Extracorporeal Membrane Oxygenation Characteristics and Outcomes in Children and Adolescents With COVID-19 or Multisystem Inflammatory Syndrome Admitted to U.S. ICUs.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) has been used successfully to support adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related cardiac or respiratory failure refractory to conventional therapies. Comprehensive reports of children and adolescents with SARS-CoV-2-related ECMO support for conditions, including multisystem inflammatory syndrome in children (MIS-C) and acute COVID-19, are needed. DESIGN: Case series of patients from the Overcoming COVID-19 public health surveillance registry. SETTING: Sixty-three hospitals in 32 U.S. states reporting to the registry between March 15, 2020, and December 31, 2021. PATIENTS: Patients less than 21 years admitted to the ICU meeting Centers for Disease Control criteria for MIS-C or acute COVID-19. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The final cohort included 2,733 patients with MIS-C ( n = 1,530; 37 [2.4%] requiring ECMO) or acute COVID-19 ( n = 1,203; 71 [5.9%] requiring ECMO). ECMO patients in both groups were older than those without ECMO support (MIS-C median 15.4 vs 9.9 yr; acute COVID-19 median 15.3 vs 13.6 yr). The body mass index percentile was similar in the MIS-C ECMO versus no ECMO groups (89.9 vs 85.8; p = 0.22) but higher in the COVID-19 ECMO versus no ECMO groups (98.3 vs 96.5; p = 0.03). Patients on ECMO with MIS-C versus COVID-19 were supported more often with venoarterial ECMO (92% vs 41%) for primary cardiac indications (87% vs 23%), had ECMO initiated earlier (median 1 vs 5 d from hospitalization), shorter ECMO courses (median 3.9 vs 14 d), shorter hospital length of stay (median 20 vs 52 d), lower in-hospital mortality (27% vs 37%), and less major morbidity at discharge in survivors (new tracheostomy, oxygen or mechanical ventilation need or neurologic deficit; 0% vs 11%, 0% vs 20%, and 8% vs 15%, respectively). Most patients with MIS-C requiring ECMO support (87%) were admitted during the pre-Delta (variant B.1.617.2) period, while most patients with acute COVID-19 requiring ECMO support (70%) were admitted during the Delta variant period. CONCLUSIONS: ECMO support for SARS-CoV-2-related critical illness was uncommon, but type, initiation, and duration of ECMO use in MIS-C and acute COVID-19 were markedly different. Like pre-pandemic pediatric ECMO cohorts, most patients survived to hospital discharge.

High-Dose Inhaled Nitric Oxide for the Treatment of Spontaneously Breathing Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19) Pneumonia.

OBJECTIVE: To evaluate whether the use of inhaled nitric oxide (iNO)200 improves respiratory function. METHODS: 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. RESULTS: 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. CONCLUSION: In pregnant patients with severe bilateral COVID-19 pneumonia, iNO200 was associated with a reduced need for oxygen supplementation and shorter hospital stay.

Safety and practicality of high dose inhaled nitric oxide in emergency department COVID-19 patients.

BACKGROUND: 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). METHODS: 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. FINDINGS: 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. CONCLUSION: 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.

Zonulin Antagonist, Larazotide (AT1001), As an Adjuvant Treatment for Multisystem Inflammatory Syndrome in Children: A Case Series

