Research Article: Strategies to Reduce Mortality from Bacterial Sepsis in Adults in Developing Countries

Date Published: August 19, 2008

Publisher: Public Library of Science

Author(s): Allen C Cheng, T. Eoin West, Direk Limmathurotsakul, Sharon J Peacock

Abstract: Sharon Peacock and colleagues discuss management of adult patients with sepsis in low- and middle-income settings, with a particular emphasis on tropical regions.

Partial Text: Sepsis is a progressive injurious process resulting from a systemic inflammatory response to infection [1]. In developed countries, sepsis is an important cause of mortality: in the United States alone, up to 750,000 people annually suffer from severe sepsis—mostly bacterial in aetiology—of whom 29% may die [2,3]. Unfortunately, data on bacterial sepsis in developing countries are notably lacking, particularly in adults. Estimates of the burden of lower respiratory tract infections, meningitis, and “other infections”, of which a significant proportion are associated with severe sepsis, show that the majority of deaths and disability-adjusted life years lost occur in low-income countries (Figure 1) [4]. Additionally, severe sepsis is likely to complicate a varying proportion of cases of malaria, HIV/AIDS, diabetes, maternal conditions, and cancer deaths globally.

Interventions performed soon after diagnosis of sepsis in developed regions have been shown to improve survival [21,22], and in developing countries, interventions to identify and treat pneumonia in children reduce mortality [23]. Thus, prompt identification of sepsis in developing countries is an essential component of any management strategy. Most studies of infection have focused on specific diseases, but sepsis itself is a clinically recognisable syndrome despite its heterogeneous causes. From a practical standpoint, sepsis is largely a clinical diagnosis [24], and implementation of strategies to promote recognition of sepsis as a clinical syndrome should be feasible even in the most resource-challenged areas where supportive radiographic imaging or laboratory measurements are not available. Education of health care providers about sepsis is critical to enhance the early identification of sick patients and may help facilitate transfer to available health care facilities. Simple algorithms tailored to local medical capacities that comprise the basic components of sepsis, such as diagnosed or suspected infection and the systemic manifestations of infection, may be useful.

Volume resuscitation is a well-established initial therapy of sepsis. Many studies have demonstrated that tissue perfusion in sepsis is partly impaired by hypovolaemia [25,26], and patients may have substantial fluid deficits requiring 6–10 l within the first 24 hours [21,27]. Guidelines suggest that hypotensive patients should receive an initial challenge of 20 ml/kg or boluses of 500–1000 ml of crystalloid with ongoing monitoring of volume status [16,28,29]. Observational evidence suggests that aggressive fluid resuscitation was associated with decreased early mortality from typhoid with ileal perforation in a rural African hospital [30].

The timely and appropriate use of antibiotics in the early management period is associated with survival from sepsis and pneumonia [22,37]. A potential barrier to the formulation of an effective empiric antimicrobial regimen is that the spectrum of bacterial pathogens in the tropics is often diverse. In one study in Kenyan children, 16 individual pathogens, each of which accounted for less than 10% of cases, accounted for over a third of bacteraemias [38]. Similarly, in a study of adults in Nepal, no single pathogen accounted for more than 13% of patients where a pathogen was identified [39].

Prophylaxis for deep venous thrombosis and for peptic “stress” ulcers can be readily implemented in many developing countries. Histamine blockers such as ranitidine are inexpensive and can be administered via nasogastric tube to intubated patients. Although some have argued that the incidence of venous thromboembolism is lower in populations of non-European origin [51–53], more recent evidence suggests that this may not be the case in post-operative and medical patients [54,55]. In the absence of studies in critically unwell patients with prolonged immobilisation, the use of subcutaneous unfractionated heparin seems warranted.

Implicit in this discussion is the need for appropriately trained health care providers at the local level. Ideally, sepsis identification and management training should be integrated into general adult health care. Such a strategy is analogous to the World Health Organization’s Integrated Management of Childhood Illness training course, which included severe infection, chronic diseases, and preventative measures for all levels of health workers including doctors, nurses, medical assistants, and literate paramedical workers at both a primary, and more recently, hospital level [73,74]. This course was integrated into a comprehensive strategy that also included measures to improve drug supply, health care infrastructure, and family behaviour in relation to sick children.

The development of critical care services has significant resource implications for developing countries. We propose a stepwise approach based on income level, from extremely limited services in Africa and parts of southeast Asia, to more extended services in lower-middle-income countries such as Thailand and some South American countries (Table 1). Some evidence suggests that critical care services may be cost-effective even in poor countries, but such a decision needs to be made on a case-by-case basis [75]. We feel that with the current paucity of evidence regarding the effectiveness of potential interventions for severe sepsis, such decisions cannot currently be made. We further note that factors other than cost-effectiveness must be considered in priority setting in health care resource allocation, including equity, ethical, and political considerations [76]. However, where such services already exist, the challenge is to integrate these into the broader health care system to ensure access and to provide a cost-effective and sustainable staffing model [77]. Further research is required to define the most effective interventions for sepsis in developing countries, as well as evaluation and quality control programmes for existing services.

Few vaccines are available against most of the common causes of severe sepsis in the tropics, and many vaccines with known substantial efficacy against common diseases such as typhoid and pneumococcal disease are not generally available to developing countries because of cost. Other preventative measures may be useful for specific diseases. In a case-control study in northeast Thailand, the use of protective clothing reduced the incidence of leptospirosis [78], and protective footwear may also help prevent melioidosis, scrub typhus, snake bite, and physical injury. Although anecdotal reports suggested that farmers found protective footwear uncomfortable, particularly during the ploughing and planting seasons (V. Wuthiekanun, personal communication), it is possible that this obstacle could be overcome through a combination of education and the development of comfortable and practical clothing. Predictive modelling has proven to be a useful tool in malaria control [79], and similar techniques have been developed for a variety of other diseases such as cholera [80] and arboviruses [81]. Such tools might allow for targeting of public health interventions that may reduce exposure or disease transmission in specific populations.

The burden of sepsis is greatest in developing countries, and there is a need to translate modern management strategies for adults with severe sepsis to this context. The majority of studies of infectious diseases to date have been pathogen-specific, but efforts are required to define the epidemiology of all-cause sepsis in developing countries and to define the most cost-effective interventions that are sustainable in these countries. Principles of management may be adapted from current guidelines, particularly low-cost interventions targeted at early sepsis. Critical care services need to be considered in the context of competing priorities for resource allocation, but where they currently exist, standardised protocols need to be developed and evaluated to make the best use of available resources.



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