Cytokine Storm 101

With the first reports of COVID-19 in China, information was sparse to say the least. When the outbreak spread to Italy and hospitals became overloaded, the Italians were much better at providing clinical case reports for their patients. We started to get our first glimpse of what we would face soon after: patients with severe pneumonia, sepsis, multiorgan collapse, and ARDS. One condition that was consistently described for ICU patients was a cytokine storm.

What Is a Cytokine?

Normally cytokines fill a specific role as an essential part of the inflammatory process. Cytokines are a large group of proteins, peptides, or glycoproteins secreted by specific cells of the immune system. They are produced by immune cells that include the innate macrophages, dendritic cells, natural killer cells, and the adaptive T and B lymphocytes, and thus they play a critical role in immune response. 

Cytokines are a category of signaling molecules that mediate and regulate immunity, inflammation, and hematopoiesis (production of the cellular components of blood and blood plasma). Think of cytokines as the on/off switch for immunity and inflammation.

While more is better for many things, having a large amount of cytokines released in the body at once can be harmful. When this happens it causes a severe immune reaction (hyperinflammation). Lung injury is one possible consequence of the cytokine storm that can progress into acute lung injury or ARDS.

The typical progression is that an increase in cytokines results in an influx of various immune cells, such as macrophages, neutrophils, and T cells, from the circulation into the site of infection. This can be very destructive. One way it manifests is in the cell interactions, causing damage to the vascular barrier, capillary damage, and diffuse alveolar damage. When we see destabilization of the endothelial cells, we then have leakage of fluid into the alveoli. When we examine patients, they will have this horrible mix of rhonchi and rales on auscultation. If a cytokine storm is left unchecked, we will see multiorgan failure and ultimately death.

Some patients who are admitted to the hospital and eventually end up in ICU will progress to having a cytokine storm. Analysis may reveal elevated cytokine levels in the plasma of COVID-19 patients. Another method to identify cytokine storm is to look for a protein called serum ferritin. It tends to get very high in this disorder. It is a cheap, easy test to run, and if the result comes back high, that is usually indicative of cytokine storm.

In EMS the patient with cytokine storm will present as someone who is in an area of the country where the emergency department and hospital resources are overloaded, and they have been discharged home with instructions to come back when they are feeling worse. Alternatively, it may be a patient who felt they could manage their COVID symptoms at home, but now their clinical course has progressed to where they are in failure. These patients may be grossly septic, in shock, or in complete respiratory failure.

Taming the Storm

Treatment of cytokine storm has always been a challenge. Patients with ARDS as a result of cytokine storms have had a poor prognosis overall. Physicians have been heard to say it was luck or the patient’s will to survive more than anything that resulted in them being discharged from the hospital. For the admitted patient who develops a cytokine storm, management is geared toward maintaining airway, breathing, and circulation.

In the hospital pre-COVID, the ability to manage patients with cytokine storm was limited. Steroids were the primary mechanism, plus supportive therapy. The intensivists who managed these patients struggled to identify what worked best.

With the advent of COVID and the numbers of patients eventually admitted to the ICU for prolonged courses of care, finding a solution to the cytokine storm was key to survival. Old standbys such as steroids were key, but timing was everything. Given too soon, steroids actually increased mortality. 

Some medications are being repurposed to see if they can affect the development and progression of cytokine storm. One example is the cancer medication acalabrutinib, although it is still under study. Some trial studies—for example, for tocilizumab, which is an interleukin-6 receptor inhibitor—have not panned out as expected (though it is still being examined in conjunction with remdesivir). Others, such as hyperimmune globulin, specifically monoclonal antibodies, are being studied and may hold promise.

Recent work with convalescent plasma has shown great potential, and there is a huge push for anyone who has recovered from COVID-19 to donate plasma. If you or anyone you know has recovered from COVID, find more information at www.coronavirus.gov/ and www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/donate-covid-19-plasma/.

An EMS Presentation

If we have a COVID patient who appears to be in acute respiratory failure with rales, rhonchi, and extremely poor pulse oximetry readings, assume this patient may be having a cytokine storm. If we have a patient with or suspected of having COVID who appears to be in sepsis and presents with hypoxia, hypotension, and fever, assume this patient is having a cytokine storm.

