Using the gli spirographic prediction equations to revisit the allometric relationships between lung volumes, height and age in adults.

The determination the forced vital capacity (FVC) and the forced expiratory volume in 1 second (FEV1) during spirometry studies, is at the core of the evaluation of the pulmonary function of patients with respiratory diseases. The Global Lung Function Initiative (GLI) offers the most extensive data set of normal lung functions available, which is currently used to determine the average expected/predicted FEV1 and FVC (predV), and their lower limit of normal (LLN, 5th percentile) at any given height and age for women and men. These prediction equations are currently expressed in a rather complex form: predV = exp [p+ (a x Ln (height) + (n x Ln (age)) + spline] and LLN = exp(Ln (predV) + Ln (1 - 1.645 x S x CV)/S); and are currently used to generate interpretations in commercialized spinographic system. However, as shown in this paper, these equations contain physiological and fundamental allometric information on lung volumes that become obvious when rewriting mean predicted values as a "simple" power function of height and LLN as a percentage of the mean predicted values. We therefore propose to present the equations of prediction obtained from the GLI data using simplified expressions in adults (18-95 years old) to reveal some of their physiological and allometric meaning. Indeed, when predicted FEV1 and FVC (predV) were expressed under the form predV= αx heightax b(age), the resulting exponent (a) ranges between 2 and 3, transforming the one dimension of a length (size) into a volume, akin to the third-order power (cubic) function of height historically used to predict lung volumes. Only one function, b (age), is necessary to replace all the factors related to age, including the tables of discrete data of spline functions original equations. Similarly, LLN can be expressed as LLN = c (age) xpredV to become a simple percentage of the predicted values, as a function of age. The equations with their respective new polynomial functions were validated in 52,764 consecutive spirometry tests performed in 2022 in 22,612 men and 30,152 women at the Cleveland Clinic. Using these equations, it become obvious that for both women and men, FEV1/FVC ratio decreases with the size as the exponent of the power function of height is lower for FEV1 than FVC. We conclude that rewriting the GLI predicted equations with simpler formulations restitutes to the GLI data some of their original allometric meaning, without altering the accuracy of their prediction.

Sleep-Disordered Breathing, Hypoxia, and Pulmonary Physiologic Influences in Atrial Fibrillation.

Background We leverage a large clinical cohort to elucidate sleep-disordered breathing and sleep-related hypoxia in incident atrial fibrillation (AF) development given the yet unclear contributions of sleep-related hypoxia and pulmonary physiology in sleep-disordered breathing and AF. Methods and Results Patients who underwent sleep studies at Cleveland Clinic January 2, 2000, to December 30, 2015, comprised this retrospective cohort. Cox proportional hazards models were used to examine apnea hypopnea index, percentage time oxygen saturation <90%, minimum and mean oxygen saturation, and maximum end-tidal carbon dioxide on incident AF adjusted for age, sex, race, body mass index, cardiopulmonary disease and risk factors, antiarrhythmic medications, and positive airway pressure. Those with spirometry were additionally adjusted for forced expiratory volume in 1 second, forced vital capacity, and forced expiratory volume in 1 second/forced vital capacity. This cohort (n=42 057) was 50.7±14.1 years, 51.3% men, 74.1% White individuals, had median body mass index 33.2 kg/m2, and 1947 (4.6%) developed AF over 5 years. A 10-unit apnea hypopnea index increase was associated with 2% higher AF risk (hazard ratio [HR], 1.02 [95% CI, 1.00-1.03]). A 10-unit increase in percentage time oxygen saturation <90% and 10-unit decreases in mean and minimum oxygen saturation were associated with 6% (HR, 1.06 [95% CI, 1.04-1.08]), 30% (HR, 1.30 [95% CI, 1.18-1.42]), and 9% (HR, 1.09 [95% CI, 1.03-1.15]) higher AF risk, respectively. After adjustment for spirometry (n=9683 with available data), only hypoxia remained significantly associated with incident AF, although all coefficients were stable. Conclusions Sleep-related hypoxia was associated with incident AF in this clinical cohort, consistent across 3 measures of hypoxia, persistent after adjustment for pulmonary physiologic impairment. Findings identify a strong role for sleep-related hypoxia in AF development without pulmonary physiologic interdependence.

