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COVID-19

by

Last updated 4/21 (recently updated text marked in green)

CONTENTS

Basic biology

Infection control
Diagnosis
Treatment: General protocols
Treatment: Specific anti-viral & immunosuppressive therapies
Treatment: Additional issues by organ system
Prognosis
Disposition
Podcasts
Questions & discussion
PDF of this chapter (or create customized PDF)

biology

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basics
  • COVID-19 is a non-segmented, positive sense RNA virus.
  • COVID-19 is part of the family of coronaviruses.  This contains:
    • (i) Four coronaviruses which are widely distributed and usually cause the common cold (but can cause viral pneumonia in patients with comorbidities).
    • (ii) SARS and MERS – these caused epidemics with high mortality which are somewhat similar to COVID-19.  COVID-19 is most closely related to SARS.
  • COVID-19 binds via the angiotensin-converting enzyme 2 (ACE2) receptor located on type II alveolar cells and intestinal epithelia (Hamming 2004).
    • This is the same receptor as used by SARS (hence the technical name for the COVID-19, “SARS-CoV-2”).
    • When considering possible therapies, SARS (a.k.a. “SARS-CoV-1”) is the most closely related virus to COVID-19.
  • COVID-19 is mutating, which may complicate matters even further (figure below).  Virulence and transmission will shift over times, in ways which we cannot predict.  New evidence suggests that there are roughly two different groups of COVID-19.  This might help explain why initial reports from Wuhan described a higher mortality than some more recent case series (Tang et al. 2020; Xu et al 2020).
    • 👁 Image showing evolution of COVID-19 here.
    • Ongoing phylogenetic mapping of new strains can be found here.
nomenclature used in this chapter
  • Technically, the virus is supposed to be called “SARS-CoV-2” and the clinical illness is called “COVID-19.”  This gets confusing, so for this chapter the term COVID-19 will be used to refer to both entities.
  • The term “SARS” will be used to refer to the original SARS virus from 2003 (which has currently been renamed SARS-CoV-1).
pathophysiology
  • (1) Hypoxemic respiratory failure
    • The primary organ failure is hypoxemic respiratory failure.
    • COVID-19 can reduce surfactant levels, potentially leading to atelectasis and de-recruitment.
    • Pneumocytes with viral cytopathic effect are seen, implying direct virus damage (rather than a purely hyper-inflammatory injury; Xu et al 2/17).
    • Autopsy studies show pathologic features of ARDS (diffuse alveolar damage and hyaline membrane formation).  It's unclear whether this is due to viral infection itself, or ventilator-induced lung injury.  
  • (2) Cytokine storm
    • Emerging evidence suggests that some patients may respond to COVID-19 with an exuberant “cytokine storm” reaction.
    • This has some similarities to hemophagocytic lymphohistiocytosis and CAR-T cell cytokine release syndrome, but it appears to be a distinct entity.  
    • Clinical markers of this may include elevations of C-reactive protein and ferritin, which appear to track with disease severity and mortality (Ruan 3/3/20).

stages of illness – this is discussed in the section on immunomodulatory therapy.

transmission

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large droplet transmission
  • COVID-19 transmission can occur via large droplet transmission (with a risk limited to ~6 feet from the patient)(Carlos del Rio 2/28).
  • This is typical for respiratory viruses such as influenza.
  • Transmission via large droplet transmission can be prevented by using a standard surgical mask.
airborne transmission
  • It appears increasingly likely that COVID may also be transmitted via an airborne route (small particles which remain aloft in the air for longer periods of time).  Airborne transmission would imply the need for N95 masks (“FFP2” in Europe), rather than surgical masks.
    • Prior evidence regarding this controversy is explored further in Shiu et al 2019.
    • A recent study on COVID19 demonstrated the ability of virus to persist in aerosols for hours, making aerosol transmission plausible (Doremalen et al. 3/17/19).
  • Guidelines disagree about whether to use airborne precautions:
    • The Canadian Guidelines and World Health Organization guidelines both recommend using only droplet precautions for routine care of COVID19 patients.  However, both of these guidelines recommend airborne precautions for aerosol-generating procedures (e.g. intubation, extubation, noninvasive ventilation, high-flow nasal cannula, CPR prior to intubation, bag-mask ventilation, bronchoscopy, and tracheostomy).
    • ANZICS recommends airborne precautions be used for critically ill patients with COVID-19.
    • The United States CDC previously recommended using airborne precautions all the time when managing COVID19 patients.  However, the CDC recently updated their position, stating that surgical facemasks are acceptable when N95 masks run out.
  • The type of personal protective equipment used will vary depending on availability.  Local guidelines should be followed.
  • Negative pressure rooms are ideal, but may not always be available.  When negative pressure rooms aren't available, portable air filtration systems may be considered (SSC guidelines).
contact transmission (“fomite-to-face”)
  • This mode of transmission has a tendency to get overlooked, but it may be incredibly important.  This is how it works:
    • (i)  Someone with coronavirus coughs, emitting large droplets containing the virus.  Droplets settle on surfaces in the room, creating a thin film of coronavirus.  The virus may be shed in nasal secretions as well, which could be transmitted to the environment.
    • (ii) The virus persists on fomites in the environment.  Depending on the type of surface, virus may persist for roughly four days (Doremalen et al. 3/17/19).
    • (iii)  Someone else touches the contaminated the surface hours or days later, transferring the virus to their hands.
    • (iv)  If the hands touch a mucous membrane (eyes, nose, or mouth), this may transmit the infection.
  • Any effort to limit spread of the virus must block contact transmission.  The above chain of events can be disrupted in a variety of ways:
    • (a) Regular cleaning of environmental surfaces (e.g. using 70% ethanol or 0.5% sodium hypochlorite solutions; for details see Kampf et al 2020 and CDC guidelines).
    • (b) Hand hygiene (high concentration ethanol neutralizes the virus and is easy to perform, so this might be preferable if hands aren't visibly soiled)(Kampf 2017).
    • (c) Avoidance of touching your face.  This is nearly impossible, as we unconsciously touch our faces constantly.  The main benefit of wearing a surgical mask could be that the mask acts as a physical barrier to prevent touching the mouth or nose.
  • Any medical equipment could become contaminated with COVID-19 and potentially transfer virus to providers.  A recent study found widespread deposition of COVID-19 in one patient's room, but fortunately this seems to be removable by cleaning with sodium dichloroisocyanurate (Ong et al 2020).
when can transmission occur?
  • (#1) Asymptomatic transmission (in people with no or minimal symptoms) is possible (Carlos del Rio 2/28).
  • (#2) Transmission appears to occur over roughly ~8 days following the initiation of illness.
    • Patients may continue to have positive pharyngeal PCR for weeks after convalescence (Lan 2/27).  However, virus culture methods are unable to recover viable virus after ~8 days of clinical illness (Wolfel 2020).  This implies that prolonged PCR positivity probably doesn't correlate with clinical virus transmission.  However, all subjects in Wolfel et al. had mild illness, so it remains possible that prolonged transmission could occur in more severe cases.
    • CDC guidance is vague on how long patients with known COVID-19 should be isolated.  Local health departments should be contacted to provide guidance regarding this.  
R⌀
  • R⌀ is the average number of people that an infected person transmits the virus to.
    • If R⌀ is <1, the epidemic will burn out.
    • If R⌀ = 1, then epidemic will continue at a steady pace.
    • If R⌀ >1, the epidemic will increase exponentially.
  • Current estimates put R⌀ at ~2.5-2.9 (Peng PWH et al, 2/28).  This is a bit higher than seasonal influenza.
  • R⌀ is a reflection of both the virus and also human behavior.  Interventions such as social distancing and improved hygiene will decrease R⌀.
    • Control of spread of COVID-19 in China proves that R⌀ is a modifiable number that can be reduced by effective public health interventions.
    • The R⌀ on board the Diamond Princess cruise ship was 15 – illustrating that cramped quarters with inadequate hygiene will increase R⌀ (Rocklov 2/28).
  • R⌀ may vary between different people infected with COVID-19, depending on their immune response and viral load.  For example:  
    • Some people carry extremely large quantities of virus, with a strong tendency to infect others (“super-spreaders”).  If present at a large social gathering, this may lead to dozens of new infections.  
    • At the other extreme:  Some people may carry low or undetectable amounts of virus, with little risk of disease transmission.  

personal protective equipment (PPE)

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gear
  • (1) Contact precautions (waterproof gown and gloves)
  • (2) Some sort of mask (discussed above in the transmission section)
    • N95 mask or a powered, air-purifying respiratory (“PAPR”).
    • An anesthesia mask might be placed in-line with a viral filter to MacGyver an N95 mask (see video below).  The main drawback is that the mask itself could become a giant fomite which is contaminated with COVID-19 (so carefully washing the entire mask in between uses).
  • (3) Goggles or eye shield.
  • (4) Hair cover for aerosol generating procedures (listed in the section above).
  • (5) Hood may be used, especially during intubations (this can be constructed out of a trash-bag, as shown in the tweet above).
  • Shoes
    • Shoe covers aren't recommended, as removing them may increase exposure (ANZICS guidelines).
    • Shoes that are easily cleaned and don't need to be touched might be preferable (e.g. Danskos).
  • Note:  The exact gear used is probably less important than using it correctly.  
applying and removing PPE (donning & doffing) 
  • Understanding how to put on (don) and remove (doff) personal protective equipment is extremely important (especially if contact transmission is a dominant mode of transmission).
  • Removing soiled PPE is the most critical and difficult aspect.
  • Applying and removing PPE should ideally be practiced before patients arrive (e.g. using simulation).
  • This video describes how to use PPE (you may skip the first 5 minutes).
some pearls about personal protective equipment
  • Pay attention to the junction between gloves and gowns.  The gown should be tucked into the gloves (leaving no gap in-between).  Using gloves with extended cuffs facilitates this (similar to sterile surgical gloves).  Gloves with long cuffs may facilitate removal of the gown and gloves as a single unit (see 12:30 in the above video if this doesn't make sense).
  • When removing PPE, always start by first applying alcohol-based hand sanitizer to your gloves.
  • After fully removing PPE, sanitize hands and wrists with alcohol-based hand sanitizer again.
  • Create a step-wise protocol for PPE removal.  Two examples are shown below, but this may very depending on your exact gear.  Follow the steps slowly.
    • 👁 Checklist for removing PPE, using a tear-away gown here (this type of gown is preferred)
    • 👁 Checklist for removing PPE, using a gown with fixed neck ties.
  • Consider doffing with someone watching you (to ensure good technique).  If this isn't possible, doffing in a mirror may be helpful.

signs and symptoms

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👁 Table of symptoms described by various studies.
signs & symptoms
  • COVID-19 may cause constitutional symptoms, upper respiratory symptoms, lower respiratory symptoms, and, less commonly, gastrointestinal symptoms.  Most patients will present with constitutional symptoms and lower respiratory symptoms (e.g. fever and cough).
  • Fever:
  • Gastrointestinal presentations:  up to 10% of patients can present initially with gastrointestinal symptoms (e.g. diarrhea, nausea), which precede the development of fever and dyspnea (Wang et al. 2/7).
  • “Silent hypoxemia” – some patients may develop hypoxemia and respiratory failure without dyspnea (especially elderly)(Xie et al. 2020).
    • This can lead to some unusual presentations (e.g. knee pain… as a result of syncope, which in turn resulted from profound hypoxemia).  
  • Physical examination is generally nonspecific.
    • ~2% of patients may have pharyngitis or tonsil enlargement (Guan et al 2/28).
typical disease course
  • Incubation is a median of ~4 days (interquartile range of 2-7 days), with a range up to 14 days (Carlos del Rio 2/28).  Rare patients may have a longer incubation, however (graphed out nicely by Lauer et al).
  • Typical evolution of severe disease (based on analysis of multiple studies by Arnold Forest).
    • Dyspnea ~ 6 days post exposure.
    • Admission after ~8 days post exposure.
    • ICU admission/intubation after ~10 days post exposure.  However, this timing may be variable (some patients are stable for several days after admission, but subsequently deteriorate rapidly).

