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Dynamic contrast-enhanced CT using a lower-viscosity contrast agent in combination with tracer-kinetic analysis by the steepest-slope model improves pulmonary blood flow measurements and assessment of regional distributions of lung perfusion.

The administration of exogenous oxygen to support adequate gas exchange is the cornerstone of respiratory care. In the past few years, other gaseous molecules have been introduced in clinical practice to treat the wide variety of physiological derangement seen in critical care patients.Inhaled nitric oxide (NO) is used for its unique selective pulmonary vasodilator effect. Recent studies showed that NO plays a pivotal role in regulating ischemia-reperfusion injury and it has antibacterial and antiviral activity.Helium, due to its low density, is used in patients with upper airway obstruction and lower airway obstruction to facilitate gas flow and to reduce work of breathing.Carbon monoxide (CO) is a poisonous gas that acts as a signaling molecule involved in many biologic pathways. CO's anti-inflammatory and antiproliferative effects are under investigation in the setting of acute respiratory distress and idiopathic pulmonary fibrosis.Inhaled anesthetics are widely used in the operative room setting and, with the development of anesthetic reflectors, are now a valid option for sedation management in the intensive care unit.Many other gases such as xenon, argon, and hydrogen sulfide are under investigation for their neuroprotective and cardioprotective effects in post-cardiac arrest syndrome.With all these therapeutic options available, the clinician must have a clear understanding of the physiologic basis, therapeutic potential, and possible adverse events of these therapeutic gases. In this review, we will present the therapeutic gases other than oxygen used in clinical practice and we will describe other promising therapeutic gases that are in the early phases of investigation.

Esophageal intubations are not an uncommon occurrence in prehospital settings, occurring as high as 17%. These "never events" are associated with significant morbidity and mortality especially when unrecognized or when there is delayed recognition. Here, we review the currently available techniques for confirming endotracheal tube intubation and their limitations, and present the case for the application of portable handheld point-of-care ultrasound as an emerging technology for detection of potentially unrecognized esophageal intubations such as during cardiac arrest. We also provide algorithms for confirmation of tracheal intubation.

Sickle cell disease (SCD) is an inherited disorder of hemoglobin (Hb); approximately 300,000 babies are born worldwide with SCD each year. In SCD, fibers of polymerized sickle Hb (HbS) form in red blood cells (RBCs), which cause RBCs to develop their characteristic "sickled" shape, resulting in hemolytic anemia and numerous vascular complications including vaso-occlusive crises. The development of novel antisickling compounds will provide new therapeutic options for patients with SCD. We developed a high-throughput "sickling assay" that is based on an automated high-content imaging system to quantify the effects of hypoxia on the shape and size of RBCs from HbSS SCD patients (SS RBCs). We used this assay to screen thousands of compounds for their ability to inhibit sickling. In the assay, voxelotor (an FDA-approved medication used to treat SCD) prevented sickling with a

Purpose of review We conducted a systematic literature review to summarize the available evidence regarding the incidence, risk factors, and clinical characteristics of ventilator-associated pneumonia (VAP) in patients undergoing mechanical ventilation because of acute respiratory distress syndrome secondary to SARS-CoV-2 infection (C-ARDS). Recent findings Sixteen studies (6484 patients) were identified. Bacterial coinfection was uncommon at baseline (50%) of developing VAP, most commonly because of Gram-negative bacteria. Further work is needed to elucidate the disease-specific risk factors for VAP, strategies for prevention, and how best to differentiate between bacterial colonization versus superinfection.

The delirium-sparing effect of nighttime dexmedetomidine has not been studied after surgery. We hypothesised that a nighttime dose of dexmedetomidine would reduce the incidence of postoperative delirium as compared to placebo.This single-centre, parallel-arm, randomised, placebo-controlled superiority trial evaluated whether a short nighttime dose of intravenous dexmedetomidine (1 μg/kg over 40 min) would reduce the incidence of postoperative delirium in patients 60 years of age or older undergoing elective cardiac surgery with cardiopulmonary bypass. Patients were randomised to receive dexmedetomidine or placebo in a 1:1 ratio. The primary outcome was delirium on postoperative day one. Secondary outcomes included delirium within three days of surgery, 30-, 90-, and 180-day abbreviated Montreal Cognitive Assessment scores, Patient Reported Outcome Measures Information System quality of life scores, and all-cause mortality. The study was registered as NCT02856594 on ClinicalTrials.gov on August 5, 2016, before the enrolment of any participants.Of 469 patients that underwent randomisation to placebo (n = 235) or dexmedetomidine (n = 234), 75 met a prespecified drop criterion before the study intervention. Thus, 394 participants (188 dexmedetomidine; 206 placebo) were analysed in the modified intention-to-treat cohort (median age 69 [IQR 64, 74] years; 73.1% male [n = 288]; 26·9% female [n = 106]). Postoperative delirium status on day one was missing for 30 (7.6%) patients. Among those in whom it could be assessed, the primary outcome occurred in 5 of 175 patients (2.9%) in the dexmedetomidine group and 16 of 189 patients (8.5%) in the placebo group (OR 0.32, 95% CI: 0.10-0.83; P = 0.029). A non-significant but higher proportion of participants experienced delirium within three days postoperatively in the placebo group (25/177; 14.1%) compared to the dexmedetomidine group (14/160; 8.8%; OR 0.58; 95% CI, 0.28-1.15). No significant differences between groups were observed in secondary outcomes or safety.Our findings suggested that in elderly cardiac surgery patients with a low baseline risk of postoperative delirium and extubated within 12 h of ICU admission, a short nighttime dose of dexmedetomidine decreased the incidence of delirium on postoperative day one. Although non-statistically significant, our findings also suggested a clinical meaningful difference in the three-day incidence of postoperative delirium.National Institute on Aging (R01AG053582).

