COVID-19 Group 1

Synopsis: SARS-CoV-2 is the virus that causes COVID-19 pneumonia, which can progress to ARDS and death. This retrospective cohort study evaluated patients admitted to one hospital in Wuhan from 12/25/19-1/26/20 with followup through 2/13/20 to evaluate for risk factors for the development of ARDS and death. The study reports on 201 patients with median age 51 (20% age 65+) and 64% male.

From the entire cohort, 42% developed ARDS, 26% required ICU admission, and 22% died in-hospital. Of patients who developed ARDS, 66% died and 21% were discharged by the end of the study period. Median hospital stay was 13 days. For O2 requirements, max needs were: 49% required nasal cannula, 40% required non-invasive mechanical ventilation, 2.5% required invasive mechanical ventilation, and 0.5% required ECMO. Adjunct therapies included antibiotics, antivirals, antioxidants, and steroids. 

Admission labs for patients demonstrated elevated ESR, CRP, D-dimer, and LDH, and lowered lymphocyte count, albumin and pre-albumin. Comparing the group with ARDS to the non-ARDS cohort, the ARDS patients were older (difference 12yr, 95% CI 8-16yrs), initially presented with dyspnea (diff 33.9%, 95% CI 19.7-48.1%), had higher fevers at home, had more comorbidities (HTN, DM), and were less likely to have received antiviral therapy (diff -14.4%). 

Of the group with ARDS who died, these patients were older, were less likely to have received antivirals or steroids, and had labs consistent with end organ dysfunction (higher LDH, D-dimer). Limitations include small sample, retrospective analysis, short-term follow-up, low proportion of patients with comorbidities, and selection bias as only patients sick enough to be hospitalized were included in the study for analysis; therefore, risk factors for ARDS amongst all infected people remains unknown.  

Synopsis: Chest CT may be helpful in establishing diagnosis of COVID while we continue to improve our timeliness of laboratory results. It may also assist in establishing severity of illness. Patients with COVID typically have findings on chest CT characteristic of viral pneumonia. In these two studies, characteristic findings on chest CT are first described and, in the second study, compared to CT findings for non-COVID viral pneumonia.

Han et al describe their series of 108 patients with COVID-19 pneumonia in their hospital in Wuhan, China. Diagnosis was confirmed with RT-PCR in all patients. The majority of patients (65%) had multilobar disease in 2-3 lobes (22%) or 4-5 lobes (43%). The remaining patients, an appreciable 35%, had unilobar disease on CT. In patients with unilobar disease, the right lower lobe was by far most commonly involved (30/38, 79%, or 30/108 overall, 28%). The most common findings were patchy (86%), groundglass opacities (GGOs; 60%), vascular thickening (80%), and air bronchograms (48%). Lesions were commonly larger than 3cm (52%). Lesions were most commonly peripherally located (90%) or peripherally and centrally located (8%), but rarely centrally located only (2%). 

Bai et al evaluated 219 chest CTs from patients with COVID and compared these to 205 chest CTs from patients with positive respiratory panel viral pneumonia other than COVID. Importantly, seven blinded radiologists from the US and China were able to effectively distinguish COVID from non-COVID based on CT alone. Discriminatory characteristics were identified; COVID pneumonia was more likely to be peripherally distributed (80% vs 57%, p<0.001), have GGOs (91% vs 68%, p<0.001), have fine reticular opacity (56% vs 22%, p<0.001), and have vascular thickening (59% vs 22%, p<0.001). In contrast, COVID pneumonia was less likely to have central and peripheral distribution (14% vs 35%, p<0.001), pleural effusion (4% vs 39%, p<0.001) or lymphadenopathy (3% vs 10%, p<0.001). This study is important in helping to distinguish this novel disease from the typical viral pneumonias that we are used to seeing.

