key: cord-0928320-hr0a2y3f
authors: Vogel, Dominik J.; Brame, Aimee; Hanks, Fraser; Remmington, Chris; Chung, Natali; Camporota, Luigi
title: Improved oxygenation with inhaled milrinone in mechanically ventilated patients with severe COVID-19
date: 2021-06-08
journal: Br J Anaesth
DOI: 10.1016/j.bja.2021.06.002
sha: 7c2093aad7433153a2fc18cd174b27cc3a6d4d70
doc_id: 928320
cord_uid: hr0a2y3f

nan

Dominik J Vogel (1) *, Aimee Brame (1) Editor -Patients with COVID-19 acute respiratory distress syndrome (C-ARDS) present with severe hypoxaemia that may be disproportionate to the loss in aerated lung. 1 The main mechanism of hypoxaemia has been attributed to a dysregulated pulmonary perfusion, and therefore inhaled pulmonary vasodilators have been used to improve gas exchange in these patients. 2 However, during the COVID-19 pandemic, the significant increase in C-ARDS resulted in national supply chain shortages of inhaled vasodilators such as iloprost, epoprostenol and nitric oxide. Bedsides the limited availability, these drugs are costly: nitric oxide (£665 perday), iloprost (£60-120 per day), epoprostenol (£45-75 per day). Milrinone, a phosphodiesterase 3 inhibitor that has shown benefit to improve oxygenation in patients with pulmonary hypertension, is a widely available and less costly alternative (£13 per day) but data in ARDS are scarce. [3] [4] [5] [6] During the pandemic we hypothesised that in mechanically ventilated patients with C-ARDS with a PaO 2 /FiO 2 ratio <20 kPa, inhaled milrinone would improve oxygenation, and reduce physiological dead-space fraction, and we therefore used inhaled milrinone as an alternative vasodilator during the drug shortages.

We describe the first 14 patients who received inhaled milrinone (2.5-5 mg every 6 h) for ≥ 12 h.

Milrinone was administered via mesh nebulisation in accordance with departmental guidance but at the discretion of the clinical team. We retrieved data on ventilation and blood gas analyses from electronic records and calculated Oxygenation Index (OI), PaO 2 /FiO 2 , and three indices of deadspace ventilation (end-tidal-CO 2 /PaCO 2 , ventilatory ratio and corrected minute ventilation). [7] [8] [9] Values were recorded prior to first milrinone dose, 1-2 h after, and subsequently at 6 h and 12 h. The closest J o u r n a l P r e -p r o o f temporally associated transthoracic echocardiograms obtained before and after initiation were reviewed by a consultant cardiologist for indices of right ventricle (RV) and left ventricle (LV) size and function. 10 Records were reviewed for potentially related adverse events including haemodynamic instability, deterioration in gas exchange, dose adjustments or early termination of therapy. For patients in whom milrinone was continued for ≥48 h (n=7), the improvement in PaO 2 /FiO 2 was maintained and this was higher by +3.9 kPa (95%CI 0.6-7.2, p<0.05) and OI was lower by -5.1

(95%CI -0.5 to -9.7, p<0.05) post 48 h dose compared to baseline, respectively.

There was a greater improvement in PaO 2 /FiO 2 compared to baseline post 6 h dose in the group with a shorter duration of mechanical ventilation (<20 days, n=7), compared to those who had been ventilated longer (>20 days, n=7) prior to receiving the first dose (mean difference +26.3%; 95%CI 0.8-51.9%; p<0.05). These patients had high indices of dead space with end-tidal CO 2 These results show that milrinone might be a useful alternative to inhaled nitric oxide, epoprostenol or iloprost for improving oxygenation even late in the course of C-ARDS, and at this late stage milrinone did not affect dead space ventilation. It is likely that given the duration of the disease and the low compliance, the predominant mechanism of hypoxaemia in these patients was venous admixture secondary to consolidation or fibrosis, and may explain why the physiological dead space was unmodified. These results are based on observational data from a case series and need to be interpreted in this context. The effects of milrinone on dead space could be tested earlier in the disease where functional vasoconstriction of ventilated areas can affect physiological dead space.

We conclude that in mechanically ventilated patients with severe COVID-19, inhaled milrinone was associated with improved oxygenation for up to 48 h of administration.

The authors have no conficts of interest to disclose. The ends of the whiskers are set at 1.5x inter-quartile range above the third quartile and below the first quartile, or the minimum or maximum value if within these limits. All values are shown as circles.

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