Intubation and invasive Mechanical ventilation of COVID-19 Acute Respiratory Distress Syndrome patients

Vijay Singh; Shibu Sasidharan; Abdul Nasser; Harpreet Singh Dhillon

doi:10.4103/mjhs.mjhs_5_21

REVIEW ARTICLE

Year : 2021 | Volume : 9 | Issue : 1 | Page : 21-33

Intubation and invasive Mechanical ventilation of COVID-19 Acute Respiratory Distress Syndrome patients

Vijay Singh¹, Shibu Sasidharan¹, Abdul Nasser², Harpreet Singh Dhillon³
¹ Department of Anaesthesia and Critical Care, Level III UN Hospital, Goma, Democratic Republic of the Congo
² Department of Anaesthesia and Critical Care, Naval Hospital, Goa, India
³ Department of Psychiatry, Level III UN Hospital, Goma, Democratic Republic of the Congo

Date of Submission	20-Jan-2021
Date of Decision	18-Feb-2021
Date of Acceptance	03-Mar-2021
Date of Web Publication	30-Mar-2021

Correspondence Address:
Dr. Shibu Sasidharan
Department of Anaesthesia and Critical Care, Level III UN Hospital, Goma
Democratic Republic of the Congo

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjhs.mjhs_5_21

Abstract

Coronavirus disease 2019 (COVID-19) is highly infectious and primarily a respiratory infection. The presentation is often in the form of atypical pneumonia which if not detected and managed effectively, progresses to acute respiratory distress syndrome (ARDS). Due to the atypical nature, rapid spread and sheer magnitude of the COVID-19 pandemic, the guidelines for mechanical ventilation in COVID-19 ARDS are still evolving. In this review, we have attempted to examine the emerging evidence on the same to further our knowledge on the subject.

Keywords: Acute respiratory distress syndrome, COVID-19, mechanical ventilation

How to cite this article:
Singh V, Sasidharan S, Nasser A, Dhillon HS. Intubation and invasive Mechanical ventilation of COVID-19 Acute Respiratory Distress Syndrome patients. MRIMS J Health Sci 2021;9:21-33

How to cite this URL:
Singh V, Sasidharan S, Nasser A, Dhillon HS. Intubation and invasive Mechanical ventilation of COVID-19 Acute Respiratory Distress Syndrome patients. MRIMS J Health Sci [serial online] 2021 [cited 2023 Mar 22];9:21-33. Available from: http://www.mrimsjournal.com/text.asp?2021/9/1/21/312606

Introduction

A novel coronavirus was identified in Wuhan, China, in December 2019. The World Health Organization designated the term coronavirus disease 2019 (COVID-19) for this pandemic. COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The major morbidity and mortality from COVID-19 is attributed to the acute viral pneumonitis that progresses to acute respiratory distress syndrome (ARDS).

This article will attempt to discuss the management of patients who develop ARDS due to COVID-19.

Definition of Acute Respiratory Distress Syndrome

COVID-19 ARDS is diagnosed when someone with a confirmed COVID-19 infection meets the Berlin 2012 ARDS diagnostic criteria,^[1] which include:

Acute hypoxemic respiratory failure
Presentation within 1 week of worsening respiratory symptoms
Bilateral airspace disease on chest X-ray, computed tomography or ultrasound that is not fully explained by effusions, lobar or lung collapse, or nodules; and
Cardiac failure is not the primary cause of acute hypoxemic respiratory failure.

Oxygenation and Ventilation for Covid-19 Acute Respiratory Distress Syndrome Patients

COVID-19 ARDS follows an anticipated time course, with a median time to intubation of 8–10 days after symptom onset.^[2] It is therefore imperative to constantly monitor patients for the development of ARDS as the day of infection progresses. The primary strategy for COVID-19 patients is supportive care, which includes oxygen therapy for hypoxemic patients. Oxygen therapy is instituted if respiratory rate is of 30 breaths/min or above and/or SpO2 of 93% on breathing air.

COVID-19 patients sometimes present with “silent or happy hypoxia” (atypical clinical features such as feeling of calm and sense of wellbeing even in presence of significant level of hypoxia). The reason for this could be the presence of low carbon dioxide levels (severe hypocapnic hypoxia) in blood, typically found in high altitude sickness.^[3] Atypical findings like these raise doubts in the minds of treating physicians to intubate or not to intubate. Mechanical ventilation of COVID-19 patients with ARDS (COVID-19 ARDS) is by itself an unprecedented and challenging task as these patients usually have non homogeneous lung pathology that requires a targeted lung-protective ventilation strategy to improve outcome. Most patients of COVID-19 ARDS require timely institution of mechanical ventilation. Undue delay in intubation and invasive mechanical ventilation will be detrimental to the patient and the risk of contagion spread to healthcare workers is high. A low threshold for intubation should be considered if the clinical condition of the patient deteriorates even with increase oxygen supplementation at high flow and at high FiO2, using noninvasive modes.

Non Invasive Modes

High-flow oxygen therapy (HFNO) should be started if there is a respiratory failure and mild-moderate ARDS. HFNO is used as first-line treatment.^[2] Noninvasive ventilation (NIV) is not recommended for patients with failed HFNO. NIV provides benefit via Positive End Expiratory Pressure (PEEP), to patients with mild-moderate ARDS by reducing the respiratory load and intubation rate, but it can cause significant aerosol generation.

High-flow nasal cannula (HFNC) for HFNO is effective in improving oxygenation, but due to reports of high amount of aerosol dispersion, it was not recommended initially. However, further studies in patients with acute hypoxemic respiratory failure, HFNC was proven to avoid intubation compared to conventional oxygen devices, and the scientific evidence of generation and dispersion of bio-aerosols via HFNC showed a similar risk to standard oxygen masks. HFNC prong with a surgical mask on the patient's face is thus a reasonable modality to benefit hypoxemic COVID-19 patients and avoid intubation.^[4]

Mechanical Ventilation

Mechanical ventilation of COVID-19 patients with ARDS is a challenging task as these patients usually have a nonhomogeneous lung pathology. This requires a targeted lung-protective ventilation strategy to improve the outcome.