labs

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👁 Table of general laboratory findings described in several studies.
complete blood count 
  • WBC count tends to be normal.
  • Lymphopenia is common, seen in ~80% of patients (Guan et al 2/28, Yang et al 2/21).
  • Mild thrombocytopenia is common (but platelets are rarely <100).  Lower platelet count is a poor prognostic sign (Ruan et al 3/3).
coagulation studies
  • Disseminated intravascular coagulation can be seem.  The most notable finding is often profoundly elevated D-dimer levels.  
  • For more see the hematology section below.
inflammatory markers 
  • C-reactive protein (CRP)
    • COVID-19 increases CRP.  This seems to track with disease severity and prognosis.  In a patient with severe respiratory failure and a normal CRP, consider non-COVID etiologies (such as heart failure).
    • Young et al. 3/3 found low CRP levels in patients not requiring oxygen (mean 11 mg/L, interquartile range 1-20 mg/L) compared to patients who became hypoxemic (mean 66 mg/L, interquartile range 48-98 mg/L).
    • Ruan et al 3/3 found CRP levels to track with mortality risk (surviving patients had a median CRP of ~40 mg/L with an interquartile range of ~10-60 mg/L, whereas patients who died had a median of 125 mg/L with an interquartile range of ~60-160 mg/L).
    • 👁 Image of prognostic labs including CRP.
  • Procalcitonin
    • Severe COVID-19 can moderately increase procalcitonin levels  (e.g., within a range of roughly ~1-10 ng/ml).  For example, among patients with severe disease, 14% had a procalcitonin level >0.5 ng/ml (Guan et al 2/28).
    • Among patients with known COVID-19, an elevated procalcitonin is a poor prognostic sign (which appears to reflect of cytokine storm)(Lippi et al. 2020).
    • A markedly elevated procalcitonin (>>10 ng/ml) might suggest the presence of a bacterial infection, rather than COVID-19.  
evaluation for competing diagnoses
  • PCR for influenza and other respiratory viruses (e.g. RSV) may be helpful.  Detection of other respiratory viruses doesn't prove that the patient isn't co-infected with COVID-19 (~5% of patients may be co-infected with both COVID-19 and another virus)(Wang et al.).  However, an alternative explanation for the patient's symptoms will reduce the index of suspicion for COVID-19 substantially.
  • Conventional viral panels available in some hospitals will test for “coronavirus.”
    • This test does not work for COVID-19!
    • This PCR test for “coronavirus” is designed to evaluate for four coronaviruses which usually cause mild illness.
    • Ironically, a positive conventional test for “coronavirus” actually makes it less likely that the patient has COVID-19.
  • Blood cultures should be performed as per usual indications.

specific testing for COVID-19

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specimens
  • (1) Nasopharyngeal swab should be sent.
  • (2) If intubated, tracheal aspirate should be performed.
  • (3) Bronchoalveolar lavage or induced sputum are other options for a patient who isn't intubated.  However, obtaining these specimens may pose substantial risk of transmission.
    • It's dubious whether these tests are beneficial if done for the sole purpose of evaluating for coronavirus (see the section below on bronchoscopy).
limitations in determining the performance of RT-PCR
  • (1) RT-PCR performed on nasal swabs depends on obtaining a sufficiently deep specimen.  Poor technique will cause the PCR assay to under-perform.
  • (2) COVID-19 isn't a binary disease, but rather there is a spectrum of illness.  Sicker patients with higher viral burden may be more likely to have a positive assay.  Likewise, sampling early in the disease course may reveal a lower sensitivity than sampling later on.
  • (3) Most current studies lack a “gold standard” for COVID-19 diagnosis.  For example, in patients with positive CT scan and negative RT-PCR, it's murky whether these patients truly have COVID-19 (is this a false-positive CT scan, or a false-negative RT-PCR?).
    • Convalescent serologies may help resolve this problem (although they may to have their own limitations as well).  
specificity
  • Specificity seems to be high (although contamination can cause false-positive results).
sensitivity may not be terrific
  • Sensitivity compared to CT scans
    • In a case series diagnosed on the basis of clinical criteria and CT scans, the sensitivity of RT-PCR was only ~70% (Kanne 2/28).
    • Sensitivity varies depending on assumptions made about patients with conflicting data (e.g. between 66-80%)(Ai et al.).
    • 👁 Image of analysis of Ai et al to determine sensitivity & specificity of PCR here.
  • Among patients with suspected COVID-19 and a negative initial PCR, repeat PCR was positive in 15/64 patients (23%).  This suggests a PCR sensitivity of <80%.  Conversion from negative to positive PCR seemed to take a period of days, with CT scan often showing evidence of disease well before PCR positivity (Ai et al.).
  • Bottom line?
    • PCR seems to have a sensitivity somewhere on the order of ~75%.
    • A single negative RT-PCR doesn't exclude COVID-19 (especially if obtained from a nasopharyngeal source or if taken relatively early in the disease course).
    • If the RT-PCR is negative but suspicion for COVID-19 remains, then ongoing isolation and re-sampling several days later should be considered.

CXR & CT scan

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general description of imaging findings on chest x-ray and CT scan
  • The typical finding is patchy ground glass opacities, which tend to be predominantly peripheral and basal (Shi et al 2/24).  The number of involved lung segments increases with more severe disease.  Over time, patchy ground glass opacities may coalesce into more dense consolidation.
  • Infiltrates may be subtle on chest X-ray.
    • 👁 Image of example chest X-ray here.
    • 👁 Image of example CT scans here.
  • Findings which aren't commonly seen, and might argue for an alternative or superimposed diagnosis:
    • Pleural effusion is uncommon (seen in only ~5%).
    • COVID-19 doesn't appear to cause masses, cavitation, or lymphadenopathy.
sensitivity and time delay
  • Limitations in the data
    • Data from different studies conflict to a certain extent.  This probably reflects varying levels of exposure intensity and illness severity (cohorts with higher exposure intensity and disease severity will be more likely to have radiologic changes).
  • Sensitivity of CT scanning?
    • Sensitivity among patients with positive RT-PCR is high.  Exact numbers vary, likely reflecting variability in how scans are interpreted (there currently doesn't seem to be any precise definition of what constitutes a “positive” CT scan).
    • Among patients with constitutional symptoms only (but not respiratory symptoms), CT scan may be less sensitive (e.g., perhaps ~50%)(Kanne 2/27).
  • CT scan abnormalities might emerge before symptoms?
    • Shi et al. performed CT scanning in 15 healthcare workers who were exposed to COVID-19 before they became symptomatic.  Ground glass opacification on CT scan was seen in 14/15 patients!  9/15 patients had peripheral lung involvement (some bilateral, some unilateral).
    • Emergence of CT abnormality before symptoms explains the existence of an asymptomatic carrier state (discussed above).
  • Chest X-ray
    • Sensitivity of chest X-ray is lower than CT scan for subtle opacities.
    • In Guan et al., the sensitivity of chest x-ray was 59%, compared to 86% for CT scan.
    • In Arentz et al. from Washington State, clear chest X-ray was only recorded in 1/21 patients.  However a variety of different findings were reported (including bilateral reticular nodular opacities, ground-glass opacities, focal consolidation, and pulmonary edema).
further information

lung ultrasonography

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technique
  • In order to achieve sensitivity, a thorough lung examination is needed (taking a “lawnmower” approach, attempting to visualize as much lung tissue as possible).
  • A linear probe may be preferable for obtaining high-resolution images of the pleural line (to make the distinction between a smooth, normal pleural line versus a thickened and irregular pleural line).
  • COVID-19 typically creates patchy abnormalities on CT scan.  These will be missed unless ultrasonography is performed overlying the abnormal lung tissue.
  • More on this from 5 minute sono here.
findings
  • The findings on lung ultrasonography appear to correlate very well with the findings on chest CT scan.
  • With increasing disease severity, the following evolution may be seen (Peng 2020)
    • (A) Least severe:  Mild ground-glass opacity on CT scan correlates to scattered B-lines.
    • (B) More confluent ground-glass opacity on CT scan correlates to coalescent B-lines (“waterfall sign”).
    • (C) With more severe disease, small peripheral consolidations are seen on CT scan and ultrasound.
    • (D) In the most severe form, the volume of consolidated lung increases.
    • 👁 Image of these patterns here.
  • Other features:
    • Peripheral lung abnormalities can cause disruption and thickening of the pleural line.
    • Areas of normal lung (with an A-line pattern) can be seen early in disease, or during recovery.
    • Tiny pleural effusions may be seen, but substantial pleural effusions are uncommon (Peng 2020).
    • As with CT scans, abnormalities are most common in the posterior & inferior lungs.
  • For excellent examples of the correlation between CT scan and lung ultrasonography see Huang et al.
performance
  • Sensitivity of lung ultrasonography isn't clearly defined.
    • Sensitivity will depend on several factors (most notably disease severity, presence of obesity, and thoroughness of scanning).
    • My guess is that a thorough ultrasound exam might have a sensitivity somewhere between CT scanning and chest X-ray (e.g., perhaps sensitivity ~75%?)(Huang et al.).  There isn't solid data yet, but it's probably reasonable to extrapolate from our experiences regarding other types of pneumonia.
  • Specificity is extremely low.  A patchy B-line or consolidation pattern can be seen in any pneumonia or interstitial lung disease.  Thus, clinical correlation is necessary (e.g., evaluation of prior chest imaging studies to see if chronic abnormalities are present).
    • Note that supine, hospitalized patients may have B-lines and consolidation in a posterior and inferior distribution due to atelectasis.  Thus, the lung ultrasonography may have greatest sensitivity and specificity among ambulatory patients.

general approach to imaging

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all imaging modalities are nonspecific
  • All of the above techniques (CXR, CT, sonography) are nonspecific.  Patchy ground-glass opacities may be caused by a broad range of disease processes (e.g. viral and bacterial pneumonias).  For example, right now in the United States, someone with patchy ground-glass opacities on CT scan would be much more likely to have a garden variety viral pneumonia (e.g. influenza or RSV) rather than COVID-19.
  • Imaging cannot differentiate between COVID-19 and other forms of pneumonia.
  • Imaging could help differentiate between COVID-19 and non-pulmonary disorders (e.g. sinusitis, non-pulmonary viral illness).
  • Ultimately, the imaging is only one bit of information which must be integrated into clinical context.
possible approach to imaging in COVID-19 
  • Below is one possible strategy to use for patients presenting with respiratory symptoms and possible COVID-19.
  • The temptation to get a CT scan in all of these patients should be resisted.  In most cases, a CT scan will probably add little to chest X-ray and lung ultrasonography (in terms of actionable data which affects patient management).
  • From a critical care perspective, CT scanning will likely add little to the management of these patients (all of whom will have diffuse infiltrates).
  • 👁 Schema for imaging patients with respiratory symptoms and suspected COVID-19.
additional information:  

bronchoscopy

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  • Risks of bronchoscopy:
    • May cause some deterioration in clinical condition (due to instillation of saline and sedation).
    • Enormous risk of transmission to providers.
    • Considerable resource allocation (requires N95 respirators, physicians, respiratory therapists) – all resources which will be in slim supply during an epidemic.
  • Benefits of bronchoscopy:
    • Benefit of diagnosing COVID-19 is dubious at this point (given that treatment is primarily supportive).
  • Bottom line on bronchoscopy?
    • Bronchoscopy might be considered in situations where it would otherwise be performed (e.g. patient with immunosuppression with concerns for Pneumocystis pneumonia or fungal pneumonia).
    • Bronchoscopy should usually not be done for the purpose of ruling COVID-19 in or out (Bouadma et al.).