OBJECTIVES: A recent study suggests that Multisystem Inflammatory Syndrome in Children (MIS-C) is triggered by gastrointestinal breach of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral particles from the gut lumen into systemic circulation. The virus remains in the gut weeks to months after respiratory infection, causing zonulin release from the intestinal epithelial cells. Zonulin loosens tight junctions, permitting trafficking of highly inflammatory viral particles into circulation. Current MIS-C treatments target the subsequent immune hyperactivation, not the causative loss of mucosal barrier integrity. Larazotide, a zonulin inhibitor, prevents breakdown of tight junctions, limiting antigen trafficking. DESIGN: Children with MIS-C were treated with larazotide as an adjuvant to steroid/intravenous immunoglobulin therapy. Clinical outcomes, SARS-CoV-2 antigenemia, and cytokine profiles are reported. Outcomes were compared with children with MIS-C receiving steroids and/or IVIG therapy alone. PATIENTS: Four children with MIS-C, ages 3–17 years, were enrolled. INTERVENTIONS: Patients were treated with open label larazotide 10 mcg/kg (maximum 500 mcg/dose) orally four times daily for 21 days. MEASUREMENTS AND MAIN RESULTS: All four patients tolerated larazotide without adverse effects and displayed reduction in Spike antigenemia to undetectable levels. When compared with 22 children with MIS-C receiving steroids and/or intravenous immunoglobulin therapy alone, larazotide-treated patients reported significantly improved time to resolution of gastrointestinal symptoms (p = 0.03), and time to clearance of Spike antigenemia (p = 0.04), plus a trend towards shorter length of stay. CONCLUSIONS: Larazotide appears safe and well-tolerated and may offer potential benefit as an adjuvant to immune-targeted therapies. Expansion of clinical trials is urgently needed to ascertain the clinical impact of larazotide on MIS-C.

Therapeutic Effects of Inhaled Nitric Oxide Therapy in COVID-19 Patients.

The global COVID-19 pandemic has become the largest public health challenge of recent years. The incidence of COVID-19-related acute hypoxemic respiratory failure (AHRF) occurs in up to 15% of hospitalized patients. Antiviral drugs currently available to clinicians have little to no effect on mortality, length of in-hospital stay, the need for mechanical ventilation, or long-term effects. Inhaled nitric oxide (iNO) administration is a promising new non-standard approach to directly treat viral burden while enhancing oxygenation. Along with its putative antiviral affect in COVID-19 patients, iNO can reduce inflammatory cell-mediated lung injury by inhibiting neutrophil activation, lowering pulmonary vascular resistance and decreasing edema in the alveolar spaces, collectively enhancing ventilation/perfusion matching. This narrative review article presents recent literature on the iNO therapy use for COVID-19 patients. The authors suggest that early administration of the iNO therapy may be a safe and promising approach for the treatment of COVID-19 patients. The authors also discuss unconventional approaches to treatment, continuous versus intermittent high-dose iNO therapy, timing of initiation of therapy (early versus late), and novel delivery systems. Future laboratory and clinical research is required to define the role of iNO as an adjunct therapy against bacterial, viral, and fungal infections.

Operational Innovation in the Provision of Pediatric Extracorporeal Membrane Oxygenation for Multisystem Inflammatory Syndrome in Children.

Treatment of multisystem inflammatory syndrome in children (MIS-C) can require significant critical care resources. Our aim is to alert mixed pediatric and adult hospitals worldwide of the possibility that pediatric and adult patients may simultaneously require cannulation to extracorporeal membrane oxygenation (ECMO) for MIS-C and severe COVID-19. We conducted a retrospective review of operations required to treat cardiogenic shock in 3 pediatric patients with a diagnosis of MIS-C admitted to a single medium-sized pediatric referral center located within a large academic medical center over a 14-day period. At this time, a large number of adult patients required ECMO for severe COVID-19 at our institution. Of the 11 pediatric patients who presented with MIS-C during the first surge of 2020, 2 patients required cannulation to venoarterial extracorporeal membrane oxygenation (VA-ECMO), and a third patient developed a life-threatening arrhythmia requiring transfer to a neighboring institution for consideration of VA-ECMO when our institution's ECMO capacity had briefly been reached. Pediatric referral centers located within institutions providing ECMO to adult patients with severe COVID-19 may benefit from frequent and direct communication with their adult and regional colleagues to devise a collaborative plan for safe and timely provision of ECMO to patients with MIS-C as the ongoing pandemic continues to consume this limited, lifesaving resource.

High-Dose Nitric Oxide From Pressurized Cylinders and Nitric Oxide Produced by an Electric Generator From Air.

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 (NO2) 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 NO2 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.

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.

Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2.

