Management of the critically ill patient with COVID-19 disease

COVID-19 disease has spread far and wide across the globe. At the time of writing, more than 225,000 patients have been affected, leading to more than 9,300 deaths (1). The number of seriously ill patients who require intensive care is likely to increase, requiring several-fold increase in the requirement for caregivers and equipment. The clinical management strategy of infected patients is evolving, and encompasses several treatment modalities, including mechanical ventilation and support of vital organs. This review attempts to summarize the intensive care management of critically ill patients with COVID-19 based on the evidence available and experience from previous epidemics of viral pneumonias. 

Location

Considering the high risk of transmission, patients with COVID-19 disease should be preferably cared for in single, negative pressure rooms. In case of non-availability of single, negative pressure rooms, standard single rooms are preferred. If the patient load is high and the above options are exhausted, the next suitable alternative is to cohort COVID-19 patients to a multi-bed area, which is physically separate from other patients. A distance of at least 2 meters should be maintained between patients. Each location should have an ante-room earmarked for staff preparation, including donning and doffing of personal protective equipment (PPE).

Staffing

As part of advance planning, staff members who would be involved with the care of COVID-19 patients should be identified. The “clean” and “isolated” teams of healthcare workers should be segregated, with back-up personnel to stand-in if shortages arise. Staff members who care for COVID-19 patients should wear clean surgical scrubs and provided with provision to shower at the end of the shift. Strong consideration should be given to allow a break of 1-2 weeks after a 1-week period of regular duty to members of the isolation team. Healthcare workers should be instructed to report any untoward symptoms early and their temperature should be checked twice a day. 

Clinical management 

The presence of pneumonic infiltrates on imaging is one of early features of severe COVID-19 disease.  In a study of 99 patients from the Jintinyan Hospital in China, 74 (75%) patients had evidence of bilateral pneumonia,  while multiple mottling  or ground-glass opacities on CT imaging was seen in 14 (14%) patients (2). The management of COVID-19 pneumonia is similar to that of other viral pneumonias based on the information available until now. 

Acute respiratory distress syndrome is seen typically seen in severe disease. 

High-flow nasal oxygen

In resource-limited situations, high-flow nasal oxygen may be initiated as early supportive therapy. However, there is a risk associated with a high level of aerosolization and disease transmission with this modality of treatment. It may be advisable to use relatively low flows (20­–30 l/min) to prevent excessive aerosolization. The patient may don a surgical mask to reduce the risk of excessive dissemination of aerosol.

Non-invasive ventilation 

Should we use non-invasive ventilation (NIV) as the initial modality of ventilatory support in patients with COVID-19 disease? Among patients with the Middle East respiratory syndrome, NIV failure rate was very high. In an observational study, 92.4% of patients who were initially managed with NIV required invasive mechanical ventilation. Besides, there was no difference in the 90-d mortality between patients who received NIV initially and those who were invasively ventilated at the outset (3). Furthermore, emergent intubation with poor preparation following failed NIV carries an increased risk of disease transmission due to a failure to follow appropriate precautions. The Australia and New Zealand Intensive Care Society (ANZICS) recommends against the use of NIV in COVID-19 infected patients (4). 

When to intubate?    

There is an absence of robust information on how to decide on the appropriate time to intubate and commence invasive mechanical ventilation among patients with severe disease. It is better to be prepared and consider early intubation if there is a lack of improvement or worsening with conventional oxygen, NIV, or high-flow nasal oxygen within an hour of commencement of therapy (5). 

Intubation protocol 

Considering the high likelihood of transmission of infection to healthcare workers, intubation of patients with COVID-19 disease must be carefully planned and carried out with utmost precautions. It is highly desirable to perform intubations in a negative pressure room; if this is not feasible, a single isolation room is preferred. It is important to create a checklist of items required and ensure readiness before commencement of the procedure. Do ensure that the intubation plan is communicated to the whole team prior to commencement. If in doubt, it is appropriate to perform intubation early during the clinical course. Emergency intubations may carry additional risk to staff from the likelihood of inadequate donning of personal protective equipment (PPE) besides subjecting a severely hypoxic patient to the risks associated with unplanned intubation. 

