Supplementary Electronic Material 3 Implications in Low- and Middle-Income Countries

Supplementary Electronic Material 3 – Implications in low- and middle-income countries

Critical care in resource-restricted areas is complex with many issues that impede optimal care, but there is also room for improvement within the current constraints (1). Leading causes of death differ largely between high-income countries (HICs) and low- and middle-income countries (LMIC). The so-called “Group I” conditions (which include communicable diseases such as lower respiratory infections (LRIs), the leading cause of sepsis) contribute to more than half of all deaths in LMIC, compared with only 7% in HICs (2). There is limited quantitative (e.g. the number of ICU beds) and qualitative (e.g. ICU case fatality rates) data available in LMIC (3). At a global level, the burden of disease of LRIs has decreased dramatically in the last ten years (4). However, mortality rates of infectious disease are higher in developing countries compared with HICs (5).

When assessing sepsis in LMICs, one must consider the different resistance patterns (6, 7) and regional variation in infection epidemiology (8). Geography and socio-economic statusmay impact on the aetiology of sepsis in LMICs. Most of the LMICs are located in tropical regions where non-bacterial pathogens, such as dengue or viral haemorrhagic fevers, malaria and measles can cause sepsis and septic shock (9). Bacterial pathogens such assalmonella, Brucella spp. and Mycobacteriumtuberculosisare more prevalent in community-acquired infections in LMICs (9-11). Additionally, Burkholderia pseudomallei is an important pathogen in northeast Thailand, being associated with about 20% of the cases of bacterial sepsis (8), but is only rarely seen in HICs.

ICUs are limited in their basic equipment and maintenance and frequently suffer from erratic supplies. Basic commodities such as oxygen or electricity are not always available (1). In some LMIC, provision of running water is not always guaranteed. The diagnosis and management of sepsis may be delayed due to a lack of appropriate ambulance and out-of-hospital care, which has been well described by Papali et al.in a “three delays” model (12).

Adequate training, in a sustainable train-the-trainer method, could contribute to better outcomes of sepsis management. Partnerships between hospitals in HICs and LMICs can help to train not only ICU physicians and nurses in clinical skills, but also to focus on management and organizational aspects (1). In a retrospective analysis of the Latin American Sepsis Institute database, including 21,103 patients and measuring 6-hour sepsis bundle compliance, quality improvement initiatives in sepsis was associated with a reduction in mortality and with improved compliance with quality indicators (13).

Development of resource-limited setting-specific recommendations for treatment of sepsis is crucial (14) and Global Sepsis registries are needed to capture sepsis causes and their associated mortality in LMIC. Several such recommendations have recently been published (14-21). The Surviving Sepsis Campaign guidelines describe the standard of care in developed countries, but do not address the limitations of these guidelines in LMICs (22-24). In a recent, randomized study from Zambia in 212 hypotensive septic patients, the in-hospital mortality rate in the experimental group (early resuscitation with intravenous fluids, careful monitoring and vasopressors) was 48.1% while the control group (usual emergency care) had a mortality of only 33.0% (p=0.03). Therefore, standard dictums in septic shock management in HICs might not translate directly into LMICs (25, 26).

In tropical settings, artemisinin drug resistance in falciparum malaria is an emerging problem and is spreading westward in Southeast Asia. Proportions of extended-spectrum beta-lactamase (ESBL) producing Gram-negative bacteria have been reported to be as high as 50% in India and 80% in China in healthcare associated infections. Methicillin-resistant Staphylococcus aureus rates have been reported to range from 50% to 85% in Sri Lanka, Thailand and India (27, 28). Carbapenem-producing Enterobacteriaceae and Acinetobacter baumannii are an increasing problem in LMIC, with antimicrobial-resistant A. baumannii being the most common cause of MDR hospital-acquired infections in LMIC, surviving for prolonged periods in the environment. Moreover, fluoroquinolone resistance in Salmonella typhi is high in Asia and rising in Africa (29). Spread of highly resistant bacteria is an increasing problem, facilitated by the high connectivity through overseas flights.

Antimicrobial stewardship should be promoted. A setting-adapted pharmacist-driven program across 47 South African Hospitals resulted in large reduction of antimicrobial use (30). Local resistance patterns should be monitored by sentinel sites and data should be reported as recommended by the WHO Global Antimicrobial Resistance Surveillance System (31).

Understaffing is common, with low staff-patient ratios, resulting in multiple breaks in infection control, increasing the risks of cross-infection. It often mandates the implication of the relatives in patients’ care, which may contribute to dissemination of MDR pathogens. It may have specific considerations among refugees (32). Finally, the lack of laboratory capacity for diagnosis represents a restriction for implementation of RDT, complicates the identification of MDR and limits de-escalation.

In summary, the majority of the world populationis living in LMICs and there is a high burden of critical illnesses with unacceptably high mortality due to lack of resources. The knowledge and awareness of sepsis in LMICs should be improved by training programmes and epidemiological studies in collaboration with HICs’ sepsis experts. The current sepsis definitions and guidelines should be modified based on epidemiological data and available resources in LMICs for the improvement in timely resuscitation of septic patients(1, 9, 33). During these improvement programmes in sepsis management, recent advances in personalized medicine in HICs should be customized to LMICs and require a different paradigm.

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