key: cord-1025509-po9q600b
authors: Hensley, Matthew K.; Prescott, Hallie C.
title: Caring for the Critically Ill Patient with COVID-19
date: 2022-04-20
journal: Clin Chest Med
DOI: 10.1016/j.ccm.2022.04.006
sha: 7b1e6830acda833f6b8a2fa2e84af546a79cdd52
doc_id: 1025509
cord_uid: po9q600b

The COVID-19 pandemic has resulted in unprecedented numbers of critically ill patients. Critical care providers have been challenged to increase the capacity for critical care, prevent the spread of SARS-CoV-2 in hospitals, determine the optimal treatment approaches for patients with critical COVID-19, and to design and implement systems for fair allocation of scarce life-saving resources when capacity is exhausted. The global burden of COVID-19 highlighted disparities, across geographic regions and among minority patient populations. Faced with a novel pathogen, critical care providers grappled with the extent to which conventional supportive critical care practices should be followed versus adapted to treat patients with COVID-19. Fiercely debated practices included the use of awake prone positioning, the timing of intubation, and optimal approach to sedation. Advances in clinical trial design were necessary to rapidly identify appropriate therapeutics for the critically ill patient with COVID-19. In this article we review the epidemiology, outcomes, and treatments for the critically ill patient with COVID-19.

Critical care requires trained clinicians, supplies, and space. Early in the pandemic, there was widespread fear that a shortage of ventilators [31] [32] [33] would contribute to excess mortality. With roughly 62,000 working ventilators in the US prior to the pandemic 34 , the feasibility of ventilator sharing was considered. In one New York hospital, 3 pairs of critically ill patients (N=6) were placed on one mechanical ventilator, using volume control mode 32 . Deep sedation and continuous paralysis were used to avoid ventilator dyssynchrony. While the authors concluded that ventilator sharing may be safe and feasible for short periods of time, multiple professional societies published a consensus statement advising against ventilator sharing due to the risk for causing more harm than good 35 . Ultimately, industry partners (e.g.

Ford, General Motors, Dyson) helped to manufacture ventilator equipment 34 and expand the U.S. supply of ventilators to nearly 120,000 by August 2020, alleviating concerns of ventilator shortage 34 .

Despite the early focus on ventilator availability, it quickly became evident that having trained clinicians, adequate space, and basic supplies were more important than ventilators. In particular, the availability of nurses 36 , respiratory therapists 37 , acute care providers 38 , and well-ventilated space 29 proved to be the most important scare resources. Many hospitals had to rapidly expand ICU bed capacity with critical care trained and non-critical care trained staff 3 . Utilizing a tiered system, the most experienced critical care provider can safely supervise mid-level or non-critically-care trained providers to care for up to 24 patients at some institutions with appropriate bed capacity and resources 3 . Alternatively, telemedicine services where an off-site hospital provides critical care expertise serves as another method for expanding capacity in resource-constrained areas 39 . To expand physical ICU space, some hospital re-purposed floor rooms to serve as ICU beds with negative pressure capabilities, while other countries such as China rapidly built new ICUs 40 . Personal protective equipment was sanitized and reused to maintain supply.

Incentive programs were developed to hire traveling nurses in areas of shortage, or to have a back-up supply of staff in the event of healthcare workers contracting COVID-19. Nevertheless, shortages of key resources required organizations to develop triage committees, in the event that critical care demand would far exceed available resources 41 .

Long-term Outcomes J o u r n a l P r e -p r o o f Data on longer-term outcomes from COVID-19 continue to accrue, but existing evidence indicates not only high in-hospital mortality, but also a high burden of subsequent morbidity among hospital survivors 42, 43 

J o u r n a l P r e -p r o o f As a result of infection precautions and high patient volume, many ICU practices changed during the COVID-19 pandemic, including delirium assessment, sedation practices, family involvement, and end-oflife care. Meanwhile, clinicians debated the optimal approach to respiratory support, including the threshold for initiation and approach to mechanical ventilation. Lastly, therapeutics were controversial and evolved rapidly as clinical trial data emerged.