Intubation should be carried out in a well-planned manner. All essential equipment must be in full readiness prior to commencement of the procedure. All staff involved must don adequate PPE including water-resistant gowns, gloves, fit-tested N95 masks or higher, goggle or face shields, and cap. Not more than three healthcare personnel should be by the bedside to carry out intubation. One staff member should administer medications while the other assists with intubation and monitors the patient during the procedure. The person who performs the intubation must be the most experienced with airway management in the team. A vasopressor infusion (e.g., noradrenaline, 4 mg/50 ml) must be set up and ready to infuse in case of hypotension after the administration of anesthetic agents. Preoxygenation is carried out using a bag-mask system to ensure maximal oxygen saturation prior to the administration of anesthetic drugs. The mask must be held tightly across the face with both hands to reduce air leak and aerosol generation. Do not attempt positive pressure ventilation with bag and mask if possible; if considered absolutely necessary, the assistant carries out insufflations while the intubator ensures an effective seal with the mask.  

Once the patient is adequately sedated, suxamethonium 1.5 mg/kg or rocuronium 1.2 mg/kg is administered for muscle relaxation. Adequate muscle relaxation must be ensured before laryngoscopy is attempted.  A video laryngoscope is preferred if the operator is skilled, as it reduces the proximity of the operator to the airway compared to direct laryngoscopy. 

It is important to place the tube correctly without undue delay; failed attempts are associated with increased risks of transmission of infection to staff. Ventilation must not be attempted before cuff inflation as this may cause a significant leak around the cuff and contamination. Closed suction must be employed to prevent the spread of aerosol. Samples for virology studies may be drawn during suctioning. Careful doffing of personal protective equipment is carried out after the procedure.

Ventilation strategies 

Based on available evidence, a low-tidal volume, lung-protective ventilation strategy is recommended for patients with COVID-19 pneumonia. Retrospective data suggests that ventilation strategies targeting driving pressure may be appropriate in patients with ARDS (6). The initial management of patients who are difficult to ventilate includes the use of deep sedation and muscle relaxants as appropriate. Initial clinical experience suggests that there is rapid improvement in the P/F ratio with initiation of mechanical ventilation, with the use of high levels of PEEP and recruitment maneuvers. Prone ventilation has also been extensively employed; early experience suggests rapid improvement in oxygenation. Extra-corporeal membrane oxygenation has been performed on a limited scale in some centers, but no data is currently available regarding clinical outcomes. A fluid-restrictive strategy is appropriate among patients who are not in shock; diuretic therapy may be considered to remove excessive fluid and aim for a negative balance. 

Extra-pulmonary organ failure

Besides pneumonia and ARDS, multiorgan failure has been frequently reported in patients with COVID-19 disease. This includes myocardial involvement, hepatic, and renal dysfunction. In a retrospective, observational study from China, there was evidence of cardiac injury (29%), hepatic dysfunction (29%), and acute kidney injury (23%) among 710 patients admitted to the Jinyintan Hospital in Wuhan. Renal replacement therapy was performed in 17% of patients with severe illness (7).

Corticosteroids

According to the guidelines of the World Health Organization (WHO) and the Center for Disease Control (CDC), corticosteroids are not recommended in patients with COVID-19 diseases (1,8). Corticosteroid use was associated with higher mortality and delay in viral clearance among patients with MERS-CoV infection. In severe acute respiratory distress syndrome (SARS) lack of benefit with corticosteroids has been demonstrated; besides, there may be short and long-term harmful effects including the requirement for mechanical ventilation, vasopressors, and renal replacement therapy (9). It is likely that the impact of corticosteroids in COVID-19 disease may also be similar. 

Anti-viral therapy under investigation

Several anti-viral drugs are being used as part of the treatment strategy in COVID-19 pneumonia in several countries. Apart from anecdotal information, there is no controlled data that supports the use of specific antiviral therapy. 

Chloroquine/hydroxychloroquine

Both chloroquine and hydroxychloroquine have been shown to have anti-viral activity in vitro against SARS-CoV-2; hydroxychloroquine may be more potent (10). Several clinical trials are in progress, but it is unclear whether these drugs may exhibit anti-viral activity and improve clinical outcomes in COVID-19 disease. 

Remdesivir

A novel nucleotide analogue, remdesivir has revealed in vitro activity against coronaviruses including SARS-CoV-2 and MERS-CoV. Besides, anti-viral activity has also been observed in animal studies. Although used sporadically in several patients across the globe, the clinical efficacy of remdesivir in COVID-19 disease is unknown. Several randomized controlled studies are currently in progress.

