Emergency Medicine COVID Updates

The following is a summary of what I have learned from seeing COVID patients on the floor, in the ICU, and reading of the literature that may help with our acute ED management. TLDR summary is at the end if you can’t read through each bullet point.

Updates 3/29 – Added section on HFNC (#2 under intubation), added section on post intubation (#7 under intubation), expanded section #2 under antibiotics, added section #2 and #3 under labs

Updates 3/30 – Changed subject headings. Added initial presentation section. Added #6 under other treatments. Added section on Operational Changes.

Update 3/31 – Included new NEJM papers. Updated imaging section with citations. Updated average vent days to 10+ to reflect most recent literature.

Update 4/2 – Added OR for comorbidities based on new Chinese paper under intubation #6.

Update 4/5 – Modified section #1 under antibiotics regarding Azithromycin after our institution changed their recommendations.

Update 4/17/20 – Changed recommendation on Hydroxychloroquine to DO NOT GIVE in the ED. Updated sections on remdesivir, thiamine, azithro, and AC.

 

Initial Presentation

 

Symptoms of Covid-19 may vary, and may include any of the following; fever, chills, headache, myalgia, rhinorrhea, throat pain, dyspnea, chest pain, cough, sputum, and less frequently loss of smell/taste, nausea, vomiting, and diarrhea.  The clinical course trends toward two different stages. The first stage typically includes the symptoms as described above and is primarily experienced during the first week after onset of symptoms. For some, the second stage starts between days 5 and 7, where sudden rapid clinical deterioration may occur. We have not yet found any predictive symptoms of subsequent deterioration.

 

Workup

 

The workup of patients suspected to have COVID-19 is variable and depends on their clinical presentation at the time of evaluation. For those that have normal vital signs, and appear clinically well, with an uncomplicated medical history, it would be reasonable to treat and release with quarantine instructions, instructions on supportive care, and strict/detailed return precautions.  We will primarily address the evaluation and treatment of those patients who will likely require hospitalization or intensive care.

 

Lab Evaluation

1. CBC with differential
   • WBC usually normal, lymphopenia is common, mild thrombocytopenia common.
   • Neutrophil to Lymphocyte ratio >3.13 [24] as well as absolute Lymphocyte count <0.8 [23] seem to be a poor prognostic factors.
2. CMP with Magnesium and Phosphorus
3. Coagulation Studies with D-dimer
   • PT/PTT/INR usually normal on intial presentation. Some develop DIC.
   • D-dimer >1000 ng/ml is a poor prognostic factor [23].
4. Covid PCR (RVP if suspect alternate viral etiology though coinfection IS possible)
   • Have found false negative Covid testing in up to 10% of cases.
5. Procalcitonin
   • Usually not increased with Covid-19.
   • If elevated, may indicate alternate diagnosis or superimposed bacterial infection.
   • Procalcitonin is not routinely elevated >0.5 ng/ml in these patients [20]. It does seem to go up as disease progresses. Washington state case series shows the average in their population was 1.8 ng/ml [28] and their series had 1 (4.8%) patient that was identified to have a bacterial co-infection. Given the available data we feel that an elevated Procalcitonin (>0.5) in the ED should lead you to strongly consider an alternative or additional diagnosis.
6. CRP (sometimes ESR as well but difficult for some as often performed manually)
   • Elevated with Covid-19 and seems to trend upward with progression of disease.
   • CRP >100 is another poor prognostic factor [23].
7. LDH, Ferritin, Urine legionella, Blood cultures, Lactate, Troponin, CK, CKMB, ABG, G6PD (chloroquine causes hemolytic anemia in G6PD) are helpful for inpatient team as well.
   • Other poor prognostic indicators include LDH >245 and Ferritin >300 ug/L [23].

 

Imaging

Chest X-ray is typically the most accessible means of imaging. Findings Include:
1. Patchy ground glass opacities – The literature suggest this is present bilaterally and predominantly peripherally around 70% of the time. [25, 26] This would fit what we are seeing as well.
2. Clear lungs – Early in disease we are seeing many mildly symptomatic patients with clear CXRs that quickly progress over days to the above.
3. Pleural effusions (UNCOMMON) – Wuhan reported pleural effusions present in 13% of cases. [26] Washing state reported no pleural effusions in their case series of 24 critically ill patients [25] and 28% of patients had pleural effusions in another study from Washington state [28]. This would indeed fit with what we are seeing that pleural effusions are only present around 15% of the time.

We initially had been progressing toward CT scans as the sensitivity is higher for picking up subtle opacities, but have moved away from this unless concern for alternate diagnosis, given no real change in management.

