Analysis of patients with severe ARDS on VV ECMO with pulmonary hypertension or right ventricular failure treated with iNO: a retrospective observational study

doi:10.21203/rs.3.rs-2231530/v2

Background: In a retrospective observational study, we investigated patients with severe acute respiratory distress syndrome (ARDS) undergoing veno-venous (VV) extracorporeal membrane oxygenation (ECMO) support with known pulmonary arterial hypertension (PAH) and/or right ventricular (RV) failure treated with iNO.

Objective: We analysed clinical characteristics such as time on mechanical ventilation, weaning from VV ECMO, organ dysfunction, the iNO therapy in terms of indication, dosing and duration, the ability of iNO to lower PAH in responder and non-responder patients, the survival rate, in-hospital mortality and long-term survival.

Results: Of the 657 patients identified with ECMO support, 292 under VV ECMO support were evaluated and n=55 patients with iNO were included. We found that in-hospital mortality and long-term survival were poor in patients with severe ARDS under VV ECMO support with persistent PAH and/or RV failure. A rescue therapy with the pulmonary vasodilator iNO showed that only one-third of the cohort responded to the therapy with a sufficient decrease of the mean PAP. Survival between iNO responder and non-responder showed a trend albeit data between the groups were not statistically significant. We did not find a higher rate of continuous renal replacement therapy as marker for acute renal failure when iNO concentrations were ≤ 20 ppm and when the treatment duration stayed ≤ 3 days.

Conclusions: This retrospective observational study suggests that persistent PAH and/or RV failure is associated with worse clinical outcome in patients with severe ARDS and VV-ECMO support. Concomitant treatment with the pulmonary vasodilator iNO reduced PAH and/or reversed RV dysfunction in only one-third of the patient population (iNO responder patients) but did not alter the rate of acute kidney failure.

Inhaled nitric oxide

ARDS

VV ECMO

right heart failure

pulmonary hypertension

iNO responder

Inhaled nitric oxide (iNO) has been widely used as a selective pulmonary vasodilator to treat pulmonary arterial hypertension (PAH) and/or right ventricular failure (RV failure).¹ iNO is only distributed to ventilated lung regions and exerts the unique ability of selectively inducing smooth muscle relaxation in the pulmonary vasculature in the said regions.^1,2 Thus, iNO improves arterial blood oxygenation, decreases intrapulmonary shunting, and enhances blood flow distribution towards ventilated alveolar regions of the lungs.^2,3 The high affinity of nitric oxide (NO) to oxyhaemoglobin in red blood cells leads to the rapid formation of nitrate and methaemoglobin; this mechanism limits the vasodilation effects to the pulmonary vasculature and thereby avoids systemic arterial hypotension.^4,5 Inhaled NO concentrations of up to 80 parts per million (ppm) have been administered safely without unfavourable systemic side effects.^6–8

Patients suffering from acute respiratory distress syndrome (ARDS) frequently present with PAH whereas increased intrapulmonary shunting caused by perfusion of non-aerated alveoli contributes to severe arterial hypoxemia.^9,10 Moreover, elevated pulmonary artery pressure raises transcapillary pressure and thereby increases the risk of alveolar oedema, which may aggravate ARDS.^11,12 In addition, PAH may lead or contribute to RV failure and is an independent risk factor for mortality in patients with ARDS.^13,14 Given its pharmacological properties, iNO may lower pulmonary arterial pressure, thereby reducing the risk of RV failure and intrapulmonary shunting.^15–17 Although randomised controlled trials (RCTs) on iNO use have shown both improved oxygenation and hemodynamics in the acute phase of ARDS in adults, all studies thus far have failed to demonstrate any clinically significant benefit of iNO on survival or ventilator-free days.^18,19

Venovenous extracorporeal membrane oxygenation (VV ECMO), widely considered a life-saving procedure, may restore oxygenation and eliminate carbon dioxide accumulation when conventional mechanical ventilation fails to ensure a sufficient gas exchange in severe ARDS.^20–22

Patients with severe ARDS and VV ECMO support with concomitant iNO administration represent a very specific and limited cohort. Data that elucidate the use of iNO in this specific cohort are lacking and little is known about survival and mortality in this population. To gain more insight into this specific and limited group of critically ill patients, we performed a retrospective observational study of patients with severe ARDS and VV ECMO support with PAH and/or RV failure treated with iNO as rescue therapy.

