats.

PURPOSE: We examined the cardiorespiratory effect of dexmedetomidine, an α2- adrenoceptor/imidazoline 1 (I1) receptor agonist, in spontaneously breathing adult rats. METHODS: Male rats (226-301 g, n = 49) under isoflurane anesthesia had their tail vein cannulated for drug administration and their tail artery cannulated for analysis of mean arterial pressure (MAP), pulse rate (PR), and arterial blood gases (PaO2, PaCO2, pH). After recovery, one set of rats received normal saline for control recording and was then divided into three experimental groups, two receiving dexmedetomidine (5 or 50 µg·kg-1) and one receiving normal saline (n = 7 per group). Another set of rats was divided into four groups receiving dexmedetomidine (50 µg·kg-1) followed 5 min later by 0.5 or 1 mg∙kg-1 atipamezole (selective α2-adrenoceptor antagonist) or efaroxan (α2-adrenoceptor/I1 receptor antagonist) (n = 6 or 8 per group). Recordings were performed 15 min after normal saline or dexmedetomidine administration. RESULTS: Compared with normal saline, dexmedetomidine (5 and 50 µg·kg-1) decreased respiratory frequency (fR, p = 0.04 and < 0.01, respectively), PR (both p < 0.01), and PaO2 (p = 0.04 and < 0.01), and increased tidal volume (both p = 0.049). Dexmedetomidine at 5 µg·kg-1 did not significantly change minute ventilation (V'E) (p = 0.87) or MAP (p = 0.24), whereas dexmedetomidine at 50 µg·kg-1 significantly decreased V'E (p = 0.03) and increased MAP (p < 0.01). Only dexmedetomidine at 50 µg·kg-1 increased PaCO2 (p < 0.01). Dexmedetomidine (5 and 50 µg·kg-1) significantly increased blood glucose (p < 0.01), and dexmedetomidine at 50 µg·kg-1 increased hemoglobin (p = 0.04). Supplemental atipamezole or efaroxan administration similarly prevented the 50 µg·kg-1 dexmedetomidine-related cardiorespiratory changes. PRINCIPAL CONCLUSION: These results suggest that dexmedetomidine-related hypoventilation and hypertension are observed simultaneously and occur predominantly through activation of α2-adrenoceptors, but not I1 receptors, in spontaneously breathing adult rats.

Inhibitory effects and mechanisms of the anti-covid-19 traditional Chinese prescription, Keguan-1, on acute lung injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Keguan-1, a new traditional Chinese medicine (TCM) prescription contained seven Chinese herbs, is developed to treat coronavirus disease 19 (COVID-19). The first internationally registered COVID-19 randomised clinical trial on integrated therapy demonstrated that Keguan-1 significantly reduced the incidence of ARDS and inhibited the severe progression of COVID-19. AIM OF THE STUDY: To investigate the protective mechanism of Keguan-1 on ARDS, a lipopolysaccharide (LPS)-induced acute lung injury (ALI) model was used to simulate the pathological state of ARDS in patients with COVID-19, focusing on its effect and mechanism on ALI. MATERIALS AND METHODS: Mice were challenged with LPS (2 mg/kg) by intratracheal instillation (i.t.) and were orally administered Keguan-1 (low dose, 1.25 g/kg; medium dose, 2.5 g/kg; high dose, 5 g/kg) after 2 h. Bronchoalveolar lavage fluid (BALF) and lung tissue were collected 6 h and 24 h after i.t. administration of LPS. The levels of inflammatory factors tumour necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1ß, keratinocyte-derived chemokine (KC or mCXCL1), macrophage inflammatory protein 2 (MIP2 or mCXCL2), angiotensin II (Ang II), and endothelial cell junction-associated proteins were analysed using ELISA or western blotting. RESULTS: Keguan-1 improved the survival rate, respiratory condition, and pathological lung injury; decreased the production of proinflammatory factors (TNF-α, IL-6, IL-1ß, KC, and MIP2) in BALF and the number of neutrophils in the lung tissues; and ameliorated inflammatory injury in the lung tissues of the mice with LPS-induced ALI. Keguan-1 also reduced the expression of Ang II and the adhesion molecule ICAM-1; increased tight junction proteins (JAM-1 and claudin-5) and VE-cadherin expression; and alleviated pulmonary vascular endothelial injury in LPS-induced ALI. CONCLUSION: These results demonstrate that Keguan-1 can improve LPS-induced ALI by reducing inflammation and pulmonary vascular endothelial injury, providing scientific support for the clinical treatment of patients with COVID-19. Moreover, it also provides a theoretical basis and technical support for the scientific use of TCMs in emerging infectious diseases.