Indications for mechanical ventilation

The indications for mechanical ventilation in COVID-19^[4] are as follows:

Acute hypoxic respiratory failure with severe respiratory distress
Worsening hypoxia associated with increased labored breathing
Increase work of breathing associated with use of accessory muscles of respiration
Failure to maintain Spo₂ >90% with >50 L/min of high flow oxygen with HFNO or with maximal supplemental oxygen
Hypoxia with altered mental status and failure to maintain airway patency
Patient with multiorgan failure, persistent hemodynamic instability requires vasopressor support, or those with multiple comorbidities such as DM, Cardiovascular disease, hypertension, advanced age, frailty, cancer or chronic respiratory disease
Arterial PH <7.3 with PaCO₂ >50 mm Hg
PaO₂/FiO₂ <200^[5]
High respiratory rate with persistent thoracoabdominal asynchrony or paradoxical respiration
Low ROX index (<4.88) with patient on HFNC (The ROX index^[6] defined as the ratio of Spo₂/FiO2 to respiratory rate and it has been used as a predictor of the intubation need in patients received HFNC oxygen therapy. A ROX index ≥4.88 after HFNC initiation is associated with a lower risk for intubation).

Indications for intubation and mechanical ventilation in COVID-19 patients are not limited to the above-mentioned conditions and should be case-specific, and at the discretion of the treating physician.^[7]

Precautions and procedures followed while intubation of COVID-19 patients

Airway management and intubation in COVID-19 patients is an aerosol generating procedure and is associated with increased risk of viral transmission to the health care providers. Hence, a high level of attentiveness is necessary to prevent infection when intubation is performed. The following points to be ensured for safety of patients and health care providers.^[8]

Health-care professional should take airborne precautions and a standard level 3 protection to be donned while performing intubation. The recommended sequence for donning of personal protective equipment is as follows: Hand sanitization/washing → head cap → protective N95 mask → surgical masks → full body isolation gown → disposable inner gloves → goggles → protective clothing → disposable outer gloves → shoe covers → disposable gown → disposable outermost gloves → full head hood or face shield
For intubation process, acronym oxygen, helper, monitor, suction, machine, airway devices, intravenous (IV) access, and drugs can be used to ease of remembrance^[9]
Tracheal intubation to be performed by the most experienced anesthesiologist, in an airborne infection isolation room, preferably a negative pressure room to ensure patient safety and health care worker (HCW)
Limit the number of health care provider in the room prior to intubation
Use 3–5 min of preoxygenation with 100% oxygen as these critical patients have poor oxygen reserve
Spontaneous ventilation is to be preserved and assisted bag mask ventilation during preoxygenation should be avoid
Rapid sequence intubation technique is to be used to avoid manual ventilation of the patient's lungs and prevent potential aerosolization of the virus from the airways
Use both hands to hold the mask to ensure a tight seal using the V-E technique rather than the C-E technique with one hand
Video laryngoscope is preferred for intubation as it increases the distance between the patient and anesthesiologist
Airway management should be safe, accurate and should be accomplished within 15–20 s
After tracheal intubation, clamp the endotracheal intubation (ETT) and inflate the cuff before instituting the ventilation
Viral and HME filter to be applied between endotracheal tube and circuit
Proper tube placement can be identified by EtCO₂ monitoring, visible bilateral chest rise and auscultation is preferably avoided to confirm tube placement
Supraglottic airway devices are to be used in can't intubate and can't oxygenate situations only and bedside tracheostomy is to be performed as early as possible.

Ventilatory strategy for COVID-19 acute respiratory distress syndrome

The most appropriate time to intubate COVID-19 patients is still not clear. Mechanical ventilation is to be considered if a COVID-19 patient develops moderate to severe ARDS (PaO2/FiO2 <200) to prevent P-SILI (patient self-induced lung injury) and viral transmission to health care provider.^[6] Endotracheal intubation and invasive mechanical ventilation are to be considered on priority in ARDS patients who are acutely deteriorating in spite of supplemental oxygen therapy with HFNC. Non-intubated spontaneously breathing ARDS patients are at increased risk of P-SILI due to high intake of inhaled tidal volume. Therefore, esophageal pressure measurement by manometer can be used in spontaneously breathing, nonintubated patients to estimate the time for intubation.^[10] The risk of infection to the HCW remains a concern. The esophageal pressure between 5 and 10 cmH₂o is generally well tolerated. However, if pressure goes more than 15 cmH₂O, then risk of P-SILI increases and therefore intubation should be carried out as soon as possible. If esophageal manometry is not available, then change in center venous pressure (CVP) with respiration or clinical assessment of excessive inspiratory effort for increased work of breathing to be considered.^[11]

Mortality is very high (67%) for COVID-19 ARDS patients on mechanical ventilation.^[12] An inappropriate ventilatory strategy in ARDS patients can lead to ventilator induced lung injury (VILI) which includes barotrauma (high airway pressure), volutrauma, atelectrauma, biotrauma, myotrauma (diaphragmatic injury), and oxytrauma (oxygen free radicles).

Non-COVID-19 ARDS have two sub phenotypes identified based on ARMA and ALVEOLI trial which respond differently to PEEP, liberal fluid therapy and identified with notable precision using four biomarkers: Interleukin-6, interferon gamma, angiopoietin 1/2, and plasminogen activator inhibitor-1.^[13],[14]

Hyperinflammatory type - this type is associated with higher levels of inflammatory biomarkers, high vasopressor use, high sepsis, lower serum bicarbonate and have worst outcome in terms of mortality, ventilator-free days and organ-free days. It responds to high PEEP and conservative fluid therapy
Hypo inflammatory type - it responds to low PEEP and liberal fluid therapy.

However, we are not recommending their proposed treatment until unless it gets published in critical care societies. Likewise, preliminary anecdotal reports mentioned^[15],[16] that in the early phase of COVID-19, atypical ARDS features are more common which includes severe hypoxemia with high compliance and low lung recruitability while in the later phase of disease, classic ARDS features are more common with low lung compliance and high alveolar recruitability. Gattinoni et al.^[15],[17] also reported that COVID-19 pneumonia is of two types and their management is also vary in terms of ventilatory strategy.

Type L-characterized by low elastance, high compliance, low lung weight, low lung recruitability, and low ventilation-to perfusion (V/Q) ratio
Type H-characterize by high elastance, low compliance, high lung weight, high lung recruitability, and high right-to-left shunt. This type of pneumonia has features similar to typical ARDS.

Currently, there are no accepted guidelines from international societies for ventilatory management of COVID-19 ARDS patients. Hence, the ventilatory strategy for ARDS patients i/e low tidal volume ventilation, best suits for managing COVID-19 ARDS. Salient features of the same are enumerated under:

Lung protective ventilation^[18]

Several randomized control trials and meta-analyses have reported survival benefits from low tidal volume lung protective ventilation. After implementation of low tidal volume ventilation in ARDS patients monitor auto-PEEP and ventilator dyssynchrony.^[19] There is no validated mode of ventilation which is markedly better than other modes in managing ARDS patients.^[20] However, most clinicians prefer to use volume-limited assist-control mode for ventilating ARDS patients.^[19] Modes of ventilation like APRV may be also be used based on physician's knowledge and experience^[21] but high frequency oscillatory ventilation is best avoided due to risk of aerosol spread and has shown no mortality benefit in ARDS patients.^[9] Even, pressure-regulated volume control is also not an accepted mode of ventilation in ARDS patients due to high tidal volume delivery surpassing the lung-protective ventilation target. The following initial ventilatory settings [Table 1] are recommended in COVID-19 patients.