BACKGROUND: High-dose (≥ 80 ppm) inhaled nitric oxide (INO) has antimicrobial effects. We designed a trial to test the preventive effects of high-dose NO on coronavirus disease 2019 (COVID-19) in health care providers working with patients with COVID-19. The study was interrupted prematurely due to the introduction of COVID-19 vaccines for health care professionals. We thereby present data on safety and feasibility of breathing 160 ppm NO using 2 different NO sources, namely pressurized nitrogen/NO cylinders (INO) and electric NO (eNO) generators. METHODS: NO gas was inhaled at 160 ppm in air for 15 min twice daily, before and after each work shift, over 14 d by health care providers (NCT04312243). During NO administration, vital signs were continuously monitored. Safety was assessed by measuring transcutaneous methemoglobinemia (SpMet) and the inhaled nitrogen dioxide (NO(2)) concentration. RESULTS: Twelve healthy health care professionals received a collective total of 185 administrations of high-dose NO (160 ppm) for 15 min twice daily. One-hundred and seventy-one doses were delivered by INO and 14 doses by eNO. During NO administration, SpMet increased similarly in both groups (P = .82). Methemoglobin decreased in all subjects at 5 min after discontinuing NO administration. Inhaled NO(2) concentrations remained between 0.70 ppm (0.63–0.79) and 0.75 ppm (0.67–0.83) in the INO group and between 0.74 ppm (0.68–0.78) and 0.88 ppm (0.70–0.93) in the eNO group. During NO administration, peripheral oxygen saturation and heart rate did not change. No adverse events occurred. CONCLUSIONS: This pilot study testing high-dose INO (160 ppm) for 15 min twice daily using eNO seems feasible and similarly safe when compared with INO.

Electronic cigarettes (e-cigarettes) have been used widely as an alternative to conventional cigarettes and have become particularly popular among young adults. A growing body of evidence has shown that e-cigarettes are associated with acute lung injury and adverse effects in multiple other organs. Previous studies showed that high emissions of aldehydes (formaldehyde and acetaldehyde) in aerosols were associated with increased usage of the same e-cigarette coils. However, the impact on lung function of using aged coils has not been reported. We investigated the relationship between coil age and acute lung injury in mice exposed to experimental vaping for 1 h (2 puffs/min, 100 ml/puff). The e-liquid contains propylene glycol and vegetable glycerin (50:50, vol) only. The concentrations of formaldehyde and acetaldehyde in the vaping aerosols increased with age of the nichrome coils starting at 1200 puffs. Mice exposed to e-cigarette aerosols produced from 1800, but not 0 or 900, puff-aged coils caused acute lung injury, increased lung wet/dry weight ratio, and induced lung inflammation (IL-6, TNF-α, IL-1β, MIP-2). Exposure to vaping aerosols from 1800 puff-aged coils decreased heart rate, respiratory rate, and oxygen saturation in mice compared to mice exposed to air or aerosols from new coils. In conclusion, we observed that the concentration of aldehydes (formaldehyde and acetaldehyde) increased with repeated and prolonged usage of e-cigarette coils. Exposure to high levels of aldehyde in vaping aerosol was associated with acute lung injury in mice. These findings show significant risk of lung injury associated with prolonged use of e-cigarette devices.

The gut microbiome is a critical modulator of host immunity and is linked to the immune response to respiratory viral infections. However, few studies have gone beyond describing broad compositional alterations in severe COVID-19, defined as acute respiratory or other organ failure. We profiled 127 hospitalized patients with COVID-19 (n=79 with severe COVID-19 and 48 with moderate) who collectively provided 241 stool samples from April 2020 to May 2021 to identify links between COVID-19 severity and gut microbial taxa, their biochemical pathways, and stool metabolites. 48 species were associated with severe disease after accounting for antibiotic use, age, sex, and various comorbidities. These included significant in-hospital depletions of Fusicatenibacter saccharivorans and Roseburia hominis, each previously linked to post-acute COVID syndrome or “long COVID”, suggesting these microbes may serve as early biomarkers for the eventual development of long COVID. A random forest classifier achieved excellent performance when tasked with predicting whether stool was obtained from patients with severe vs. moderate COVID-19. Dedicated network analyses demonstrated fragile microbial ecology in severe disease, characterized by fracturing of clusters and reduced negative selection. We also observed shifts in predicted stool metabolite pools, implicating perturbed bile acid metabolism in severe disease. Here, we show that the gut microbiome differentiates individuals with a more severe disease course after infection with COVID-19 and offer several tractable and biologically plausible mechanisms through which gut microbial communities may influence COVID-19 disease course. Further studies are needed to validate these observations to better leverage the gut microbiome as a potential biomarker for disease severity and as a target for therapeutic intervention.

Nitric oxide (NO) is a biologically active molecule approved for the treatment of pulmonary hypertension in newborn patients. Commercially available NO delivery systems use pressurized cylinders as the source of NO and a sensor to control the concentrations of NO and nitrogen dioxide (NO2) delivered. Cylinder-based delivery systems are safe and widely used around the world, but they are bulky, expensive, and reliant on a robust supply chain. In the past few years, novel NO generators and delivery systems have been developed to overcome these limitations. Electric NO generators produce NO from ambient air using high-voltage electrical discharge to ionize air, which leads to the formation of NO, NO2, and ozone (O3). A scavenging system is incorporated to reduce the concentration of the toxic byproducts generated in this type of system. NO can also be generated by the reduction of NO2 by ascorbic acid or released from liquid solutions or solid nanoparticles. The development of easy-to-use, safe, and portable NO delivery systems may enable the delivery of NO in the out-patient setting or at home. Furthermore, non-cylinder-based NO generators reduce the cost of NO production and storage and may therefore make NO delivery feasible in low-resource settings. Here we review commercially available systems that can generate and administer inhalable NO.