Which Inotropic Drug, Dobutamine or Milrinone, Is Clinically More Effective in the Treatment of Postligation Cardiac Syndrome in Preterm Infants?

OBJECTIVE: This study aimed to detect which of the two main medicines suggested in the treatment of postligation cardiac syndrome (PLCS)-dobutamine or mirinone-possesses a more therapeutic effect. While doing this, clinicians are provided with a broader perspective on the treatment and follow-up of cases. The desire was to increase the treatability and monitor ability of the cases in question and hence their survivability. STUDY DESIGN: A retrospective review of a cohort of infants with PLCS was conducted between March 2012 and December 2018. In the treatment of infants with PLCS, dobutamine (dobutamine study group-DSG) or milrinone (milrinone study group-MSG) was used. The respiration, cardiac, echocardiography, and perfusion parameters of the cases were assessed both before and after ligation. Based on the data obtained, both the effects of the medicines on PLCS and the difference between their therapeutic effects were studied. The accuracy of prognostication was assessed with receiver operating characteristic analyses. RESULTS: PLCS was detected in 29 (34.1%) of 85 patent ductus arteriosus ligation cases in total. Of all the PLCS cases, 13 (44.8%) were treated with dobutamine and 16 (55.2%) with milrinone. It was observed that the effects of the medicines on the respiratory system and cardiovascular system manifested in the third and 6th hour, respectively. It was detected that both medicines had more effect on the systolic blood pressure (SBP) (area under the curve [AUC]: 0.997/0.996, p = 0.001/0.002) than on the diastolic blood pressure (AUC: 0.911/0.843, p = 0.032/0.046). CONCLUSION: Dobutamine and milrinone, two primary medicines that can be used in the treatment of cases with PLCS, possess similar therapeutic effects on this pathology. In addition, their postoperative therapeutic effects on the SBP are more in the foreground.

Volatile anesthetics maintain tidal volume and minute ventilation to a greater degree than propofol under spontaneous respiration.

BACKGROUND: Although general anesthetics depress spontaneous respiration, the comprehensive effect of general anesthetics on respiratory function remains unclear. We aimed to investigate the effects of general anesthetics on spontaneous respiration in non-intubated mice with different types and doses of general anesthetic. METHODS: Adult C57BL/6 J mice were administered intravenous anesthetics, including propofol and etomidate, and inhalational anesthetics, including sevoflurane and isoflurane in vivo at doses of 0.5-, 1.0-, and 2.0-times the minimum alveolar concentration (MAC)/median effective dose (ED50) to induce loss of the righting reflex (LORR). Whole-body plethysmography (WBP) was applied to measure parameters of respiration under unrestricted conditions without endotracheal intubation. The alteration in respiratory sensitivity to carbon dioxide (CO2) under general anesthesia was also determined. The following respiratory parameters were continuously recorded during anesthesia or CO2 exposure: respiratory frequency (FR), tidal volume (TV), minute ventilation (MV), expiratory time (TE), inspiratory time (TI), and inspiratory-expiratory time ratio (I/E), and peak inspiratory flow. RESULTS: Sub-anesthetic concentrations (0.5 MAC) of sevoflurane or isoflurane increased FR, TV, and MV. With isoflurane and sevoflurane exposure, the CO2-evoked increases in FR, TV, and MV were decreased. Compared with inhalational anesthetics, propofol and etomidate induced respiratory suppression, affecting FR, TV, and MV. In 100% oxygen (O2), FR in the group that received propofol 1.0-times the ED50 was 69.63 ± 33.44 breaths/min compared with 155.68 ± 64.42 breaths/min in the etomidate-treated group. In the same groups, FR was 88.72 ± 34.51 breaths/min and 225.10 ± 59.82 breaths/min, respectively, in 3% CO2 and 144.17 ± 63.25 breaths/min and 197.70 ± 41.93 breaths/min, respectively, in 5% CO2. A higher CO2 sensitivity was found in etomidate-treated mice compared with propofol-treated mice. In addition, propofol induced a greater decrease in FR, MV, and I/E ratio compared with etomidate, sevoflurane, and isoflurane at equivalent doses (all P < 0.05). CONCLUSIONS: General anesthetics differentially modulate spontaneous breathing in vivo. Volatile anesthetics increase FR, TV, and MV at sub-anesthetic concentrations, while they decrease FR at higher concentrations. Propofol consistently depressed respiratory parameters to a greater degree than etomidate.

