key: cord-0883493-qtl9sq9u
authors: Weiss, Scott L.; Peters, Mark J.; Agus, Michael S. D.; Alhazzani, Waleed; Choong, Karen; Flori, Heidi R.; Inwald, David P.; Nadel, Simon; Nunnally, Mark E.; Schlapbach, Luregn J.; Tasker, Robert C.; Tissieres, Pierre; Kissoon, Niranjan
title: Perspective of the Surviving Sepsis Campaign on the Management of Pediatric Sepsis in the Era of Coronavirus Disease 2019*
date: 2020-07-27
journal: Pediatr Crit Care Med
DOI: 10.1097/pcc.0000000000002553
sha: 48c0a400698d8469f0665bfb48c5224cf842a4f7
doc_id: 883493
cord_uid: qtl9sq9u

Severe acute respiratory syndrome coronavirus 2 is a novel cause of organ dysfunction in children, presenting as either coronavirus disease 2019 with sepsis and/or respiratory failure or a hyperinflammatory shock syndrome. Clinicians must now consider these diagnoses when evaluating children for septic shock and sepsis-associated organ dysfunction. The Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-associated Organ Dysfunction in Children provide an appropriate framework for the early recognition and initial resuscitation of children with sepsis or septic shock caused by all pathogens, including severe acute respiratory syndrome coronavirus 2. However, the potential benefits of select adjunctive therapies may differ from non-coronavirus disease 2019 sepsis.

M ore than 5 million cases of coronavirus disease 2019 have been confirmed worldwide, with over 320,000 deaths (1). Studies from China, Italy, and the United States found that 1.7-2.0% of these cases occurred in those less than 19 years old, translating to ~90,000 known COVID-19 illnesses in children (2) (3) (4) . Approximately 5-7% of these children have presented with or developed severe/critical COVID-19 with myocardial dysfunction, shock, pediatric acute respiratory distress syndrome (PARDS), altered mental status, and/or multiple organ dysfunction syndrome (2, 4, 5) . Organ dysfunctions triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) should be considered a phenotype of pediatric sepsis or septic shock. More recently, there has been a surge in children presenting with hyperinflammatory shock resembling atypical Kawasaki disease, Kawasaki-shock, and/or toxic shock syndrome, alternatively termed Pediatric Inflammatory Multisystem Syndrome Temporally associated with Severe acute respiratory syndrome coronavirus 2 infection (PIMS-TS) or Multisystem Inflammatory Syndrome in Children (MIS-C) (6) (7) (8) (9) . Although this syndrome may represent a postinfectious host response, it also shares features with pediatric sepsis.

While COVID-19 and PIMS-TS/MIS-C have justifiably dominated attention, we cannot overlook that the incidence of non-COVID-19 sepsis continues to exceed these novel cases in children. For example, using population-level data on the prevalence of sepsis among children, an estimated 27,444 children would have been hospitalized for sepsis in the United States over the last 5 months (10) . Even if social distancing reduced the incidence of sepsis by up to 50% by limiting transmission of more typical pathogens, the number of children hospitalized for sepsis in the United States would have remained at least 10-fold higher than for COVID-19. Furthermore, fear to seek medical attention, lack of accessible transportation, overwhelmed local resources, and disrupted supply chains risk delaying sepsis recognition and exacerbating inequities in health. For example, reduced access to preventive care, vaccinations, and proper nutrition are predicted to increase the number of sepsis cases in children worldwide (11) .

With the background incidence of sepsis now superimposed upon by COVID-19 and PIMS-TS/MIS-C-both of which overlap with non-COVID-19 sepsis-clinicians face new challenges to recognition and resuscitation of sepsis in children.

Here, we examine the application of the "Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-associated Organ Dysfunction in Children" (12, 13) in the era of COVID-19.

The Surviving Sepsis Campaign suggests that systematic screening should be implemented for timely recognition of septic shock and other sepsis-associated organ dysfunction (12, 13) . The underlying rationale for this guideline is grounded in the often subtle and nonspecific manner in which sepsis and septic shock may present in children. This is critical at the current time when there is a high risk of diagnostic fixation or anchoring bias that a child with cardiopulmonary dysfunction must have acute COVID-19 illness or PIMS-TS/MIS-C (14) . Applying a systematic process to clinical assessment that includes non-COVID-19 sepsis will ensure that all possible diagnoses are considered. This assessment should include elements that may help to reveal if the acute illness is attributable to acute COVID-19 illness, PIMS-TS/MIS-C, or a more typical sepsis syndrome ( Table 1 ). In addition, increased attention to infection control measures and personal protective equipment during screening and through resuscitation is needed to protect healthcare workers and limit transmission of SARS-CoV-2, along with other contagious pathogens (15, 16) .