diagnostic approach for admitted patients

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👁 Checklist of tests to consider when evaluating a patient with respiratory failure and suspected COVID-19
👁 One possible diagnostic flow chart for an ill patient admitted to hospital with suspected COVID-19.
  • This approach is based on the availability of a PCR assay for COVID with a reasonably short turn-around time.  This currently isn't a reality in most locations in the United States.  Hopefully it will be soon.
  • Requiring a negative influenza PCR before testing for COVID isn't desirable, because ~5% of patients may be co-infected (Wang et al.).  Thus, a positive influenza PCR cannot exclude COVID.  The rate of double-positivity may decrease over time, as the rate of influenza in the community decreases.   
  • The largest challenge may be determining who needs to be ruled out for COVID (i.e., who needs to be entered into this algorithm in the first place).  Currently there is no simple answer for this – clinical judgement is required.
    • Ruling out too many patients will result in excessive consumption of masks in patients who don't have COVID.  Additionally, placing patients under COVID precautions may impair their care (e.g., isolation may serve as a barrier to obtaining scans or to family visitation).
    • Ruling out too few patients may result in nosocomial transmission of COVID.

approach to ED patients getting admitted to the hospital

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diagnostic tests
  • Chest X-ray (useful to prognosticate patients and avoid missing non-COVID pathology – even in the era of POCUS).
  • Labs
    • CBC with differential.
    • Electrolytes, coagulation studies.
    • COVID prognostication labs:  C-reactive protein, Lactate dehydrogenase (LDH), D-dimer, Ferritin.
    • Blood cultures x2.
    • Swab for COVID & respiratory viruses.
  • Additional studies as clinically warranted (EKG, POCUS, etc.).
  • CT chest
    • Generally not needed solely for purpose of diagnosing COVID (especially if there are characteristic abnormalities on CXR and POCUS).
    • However:  if the patient is going to the scanner for another reason (e.g. trauma, abdominal pain, etc) and you are concerned about COVID – then strongly consider adding a chest CT while the patient is in the scanner.
cardiovascular & Bp support
  • IV fluid resuscitation should generally be avoided.
  • For patients with a history of diarrhea and clinical evidence of hypovolemia, titrated fluid administration may be beneficial.
pulmonary
  • For patients with significant dyspnea or hypoxemia, try to stabilize with one of the following techniques:
  • When in doubt, err on the side of avoiding intubation.
  • For patients with severe hypoxemia and bilateral infiltrates: start steroid (e.g., 60 mg methylprednisolone IV or 10 mg dexamethasone IV).
  • Treatment pathways are evolving rapidly – have a low threshold to consult with MICU to assess the patient and collaborate on plan (i.e. ward vs. ICU).
    • Beware of “silent hypoxemia” – patients may be very hypoxemic but look good (without much dyspnea).  The first sign of deterioration is often escalating oxygen requirement, rather than dyspnea.
renal
  • There is an enormous tendency for patients to develop acute kidney injury.
  • Aggressively avoid all nephrotoxins (especially NSAIDs and vancomycin).
    • (Note: Contrast dye probably isn't nephrotoic.  If you need to get a scan with contrast, then just get it with contrast.)
infectious disease
  • For patients with infiltrates and possible bacterial pneumonia:  usual treatment is azithromycin plus ceftriaxone.
  • Avoid vancomycin (if high index of suspicion for MRSA pneumonia consider linezolid or ceftaroline).

approach to inpatient management of non-intubated patient

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daily examination:  focus on
  • Do not use a stethescope (this is a fomite that poses risk of disease transmission).
  • Cardiac and lung ultrasonography may be performed as indicated for changes in clinical status.
    • Lung ultrasonography (not ascultation) is the preferred modality for evaluating pulmonary status.
labs
  • Daily labs
    • Electrolytes, Creatinine, Magnesium, Phosphate
    • CBC with differential
    • D-dimer
    • C-reactive protein
  • Admission labs: all of the above plus:
    • Urine pregnancy test in reproductive-age women
    • Blood culture x2
    • Tracheal aspirate for gram stain & culture
    • Urine legionella & pneumococcal antigens
    • Liver function tests
    • Coagulation tests including INR, PTT, fibrinogen
    • Ferritin, LDH
cardiovascular
  • Target even or negative fluid balance.
  • Consider discontinuation of home antihypertensive agents (especially ACE-inhibitors or ARBs).
pulmonary
  • Oxygen supplementation
    • (1) Start with low-flow nasal cannula (e.g. 1-6 liters/minute)
    • (2) For dyspnea or worsening desaturation, consider early implementation of either HFNC (ideally with awake proning) or CPAP/BiPAP.
    • The approach to respiratory support is discussed further below.
    • Consult ICU early for deteriorating patients, as this can escalate rapidly.  
  • Avoid nebulized bronchodilators
    • Only use bronchodilators if truly indicated.
    • Instead of nebulizers, use a metered dose inhaler (4-8 puffs may be roughly equivalent to one nebulizer treatment).
renal
  • Avoid nephrotoxins (especially NSAIDs).
infectious diseases
  • Initially most patients will be on empiric antibiotics for bacterial pneumonia (e.g. azithromycin plus ceftriaxone).
  • May consider anti-viral therapy if available (e.g. hydroxychloroquine or remdesivir).
  • Follow microbiologic studies.
heme
  • DVT prophylaxis (continue unless platelets <30, as COVID-19 may cause a pro-coagulable form of DIC despite low platelet count)(B&W; guidelines).
  • For patients with marked D-dimer elevation, consider higher doses of enoxaparin (more on this below).
  • Conservative transfusion strategy (generally avoid transfusion unless HgB <7 mg/dL, or <8 mg/dL with active myocardial ischemia).  Consider diuretic with transfusion to achieve even fluid balance.
neurology
  • May use acetaminophen 1 gram enterally q6hr for antipyretic and analgesic effects.
  • Melatonin 5 mg QHS for sleep (Zhang et al 2020, Zhou et al. 2020).
  • Avoid NSAIDs (may cause nephrotoxicity and possibly up-regulate the ACE2 receptor, thereby worsening infection)

approach to intubated ICU patient

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daily examination: focus on
  • Ventilator
    • Ventilator settings & synchrony with ventilator.
    • Confirm ETT depth at the upper teeth (ensure no migration of the tube).
    • Tighten connections between ETT, connecting tubing, and ventilator (to prevent accidental disconnection).
  • Neurologic status.
  • Cardiac and lung ultrasonography if clinical question.
  • Do not use a stethescope (this is a fomite that poses risk of disease transmission).
labs
  • Daily labs
    • Electrolytes, Creatinine, Magnesium, Phosphate
    • CBC with differential
    • D-dimer
    • HLH labs (C-reactive protein, Ferritin, LDH)
    • Possibly troponin (to surveil for development of myocarditis, not acute coronary syndrome)
  • Intermittent labs
    • Triglycerides every 72 hours for patients on propofol (surveillance for propofol infusion syndrome).
    • Liver function tests every other day.
    • Thromboelastography (TEG) if questions arise about the overall balance of coagulation.
  • Admission labs:  all of the above plus:
    • Urine pregnancy test in reproductive-age women
    • Blood culture x2
    • Tracheal aspirate for gram stain & culture
    • Urine legionella & pneumococcal antigens)
    • Complete set of coagulation labs (INR, PTT, fibrinogen)
cardiovascular
  • ⚠️ Avoid fluid boluses (more on this here and here) & avoid maintenance fluid infusions (ANZICS guidelines).
  • Follow input/output balance carefully, targeting euvolemia.
  • Consider using low-dose vasopressor as necessary to support MAP (rather than fluid).
  • Consider discontinuation of home antihypertensive agents (especially ACE-inhibitors or ARBs).  Sedation and positive-pressure ventilation will tend to reduce the blood pressure, so antihypertensive agents may be unnecessary.
pulmonary
  • Lung-protective ventilation
    • APRV may be the preferred ventilator mode (the primary pathophysiological problem is atelectasis, which APRV manages beautifully).
    • If APRV is unavailable or practitioners are unfamiliar with it: low-tidal volume ventilation with high-PEEP scale.
  • Steroid
    • Moderate-dose steroid is recommended for intubated patients with ARDS (e.g. preferably 10 mg dexamethasone daily, or 60 mg/day methylprednisolone)(SSC guidelines).
    • Consider higher dose of steroid for patients with ARDS and severely elevated inflammatory markers (more on this in the figure below and in  this section).
  • ⚠️ Avoid ABG/VBG if possible.
    • Consider trending etCO2 and minute ventilation instead of obtaining serial ABG/VBG measurements.
gastrointestinal
  • Enteral nutrition.
  • Stress ulcer prophylaxis.
renal
  • ⚠️ Avoid nephrotoxins (especially NSAIDs).
  • Diuresis as necessary to achieve euvolemia (if tolerated by hemodynamics).
  • Aggressive repletion of K and Mg in patients on QT-prolonging medications (e.g. chloroquine, hydroxychloroquine).
infectious diseases
  • Initially most patients will be on empiric antibiotics for bacterial pneumonia (typically azithromycin plus ceftriaxone).
    • Discontinue ceftriaxone after 48 hours if no evidence of bacterial infection.
    • Continue a full course of azithromycin.
    • ⚠️ Avoid vancomycin.  These patients don't tend to have MRSA, but they do often develop kidney injury.  If MRSA coverage is truly necessary, consider linezolid or ceftaroline.
  • May consider antiviral therapy (e.g., hydroxychloroquine).
  • Follow microbiologic studies.
heme
  • DVT prophylaxis (continue unless platelets <30, as COVID-19 may cause a pro-coagulable form of DIC despite low platelet count)(B&W; guidelines).
  • Consider anticoagulation for DIC:  Little evidence, but patients with D-dimer >1,000-2,000 ng/ml may benefit from therapeutic anticoagulation (e.g. therapeutic doses of low molecular-weight heparin)(see figure below & this section).
  • Conservative transfusion strategy (generally avoid transfusion unless HgB <7 mg/dL, or <8 mg/dL with active myocardial ischemia).
    • Consider diuretic with transfusion to achieve even fluid balance.

endocrine
  • Follow glucose levels periodically.
  • Insulin as needed to avoid severe hyperglycemia.
neurology
  • Acetaminophen 1 gram enterally q6hr scheduled (for antipyretic and analgesic effects).
  • Opioid bolus PRN pain (e.g. fentanyl 50 mcg IV q30 min PRN breakthrough pain).
  • Low-dose propofol as a titratable sedative (e.g. ideally around 0-30 mcg/kg/min).
    • COVID-19 patients appear prone to developing hypertriglyceridemia (possibly due to hemophagocytosis).
    • Ideally keep propofol doses low, to avoid hypertriglyceridemia (which may necessitate stopping propofol entirely).
  • Adjunctive atypical antipsychotic (e.g. 10 mg olanzapine per tube QHS or BID, or quetiapine).
  • For ongoing pain, consider adding a pain-dose ketamine infusion (0.1-0.3 mg/kg/hr)(more on this here).
  • Melatonin 5 mg QHS for sleep (Zhang et al 2020, Zhou et al. 2020).
  • ⚠️  Avoid NSAIDs (may cause nephrotoxicity and possibly up-regulate the ACE2 receptor, thereby worsening infection).
  • (Dexmedetomidine could be used when close to extubation, if needed to provide anxiolysis during spontaneous breathing trials.)
lines & tubes
  • (1) Orogastric tube or small-bore post-pyloric feeding tube.
  • (2) Central line
    • Low threshold to place a quad-lumen central line with meticulous sterility.
    • Best site may be left internal jugular vein (save the right internal jugular for dialysis or ECMO).
  • (3) Arterial line
    • Avoid if possible, as this may tend to encourage frequent ABG/VBG draws (which are unlikely to materially improve care and will cause anemia).