Acute L-Citrulline Supplementation Increases Nitric Oxide Bioavailability but Not Inspiratory Muscle Oxygenation and Respiratory Performance.

The present study aimed to investigate whether acute L-citrulline supplementation would affect inspiratory muscle oxygenation and respiratory performance. Twelve healthy males received 6 g of L-citrulline or placebo in a double-blind crossover design. Pulmonary function (i.e., forced expired volume in 1 s, forced vital capacity and their ratio), maximal inspiratory pressure (MIP), fractional exhaled nitric oxide (NO•), and sternocleidomastoid muscle oxygenation were measured at baseline, one hour post supplementation, and after an incremental resistive breathing protocol to task failure of the respiratory muscles. The resistive breathing task consisted of 30 inspirations at 70% and 80% of MIP followed by continuous inspirations at 90% of MIP until task failure. Sternocleidomastoid muscle oxygenation was assessed using near-infrared spectroscopy. One-hour post-L-citrulline supplementation, exhaled NO• was significantly increased (19.2%; p < 0.05), and this increase was preserved until the end of the resistive breathing (16.4%; p < 0.05). In contrast, no difference was observed in the placebo condition. Pulmonary function and MIP were not affected by the L-citrulline supplementation. During resistive breathing, sternocleidomastoid muscle oxygenation was significantly reduced, with no difference noted between the two supplementation conditions. In conclusion, a single ingestion of 6 g L-citrulline increased NO• bioavailability but not the respiratory performance and inspiratory muscle oxygenation.

Effects of acetazolamide on control of breathing in sleep apnea patients: Mechanistic insights using meta-analyses and physiological model simulations.

Obstructive and central sleep apnea affects ~1 billion people globally and may lead to serious cardiovascular and neurocognitive consequences, but treatment options are limited. High loop gain (ventilatory instability) is a major pathophysiological mechanism underlying both types of sleep apnea and can be lowered pharmacologically with acetazolamide, thereby improving sleep apnea severity. However, individual responses vary and are strongly correlated with the loop gain reduction achieved by acetazolamide. To aid with patient selection for long-term trials and clinical care, our goal was to understand better the factors that determine the change in loop gain following acetazolamide in human subjects with sleep apnea. Thus, we (i) performed several meta-analyses to clarify how acetazolamide affects ventilatory control and loop gain (including its primary components controller/plant gain), and based on these results, we (ii) performed physiological model simulations to assess how different baseline conditions affect the change in loop gain. Our results suggest that (i) acetazolamide primarily causes a left shift of the chemosensitivity line thus lowering plant gain without substantially affecting controller gain; and (ii) higher controller gain, higher paCO2 at eupneic ventilation, and lower CO2 production at baseline result in a more pronounced loop gain reduction with acetazolamide. In summary, the combination of mechanistic meta-analyses with model simulations provides a unified framework of acetazolamide's effects on ventilatory control and revealed physiological predictors of response, which are consistent with empirical observations of acetazolamide's effects in different sleep apnea subgroups. Prospective studies are needed to validate these predictors and assess their value for patient selection.

Disordered breathing in a Pitt-Hopkins syndrome model involves Phox2b-expressing parafacial neurons and aberrant Nav1.8 expression.