Importance: Multisystem inflammatory syndrome in children (MIS-C) is associated with recent or current SARS-CoV-2 infection. Information on MIS-C incidence is limited. Objective: To estimate population-based MIS-C incidence per 1 000 000 person-months and to estimate MIS-C incidence per 1 000 000 SARS-CoV-2 infections in persons younger than 21 years. Design, Setting, and Participants: This cohort study used enhanced surveillance data to identify persons with MIS-C during April to June 2020, in 7 jurisdictions reporting to both the Centers for Disease Control and Prevention national surveillance and to Overcoming COVID-19, a multicenter MIS-C study. Denominators for population-based estimates were derived from census estimates; denominators for incidence per 1 000 000 SARS-CoV-2 infections were estimated by applying published age- and month-specific multipliers accounting for underdetection of reported COVID-19 case counts. Jurisdictions included Connecticut, Georgia, Massachusetts, Michigan, New Jersey, New York (excluding New York City), and Pennsylvania. Data analyses were conducted from August to December 2020. Exposures: Race/ethnicity, sex, and age group (ie, ≤5, 6-10, 11-15, and 16-20 years). Main Outcomes and Measures: Overall and stratum-specific adjusted estimated MIS-C incidence per 1 000 000 person-months and per 1 000 000 SARS-CoV-2 infections. Results: In the 7 jurisdictions examined, 248 persons with MIS-C were reported (median [interquartile range] age, 8 [4-13] years; 133 [53.6%] male; 96 persons [38.7%] were Hispanic or Latino; 75 persons [30.2%] were Black). The incidence of MIS-C per 1 000 000 person-months was 5.1 (95% CI, 4.5-5.8) persons. Compared with White persons, incidence per 1 000 000 person-months was higher among Black persons (adjusted incidence rate ratio [aIRR], 9.26 [95% CI, 6.15-13.93]), Hispanic or Latino persons (aIRR, 8.92 [95% CI, 6.00-13.26]), and Asian or Pacific Islander (aIRR, 2.94 [95% CI, 1.49-5.82]) persons. MIS-C incidence per 1 000 000 SARS-CoV-2 infections was 316 (95% CI, 278-357) persons and was higher among Black (aIRR, 5.62 [95% CI, 3.68-8.60]), Hispanic or Latino (aIRR, 4.26 [95% CI, 2.85-6.38]), and Asian or Pacific Islander persons (aIRR, 2.88 [95% CI, 1.42-5.83]) compared with White persons. For both analyses, incidence was highest among children aged 5 years or younger (4.9 [95% CI, 3.7-6.6] children per 1 000 000 person-months) and children aged 6 to 10 years (6.3 [95% CI, 4.8-8.3] children per 1 000 000 person-months). Conclusions and Relevance: In this cohort study, MIS-C was a rare complication associated with SARS-CoV-2 infection. Estimates for population-based incidence and incidence among persons with infection were higher among Black, Hispanic or Latino, and Asian or Pacific Islander persons. Further study is needed to understand variability by race/ethnicity and age group.

Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19.

Importance: Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes. Objective: To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19). Setting, Design, and Participants: Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement. Exposure: SARS-CoV-2. Main Outcomes and Measures: Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19. Results: Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P < .001), higher C-reactive protein level (median, 152 mg/L vs 33 mg/L; P < .001), and lower platelet count (<150 ×103 cells/µL [212/523 {41%} vs 84/486 {17%}, P < .001]). A total of 398 patients (73.8%) with MIS-C and 253 (43.8%) with COVID-19 were admitted to the intensive care unit, and 10 (1.9%) with MIS-C and 8 (1.4%) with COVID-19 died during hospitalization. Among patients with MIS-C with reduced left ventricular systolic function (172/503, 34.2%) and coronary artery aneurysm (57/424, 13.4%), an estimated 91.0% (95% CI, 86.0%-94.7%) and 79.1% (95% CI, 67.1%-89.1%), respectively, normalized within 30 days. Conclusions and Relevance: This case series of patients with MIS-C and with COVID-19 identified patterns of clinical presentation and organ system involvement. These patterns may help differentiate between MIS-C and COVID-19.