stages of illness & timing of therapies

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The above staging system was proposed by Siddiqi et al.  Patient courses may vary, making discrete staging challenging.  However, this provides a useful conceptualization of the disease process.  

stage I (early infection)
  • Clinically:  Incubation followed by non-specific symptoms (e.g. malaise, fever, dry cough).  This phase may last for several days, with fairly mild symptoms.  Patients often don't require hospital admission.
  • Biologically:  Viral replication occurs.  An innate immune response follows, but this fails to contain the virus.  Symptoms reflect a combination of direct viral cytopathic effect and innate immune responses (e.g. Type-I interferon release).
  • Treatment:
    • Anti-viral therapies could be beneficial, especially in patients predicted to be at higher risk for poor outcome.  Anti-viral therapies probably have maximal efficacy when given early, during this phase.
    • Interferon I-beta could theoretically be useful to augment the innate immune system response to the virus.  This involves rendering cells resistant to viral infection, an intervention which would probably be most effective if deployed as early as possible (however this is a theoretical consideration, which currently is not recommended).
    • Immunosuppression could theoretically be dangerous at this point, as it could delay the development of an adequate adaptive immune response.  For example, early initiation of steroid has been shown to prolong virus shedding in SARS (Lee et al 2004).
stage II (pulmonary phase)
  • Clinically:  Despite being stable for several days during Stage I, as patients enter Stage II they may abruptly deteriorate (often with worsening hypoxemic respiratory failure).  Patients will often present to the hospital at this point.  They may progress rapidly to ARDS, requiring intubation.  Markers of systemic inflammation are often moderately elevated (e.g. C-reactive protein, ferritin).
  • Biologically:  An adaptive immune response occurs, which causes a reduction in viral titers.  However, this also leads to increased levels of inflammation and tissue damage.
  • Treatment:
    • Antiviral-therapy could be beneficial (although the later on that antiviral treatment is initiated, the less effective it is likely to be).
    • Some immunosuppression could be beneficial for patients with more severe manifestations (e.g., moderate dose steroid for patients with ARDS).
stage III (hyperinflammation phase / cytokine storm)
  • Clinically:  Patients deteriorate with progressive disseminated intravascular coagulation and multi-organ failure (e.g. vasodilatory shock, myocarditis).  Laboratory abnormalities include marked elevation of D-dimer, C-reactive protein, and ferritin.  Patients may initially respond well to intubation and ventilation during stage II, but subsequently develop increasing levels of inflammation, which leads to clinical deterioration.
  • Biologically:  The adaptive immune response spirals into an immunopathological dysregulated cytokine storm.  This likely represents a form of virus-induced hemophagocytic lymphohistiocytosis (HLH)(Mehta et al.).
  • Treatment:
    • All the treatments from Stage II may be continued (e.g. moderate-dose steroid and antiviral therapy).
    • More aggressive immunomodulatory therapy is likely required – more on this below.

steroid for severe hypoxemic respiratory failure

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steroid isn't indicated in early disease 
  • Early administration of steroid may increase viral shedding (e.g. administration during the replicative phase)(Lee et al 2004)
  • Most patients recover well without severe sequelae – so obviously steroid cannot benefit such patients.
  • Steroid should be used in patients with an independent indication for steroid, such as:
    • Vasopressor-refractory shock
    • Asthma or COPD exacerbation
low dose steroid for patients with substantial hypoxemia
  • Surviving Sepsis Campaign guidelines recommend steroid for intubated patients with ARDS.
  • Currently, the best evidence with COVID-19 comes from Wu et al 3/13/20.
    • Retrospective, single-center study describing 201 patients with COVID-19 pneumonia.
    • Among patients with ARDS, the use of methylprednisolone correlated with reduced mortality.
    • Typically steroid is used in the sickest patients, so this will create a bias towards seeing worse outcomes in patients treated with steroid.  A correlation in the opposite direction is surprising, suggesting that steroid could be causing benefit.
  • Thus, it may be sensible to use low-dose corticosteroid in patients with substantial hypoxemia and elevated inflammatory markers (e.g. C-reactive protein).
  • Regimens used in China were typically methylprednisolone 40-80 mg IV daily for a course of 3-6 days, which seems reasonable (Shang et al. 2/29).  Equivalent doses of dexamethasone (7-15 mg daily, typically 10 mg daily) could have an advantage of stimulating less fluid retention, since dexamethasone has less mineralocorticoid activity.  Notably, this dose of steroid is consistent with doses used in the DEXA-ARDS trial.
    • 👁 Illustration of why dexamethasone could be superior to other corticosteroids for ARDS.
ascorbic acid ?
  • Ascorbic acid did appear to improve mortality in the multi-center CITRIS-ALI trial.  However, interpretation of this trial remains hopelessly contentious due to nearly unsolvable issues with survival-ship bias (discussed here).
  • Extremely limited evidence suggests that ascorbic acid could be beneficial in animal models of coronavirus (Atherton 1978).
  • Administration of a moderate dose of IV vitamin C could be considered (e.g. 1.5 grams IV q6 ascorbic acid plus 200 mg thiamine IV q12).  This dose seems to be safe.

cytokine storm: diagnosis & treatment overview

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using scoring systems from other disease states isn't a good fit
  • COVID-19 cytokine storm has similarities to hemophagocytic lymphohistiocytosis (HLH) and also cytokine release syndrome following CAR-T cell therapy.  However, there are also important distinctions between these entities.  Trying to apply scoring systems from other disease states to COVID-19 doesn't seem like a good strategy, for example:
    • CAR-T cell cytokine release scores tend to attribute all organ failure to cytokine release syndrome.  However, COVID-19 has the capacity to cause respiratory failure without necessarily involving a cytokine storm.  Therefore, CAR-T cell cytokine release scoring systems may tend to over-diagnose cytokine storm in patients with COVID-19 (because respiratory failure will be attributed to cytokine storm).
    • Diagnostic scoring systems designed for hemophagocytic lymphohistiocytosis (HLH) have rather poor diagnostic sensitivity in general.  They tend to become positive late in the disease course, often after the patient has developed refractory multi-organ failure.  These scoring systems are unlikely to be helpful in COVID-19.
evidence-based diagnosis of cytokine storm in COVID-19 ?
  • Cytokine storm seems to be a major driver of mortality in COVID-19.  This implies that validated prognostic markers in COVID-19 related to inflammation can be used to define patients with COVID-19 cytokine storm.
    • This strategy has the advantage of being disease-specific to COVID-19 (rather than trying to retrofit another scoring system onto COVID-19).
  • A diagnosis of cytokine storm could therefore be based upon the presence of severe respiratory failure plus abnormalities in ferritin, C-reactive protein, D-dimer, lactate dehydrogenase (LDH), and absolute lymphocyte count (figure above).
    • Cutoff values aren't intended to drive absolute binary decisions, but rather as rough guidelines.  These cutoff values are derived from several studies on prognostication in COVID-19 (see section on prognosis).  This diagnostic strategy is consistent with some ongoing RCTs investigating tocilizumab (here and here).
    • Rapid deterioration in the laboratories supports the presence of cytokine storm (especially if this occurs despite the use of low-dose steroid).
  • Using this approach, patients diagnosed with cytokine storm will have a high likelihood of mortality.  This may constitute an evidence-grounded rationale for more aggressive treatment of this subset of patients.
treatment of cytokine storm in COVID-19 ?
  • There is no well-established or evidence-based treatment for cytokine storm in COVID-19.
  • Patients with COVID-19 and cytokine storm are at high risk of death without aggressive therapy.  Low-dose steroid appears inadequate to quell inflammation in these patients (e.g. 50 mg hydrocortisone q6hr or 1 mg/kg/day prednisone).
  • More powerful immunosuppression may be beneficial.  Possible options include:
    • Higher doses of steroid (e.g. 60-125 mg IV methylprednisolone q6hr for up to 3 days, with tapering as soon as the C-reactive protein starts falling).  Pulse-dose steroid has been described for the treatment of influenza-induced hemophagocytic lymphohistiocytosis, so there is some precedent for this in the literature (Ando 2006, Asai 2012)
    • Tocilizumab (more on this below).  Theoretically this may be the best strategy, but supplies of tocilizumab are severely limited.
    • IL-1 inhibitors (e.g. anakinra)(Shakoory 2016).
    • JAK inhibitors (e.g. ruxolitinib)(Zandvakili 2018).
additional information
  • Influenza chapter section on virus-induced HLH is here.

tocilizumab

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basics
  • Tocilizumab is a recombinant humanized monoclonal antibody which binds to the interleukin-6 (IL-6) receptor and blocks it from functioning.
  • Tocilizumab is most commonly used to treat rheumatoid arthritis.  It may also be used to treat cytokine release syndrome following CAR-T therapy.
  • Mechanistically, tocilizumab would be expected to benefit patients with COVID-19 who develop a cytokine storm (which involves elevated levels of IL-6, a major pro-inflammatory cytokine).
evidentiary support
  • No high-level evidence is currently available.
  • Tocilizumab has been used in Italy (podcast discussions regarding this are here and here).
  • Case series from China (Xu et al.)
    • 21 hypoxemic patients were treated with tocilizumab 400 mg as an intravenous infusion (most patients received a single dose, but 3 patients received two doses).
    • Patients appeared to improve clinically, with rapid reduction in inflammatory markers.  No adverse effects were noted.
dose
  • 4-8 mg/kg IV x1 (commonly used dose is 400 mg)
  • Dose can be repeated 12-hours later if inadequate response to first dose.  Total dose shouldn't exceed 800 mg (B&W; guidelines)
adverse events
  • Elevated AST, ALT commonly seen.
  • Infusion reaction (~10% of patients), which can include anaphylaxis.
  • Increased risk of certain opportunistic infections (e.g. tuberculosis or invasive fungal infections).
  • Spontaneous gastrointestinal perforation.
indications ???
  • This is unclear.  Features which might favor the use of tocilizumab include the following:
    • ARDS, especially if progressively more severe.
    • Progressive elevation of inflammatory markers (e.g. C-reactive protein, ferritin, possibly IL-6 if you can measure this rapidly).  Lack of a marked elevation in ferritin strongly argues against cytokine storm.
    • Increasing vasopressor requirement, shock.
    • Two cell lines down (“bi-cytopenia” – e.g. thrombocytopenia plus leukopenia, or thrombocytopenia plus anemia).
    • Persistent fevers which may be refractory to antipyretics.
    • Clinical deterioration despite other supportive measures (not explained by another event, such as hospital-acquired bacterial infection).
siltuximab
  • Alternative agent with similar clinical effects (it is an anti-IL6 monoclonal antibody).
  • Dose 11 mg/kg IV x1.
  • Common adverse events:  edema (>26%), respiratory infection, pruritus or skin rash (28%), thrombocytopenia (8%), hypotension (4%) (B&W; guidelines).