Table 1: Ventilator settings for lung protective ventilation

Click here to view

Role of PEEP in COVID-19 acute respiratory distress syndrome

There is an ambiguity with respect to the usage of adequate PEEP for COVID-19 ARDS patients. Using higher PEEP (any PEEP >10 cm H2O) was not recommended based on the heterogenicity of lung involvement in COVID-19 patients with simultaneous existence of severely affected areas with non-affected areas in the lung (Arjen M. Dondorp, Muhammad Hayat, Diptesh Aryal, .-Google Scholar n. d.).^[22] However, surviving sepsis campaign guidelines on management of critically ill adults from COVID-19, European intensive and critical care guidelines, advise PEEP >10 cm H2O for the management of ARDS due to SARS-CoV-2. Titrations need to done by checking the lung compliance of COVID-19 patients. If it is high or normal with the existence of hypoxemia which is more common in L-phenotype, then the use of PEEP <10 cm H₂O is recommended to avoid over-distention of normal healthy alveoli. However, if compliance is low, which is more common in H-phenotype of COVID-19 pneumonia likely also seen in ARDS, then use adequate PEEP of just above the lower inflection point on pressure volume loop on the ventilator to recruit collapsed alveoli, to prevent atelectasis and thereby, improve oxygenation. Monitor for alveolar over-distension by seeing “Beaking'” pattern on pressure-volume loop which can be corrected either by decreasing tidal volume or PEEP [Figure 1].

Figure 1: Pressure-volume loop with lower inflection point

Click here to view

FiO₂/PEEP ladder for oxygenation

ARDSNet trial^[23] recommends to consider two types of FiO₂/PEEP ladder to achieve the goal of PaO₂ >55 mm Hg in ARDS patients and to avoid the side effects of hyperoxia. D Trasy et al.'s study^[24] recommends use of FiO₂/PEEP index ≤7 which is similar to the ARDSNet trials of minimum FiO₂/PEEP settings (35%/5 cmH₂O). The details of FiO₂/PEEP ladder are tabulated below:

Higher FiO₂/lower PEEP

Lower FiO₂/higher PEEP

Once the initial ventilator settings are entered, then monitoring of the following parameters is done along with their target levels:

Plateau pressure - Plateau pressure should be below 30 cm H₂O. It is defined as the pressure that is maintained in the alveoli when there is no airflow and it is slightly lower than P_peak pressure. It is measured by adding an inspiratory pause of 0.5-1 s on volume control mode showing pressure time scalar
Driving pressure - It is measured by formula: Driving pressure= (P_plat pressure – PEEP).

₂

Compliance – It is a measure of ease of distensibility of lung elastic tissue. The easier a lung able to expand or stretch, more will be its compliance. Normally, the total compliance of both lungs in an adult is about 200 ml/cm H₂O. Low compliance usually found in ARDS patients with stiff lung and there are two types of lung compliance.

^[15],[17]

₂

P0.1 (Airway occlusion pressure)-It is defined as the pressure generated at the airways during the first 100 msec of an inspiratory effort against an occluded airway and its value can be measured in most modern ventilators. The normal value of P0.1 in spontaneously breathing patients is about 1 cm H₂O. However, in mechanically ventilated patients' values above 3.5 cm H₂O are usually associated with increased effort. Therefore, airway occlusion pressure value in COVID-19 ARDS patients should be kept <3.5 cm H2O to obtain a ventilatory strategy protective for the lung to prevent it from VILI and diaphragmatic injury (myotrauma).

Target goals of mechanical ventilation

Target SPO₂ = 90%–94%
PaO2 >55 mm Hg
pH >7.25
FiO2 <0.4
PaO₂/FiO₂ >300 mm Hg.

Subsequent ventilatory settings

Subsequent ventilatory settings can be decided by periodic assessment of P_plat pressure, driving pressure, compliance, and ABG (pH, oxygenation level) like it is done in non-COVID-19 ARDS.^[23]

If Pplat ≤30 cm H₂O, tidal volume (6 mL/kg) and normal PH-No further adjustments
If Pplat >30 cm H₂O and tidal volume (6 mL/kg or higher)– Decrease tidal volume to 5 ml/kg or if required, further decrease it to 4 ml/kg. Consider increase in respiratory rate till up to 35/min to maintain an acceptable minute ventilation
If ventilator dyssynchrony present with P_plat <25 cm H₂O and tidal volume (<6 mL/kg)-increase tidal volume to 1 mL/kg increments up to 8 ml/kg to achieve P_plat >25 and ≤30 cm H₂O
If pH >7.45 with respiratory alkalosis-decrease respiratory rate to target pH 7.25–7.45
If pH <7.25 with respiratory acidosis-increase respiratory rate up to 35/min (concern auto-PEEP) to target pH 7.25–7.45
If pH <7.15 with respiratory acidosis-after maximum respiratory rate (35/min), increase tidal volume in 1 ml/kg increments (target Pplat <30 mm Hg and PH 7.25–7.45) or administer NaHCO₃ if metabolic acidosis also present.

Other adjuvant therapies

Sedation and analgesia

Propofol and midazolam are two most commonly used drugs for intensive care unit (ICU) sedation of mechanically ventilated patients and may be useful for sedation of COVID-19 patients who are on mechanical ventilator. Even melatonin has been considered as a supportive therapy to improve sleep of COVID-19 patients in ICU, although more studies are required to support this recommendation.^[25] In an ongoing pandemic like COVID-19, there is an acute shortage of sedatives and analgesics. Keeping this in mind, many physician/intensivists have started considering inhalational volatile anesthetic agents as an alternative to sedate and manage these critically ill patients. Volatile anesthetic agents like isoflurane, sevoflurane have advantages beyond sedation which includes decrease airway resistance, bronchodilatation in dose-dependent manner, improve oxygenation, reduction of proinflammatory markers and decrease lung epithelial injury.^[26] However, they have not shown improvement in the length of ICU stay and mortality benefit. Thus, further clinical studies or randomized controlled trials (RCTs) are required to interpret favorable outcome.^[27] To institute inhaled anesthetics in ICU patients, anesthesiology trained staff and intensivist, anesthesia machine or ventilator with miniature vaporizer, with scavenging systems should be available. The main purpose of using sedation in COVID-19 patients with ARDS is to ensure patient comfort, alleviate anxiety, and to avoid ventilator asynchrony. The two tools to assess level of sedation in ICU patients are as under:

Richmond Agitation Sedation Scale

Target of-3 to-4 points are used for deep sedation of mechanically ventilated ICU patients and a target of-5 may be required when patients receive NMBA to prevent patient-ventilator asynchrony.^[28],[29]

Riker Sedation-Agitation Scale

A target of 2 points is required to achieve deep sedation and Sedation-Agitation Scale (SAS) 1 is used for very deep sedation like patients on prone ventilation or ECMO. Light sedation by Dexmedetomidine with target value of SAS 3–4 may be suitable for COVID-19 patient on HFNC oxygen supplement therapy to control the physiological stress response.^[28]

However, in resource deficit, some authors advise use of processed EEG devices (bispectral index, entropy, and narcotrend-derived variables) in ICU for COVID-19 patients as a valuable monitoring device to reduce drug utilization and to monitor exact sedative requirement.^[30],[31] Besides sedation, providing adequate analgesia is also equally important to manage pain, agitation of COVID-19 mechanically ventilated patients and a combination of agents (ketamine, fentanyl, morphine, hydromorphone, dexmedetomidine, remifentanil, and sufentanil) may be considered for adequate management. According to PADIS guidelines,^[32] remifentanil and sufentanil are first choice analgesics for ICU patients. Three pain scoring scales along with their target range mentioned below may be used to assess the subjective nature of pain in COVID-19.^[28]

Numeric rating scale (NRS)-Target range <4. This may be considered for nonventilated spontaneously breathing COVID-19 patients who can express pain themselves
Behavioral pain scale-Target range <5 and can be used for mechanically ventilated patients
Critical care pain observation tool-Target range <3 and can be used in critically ill patients on invasive ventilation.

Neuromuscular blocker agents

No clinical trials have been conducted on the use of neuromuscular blocker agents (NMBA) in COVID-19 patients with ARDS. Therefore, on the basis of indirect evidence, several intensive and critical care societies worldwide^[33],[34] have made recommendations on the use of NMBA to improve oxygenation and to reduce ventilator dyssynchrony in ARDS patients. NMBA may be used in boluses but not in continuous infusion in moderate to severe ARDS patients with refractory hypoxemia (PaO2/FIO2 <120 mmHg) to facilitate oxygenation, improved lung ventilation^[35] and to avoid critical illness neuropathy. Routine use of neuromuscular blocking agents is not advised as it does not reduce duration of mechanical ventilation and survival benefit in ARDS patients. For intubation of COVID-19 ARDS patients, rapid sequence induction technique practiced, and therefore, succinylcholine and rocuronium are the preferred choice of NMBA in COVID-19 patients^[8],[36] However, for intermittent boluses, rocuronium, vecuronium, and atracurium are more preferred compared to succinylcholine. TOF monitoring in ICU can contribute to better utilization of NMBA.^[31]

Recruitment maneuvers

Recruitment maneuvers (RMs) with high PEEP are used to improve oxygenation in ARDS patients by increasing transpulmonary pressure to open atelectatic or collapsed alveoli. Until now, no studies have found out the exact role of RMs in patients with ARDS secondary to SARS-CoV-2. Therefore, in the absence of justified use of RMs in COVID-19 patients with worsening PaO2/FiO2 ratio on lung protective ventilation, Surviving Sepsis Campaign guidelines^[37] advise to use RMs with high PEEP to open collapsed alveoli and against the use of incremental PEEP titration RMs in COVID-19 patients. Similarly, some intensive and critical care journals worldwide are also against the use of incremental PEEP for RMs but in favor of RMs with high PEEP in COVID-19 patients. WHO interim guidelines also advise use of intermittent RMs with high PEEP to improve oxygenation in ARDS due to COVID-19. It is essential to watch for hypotension, desaturation, and lung barotrauma during RMs. The two types of RMs used in ARDS patients are as under:^[37]

Traditional RMs – High level of CPAP (35–40 cm H2O) along with prolonged inspiratory pause (40 sec) applied is preferred in COVID-19 patients
Incremental PEEP titration RMs-In this RM, incremental PEEP is used from 25 to 35 to 45 cm H₂O for 1–2 min each and not recommended for COVID-19.

Steroids administration

The WHO recommends^[18] steroid administration in COVID-19 ARDS patients on mechanical ventilator who have developed septic shock and require increasing dose of vasopressors to maintain MAP >65 mm Hg. Inj. Hydrocortisone 200 mg/day or prednisolone 75 mg/day is advised. Surviving Sepsis Campaign guidelines^[37] also suggest use of systemic corticosteroids in COVID-19 ARDS and advise to use corticosteroids in lower doses for short duration. However, routine use of corticosteroids for COVID-19 mechanically ventilated patients with respiratory insufficiency without ARDS is not recommended, which is most likely due to their wide range of adverse effects including increase viral shredding.

Fluid therapy

WHO^[19] and Surviving Sepsis Campaign guidelines^[37] recommends use of conservative or restricted fluid therapy, over liberal fluid as it decreases the number of days on ventilator and shortens ICU stay. In the absence of direct conclusive evidence between shock and COVID-19 ARDS related to optimal resuscitation strategy, Surviving Sepsis Campaign guidelines used indirect evidence and recommend to use dynamic parameters (skin temperature, capillary refill time, serum lactate, stroke volume variation, pulse pressure variation (PPV), and stroke volume change with passive leg raising) over static parameters (CVP) to assess fluid responsiveness in COVID-19 patients with septic shock.

Nutritional support

According to ESPEN expert statements^[38] and ESPEN guidelines,^[39] the nutritional support for SARS CoV-2 infected patients in ICU are as under-

Malnutrition assessment in polymorbid patients - Two criteria (MUST criteria, NRS criteria) to be used to check or screen individuals with COVID-19 for malnutrition
Patients on NIV - Peripheral parenteral nutrition preferred as NIV along with enteral feed are associated with complications like stomach dilatation (prone for aspiration) and ineffective ventilation though due to air leak from the side of the facemask
For patients on HFNC, flow nasal cannula - Manage with oral nutritional supplements after assessing the nutritional status of COVID-19 patient or start enteral feed if orally not possible
Patients on ventilator