Adult COVID-19 Patients Cared for in a Pediatric ICU Embedded in a Regional Biothreat Center: Disease Severity and Outcomes.

The objective of this study was to describe the clinical characteristics and outcomes of adult coronavirus disease 2019 (COVID-19) patients admitted to a pediatric intensive care unit (PICU), with assessment of respiratory clinical severity and outcomes when cared for by pediatric intensivists utilizing specific care processes. We conducted a retrospective cohort study of adult patients admitted to the 14-bed PICU of a quaternary referral center during the COVID-19 surge in Boston between April and June 2020. A total of 37 adults were admitted: 28 tested COVID-19 positive and 9 tested COVID-19 negative. Of the COVID-19-positive patients, 21 (75%), were male and 12 (60.7%) identified as Hispanic/Latino. Comorbidities in the patients included diabetes mellitus (39.3%), hyperlipidemia (39.3%), and hypertension (32.1%). Twenty-four (85.7%) required mechanical ventilation, in whom the lowest median ratio of arterial oxygen partial pressure to fractional inspired pressure was 161.5 (141.0 to 184.5), the median peak positive end-expiratory pressure (PEEP) was 14 (12.0 to 15.8) cmH2O and 15 (62.5%) underwent an optimal PEEP maneuver. Twelve (50%) patients were proned for a median of 3.0 (3.0 to 4.8) days. Of the 15 patients who were extubated, 3 (20%) required reintubation. Tracheostomy was performed in 10 patients: 3 after extubation failure and 7 for prolonged mechanical ventilation and weakness. Renal replacement therapy was required by 4 (14.3%) patients. There were 2 (7.1%) mortalities. We report detailed clinical outcomes of adult patients when cared for by intact pediatric critical care teams during the COVID-19 pandemic. Good clinical outcomes, when supported by adult critical care colleagues and dedicated operational processes are possible.

Rescue Treatment With High-Dose Gaseous Nitric Oxide in Spontaneously Breathing Patients With Severe Coronavirus Disease 2019.

Treatment options are limited for patients with respiratory failure due to coronavirus disease 2019. Conventional oxygen therapy and awake proning are options, but the use of high-flow nasal cannula and continuous positive airway pressure are controversial. There is an urgent need for effective rescue therapies. Our aim is to evaluate the role of inhaled nitric oxide 160 ppm as a possible rescue therapy in nonintubated coronavirus disease 2019 patients. DESIGN: Retrospective evaluation of coronavirus disease 2019 patients in respiratory distress receiving nitric oxide gas as rescue therapy. SETTING: Massachusetts General Hospital, between March 18, 2020, and May 20, 2020, during the local coronavirus disease 2019 surge. PATIENTS: Coronavirus disease 2019 patients at high risk for acute hypoxemic respiratory failure with worsening symptoms despite use of supplemental oxygen and/or awake proning. INTERVENTIONS: Patients received nitric oxide at concentrations of 160 ppm for 30 minutes twice per day via a face mask until resolution of symptoms, discharge, intubation, or the transition to comfort measures only. MEASUREMENTS AND MAIN RESULTS: Between March 18, 2020, and May 20, 2020, five patients received nitric oxide inhalation as a rescue therapy for coronavirus disease 2019 at Massachusetts General Hospital. All received at least one dosage. The three patients that received multiple treatments (ranging from five to nine) survived and were discharged home. Maximum methemoglobin concentration after 30 minutes of breathing nitric oxide was 2.0% (1.7-2.3%). Nitrogen dioxide was below 2 ppm. No changes in mean arterial pressure or heart rate were observed during or after nitric oxide treatment. Oxygenation and the respiratory rate remained stable during and after nitric oxide treatments. For two patients, inflammatory marker data were available and demonstrate a reduction or a cessation of escalation after nitric oxide treatment. CONCLUSIONS: Nitric oxide at 160 ppm may be an effective adjuvant rescue therapy for patients with coronavirus disease 2019.

High Concentrations of Nitric Oxide Inhalation Therapy 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.