Purpose of review Obesity prevalence is increasing in most countries in the world. In the United States, 42% of the population is obese (body mass index (BMI) > 30) and 9.2% is obese class III (BMI > 40). One of the greatest challenges in critically ill patients with obesity is the optimization of mechanical ventilation. The goal of this review is to describe respiratory physiologic changes in patients with obesity and discuss possible mechanical ventilation strategies to improve respiratory function. Recent findings Individualized mechanical ventilation based on respiratory physiology after a decremental positive end-expiratory pressure (PEEP) trial improves oxygenation and respiratory mechanics. In a recent study, mortality of patients with respiratory failure and obesity was reduced by about 50% when mechanical ventilation was associated with the use of esophageal manometry and electrical impedance tomography (EIT). Summary Obesity greatly alters the respiratory system mechanics causing atelectasis and prolonged duration of mechanical ventilation. At present, novel strategies to ventilate patients with obesity based on individual respiratory physiology showed to be superior to those based on standard universal tables of mechanical ventilation. Esophageal manometry and EIT are essential tools to systematically assess respiratory system mechanics, safely adjust relatively high levels of PEEP, and improve chances for successful weaning.

Rationale: Obesity is characterized by elevated pleural pressure (Ppl) and worsening atelectasis during mechanical ventilation in patients with acute respiratory distress syndrome (ARDS). Objectives: To determine the effects of a lung recruitment maneuver (LRM) in the presence of elevated Ppl on hemodynamics, left and right ventricular pressure, and pulmonary vascular resistance. We hypothesized that elevated Ppl protects the cardiovascular system against high airway pressure and prevents lung overdistension. Methods: First, an interventional crossover trial in adult subjects with ARDS and a body mass index ≥ 35 kg/m2 (n = 21) was performed to explore the hemodynamic consequences of the LRM. Second, cardiovascular function was studied during low and high positive end-expiratory pressure (PEEP) in a model of swine with ARDS and high Ppl (n = 9) versus healthy swine with normal Ppl (n = 6). Measurements and Main Results: Subjects with ARDS and obesity (body mass index = 57 ± 12 kg/m2) after LRM required an increase in PEEP of 8 (95% confidence interval [95% CI], 7–10) cm H2O above traditional ARDS Network settings to improve lung function, oxygenation and V./Q. matching, without impairment of hemodynamics or right heart function. ARDS swine with high Ppl demonstrated unchanged transmural left ventricular pressure and systemic blood pressure after the LRM protocol. Pulmonary arterial hypertension decreased (8 [95% CI, 13–4] mm Hg), as did vascular resistance (1.5 [95% CI, 2.2–0.9] Wood units) and transmural right ventricular pressure (10 [95% CI, 15–6] mm Hg) during exhalation. LRM and PEEP decreased pulmonary vascular resistance and normalized the V./Q. ratio. Conclusions: High airway pressure is required to recruit lung atelectasis in patients with ARDS and class III obesity but causes minimal overdistension. In addition, patients with ARDS and class III obesity hemodynamically tolerate LRM with high airway pressure. Clinical trial registered with www.clinicaltrials.gov (NCT 02503241).

Perioperative organ injury remains a medical, social and economic problem in cardiac surgery. Patients with postoperative organ dysfunction have increases in morbidity, length of stay, long-term mortality, treatment costs and rehabilitation time. Currently, there are no pharmaceutical technologies or non-pharmacological interventions that can mitigate the continuum of multiple organ dysfunction and improve the outcomes of cardiac surgery. It is essential to identify agents that trigger or mediate an organ-protective phenotype during cardiac surgery. The authors highlight nitric oxide (NO) ability to act as an agent for perioperative protection of organs and tissues, especially in the heart–kidney axis. NO has been delivered in clinical practice at an acceptable cost, and the side effects of its use are known, predictable, reversible and relatively rare. This review presents basic data, physiological research and literature on the clinical application of NO in cardiac surgery. Results support the use of NO as a safe and promising approach in perioperative patient management. Further clinical research is required to define the role of NO as an adjunct therapy that can improve outcomes in cardiac surgery. Clinicians also have to identify cohorts of responders for perioperative NO therapy and the optimal modes for this technology.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with a high risk of postoperative acute kidney injury (AKI). Due to limitations of current diagnostic strategies, we sought to determine whether free hemoglobin (fHb) ratio (ie, levels of fHb at the end of CPB divided by baseline fHb) could predict AKI after on-pump cardiac surgery. METHODS: This is a secondary analysis of a randomized controlled trial comparing the effect of nitric oxide (intervention) versus nitrogen (control) on AKI after cardiac surgery (NCT01802619). A total of 110 adult patients in the control arm were included. First, we determined whether fHb ratio was associated with AKI via multivariable analysis. Second, we verified whether fHb ratio could predict AKI and incorporation of fHb ratio could improve predictive performance at an early stage, compared with prediction using urinary biomarkers alone. We conducted restricted cubic spline in logistic regression for model development. We determined the predictive performance, including area under the receiver-operating-characteristics curve (AUC) and calibration (calibration plot and accuracy, ie, number of correct predictions divided by total number of predictions). We also used AUC test, likelihood ratio test, and net reclassification index (NRI) to compare the predictive performance between competing models (ie, fHb ratio versus neutrophil gelatinase-associated lipocalin [NGAL], N-acetyl-β-d-glucosaminidase [NAG], and kidney injury molecule-1 [KIM-1], respectively, and incorporation of fHb ratio with NGAL, NAG, and KIM-1 versus urinary biomarkers alone), if applicable. RESULTS: Data stratified by median fHb ratio showed that subjects with an fHb ratio >2.23 presented higher incidence of AKI (80.0% vs 49.1%; P =.001), more need of renal replacement therapy (10.9% vs 0%; P =.036), and higher in-hospital mortality (10.9% vs 0%; P =.036) than subjects with an fHb ratio ≤2.23. fHb ratio was associated with AKI after adjustment for preestablished factors. fHb ratio outperformed urinary biomarkers with the highest AUC of 0.704 (95% confidence interval [CI], 0.592-0.804) and accuracy of 0.714 (95% CI, 0.579-0.804). Incorporation of fHb ratio achieved better discrimination (AUC test, P =.012), calibration (likelihood ratio test, P