Ultrasound may be used as an alternate modality as well, and there is emerging evidence of findings with Covid 19, though not yet well documented. [27]

EKG

EKG primarily to assess QTC.

 

Treatment

 

FLUIDS

Patients with Covid-19 appear to be very sensitive to fluid overload. We have found success at preventing the need for intubation by keeping patients net negative despite tachycardia and AKI. Hypotension is not the most common presentation we have seen, but is certainly a feature for some.  We have been leaning toward starting patients on low-dose pressors to support MAP, rather than multiple fluid boluses, if they are on the verge of intubation due to hypoxia.

1. For the ED patient with suspected Covid-19, we have been utilizing the following approach for fluid resuscitation:
   • If they are normotensive DO NOT give a fluid bolus.
   • Patients that are hypotensive or appear hypovolemic on clinical exam, carefully consider very small fluid bolus vs pressor (especially if clinically volume overloaded).
   • In COVID patients that are requiring oxygen who are normotensive and mildly tachycardic or not tachy I would consider giving a dose of Lasix. Anecdotally this seems to delay intubation hours to days. AKI from COVID seems out of proportion with that seen in normal viral PNA suggesting another contributing factor, possibly microangiopathic component. If this is the case, AKI shouldn’t trigger us to give fluids or avoid lasix.
2. Do not fluid resuscitate to clear lactate. The elevated lactate in a non-hypotensive patient is not from hypovolemia, this is likely from catecholamine surge, severe hypoxia, and/or respiratory distress. DO NOT BOLUS for lactate please.
3. The WHO recommendations [3] suggests a fluid bolus only in patients with septic shock, however this recommendation likely carries the same caveat used in the 2016 Surviving Sepsis campaign. The idea was that some patients would need to be intubated for the sole purpose of giving more fluids. In the setting of a pandemic with a huge uptick in ventilator need this is particularly troublesome. In this disease state the pathophysiology of shock being due to hypovolemia does not seem to be playing out. Shock at presentation is rare [6]. If patient is in shock state consider late stage covid complications such as, myocarditis or cytokine storm, both of which will not respond to fluids. Obviously consider other causes of shock as well.
4. Not that any of us normally do….but DO NOT start maintenance fluids.

 

ANTIBIOTICS

1. Generally in an undifferentiated hypoxic febrile patient, our ER training would tell us to initiate CAP coverage upfront. In the era of COVID I don’t think that we should discontinue this practice. Our job in the ED is to cast a wide life saving net while minimizing harm from our interventions. Our hospital system has now (4/3) recommended AGAINST the use of Azithromycin in COVID-19. The reasoning in the email sent out to us was “…discouraging the use of azithromycin at all, since strong evidence for efficacy is lacking and it can contribute to QT prolongation.” I would like to address this treatment update in two parts:
   • First the risk of QT prolongation from Azithromycin is present, however minimal, and likely does not contribute to increased risk of cardiac events. A paper from Korea [31] evaluated 402,607 patients EKGs where they compared before and after EKGs of patients taking Azithromycin vs those prescribed Amoxicillin. They found that risk of mild QT prolongation (>450 males, >460 females) was increased by OR 1.4 and severe (>500) carried OR of 1.43 for Azithromycin. This risk was not seen in the subgroup <29 years old. The highest risk group was patients in the 60-80 year range. Even though this paper showed a mild increased risk of QT prolongation, not all QT prolongation is created equal. Rather than prolonging repolarization, which can lead to Torsades, azithromycin prolongs the action potential itself. A meta-analysis from 2014 [30] found that across 15,588 patients when compared with placebo, Azithromycin had no increased risk of death and no increased risk of cardiovascular events. Indeed several papers have now published data that argues against the original NEJM paper from 2012 that started the controversy of Azithro and increased risk of cardiac death.
   • Second in the era of COVID severe CAP is still a concern. Legionella is not an insignificant cause of severe CAP, possibly up to 15% of cases. Even extremely broad spectrum beta-lactams will not cover for legionella. Azithromycin should still be the first line treatment for severe CAP while legionella antigen is pending. Additionally, Azithromycin has shown a mortality benefit in pneumococcal pneumonia likely from an anti-inflammatory effect. Even if the legionella antigen is negative Azithromycin should likely be continued if pneumococcal pneumonia is suspected. If there is significant concern over the QT prolonging properties of Azithromycin at your institution then Doxycycline should replace Azithromycin in your initial CAP coverage.
   • Therefore from and ED perspective, for severely ill patients I would still utilize early Ceftriaxone and Azithromycin for patients that you are going to admit. Remember PO Azithromycin is just as good as IV. This also allows you to limit volume of IVF by using PO instead. Don’t forget to send blood cultures as well as procalcitonin and urine legionella antigen. As these results come back the inpatient team can quickly de-escalate your antibiotics. Early antibiotic administration is still one of the few interventions that has shown to save lives in sepsis. I would discourage assuming every severe respiratory sepsis case you see from now on has COVID and nothing else that we used to worry about.
   • I would STILL consider sending not critically ill patients home on Azithro because of the French study that showed Hydroxychloroquine plus Azithromycin resulted in lower viral loads [17]. Of note a bayesian reanalysis [31] of that paper addresses some of the controversies surrounding the original data showed likely no-benefit, until better data is available I fear we are left to draw our own conclusions. There is some data that hospitalized patients [32] show no benefit from this drug combination when it comes to viral clearance. Indeed the email from our institution would suggest the same, however I have not seen their data. I think that the best evidence we currently have on non-severe patients still suggests that Azithromycin may be helpful.
2. AVOID vancomycin – We historically tend to give this to our undifferentiated infectious patients but Covid-19 patients are developing renal failure upstairs. CAP caused by MRSA is practically unheard. Consider calculating the patient’s SHORR score to see how worried you should be about MRSA PNA. If MRSA PNA is still high on your list than you should consider using Linezolid instead.
3. As listed above, send a Procalcitonin if you are admitting the patient. This will help to decide if CAP coverage needs to be continued by the floor teams.