The approach to the initial resuscitation of children with clinical features of sepsis or septic shock should be similar regardless of a COVID-19-related or alternative etiology. A consistent approach will ensure that all possible etiologies are addressed in a timely fashion. Specifically, the six key management steps are as follows: 1) obtain IV (or, if necessary, intraosseous) access; 2) collect blood culture; 3) start broad-spectrum antimicrobials; 4) measure lactate; 5) administer fluid boluses if shock is present; and 6) start inotrope/vasoactive agents if shock persists (Fig. 1A) . These six steps are relevant for both COVID-19 and non-COVID-19-related illness. Although not specifically addressed by the Surviving Sepsis Campaign, all acutely ill children should also be given oxygen for hypoxia and dextrose if hypoglycemia is present. Even in cases where SARS-CoV-2 is the most likely pathogen or has already been confirmed, patients with COVID-19 are at risk for bacteremia or other secondary bacterial or viral coinfections (e.g., pneumonia) (17, 18) . Thus, it is appropriate to collect a blood culture and start empiric broad-spectrum antimicrobials. For children with clinical evidence of shock, antimicrobial therapy for all likely pathogens should be administered within 1 hour of initial recognition of shock. For children without shock in whom organ dysfunction is suspected, an expedited diagnostic evaluation should commence to confirm or exclude the presence of sepsis and seek evidence of acute infection. If acute bacterial (or fungal) infection is deemed likely based on clinical or laboratory findings or sepsis-associated organ dysfunction is identified, appropriate antimicrobial therapy should be administered as soon as possible, but no later than three hours from initial suspicion of sepsis. If SARS-CoV-2 is the only likely pathogen or the child's symptoms are most consistent with PIMS-TS/MIS-C, then it may be appropriate to forego empiric antimicrobial therapy. However, we caution against premature exclusion of alternative or concurrent pathogens that could benefit from early antimicrobial therapy. For example, antibiotics targeting Staphylococcus and Streptococcus are indicated if symptoms overlap with toxic shock syndrome. If antimicrobial therapy is started, the Surviving Sepsis Campaign guidelines recommendations to narrow or stop such therapy according to microbial results, site of infection, host risk factors, and adequacy of clinical improvement in discussion with infectious disease and/or microbiological expert advice are appropriate in children with and without COVID-19.

Regardless of etiology, shock should be treated with judicious fluid administration guided by frequent reassessment of clinical markers of organ perfusion, blood lactate measurement, and advanced hemodynamic monitoring, when available. In healthcare systems with the ability to provide intensive care (either locally or via interhospital transport), the Surviving Sepsis Campaign suggests administering up to 40-60 mL/kg in bolus fluid (10-20 mL/ kg per bolus) over the first hour, titrated to clinical markers of organ perfusion and discontinued if signs of fluid overload develop. In healthcare systems without capacity to locally administer or transfer to access ventilator and hemodynamic support, fluid bolus therapy should be avoided unless hypotension is present. Early assessment of myocardial contractility is also necessary to assess for sepsis-induced cardiac dysfunction that may benefit from early initiation of inotropic support (see below). Either epinephrine or norepinephrine may be administered through a peripheral vein or intraosseous access if central venous access is not readily accessible. This framework of deliberate-rather than reflexive-fluid resuscitation and vasoactive support is appropriate for children with and without COVID-19 or PIMS-TS/MIS-C (Fig. 2) .

Decreased cardiac output is common in pediatric sepsis (19, 20) . In addition to absolute or relative hypovolemia from reduced intake, increased losses (fever, vomiting, diarrhea), and capillary leak, many children with sepsis experience myocardial dysfunction requiring inotropic support. This seems to be especially prevalent in COVID-19 and PIMS-TS/MIS-C, where reports indicate acute myocardial injury with higher levels of troponin and brain natriuretic peptide than are typically seen in non-COVID-19 sepsis (6, 21, 22) . Thus, early echocardiography, electrocardiogram, and cardiac-specific biomarkers is especially important when treating a child for septic shock or suspected sepsis in the era of COVID-19. In addition, because hyperlactatemia can suggest impaired cardiac output, early measurement of blood lactate, when available, is recommended for all children. In children with signs of PIMS-TS/ MIS-C, cardiology expertise will be required to assess for coronary artery aneurysms.