Pitt-Hopkins syndrome (PTHS) is a rare autism spectrum-like disorder characterized by intellectual disability, developmental delays, and breathing problems involving episodes of hyperventilation followed by apnea. PTHS is caused by functional haploinsufficiency of the gene encoding transcription factor 4 (Tcf4). Despite the severity of this disease, mechanisms contributing to PTHS behavioral abnormalities are not well understood. Here, we show that a Tcf4 truncation (Tcf4tr/+) mouse model of PTHS exhibits breathing problems similar to PTHS patients. This behavioral deficit is associated with selective loss of putative expiratory parafacial neurons and compromised function of neurons in the retrotrapezoid nucleus that regulate breathing in response to tissue CO2/H+. We also show that central Nav1.8 channels can be targeted pharmacologically to improve respiratory function at the cellular and behavioral levels in Tcf4tr/+ mice, thus establishing Nav1.8 as a high priority target with therapeutic potential in PTHS.

Evaluation of G protein bias and ß-arrestin 2 signaling in opioid-induced respiratory depression.

Respiratory depression is a potentially fatal side effect of opioid analgesics and a major limitation to their use. G protein-biased opioid agonists have been proposed as "safer" analgesics with less respiratory depression. These agonists are biased to activate G proteins rather than ß-arrestin signaling. Respiratory depression has been shown to correlate with both G protein bias and intrinsic efficacy, and recent work has refuted the role of ß-arrestin signaling in opioid-induced respiratory depression. In addition, there is substantial evidence that G proteins do, in fact, mediate respiratory depression by actions in respiratory-controlling brainstem neurons. Based on these studies, we provide the perspective that protection from respiratory depression displayed by newly developed G protein-biased agonists is due to factors other than G protein versus arrestin bias.

The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants.

Fucosylated glycosaminoglycan (FG) from sea cucumber is a potent anticoagulant by inhibiting intrinsic coagulation tenase (iXase). However, high-molecular-weight FGs can activate platelets and plasma contact system, and induce hypotension in rats, which limits its application. Herein, we found that FG from T. ananas (TaFG) and FG from H. fuscopunctata (HfFG) at 4.0 mg/kg (i.v.) could cause significant cardiovascular and respiratory dysfunction in rats, even lethality, while their depolymerized products had no obvious side effects. After injection, native FG increased rat plasma kallikrein activity and levels of the vasoactive peptide bradykinin (BK), consistent with their contact activation activity, which was assumed to be the cause of hypotension in rats. However, the hemodynamic effects of native FG cannot be prevented by the BK receptor antagonist. Further study showed that native FG induced in vivo procoagulation, thrombocytopenia, and pulmonary embolism. Additionally, its lethal effect could be prevented by anticoagulant combined with antiplatelet drugs. In summary, the acute toxicity of native FG is mainly ascribed to pulmonary microvessel embolism due to platelet aggregation and contact activation-mediated coagulation, while depolymerized FG is a safe anticoagulant candidate by selectively targeting iXase.

Mechanism deconvolution of Qing Fei Pai Du decoction for treatment of Coronavirus Disease 2019 (COVID-19) by label-free integrative pharmacology assays.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) has a long history in the prevention and treatment of pandemics. The TCM formula Lung Cleansing and Detoxifying Decoction (LCDD), also known as Qing Fei Pai Du Decoction, has been demonstrated effective against Coronavirus Disease 2019 (COVID-19). AIM OF THE STUDY: This work aimed to elucidate the active ingredients, targets and pathway mechanism of LCDD related to suppression of inflammatory, immunity regulation and relaxation of airway smooth muscle for the treatment of COVID-19. MATERIALS AND METHODS: Mining chemical ingredients reported in LCDD, 144 compounds covering all herbs were selected and screened against inflammatory-, immunity- and respiratory-related GPCRs including GPR35, H1, CB2, B2, M3 and ß2-adrenoceptor receptor using a label-free integrative pharmacology method. Further, all active compounds were detected using liquid chromatography-tandem mass spectrometry, and an herb-compound-target network based on potency and content of compounds was constructed to elucidate the multi-target and synergistic effect. RESULTS: Thirteen compounds were identified as GPR35 agonists, including licochalcone B, isoliquiritigenin, etc. Licochalcone B, isoliquiritigenin and alisol A exhibited bradykinin receptor B2 antagonism activities. Atractyline and shogaol showed as a cannabinoid receptor CB2 agonist and a histamine receptor H1 antagonist, respectively. Tectorigenin and aristofone acted as muscarinic receptor M3 antagonists, while synephrine, ephedrine and pseudoephedrine were ß2-adrenoceptor agonists. Pathway deconvolution assays suggested activation of GPR35 triggered PI3K, MEK, JNK pathways and EGFR transactivation, and the activation of ß2-adrenoceptor mediated MEK and Ca2+. The herb-compound-target network analysis found that some compounds such as licochalcone B acted on multiple targets, and multiple components interacted with the same target such as GPR35, reflecting the synergistic mechanism of Chinese medicine. At the same time, some low-abundance compounds displayed high target activity, meaning its important role in LCDD for anti-COVID-19. CONCLUSIONS: This study elucidates the active ingredients, targets and pathways of LCDD. This is useful for elucidating multitarget synergistic action for its clinical therapeutic efficacy.