Mitochondrial dysfunction has been implicated in the pathogenesis of inflammation and multi-organ dysfunction in major trauma, including burn injury. Coenzyme Q10 (CoQ10) is a metabolite of the mevalonate pathway and an essential cofactor for the electron transport in the mitochondria. In addition, its reduced form (ubiquinol) functions as an antioxidant. Little is known as to whether oral CoQ10 supplementation effectively increases intracellular CoQ10 levels in humans. To study the bioavailability of CoQ10 supplementation, we conducted a randomized, double-blind, placebo-controlled study of reduced CoQ10 (ubiquinol-10) (1800 mg/day, t.i.d.) in burn patients at a single, tertiary-care hospital. Baseline plasma CoQ10 levels were significantly lower in burn patients than in healthy volunteers, although plasma CoQ10/cholesterol ratio did not differ between the groups. CoQ10 supplementation increased plasma concentrations of total and reduced CoQ10 and total CoQ10 content in peripheral blood mononuclear cells (PBMCs) in burn patients compared with the placebo group. CoQ10 supplementation did not significantly change circulating levels of mitochondrial DNA, inflammatory markers (e.g., interleukins, TNF-α, IFN-γ), or Sequential Organ Failure Assessment (SOFA) scores compared with the placebo group. This study showed that a relatively high dose of reduced CoQ10 supplementation increased the intracellular CoQ10 content in PBMCs as well as plasma concentrations in burn patients.

Electrical impedance tomography (EIT) is a novel, noninvasive, radiation-free, bedside imaging and monitoring tool to assess and visualize regional distribution of lung ventilation and perfusion. Although primarily a research tool, rapidly emerging data are beginning to define its clinical role, and it is poised to become a ubiquitous addition to the arsenal of the intensive care unit (ICU). In this review, we summarize the data supporting clinical use of EIT in adult ICUs, with an emphasis on appropriate application while highlighting future directions.Recent major studies have primarily focused on the role of EIT in setting correct positive end-expiratory pressure to balance regional overdistention and collapse. Over the last few years, our Lung Rescue Team has demonstrated that incorporating EIT into a multimodal approach to individualizing ventilator management can improve outcomes, particularly in the obese. We also review recent data surrounding EIT use during COVID, as well as other broad potential applications.As EIT becomes more common and its clinical role more defined, intensivists will benefit from a clear understanding of its applications and limitations.

Background Preclinical studies suggest that ketamine stimulates breathing. We investigated whether adding a ketamine infusion at low and high doses to propofol sedation improves inspiratory flow and enhances sedation in spontaneously breathing critically ill patients. Methods In this prospective interventional study, twelve intubated, spontaneously breathing patients received ketamine infusions at 5 mcg/kg/min, followed by 10 mcg/kg/min for 1 h each. Airway flow, pressure, and esophageal pressure were recorded during a spontaneous breathing trial (SBT) at baseline, and during the SBT conducted at the end of each ketamine infusion regimen. SBT consisted of one-minute breathing with zero end-expiratory pressure and no pressure support. Changes in inspiratory flow at the pre-specified time points were assessed as the primary outcome. Ketamine-induced change in beta-gamma electroencephalogram power was the key secondary endpoint. We also analyzed changes in other ventilatory parameters respiratory timing, and resistive and elastic inspiratory work of breathing. Results Ketamine infusion of 5 and 10 mcg/kg/min increased inspiratory flow (median, IQR) from 0.36 (0.29-0.46) L/s at baseline to 0.47 (0.32-0.57) L/s and 0.44 (0.33-0.58) L/s, respectively ( p = .013). Resistive work of breathing decreased from 0.4 (0.1-0.6) J/l at baseline to 0.2 (0.1-0.3) J/l after ketamine 10 mcg/kg/min ( p = .042), while elastic work of breathing remained unchanged. Electroencephalogram beta-gamma power (19-44 Hz) increased compared to baseline ( p Conclusions In intubated, spontaneously breathing patients receiving a constant rate of propofol, ketamine increased inspiratory flow, reduced inspiratory work of breathing, and was associated with an “activated” electroencephalographic pattern. These characteristics might facilitate weaning from mechanical ventilation.

To evaluate whether the use of inhaled nitric oxide (iNO)200 improves respiratory function.This retrospective cohort study used data from pregnant patients hospitalized with severe bilateral coronavirus disease 2019 (COVID-19) pneumonia at four teaching hospitals between March 2020 and December 2021. Two cohorts were identified: 1) those receiving standard of care alone (SoC cohort) and 2) those receiving iNO200 for 30 minutes twice daily in addition to standard of care alone (iNO200 cohort). Inhaled nitric oxide, as a novel therapy, was offered only at one hospital. The prespecified primary outcome was days free from any oxygen supplementation at 28 days postadmission. Secondary outcomes were hospital length of stay, rate of intubation, and intensive care unit (ICU) length of stay. The multivariable-adjusted regression analyses accounted for age, body mass index, gestational age, use of steroids, remdesivir, and the study center.Seventy-one pregnant patients were hospitalized for severe bilateral COVID-19 pneumonia: 51 in the SoC cohort and 20 in the iNO200 cohort. Patients receiving iNO200 had more oxygen supplementation-free days (iNO200: median [interquartile range], 24 [23-26] days vs standard of care alone: 22 [14-24] days, P=.01) compared with patients in the SoC cohort. In the multivariable-adjusted analyses, iNO200 was associated with 63.2% (95% CI 36.2-95.4%; P.001) more days free from oxygen supplementation, 59.7% (95% CI 56.0-63.2%; P.001) shorter ICU length of stay, and 63.6% (95% CI 55.1-70.8%; P.001) shorter hospital length of stay. No iNO200-related adverse events were reported.In pregnant patients with severe bilateral COVID-19 pneumonia, iNO200 was associated with a reduced need for oxygen supplementation and shorter hospital stay.