Supportive Care: ABCDEF Bundle

The ABCDEF bundle 53 is a collection of six evidence-based practices (pain assessment and treatment, spontaneous awakening and breathing trials, choice of sedation, delirium assessment, early mobility, and family engagement) which serve as the cornerstone for supportive care in the ICU. In a 2-day point prevalence study of ABCDEF bundle implementation in 212 ICUs in 38 countries on June 3 and July 1 of 2020, there was low implementation of all elements, including pain assessment (45%), spontaneous breathing trials (28%), sedation assessment (52%), delirium assessment (35%), early mobility (47%), and family engagement (16%) 54 . The study did not assess reasons for low compliance, but hypothesized reasons include high patient census, scarcity of personnel, drug shortages, and time needed to don/doff PPE.

Sedation practices have differed during the pandemic as well. In a multi-national study of 2,088 patients admitted to 69s ICU across 14 countries (January 20, 2020 through April 28, 2020) 55 , the majority (64%, 1,337 of 2,088) were treated with benzodiazepine infusions, for a median of 7 days (IQR 4-12 days) 55 . As would be expected, benzodiazepine infusion [OR 1.59 (95% CI: 1.33-1.91)] was associated risk of acute brain dysfunction 55 . Despite guidelines 56 recommending against benzodiazepine infusions, their use has increased during the pandemic due to drug shortages, need for multiple sedating medications to prevent self-extubation, and high patient-to-nurse ratios limiting the ability to re-orient and calm patients. There was much debate about the pathophysiology of acute hypoxic respiratory failure due to COVID-19.

Some believed the primary etiology was due to endothelial dysfunction and hypoxic vasoconstriction with increased compliance relative to historical cohorts [58] [59] [60] . This led to the theoretical subphenotypes of COVID-19 respiratory failure: a) "L" phenotype with low elastance, normal compliance; b) "H" phenotype with high elastance and low compliance 61 . Investigators further postulated a need for differing ventilation strategies in each group, with the "L" phenotype requiring liberalized tidal volume with lower PEEP and the "H" phenotype requiring typical ventilation strategies including higher PEEP and low tidal volume ventilation 58 . As further evidence emerged, significant heterogeneity of disease was observed, with varying compliance consistent with prior cohorts of patients with ARDS 62, 63 . This resulted in a call to study the disease further before changing decades of critical care practice, and continuing to advocate for lung protective low tidal volume ventilation 64 . In a study comparing 130 critically ill mechanically ventilated patients with COVID-19 ARDS to 382 non-COVID ARDS mechanically ventilated patients, there was no difference in time-to-breathing unassisted at 28 days or 28-day mortality 65 . Other studies have likewise found similar outcomes when comparing COVID-19 ARDS to other viral ARDS cohorts 66 . Further investigation using semi-quantitative methods found the "L" and "H" phenotypes were not mutually J o u r n a l P r e -p r o o f exclusive and likely represent a spectrum of disease 67 . Furthermore, historical investigation of personalized mechanical ventilation techniques have not improved outcomes in ARDS patients when compared to typical lung protective ventilation techniques 68 . In summary, there is not enough evidence to suggest acute hypoxic respiratory failure from COVID-19 is different from historical ARDS cohorts, or that mechanical ventilation strategies should deviate from current best practice guidelines.

When should the hypoxic patient with COVID-19 be intubated?

Early in the pandemic, there was widespread concern that heated high flow nasal cannula (HHFNC) and non-invasive ventilation (NIV) may increase risk for aerosolization of SARS-CoV-2, and thereby drive transmission of COVID-19 to healthcare workers. This concern led many clinicians to electively intubate patients and initiate mechanical ventilation once oxygenation saturation could not be maintained with low levels of nasal cannula oxygen. However, subsequent studies have not borne out this early concern.