Study design

This retrospective observational study was conducted following the Strengthening the Reporting of Observational Studies in Epidemiology statement.

Objectives

The objectives were:

to describe iNO treatment in terms of indication, dosing, and duration of application.
to measure the iNO ability to lower mean pulmonary arterial pressure (PAP) in patients under VV ECMO support who are responders and non-responders to iNO.
to describe the clinical characteristics, such as time on mechanical ventilation, weaning from VV ECMO, and organ dysfunction, as defined using the sequential organ failure assessment (SOFA) score,²³
to measure outcome parameters, such as survival on ICU, in-hospital mortality, and long-term survival;

Study population

Data on all ECMO patients treated on the intensive care unit of the Department of Anaesthesiology and Intensive Care Medicine at the quaternary level of the University Hospital, Bonn, Germany, between May 2015 and May 2021 were collected.

Inclusion criteria

Age >18 years old;
Electronic medical records available, including VV ECMO run parameters, vital parameters, and laboratory measurements (both point-of-care and laboratory diagnostics);
VV ECMO support;
ARDS following the Berlin definition,²⁰ and
iNO administration.

Exclusion criteria

Veno-arterial ECMO support.

Indication for ECMO

Indications for VV ECMO support complied with the Extracorporeal Life Support Organization General Guidelines.²⁴ Indications included treatment of severe hypoxaemia and hypercapnia and prevention of possible harmful mechanical ventilation (i.e., prolonged use of exceedingly high peak inspiratory pressures or driving pressure > 15 cmH₂O) to ensure sufficient gas exchange according to ARDS network definitions.²⁵ All decisions for initiating VV ECMO support were based on the consensus between at least two experienced senior critical care physicians of the ARDS/ECMO team of the current study.

Indication for iNO delivery and definition of PAH and RV failure

iNO (NO-A nitric oxide delivery system, EKU Elektronik GmbH, Germany) was administered at the treating physician’s discretion after bedside evaluation of pulmonary hemodynamics and right heart function, as indicated by invasive pulmonary hemodynamics (assessed using a Swan–Ganz catheter) and/or transoesophageal echocardiography. A mean PAP (mPAP) ≥ 25 mmHg was used as a cut-off value for iNO application.²⁶ A positive response to iNO was determined as an mPAP reduction of ≥ 6 mmHg following administration of iNO within 30min. Other indicators, such as pulmonary vascular resistance or cardiac index, were not used due to insufficient data regarding their validity during extracorporeal life support.

In the present study, RV failure is defined by transoesophageal echocardiography, as suggested by Vieillard-Baron et al.²⁷ In severe ARDS, acute cor pulmonale or severe RV dilatation accurately reflects RV failure, particularly when right atrial pressure is increased.

Ethical approval/informed consent

Ethical approval for the current study was provided by the ethics committee (no. 492/20) of the University Hospital of Bonn, Germany, and the need for informed consent was waived.

Statistical analyses

All data are presented as the median and interquartile range (IQR) for non-normally distributed variables or mean ± standard deviation for normally distributed continuous variables, as appropriate, and frequency distributions with percentages for categorical variables. The paired t-test was used to analyse group differences in normally distributed variables, whereas the Wilcoxon test was used for non-normally distributed variables. Nominal variables were assessed using McNemar’s test for 2 × 2 tables.

The Kaplan–Meier method and the stratified log-rank test were performed to analyse survival.²⁸ All analyses were performed on R version 4.1.2.²⁹ All tests were two-sided, and p < 0.05 was determined as the cut-off for significance. No adjustments were made for multiple tests, and P values should be interpreted as exploratory only.

Identification and characteristics of the eligible study cohort

To identify the eligible study cohort, 657 patients under ECMO were screened during the study period. Patients with complete electronic medical records were analysed (Figure 1). In addition, 292 patients who underwent VV ECMO support were identified as the eligible study cohort, which included 55 individuals with known PAH and/or RV failure administered with iNO as rescue therapy. This study cohort will be further analysed and discussed and represents the group of interest for the retrospective observational analysis. Both the baseline and clinical characteristics are provided in Tables 1 and 2.

Indication, dosing, and duration of iNO treatment in patients under VV ECMO

To evaluate whether patients under VV ECMO support may benefit from iNO administration, transoesophageal echocardiography, and/or invasive monitoring using a pulmonary artery catheter were performed before the start of iNO. Subsequently, three groups of indications were identified for the use of iNO in patients undergoing VV ECMO (Table 1): PAH, RV failure, or a combination of both pathologies.