antiviral therapy

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background on antiviral therapy 
  • For maximal benefit, antiviral therapy probably needs to be started very early after the initial develop of symptoms (i.e. during the viral response phase).  Unfortunately, most patients present to the hospital with severe illness after about a week of clinical illness.
  • To date, evidence with numerous anti-viral therapies has proven to be dissapointing (listed below).
  • Overall, the use of antiviral therapy for critically ill patients with COVID-19 may be limited.
hydroxychloroquine
  • Currently, best available evidence suggests that hydroxychloroquine is ineffective (Tang et al., discussed further here).
  • Additional studies on hydroxychloroquine are underway.  Pending further evidence, hydroxychloroquine should probably be restricted to use within randomized controlled trials.  
  • Some older, background material on hydroxychloroquine can be found here.
remdesivir
  • Remdesivir could be an effective antiviral, based on a study involving in vitro and animal data with MERS (Sheahan 2020; Holshue 2020).
  • This is currently an experimental agent which is not commercially available.
  • Initial results using remdesivir in a “compassionate-use” capacity are unimpressive (further discussion here).  
  • Currently, remdesivir should probably be restricted to use within randomized controlled trials (IDSA guidelines).  
lopinavir/ritonavir
  • This doesn't seem to work and is not recommended outside of a clinical trial.
  • More material on lopinavir/ritonavir can be found here.
oseltamavir & other neuraminidase inhibitors
  • Neuraminidase inhibitors don't seem to work against COVID-19 (Tan et al 2004).
  • Initial empiric therapy with neuraminidase inhibitors could be reasonable during influenza season in critically ill patients, if there is concern that the patient might have influenza pneumonia.
    • Currently, in many locations, patients presenting with viral pneumonia are much more likely to have influenza than COVID-19.

cardiovascular

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avoid fluid resuscitation
  • Patients rarely are shocked on admission (even among critically ill patients, admission blood pressure is generally normal and lactate elevations are mild-moderate)(Yang et al 2/21).
    • Overall, the rate of reported “sepsis” is generally low (<5%).  The virus doesn't seem to generally cause a septic shock picture (but of course, patients may always suffer from superimposed bacterial septic shock).
  • The primary physiologic problem in COVID-19 is generally hypoxemic respiratory failure – which may be exacerbated by fluid administration.
  • Gentle fluid administration could be considered for patients with evidence of hypoperfusion and a history suggestive of total body hypovolemia (e.g. prolonged nausea/vomiting and diarrhea).
  • More discussion on fluid therapy for COVID-19 is here.
troponin elevation
  • Troponin elevation is common (especially high-sensitivity troponin).
    • This is a strong predictor of mortality.  Among non-survivors, troponin tends to increase steadily from day 4 of illness through day 22 (Zhou et al. 2020).
  • Potential causes of troponin elevation in COVID-19 patients may include:
    • Myocardial injury (troponin elevation without symptoms/ EKG/echo findings of myocardial ischemia)
    • Type-I MI (plaque rupture) – this is probably among the least common causes.
    • Type-II MI (stress MI)
    • Stress cardiomyopathy (a.k.a. Takotsubo cardiomyopathy)
    • Viral cardiomyopathy
  • Investigation should focus on integration of EKG and echocardiographic findings as well as clinical context.
  • In most cases, specific therapies for acute coronary syndrome will not be indicated.
cardiomyopathy
  • Fulminant cardiomyopathy can occur.  This may be a late feature, which can occur even after patients are recovering from respiratory failure.
  • Cardiogenic shock appears to be an important cause of death, contributing to ~7-33% of deaths (Ruan 3/3/20).
  • It's unclear whether this represents a viral cardiomyopathy (virus can be recovered from myocardial tissue), stress/Takotsubo cardiomyopathy, or cardiac dysfunction due to cytokine storm (i.e., a feature of virus-induced hemophagocytic lymphohistiocytosis).
  • Evaluation:  EKG, echocardiography, and troponin levels to evaluate for acute coronary occlusion.
  • Treatment:  If other clinical and laboratory features of cytokine storm, could consider treatment for this syndrome (e.g. with tocilizumab).
arrhythmia ??
  • Palpitations were reported in 7% of patients in one cohort (Liu 2020).
  • A large series reported arrhythmia in 17% of patients, but didn't specify further (Wang 2/7/30).
  • These studies lack control groups, so it's unclear to what extent COVID may be causing arrhythmias (or whether arrhythmias simply occur in sick patients).
shock
  • Rarely present upon admission, but can be a late finding among critically ill patients in ICU.
  • Potential causes:
    • Cardiogenic shock (i.e. myocarditis)
    • Secondary bacterial infection with septic shock
    • Cytokine storm / hemophagocytic lymphohistiocytosis
    • Pulmonary embolism
    • Pulmonary hypertension due to excessive mean airway pressures (e.g. PEEP or APRV)
    • Anaphylactic reaction to medication
  • Evaluation
    • Complete septic workup (e.g. blood cultures, sputum culture, chest X-ray, examination of line sites)
    • Bedside echocardiogram and physical examination
    • Review of serial labs (hemophagocytic lymphohistiocytosis labs should be measured routinely).
  • Treatment
    • Vasopressor support as guided by echocardiography and physical examination.
    • Empiric antibiotic therapy if concern for septic shock.
    • Corticosteroid therapy may be considered (especially if vasopressor refractory, or if sepsis or cytokine storm are considered likely).
    • Inhaled pulmonary vasodilator could be considered for intubated patients with acute cor pulmonale.  
additional information:

high flow nasal cannula

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safety of HFNC
  • There is widespread concern that using HFNC could increase the risk of viral transmission.  This doesn't appear to be evidence-based.
  • Guidelines recommend HFNC
    • ANZICS guidelines on COVID-19 state the following:
      • “High flow nasal oxygen (HFNO) therapy (in ICU): HFNO is a recommended therapy for hypoxia associated with COVID-19 disease, as long as staff are wearing optimal airborne PPE.”
      • “The risk of airborne transmission to staff is low with well fitted newer HFNO systems when optimal PPE and other infection control precautions are being used. Negative pressure rooms are preferable for patients receiving HFNO therapy.”
    • Surviving Sepsis Guidelines state:  “For acute hypoxemic respiratory failure despite conventional oxygen therapy, we suggest using HFNC over conventional oxygen therapy (weak recommendation, low quality of evidence”
    • WHO guidelines on COVID-19 state that “Recent publications suggest that newer HFNC and NIV systems with good interface fitting do not create widespread dispersion of exhaled air and therefore should be associated with low risk of airborne transmission.”
  • Reasons that HFNC might not increase viral transmission are:
    • HFNC supplies gas at a rate of ~40-60 liters/minute, whereas a normal cough achieves flow rates of ~400 liters/minute (Mellies 2014).  Therefore, it's doubtful that a patient on HFNC is more contagious than a patient on standard nasal cannula who is coughing.
    • HFNC typically requires less maintenance than invasive mechanical ventilation.  For example, a patient who is on HFNC watching television may be less likely to spread the virus compared to an intubated patient whose ventilator is alarming every 15 minutes, requiring active suctioning and multiple providers in the room.
    • The intubation procedure places healthcare workers at enormous risk of acquiring the virus, so intubation with a goal of reducing transmission is probably counterproductive (see figure above from Tran 2012).
      • 👁 Image of risk factors for nosocomial SARS transmission from Tran et al. here.
    • Existing evidence does not support the concept that HFNC increases pathogen dispersal substantially (although the evidence is extremely sparse).  This includes a small study of patients with bacterial pneumonia (Leung 2018) and an abstract regarding particulate dispersal by volunteers (Roberts 2015).
  • One possible compromise might be to use HFNC with a moderate rate of flow (e.g. 15-30 liters/minute, rather than 40-60 liters/minute).  Since 15-30 liters/minute flow is close to a baseline minute ventilation for a sick respiratory failure patient, adding this level of flow is unlikely to affect matters substantially.
evidentiary basis for HFNC
  • HFNC is generally a rational front-line approach to noninvasive support in patients with ARDS (based partially on the FLORALI trial).
  • One case series from China suggested that HFNC was associated with higher rates of survival than either noninvasive or invasive ventilation (of course, this could reflect its use in less sick patients)(Yang et al, see table 2).
  • A management strategy for COVID-19 by a French group used HFNC preferentially, instead of BiPAP (Bouadma et al.).

noninvasive ventilation (BiPAP & CPAP)

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traditional BiPAP probably isn't useful for most patients
  • Reasons to avoid BiPAP:
    • In a multicenter cohort of 302 patients with MERS coronavirus, 92% of patients treated with BiPAP failed this modality and required intubation (Alraddadi 2019).
    • In the FLORALI trial of ARDS patients (with mostly pneumonia of various etiologies), patients randomized to BiPAP did worse compared to patients randomized to HFNC.
  • BiPAP could have a niche role in patients with combined syndromes (e.g. COPD plus COVID-19).  For more on the selection of BiPAP vs. HFNC, see this chapter on noninvasive respiratory support.
continuous positive airway pressure (CPAP) might be the best modality of noninvasive support ??
  • Atelectasis leading to hypoxemia seems to be a major problem among these patients.
    • 👁 Image of progressive alveolar collapse.
  • CPAP could have major advantages here:
    • CPAP can provide the greatest amount of mean airway pressure, and thus most effective recruitment.
      • 👁 Image comparing mean airway pressure due to CPAP vs. BiPAP.
    • CPAP doesn't augment tidal volumes, so this could facilitate more lung-protective ventilation.
  • Possible approach to CPAP therapy in COVID-19:
    • Increase the CPAP pressure to 15-18 cm if tolerated.
    • Titrate FiO2 against oxygen saturation.  Falling FiO2 requirements indicate effective recruitment, whereas rising FiO2 requirements suggest CPAP failure.
    • Monitor tidal volumes and minute ventilation
      • 👁 Image illustrating how a noninvasive ventilator can be used as a monitor.
  • Further discussion of CPAP in COVID-19.
helmet interface
  • A helmet interface may have several advantages:
    • It could reduce environmental contamination (Cabrini 2020; Hui 2015).
    • There is a decreased risk of aspiration if emesis occurs.
    • In one RCT investigating ARDS, the helmet reduced intubation rates and possibly mortality (Patel 2016).
  • Unfortunately, access to these devices is limited in the United States.  It may be possible to MacGyver a helmet device as shown below.
safety when using CPAP and BiPAP
  • Viral filters are essential to create a closed system and limit transmission.
    • A discussion of how to configure this is located here.
    • This is possible with either a two-limb system involving a full featured mechanical ventilator, or a one-limb system involving a dedicated BiPAP machine (e.g. Respironics V60).
  • Improved mask seal may improve safety.
  • Helmet masks might theoretically have an advantage here.

awake prone positioning

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basics
  • This involves a non-intubated patient on nasal cannula who prone themselves by lying on their belly.  For patients with difficult lying in a prone position, alternating between lying on different sides might also be beneficial.
  • Can be combined with simultaneous use of any other noninvasive support device (e.g. low-flow nasal cannula, high-flow nasal cannula, BiPAP, or CPAP).
  • Requires cooperative patient with intact mentation.
  • Could be useful especially in situations where access to invasive ventilation is limited.
 physiology: why it works?
  • Same physiology as proning a patient who is intubated (proning is proning).  For example:
    • May improve secretion clearance.
    • May recruit atelectatic lung tissue in the dependent lung basis (this seems to be a major issue in COVID-19 patients).
  • Proning intubated patients with COVID-19 is widely reported to be successful in improving oxygenation.  It stands to reason that similar success could be obtained by proning a patient who isn't intubated.
  • Awake proning was recommended by Sun et al. as one technique which could be used to avoid intubation for patients with COVID-19 (Sun et al.).
nuts and bolts
  • Help patient lie on their belly in a prone position.  For patients with difficulty maintaining this position, other positions may be used (e.g. rotating between lying on alternate sides).
  • Make sure support devices are well secured to the patient (e.g. it could be helpful to use tegaderm to anchor a nasal cannula).
  • Encourage proning as much as is tolerated (ideally ~12-18 hours/day, but this may be difficult for some patients).
  • Follow oxygenation and FiO2 requirement.  Ideally an improvement in oxygenation should be seen within a few hours.  If no change in oxygenation is observed, ongoing pronation may have less merit.
additional information

overall schema for noninvasive support

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general comments
  • Many “rules” are circulating regarding COVID-19 (e.g. you must never use HFNC).  These don't appear to be evidence-based or guideline-supported.
  • Patients vary widely, so use common sense.
  • Immediately intubating every patient who requires >6 liters nasal cannula will overwhelm ICU capacity and lead to unnecessary intubations.  For patients with single-organ failure who are comfortable and requiring moderate amounts of oxygen, attempts to avoid intubation are probably warranted.