Clinicians should titrate respiratory support, assess for and treat PARDS (12, 13, 23) , continue to titrate fluid and vasoactive therapy, ensure adequate source control, and consider extracorporeal membrane oxygenation if shock is refractory ( Fig. 1B) for children with and without SARS-CoV-2. However, for children with COVID-19 and PIMS-TS/MIS-C, the potential benefits of select adjunctive therapies, such as corticosteroids, anticoagulation, plasma exchange, IV immunoglobulins, convalescent plasma, and other immunotherapies, may differ from non-COVID-19 sepsis (6, (24) (25) (26) (27) (28) . Given the current uncertainty of such therapies, early consultation with additional subspecialists, such as rheumatology, cardiology, and hematology, is appropriate in acute COVID-19 and PIMS-TS/MIS-C. Finally, as with non-COVID-19 sepsis, enrollment in clinical trials is also encouraged for children COVID-19-related illness.

The Surviving Sepsis Campaign provides an appropriate framework for the initial management of children with sepsis and septic shock caused by all pathogens, including SARS-CoV-2. However, clinicians should thoughtfully tailor and augment these guidelines as experience and knowledge develop about the unique ways in which SARS-CoV-2 leads to sepsis, respiratory failure, and hyperinflammatory shock in children.

Dr. Weiss's institution received funding from National Institute of General Medical Sciences K23GM110496. Drs. Agus and Flori received support for article research from the National Institutes of Health. Dr. Choong's institution received funding from Academic Health Science Centre Alternative Funding Plan Innovation Fund; and she received funding from McMaster University. Dr. Flori's institution received funding from the National Heart, Lung, and Blood Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development and she received funding from the Society of Critical Care Medicine. The remaining authors have disclosed that they do not have any potential conflicts of interest. 

CDC COVID-19 Response Team: Coronavirus disease 2019 in children -United States

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention

Coronavirus Infection in Pediatric Emergency Departments (CONFIDENCE) Research Group: Children with Covid-19 in pediatric emergency departments in Italy

Epidemiology of COVID-19 among children in China

Hyperinflammatory shock in children during COVID-19 pandemic

Guidance: Paediatric Multisystem Inflammatory Syndrome Temporally Associated With COVID-19

Centers for Disease Control and Prevention Health Alert Network: Multisystem Inflammatory Syndrome in Children (MIS-C) Associated With Coronavirus Disease 2019 (COVID-19). 2020. Available at

Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2

Trends in the epidemiology of pediatric severe sepsis*

Early estimates of the indirect effects of the COVID-19 pandemic on maternal and child mortality in low-income and middle-income countries: A modelling study

Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children

Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children

Why do doctors make mistakes? A study of the role of salient distracting clinical features

Centers for Disease Control and Prevention: Infection Control Guidance for Healthcare Professionals About Coronavirus (COVID-19). 2020. Available at

infection-prevention-andcontrol-during-health-care-when-novel-coronavirus-(ncov)-infectionis-suspected-20200125

Rates of co-infection between SARS-CoV-2 and other respiratory pathogens

Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area

Hemodynamic support in fluid-refractory pediatric septic shock

Multimodal monitoring for hemodynamic categorization and management of pediatric septic shock: A pilot observational study*

Analysis of heart injury laboratory parameters in 273 COVID-19 patients in one hospital in Wuhan

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

Pediatric Acute Lung Injury Consensus Conference Group: Pediatric acute respiratory distress syndrome: Consensus recommendations from the pediatric acute lung injury consensus conference

Towards treatment planning of COVID-19: Rationale and hypothesis for the use of multiple immunosuppressive agents: Anti-antibodies, immunoglobulins, and corticosteroids

International COVID-19 PICU Collaborative: Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted to US and Canadian pediatric intensive care units

Cytokine release syndrome in severe COVID-19

Cardiac dysfunction and thrombocytopenia-associated multiple organ failure inflammation phenotype in a severe paediatric case of COVID-19

Get rid of the bad first: Therapeutic plasma exchange with convalescent plasma for severe COVID-19

Listed are subject matter experts from the Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children Task Force have voted to affirm this work

Christopher's Hospital for Children

Akash Deep, MD (Kings College Hospital

Connecticut Children's Medical Center

MD (Nationwide Children's Hospital

and Beatrix Children's Hospital

PhD (All India Institute of Medical Sciences

MD, PhD, FCCM (Beatrix Children's Hospital

Children's Hospital of Richmond at VCU

Singapore and Royal Children's Hospital

MD (Boston Children's Hospital and Harvard Medical School

Children's Hospital of Los Angeles

MD, FAAP (Texas Children's Hospital

Children's Hospital of Philadelphia

Advocate Children's Hospital

MD (Johns Hopkins Children's Center

Children's Hospital Colorado

Jude Children's Hospital

MD, PhD, FCCM (Seattle Children's Hospital