Early enteral feed (within 48 h of ICU admission) through nasogastric tube preferred over late enteral and early parenteral feed
Post pyloric feed to be started in patients prone for gastric aspiration or in gastric intolerance after prokinetic drugs
Parenteral nutrition can be administered within 3–7 days if contraindications to enteral nutrition present
Indirect calorimetry, VO2 or VCO2 estimation is recommended to guide daily energy expenditure (EE). If not available, weight-based equations to be used to estimate daily calorie expenditure (20–25 kcal/kg/day)
Enteral nutrition can be delivered in prone ventilated patients and is verified to be safe in COVID-19 ARDS, although difficult to execute in daily practice.
In the early phase of illness (1^st week), hypocaloric nutrition (not exceeding 70% of EE) is to be administered
After the early phase of acute illness, implement isocaloric nutrition rather than hypocaloric nutrition
In frail patients, protein administration (1.3 g/kg/day) can be considered progressively during critical illness and for obese patient, requirement of protein is 1.3 g/kg (adjusted body weight)/day. Adjusted body weight = Ideal body weight + 0.33 x (actual body weight-ideal body weight)
EN can be delayed in hemodynamic unstable patients with shock on vasopressors, severe hypoxemia, and severe acidosis.
Postextubation patients - Texture adapted food to be considered orally and if dysphagia present, which is most common in post-extubation, implement enteral nutrition.

Management of septic shock

In the absence of direct evidence on COVID-19 patients and septic shock, WHO interim guidelines^[18] and Surviving Sepsis Campaign guidelines^[37] recommends on the use of crystalloid IV balanced fluids such as Normal Saline, Ringer's Lactate as fluid bolus (1liter over 30 min or faster) for septic shock to check for fluid responsiveness. Hypotonic fluids, colloids, hydroxyethyl starches, gelatin, dextrans, and albumin are to be avoided for resuscitation. If there is no fluid response and signs of fluid overload appear like crackles on auscultation, then discontinue the fluid and consider using vasopressors. In vasopressors, Norepinephrine is the first choice followed by vasopressin and adrenaline, to maintain MAP >65 mm Hg. Consider dobutamine in shock with evidence of cardiac dysfunction associated with persistent tissue hypoperfusion. Surviving Sepsis Campaign guidelines^[37] does not recommend dopamine in COVID-19 with shock possibly due to an increase risk of arrhythmias and lack of evidence of mortality benefit. These vasopressors are to be given as per strict titration to targeted blood pressure to maintain tissue perfusion. When peripheral lines are used for infusion, watch for necrosis of skin or extravasation of vasopressors.

Prone ventilation

If lung protective ventilation fails to maintain adequate oxygenation and PaO₂/FiO₂ <150 mm Hg with PEEP >5 and FiO2 >0.6, then prone ventilation is to be considered. Guérin et al. PROSEVA trial^[40] has shown promising results in patients with severe ARDS. It is a well-known fact that prone ventilation along with early NMB agents has improved survivability in ARDS.^[13] Prone ventilation also enhances oxygenation and decreases V/Q mismatch in ARDS patients. In COVID-19 patients' good response to prone positioning may be due to their well-preserved lung compliance compared with patients who develop ARDS from other causes. Therefore, patients are ventilated in prone position for at least 16 h per day if patient fail to maintain oxygenation in supine position. However, utmost due care should be taken to avoid ventilator disconnections during position change, minimum staff should be kept for turning the patient to prone, and contraindications to prone ventilation (cervical spine injury, open chest, unstable airway, raised ICP, raised intra-abdominal pressure) should be addressed. It is imperative to mention that these patients should be well sedated to tolerate the tube and boluses of neuromuscular agents can also be considered to avoid unnecessary coughing while turning to prone position. The optimal time and criteria to discontinue prone ventilation is when PaO2/FiO2 >150 mm Hg with FiO2 <0.6 and PEEP <10 cm H₂O for at least 4 h in supine position after prone position.^[40]

Role of pulmonary vasodilators

The two most commonly used vasodilators in mechanically ventilated patients are inhaled nitric oxide gas (iNO) and epoprostenol which are administered by continuous inhalation. Although, their rescue therapy is considered to improve oxygenation when PaO2/FiO2 <100 mm Hg despite prone ventilation or if it is associated with acute pulmonary arterial hypertension.^[37] If there is no improvement in oxygenation after instituting inhaled pulmonary vasodilators, then it should be tapered off without undue delay to avoid rebound pulmonary vasoconstriction. Epoprostenol has mild antiplatelet action, so it should be avoided in alveolar hemorrhage. The risk of aerosolization and clogging of HME filters is particularly more with epoprostenol and it remains a concern in COVID-19 patients. That is why iNO is more preferred due to less frequent chance of filters and less risk of acquired infection in the HCWs. It is also essential to explain that the routine use of iNO in COVID-19 ARDS patients is not recommended by some intensive and critical care guidelines in the world as there is no evidence of survival benefit.^[37]

Role of ECMO

Even after prone ventilation and other evidence-based supportive care, oxygenation does not improve and hypoxia still persists then VV-ECMO (veno-venous extracorporeal membrane oxygenation) can be considered but it is subject to availability.

Indications of ECMO in COVID-19:^[41]

PaO₂/FiO₂ >150 but pH <7.25 with PaCO₂ >60 for more than 6 h
PaO₂/FiO₂ <80 mm Hg for 6 h, PaO₂/FiO₂ <50 mm Hg for 3 h, and other adjunctive measures fail (prone position, NMB, RMs, inhaled pulmonary vasodilators).

ECMO is expensive and extremely resource-limited treatment modality along with need of additional trained professional staff to operate ECMO. Therefore, its use as rescue therapy should be considered only in refractory hypoxic respiratory failure group of patients.^[42] So far, there are no RCTs or meta-analyses have been conducted on ECMO in COVID-19 ARDS. A report from China mentions that an ARDS patient due to COVID-19 has received ECMO. However, their course of hospital stay, clinical course, and outcome were not discussed.^[43]

Ventilator weaning and extubation of COVID-19

Special focus to avoid viral transmission to the health care providers during extubation in mandatory. Extubation is an aerosol generating procedure, so keep a high threshold for extubation of these patients to avoid unnecessary reintubation. Some physicians use cuff leak test criteria along with spontaneous breathing trials (SBT) to assess the readiness for weaning from mechanical ventilation on the assumption that these patients could have been developed airway edema due to prolong ventilation. Since the risk of aerosol generation in cuff leak test is similar to extubation, it is advised to perform SAT (Spontaneous awakening trial) and SBT without T-piece at lower pressure support (0-3 cm H₂O) along with use steroids prior to extubation. The following weaning criteria is recommended before extubation-

Patient should be conscious, comfortable, and oriented.
PaO2/FiO2 >300 mm Hg with PEEP <5 cm H₂O.
Hemodynamically stable and maintaining SPO₂ with FiO2 <0.4.
RSBI (Rapid shallow breathing index < 105)– calculated by respiratory rate/tidal volume in liters when the intubated patient is breathing spontaneously.
No signs of increase work of breathing or respiratory distress like use of accessory muscle, paradoxical or asynchronous respiration, nasal flaring, profuse diaphoresis, agitation, tachypnea, tachycardia, and cyanosis.
Good cough reflex with absence of unwarranted secretion.

