High-Dose Inhaled Nitric Oxide in Acute Hypoxemic Respiratory Failure Due to COVID-19: A Multicenter Phase II Trial.

Rationale: The effects of high-dose inhaled nitric oxide on hypoxemia in coronavirus disease (COVID-19) acute respiratory failure are unknown. Objectives: The primary outcome was the change in arterial oxygenation (PaO2/FiO2) at 48 hours. The secondary outcomes included: time to reach a PaO2/FiO2.300mmHg for at least 24 hours, the proportion of participants with a PaO2/FiO2.300mmHg at 28 days, and survival at 28 and at 90 days. Methods: Mechanically ventilated adults with COVID-19 pneumonia were enrolled in a phase II, multicenter, single-blind, randomized controlled parallel-arm trial. Participants in the intervention arm received inhaled nitric oxide at 80 ppm for 48 hours, compared with the control group receiving usual care (without placebo). Measurements and Main Results: A total of 193 participants were included in the modified intention-to-treat analysis. The mean change in PaO2/FiO2 ratio at 48 hours was 28.3mmHg in the intervention group and 21.4mmHg in the control group (mean difference, 39.1mmHg; 95% credible interval [CrI], 18.1 to 60.3). The mean time to reach a PaO2/FiO2.300mmHg in the interventional group was 8.7 days, compared with 8.4 days for the control group (mean difference, 0.44; 95% CrI, 23.63 to 4.53). At 28 days, the proportion of participants attaining a PaO2/FiO2.300mmHg was 27.7% in the inhaled nitric oxide group and 17.2% in the control subjects (risk ratio, 2.03; 95% CrI, 1.11 to 3.86). Duration of ventilation and mortality at 28 and 90 days did not differ. No serious adverse events were reported. Conclusions: The use of high-dose inhaled nitric oxide resulted in an improvement of PaO2/FiO2 at 48 hours compared with usual care in adults with acute hypoxemic respiratory failure due to COVID-19.

Pre-oxygenation using high-flow nasal oxygen in parturients undergoing caesarean section in general anaesthesia: A prospective, multi-centre, pilot study.

BACKGROUND: Parturients undergoing caesarean section in general anaesthesia have an increased risk of desaturating during anaesthesia induction. Pre- and peri-oxygenation with high-flow nasal oxygen prolong the safe apnoea time but data on parturients undergoing caesarean section under general anaesthesia are limited. This pilot study aimed to investigate the clinical effects and frequency of desaturation in parturients undergoing caesarean section in general anaesthesia pre- and peri-oxygenated with high-flow nasal oxygen and compare this to traditional pre-oxygenation using a facemask. METHODS: In this prospective, non-randomised, multi-centre study we included pregnant women with a gestational age ≥30 weeks undergoing caesarean section under general anaesthesia. All parturients were asked to participate in the intervention group consisting of pre-oxygenation using high-flow nasal oxygen. Parturients declining participation were pre-oxygenated with a traditional facemask. Primary outcome was the proportion of parturients desaturating below 93% from start of pre-oxygenation until 1 min after tracheal intubation. Secondary outcomes investigated end-tidal oxygen concentrations after tracheal intubation and the proportion of parturients with signs of regurgitation. RESULTS: A total of 34 parturients were included, 25 pre- and peri-oxygenated with high-flow nasal oxygen and 9 pre-oxygenated with facemask. No difference in patient or airway characteristics could be seen except for a higher BMI in the high-flow nasal oxygen group (31.4 kg m-2 [4.7] vs. 27.7 kg m-2 [3.1]; p = .034). No woman in any of the two groups desaturated below 93%. The lowest peripheral oxygen saturation observed, in any parturient, was 97%. There was no difference detected in end-tidal oxygen concentration after tracheal intubation, 87% (6) in the high-flow nasal oxygen group vs 80% (15) in the facemask group (p = .308). No signs of regurgitation, in any parturient, were seen. CONCLUSION: Pre- and peri-oxygenation with high-flow nasal oxygen maintain adequate oxygen saturation levels during induction of anaesthesia also in parturients. Regurgitation of gastric content did not occur in any parturient and no other safety concerns were observed in this pilot study.