In addition, the iNO doses administered in the VV ECMO patient cohort were investigated (Figure 2A). iNO was administered at an average dose of 14.5 ± 5.5 ppm (ranging from a minimum dose of 6.9 ppm to a maximum of 20 ppm). The duration of treatment was 3 days (IQR, 1.76–4.41; Figure 2B).

Ability of iNO to lower mean PAP in responder and nonresponder patients

As mentioned in the Methods section, a positive response to iNO was defined as a mPAP decrease ≥ 6 mmHg. In n=37 patients, a Swan-Ganz catheter was inserted to continuously monitor pulmonary hemodynamics, allowing us to distinguish between iNO responders and nonresponders in these cases (in contrast to patients who were monitored discontinuously and solely by echocardiography). Responder patients with ARDS under VV ECMO showed a significant decrease in mPAP when iNO was administered (mPAP before iNO [40.1 ± 5.6 mmHg] vs. mPAP during iNO [30.5 ± 5.0 mmHg]; p < 0.0001; Figure 2C). In contrast, nonresponder patients with ARDS did not show a significant decrease in mPAP during iNO treatment (mPAP before iNO [36.9 ± 8.1 mmHg] vs. mPAP during iNO [35.9 ± 8.2 mmHg]; p = 0.1873; Figure 2D).

Organ failure, ECMO circuit weaning, and rate of tracheostomy

Weaning failure from VV ECMO support was observed in n = 37 [67.3%] iNO-treated patients. The total time on mechanical ventilation was 24 days. Also, the time on mechanical ventilation before VV ECMO, duration of VV ECMO, and rate of tracheostomy in iNO-treated patients have been reported in Table 2.

Adjunctive therapies, i.e., continuous kidney replacement therapy and prone positioning before or during VV ECMO support, were also reported in Table 2. Apart from the SOFA score on ICU admission, the severity of further organ failure was assessed using the cardiopulmonary resuscitation rate before ECMO and the rate of sepsis, as defined by SEPSIS-3.³⁰ Values obtained can be found in Table 2.

Standard ventilation parameters and blood gas analyses both on days 1, 3, and 7 during VV ECMO

To avoid the onset of PAH and/or RV failure, optimizing respiratory conditions in patients with ARDS is strongly recommended because a driving pressure ≥ 18 cmH₂O,arterial partial pressure of carbon dioxide (P_aCO₂) ≥ 48 mmHg, and P_aO₂/F_IO₂ < 150 mmHg have been reported as risk factors.³¹

Ventilation parameters and arterial blood gas analyses were both recorded on days 1, 3, and 7 during VV ECMO with iNO treatment (Table 3). These findings showed no differences in minute ventilation, positive end-expiratory pressure (PEEP), or peak inspiratory pressure between the different days. Ventilation parameters, as well as arterial blood gas analyses, showed results that comply with the respective ARDS guidelines on mechanical ventilation.³²

Outcomes

Table 4 presents the data on the length of ICU and hospital stay, in-hospital mortality rate, and median survival time of the study cohort. The length of ICU stay was 23 days and total hospital stay 27 days in iNO treated patients. The in-hospital mortality rate was n=38 (69.1%). Median survival was 22 days [95% CI, 14,37] in patients with iNO breathing.

To evaluate whether survival may depend on the ability of iNO to lower elevated mPAP, a subgroup analysis of the survival rates was performed in the iNO responder and non-responder groups. Figure 3B shows that the survival in iNO treated patients differed between iNO responders (36.4%) and non-responders (23.1%), albeit not statistically significant (p = 0.0623, Figure 3).

The Kaplan–Meier curve in Figure 4 shows the long-term survival rate (90 days) of patients with severe ARDS on VV ECMO support with PAH and/or RV failure treated with iNO.