Synopsis: This article describes a randomized, controlled, open-label trial of either lopinavir-ritonavir twice a day for 14 days vs. standard care alone in adult patients with confirmed SARS-CoV-2. The trial included adults patients with confirmed SARS-CoV-2 infection, and an oxygen saturation (SaO2) of 94% or less while breathing room air or a partial pressure of oxygen (PaO2) to fraction of inspired oxyg en (FiO2) ratio of less than 300 mm Hg.

Patients were randomly assigned in a 1:1 ration to receive either lopinavir-ritonavir (400mg and 100mg, respectively) twice a day for 14 days and standard care, or standard care alone. The primary end point was time to clinical improvement, which was defined as either time from randomization to improvement of two points on a seven-category ordinal scale or discharge from the hospital. A total of 199 patients with confirmed SARS-CoV-2 infection were randomized; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard care group. 

Treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was not significantly different between the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir–ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91. 

The authors conclude that there was no benefit observed with lopinavir-ritonavir treatment beyond standard care in hospitalized adult patients with severe Covid-19. However, given the trend towards improved 28-day mortality (19.2% vs. 25.0%) and the relatively small number of patients enrolled in the trial, this combination therapy seems to at least warrant further study in a larger trial, if not off-label use, especially given the lack of proven treatment options for this disease.  

Synopsis: Person-to-person spread of SARS-CoV-2 is thought to occur mainly via respiratory droplets, thus understanding its aerosol dynamics and surface stability is critical to guiding appropriate protections for medical professionals taking care of infected patients. In a letter to the editor to NEJM, the authors describe simulated laboratory conditions of aerosols containing SARS-CoV-2 and their viability on various surfaces (plastic, stainless steel, copper, and cardboard). The virus remained viable in aerosols throughout the 3-hour duration of the experiment, with a half-life of 1.1 hours. The longest viability of the virus was on stainless steel and plastic; the estimated median half-life of SARS-CoV-2 was approximately 5.6 hours on stainless steel and 6.8 hours on plastic. These results indicate that aerosol and fomite transmission of SARS-CoV-2 is plausible, since the virus can remain viable and infectious in aerosols for hours and on surfaces up to days. Given that intubations are aerosolizing events, these data may have implications for the use of PPE amongst the surgical staff.

Synopsis: An expert panel of 36 members from 12 countries reviewed the literature for direct and indirect evidence on the management of critically ill COVID-19 patients. Based on the quality of available evidence, recommendations made are classified as either ”strong” or “weak” as they pertain to the care of COVID-19 positive adults in an ICU setting.

STRONG Recommendations for the care of COVID-19 patient in the ICU

• Target SpO2 for patients in acute hypoxemic respiratory failure on oxygen should be no higher than 96%; threshold to initiate supplemental O2 90-92%
• Ventilation strategy for adults with COVID-19 and ARDS:
  • Low tidal volume ventilation (4-8mL/kg of predicted body weight)
  • Target plateau pressures <30cm H2O
  • Higher PEEP strategy (with monitoring for barotrauma at PEEP >10)
  • If recruitment maneuvers are used, recommend AGAINST staircase (incremental PEEP) manuevers
• Recommend AGAINST the use of hydroxyethyl starches for acute resuscitation of patients in shock
• Recommend AGAINST the use of dopamine if norephinephrine is available

Notable best practice guidelines

• Those performing aerosol-generating procedures on patients with COVID-19 should wear fitted respirator masks (N95 respirators, FFP2, or equivalent), as opposed to surgical/medical masks, in addition to other personal protective equipment (i.e. gloves, gown, and eye protections, such as face shield or safety goggles)
• Recommend performing aerosol-generating procedures in a negative pressure room
• Endotracheal intubation should be performed by the HCW with the most experience in airway management to minimize number of attempts and risk of transmission

Notable suggestions (weak recommendations):