Humans are highly effective at generating aerosols via coughing, but HHFNC and NIV do not cause meaningful increases in aerosol generation over and beyond what is produced by patients on room air 69 .

Even after HHFNC and NIV were shown safe from aerosol-generation standpoint, there remained equipoise regarding the optimal threshold for initiation of invasive mechanical ventilation 70 . Some clinicians opt for earlier intubation, recognizing the added time associated with intubation under airborne precautions. Other clinicians delay intubation as long as possible, recognizing that some patients may be able to avoid invasive mechanical ventilation altogether.

Several observational studies have examined outcomes by timing of intubation. In a study of 47 patients with hypoxic respiratory failure in Korea (February 17, 2020 through April 23, 2020), 23 (48.9%) were intubated on the first day meeting ARDS criteria (P/F ≤300 with bilateral infiltrates not fully explained by heart failure), while 24 (51.1%) were intubated on a subsequent day, >24 hours after suspected ARDS diagnosis 71 . In-hospital mortality was numerically higher (56.5% vs. 43.8%, p=0.43), while ventilator free days were lower in the early intubation group (median 9 days vs. 28 days, p=0.008) 71 . outcomes including ICU length of stay and need for renal replacement therapy were similar between groups 74 . One significant limitation, however, is that observational data may have residual confounding by indication. Patients with higher illness severity may be intubated sooner, while also having higher risk of mortality, thereby introducing bias, and limiting our overall interpretation of these studies.

Taken together, observational data suggests later intubation is associated with worse respiratory mechanics 73 , though mortality among invasive mechanically ventilated patients may be the same regardless of timing of intubation 63, 72, 74 . Non-invasive support modalities (HHFNC, NIV) appear safe, though it is unclear whether they reduce mortality and may prolong length of stay 63, 72 . Bias associated with observational data limits interpretation of whether patients should be intubated early or late in their course, and randomized trials are not available presently.

Is proning the non-intubated patient with COVID-19 safe and does it prevent intubation?

Given the benefits seen in historical groups of ARDS patients placed in the prone position 75 , providers began proning the awake non-intubated patient with respiratory failure from COVID-19 ("self-proning"), hoping to prevent intubation and utilization of scarce resources. New York city emergency medicine providers enrolled 50 consecutive patients with respiratory failure from COVID-19 between March 1, 2020 and April 1, 2020, excluding those with limited code status, those requiring non-invasive ventilation, and including those who remained hypoxic (saturation <94% with supplemental oxygen) 76 . Of the 50 patients who self-proned, 13 (24%) were intubated within 24 hours of arrival to the emergency room 76 . Of the remaining 37 patients admitted to the hospital, 5 (13.5%) were intubated during their hospital stay, 36% in total requiring intubation. Notably, 7 (14%) patients required intubation within 1 hour of proning 76 . Lack of a control group limits interpretation.

A separate case series of 24 awake non-intubated spontaneously breathing French patients with respiratory failure due to COVID-19 between March 27, 2020 and April 8, 2020 examined tolerance of prone positioning and outcomes 10 . Of the 24 patients enrolled, 4 (17%) did not tolerate prone positioning for more than 1 hour, 5 (21%) tolerated it for 1 to 3 hours, and 15 (63%) tolerated it for more than 3 hours.

Of the 24 patients, 6 (25%) were considered responders defined as a PaO2 increase ≥20% during proning, with half of those non-sustained after re-supination 10 . Lack of control group and lack of outcomes data are limiting factors.

An Italian series of 15 non-ICU patients with respiratory failure due to COVID-19 demonstrated that CPAP administration outside the ICU (10 cm H2O and FiO2 0.6) while prone was feasible 77 . Of the 15 patients J o u r n a l P r e -p r o o f who were proned for 3 hours with CPAP, all patients had reduction in respiratory rate, and improved p/f ratio while proned (p<0.001). At 14-day follow-up, 9 (60%) were discharged home, 1 (6%) improved and stopped proning but remained hospitalized, 3 (20%) continued proning, 1 (6%) patient was intubated, and 1 (6%) patient died 77 . Of 29 patients enrolled in a New York city hospital with respiratory failure from COVID-19 between April 6, 2020 and April 14, 2020, 25 completed at least 1 hour of self-proning 78 . All patients had improvement in oxyhemoglobin saturation with a median improvement of 7% (range 1-34%).