[Appendix 1] explains the above steps in way of a flowchart.

Prevention of complications

The following intervention is to be considered to prevent complications associated with mechanical ventilation in COVID-19 patients-

Prevention of VAP^[44]

Spontaneous awakening and spontaneous breathing trails
Head of bed elevation
Selective digestive decontamination
Thromboprophylaxis
Oral care without chlorhexidine as some patients develops ARDS due to aspiration of chlorhexidine
Use a new ventilator circuit for each patient
Change HMEs filter when soiled
Oral intubation preferred compare to nasal intubation.

Reduce pressure sores and ulcers by frequent change of position every 2 hourly
Reduce stress ulcer, gastric bleeding by early enteral feeding within 24-48 h of ICU admission and consider PPI or H2 blocker
Reduce ICU related weakness by early mobilization
Reduce catheter related infection by using sterile aseptic technique while insertion and consider removal when not needed
Reduce the number of days on mechanical ventilation by daily assessment for readiness of extubation through spontaneous breathing trials
Reduce the incidence of venous thromboembolism by use of pharmacological agents or mechanical compression devices
Suctioning of mechanically ventilated patients is to be done with closed inline suction catheters to prevent aerosol spread and unnecessary ventilator disconnection is to be avoided to prevent alveolar recruitment.^[21]

Understanding recent advances in acute respiratory distress syndrome treatment

Salient features from various RCTs and clinical trials that reflect recent advances and consensus in the understanding and management of ARDS.

Multiple trials^[45],[46] have failed to confirm the benefit of using RMs in ARDS patients
The LUNG-SAFE study:^[13],[47] Shown increased mortality with NIV in severe ARDS patients
Liberal oxygen or conservative oxygen (LOCO₂) trial:^[48] Conservative oxygenation strategy did not reveal increased survival benefits. So, hyperoxia (SpO2 >97%) and hypoxemia (SpO2 <90%) should be avoided
SUPERNOVA study:^[49] Use of extracorporeal carbon dioxide removal can be possible to enable ultra-protective ventilation (Tidal volume = 4 mL/kg and P_PLAT ≤25 cmH₂O) in ARDS
(EOLIA) trial:^[50] Fails to approve the superiority of routine use of ECMO therapy in severe ARDS over rescue ECMO therapy.

Therefore, it is prudent to look for similar above-mentioned trials and RCTs for COVID-19 ARDS as well for improved treatment, and this area of research has the potential to directly enlighten everyone with better management of novel corona virus ARDS.

Neuropsychiatric Symptoms in Covid-19 Acute Respiratory Distress Syndrome

Long-term outcomes of patients with ARDS are being increasingly recognized as important research targets, as many patients survive ARDS only to have ongoing functional and/or psychological sequelae.

Delirium - The prevalence of delirium in intubated patients is up to 80%^[51],[53] which expectedly upswings in a COVID-19 patient with ARDS.

The risk factors include old age (>65 years), medical co-morbidity, drugs (propofol, opioids, and high-dose benzodiazepines, which are routinely used during mechanical ventilation), hydroxychloroquine.^[52]

Scales for assessment of delirium

The time tested Confusion Assessment Method for the ICU^[53] should be followed routinely. Other useful scales are Intensive Care Delirium Screening Checklist^[54] and the Stanford Proxy Test for Delirium.^[30]

Pharmacological management

Sleep cycle

Melatonin should be used for regularizing sleep-wake cycle in delirium as it has a short half-life, has additional mild anti-inflammatory properties, and does not cause respiratory depression. Suvorexant (Orexin antagonist) has also been used especially in conjunction with Melatonin.^[55] Benzodiazepines should be avoided (except in cases of delirium tremens), as cumulative doses run the risk of respiratory depression and may cause paradoxical disinhibition. Zolpidem (2.5–5 mg) is relatively safer in terms of respiratory functioning, but levels are increased in patients taking ritonavir.

Acute agitation/disruptive behavior

Antipsychotic drugs like haloperidol, olanzapine, or quetiapine are found to be beneficial in the management of the agitation. However, monitoring of QTc interval, neurologic side effects (EPS), and sedation are required. The risk of QTc prolongation gets further amplified, given the potential use of COVID-19–specific medications that themselves prolong QTc (hydroxychloroquine, azithromycin), leading to a potentially increased risk of torsades de pointes.^[56]

Haloperidol being a potent dopamine receptor blocker with insignificant anticholinergic and antihistaminic activity (2.5–5 mg) can be used orally or intramuscularly. IV administration should be accompanied by ECG monitoring. Recent research has also shown that haloperidol, due to its effects on sigma receptors, is investigated as a treatment for COVID 19^[57]
Olanzapine 5–10 mg can also be considered either orally or parenterally. In an acutely disturbed patients, intramuscular (IM) is the preferred route of administration compared to IV route and gluteal IM injections may be preferred over deltoid injections to increase the distance between respiratory secretion/droplet. IM olanzapine has minimal effect on QTc interval and lesser risk for EPS compared to haloperidol
Quetiapine (25–50 mg) can be given orally
Dexmedetomidine is alpha-2 agonist and reduces the release of noradrenaline and helps curtailing restlessness. Clonidine can also be used for the same reason and is more convenient as it is available in skin patches form
Valproic acid is known for its neuroprotective potential and can be used to control extreme emotional fluctuations. It also provides prophylaxis against the potentially epileptogenic state by increasing the seizure threshold. However, liver function tests and platelets need to be constantly monitored
In extreme cases not responding to the above measures, only short acting low dose oral benzodiazepines (e.g., lorazepam 1–2 mg) may be considered with close monitoring for respiratory distress and respiratory failure
Mechanical restraint: Mechanical restraint should be used as a last resort for minimum possible time.

Mechanical ventilation

Weaning off mechanical ventilation at times can be associated with acute and severe anxiety that could result in delay in extubation. A very low dose of antipsychotic-Tab Olanzapine 2.5 mg is advisable for anxiolysis.

Drug treatment of patients with preexisting psychiatric illness

Most psychiatric illnesses are remitting and relapsing in nature and generally require long-term prophylaxis. In the absence of a confirmed treatment for the management of COVID-19, a multitude of pharmacotherapeutic agents have been tried in the recent past and can have significant drug interactions with psychotropics and can precipitate a relapse of the illness. Hence, it is imperative to be mindful of such interactions.