 

OTHER TREATMENTS

1. Vitamin C – Two reasons that I feel strongly about using Vitamin C in COVID patients is the CITRIS-ALI trial [8] as well as the data that high serum levels of vitamin C seem to protect the lung epithelium in mice models [5]. Given the strong safety profile of IV vitamin C, other than resource utilization I do not see a downside to giving it. Dose is IV Vitamin C 1500mg Q6 x 6 days. Despite the trial safety data, as mentioned by Paul Marik [10] vitamin C does pose the theoretical threat of working as a prooxidant when there are high levels of serum iron. He suggests monitoring ferritin and CRP and then possibly reducing the dose of vitamin C if this is a concern. From an ED perspective a single dose of 1500 mg is a good idea especially when reviewing the animal data [5], which suggests that you need to reach a steady serum state before you see an effect. Of note effective concentrations were not reached through PO dosing in those studies.
2. NSAIDs – While I agree there isn’t really evidence of harm, in patients that do not absolutely need NSAIDs please try and avoid them. We know that they are nephrotoxic and downstream renal failure in these patients is a real thing. There is also an increase of ACE2 receptor expression theoretically leading to higher availability of viral binding sites.
3. Hydroxychloroquine – The evidence of benefit seems to be lacking now especially with the first RCT out of China [34]. Prior data was based off of a case series in France showing possible earlier viral clearance [17] and in vitro data suggesting the drug inhibits viral entry into cells. The Chinese RCT showed no benefit to viral clearance and among the multiple lab trends only a possibly lower CRP in the treatment group but no clinically significant differences. Secondary outcomes showed possible reduction in duration of cough and fever. Adverse events were found in 30% of the treatment group and 9% of the control group with the most common adverse event being diarrhea. It still stands that Anti-viral therapy may be effective primarily early in the disease course since treatment was initiated on average after 2 weeks of illness in this RCT. At this point it seems that the best available evidence suggests Hydroxychloroquine is not helpful and therefore we feel that it should not be started in the ED. If you are still going to give start Hydroxychloroquine make sure that you consider baseline QTc as well as G6PD for patient’s getting chloroquine -that is why it should be sent with labs at admission.
4. Remdesivir – This is being given on a clinical trial basis. Data from the NEJM article published on April 10th [35] gives no evidence of benefit given lack of control group and no strong inclusion or exclusion criteria.
5. Thiamine – Of unclear benefit currently being used in some of our ICUs. Thiamine 200 mg IV Q12 x 6 days.
6. Azithromycin –  We should be starting this (or doxy) on everyone who meets SIRs criteria with a presumed respiratory infection. As we discussed above just because the rate of bacterial co-infection in COVID is very low doesn’t mean that we should ignore our job as ED providers to have a broad differential.
7. Steroids – The evidence is definitely mixed here. I am saying that we SHOULD NOT be giving steroids in the ED for the majority of cases. Unless there is clear adrenal suppression or the patient is in late stage of disease (severely elevated D-dimer, CRP, ferritin, or ARDS requiring intubation). Even then I would still probably defer to the ICU team.  One reason I am against giving steroids in early disease is that early steroids increased viral load in SARS patients [7]. Theoretically during the early stage of illness steroids would only serve to suppress adaptive immunity and not help modulate inflammatory response. The case study out of Wuhan [6] suggested that steroids might help those with ARDS. They used methylprednisolone 40-80 mg IV daily. As Josh Farkas noted [1] dexamethasone could be preferable (7-15 mg daily) since it causes less fluid retention due to lower mineralocorticoid effect and fluid is a huge issue in these patients as we already discussed.
8. Anticoagulation – There is still no strong evidence on the importance of anticoagulation in these patients. Indeed we are seeing more and more cases of arterial and venous thrombi in both the ED and ICU. It is unclear when the best time to initiate anticoagulation is. It is also unclear if we should be sending patients home on anticoagulation that have elevated D-dimers and no evidence of thrombi on imaging. At this time I would strongly consider anticoagulation for patients with a D-dimer >1,500 ng/mL. Calculate the patient’s HAS-BLED score prior to initiating AC. If admitting you should speak with the hospitalist prior to starting in the ED to make sure that it will be continued on the floor. If you are planning on discharging the patient it may be reasonable to speak with the patient’s PCP about starting them on a DOAC and having them follow up for repeat labs.