An observational study of intensivists' expectations and effects of fluid boluses in critically ill patients.

BACKGROUND: Fluid bolus therapy (FBT) is common in ICUs but whether it achieves the effects expected by intensivists remains uncertain. We aimed to describe intensivists' expectations and compare them to the actual physiological effects. METHODS: We evaluated 77 patients in two ICUs (Sweden and Australia). We included patients prescribed a FBT ≥250 ml over ≤30 minutes. The intensivist completed a questionnaire on triggers for and expected responses to FBT. We compared expected with actual values at FBT completion and after one hour. RESULTS: Median bolus size (IQR) was 300 ml (250-500) given over a median (IQR) of 21 minutes (15-30 mins). Boluses were 57% Ringer´s Acetate and 43% albumin (40-50g/L). Hypotension was the most common trigger (47%), followed by oliguria (21%). During FBT, 55% of patients received noradrenaline and 38% propofol. Intensivists expected a median MAP increase of 2.6 mmHg (IQR: -3.1 to +6.8) at end of bolus and of 1.3 mmHg (-3.5 to + 4.1) after one hour. Intensivist´s' expectations were judged to be accurate if they were within 5% above or below measured values. At FBT completion, 33% of MAP expectations were overestimations and 42% were underestimations. One hour later, 19% were overestimations and 43% were underestimations. Only 8% of expectations of measured urine output (UO) were accurate and 44% were overestimations. Correction for sedation or vasopressors did not modify these findings. CONCLUSIONS: The physiological expectations of intensivists after FBT carried a high risk of both over and underestimation. Since the physiological effect FBT was often small and did not meet clinical expectations, a reassessment of its rationale, effect, duration, and role appears justified.

Wedging the pulmonary artery catheter: changes in left atrial and pulmonary artery pressures and risk for perforation.

OBJECTIVE: Clinical and experimental data indicate that when there is lung disease, wedging the pulmonary artery catheter (PAC) could cause decreases in cardiac output and systemic arterial blood pressure and an increase in mean pulmonary artery pressure (PAP). The authors studied whether wedging would alter mean left atrial pressure (LAP), and report perforations with PACs in their unit since 1975. DESIGN: Observational study. SETTING: University hospital operating room and intensive care unit. PARTICIPANTS: Ten adult patients undergoing cardiac surgery. INTERVENTIONS: Placement of epidural catheters in the left atrium and pulmonary artery, and a PAC. MEASUREMENTS AND MAIN RESULTS: After weaning from cardiopulmonary bypass, mean LAP, mean PAP, and cardiac output were measured before and during wedging with the chest open and closed. Mean LAP decreased during wedging, from 13.5 +/- 2.8 (SD) mmHg to 13.0 +/- 3.0 mmHg (open chest) and from 15.8 +/- 3.2 mmHg to 15.3 +/- 3.1 mmHg (closed chest; p < 0.001), and mean PAP increased, from 18.8 +/- 3.5 mmHg to 19.7 +/- 3.5 mmHg (open chest) and from 21.3 +/- 4.3 mmHg to 21.9 +/- 4.2 mmHg (closed chest; p < 0.001). Mean PAP-mean LAP increased by 20% to 25%. Wedge pressure did not differ from mean LAP. Cardiac output and systemic arterial pressure did not change. Four perforations due to PACs occurred since 1975. CONCLUSIONS: In adult patients undergoing cardiac surgery, wedging of a PAC resulted in a small decrease in mean LAP and a small increase in mean PAP. The wedging maneuver carries a small risk. How wedging is performed could influence the risk for perforation.

Intragastric nitric oxide is abolished in intubated patients and restored by nitrite.

