The Global Burden of Sepsis: Barriers and Potential Solutions

Kristina E. Rudd; Niranjan Kissoon; Direk Limmathurotsakul; Sotharith Bory; Birungi Mutahunga; Christopher W. Seymour; Derek C. Angus; T. Eoin West


Crit Care. 2018;22(232) 

In This Article

Sepsis Care in High-resource Settings may not be Effective in Low-resource Settings

In the absence of robust data to guide optimal sepsis care in low-resource settings, caution must be taken in extrapolating from data generated in high-resource settings. Several characteristics of sepsis in low-resource settings, such as differences in populations at risk, infecting pathogens, and clinical circumstances, suggest that sepsis care in high-resource settings may not be effective in low-resource settings (Table 1).

Differences in Hosts

Key patient characteristics—comorbidities such as human immunodeficiency virus (HIV) or malnutrition, variability in environmental factors, or genetic features of host response—modify how sepsis presents in some LMIC settings. The high prevalence of HIV among patients with sepsis in some parts of the world dramatically changes the microbiologic profile and thus the antimicrobial strategy. Malnutrition significantly alters the presentation and management of sepsis, particularly among pediatric patients.[60] Fluid resuscitation and antimicrobial strategies must take this important comorbidity into account.

Differences in Pathogens

While bacterial infections account for a large majority of sepsis in HICs,[61] sepsis in LMICs is characterized by different types of bacteria, including mycobacteria, and much higher proportions of nonbacterial organisms such as parasites and viruses.[62] Escherichia coli, Enterococcus faecalis, and Staphylococcus aureus are commonly isolated causes of sepsis in the United States,[61,63] and E. coli and S. aureus have also been found to be common causes of bacteremia in Thailand.[64] However, invasive nontyphoidal salmonella is an important cause of bacteremia in Africa; a meta-analysis of community-acquired bloodstream infections in Africa found that Salmonella enterica was the most prevalent isolate overall and in adults, and Streptococcus pneumonia was the most common isolate in children.[65,66] Melioidosis (infection with Burkholderia pseudomallei) is the second most common cause of bacteremia in northeast Thailand.[67] There is a very high prevalence of tuberculous mycobacteremia among septic patients in Uganda and Malawi.[68,69]

Many patients in LMICs develop sepsis due to nonbacterial infections. For example, rickettsiosis is commonly found in sepsis patients throughout Southeast Asia.[70] Some studies have reported decreased sepsis mortality by empirically treating malaria.[71] Malaria and other acute parasitic infections, while often presenting in comparable fashion to bacterial sepsis, merit specific treatment.[72] Dengue virus is another common cause of sepsis in LMICs. This infection, characterized by severe thrombocytopenia and sometimes associated with profound extravasation of intravascular fluid, may require unique resuscitation strategies.

Differences in Clinical Environments

The very different clinical environments in low-resource settings may also contribute to the nonapplicability of standard management strategies in high-resource settings. RCTs conducted in critically ill patients in low-resource settings reinforce this concern. A single-center RCT of adult patients with severe sepsis in Zambia was stopped early due to higher mortality among patients with hypoxemic respiratory failure in the IV fluid intervention arm.[38] An RCT of early versus late enteral feeding among cerebral malaria patients in Bangladesh found increased incidence of aspiration pneumonia in the group receiving early feeding.[73] Limited nursing personnel, ICU capacity, and availability of mechanical ventilation may have contributed to these adverse outcomes in the intervention groups.

The Fluid Expansion as Supportive Therapy trial demonstrated the dangers of aggressive IV fluid resuscitation in a population of East African febrile children who had some features of impaired circulation.[74] Additionally, a protocol for early resuscitation with IV fluids and vasopressors among adults (most of whom were HIV-positive) with sepsis and hypotension in Zambia resulted in higher in-hospital mortality compared with usual care.[75] With this evidence of harm in both adult and pediatric patients with sepsis and septic shock in Africa, and the absence of high-quality clinical trials in similar settings demonstrating any benefit of aggressive fluid resuscitation in sepsis, there is essentially no context-specific evidence supporting recommendations for fluid resuscitation in sepsis. Despite this lack of evidence, aggressive fluid resuscitation is advocated in some international and local LMIC sepsis management guidelines.[37,76] These examples underscore the need for caution in the implementation of best practices from high-resource settings to other settings and populations in which they have not been validated.