• Use a conservative over liberal fluid resuscitation strategy in the acute resuscitation of a patient in shock
• Suggest norepinephrine as the first line vasoactive agent; vasopressin or epinephrine as alternatives if norepinephrine is not available
• For mechanically ventilated adults with moderate to severe ARDS, suggest prone ventilation for 12 to 16 hours, over no prone ventilation
• For mechanically ventilated adults with moderate to severe ARDS, suggest intermittent boluses of neuromuscular blocking agents (NMBA) over continuous NMBA to facilitate protective lung ventilation
  • In event of persistent dyssynchrony with ventilator, ongoing deep sedation, prone ventilation or persistently high plateau pressures, suggestion continuous NMBA infusion for up to 48 hours
• In mechanically ventilated adults with refractory hypoxemia despite optimizing ventilation, use of rescue therapies, and proning, suggest venovenous ECMO
• In mechanically ventilated patients with respiratory failure, suggest empiric antimicrobials/antibacterial agents, over no antimicrobials (with daily assessment for de-escalation)  

Synopsis

Clinical Summary:
Mortality from ARDS remains high, ranging from 35% to 46% with higher mortality being associated with greater degrees of lung injury severity at onset.

Berlin Definition of ARDS:

1. Acute onset within 7 days of known clinical insult or worsening respiratory symptoms
2. Bilateral opacities on radiograph
3. Respiratory failure not fully explained by cardiac etiology
4. ALI category (with PEEP or CPAP ≥5cm H20)
   1. Mild (200 mm Hg<PaO2 /FIO2 ≤300 mm Hg)
   2. Moderate (100 mm Hg<PaO2/FIO2 ≤200 mm Hg)
   3. Severe (PaO2/FIO2 ≤100 mm Hg)

Principles of Management
The cornerstone of management is mechanical ventilation, with a goal to minimize ventilator-induced lung injury (VILI). Ventilator management is based upon the “open lung hypothesis” which focuses on recruitment of collapsed ung units and aims to maintain them open throughout the respiratory cycle.

Initial Ventilator Management

1. Mode
   1. Either volume control (VC) or pressure control (PC) may be used
2. Tidal volume
   1. Initial tidal volume should be set at 6 cc/kg PBW, as low tidal volume (6-8 cc/kg PBW) significantly reduces mortality.
   2. Initial tidal volume should be reduced to ensure a plateau pressure (Pplat) ≤ 30 cmH2O.
3. PEEP
   1. Higher PEEP is used to facilitate alveolar recruitment and minimize atelectasis that occurs during the respiratory cycle.
   2. There is no optimal strategy for setting PEEP, but in general, higher FIO2 should be accompanied by higher PEEP. The ARDSnet PEEP titration tables shown below can be used as a guide.
   3. The goal driving pressure (Pplat – PEEP) should be ≤ 16 cmH2O, as this is associated with ignificant reduction in mortality

   

4. Oxygenation
   1. FIO2 should be set to achieve PaO2 55-80 mmHg and SpO2 88-95%
5. Respiratory rate
   1. Respiratory rate should be set to achieve a goal pH≥7.25 and allowing for permissive hypercapnia, as necessary. In general, this will be 20-30 breaths/minute. 

Synopsis: This is a summary of trials, observational studies, and reviews of treatments for ARDS, an entity with a mortality of 40%, even in the modern era. Specifically, the authors break the discussion down into three persistent derangements despite low-stretch ventilation per the ARDSNet protocol: hypoxemia (PaO2<60mmHg for an hour despite 100% FiO2), respiratory acidosis (pH<7.20 for over an hour despite ‘modest’ increases in Tv and respiratory rate), and elevated plateau pressures (>30mmHg). The summary recommendations are as follows.

Increasing intrathoracic pressures – PEEP and recruitment maneuvers
For refractory hypoxemia, the recommended strategies to consider first are increasing the PEEP, by no more than 2cm H2O q15min, and using recruitment maneuvers. The evidence for a high PEEP strategy is mixed; no study has shown a mortality benefit in a high PEEP cohort as compared with a similarly low-stretch control group and some evidence from a study using an aggressive PEEP/recruitment maneuver protocol (ART) has suggested an increase in mortality. However, a high-quality meta-analysis demonstrated some benefit and high PEEP is recommended by SCCM and ATS. Similarly, recruitment maneuvers have shown some potential for mild benefit, though an intensive strategy was shown to be associated with harm. High-frequency oscillatory ventilation (HFOV) was addressed in this summary and not recommended.