We investigated in a retrospective observational study patients with severe ARDS undergoing VV ECMO support with concomitant iNO administration to gain more insight into this specific population. We analysed clinical characteristics such as time on mechanical ventilation, weaning from VV ECMO, organ dysfunction, the iNO treatment in terms of indication, dosing and duration, the ability of iNO to lower PAP in responder and non-responders patients, the survival rate, in-hospital-mortality and long-term survival. We found that in-hospital mortality and long-term survival were generally poor in patients with severe ARDS under VV ECMO support with persistent PAH and/or RV failure. A rescue therapy with the pulmonary vasodilator iNO showed that only one-third of the cohort responded to the therapy with a sufficient decrease of the mean PAP. Survival between iNO responder and non-responder showed a trend albeit data between the groups were not statistically significant. We did not find an increased rate of continuous kidney replacement therapy as marker for acute renal failure when iNO concentrations were ≤ 20 ppm and when the treatment duration stayed ≤ 3 days.

Pulmonary vascular dysfunction is one of the pathophysiological hallmarks of ARDS and ultimately leads to a certain degree of PAH.³³ Recent data suggest that PAH and subsequent RV failure are medical burdens that occur in every second patient with moderate to severe ARDS and are independently associated with the risk of mortality.^33,34 In ARDS, multiple pathophysiological mechanisms that directly cause injury to pulmonary circulation include endothelial dysfunction, distal pulmonary vascular occlusion at the capillary level, pulmonary vasoconstriction, extrinsic vessel occlusion by alveoli distention, and, ultimately, vascular remodeling.³⁵ These mechanisms lead to increased pulmonary vascular resistance, precapillary pulmonary hypertension, and increased RV afterload.³⁵ The uncoupling between pulmonary circulation and the right heart ultimately leads to the breakdown of oxygen delivery.

Various strategies, including limiting volume loading and correcting blood pressure by infusing norepinephrine, have been suggested to decrease RV wall stress and RV end-diastolic pressure, thereby improving RV stroke volume.³⁶ The patients of the current study received a restrictive fluid regimen and norepinephrine to avoid hypotension, as described previously.³²

Both hypoxia and hypercapnia strongly increase pulmonary vasoconstriction and contribute to PAH.³⁷ Severe ARDS per se is associated with profound hypoxia, which may be accompanied by hypercapnia.³⁸ Hypercapnia is the consequence of protective ventilatory strategies designed to reduce ventilator-induced lung injury. It also reflects increased dead space due to alveolar overdistension and ARDS severity.³⁹

Higher PEEP levels are frequently required in severe ARDS to avoid life-threatening hypoxia. However, transpulmonary pressure, despite low tidal ventilation when lung compliance decreases due to alveolar collapse, may be associated with increased end-inspiratory airway pressure.⁴⁰ Consequently, pulmonary capillaries become stretched and their caliber is reduced, resulting in increased pulmonary vasoconstriction.^41,42

By controlling arterial oxygenation and decarboxylation, even during ultraprotective ventilation,³⁸ VV ECMO suppresses the major factors that increase pulmonary vascular resistance and cause PAH in severe ARDS, thereby sufficiently unloading the RV.⁴³ In this study cohort, VV ECMO was indicated to correct hypoxaemia and hypercapnia, as well as allow ultraprotective ventilation, to prevent peak inspiratory (>27 cmH₂O) and/or driving (>15 cmH₂O) pressure (Table 3). Although VV ECMO initiation in the current study resulted in adequate arterial oxygenation and normocapnia at a peak inspiratory and driving pressures < 25 cmH₂O and < 10 cmH₂O, respectively, PAH with or without RV failure persisted in these patients with severe ARDS.

Although iNO in ARDS has been widely abandoned by intensivists because RCTs and meta-analyses have demonstrated no benefits for survival despite temporal improvement in oxygenation,^18,19 it may be an option for decreasing RV afterload by lowering PAH.³³ Intriguingly, a positive response to iNO was observed in only 30% of the patients of the current study. Similar findings were reported by Manktelow⁴⁴ on severe ARDS with septic shock. These studies were conducted before the widespread availability of VV ECMO and ultraprotective ventilator strategy. The data of the current study confirms the validity of this observation despite the use of current protective ventilation treatment regimens.

iNO use in ARDS has been widely studied over the last decades, and no evidence of direct NO toxicity has been observed at clinically relevant doses below 20 ppm.⁴⁵ However, conflicting evidence has been reported on whether iNO contributes to increased acute kidney injury.^46–48 CKRT in this study did not indicate an increased rate of acute kidney injury during VV ECMO (Table 2). Thus, the potentially detrimental effects of iNO on kidney function cannot be confirmed in our study. Indeed, the rate of CKRT during VV ECMO and concomitant iNO treatment reflects similar reported rates in other cohort studies on severe ARDS and VV ECMO without iNO therapy.⁴⁹