Inhaled high dose nitric oxide is a safe and effective respiratory treatment in spontaneous breathing hospitalized patients with COVID-19 pneumonia.

BACKGROUND: Inhaled nitric oxide (NO) is a selective pulmonary vasodilator. In-vitro studies report that NO donors can inhibit replication of SARS-CoV-2. This multicenter study evaluated the feasibility and effects of high-dose inhaled NO in non-intubated spontaneously breathing patients with Coronavirus disease-2019 (COVID-19). METHODS: This is an interventional study to determine whether NO at 160 parts-per-million (ppm) inhaled for 30 min twice daily might be beneficial and safe in non-intubated COVID-19 patients. RESULTS: Twenty-nine COVID-19 patients received a total of 217 intermittent inhaled NO treatments for 30 min at 160 ppm between March and June 2020. Breathing NO acutely decreased the respiratory rate of tachypneic patients and improved oxygenation in hypoxemic patients. The maximum level of nitrogen dioxide delivered was 1.5 ppm. The maximum level of methemoglobin (MetHb) during the treatments was 4.7%. MetHb decreased in all patients 5 min after discontinuing NO administration. No adverse events during treatment, such as hypoxemia, hypotension, or acute kidney injury during hospitalization occurred. In our NO treated patients, one patient of 29 underwent intubation and mechanical ventilation, and none died. The median hospital length of stay was 6 days [interquartile range 4-8]. No discharged patients required hospital readmission nor developed COVID-19 related long-term sequelae within 28 days of follow-up. CONCLUSIONS: In spontaneous breathing patients with COVID-19, the administration of inhaled NO at 160 ppm for 30 min twice daily promptly improved the respiratory rate of tachypneic patients and systemic oxygenation of hypoxemic patients. No adverse events were observed. None of the subjects was readmitted or had long-term COVID-19 sequelae.

Extracorporeal membrane oxygenation use in poisoning: a narrative review with clinical recommendations.

CONTEXT: Poisoning may lead to respiratory failure, shock, cardiac arrest, or death. Extracorporeal membrane oxygenation (ECMO) may be used to provide circulatory support, termed venoarterial (VA) ECMO; or respiratory support termed venovenous (VV) ECMO. The clinical utility of ECMO in poisoned patients remains unclear and guidelines on its use in this setting are lacking. OBJECTIVES: To perform a literature search and narrative review on the use of ECMO in poisonings. Additionally, to provide recommendations on the use of ECMO in poisonings from physicians with expertise in ECMO, medical toxicology, critical care, and emergency medicine. METHODS: A literature search in Ovid MEDLINE from 1946 to October 14, 2020, was performed to identify relevant articles with a strategy utilizing both MeSH terms and adjacency searching that encompassed both extracorporeal life support/ECMO/Membrane Oxygenation concepts and chemically-induced disorders/toxicity/poisoning concepts, which identified 318 unique records. Twelve additional manuscripts were identified by the authors for a total of 330 articles for screening, of which 156 were included for this report. NARRATIVE LITERATURE REVIEW: The use of ECMO in poisoned patients is significantly increasing over time. Available retrospective data suggest that patients receiving VA ECMO for refractory shock or cardiac arrest due to poisoning have lower mortality as compared to those who receive VA ECMO for non-poisoning-related indications. Poisoned patients treated with ECMO have reduced mortality as compared to those treated without ECMO with similar severity of illness and after adjusted analyses, regardless of the type of ingestion. This is especially evident for poisoned patients with refractory cardiac arrest placed on VA ECMO (termed extracorporeal cardiopulmonary resuscitation [ECPR]). INDICATIONS: We suggest VA ECMO be considered for poisoned patients with refractory cardiogenic shock (continued shock with myocardial dysfunction despite fluid resuscitation, vasoactive support, and indicated toxicologic therapies such as glucagon, intravenous lipid emulsion, hyperinsulinemia euglycemia therapy, or others), and strongly considered for patients with cardiac arrest in institutions which are structured to deliver effective ECPR. VV ECMO should be considered in poisoned patients with ARDS or severe respiratory failure according to traditional indications for ECMO in this setting. CONTRAINDICATIONS: Patients with pre-existing comorbidities with low expected survival or recovery. Relative contraindications vary based on each center's experience but often include: severe brain injury; advanced age; unrepaired aortic dissection or severe aortic regurgitation in VA ECMO; irreversible organ injury; contraindication to systemic anticoagulation, such as severe hemorrhage. CONCLUSIONS: ECMO may provide hemodynamic or respiratory support to poisoned patients while they recover from the toxic exposure and metabolize or eliminate the toxic agent. Available literature suggests a potential benefit for ECMO use in selected poisoned patients with refractory shock, cardiac arrest, or respiratory failure. Future studies may help to further our understanding of the use and complications of ECMO in poisoned patients.