Neuromuscular Blockade
If the above strategies fail to improve oxygenation or the patient is also experiencing severe acidosis or elevated plateau pressures, the next recommendation is to attempt neuromuscular blockade, using cisatracurium for a time-limited course of 48 hours. This is based on evidence of decreased mortality from the ACURASYS trial, which compared paralysis to deep sedation control patients (HR 0.68, p=0.04).

Prone Positioning
The authors recommend prone positioning for hypoxemia refractory to the above strategies, respiratory acidosis, or elevated plateau pressures, as this improves V/Q matching and provides a more uniform distribution of Tv. The evidence comes primarily from the PROSEVA trial, which demonstrated a significant mortality benefit (HR 0.39, p<0.001) to proning among patients with P/F<150mmHg. Of note, about 85% of these patients were paralyzed. Other trials and meta-analyses have clouded the picture a bit with heterogeneous strategies for Tv management, PEEP management, and duration of prone positioning; in the end, the authors recommend consideration of proning for at least 12-16/d.

Inhaled Pulmonary Vasodilators – Prostaglandins and NO
The evidence is weak; though no mortality benefit has been shown with these adjuncts, multiple metaanalyses have demonstrated an improvement in P/F ratio. The authors note the potential risks of renal failure associated with NO and hypotension with inhaled prostaglandins, but do recommend consideration of NO (starting dose: 5ppm, uptitrating q30min to a max of 20) in those with refractory hypoxemia, particularly when accompanied by right heart failure. Though a specific recommendation for or against inhaled prostaglandins is not given here, these are commonly used at Penn.

Corticosteroids
The authors recommend steroid therapy (1mg/kg/d methylprednisolone x 3days) for hypoxemia refractory to everything described thus far, but prior to day 14 following ARDS diagnosis. However, the data behind this is very mixed, both in results and in timing of administration (early vs late). Perhaps most applicable to this discussion, a 2011 paper by Brun-Buisson et al showed harm associated with steroid administration in patients with viral pneumonia (HR for mortality 2.82 in a propensity score adjusted analysis, p=0.002).

Renal Replacement Therapy
Noting the potential for RRT to treat acidosis as well as manage volume status, the authors recommend consideration of this therapy in patients with refractory acidosis and/or volume overload, regardless of renal status. The evidence for this is not strong; a recent small randomized trial did show an association with improved oxygenation and increased ventilator-free days.

Extracorporeal Membranous Oxygenation (ECMO)
The two trials discussed here are the Conventional Ventilatory Support Versus ECMO for Severe Adult Respiratory Failure trial and the ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial. The former demonstrated improved 6-month survival; however, the ‘intervention’ was transfer to an ECMO-capable institution (only 75% of patients in this group were actually cannulated and there may have been confounding by more uniform application of low-stretch protocols at tertiary referral centers). EOLIA addressed this by randomizing patients with severe ARDS to VV ECMO vs conventional ventilation strategies. Though no statistically significant mortality benefit was shown, a) results trended towards a benefit (35% mortality in ECMO group vs 46% in control group, p=0.09); and b) there was a 28% crossover rate from control to ECMO. Newer trials are ongoing; given both the abilities of ECMO to treat refractory hypoxemia and hypercarbia as well as the ability to use ‘ultraprotective’ ventilation strategies when on VV ECMO, the authors recommend its use for refractory cases. VA ECMO can be considered in patients with cardiac compromise.

The article itself has several useful figures, including 3 algorithms for treatment of hypoxemia, respiratory acidosis, and high plateau pressures, and a table summarizing the adjuncts described above.