The effect of hospital-associated SARS-CoV-2 infections in cardiac surgery patients remains poorly investigated, and current data are limited to small case series with conflicting results.A multicenter European collaboration was organized to analyze the outcomes of patients who tested positive with hospital-associated SARS-CoV-2 infection after cardiac surgery. The study investigators hypothesized that early infection could be associated with worse postoperative outcomes; hence 2 groups were considered: (1) an early hospital-associated SARS-CoV-2 infection group comprising patients who had a positive molecular test result ≤7 days after surgery, with or without symptoms; and (2) a late hospital-associated SARS-CoV-2 infection group comprising patients whose test positivity occurred7 days after surgery, with or without symptoms. The primary outcome was 30-day mortality. Secondary outcomes included all-cause mortality or morbidity at early follow-up and SARS-CoV-2-related hospital readmission.A total of 87 patients were included in the study. Of those, 30 were in the early group and 57 in the late group. Overall, 30-day mortality was 8%, and in-hospital mortality was 11.5%. The reintubation rate was 11.4%. Early infection was significantly associated with higher mortality (adjusted OR, 26.6; 95% CI, 2, 352.6; P.01) when compared with the late group. At 6-month follow-up, survival probability was also significantly higher in the late infection group: 91% (95% CI, 83%, 98%) vs 75% (95% CI, 61%, 93%) in the early infection group (P = .036). Two patients experienced COVID-19-related rehospitalization.In this multicenter analysis, hospital-associated SARS-CoV-2 infection resulted in higher than expected postoperative mortality after cardiac surgery, especially in the early infection group.

High-dose nitric oxide is a novel treatment associated with improved oxygenation and decreased tachypnea in pregnant patients with severe coronavirus disease 2019 (COVID-19)., BACKGROUND: Rescue therapies to treat or prevent progression of coronavirus disease 2019 (COVID-19) hypoxic respiratory failure in pregnant patients are lacking. METHOD: To treat pregnant patients meeting criteria for severe or critical COVID-19 with high-dose (160–200 ppm) nitric oxide by mask twice daily and report on their clinical response. EXPERIENCE: Six pregnant patients were admitted with severe or critical COVID-19 at Massachusetts General Hospital from April to June 2020 and received inhalational nitric oxide therapy. All patients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A total of 39 treatments was administered. An improvement in cardiopulmonary function was observed after commencing nitric oxide gas, as evidenced by an increase in systemic oxygenation in each administration session among those with evidence of baseline hypoxemia and reduction of tachypnea in all patients in each session. Three patients delivered a total of four neonates during hospitalization. At 28-day follow-up, all three patients were home and their newborns were in good condition. Three of the six patients remain pregnant after hospital discharge. Five patients had two negative test results on nasopharyngeal swab for SARS-CoV-2 within 28 days from admission. CONCLUSION: Nitric oxide at 160–200 ppm is easy to use, appears to be well tolerated, and might be of benefit in pregnant patients with COVID-19 with hypoxic respiratory failure.

Background. Individuals with cystic fibrosis (CF) have persistent lung infections, necessitating the frequent use of antibiotics for pulmonary exacerbations. Some respiratory pathogens have intrinsic resistance to the currently available antibiotics, and any pathogen may acquire resistance over time, posing a challenge to CF care. Gaseous nitric oxide has been shown to have antimicrobial activity against a wide variety of microorganisms, including common CF pathogens, and offers a potential inhaled antimicrobial therapy. Case Presentation. Here, we present the case of a 16-year-old female with CF who experienced a precipitous decline in lung function over the prior year in conjunction with worsening antibiotic resistance of her primary pathogen, Burkholderia multivorans. She received 46 intermittent inhalations of 160 parts-per-million nitric oxide over a 28-day period. The gas was administered via a mechanical ventilator fitted with nitrogen dioxide scavenging chambers. Conclusions. High-dose inhaled nitric oxide was safe, well tolerated, and showed clinical benefit in an adolescent with cystic fibrosis and pulmonary colonization with Burkholderia multivorans.

A brief review of how central adiposity affects intrathoracic pressures and its effects on spontaneous breathing and artificial ventilation.

This review highlights the ultrasound findings reported from a number of studies and case reports and discusses the unifying findings from coronavirus disease (COVID-19) patients and from the avian (H7N9) and H1N1 influenza epidemics. We discuss the potential role for portable point-of-care ultrasound (PPOCUS) as a safe and effective bedside option in the initial evaluation, management, and monitoring of disease progression in patients with confirmed or suspected COVID-19 infection.

Objectives To test the feasibility, safety, and efficacy of intratracheal delivery of nitric oxide (NO) generated from air by pulsed electrical discharge via a Scoop catheter. Study design We studied healthy 3- to 4-month-old lambs weighing 34 ± 4 kg (mean ± SD, n = 6). A transtracheal Scoop catheter was inserted through a cuffed tracheostomy tube. U46619 was infused to increase mean pulmonary arterial pressure (mPAP) from 16 ± 1 to 32 ± 3 mmHg (mean ± SD). Electrically generated NO was delivered via the Scoop catheter to awake lambs. A sampling line, to monitor NO and nitrogen dioxide (NO2) levels, was placed in the distal trachea of the lambs. The effect of varying doses of electrically generated NO, produced continuously, on pulmonary hypertension was assessed. Results In awake lambs with acute pulmonary hypertension, NO was continuously delivered via the Scoop catheter at 400 ml/min. NO induced pulmonary vasodilation. NO2 levels, measured in the trachea, were below 0.5 ppm at intratracheal NO doses of 10–80 ppm. No changes were detected in the levels of methemoglobin in blood samples before and after 5 min of NO breathing. Conclusions Continuously delivering electrically generated NO through a Scoop catheter produces vasodilation of the pulmonary vasculature of awake lambs with pulmonary hypertension. Transtracheal NO delivery may provide a long-term treatment for patients with chronic pulmonary hypertension as an outpatient without requiring a mask or tracheal intubation.

Nitric oxide (NO) activity in vivo is the combined results of its direct effects, the action of its derivatives generated from NO autoxidation, and the effects of nitrosated compounds. Measuring NO metabolites is essential to studying NO activity both at vascular levels and in other tissues, especially in the experimental settings where exogenous NO is administered. Ozone-based chemiluminescence assays allow precise measurements of NO and NO metabolites in both fluids (including plasma, tissue homogenates, cell cultures) and gas mixtures (e.g., exhaled breath). NO reacts with ozone to generate nitrogen dioxide in an excited state. The consequent light emission allows photodetection and the generation of an electric signal reflecting the NO content of the sample. Aliquots from the same sample can be used to measure specific NO metabolites, such as nitrate, nitrite, S-nitrosothiols, and iron-nitrosyl complexes. In addition, NO consumed by cell-free hemoglobin is also quantified with chemiluminescence analysis. An illustration of all these techniques is provided.