Lopinavir-ritonavir

This protease receptor drug combination is used in retroviral infection and has been demonstrated to have in vitro activity against SARS-CoV. Animal data also suggest efficacy. There are several case reports of the use of this combination in COVID-19 disease. Young et al. reported use among five hypoxemic patients with COVID-19 disease in Singapore. Among these, three patients revealed improvement in oxygenation and two had viral clearance from the nasopharynx within two days of commencement of treatment. The condition of two patients worsened and one required intubation and ventilation. Both these patients exhibited viral carriage in the nasopharynx throughout their stay in the ICU. Adverse effects included gastrointestinal symptoms and abnormal liver function tests (11). 

In a recently published randomized controlled trial, Cao et al. evaluated the efficacy of the lopinavir-ritonavir combination among patients with an oxygen saturation of less than 94% while breathing room air or P/F ratio of less than 300 mm Hg. The primary endpoint was the time interval from randomization to improvement by two points on a seven-category scale or hospital discharge, whichever occurred earlier. There was no difference between the anti-viral combination and standard care in the primary outcome. No significant difference was observed in the 28-d mortality between groups. Besides, there was no difference in the number of patients with detectable viral RNA at different points of time during the course of treatment. This study suggests that the lopinavir-ritonavir combination may not improve clinical outcomes or reduce viral shedding in patients with COVID-19 disease. 

Tocilizumab

The interleukin-6 (IL-6) pathway may mediate the intensive inflammatory response that occurs in the lungs of critically ill patients with COVID-19 disease. Tocilizumab, an IL-6 inhibitor may have a beneficial effect among such patients. The guidelines of the National Health Commission in China recommends the use of tocilizumab, and is being currently evaluated in a clinical trial (12). 

Summary

  • Considering the likelihood of an increasing number of critically ill patients, it is important to identify appropriate care locations. Negative pressure isolation rooms are preferred; if this is not feasible, single isolation rooms are the next best option. 
  • A team of staff members needs to be identified and offered training in the management of COVID-19 patients as part of the initial plan. 
  • Initial supportive measures include oxygen therapy; if no improvement is observed or the patient deteriorates, early intubation must be considered. High flow nasal oxygen and NIV must be used judiciously considering the increased risk of aerosol generation and possible disease transmission.
  • Conventional ventilation strategies including the use of low tidal volumes and titration of PEEP levels may be followed; prone ventilation may help improve oxygenation.
  • Extrapulmonary organ failure including shock and acute kidney injury may occur and require appropriate levels of support.
  • Corticosteroids are generally not indicated in COVID-19 disease; several virus-specific treatment modalities are currently being evaluated in clinical trials

References:

1.         Coronavirus Update (Live): 107,490 Cases and 3,652 Deaths from COVID-19 Wuhan China Virus Outbreak – Worldometer [Internet]. [cited 2020 Mar 8]. Available from: https://www.worldometers.info/coronavirus/

2.         Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet. 2020 Feb;395(10223):507–13. 

3.         Alraddadi BM, Qushmaq I, Al-Hameed FM, Mandourah Y, Almekhlafi GA, Jose J, et al. Noninvasive ventilation in critically ill patients with the Middle East respiratory syndrome. Influenza Other Respir Viruses. 2019;13(4):382–90. 

4.         ANZICS-COVID-19-Guidelines-Version-1.pdf.

5.         Jin Y-H, Cai L, Cheng Z-S, Cheng H, Deng T, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res. 2020 Dec;7(1):4. 

6.         Amato MBP, Meade MO, Slutsky AS, Brochard L, Costa ELV, Schoenfeld DA, et al. Driving Pressure and Survival in the Acute Respiratory Distress Syndrome. N Engl J Med. 2015 Feb 19;372(8):747–55. 

7.         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 Feb;S2213260020300795. 

8.         CDC. Coronavirus Disease 2019 (COVID-19) [Internet]. Centers for Disease Control and Prevention. 2020 [cited 2020 Mar 19]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html

9.         Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. The Lancet. 2020 Feb 15;395(10223):473–5. 

10.       Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis Off Publ Infect Dis Soc Am. 2020 Mar 9; 

11.       Young BE, Ong SWX, Kalimuddin S, Low JG, Tan SY, Loh J, et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA [Internet]. 2020 Mar 3 [cited 2020 Mar 8]; Available from: https://jamanetwork.com/journals/jama/fullarticle/2762688

12.       China approves use of Roche drug in battle against coronavirus complications – Reuters [Internet]. [cited 2020 Mar 19]. Available from: https://www.reuters.com/article/us-health-coronavirus-china-roche-hldg/china-approves-use-of-roche-arthritis-drug-for-coronavirus-patients-idUSKBN20R0LF

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