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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: 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.

IntroductionPostoperative acute kidney injury (AKI) is a common complication in cardiac surgery. Levels of intravascular haemolysis are strongly associated with postoperative AKI and with prolonged (>90 min) use of cardiopulmonary bypass (CPB). Ferrous plasma haemoglobin released into the circulation acts as a scavenger of nitric oxide (NO) produced by endothelial cells. Consequently, the vascular bioavailability of NO is reduced, leading to vasoconstriction and impaired renal function. In patients with cardiovascular risk factors, the endothelium is dysfunctional and cannot replenish the NO deficit. A previous clinical study in young cardiac surgical patients with rheumatic fever, without evidence of endothelial dysfunction, showed that supplementation of NO gas decreases AKI by converting ferrous plasma haemoglobin to ferric methaemoglobin, thus preserving vascular NO. In this current trial, we hypothesised that 24 hours administration of NO gas will reduce AKI following CPB in patients with endothelial dysfunction.MethodsThis is a single-centre, randomised (1:1) controlled, parallel-arm superiority trial that includes patients with endothelial dysfunction, stable kidney function and who are undergoing cardiac surgery procedures with an expected CPB duration >90 min. After randomisation, 80 parts per million (ppm) NO (intervention group) or 80 ppm nitrogen (N2, control group) are added to the gas mixture. Test gases (N2or NO) are delivered during CPB and for 24 hours after surgery. The primary study outcome is the occurrence of AKI among study groups. Key secondary outcomes include AKI severity, occurrence of renal replacement therapy, major adverse kidney events at 6 weeks after surgery and mortality. We are recruiting 250 patients, allowing detection of a 35% AKI relative risk reduction, assuming a two-sided error of 0.05.Ethics and disseminationThe Partners Human Research Committee approved this trial. Recruitment began in February 2017. Dissemination plans include presentations at scientific conferences, scientific publications and advertising flyers and posters at Massachusetts General Hospital.Trial registration numberNCT02836899.

BACKGROUND: Orthotopic liver transplantation (OLT) is characterized by significant intraoperative hemodynamic variability. Accurate and real-time cardiac output (CO) monitoring aids clinical decision making during OLT. The purpose of this study is to compare accuracy, precision, and trending ability of CO estimation obtained noninvasively using pulse wave transit time (estimated continuous cardiac output [esCCO; Nihon Kohden, Tokyo, Japan]) or thoracic bioimpedance (ICON; Osypka Medical GmbH, Berlin, Germany) to thermodilution cardiac output (TDCO) measured with a pulmonary artery catheter. METHODS: Nineteen patients undergoing OLT were enrolled. CO measurements were collected with esCCO, ICON, and thermodilution at 5 time points: (T1) pulmonary artery catheter insertion; (T2) surgical incision; (T3) portal reperfusion; (T4) hepatic arterial reperfusion; and (T5) abdominal closure. The results were analyzed with Bland-Altman plot, percentage error (the percentage of the difference between the CO estimated with the noninvasive monitoring device and CO measured with the thermodilution technique), 4-quadrant plot with concordance rate (the percentage of the total number of points in the I and III quadrant of the 4-quadrant plot), and concordance correlation coefficient (a measure of how well the pairs of observations deviate from the 45-degree line of perfect agreement). RESULTS: Although TDCO increased at T3-T5, both esCCO and ICON failed to track the changes of CO with sufficient accuracy and precision. The mean bias of esCCO and ICON compared to TDCO were -2.0 L/min (SD, ±2.7 L/min) and -3.3 L/min (SD, ±2.8 L/min), respectively. The percentage error was 69% for esCCO and 77% for ICON. The concordance correlation coefficient was 0.653 (95% confidence interval [CI], 0.283-0.853) for esCCO and 0.310 (95% CI, -0.167 to 0.669) for ICON. Nonetheless, esCCO and ICON exhibited reasonable trending ability of TDCO (concordance rate: 95% [95% CI, 88-100] and 100% [95% CI, 93-100]), respectively. The mean bias was correlated with systemic vascular resistance (SVR) and arterial elastance (Ea) for esCCO (SVR, r = 0.610, 95% CI, 0.216-0.833, P

Objectives Prolonged cardiopulmonary bypass (CPB) is associated with hemolysis, resulting in increased plasma oxyhemoglobin and vascular nitric oxide depletion. The authors hypothesized that hemolysis associated with CPB would reduce nitric oxide bioavailability, resulting in high pulmonary and systemic vascular resistances that after CPB would normalize gradually over time, due to clearance of plasma oxyhemoglobin. The authors also investigated whether prolonged CPB (≥140 min) produced increased levels of hemolysis and greater pulmonary and systemic vasoconstriction. Design Prospective cohort study. Setting Single-center university hospital. Patients The study comprised 50 patients undergoing elective cardiac surgery requiring CPB. Interventions Plasma hemoglobin and plasma nitric oxide consumption were measured before surgery and after CPB. Pulmonary and systemic hemodynamics were measured after CPB. The effects of short (