Of the 25 patients, 12 (48%) required intubation, 5 (20%) after the initial hour of proning 78 .

While self-proning seems feasible with improvement in oxygenation for some patients, it is difficult to draw conclusions with lack of comparison groups, randomization, and long-term outcomes 4 To date, there are no well-controlled trials randomizing patients to various hemodynamic treatment strategies. Extrapolation from septic shock studies has guided authors to recommend assessing for fluid responsiveness 79 , giving balanced crystalloids over colloids 80 , and using norepinephrine as a first-line vasopressor targeting a mean arterial pressure of 60-65 mmHg 79, 80 . Similarly, use of stress dose steroids is a clinical decision and no different in patients with COVID-19 and distributive shock 80 . There are several opinions on how much volume should be given 81,82 , but there is a paucity of data presently to make conclusions. Similar to historic cohorts of septic shock, the resuscitation volume and type will likely be an ongoing debate. Once shock has resolved, there is a question of the utility of diuresis with loop diuretics, which has been shown to reduce duration of mechanical ventilation in non-COVID-19 ARDS trials 83 . Investigation regarding the utility of nebulized furosemide in respiratory failure from COVID-19 is ongoing 84 .

The COVID-19 pandemic brought about rapid investigation in therapeutics. Early reports of hydroxychloroquine, a medication used to treat autoimmune diseases, showed promise in small noncontrolled studies. However, large observational 85 (Table 2) . Furthermore, a recent meta-analysis including 73 studies and 21, 350 patients hospitalized with COVID-19 found corticosteroids were used with increasing frequency in mechanically ventilated patients (35%), ICU patients (51.3%), and severely ill patients (40%), demonstrating an overall mortality benefit (OR 0.65; 95%CI: 0.51-0.83) 94 . Notably, steroids were not found to prolong viral shedding, but interpretations are somewhat limited due to heterogeneity of study methodologies and reporting. As a result, the World Health Organization (WHO) recommends dexamethasone 6mg daily or 50mg hydrocortisone every 8 hours for 7-10 days in severely or critically ill patients with COVID-19 95 . The optimal dose and duration of corticosteroids are not yet fully known 96 .

Remdesivir, an inhibitor of RNA-polymerase, was the next drug to show promise against the COVID-19 pandemic. Across 13 countries, 1,062 patients hospitalized with COVID-19 from February 21, 2020 through April 19, 2020 were randomized to remdesivir vs. placebo 97 The pandemic has taken a global toll, both from a health perspective and from an economic standpoint.

As vaccinations have become widespread in certain parts of the world, restrictions will be lifted, and life will begin to normalize for many. However, we cannot forget the lessons learned from this global pandemic. We need to maintain a public health infrastructure capable of responding rapidly with resources, train and maintain staff to respond with appropriate bed capacity, understand the importance of isolation precautions for infection prevention, and utilize research techniques such as REMAP to rapidly assess therapeutics to improve care and outcomes for our patients.

Clinics Care Points -• 1 in 4 patients hospitalized with COVID-19 become critically ill, with up to 80% of those requiring mechanical ventilation.

• In-hospital mortality varies, but with appropriate resources and capacity, can be as low as 12% in some cohorts.

• Long-term outcomes after COVID-19 remain poor, with 50-70% reporting persistent symptoms such as shortness of breath or fatigue.

• Acute respiratory failure from COVID-19 represents a similar spectrum of disease to other historical cohorts of viral ARDS.

• Corticosteroids remain the mainstay of treatment for COVID-19, though optimal dosing and duration remain unknown.

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