The COVID-19 pandemic has caused tremendous disruptions to non-COVID-19 clinical research. However, there has been little investigation on how patients themselves have responded to clinical trial recruitment during the COVID-19 pandemic. To investigate the effect of the COVID-19 pandemic on rates of patient consent to enrollment into non-COVID-19 clinical trials, we carried out a cross-sectional study using data from the Nitric Oxide/Acute Kidney Injury (NO/AKI) and Minimizing ICU Neurological Dysfunction with Dexmedetomidine-Induced Sleep (MINDDS) trials. All patients eligible for the NO/AKI or MINDDS trials who came to the hospital for cardiac surgery and were approached to gain consent to enrollment were included in the current study. We defined “Before COVID-19” as the time between the start of the relevant clinical trial and the date when efforts toward that clinical trial were deescalated by the hospital due to COVID-19. We defined “During COVID-19” as the time between trial de-escalation and trial completion. 5,015 patients were screened for eligibility. 3,851 were excluded, and 1,434 were approached to gain consent to enrollment. The rate of consent to enrollment was 64% in the “Before COVID-19” group and 45% in the “During COVID-19” group (n = 1,334, PP

Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator and mild bronchodilator that has been shown to improve systemic oxygenation, but has rarely been administered in the Emergency Department (ED). In addition to its favorable pulmonary vascular effects, in-vitro studies report that NO donors can inhibit replication of viruses, including SARS Coronavirus 2 (SARS-CoV-2). This study evaluated the administration of high-dose iNO by mask in spontaneously breathing emergency department (ED) patients with respiratory symptoms attributed to Coronavirus disease 2019 (COVID-19).We designed a randomized clinical trial to determine whether 30 min of high dose iNO (250 ppm) could be safely and practically administered by emergency physicians in the ED to spontaneously-breathing patients with respiratory symptoms attributed to COVID-19. Our secondary goal was to learn if iNO could prevent the progression of mild COVID-19 to a more severe state.We enrolled 47 ED patients with acute respiratory symptoms most likely due to COVID-19: 25 of 47 (53%) were randomized to the iNO treatment group; 22 of 47 (46%) to the control group (supportive care only). All patients tolerated the administration of high-dose iNO in the ED without significant complications or symptoms. Five patients receiving iNO (16%) experienced asymptomatic methemoglobinemia (MetHb)5%. Thirty-four of 47 (72%) subjects tested positive for SARS-CoV-2: 19 of 34 were randomized to the iNO treatment group and 15 of 34 subjects to the control group. Seven of 19 (38%) iNO patients returned to the ED, while 4 of 15 (27%) control patients did. One patient in each study arm was hospitalized: 5% in iNO treatment and 7% in controls. One patient was intubated in the iNO group. No patients in either group died. The differences between these groups were not significant.A single dose of iNO at 250 ppm was practical and not associated with any significant adverse effects when administered in the ED by emergency physicians. Local disease control led to early study closure and prevented complete testing of COVID-19 safety and treatment outcomes measures.

The significant mortality rate and prolonged ventilator days associated with invasive mechanical ventilation (IMV) in patients with severe COVID-19 have incited a debate surrounding the use of noninvasive respiratory support (NIRS) (i.e., HFNC, CPAP, NIV) as a potential treatment strategy. Central to this debate is the role of NIRS in preventing intubation in patients with mild respiratory disease and the potential beneficial effects on both patient outcome and resource utilization. However, there remains valid concern that use of NIRS may prolong time to intubation and lung protective ventilation in patients with more advanced disease, thereby worsening respiratory mechanics via self-inflicted lung injury. In addition, the risk of aerosolization with the use of NIRS has the potential to increase healthcare worker (HCW) exposure to the virus. We review the existing literature with a focus on rationale, patient selection and outcomes associated with the use of NIRS in COVID-19 and prior pandemics, as well as in patients with acute respiratory failure due to different etiologies (i.e., COPD, cardiogenic pulmonary edema, etc.) to understand the potential role of NIRS in COVID-19 patients. Based on this analysis we suggest an algorithm for NIRS in COVID-19 patients which includes indications and contraindications for use, monitoring recommendations, systems-based practices to reduce HCW exposure, and predictors of NIRS failure. We also discuss future research priorities for addressing unanswered questions regarding NIRS use in COVID-19 with the goal of improving patient outcomes. Supplementary Information The online version contains supplementary material available at 10.1186/s40560-021-00593-1.

Pendelluft phenomenon is defined as the displacement of gas from a more recruited nondependent (ND) lung region to a less recruited dependent (D) lung region. This phenomenon may cause lung injury. Thus, a lung model for pendelluft was established, and the effects of ventilatory settings on pendelluft were examined.Two sets of the twin-bellows-type training test lung (TTL) model were utilized. One set of bellows simulated the diaphragm, and the other simulated the lung. One TTL model represented the ND region, and the other represented the D region. The lung bellows were connected to each other and were ventilated with 1 ventilator. The diaphragm bellows were ventilated with 2 synchronized ventilators that regulated pleural pressure levels. We simulated pendelluft by applying different pleural pressure levels to the D and ND bellows. The increment of the tidal volume in the D region from the "no breathing effort" condition was defined as the pendelluft volume. The effects of ventilator settings, such as ventilatory modes, triggering sensitivity, inspiratory pressurization, and inspiratory cycling-off, were examined. The changes in tidal volumes in the D region based on the control settings were compared to assess the severity of pendelluft.The gas flow from the D region to the ND region was found to be essential in pendelluft, but the severity of this phenomenon was not always proportional to gas flows. The severity increased with the increase in the differences in pleural pressure levels between the ND and D regions, and it was amplified by the difference in lung mechanics between the ND and D regions. However, the ventilator settings had minimal effect on the severity of pendelluft.The pendelluft was affected by the heterogeneity of lung mechanics and pleural pressure. Furthermore, a minimal association was observed between the ventilator settings and the severity of pendelluft.

