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.

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.

Haemodynamic effects of cold versus warm fluid bolus in healthy volunteers: a randomised crossover trial.

OBJECTIVE: To test the hypothesis that changes in cardiac index and mean arterial pressure (MAP) during and after a fluid bolus (FB) are altered by fluid temperature. DESIGN: Randomised, controlled, crossover trial. SETTING: Research laboratory at Swedish teaching hospital. PARTICIPANTS: Twenty-one healthy adult volunteers. INTERVENTIONS: Subjects were randomly allocated to 500 mL of Ringer's acetate at room temperature (22°C; cold) or body temperature (38°C; warm). MAIN OUTCOME MEASURES: For 2 hours after starting the FB, we measured cardiac index, MAP, systolic blood pressure, diastolic blood pressure and pulse rate (PR) continuously. We recorded temperature and O2 saturation every 5 minutes during infusion and every 15 minutes thereafter. In a second session, volunteers crossed over. RESULTS: During the first 15 minutes, mean cardiac index increased more with warm FB (0.09 L/min/m2 [95% CI, 0.06-0.11] v 0.03 L/min/m2 [95% CI, 0.01-0.06]; P < 0.001). This effect was mediated by a significant difference in mean PR (+0.80 beats/min [95% CI, 0.47-1.13] v -1.33 beats/ min [95% CI, -1.66 to -1.01]; P < 0.010). In contrast, MAP increased more with cold FB (4.02 mmHg [95% CI, 3.63-4.41] v 0.60 mmHg [95% CI, 0.26-0.95]; P < 0.001). Cardiac index and MAP returned to baseline after a median of 45.3 min (interquartile range [IQR], 10.7-60.7 min) and 27.7 min (IQR, 5.3-105.0 min), respectively, after cold FB, and by 15.8 min (IQR, 3.8-64.3 min) and 22.7 min (IQR, 3.3-105.0 min), respectively, after warm FB. CONCLUSION: Intravenous FB at body temperature leads to a greater increase in cardiac index compared with room temperature, while the reverse applies to MAP. These findings imply that in healthy volunteers, when a room temperature FB is given, the temperature of the fluid rather than its volume accounts for most of the MAP increase. TRIAL REGISTRATION: EudraCT no. 2016-002548-18 and Clinicaltrials.gov NCT03209271.

Impact of hemodynamic goal-directed resuscitation on mortality in adult critically ill patients: a systematic review and meta-analysis.

The effect of hemodynamic optimization in critically ill patients has been challenged in recent years. The aim of the meta-analysis was to evaluate if a protocolized intervention based on the result of hemodynamic monitoring reduces mortality in critically ill patients. We performed a systematic review and meta-analysis according to the Cochrane Handbook for Systematic Reviews of Interventions. The study was registered in the PROSPERO database (CRD42015019539). Randomized controlled trials published in English, reporting studies on adult patients treated in an intensive care unit, emergency department or equivalent level of care were included. Interventions had to be protocolized and based on results from hemodynamic measurements, defined as cardiac output, stroke volume, stroke volume variation, oxygen delivery, and central venous-or mixed venous oxygenation. The control group had to be treated without any structured intervention based on the parameters mentioned above, however, monitoring by central venous pressure measurements was allowed. Out of 998 screened papers, thirteen met the inclusion criteria. A total of 3323 patients were enrolled in the six trials with low risk of bias (ROB). The mortality was 22.4% (374/1671 patients) in the intervention group and 22.9% (378/1652 patients) in the control group, OR 0.94 with a 95% CI of 0.73-1.22. We found no statistically significant reduction in mortality from hemodynamic optimization using hemodynamic monitoring in combination with a structured algorithm. The number of high quality trials evaluating the effect of protocolized hemodynamic management directed towards a meaningful treatment goal in critically ill patients in comparison to standard of care treatment is too low to prove or exclude a reduction in mortality.