 

INTUBATION AND OXYGEN THERAPY

1. Vents are a resource and many patients need 10+ days of of ventilation [6, 19, 25]. Saving a vent for several days is meaningful. Try to utilize every resource available to prevent intubation of these patients.  At our hospital, there is no need to call the MICU for severe hypoxia at this point. Unfortunately, every patient on the floor is developing severe hypoxia. Currently we are recommending a NRB at 15L with a NC at 10L underneath with persistent 02 saturation <90% before we even consider intubating for hypoxia. Patients that have low SpO2s and appear well, please send an ABG and look for other signs of low O2 delivery to organs such as tachycardia and altered mental status before intubating.
2. High Flow Nasal Cannula (HFNC) – We are currently not allowed to use HFNC at our facilities due to concern that this will cause aerosolization of viral particles. Surviving Sepsis Campaign and ANZICS guidelines both currently recommend the use of HFNC prior to intubation [11, 4]. Michelle Gong (Chief of CC at Montefiore) also recommends HFNC for COVID patients [18]. WHO guidelines [3] currently recommend HFNC in select patients as there is unknown amount of aerosolization. Some literature [12, 13, 14] suggests that HFNC does not increase the risk of infection to healthcare workers in other disease processes. Given the increasing degree of hypoxia in these patients, we believe  that we should begin allowing HFNC. More adjuncts will save us more ventilators and more ICU beds. HFNC may increase aerosolization but likely not by much, definitely less than intubation, and likely does not increase the risk of infecting health care workers if airborne precautions are maintained. At a minimum we should be using HFNC on floors where there are only COVID patients. The practicality of utilizing this in the ED with undifferentiated patients is unclear at this time.
3. If the patient is able, have them prone themselves while on supplemental O2. We have seen significant symptomatic improvement as well as improvement in 02 saturation on patients we prone even if they are not on ventilators.
4. In the ED, if a patient requires a significant amount of supplemental O2, please send an ABG. We are considering intubating these patients if they have paO2 <60 despite the NRB and NC.
5. We are not intubating anyone just for work of breathing. These patients generally look terrible on the floor. Please get an ABG and if they are developing respiratory acidosis then they should be intubated. If on arrival they are obtunded, they should be intubated. If the ABG shows low CO2 or normal CO2, please try and hold off on intubating. See how they do with all the CO2 flushed out of their system by the NRB and NC first.
6. Very few people are getting extubated upstairs so please try and have a goals of care conversation with families when appropriate. This should be the priority in patients with a very poor expected clinical course (Age >80, COPD, DM, CAD) [9, 20, 21, 23, 29]. A meta analysis of chinese data generated the following odds ratios for severe vs non-severe COVID: DM OR = 3.04, HTN OR = 2.31, CAD OR = 2.76, COPD OR = 3.56, OF NOTE smoking showed no increase in risk of severe PNA OR = 1.4, elevated BMI increased risk of severe disease as well. Some things you can let them know are: if this is COVID then we are likely talking about 10+ days on the vent [6, 19, 25], likely mortality of between 50-80% for patients needing intubation [9, 20, 21, 25, 28] especially those with pre-existing lung or cardiac comorbidities.
7. If you have to intubate in the ED consider using Rocuronium over succinylcholine. I am sure most of you have read extensively about intubating these patients (if not see the following [15]) but this is not the time to be re-dosing paralytics. Make sure to target deep sedation post-intubation and assume paralysis for at least 60 minutes after using Roc. After paralytics have worn off you need to pay close attention to vent synchrony. Target RASS -5 with your sedation package and if the patient is still asynchronous with the vent you should discuss starting Nimbex drip. Start patients on higher PEEPs early. For a good summary of how to adjust the Vent settings see “Changing Ventilation Parameters” section on the Brigham and Women’s Hospital Critical care guidelines [16].