The optimal dose and time of iNO treatment in ARDS remains controversial. A European expert recommendation on the use of iNO in adults with ARDS suggested that toxic side effects (e.g., methemoglobinaemia and the formation of relevant nitrogen dioxide levels) are less likely when inhaled NO doses stay <20 ppm.⁴⁵ Initiating iNO treatment as early as 24–72 h after the onset of ARDS has been suggested because iNO is mainly effective during the early onset of ARDS. In this study, an average iNO dose of 14.5 ppm was administered, and iNO delivery was performed for a median duration of 3 days. iNO was initiated within 24 h after the diagnosis of either PAH and/or RV failure. In most of the patients, iNO was initiated during VV ECMO, as opposed to before or after VV ECMO, as administered in a small cohort.

In terms of survival, persistent PAH and/or RV failure are known to contribute to worse outcome such as in-hospital death, length of ICU and hospital stay. In this study, we found an in-hospital mortality rates comparable to those reported in a recently published small single-centre retrospective trial.⁵⁰ In a subgroup analysis, we found that the survival in iNO treated patients might differ between iNO responders and non-responders but results were not statistically significant; likely because the subgroups were too small. Of note, this cohort suffers from multiple comorbidities, all of which will worsen the clinical course of the patient regardless of iNO administration (please refer to Table S1 which reports the Charlson Comorbidity index for the study cohort).

A limitation of this study is the retrospective and monocentric nature of the analyses. The availability of RCTs involving patients with severe ARDS is limited after initial RCTs failed to demonstrate any beneficial effects of iNO on survival and mortality. Also, retrospective analyses are difficult to control for an unbiased selection process of patients.⁵¹ However, in this study all included patients were analysed depending on treatment and thus were not subjected to selection bias for iNO treatment. Lastly, a major limitation of this study is the small number of participants because patients with VV EMO with persistent PAH and/or RV failure treated with iNO represents a very limited patient cohort.

In conclusion, this retrospective observational study suggests that persistent PAH and/or RV failure is associated with poor clinical outcome in patients with severe ARDS and VV-ECMO support. Surprisingly, only one-third of the patient population responded to iNO with a significant decrease of PAH and/or RV failure. In other words, elevated pulmonary arterial pressure or onset of RV failure in ECMO-supported ARDS patients appears to be very difficult to treat with the pulmonary vasodilator iNO. Further research will be needed to elucidate the underlying potential mechanisms. We did not find an increased rate of continuous renal replacement therapy as marker for acute renal failure when iNO concentrations stayed below 20 ppm and when the duration of treatment was less then 3 days.

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Table 1. baseline characteristics.
characteristic	severe ARDS patients on VV ECMO with PAH and/or RV failure - concomitant iNO rescue therapy (n=55)
demographics
age – (mean ± SD) [years]	54.6 ± 11.6
male sex – n (%) [male]	40 (72.7)
weight – (mean ± SD) [kg]	107.9 ± 40.2
height – (mean ± SD) [cm]	175.76 ± 8.5
BMI – (mean ± SD)	34.8 ± 12.6
cause of ARDS
viral pneumonia – n (%)	22 (40)
bacterial pneumonia – n (%)	8 (14.5)
others – n (%)	25 (45.5)
indication for iNO administration
pulmonary arterial hypertension (PAH)– no. [%]	26 (47)
RV failure – no. [%]	20 (36)
PAH and RV failure – no. [%]	9 (16)

iNO, inhaled nitric oxide; SD, standard deviation; BMI, body mass index; ARDS, acute respiratory distress syndrome; PAH, pulmonary arterial hypertension; RV failure, right ventricular failure.