Hypoxemia of the acute respiratory distress syndrome can be reduced by turning patients prone. Prone positioning (PP) is labor intensive, risks unplanned tracheal extubation, and can result in facial tissue injury. We retrospectively examined prolonged, repeated, and early versus later PP for 20 patients with COVID-19 respiratory failure. Blood gases and ventilator settings were collected before PP, at 1, 7, 12, 24, 32, and 39 h after PP, and 7 h after completion of PP. Analysis of variance was used for comparisons with baseline values at supine positions before turning prone. PP for &gt, 39 h maintained PaO2/FiO2 (P/F) ratios when turned supine, the P/F decrease at 7 h was not significant from the initial values when turned supine. Patients turned prone a second time, when again turned supine at 7 h, had significant decreased P/F. When PP started for an initial P/F ≤ 150 versus P/F &gt, 150, the P/F increased throughout the PP and upon return to supine. Our results show that a single turn prone for &gt, 39 h is efficacious and saves the burden of multiple prone turns, and there is no significant advantage to initiating PP when P/F &gt, 150 compared to P/F ≤ 150.

Supplemental Digital Content is available in the text., IMPORTANCE: Prone positioning improves clinical outcomes in moderate-to-severe acute respiratory distress syndrome and has been widely adopted for the treatment of patients with acute respiratory distress syndrome due to coronavirus disease 2019. Little is known about the effects of prone positioning among patients with less severe acute respiratory distress syndrome, obesity, or those treated with pulmonary vasodilators. OBJECTIVES: We characterize the change in oxygenation, respiratory system compliance, and dead-space-to-tidal-volume ratio in response to prone positioning in patients with coronavirus disease 2019 acute respiratory distress syndrome with a range of severities. A subset analysis of patients treated with inhaled nitric oxide and subsequent prone positioning explored the influence of pulmonary vasodilation on the physiology of prone positioning. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of all consecutively admitted adult patients with acute respiratory distress syndrome due to coronavirus disease 2019 treated with mechanical ventilation and prone positioning in the ICUs of an academic hospital between March 11, 2020, and May 1, 2020. MAIN OUTCOMES AND MEASURES: Respiratory system mechanics and gas exchange during the first episode of prone positioning. RESULTS: Among 122 patients, median (interquartile range) age was 60 years (51–71 yr), median body mass index was 31.5 kg/m2 (27–35 kg/m2), and 50 patients (41%) were female. The ratio of Pao2 to Fio2 improved with prone positioning in 90% of patients. Prone positioning was associated with a significant increase in the ratio of Pao2 to Fio2 (from median 149 [123–170] to 226 [169–268], p < 0.001) but no change in dead-space-to-tidal-volume ratio or respiratory system compliance. Supine ratio of Pao2 to Fio2, respiratory system compliance, positive end-expiratory pressure, and body mass index did not correlate with absolute change in the ratio of Pao2 to Fio2 with prone positioning. However, patients with ratio of Pao2 to Fio2 less than 150 experienced a greater relative improvement in oxygenation with prone positioning than patients with ratio of Pao2 to Fio2 greater than or equal to 150 (median percent change in ratio of Pao2 to Fio2 62 [29–107] vs 30 [10–70], p = 0.002). Among 12 patients, inhaled nitric oxide prior to prone positioning was associated with a significant increase in the ratio of Pao2 to Fio2 (from median 136 [77–168] to 170 [138–213], p = 0.003) and decrease in dead-space-to-tidal-volume ratio (0.54 [0.49–0.58] to 0.46 [0.44–0.53], p = 0.001). Subsequent prone positioning in this subgroup further improved the ratio of Pao2 to Fio2 (from 145 [122–183] to 205 [150–232], p = 0.017) but did not change dead-space-to-tidal-volume ratio. CONCLUSIONS AND RELEVANCE: Prone positioning improves oxygenation across the acute respiratory distress syndrome severity spectrum, irrespective of supine respiratory system compliance, positive end-expiratory pressure, or body mass index. There was a greater relative benefit among patients with more severe disease. Prone positioning confers an additive benefit in oxygenation among patients treated with inhaled nitric oxide.

Summary: Acute kidney injury is a common complication after cardiac surgery that is associated with high postoperative morbidity and mortality. Levels of hemolysis are associated closely with the incidence and severity of kidney injury after cardiac surgery. Hemolysis is caused by prolonged surgical procedures and blood transfusions from cell-saver devices and is associated with the use of cardiopulmonary bypass. Plasma oxyhemoglobin is released into the circulation by damaged red blood cells that, via a dioxygenation reaction, depletes vascular nitric oxide (NO), a potent vasodilator molecule responsible for modulating organ perfusion and vascular homeostasis. Depleted plasma NO and increased levels of plasma oxyhemoglobin in the bloodstream lead to impairment of organ perfusion, inflammation, oxidative stress, and direct tubular injury, which, together, contribute to the development of renal injury after cardiac surgery. The administration of NO, a gas originally approved to treat pulmonary hypertension, maintains organ perfusion by preventing vascular NO depletion. In addition, this treatment improves cardiac output by reducing pulmonary vascular resistance and right heart workload. The clinical evidence of renal protection of NO gas therapy is supported by preclinical animal studies exploring the extrapulmonary protective effects of NO. Recent clinical trials showed a significant reduction of postoperative acute kidney injury when NO gas was administered during and after cardiac surgery.

Independent lung ventilation, though infrequently used in the critical care setting, has been reported as a rescue strategy for patients in respiratory failure resulting from severe unilateral lung pathology. This involves isolating and ventilating the right and left lung differently, using separate ventilators. Here, we describe our experience with independent lung ventilation in a patient with unilateral diffuse alveolar hemorrhage, who presented with severe hypoxemic respiratory failure despite maximal ventilatory support. Conventional ventilation in this scenario leads to preferential distribution of tidal volume to the non-diseased lung causing over distension and inadvertent volume trauma. Since each lung has a different compliance and respiratory mechanics, instituting separate ventilation strategies to each lung could potentially minimize lung injury. Based on review of literature, we provide a detailed description of indications and procedures for establishing independent lung ventilation, and also provide an algorithm for management and weaning a patient from independent lung ventilation.