Treatment of life-threatening H2S intoxication: Lessons from the trapping agent tetranitrocobinamide.

We sought to evaluate the efficacy of trapping free hydrogen sulfide (H2S) following severe H2S intoxication. Sodium hydrosulfide solution (NaHS, 20 mg/kg) was administered intraperitoneally in 69 freely moving rats. In a first group (protocol 1), 40 rats were randomly assigned to receive saline (n = 20) or the cobalt compound tetranitrocobinamide (TNCbi) (n = 20, 75 mg/kg iv), one minute into coma, when free H2S was still present in the blood. A second group of 27 rats received TNCbi or saline, following epinephrine, 5 min into coma, when the concentration of free H2S has drastically decreased in the blood. In protocol 1, TNCbi significantly increased immediate survival (65 vs 20 %, p < 0.01) while in protocol 2, administration of TNCbi led to the same outcome as untreated animals. We hypothesize that the decreased efficacy of TNCbi with time likely reflects the rapid spontaneous disappearance of the pool of free H2S in the blood following H2S exposure.

Effects of fentanyl overdose-induced muscle rigidity and dexmedetomidine on respiratory mechanics and pulmonary gas exchange in sedated rats.

The objective of our study was to establish in sedated rats the consequences of high-dose fentanyl-induced acute muscle rigidity on the mechanical properties of the respiratory system and on the metabolic rate. Doses of fentanyl that we have previously shown to produce persistent rigidity of the muscles of the limbs and trunk in the rat (150-300 µg/kg iv), were administered in 23 volume-controlled mechanically ventilated and sedated rats. The effects of a low dose of the FDA-approved central α-2 agonist, dexmedetomidine (3 µg/kg iv), which has been suggested to oppose fentanyl-induced muscle rigidity, were determined after fentanyl administration. Fentanyl produced a significant decrease in compliance of the respiratory system (Crs) in all the rats that were studied. In 13 rats, an abrupt response occurred within 90 s, consisting of rapid rhythmic contractions of most skeletal muscles that were replaced by persistent tonic/tetanic contractions leading to a significant decrease of Crs (from 0.51 ± 0.11 mL/cmH2O to 0.36 ± 0.08 mL/cmH2O, 3 min after fentanyl injection). In the other 10 animals, Crs progressively decreased to 0.26 ± 0.06 mL/cmH2O at 30 min. There was a significant rise in oxygen consumption (V̇o2) during these muscle contractions (from 8.48 ± 4.31 to 11.29 ± 2.57 mL/min), which led to a significant hypoxemia, despite ventilation being held constant. Dexmedetomidine provoked a significant and rapid increase in Crs toward baseline levels, whereas decreasing the metabolic rate and restoring normoxemia. We propose that the changes in respiratory mechanics and metabolism produced by opioid-induced muscle rigidity contribute to fentanyl lethality.NEW & NOTEWORTHY The decrease in respiratory compliance and increased metabolism-induced hypoxemia produced by an overdose of fentanyl, in and of themselves, contribute to fentanyl toxicity.

Diabetes, Drug Treatment, and Mortality in COVID-19: A Multinational Retrospective Cohort Study.

Patients with type 2 diabetes mellitus (T2DM) are at increased risk of severe coronavirus disease 2019 (COVID-19) outcomes possibly because of dysregulated inflammatory responses. Glucose-regulating medications, such as glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and pioglitazone, are known to have anti-inflammatory effects that may improve outcomes in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In a multinational retrospective cohort study, we used the TriNetX COVID-19 Research Network of 56 large health care organizations to examine these medications in relation to the incidence of hospital admissions, respiratory complications, and mortality within 28 days after a COVID-19 diagnosis. After matching for age, sex, race, ethnicity, BMI, and significant comorbidities, use of GLP-1R agonists and/or pioglitazone was associated with significant reductions in hospital admissions (GLP-1R: 15.7% vs. 23.5%, risk ratio [RR] 0.67 [95% CI 0.57-0.79; P < 0.001]; pioglitazone: 20.0% vs. 28.2%; RR 0.71 [95% CI 0.54-0.93; P = 0.01]). Use of GLP-1R agonists was also associated with reductions in respiratory complications (15.3% vs. 24.9%, RR 0.62 [95% CI 0.52-0.73]; P < 0.001) and incidence of mortality (1.9% vs. 3.3%, RR 0.58 [95% CI 0.35-0.97]; P = 0.04). Use of DPP-4 inhibitors was associated with a reduction in respiratory complications (24.0% vs. 29.2%, RR 0.82 [95% CI 0.74-0.90]; P < 0.001), and continued use of DPP-4 inhibitors after hospitalization was associated with a decrease in mortality compared with those who discontinued use (9% vs. 19%, RR 0.45 [95% CI 0.28-0.72]; P < 0.001). In conclusion, use of glucose-regulating medications, such as GLP-1R agonists, DPP-4 inhibitors, or pioglitazone, may improve COVID-19 outcomes for patients with T2DM; randomized clinical trials are needed to further investigate this possibility.