Drug Interactions

Antipsychotics

Haloperidol, quetiapine, ziprasidone, etc., can prolong QTc interval. Hence, chloroquine, hydroxychloroquine, azithromycin, etc. can have a synergistic effect and should be used with caution. Certain protease inhibitors such as atazanavir, sequinavir, lopinavir/ritonavir can also cause QTc prolongation. The safer alternatives are lurasidone followed by aripiprazole, olanzapine, and risperidone.

Antidepressants

Citalopram, tricyclic antidepressants, and mirtazapine can prolong QTc interval, which might be augmented when combined with hydroxychloroquine, chloroquine. Escitalopram and sertraline are safer in view of lesser drug interactions and side effects.

Mood stabilizers

Non-steroidal anti-inflammatory drugs increase lithium levels, which may lead to toxicity. Valproate levels may be reduced with lopinavir/ritonavir.

Sedatives/hypnotics

Longer acting benzodiazepines such as diazepam or clonazepam may be avoided. Lorazepam is preferred as it has the least interaction with antiviral drugs and shorter half-life.

Conclusion

COVID-19 ARDS is an anticipated severe complication of COVID-19 that requires prompt recognition and comprehensive multi-specialty management. Extensive research and studies are required to address the vital unanswered queries about the treatment of mechanically ventilated patients of COVID-19 ARDS. Because of the high mortality in mechanically ventilated patients, the above recommendations and findings direct the potential for improvement in the management of patients with COVID-19 ARDS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Ferguson ND, Fan E, Camporota L, Antonelli M, Anzueto A, Beale R, et al. The Berlin definition of ARDS: An expanded rationale, justification, and supplementary material. Intensive Care Med 2012;38:1573-82.
2.	Li J, Fink JB, Ehrmann S. High-flow nasal cannula for COVID-19 patients: low risk of bio-aerosol dispersion. European Respiratory Journal. 2020 May 1;55(5). [doi: 10.1183/13993003.00892-2020].
3.	Ottestad W, Anaesthesia SS-BJ of, 2020 Undefined. COVID-19 Patients with Respiratory Failure: What Can We Learn from Aviation Medicine? Available from: https://bjanaesthesia.org/article/S0007-0912(20) 30226-9/abstract. [Last accessed on 2020 Jul 20].
4.	Whittle JS, Pavlov I, Sacchetti AD, Atwood C, Rosenberg MS. Respiratory support for adult patients with COVID-19. J Am Coll Emerg Physicians Open 2020;1:95-101.
5.	Möhlenkamp S, Thiele H. Ventilation of COVID-19 patients in intensive care units. Herz 2020;45:329-31.
6.	Roca O, Caralt B, Messika J, Samper M, Sztrymf B, Hernández G, et al. An index combining respiratory rate and oxygenation to predict outcome of nasal high-flow therapy. Am J Respir Crit Care Med 2019;199:1368-76.
7.	Alhazzani W, Al-Suwaidan FA, Al Aseri ZA, Al Mutair A, Alghamdi G, Rabaan AA, et al. The saudi critical care society clinical practice guidelines on the management of COVID-19 patients in the intensive care unit. Saudi Critical Care Journal 2020;4:27.
8.	Luo M, Cao S, Wei L, Tang R, Hong S, Liu R, et al. Precautions for intubating patients with COVID-19. Anesthesiology 2020;132:1616-8.
9.	Meng L, Qiu H, Wan L, Ai Y, Xue Z, Guo Q, et al. Intubation and ventilation amid the COVID-19 outbreak: Wuhan's experience. Anesthesiology 2020;132:1317-32.
10.	Gattinoni L, Giosa L, Bonifazi M, Pasticci I, Busana M, Macri M, et al. Targeting transpulmonary pressure to prevent ventilator-induced lung injury. Expert Rev Respir Med 2019;13:737-46.
11.	Walling PT, Savege TM. A comparison of oesophageal and central venous pressures in the measurement of transpulmonary pressure change. Br J Anaesth 1976;48:475-9.
12.	Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State. JAMA 2020;323:1612-4.
13.	Nanchal RS, Truwit JD. Guidelines for the management of adult acute and acute-on-chronic liver failure in the ICU: cardiovascular, endocrine, hematologic, pulmonary, and renal considerations.” Critical care medicine 48.3 (2020): e173-e191.
14.	Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: A randomized controlled trial. JAMA 2008;299:637-45.
15.	Gattinoni L, Chiumello D, Caironi P, Busana M, Romitti F, Brazzi L, et al. COVID-19 pneumonia: Different respiratory treatments for different phenotypes? Intensive Care Med 2020;46:1099-102.
16.	Gattinoni L, Quintel M, Marini JJ. “Less is more” in mechanical ventilation. Intensive Care Med 2020;46:780-2.
17.	Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. COVID-19 does not lead to a “Typical” acute respiratory distress syndrome. Am J Respir Crit Care Med 2020;201:1299-300.
18.	Organization WH. Clinical Management of Severe Acute Respiratory Infection When Novel Coronavirus (nCoV) Infection Is Suspected: Interim Guidance; January 25, 2020. Available from: https://www.who.int/health-topics/coronavirus. [Last accessed on 2020 Jul 20].
19.	Robertson TE, Mann HJ, Hyzy R, Rogers A, Douglas I, Waxman AB, et al. Multicenter implementation of a consensus-developed, evidence-based, spontaneous breathing trial protocol. Crit Care Med 2008;36:2753-62.
20.	Chacko B, Peter JV, Tharyan P, John G, Jeyaseelan L. Pressure-controlled versus volume-controlled ventilation for acute respiratory failure due to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Cochrane Database Syst Rev 2015;1:CD008807.
21.	Warrillow S, Austin D, Cheung WY, Close E, Holley A, Horgan B, et al. ANZICS guiding principles for complex decision making during the COVID-19 pandemic.
22.	Aryal D, Beane A, Dondorp AM, Green C, Haniffa R, Hashmi M, et al. Operationalisation of the Randomized Embedded Multifactorial Adaptive Platform for COVID-19 trials in a low and lower-middle income critical care learning health system. Wellcome open research 2021;6.
23.	Slutsky AS, Ranieri VM. Mechanical ventilation: Lessons from the ARDSNet trial. Respir Res 2000;1:73-7.
24.	Trasy D, Nemeth M, Kiss K, Till Z, Molnar Z. FiO2/PEEP index: A simple tool for opitimizing ventilator settings. Crit Care 2013;17:1-200.
25.	Zhang R, Wang X, Ni L, Di X, Ma B, Niu S, et al. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci 2020;250:117583.