“Do I Need Mercy to be a Physician?” is the title of a reflection Dr. Berra offered of his own work as a physician during the “2016 Jubilee of Mercy” in Rome. Mercy, patient-physician relationship, medical education and mentorship are presented in relations to patients’ encounters and life experiences.

Background: The biological effects of nitric oxide are mediated via protein S-nitrosylation. Levels of S-nitrosylated protein are controlled in part by the denitrosylase, S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine whether GSNOR inhibition improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Methods: Adult wild-type C57BL/6 and GSNOR-deleted (GSNOR −/− ) mice were subjected to potassium chloride-induced CA and subsequently resuscitated. Fifteen minutes after a return of spontaneous circulation, wild-type mice were randomized to receive the GSNOR inhibitor, SPL-334.1, or normal saline as placebo. Mortality, neurological outcome, GSNOR activity, and levels of S-nitrosylated proteins were evaluated. Plasma GSNOR activity was measured in plasma samples obtained from post-CA patients, preoperative cardiac surgery patients, and healthy volunteers. Results: GSNOR activity was increased in plasma and multiple organs of mice, including brain in particular. Levels of protein S-nitrosylation were decreased in the brain 6 hours after CA/CPR. Administration of SPL-334.1 attenuated the increase in GSNOR activity in brain, heart, liver, spleen, and plasma, and restored S-nitrosylated protein levels in the brain. Inhibition of GSNOR attenuated ischemic brain injury and improved survival in wild-type mice after CA/CPR (81.8% in SPL-334.1 versus 36.4% in placebo; log rank P =0.031). Similarly, GSNOR deletion prevented the reduction in the number of S-nitrosylated proteins in the brain, mitigated brain injury, and improved neurological recovery and survival after CA/CPR. Both GSNOR inhibition and deletion attenuated CA/CPR-induced disruption of blood brain barrier. Post-CA patients had higher plasma GSNOR activity than did preoperative cardiac surgery patients or healthy volunteers ( P P =0.045). Conclusions: CA and CPR activated GSNOR and reduced the number of S-nitrosylated proteins in the brain. Pharmacological inhibition or genetic deletion of GSNOR prevented ischemic brain injury and improved survival rates by restoring S-nitrosylated protein levels in the brain after CA/CPR in mice. Our observations suggest that GSNOR is a novel biomarker of postarrest brain injury as well as a molecular target to improve outcomes after CA.

Purpose of review Severe bleeding events, which require blood transfusions, are a challenge faced by many critical care physicians on a daily basis. Current transfusion guidelines generally recommend rather strict transfusion thresholds and strategies, which can appear opposing to a patient in need for urgent transfusion at first sight. Moreover, applied guidelines are lacking evidence and specificity for the typical ICU patient population and its comorbidities. Transfusion decisions, which are pivotal for clinical outcome, are often unsatisfactorily based on hemoglobin levels only. Recent findings Recent publications generally support previous studies that a strict transfusion regimen is superior to a liberal one for the majority of cases. Newly developed and easily feasible techniques are currently in clinical trials and have the potential to become a valuable supplementation to hemoglobin-guided decision-making. In addition to the choice of the ideal transfusion strategy, physiological status and comorbidities were found to have a major impact on the outcome of severe bleedings in the ICU. Summary The body of evidence for ICU-specific transfusion guidelines is scarce. Critical care physicians should properly evaluate their patient's comorbidities and consider extended point-of-care testing for transfusion decisions in indistinct anemic situations. A strict transfusion strategy should, however, be applied whenever possible.

Nitric Oxide (NO) is administered as gas for inhalation to induce selective pulmonary vasodilation. It is a safe therapy, with few potential risks even if administered at high concentration. Inhaled NO gas is routinely used to increase systemic oxygenation in different disease conditions. The administration of high concentrations of NO also exerts a virucidal effect in vitro. Owing to its favorable pharmacodynamic and safety profiles, the familiarity in its use by critical care providers, and the potential for a direct virucidal effect, NO is clinically used in patients with coronavirus disease-2019 (COVID-19). Nevertheless, no device is currently available to easily administer inhaled NO at concentrations higher than 80 parts per million (ppm) at various inspired oxygen fractions, without the need for dedicated, heavy, and costly equipment. The development of a reliable, safe, inexpensive, lightweight, and ventilator-free solution is crucial, particularly for the early treatment of non-intubated patients outside of the intensive care unit (ICU) and in a limited-resource scenario. To overcome such a barrier, a simple system for the non-invasive NO gas administration up to 250 ppm was developed using standard consumables and a scavenging chamber. The method has been proven safe and reliable in delivering a specified NO concentration while limiting nitrogen dioxide levels. This paper aims to provide clinicians and researchers with the necessary information on how to assemble or adapt such a system for research purposes or clinical use in COVID-19 or other diseases in which NO administration might be beneficial.

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.

Obesity prevalence is increasing in most countries in the world. In the United States, 42% of the population is obese (body mass index (BMI) 30) and 9.2% is obese class III (BMI 40). One of the greatest challenges in critically ill patients with obesity is the optimization of mechanical ventilation. The goal of this review is to describe respiratory physiologic changes in patients with obesity and discuss possible mechanical ventilation strategies to improve respiratory function.Individualized mechanical ventilation based on respiratory physiology after a decremental positive end-expiratory pressure (PEEP) trial improves oxygenation and respiratory mechanics. In a recent study, mortality of patients with respiratory failure and obesity was reduced by about 50% when mechanical ventilation was associated with the use of esophageal manometry and electrical impedance tomography (EIT).Obesity greatly alters the respiratory system mechanics causing atelectasis and prolonged duration of mechanical ventilation. At present, novel strategies to ventilate patients with obesity based on individual respiratory physiology showed to be superior to those based on standard universal tables of mechanical ventilation. Esophageal manometry and EIT are essential tools to systematically assess respiratory system mechanics, safely adjust relatively high levels of PEEP, and improve chances for successful weaning.