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

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.

Respiratory effects of low and high doses of fentanyl in control and ß-arrestin 2-deficient mice.

We have investigated the potential acute desensitizing role of the ß arrestin 2 (ß-arr2) pathway on the ventilatory depression produced by levels of fentanyl ranging from analgesic to life-threatening (0.1 to 60 mg/kg ip) in control and ß-arr2-deficient nonsedated mice. Fentanyl at doses of 0.1, 0.5, and 1 mg/kg ip-corresponding to the doses previously used to study the role of ß-arr2 pathway-decreased ventilation, but along the V̇e/V̇co2 relationship established in baseline conditions. This reduction in ventilation was therefore indistinguishable from the decrease in breathing during the periods of spontaneous immobility. Above 1.5 mg/kg, however, ventilation was depressed out of proportion of the changes in metabolic rate, suggesting a specific depression of the drive to breathe. The ventilatory responses were similar between the two groups. At high doses of fentanyl (60 mg/kg ip) 1 out of 20 control mice died by apnea versus 8 out of 20 ß-arr2-deficient mice (P = 0.008). In the surviving mice, ventilation was however identical in both groups. The ventilatory effects of fentanyl in ß-arr2-deficient mice, reported in the literature, are primarily mediated by the "indirect" effects of sedation/hypometabolism on breathing control. There was an excess mortality at very high doses of fentanyl in the ß-arr2-deficient mice, mechanisms of which are still open to question, as the capacity of maintaining a rhythmic, although profoundly depressed, breathing activity remains similar in all of the surviving control and ß-arr2-deficient mice.NEW & NOTEWORTHY When life-threatening doses of fentanyl are used in mice, the ß-arrestin 2 pathway appears to play a critical role in the recovery from opioid overdose. This observation calls into question the use of G protein-biased µ-opioid receptor agonists, as a strategy for safer opioid analgesic drugs.

Azure B as a novel cyanide antidote: Preclinical in-vivo studies.

We have determined the effects of azure B (AzB), the main demethylated metabolite of methylene blue (MB), on a model of lethal cyanide intoxication. Our rationale was the following: AzB 1- possesses redox properties very similar to those of MB, which is a potent cyanide antidote, 2- may present a higher intracellular diffusibility than MB, 3- is already present in commercially available solutions of MB, and 4- appears very quickly in the blood after MB administration. AzB could therefore be a member of the phenothiazium chromophore family of interest to treat cyanide intoxication. We found, in spontaneously breathing urethane sedated rats, that AzB mimicked the effects of MB by increasing metabolism, ventilation and cardiac contractility up to 30-40 mg/kg. AzB had a lethal toxicity when the dose of 60 mg/kg was reached. Doses of AzB were therefore chosen in keeping with these data and the doses of MB previously used against cyanide intoxication (4-20 mg/kg) in the rat - doses corresponding to those used in humans to treat methemoglobinemia. KCN, infused at the rate of 0.375 mg/kg/min iv for 13 min, was fatal within 15 min in 100 % of our un-anesthetized rats. AzB at the dose of 4 mg/kg (n = 5) or 10 mg/kg (n = 5) administered 3 min into cyanide infusion allowed 100 % of the animals to survive with no clinical sequelae. The onset of coma was also significantly delayed and no apnea or gasping occurred. At the dose of 20 mg/kg, AzB was much less effective. At 4 mg/kg, the antidotal effects of AzB were significantly better than those produced by MB at the same dose and were not different from the effects produced by 20 mg/kg MB. We conclude that AzB is a potent cyanide antidote at relatively low doses.