Ethanol's disruptive effects upon early breathing plasticity and blood parameters associated with hypoxia and hypercapnia.

Early ethanol exposure affects respiratory neuroplasticity; a risk factor associated with the Sudden Infant Death Syndrome. High and chronic ethanol doses exert long-lasting effects upon respiratory rates, apneic episodes and ventilatory processes triggered by hypoxia. The present study was performed in 3-9-day-old rat pups. Respiratory processes under normoxic and hypoxic conditions were analyzed in pups intoxicated with different ethanol doses which were pre-exposed or not to the drug. A second major goal was to examine if acute and/or chronic early ethanol exposure affects blood parameters related with hypercapnic or hypoxic states. In Experiment 1, at postnatal day 9, animals previously treated with ethanol (2.0 g/kg) or vehicle (0.0 g/kg) were tested sober or intoxicated with 0.75, 1.37 or 2.00 g/kg ethanol. The test involved sequential air conditions defined as initial normoxia, hypoxia and recovery normoxia. Motor activity was also evaluated. In Experiment 2, blood parameters indicative of possible hypoxic and hypercapnic states were assessed as a function of early chronic or acute experiences with the drug. The main results of Experiment 1 were as follows: i) ethanol's depressant effects upon respiratory rates increased as a function of sequential treatment with the drug (sensitization); ii) ethanol inhibited apneic episodes even when employing the lowest dose at test (0.75 g/kg); iii) the hyperventilatory response caused by hypoxia negatively correlated with the ethanol dose administered at test; iv) ventilatory long-term facilitation (LTF) during recovery normoxia was observed in pups pre-exposed to the drug and in pups that received the different ethanol doses at test; v) self-grooming increased in pups treated with either 1.37 or 2.00 g/kg ethanol. The main result of Experiment 2 indicated that acute as well as chronic ethanol exposure results in acidosis-hypercapnia. The results indicate that early and brief experiences with ethanol are sufficient to affect different respiratory plasticity processes as well as blood biomarkers indicative of acidosis-hypercapnia. An association between the LTF process and the acidosis-hypercapnic state caused by ethanol seems to exist. The mentioned experiences with the drug are sufficient to result in an anomalous programming of respiratory patterns and metabolic conditions.

Acute Beetroot Juice Ingestion Does Not Alter Renal Hemodynamics during Normoxia and Mild Hypercapnia in Healthy Young Adults.