26.	Jerath A, Ferguson ND, Cuthbertson B. Inhalational volatile-based sedation for COVID-19 pneumonia and ARDS. Intensive Care Med 2020;46:1563-6.
27.	Jabaudon M, Boucher P, Imhoff E, Chabanne R, Faure JS, Roszyk L, et al. Sevoflurane for sedation in acute respiratory distress syndrome. A randomized controlled pilot study. Am J Respir Crit Care Med 2017;195:792-800.
28.	Shang Y, Pan C, Yang X, Zhong M, Shang X, Wu Z, et al. Management of critically ill patients with COVID-19 in ICU: Statement from front-line intensive care experts in Wuhan, China. Ann Intensive Care 2020;10:73.
29.	Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41:263-306.
30.	Rubulotta F, Soliman-Aboumarie H, Filbey K, Geldner G, Kuck K, Ganau M, et al. Technologies to optimize the care of severe COVID-19 patients for health care providers challenged by limited resources. Anesth Analg 2020;131:351-64.
31.	Kaplan L, Bailey H. Bispectral index (BIS) monitoring of ICU patients on continuous infusion of sedatives and paralytics reduces sedative drug utilization and cost. Crit Care 2000;4 Suppl 1:190.
32.	Balas MC, Weinhouse GL, Denehy L, Chanques G, Rochwerg B, Misak CJ, et al. Interpreting and implementing the 2018 pain, agitation/sedation, delirium, immobility, and sleep disruption clinical practice guideline. Crit Care Med 2018;46:1464-70.
33.	Papazian L, Aubron C, Brochard L, Chiche JD, Combes A, Dreyfuss D, et al. Formal guidelines: Management of acute respiratory distress syndrome. Ann Intensive Care 2019;9:69.
34.	Mehta S, Burns KE, Machado FR, Fox-Robichaud AE, Cook DJ, Calfee CS, et al. Critical care perspective gender parity in critical care medicine. Am J Respir Crit Care Med 2017;17:425-9.
35.	Ho AT, Patolia S, Guervilly C. Neuromuscular blockade in acute respiratory distress syndrome: A systematic review and meta-analysis of randomized controlled trials. J Intensive Care 2020;8:12.
36.	Yu IT, Xie ZH, Tsoi KK, Chiu YL, Lok SW, Tang XP, et al. Why did outbreaks of severe acute respiratory syndrome occur in some hospital wards but not in others? Clin Infect Dis 2007;44:1017-25.
37.	Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving sepsis campaign: Guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Intensive Care Med 2020;46:854-87.
38.	Barazzoni R, Bischoff SC, Breda J, Wickramasinghe K, Krznaric Z, Nitzan D, et al. ESPEN expert statements and practical guidance for nutritional management of individuals with SARS-CoV-2 infection. Clin Nutr 2020;39:1631-8.
39.	Singer P, Blaser AR, Berger MM, Alhazzani W, Calder PC, Casaer MP, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr 2019;38:48-79.
40.	Guérin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368:2159-68.
41.	Fredericks AS, Bunker MP, Gliga LA, Ebeling CG, Ringqvist JR, Heravi H, et al. Airway pressure release ventilation: A review of the evidence, theoretical benefits, and alternative titration strategies. Clin Med Insights Circ Respir Pulm Med 2020;14:1179548420903297.
42.	MacLaren G, Fisher D, Brodie D. Preparing for the most critically ill patients with COVID-19: The potential role of extracorporeal membrane oxygenation. JAMA 2020;323:1245-6.
43.	Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir Med 2020;8:475-81.
44.	Klompas M. What is new in the prevention of nosocomial pneumonia in the ICU? Curr Opin Crit Care 2017;23:378-84.
45.	Ferrando C, Blanco J. Open Lung Approach for the Acute Respiratory Distress Syndrome; 2017. Available from: https://www.researchgate.net/publication/283748635. [Last accessed on 2020 Jul 20].
46.	Walkey AJ, Del Sorbo L, Hodgson CL, Adhikari NKJ, Wunsch H, Meade MO, et al. Higher PEEP versus Lower PEEP strategies for patients with acute respiratory distress syndrome. A systematic review and meta-analysis. Ann Am Thorac Soc 2017;14:S297-303.
47.	Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 2016;315:788-800.
48.	Barrot L, Asfar P, Mauny F, Winiszewski H, Montini F, Badie J, et al. Liberal or conservative oxygen therapy for acute respiratory distress syndrome. N Engl J Med 2020;382:999-1008.
49.	Combes A, Fanelli V, Pham T, Ranieri VM, European Society of Intensive Care Medicine Trials Group and the “Strategy of Ultra-Protective lung ventilation with Extracorporeal CO2 Removal for New-Onset Moderate to Severe ARDS” (SUPERNOVA) Investigators. Feasibility and safety of extracorporeal CO 2 removal to enhance protective ventilation in acute respiratory distress syndrome: The SUPERNOVA study. Intensive Care Med 2019;45:592-600.
50.	Combes A, Hajage D, Capellier G, Demoule A, Lavoué S, Guervilly C, et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med 2018;378:1965-75.
51.	Maldonado J, Maldonado JR, Maldonado JR. Psychosocial assessment of organ transplant candidates view project biomarkers of chronic fatigue syndrome view project delirium pathophysiology: An updated hypothesis of the etiology of acute brain failure. Artic Int J Geriatr Psychiatry 2017;33:1428-57.
52.	LaHue SC, James TC, Newman JC, Esmaili AM, Ormseth CH, Ely EW. Collaborative Delirium Prevention in the Age of COVID-19. J Am Geriatr Soc 2020;68:947-9.
53.	van Eijk MM, van Marum RJ, Klijn IA, de Wit N, Kesecioglu J, Slooter AJ. Comparison of delirium assessment tools in a mixed intensive care unit. Crit Care Med 2009;37:1881-5.
54.	Maldonado JR, Sher YI, Benitez-Lopez MA, Savant V, Garcia R, Ament A, et al. A study of the psychometric properties of the “Stanford Proxy Test for Delirium” (S-PTD): A new screening tool for the detection of delirium. Psychosomatics 2020;61:116-26.
55.	Roden DM, Harrington RA, Poppas A, Russo AM. Considerations for drug interactions on QTc interval in exploratory COVID-19 treatment. Heart Rhythm 2020;17:e231-2.
56.	Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020;583:459-68.
57.	Sher Y, Miller Cramer AC, Ament A, Lolak S, Maldonado JR. Valproic acid for treatment of hyperactive or mixed delirium: Rationale and literature review. Psychosomatics 2015;56:615-25.

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