Table 2. clinical characteristics.
characteristic	severe ARDS patients under VV ECMO with PAH and/or RV failure - concomitant iNO rescue therapy (n=55)
invasive mechanical ventilation
total time on mechanical ventilation – (median (IQR)) [days]	24 (14 – 41.5)
time on mechanical ventilation prior to VV ECMO support – (median (IQR)) [days]	2 (0.79 – 8)
tracheostomy during stay on ICU – n (%)	21 (38.2)
VV ECMO
duration of VV ECMO support – (median (IQR)) [days]	13.6 (9 – 19.9)
weaning failure from VV ECMO support – n (%)	37 (67.3)
adjunctive therapies
CKRT during VV ECMO – n (%)	29 (52.7)
proning prior to VV ECMO	21 (38.2)
proning during VV ECMO	30 (54.5)
organ dysfunction
SOFA-score on ICU admission– (mean ± SD)	8 ± 3
RESP-score – (mean ± SD)	-1 ± 4
CPR prior to ECMO – n (%)	0 (0.0)
sepsis – n (%)	7 (14)

iNO, inhaled nitric oxide; SD, standard deviation; IQR, interquartile range; VV, venovenous; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; CKRT, continuous kidney replacement therapy; SOFA, sequential organ failure assessment; RESP, Respiratory ECMO Survival Prediction; CPR, cardiopulmonary resuscitation.

Table 3. ventilation parameters and blood gas analysis.
characteristic	severe ARDS patients under VV ECMO with PAH and/or RV failure - concomitant iNO rescue therapy (n=55)
	day 1	day 3	day 7
ventilation parameters
minute ventilation – (median (IQR)) [l/min]	2.04 (1.6-3.2)	2.21 (1.8-4.1)	3.82 (2.9-4.8)
PEEP – (median (IQR)) [mbar]	20 (18-20)	20 (17-20)	18 (16-20)
peak inspiratory pressure – (median (IQR)) [mbar]	26 (25-28)	26 (25-28)	26 (26-28)
blood gas analysis
PaO₂ – (median (IQR)) [mmHg]	103 (100-107)	102 (77-117)	101 (90-113)
PaCO₂ – (median (IQR)) [mmHg]	39 (35-43)	39 (36-43)	41 (35-46)
pH – (median (IQR))	7.30 (7.3-7.4)	7.34 (7.3-7.4)	7.32 (7.3-7.4)
PaO₂/F_IO₂ – (median (IQR))	84 (35-103)	92 (75-111)	95 (77-130)
minimal F_IO₂ of a 24 hrs period	80 (70-90)	70 (60-85)	70 (50-85)

iNO, inhaled nitric oxide; IQR, interquartile range; PEEP, positive end-expiratory pressure; PaO₂, arterial partial pressure of oxygen; PaCO₂, arterial partial pressure of carbon dioxide; F_IO₂, fraction of inspired oxygen.

Table 4. survival analysis.
characteristic	severe ARDS patients under VV ECMO with PAH and/or RV failure - concomitant iNO rescue therapy (n=55)
outcome
length of ICU stay – (median (IQR)) [days]	23.3 (13.55 – 39.1)
length of hospital stay – (median (IQR)) [days]	27.1 (13.75 – 40)
in-hospital death – n(%)	38 (69.1)
median survival time – [95% CI] [days]	22 [14; 37]

iNO, inhaled nitric oxide; ICU, intensive care unit; IQR, interquartile range; CI, confidence interval.

Author Contributions: All authors meet the ICMJE recommendations regarding authorship. S.M., J.N., J-C.S., H.E., S.K., C.P., S.F.E made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND

S.M., J.N., J-C.S., H.E., S.K., C.P., S.F.E drafted the work or revised it critically for important intellectual content; AND

All authors gave final approval of the version to be published; AND

All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding: The Data Integration Centre of the University Hospital Bonn was funded by the Federal Ministry of Education and Research of the Federal Republic of Germany (grant number: 01ZZ1803Q).

Institutional Review Board Statement: Ethical approval for the current study was provided by the ethics committee (no. 492/20) of the University Hospital of Bonn, Germany, and the need for informed consent was waived.

Informed Consent Statement: Patient consent was waived due to the retrospective nature of the study.

Data Availability Statement: The clinical datasets generated and/or analysed during the current study are not publicly available due to the local data protection law but are available from the corresponding author on reasonable request.

Conflicts of Interest: Stefan Muenster, M.D. is currently a member of the scientific advisory board that advises Air Liquide in the use of inhaled nitric oxide in adult patients undergoing cardiac surgery. All the other authors have no conflicts of interest to declare.

Competing interest reported. Stefan Muenster, M.D. is currently a member of the scientific advisory board that advises Air Liquide in the use of inhaled nitric oxide in adult patients undergoing cardiac surgery. All the other authors have no conflicts of interest to declare.

Analysis of patients with severe ARDS on VV ECMO with pulmonary hypertension or right ventricular failure treated with iNO: a retrospective observational study

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