 

Operational Changes

Covid-19 hit us hard and fast. We have found that the key to successfully addressing the challenges that came along with the onslaught of Covid-19 patients is the ability to adapt to rapidly changing environment and reevaluating available resources and layout on a daily basis. Mobilizing resources early and quickly ensured that we had the best chance at safely and quickly evaluating and treating patients. Some examples of changes within our hospital and hospital system included immediate cancellation of all elective surgeries in efforts to open up beds within the hospital with redeployment of all newly available health care providers to assist with Covid care, mobilized as many ventilators as possible, accumulated PPE as this is already in short supply and needs to be utilized for every potential Covid-19 patient, reformatted spaces (including our lobby) near the ED within the hospital to be utilized for screening lower acuity, treat and release type patients in order to keep them separated from the general populace, and designated specific spaces in the ED for non-covid patients, as these are now in the minority.  

The findings we describe above are dynamic and are subject to rapid changes based on new evidence as it emerges over time.

 

Summary of our Recommendations

Suspect COVID?

• Don’t give fluids unless you KNOW they are hypovolemic (diarrhea, vomiting, no drinking x 1 week).
• Don’t intubate a patient with hypoxia that looks ok. Keep sat >90 by escalating from NC 2L > NC at 10L plus NRB at 15L over it. Have them prone themselves. Send an ABG
• Don’t intubate tachypneic patients that look bad unless they have AMS. If they do have a mental status, then send an ABG and only intubate if developing resp acidosis.
• Send the following labs CBC w/ diff, CMP with Mg and Phos, Coags, D-Dimer, Procalcitonin, ESR, CRP, LDH, Ferritin, Urine legionella, Blood cultures, Lactate, Troponin, RVP, CK, CKMB, ABG, G6PD
• Get an EKG for baseline QTC, replete Mg until >3, replete K until >4, be cautious in renal failure.
• Start patient on Vitamin C 1500mg, Ceftriaxone 1 G IV, Azithromycin 500 mg PO, DON’T use Vancomycin.

 

[1] IBCC COVID-19 updates

[2] EM:RAP Corependium Covid chapter

[3] WHO recommendations on novel coronavirus

[4] ANZICS COVID-19 Guidelines

[5] VCU Vitamin C research summary on YouTube

[6] Lancet 52 COVID-19 Critically Ill Wuhan Patients (2/21)

[7] Virology early steroids and SARS

[8] JAMA Citris-ALI

[9] JAMA Risk factors for ARDS and Death in COVID-19 from Wuhan (3/13)

[10] Marik approach to COVID

[11] Surviving Sepsis COVID-19

[12] Aerosol generating procedures review

[13] HFNC vs Oxygen face mask for spreading bacteria in PNA

[14] H1N1 HFNC

[15] Weingart COVID Airway

[16] Brigham and Women’s Hospital Critical care guidelines

[17] French Azithro and Hydroxychloroquine (Gautret)

[18] Michelle Gong video interview on JAMA

[19] Convalescent Plasma in COVID-19

[20] NEJM Clinical Characteristics in Chinese cases 2/28

[21] Chinese CDC Data

[22] Dysregulation of Immune Response in Wuhan

[23] Lancet Risk Factors for Mortality in Wuhan

[24] Pre-Print NLR in Early Disease

[25] 24 Critical Seattle Patients 3/30

[26] Radiological findings from 81 Wuhan patients 2/24

[27] Ultrasound findings in COVID

[28] 21 Critically ill patients in Washington State 3/19

[29] Pre-Print Meta Analysis of 20 Chinese Studies 4/1

[30] Azithromycin Meta Analysis on CV events

[31] Azithromycin and QT data from Korea

[32] French Azithro and Hydroxychloroquine in Severe Covid-19

[33] Bayesian reanalysis of original French HCQ AZ study

[34] Tang Hydroxychloroquine RCT 4/14

[35] NEJM Compassionate Remdesivir

 

 

	Steven Johnson, DO Dr. Johnson is a PGY3 and Chief Resident in Emergency Medicine at NS/LIJ.
	Dana Gottlieb, MD Dr. Gottlieb is an Assistant Professor and Attending in Emergency Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.