What should we do to manage it? Steroids are off the table, since the timing may actually increase mortality. We need to concentrate on three things, summarized by the acronym VIP:

• V—Ventilations/oxygenation
• I—Infusion
• P—Pressors

Ventilations must be approached carefully. The alveoli cannot tolerate the higher pressures, and the leakage of fluid we see during the clinical course of this disease is hastened. Noninvasive positive-pressure ventilation (NIPPV or CPAP) may make our patients worse. Consider NIPPV a short trial of CPAP with an eye on terminating it quickly if the patient doesn’t show signs of immediate improvement or starts to decompensate.

Oxygenation is key. High-flow oxygen and proning of the nonintubated patient will help improve gas exchange. Transporting the patient on their abdomen would be even better. Proning the patient takes advantage of the larger surface area of the posterior lungs but is generally not practical prehospital. Will the patient tolerate lying on their left or right side to improve respiratory recruitment? This will still help improve V/Q matching and reduce atelectasis, resulting in improved pulmonary gas exchange. You will see a noticeable improvement immediately.

Before proceeding to vasopressors, volume infusion using a conservative approach to fluid is vital. Use crystalloids but don’t bolus a patient with too much too fast. That will intensify the leakage in the alveoli. 

If you must transition to vasopressors, norepinephrine is the vasopressor of choice. If it’s unavailable, epinephrine and vasopressin are acceptable alternatives. The Society of Critical Care Medicine strongly recommends against the use of dopamine. Push-dose pressors or infusion via an IV pump is best.

Our metrics for success should focus on:

• Change/improvement in mental status; 
• Resolution of shortness of breath at rest; 
• Improvement in hypotension from baseline. 

Our down-and-dirty way to determine the effectiveness of fluid resuscitation is to utilize dynamic parameters such as radial pulse (absent or present, weak or strong), skin temperature, and capillary refill time to determine the patient’s response.

Summary

Cytokine storms are a challenge in the resuscitation of any critical patient with COVID. In systems overloaded with COVID patients, we may see patients who present with cytokine storm in the field. Consider cytokine storm in any patient with a current diagnosis of active COVID or who has signs and symptoms of COVID and is either in respiratory failure or appears to be in sepsis or septic shock. Prehospital treatment concentrates on the ABCs, using the acronym VIP to treat patients. Avoid or use caution with CPAP, terminating it if it doesn’t demonstrate any benefit; prone patients to improve oxygenation; carefully bolus patients with fluid; and proceed with pressors but never use dopamine to maintain circulation. 

Resources

Alhazzani WA, Moller MH, Rhodes A. Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults With Coronavirus Disease 2019 (COVID-19). Intensive Care Medicine, 2020; 46: 854–87. 

Aoyagi T, Sato Y, Toyama M, et al. Etoposide and Corticosteroid Combination Therapy Improves Acute Respiratory Distress Syndrome in Mice. Shock, 2019; 52(1): 83–91.

Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol, 2017; 39(5): 529–39.

Dinarello CA. Historical Review of Cytokines. Eur J Immunol, 2007 Nov; 37(Suppl 1): S34–S45. 

Gerard DR. COVID-19: The Clinical Presentation for EMS. EMS World, www.emsworld.com/article/1224466/covid-19-symptoms-presentation-EMS. 

National Institutes of Health. Care of Critically Ill Patients with COVID-19, www.covid19treatmentguidelines.nih.gov/critical-care/. 

Owen JA, Punt J, Stranford SA. Kuby Immunology. New York: W.H. Freeman & Company, 2013. 

Oxford University. Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19, www.recoverytrial.net/files/recovery_dexamethasone_statement_160620_v2final.pdf. 

Rojas M, Rodríguez Y, Monsalve DM, et al. Convalescent plasma in Covid-19: Possible mechanisms of action. Autoimmunity Reviews, 2020 Jul; 19(7): 102554. 

Society of Critical Care Medicine, European Society of Intensive Care Medicine. COVID-19 Resources, https://journals.lww.com/ccmjournal/Documents/Combined%20COVID-19%20Infographics.pdf. 

Daniel R. Gerard, MS, RN, NRP, is EMS coordinator for Alameda, Calif. He is a recognized expert in EMS system delivery and design, EMS/health-service integration, and service delivery models for out-of-hospital care.