indications for intubation?  
  • COVID-19 may cause hypoxemia with relatively little respiratory distress (“silent hypoxemia”).  For example, patients may be profoundly hypoxemic yet not be dyspneic – and such patients may “look” fine.  Therefore, work of breathing cannot be relied upon to detect patients who are failing HFNC.
  • There should probably be a lower threshold to intubate in COVID-19 than in most patients, for the following reasons:
    • Patients can develop worsening “silent” atelectasis and decline rather abruptly, without lots of symptoms.
    • Oxygenation techniques used to maintain saturation during intubation (e.g. mask ventilation) may increase virus aerosolization.  Thus, “pure” rapid sequence intubation without bagging is preferred.  This will be safer if the patient is starting out with more oxygenation reserve.
    • Intubation requires considerable preparation, so a semi-elective intubation is preferred to crash intubation.
  • Exactly when to intubate is always a clinical decision.  Potential indications would include:
    • Progressively rising FiO2 requirements.
    • Increasing work of breathing & clinical distress.
    • High absolute oxygen requirement.

intubation procedure

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See the new COVID-19 Airway Page by Scott Weingart for this.

invasive mechanical ventilation

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pathophysiology:  COVID does not cause typical ARDS
  • COVID doesn't appear to cause substantially reduced lung compliance (which is generally a hallmark finding of ARDS).
  • A predominant problem seems to be atelectasis.  Any strategy to increase the mean airway pressure will treat atelectasis (e.g. APRV or conventional ARDSnet ventilation using a high-PEEP strategy).
    • Early COVID may most closely resemble pseudoARDS (pseudoARDS presents similarly to ARDS, but the P/F ratio increases above 150 following 12-24 hours of ventilator optimization).  
    • Further discussion of various types of ARDS and how COVID fits into this rubric here.  
airway pressure release ventilation (APRV)
  • My opinion is that early APRV could be very useful for these patients (i.e. used as the initial ventilator mode, rather than a salvage mode).
  • Benefits of APRV include:
    • (1) A primary physiologic problem in COVID appears to be de-recruitment, which is well managed by APRV.  A drop in FiO2 requirement to ~50% is often seen within 6-12 hours on APRV (full recruitment takes time).
    • (2) APRV often allows for improvement in hypoxemia without paralysis and/or proning.  This may avoid iatrogenic complications from these interventions (e.g. delirium, myopathy).
    • (3) APRV is a more comfortable mode than conventional volume-cycled ventilation.  This may allow us to render patients comfortable and awake on the ventilator more easily, while using fewer medications (an especially important challenge as we run out of many sedatives).
  • A practical guide to using APRV in COVID can be found here.
    • APRV initiation can cause hemodynamic shifts, so pay careful attention to blood pressure during initiation.
  • True failure to respond to APRV within 12-24 hours (e.g. with PaO2/FiO2 <100-150) would be a strong argument to move towards prone ventilation (discussed here).  However, when started early APRV may be more likely to succeed – thereby avoiding the need for proning.
conventional ARDSnet ventilation
  • Tidal volumes should be targeted to a lung-protective range (6 cc/kg ideal body weight).
    • MDCalc can be used to calculate appropriate endotracheal tube depth & tidal volumes.
  • High PEEPs should be utilized (SSC guidelines).  An ARDSnet “high PEEP” table is shown below.  This table doesn't need to be followed exactly, but it may be useful as a general guide.
    • 👁 Image of ARDSnet low-PEEP & high-PEEP tables here.
permissive hypercapnia & optimization of metabolic acid/base status
  • Regardless of the ventilator mode, permissive hypercapnia may be useful.  The safe extent of permissive hypercapnia is unknown, but as long as hemodynamics are adequate, a pH above roughly ~7.15 may be tolerable (hypercapnia is preferred over lung-injurious ventilation).
  • A common error is to focus solely on respiratory parameters in order to improve the pH, while ignoring metabolic acid/base status.  For example:
    • ICU patients often have non-anion-gap metabolic acidosis (NAGMA).  Treatment of NAGMA with bicarbonate may be the safest way to address a low pH (rather than increasing the intensity of mechanical ventilation and thereby threatening the lung).
    • Even if the metabolic acid/base status is normal, IV bicarbonate may still be considered to improve pH, while simultaneously continuing lung-protective ventilation (discussed here).  Targeting a mildly elevated serum bicarbonate can facilitate safe ventilation with low tidal volumes (more on different forms of IV bicarbonate here).
proning
  • Prior to consideration of proning, optimization on the ventilator for 12-24 is generally preferable (discussed here).
  • For failure to respond to initial ventilator optimization (e.g. with persistent PaO2/FiO2 below 150 mm), prone ventilation should be considered.
  • Reports from Italy describe proning as extremely effective.
    • This makes sense, because proning is expected to be effective for basilar lung recruitment (which seems to be a major problem with these patients).
    • The question is whether the same effect could be achieved more easily using APRV.
additional information:  

disaster ventilation strategies

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[1] splitting ventilators
  • In a dire emergency, one ventilator can be used to support several patients.
  • Pressure-cycled ventilation should be used, with a driving pressure <13-15 cm (Aoyama et al. 2018).
  • Blog exploring the general strategy to setting the ventilators here.
  • Columbia Presbyterian protocol for splitting ventilators here.
  • Some additional ideas about how to hook everything up here.
[2] outpatient-design BiPAP machines for intubated patients?
  • It could be concievable to connect outpatient BiPAP machines to endotracheal tubes.
  • FiO2 might be limited (bleeding in wall oxygen might only achieve a limited FiO2, maybe around 50-60%) ???
  • This would require the patient to spontaneously trigger breaths, so light sedation would be needed.
  • Compared to the split ventilator technique (above), BiPAP devices could be used with less ill patients:
    • Splitting the ventilator requires deep sedation and provides full ventilator support – this is better for the sickest patients.
    • BiPAP machines require light sedation and provides partial support – this could be used for less ill patients.
    • Home-design BiPAP masks are often unable to generate high flow rates, so they won't be able to support patients who are dyspneic with high flow demands.
  • On a related note, Trilogy devices could probably easily be repurposed to be used as ventilators.
[3] oxylator resuscitator
  • Small automated device which can provide pressure-cycled ventilation.
  • Relatively inexpensive and there still seems to be a reasonable supply available.
  • Allows for delivering titratable levels of PEEP.
  • More information:
    • How to use the oxylator resuscitator with PEEP valve and HEPA filters here.
    • EMCrit page on the oxylator here.
[4] votran automatic resuscitator
  • These are small plastic devices which can provide pressure cycled ventilation (more here).  In some ways, they may be conceptualized as a simplified and primitive version of an oxylator resuscitator.  They are designed for field use in a disaster.
  • Unlike the oxylator resuscitator, this device doesn't allow for the addition of higher levels of PEEP (PEEP is fixed at a relatively low level, around ~5-8 cm).
    • i) This renders it unsuitable for use in patients with ARDS.
    • ii) In a dire emergency, the votran automatic resuscitator might be used in less ill patients (e.g. a patient with trauma or drug intoxication), thereby freeing up other ventilators to be used on sicker COVID patients.
overall strategy for ventilator shortage
  • There is no one-size-fits all solution.
    • Different strategies may work for different types of patients.
    • Any way that we can free up ventilators is beneficial.
  • For example:
    • Splitting ventilators:  Could be used for extremely ill patients (intubated, on deep sedation).
    • BiPAP machines attached to endotracheal tubes:  Could be used for patients who are close to weaning off ventilation.
    • Votran automatic resuscitator:  Might be used for patients intubated for non-pulmonary reasons (patients with normal lungs).

extubation

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potential pitfalls 
  • Patients with COVID-19 often respond well to intubation and positive pressure ventilation (probably reflecting lung recruitment).  Unfortunately, they may continue to have a tendency to de-recruit their lungs.  Consequently, there may be an increased risk of deterioration after extubation.
  • According to a webinar with Italian intensivists, “Do not trust the first improvement,” because patients may have early relapses.
    • However, prolonged intubation also carries risk.
    • Can inflammatory markers predict who will relapse?  For example, if the patient is improving clinically but CRP, LDH, and lymphopenia are all worsening – perhaps this predicts clinical worsening and suggests that extubation should be deferred?
post-extubation support
  • ANZICS guidelines state that HFNC and/or noninvasive ventilation (with a well fitted facemask and separate inspiratory and expiratory limbs) can be considered as bridging therapy post-extubation, but must be provided with strict airborne PPE.
    • CPAP therapy or BiPAP (with high end-expiratory pressure) might be useful to prevent de-recruitment in these patients. (More on COVID-19 & CPAP here).
    • By the time of extubation, patients will often have been ill for well over a week.  It's likely that their viral load will be decreasing at that point, so the risk of virus transmission may be lower (compared to the initial intubation).  More on transmission above.

gastrointestinal

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transaminase elevation
  • COVID can cause mild elevation of transaminases (e.g. in 200's).  However, fulminant hepatitis or liver failure hasn't been reported (B&W; guidelines).
  • Potential mechanisms of liver injury include (B&W; guidelines)
    • Direct viral infection
    • Drug hepatotoxicity
    • Shock liver
    • Cytokine storm / hemophagocytic lymphohistiocytosis (this might be associated more closely with bilirubin elevation)
  • Many medications used in these patients may also elevate transaminases, so liver function test abnormality mandates medication review.