OBJECTIVE: Nitrite in saliva is reduced to nitric oxide (NO) in the acidic stomach, and this NO may serve gastroprotective functions. We studied intragastric NO levels in healthy controls and in intubated intensive care unit patients before and after supplementation with nitrite. DESIGN: Prospective observational study involving patients and controls. SETTING: A mixed intensive care unit and a university laboratory. PATIENTS AND SUBJECTS: Eight healthy volunteers and ten intubated, mechanically ventilated intensive care unit patients. INTERVENTIONS: A tonometric catheter was first evaluated in vitro and then used for all NO measurements. In fasting controls, gastric NO levels were measured repeatedly during periods of saliva depletion and after an intragastric nitrite infusion. In patients, changes in levels of intragastric NO, nitrite in plasma and gastric juice, and S-nitrosothiols in gastric juice were measured in response to an intragastric nitrite infusion. MEASUREMENTS AND MAIN RESULTS: The tonometric catheter had a recovery of 80% with a high intraclass and interclass correlation. Median baseline NO levels in healthy volunteers were 21.6 ppm (interquartile range, 11.4-22.3 ppm) and decreased by 90% to 3.3 ppm (2.0-5.2 ppm) during 25-50 mins of saliva depletion. The NO level was restored by an intragastric nitrite infusion. Baseline NO levels in patients were almost abolished (0.1 ppm [0.07-0.4 ppm]) but increased rapidly to 124 ppm (range, 65-180 ppm) during intragastric nitrite infusion. Nitrite levels in plasma increased from 0.18 +/- 0.03 to 1.3 +/- 0.2 microM (p < .01), and levels of S-nitrosothiols in gastric juice increased from 0.12 +/- 0.09 to 6.7 +/- 1.8 microM. CONCLUSIONS: Intragastric generation of NO requires continuous delivery of nitrite-containing saliva and is almost abolished in critically ill, intubated patients. Enteral supplementation with nitrite could however fully restore gastric NO levels. Future studies will reveal if low NO levels contribute to stress ulcers and gastric overgrowth of bacteria often seen in these patients and in turn if restoring gastric NO with nitrite could be a useful therapeutic approach.

Multiple single-breath measurements of nitric oxide in the intubated patient.

Multiple flow rate measurements of exhaled nitric oxide (NO) have been advocated to fractionate NO from alveolar and bronchial sources. The aim of this study was to develop a method by which multiple single-breath exhalations at various flow rates could be performed in intubated, mechanically ventilated patients. Nine patients without lung disease were studied awake and after intubation, during general anesthesia. A suction ejection system connected to a restrictor valve was used to control the exhalation flow rate. From these measurements the fraction of alveolar NO (FANO), the fraction of airway wall NO (FawNO), and the airway wall transfer rate (DNO) were calculated. The fraction of exhaled NO was reduced by 50% after intubation. DNO was also reduced by intubation (from 10 +/- 1.3 to 6.4 +/- 2.1 nl second(-1) ppb(-1) x 10(-3)) whereas neither FawNO nor FANO was affected. The peak NO concentration after 20 seconds of apnea during general anesthesia was similar to calculated FawNO. The vacuum aspiration method used in this study allowed for reproducible multiple single-breath measurements and calculation of alveolar and bronchial NO parameters. Further studies will reveal whether this methodology will improve the value of exhaled NO analysis in intubated, mechanically ventilated patients with pulmonary disease.

Endogenous nitric oxide release by vasoactive drugs monitored in exhaled air.

Direct measurements of endogenous nitric oxide (NO) release is of great interest but difficult to perform in vivo. We hypothesized that endogenous NO release from vasoactive substances would be detectable in exhaled air. Exhaled NO was measured after intravenous injections of various endothelium-dependent and endothelium-independent vasoactive drugs, in anesthetized pigs and humans. In pigs, a dose-dependent release of exhaled NO was observed for acetylcholine (ACh), bradykinin, substance P, endothelin (ET)-1, and nitroglycerine. Each compound had an individual and highly reproducible release pattern. Bradykinin-induced NO release was enhanced by angiotensin converting enzyme inhibition. ET receptor antagonism markedly reduced the response in exhaled NO to ET-1, whereas atropin abolished the NO response to ACh. NO synthase inhibition abolished basal levels of exhaled NO as well as the responses in exhaled NO to all compounds except nitroglycerine. In humans, ACh evoked a dose-dependent increase of NO levels in exhaled air. NO release by endogenous vasoactive agonists can be measured online in the exhaled air of pigs and humans. These novel findings may be useful when characterizing NO release from compounds that interfere with NO synthesis or drugs that act as donors of NO. Moreover, the possibility of using exhaled NO as an indicator of pulmonary endothelial dysfunction merits further studies.