Arterial hypercapnia reduces renal perfusion. Beetroot juice (BRJ) increases nitric oxide bioavailability and may improve renal blood flow. We tested the hypothesis that acute consumption of BRJ attenuates both decreases in blood velocity and increases in vascular resistance in the renal and segmental arteries during acute hypercapnia. In fourteen healthy young adults, blood velocity and vascular resistance were measured with Doppler ultrasound in the renal and segmental arteries during five minutes of breathing a carbon dioxide gas mixture (CO2) before and three hours after consuming 500 mL of BRJ. There was no difference between pre- and post-BRJ consumption in the increase in the partial pressure of end-tidal CO2 during CO2 breathing (pre: +4 ± 1 mmHg; post: +4 ± 2 mmHg, p = 0.4281). Segmental artery blood velocity decreased during CO2 breathing in both pre- (by -1.8 ± 1.9 cm/s, p = 0.0193) and post-BRJ (by -2.1 ± 1.9 cm/s, p = 0.0079), but there were no differences between pre- and post-consumption (p = 0.7633). Segmental artery vascular resistance increased from room air baseline during CO2 at pre-BRJ consumption (by 0.4 ± 0.4 mmHg/cm/s, p = 0.0153) but not post-BRJ (p = 0.1336), with no differences between pre- and post-consumption (p = 0.7407). These findings indicate that BRJ consumption does not attenuate reductions in renal perfusion during acute mild hypercapnia in healthy young adults.

Thyroid hormones during the perinatal period are necessary to respiratory network development of newborn rats.

Thyroid hormones (THs) are essential for foetal brain development. Because the gestating mother is the main source of THs to the foetus, maternal hypothyroidism and/or premature birth compromise neurological outcomes in the offspring. Respiratory instability and recurrent apneas due to immaturity of the respiratory control network are major causes of morbidity in infants. Inadequate TH supply may be sufficient to delay perinatal maturation of the respiratory control system; however, this hypothesis remains untested. To address this issue, maternal hypothyroidism was induced by adding methimazole (MMI; 0.02% w/v) to the drinking water of pregnant dams from conception to postpartum day 4 (P4). The effect of TH supplementation on respiratory function was tested by injecting levothyroxine (L-T4) in newborns at P1. Respiratory function was assessed by plethysmography (in vivo) and recording of phrenic output from medullary preparations (in vitro). By comparison with controls, TH deficiency increased the frequency of apneas and decreased basal ventilation in vivo and prevented the age-dependent increase in phrenic burst frequency normally observed in vitro. The effects of TH deficiency on GABAergic modulation of respiratory activity were measured by bath application of muscimol (GABAA agonist) or bicuculline (GABAA antagonist). The phrenic burst frequency responses to GABAergic agents were consistently greater in preparations from TH deficient pups. L-T4 supplementation reversed part of the respiratory anomalies related to MMI treatment in vitro. We conclude that TH deficiency during the perinatal period is sufficient to delay maturation of the respiratory control network development. Excessive GABAergic inhibition may contribute to this effect.

In vivo evidence for the cellular basis of central hypoventilation of Rett syndrome and pharmacological correction in the rat model.

Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by mutations in the MECP2 gene. RTT patients show periodical hypoventilation attacks. The breathing disorder contributing to the high incidence of sudden death is thought to be due to depressed central inspiratory (I) activity via unknown cellular processes. Demonstration of such processes may lead to targets for pharmacological control of the RTT-type hypoventilation. We performed in vivo recordings from medullary respiratory neurons on the RTT rat model. To our surprise, both I and expiratory (E) neurons in the ventral respiratory column (VRC) increased their firing activity in Mecp2-null rats with severe hypoventilation. These I neurons including E-I phase-spanning and other I neurons remained active during apneas. Consistent with enhanced central I drive, ectopic phrenic discharges during expiration as well as apnea were observed in the Mecp2-null rats. Considering the increased I neuronal firing and ectopic phrenic activity, the RTT-type hypoventilation does not seem to be caused by depression in central I activity, neither reduced medullary I premotor output. This as well as excessive E neuronal firing as shown in our previous studies suggests inadequate synaptic inhibition for phase transition. We found that the abnormal respiratory neuronal firing, ectopic phrenic discharge as well as RTT-type hypoventilation all can be corrected by enhancing GABAergic inhibition. More strikingly, Mecp2-null rats reaching humane endpoints with severe hypoventilation can be rescued by GABAergic augmentation. Thus, defective GABAergic inhibition among respiratory neurons is likely to play a role in the RTT-type hypoventilation, which can be effectively controlled with pharmacological agents.