renal failure

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epidemiology & timing
  • Renal failure requiring dialysis is reported in a subset of patients admitted to ICU (probably ~5%).
  • It tends to be a late finding, occurring 1-2 weeks after admission.
pathology & pathogenesis
  • Acute tubular necrosis due to generalized multi-organ failure is probably the predominant mechanism.
  • Complement deposition in the tubules was observed in six patients within an autopsy study, raising the question of whether this may be a contributory mechanism (Diao B et al.).
  • Virus can bind to proximal tubular epithelial cells (which express the ACE2 receptor), so direct viral infection is possible.
treatment is supportive
  • Avoid nephrotoxins.
  • Re-dose renally cleared medications.
  • Hemodialysis indications seem to be the same as for other patients.
    • The prognosis of patients requiring dialysis appears poor.
      • COVID-19:  one study found a mortality of 10/10 patients in a recent study on COVID-19 (Zhou et al).
      • SARS:  Renal failure correlated with poor prognosis (92% mortality with renal failure versus 9% without).  In multivariable analysis, renal failure was the strongest predictor of mortality (more-so even than ARDS)(Chu et al. 2005).
    • Goals of care should be explored prior to proceeding to hemodialysis.
    • Avoid giving excess fluid, as this may necessitate dialysis to remove fluid.
    • COVID-19 patients may be hyper-coagulable, so heparin or citrate anticoagulation anticoagulation may be important to maintain a CRRT circuit.
further information

anti-bacterial therapy

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initial empiric antibiotics
  • Initially, there may be concerns regarding the possibility of a superimposed bacterial pneumonia.  When in doubt, it may be sensible to obtain bacterial cultures, prior to initiation of empiric antibiotic therapy.  Based on culture results, antibiotics might be discontinued in <48 hours if there isn't evidence of a bacterial infection (this is exactly the same as management of influenza pneumonia).
  • Azithromycin may possibly have beneficial anti-viral properties and/or immunomodulatory properties.
    • This will generally be initiated initially, for coverage of possible bacterial pneumonia.
    • It may be reasonable to complete a course of azithromycin.
    • Azithromycin is the preferred macrolide agent because of lack of clinically meaningful effects on the QTc (discussed here and here).
  • MRSA coverage?
    • COVID doesn't seem to increase the risk of MRSA (unlike influenza).  This based on anecdotal reports, with a very low level of evidence.
    • MRSA therapy could be instituted based on typical indications for a patient with community-acquired pneumonia (further discussion here and here).
    • Excessive use of vancomycin should be discouraged, as patients are at substantial risk of developing renal failure.
    • 👁 Algorithm for who needs MRSA coverage in context of community-acquired pneumonia.
delayed bacterial superinfection
  • Bacterial pneumonia can emerge during the hospital course (especially ventilator-associated pneumonia in patients who are intubated).
    • Among patients who died from COVID-19, one series found that 11/68 (16%) had secondary infections (Ruan 3/3/20).
  • This may be investigated and treated similarly to other ventilator-associated pneumonias, or hospital-acquired pneumonias.

disseminated intravascular coagulation

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pathophysiology
  • COVID produces a form of disseminated intravascular coagulation (DIC) which is usually marked by hypercoagulability.
  • The exact causes of this are unclear and likely numerous.  They could include the following:
    • (1) Inflammation (e.g. IL-6) stimulates up-regulation of fibrinogen synthesis by the liver (Carty 2010).
    • (2) Virus may bind directly to endothelial cells.
  • There is likely a bi-directional, synergistic relationship between DIC and cytokine storm (wherein each exacerbates the other).
  • DIC appears to be a driver of disease severity.  As might be expected, it is a strong prognostic factor for poor outcome (Tang et al. 2020).
    • Microthrombi have been reported as autopsy findings in patients with COVID-19 (Luo et al.)
hematologic abnormalities seen in COVID-19

  • D-dimer:  The diagnostic hallmark of COVID-DIC is a rapidly rising D-dimer (figure above).
    • Patients with D-dimer >1,000 at admission are twenty times more likely to die than patients with lower D-dimer values (Zhou et al.).
  • Fibrinogen: is generally elevated.  However, in extremely severe and late-stage disease, consumption of fibrinogen may occur leading to hypofibrinogenemia (Han et al. 2020)
  • Thrombocytopenia can occur, but this is less common than in other forms of DIC.
  • PT and INR is often slightly elevated, whereas the activated partial thromboplastin time (aPTT) may be shortened.
  • Thromboelastography (TEG) – No published data, but anecdotally this may show a hyper coagulable pattern (usually with a low R-time, and often with an elevated maximal amplitude as well).
    • 👁 Image of DIC labs in survivors versus non-survivors over time.
    • 👁 Image of D-dimer, ferritin, LDH, and Lymphocyte trends over time in survivors & non-survivors.
    • 👁 Image of WBC, lymphocytes, and D-dimer over time in survivors vs. non-survivors.
ISTH diagnostic scoring system for DIC

  • Various scoring systems for DIC exist, this seems to be the most widely accepted.  Note that DIC can exist without abnormal fibrinogen (Levi et al. 2009).
  • In one patient series, 71% of COVID patients who died met ISTH criteria for DIC, whereas only 0.6% of survivors did (Tang et al. 4/18).
evaluation for clinical thrombosis
  • Bedside ultrasonography to evaluate for deep vein thrombosis may be considered, especially if there are other clinical features of DVT/PE.
  • CT pulmonary angiography
    • May be useful in select patients.
    • Logistically, large-volume CT scanning of patients with COVID is often impossible (e.g. risk of disease transmission and inability to transport unstable patients to the scanner).
DVT prophylaxis
  • DVT prophylaxis should generally be maintained – unless platelets are below 25 (ISTH guidelines 3/25).
  • DVT prophylaxis alone will very frequently fail in patients with COVID-19.  Klok et al found that despite DVT prophylaxis, about 27% of patients had venous thromboembolic events and 4% had arterial thromboembolic events (which is likely an underestimate, due to lack of systematic screening for these events and truncated observation periods for some patients).  Consequently, these authors suggested doubling the typical dose of prophylactic heparin (e.g. enoxaparin 40 mg twice daily, rather than once daily).  
  • Higher doses of prophylactic heparin may be considered in patients with moderately elevated D-dimer (e.g. ~500-1,500 ng/ml).  For example:
    • GFR > 30 ml/min:  Enoxaparin 0.5 mg/kg BID.  Check an Xa level four hours after the third dose, targeting a level of ~0.5-0.8 IU/ml.
    • GFR < 30 ml/min:  Unfractionated heparin ~7,500 units q8hr (consider adjusting dose for patients with atypical weight).
empiric heparin anticoagulation?  
  • Therapeutic anticoagulation with heparin has been suggested for patients with D-dimer over 2,000 ng/ml, but this remains unproven (Lin et al., Tang et al. 3/27).
  • Most patients with COVID seem to be extremely hypercoagulable.  This would support a potential role for heparin anticoagulation, and also bolster the safety of heparin administration (some patients appear heparin-resistant – again suggesting that heparin is probably fairly safe here).
  • Very late-stage, profound disease may be marked by low fibrinogen levels, which could produce a hemorrhagic phenotype.  Anticoagulation could theoretically be harmful in that situation.
  • One possible approach to anticoagulation in COVID-19 is shown below.  This is not supported by any high-level evidence.  Anticoagulation decisions should ideally be individualized, so this is merely intended as one schema for approaching these patients.
  • In addition to prevention of thrombosis, heparin could reduce cytokine levels, thereby improving cytokine storm (Shi et al. 4/7).  Further discussion of multiple possible benefits of heparin in COVID-19 in this article by Thachil.

thrombolysis (tissue plasminogen activator, i.e. tPA) ???
  • This could be considered for a patient who was peri-arrest with a high suspicion for pulmonary embolism.
  • RCTs may be warranted to evaluate this further (for discussion see Moore et al. 3/20).
purpura fulminans
  • Extreme, pro-thrombotic form of DIC causing widespread subcutaneous purpura which may progress to ischemic necrosis of the fingers and toes.
  • This can occur in COVID-19.  Diagnosis is clinical based on characteristic appearance of the extremities as well as laboratory derangements (e.g. marked elevation of D-dimer).
  • Treatment of purpura fulminans is challenging:
    • Heparin anticoagulation is generally recommended.  However, antithrombin-3 deficiency is common, so these patients are often heparin resistant.  Achieving a therapeutic heparin level may require large doses of heparin, or even supplementation of anti-thrombin levels.
    • Topical nitroglycerine and possibly intravenous epoprostanol might be used to cause cutaneous vasodilation and avoid digit loss.
    • More on purpura fulminans here.
additional information
  • Comments & discussion page on COVID-DIC here.
  • IBCC chapter on DIC here.

glycemic control & diabetes

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  • Background
    • ACE2 receptor is present in the islets of langerhans within pancreas, raising the possibility that virus could directly affect the endocrine pancreas (Yang et al. 2010).
    • SARS has been shown to induce a transient state of insulin resistance.
    • Currently there isn't any evidence available regarding COVID-19.
  • Possible predictions regarding COVID-19??  (Currently these are guesses).
    • (1) Patients with Type-I diabetes and COVID-19 might present with diabetic ketoacidosis (rather than with typical pulmonary symptoms).
    • (2) Patients without diabetes may develop hyperglycemia in the ICU which requires more aggressive management than the average patient.

analgosedation for the intubated patient

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why optimal analgosedation is essential
  • Achieving a patient who is mentating normally and is comfortable on the ventilator is enormously beneficial, for numerous reasons:
    • (1) This may reduce the respiratory rate and thereby promote lung-protective ventilation.
    • (2) An awake and cooperative patient is vastly easier to extubate.
    • (3) Avoidance of delirium may improve long-term neurocognitive function?
    • (4) It's just a nice thing to do for the patient.
unique challenges faced in COVID patients
  • (1) Patients often remain on the ventilator for relatively long periods of time (e.g. >7-14 days).  Prolonged use of some medications may cause dependence and even withdrawal (e.g. opioids or dexmedetomidine).
  • (2) Patients seem to develop hyperlipidemia rapidly if exposed to higher doses of propofol (possibly related to a component of hemophagocytic lymphohistiocytosis).
  • (3) Medication shortages are beginning to emerge (especially intravenous medications).  This may necessitate a transition to oral agents (which seem to be in better supply).
construction of a multi-modal analgosedative regimen
  • The key concept here is using relatively low doses of multiple different medications to function in a synergistic fashion.
  • Using relatively low doses of each individual medication optimizes the efficacy/toxicity ratio of that medication.
  • One example of an analgosedative ladder for COVID is shown below;
    • For ongoing pain, analgesics are added on sequentially.
    • For ongoing anxiety, sedatives are added on sequentially.
  • A useful combination may be:  melatonin, olanzapine, propofol, acetaminophen, ketamine, and PRN opioid.  A surprising number of patients can be rendered awake and comfortable on the ventilator with this combination (especially when using a comfortable ventilator mode, such as APRV).
analgesic #1:  scheduled acetaminophen
  • Acetaminophen should be scheduled at a dose of 1 gram q6hr.  In cirrhosis or severe alcoholism, the dose may be cut in half (500 mg q6hr).
  • Acetaminophen provides mild analgesia as well as antipyresis (both effects with a goal of improving patient comfort).
analgesic #2:  pain-dose ketamine infusion
  • A low-dose ketamine infusion has numerous potential benefits:
    • (1) Provides mild analgesia (reducing the amount of opioid required).
    • (2) Ketamine attenuates the development of opioid tolerance and opioid-induced hyperalgesia, thereby blunting opioid side-effects. (Barr 2013, Angst 2003).
    • (3) Ketamine exerts anti-depressant effects which may improve patient mood, even at low doses (Rasmussen 2013, Zarate 2006).
    • (4) Ketamine might weakly inhibit IL-6 (deep dive on this by Adam Thomas et al. here).  This isn't a real reason to use ketamine, but perhaps a fringe benefit.
  • The usual dose is 0.1-0.3 mg/kg/hr.  At the higher end of this range, mild psychotomimetic effects may be seen.  These effects are often beneficial (e.g. mild sedative effect), but occasional patients will have disturbing hallucinations.
    • Empirical dose-titration can generally find a sweet spot where there is analgesia, but no problematic psychotomimetic side-effects.
    • When in doubt, it's safer to stay closer to the 0.1 – 0.15 mg/kg dose range.
analgesic #3-4:  opioids
  • PRN boluses of opioid are generally preferable:
    • Since bolus doses given only when necessary, this limits the total dose of opioid.  Thus, it's probably preferable to use large PRN boluses, compared to a continuous infusion.
  • Opioid infusions are prone to numerous problems:
    • They tend to run longer and at higher doses than necessary, thereby increasing toxicity.
    • Fentanyl tends to accumulate in fat tissue over time, which can be extremely problematic.
    • Fentanyl infusions expose patients to massive cumulative doses of opioid (e.g. 50 mcg/hr fentanyl for a day is equivalent to ~240 mg oxycodone).
    • If opioid infusions are used, a daily interruption or dose-reduction should be performed (to verify that the dose of opioid being used is indeed necessary).
    • For patients on an opioid infusion, always ensure that a substantial amount of opioid (e.g. ~25-50%) is being given in the form of PRN boluses.  If a patient is on a continuous infusion and receiving no PRN boluses, that implies that the infusion rate is unnecessarily high.
sedative #1:  melatonin
  • Effects:
  • The usual dose is 5 mg QHS.
sedative #2:  atypical antipsychotics with sedative-predominant properties (olanzapine, quetiapine)
  • Rationale:
    • (1) These may promote a hemodynamically stable sedative regimen (by reducing the dose of propofol required).
    • (2) Antipsychotics provide sedation without promoting delirium (“non-deleriogenic sedatives”).
    • (3) Timed administration may promote sleep.
  • Olanzapine
    • The major advantage of olanzapine is that it doesn't prolong QT or cause Torsades de Pointes (relevant for patients on hydroxychloroquine).
    • The most logical dosing schedule might be 5-20 mg QHS.
    • The drawback of olanzapine is that it has a relatively low maximum dose (20 mg), which may limit its potency.
  • Quetiapine
    • The major advantage of quetiapine may be a higher maximum dose (800 mg/day).  At these doses, it may be a bit more powerful than olanzapine.
    • The drawback of quetiapine is that it does increase the QT interval.
    • Quetiapine has a shorter half-life than olanzapine, so it should be dosed twice daily (for use as a maintenance sedative).  A higher dose may be given at night to promote sleep (e.g. 50 mg in the morning and 100 mg before sleep).
sedative #3:  propofol or dexmedetomidine infusion
  • Dexmedetomidine
    • Generally not ideal in COVID patients, due to the long duration of sedation necessary (patients will become dependent on dexmedetomidine and subsequently withdraw from it).
  • Propofol infusion is generally preferable here.
    • COVID patients appear prone to developing hypertriglyceridemia due to propofol (possibly because of underlying hemophagocytosis).  This is problematic, because severe hypertriglyceridemia may necessitate completely stopping propofol.
    • Using low doses of propofol (e.g. 5-30 mcg/kg/min) may avoid the development of hypertriglyceridemia.
sedative #4:  PRN IV haloperidol
  • IV haloperidol could be useful for patients with agitated delirium.
  • Haloperidol may increase the QT interval, so caution is required.
sedative #5:  phenobarbital
  • Phenobarbital is particularly effective in patients with a history of alcoholism.  However, as we encounter shortages of other sedatives, low-dose phenobarbital as an adjunctive, general-purpose sedative may become increasingly useful (Gagnon et al. 2017).
    • Due to balanced effects on the glutamate and GABA systems, phenobarbital may be less deleriogenic than benzodiazepines.
  • Typical dosing regimen:
    • Loading dose:  5-10 mg/kg once.
    • Maintenance dose:  1-2 mg/kg q8-q12 hr.
    • For patients on ongoing maintenance therapy, check levels occasionally (targeting a level of ~5-20 mg/L).
    • Phenobarbital may also be given enterally with 100% bioavailability and fairly rapid absorption.
sedative #6:  benzodiazepines
  • Benzodiazepines are generally an agent of last resort in the ICU, due to their tendency to cause delirium.
  • Sometimes PRN benzodiazepines are necessary.  In this situation, the dose of benzodiazepine should be minimized.  Simultaneous efforts should be made to augment other sedatives and analgesics, with a goal of minimizing benzodiazepine exposure.

