Avoiding, Not Managing, Drug Withdrawal Syndrome in the Setting of COVID-19 Acute Respiratory Distress Syndrome. Comment on Ego et al. How to Manage Withdrawal of Sedation and Analgesia in Mechanically Ventilated COVID-19 Patients? J. Clin. Med. 2021, 10, 4917.

The management of sedation in the setting of COVID-19 ("COVID") by Ego et al. [...].

The management of sedation in the setting of COVID-19 (“COVID”) by Ego et al. [1] does not combine pathophysiology and pharmacology. Their premise rests on «decreasing the work of breathing, applying lung protective ventilation and limiting asynchronies [to] minimize the risk of ventilator-induced lung injury (VILI)……COVID-19 patients require high [doses] of sedatives, analgesics and neuromuscular blocking agents (NMBA)……frequently for more than 7 days» [1]. Ego manages the drug withdrawal syndrome but does not avoid it.

First, the requirements allowing for optimal ventilation in the setting of acute respiratory distress syndrome (ARDS), delineated earlier [2,3,4], are not addressed: (Vt, f) = f(temperature, agitation, inflammation, lung water, pH, microcirculation, PaCO. Briefly, temperature is lowered to low normal (35–36 °C). Alpha-2 agonists suppress the tonic activity of the dorsal noradrenergic bundle [5], control agitation and avoid emergence delirium and withdrawal syndrome [6] («cooperative » sedation from endotracheal intubation onward, i.e., alpha-2 agonist as first-line sedative [7]: clonidine 2 μg kg−1 h−1 or dexmedetomidine 1.5 μg kg−1 h−1). To achieve −2 < RASS < 0 (stringent restlessness), alpha-2 agonists are supplemented with neuroleptics, if required (appendix in [8]), as in refractory delirium tremens [9]. Both drugs do not depress respiratory genesis [10]. Thus, conventional sedation is not needed following intubation. Adequate iterative circulatory optimization combined to the sympatholysis evoked by alpha-2 agonists normalizes the microcirculation, systemic pH, lactate concentration, CO2 gap and venous O2 saturation. Alpha-2 agonists present anti-inflammatory properties [11], either at the systemic or central nervous system or lung (tissue or receptors) level. In turn, normalized microcirculation eases diapedesis and improves the innate immune function: a return to normal functioning of the adrenergic receptors of immune cells possibly occurs (“upregulation”).

Second, alpha-2 agonists act via the sympathetic and the parasympathetic systems, beginning with intubation: cooperative sedation [12], with improved cognition [13,14], diuresis, lowered VO2 and inflammation, etc. As alpha-2 agonists evoke indifference to the environment and pain, opioids are counterproductive. Should the patient need analgesia, opioid free analgesia (appendix in [8]) does not depress respiratory genesis. Consequently, the duration of paralysis is reduced to a few hours in the setting of conventional ARDS (e.g., aspiration, etc.). Once the vicious circle of self-induced lung injury (SILI) is broken, spontaneous breathing resumes (e.g., pressure support delineated in [2,3,4]). PEEP is adjusted to a high level if diffuse ARDS is present. Upright position is set, meticulously.

Early COVID-ARDS presents with a high VA/Q ratio (lowered perfusion with near-normal ventilation, compliance, and lung mechanics). The inflammation of the lung capillaries and receptors and alveoli is addressed non-specifically. As COVID-19 does not weaken the ventilatory muscles, and as compliance is relatively high, brief paralysis just breaks the SILI and the high inspiratory drive. Spontaneous breathing avoids ventilator-induced lung injury. First-line, high-dose alpha-2 agonists combined to low normal temperature and normalized inflammation do not lead to «high regimen and prolonged use of sedative, analgesics and neuromuscular agents» [1]. In our hands [3], breaking up the SILI is achieved within 2 days with a low toll (mortality: 8.5% [3]), at variance with general anesthesia, paralysis and proning for weeks with critical care clogging and societal consequences. This [3,4] requires demonstration.