key: cord-315093-ifeulv55
authors: Longobardo, Alessia; Montanari, Cecilia; Shulman, Robert; Benhalim, Suzanne; Singer, Mervyn; Arulkumaran, Nishkantha
title: Inhaled nitric oxide produces minimal improvement in oxygenation in COVID-19 related ARDS
date: 2020-10-14
journal: Br J Anaesth
DOI: 10.1016/j.bja.2020.10.011
sha: 
doc_id: 315093
cord_uid: ifeulv55

nan

related to COVID-19 (3 (-17 to 26) % vs. 47 (6 to 54) %; p<0.05) (Figure 1; Supplementary Table 1 ).

Venous thromboembolism (VTE) was diagnosed in 7 (35%) COVID-19 patients. Seven patients underwent computed tomography (CT) pulmonary angiography of which 2 patients had evidence of pulmonary emboli. A further 10 patients underwent lower limb Doppler ultrasonography, of whom 5 patients had a diagnosis of deep vein thrombosis.

Only eight (40%) patients with COVID-19 related ARDS had an increment in PaO 2 : FiO 2 ratio >10% compared to 10 patients (77%) with ARDS not related to ARDS (p=0.07). Baseline PaO 2 : FiO 2 ratio, dose of iNO, use of steroid, prone position ventilation, C-reactive protein, D-dimer levels, N-terminal B-type natriuretic peptide (NT-BNP) levels, fluid balance, driving pressure, days from ICU admission to iNO, pulmonary compliance, diagnosis of VTE, or body mass index did not discriminate between COVID-19 patients who responded to iNO or not (Supplementary Figure 1) .

The potential benefit of iNO in reducing pulmonary shunt in COVID-19 related ARDS has been postulated. 5 However, we found that the increase in PaO 2 :FiO 2 ratio in COVID-19 ARDS patients in response to iNO was significantly lower compared to ARDS patients without ARDS, consistent with another published series. 6 Pulmonary vascular endothelial dysfunction and microthrombi are hallmarks of COVID-19 induced lung damage, and this may impair iNO-induced pulmonary vasodilation. 4, 7 In contrast, patients with coronavirus-related SARS, where increased thrombosis was not a hallmark, demonstrated significant PaO 2 :FiO 2 ratio improvements in response to iNO. 8 Early in the COVID-19 disease process, hypoxaemia develops despite good pulmonary compliance, and a pulmonary vasculopathy is implicated 9 . Later on, compliance decreases to that seen with 'classical' ARDS. 9,10 Our COVID-19 patients who received iNO did so as a rescue treatment late in the disease, 12 days following ICU admission. While no differences were seen in D-dimer values between responders and non-responders, levels were significantly elevated in most patients. The benefits of iNO in COVID-19 related ARDS may extend beyond its effects on pulmonary vasculature 11 . However, the theoretical benefits of iNO in inhibiting early stage viral replication is unlikely to have benefitted patients where iNO was administered 12 (8-18) days following ICU admission.

As with all retrospective analyses, we acknowledge the possibility of residual confounding, and that results are associative. The small number of COVID-19 related ARDS patients included also warrants caution in interpreting the findings. CT imaging was not performed on all patients either due to clinical instability or lack of a clear indication, thus the presence of major emboli may have been missed in some patients. Alternatively, lack of identification by CT does not exclude the presence of multiple pulmonary microthrombi contributing to raised pulmonary vascular resistance and right heart dysfunction. Echocardiography was not performed systematically to assess impact on cardiac anatomy and function, but NT-BNP levels were significantly elevated and raised pulmonary pressures were commonplace findings when measured. NT-BNP and D-dimer values were not routinely collected in ARDS patients prior to the COVID-19 pandemic so comparisons cannot be made.

In summary, more than half of patients with refractory hypoxaemia secondary to COVID-19 ARDS did not show an increase in PaO 2 :FiO 2 ratio in response to iNO. This response was much lower compared to a cohort with ARDS not related to COVID-19. Further work is required to ascertain if this lack of response to iNO is diagnostic for degree of pulmonary thromboembolism.

Study design (NA), data collection (AL, CM, RS, SB), statistics (NA), drafting manuscript (NA), finalising manuscript (MS, NA). 

Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults

Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction

Treatment of COVID-19 by Inhaled NO to Reduce Shunt?

Inhaled nitric oxide in patients admitted to intensive care unit with COVID-19 pneumonia

Pulmonary Angiopathy in Severe COVID-19: Physiologic, Imaging and Hematologic Observations

Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing

Covid-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome

COVID-19 pneumonia: different respiratory treatments for different phenotypes?

Nitric oxide dosed in short bursts at high concentrations may protect against Covid 19

The authors declare not conflicts of interest.J o u r n a l P r e -p r o o f