other neurologic problems

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overview
  • Patients with COVID-19 are at risk for a variety of neurological problems, especially if critically ill.  It will be difficult sorting out common complications of critical illness versus unique features of COVID-19 (Aaroe et al. 4/16).
    • Common complications  of critical illness
      • Delirium
      • Critical illness myopathy and neuropathy (especially among patients receiving extended paralysis)
      • Cerebrovascular disease
    • More unique complications related specifically to COVID-19
      • Guillain-Barre Syndrome
      • Acute Disseminated Encephalomyelitis (ADEM)
      • Acute necrotizing encephalopathy
Guillain-Barre Syndrome (GBS)
  • Data is currently limited to a five-patient case series (Toscano et al. 4/17).
  • This seems to begin ~5-10 days after the initiation of clinical illness (coincident with development of adaptive immunity).
  • Weakness is the predominant clinical finding (most often ascending paralysis).  Dysautonomia doesn't seem to be a prominent issue.
  • Guillain-Barre Syndrome may tend to blend in with critical illness neuropathy & myopathy, which may be more frequent (especially among intubated patients).
  • The diagnosis may be supported by neuroimaging (excluding other lesions) and bedside electrophysiologic studies.
  • Intravenous immune globulin (IVIG) is generally the front-line therapy for Guillain-Barre Syndrome (with equal efficacy compared to plasmapheresis and superior tolerability).
Acute Disseminated Encephalomyelitis (ADEM)
  • This has only been reported in a single patient with COVID-19, so its incidence remains unclear (Zhang et al.).  
  • Acute Disseminated Encephalomyelitis is often seen after viral illnesses.  It causes multifocal demyelinating lesions scattered throughout the white matter within the brain, spinal cord, and optic nerves.
  • A variety of symptoms may occur, depending on the location of the lesions (e.g., confusion, coma, seizure, weakness, sensory abnormality).
  • The diagnosis is based largely on neuroimaging (with multiple lesions present, resembling those of multiple sclerosis).
  • This may be treated with steroid.  
Acute necrotizing encephalopathy
  • This is a rare disorder caused by various viral infections.  It has only been reported in a single patient with COVID-19, so its incidence in this situation remains unclear (Poyiadji et al.).
  • The pathogenesis seems to involve a systemic cytokine storm, which damages the blood-brain barrier (Wu et al. 2015).
  • Clinical features may include confusion, seizure, or focal neurologic deficits.
  • Radiographically this causes multi-focal, symmetric lesions on CT scan and MRI involving the thalami, brainstem, cerebral white matter, and cerebellum (with involvement of the bilateral thalami being the most consistent finding).  At various stages, there may be edema, petechial hemorrhages, or eventually necrosis.
  • There is no established therapy.  Steroids have been utilized with mixed results.
Cerebrovascular disease
  • A report of 221 patients with COVID-19 detected acute ischemic stroke in 11/221 patients (5%), cerebral venous sinus thrombosis in one patient (0.5%), and intracranial hemorrhage in one patient (0.5%)(Li et al 3/13).  
  • It's unclear to what extent these findings could be related to COVID-19.  For example, ischemic stroke may simply occur in patients with vascular disease who are exposed to physiological stressors.  However, hypercoagulability due to COVID-19 could theoretically increase the risk further.  Notably, in the above study 12/13 patients with cerebrovascular complications from COVID-19 had extremely high levels of D-dimer (with an average level of 6,900 ug/L).  

ECMO

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  • Patients with COVID-19 can be relatively young and suffering from single-organ failure due to a reversible etiology, so many would be excellent candidates for ECMO.
    • VV ECMO could be used for respiratory failure (although it's unclear how common true refractory hypoxemia is).
    • VA ECMO could be useful in patients with fulminant cardiomyopathy and cardiogenic shock
  • Exact indications and timing are unclear.
  • In an epidemic, ECMO capabilities would probably rapidly become saturated.  Very thorny ethical issues could arise (e.g. how long of an ECMO run is one patient allowed to have before the withdrawal of life-sustaining therapy, in order to allow the circuit to be used for another patient).
going further

prognostication of individual patients

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overview:  three general domains
  • Epidemiological risk factors
    • Age above ~55-60 years old
    • Chronic pulmonary disease
    • Chronic kidney disease
    • Diabetes
    • Hypertension
    • Coronary artery disease
    • Transplant or other form of immunosuppression
    • HIV
  • Vital signs
    • Respiratory rate >24 breaths/min
    • Heart rate > 125 b/m
    • Oxygen saturation <90% on room air
  • Labs (rough cutoffs only; greater elevations are worse prognostically)
    • D-dimer > 1000 ng/ml
    • Ferritin >300 ug/L
    • LDH >245 IU/L
    • Absolute lymphocyte count < 0.8
    • C-reactive protein >100 mg/L
more on laboratory prognostication
  • Blood cell count abnormalities
    • Lymphopenia and its trends over time (prolonged or worsening lymphopenia portends poor outcome)(Chu et al. 2004)
    • Neutrophil/lymphocyte ratio (NLR) appears to be a superior prognosticator when compared to either lymphopenia or C-reactive protein (Liu et al. pre-print).  As shown in the second figure below, neutrophil/lymphocyte ratios >3 could suggest a worse prognosis.
  • Other predictors of poor outcome include markers of inflammation (C-reactive protein and ferritin), lactate dehydrogenase, and D-dimer.  D-dimer elevation over 1 ug/L was the strongest independent predictor of mortality in Zhou et al. 3/9/20.
  • Troponin is a prognostic factor, but it may be challenging to compare values obtained across different laboratories.
  • 👁 Image of prognostic labs
additional information

general prognosis

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  • (1) It remains unclear what fraction of patients are hospitalized.
    • There may be lots of patients with mild illness who don't present to medical attention and aren't counted.
    • The vast majority of infected patients (e.g. >80%) don't get significantly ill and don't require hospitalization.
  • (2) Among hospitalized patients (Guan et al 2/28)
    • ~10-20% of patients are admitted to ICU (note – as the pandemic progresses and fewer patients present to hospital, this percentage is growing).
    • ~3-10% require intubation.
    • ~2-5% die.
  • (3) Longer term outcomes:  Prolonged ventilator dependency ?
    • Patients who survive the initial phases of the illness may still require prolonged ventilator support (possibly developing some radiographic elements of fibrosis)(Zhang 2020).
    • As the epidemic progresses, an issue which may arise is a large volume of patients unable to wean from mechanical ventilation.
  • Overall mortality
    • The largest series of mortality data comes from the Chinese CDC (table below).  The absolute numbers may vary depending on whether some cases were missed, but the relative impact of various risk factors is probably accurate.
    • 👁 Image of mortality related to age and comorbidity.
  • (Caveat:  There are numerous sets of numbers published and they vary a lot.  However, from the clinician's standpoint the precise numbers don't really matter.)

disposition

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avoidance of unnecessary emergency department or clinic visits
  • Health systems should ideally be put in place to dissuade patients from presenting to the clinic or emergency department for testing to see if they have COVID-19 (e.g. if they have mild constitutional symptoms and don't otherwise require medical attention).
  • Many centers have developed drive-thru testing, which avoids exposure of other patients in the emergency department.  Outdoor testing also ensures ongoing circulation of fresh air.
home disposition
  • The vast majority of patients with coronavirus will recover spontaneously, without requiring any medical attention (perhaps >80% of patients).
  • Patients with mild symptoms can generally be discharged home, with instructions to isolate themselves.  These decisions should be made in coordination with local health departments, who can assist in follow-up.
  • Features favoring home discharge may include:
    • Ability to understand and comply with self-isolation (e.g. separate bedroom and bathroom).
    • Ability to call for assistance if they are deteriorating.
    • Having household members who aren't at increased risk of complications from COVID-19 (e.g. elderly, pregnant women, or people with significant medical comorbidities).
    • Lack of hypoxemia, marked chest infiltrates, or other features that would generally indicate admission.
  • For more, see CDC interim guidance for disposition of patients with COVID-19 here and here.

podcast

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Update #4,  4/21:

Update #3,  4/13:

Update #2,  3/30:

Update #1,  3/22:

First COVID cast, 3/11:

questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

Going further:

The Internet Book of Critical Care is an online textbook written by Josh Farkas (@PulmCrit), an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont.


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