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Sepsis is a major cause of critical illness worldwide, especially in resource-poor settings. Intensive care units (ICUs) in low- and middle-income countries (LMICs) face many challenges that could affect patient outcome. The aim of this review is to describe differences between resource-poor and resource-rich settings regarding the epidemiology, pathophysiology, economics, and research aspects of sepsis. We restricted this manuscript to the ICU setting although we are aware that many sepsis patients in LMICs are treated outside an ICU. Although many bacterial pathogens causing sepsis in LMICs are similar to those in high-income countries, resistance patterns to antimicrobial drugs can be very different; in addition, causes of sepsis in LMICs often include tropical diseases in which direct damaging effects of pathogens and their products can be more important than the host response. There are differences in ICU capacities around the world; not surprisingly the lowest capacities are found in LMICs with important heterogeneity within individual LMICs. Although many aspects of sepsis management developed in resource-rich countries are applicable in LMICs, implementation requires strong consideration of cost implications and important differences in resources. Addressing both disease-specific and setting-specific factors is important to improve performance of ICUs in LMICs. Although critical care for sepsis is likely cost-effective in LMIC setting, more detailed evaluation at both a macro- and micro-economy level is necessary. Sepsis management in resource-limited settings is a largely unexplored frontier with important opportunities for research, training, and other initiatives for improvement.

This chapter gives an overview of the organization and functioning of our working group on developing guidelines on “Sepsis in Resource-Limited Settings,” the methods used for the systematic reviews and for grading of the evidence.

In this chapter, we provide guidance on some basic structural requirements, focusing on organization, staffing, and infrastructure. We suggest a closed-format intensive care unit (ICU) with dedicated physicians and nurses, specifically trained in intensive care medicine whenever feasible. Regarding infrastructural components, a reliable electricity supply is essential, with adequate backup systems. Facilities for oxygen therapy are crucial, and the choice between oxygen concentrators, cylinders, and a centralized system depends on the setting. For use in mechanical ventilators, a centralized piped system is preferred. Facilities for proper hand hygiene are essential. Alcohol-based solutions are preferred, except in the context of Ebola virus disease (chloride-based solutions) and infection (soap and water). Availability of disposable gloves is important for self-protection; for invasive procedures masks, caps, sterile gowns, sterile drapes, and sterile gloves are recommended. Caring for patients with highly contagious infectious diseases requires access to personal protective equipment. Basic ICU equipment should include vital signs monitors and mechanical ventilators, which should also deliver noninvasive ventilator modes. We suggest that ICUs providing invasive ventilatory support have the ability to measure end-tidal carbon dioxide and if possible can perform blood gas analysis. We recommend availability of glucometers and capabilities for measuring blood lactate. We suggest implementation of bedside ultrasound as diagnostic tool. Finally, we recommend proper administration of patient data; suggest development of locally applicable bundles, protocols, and checklists for the management of sepsis; and implement systematic collection of quality and performance indicators to guide improvements in ICU performance.

In this chapter, we summarize recommendations on sepsis recognition, identification of the underlying infection and causative microbiological pathogen, as well as recognition of septic shock in resource-limited settings. Early recognition of sepsis is based on the quick Sequential (Sepsis-related) Organ Failure Assessment (qSOFA): respiratory rate ≥22 bpm, systolic blood pressure ≤100 mmHg, and any acute change in mental state. For patients with severe malaria and severe dengue, more disease-specific criteria are of additional value. Identifying the cause and source of infection is important for the choice of treatment, to which knowledge of the local epidemiology, physical examination, and, depending on their availability, laboratory testing and imaging can contribute. If feasible, microbiological cultures before antimicrobial therapy, microscopy, and Gram staining of secretions sampled from the suspected source of infection should be performed. Empirical antibiotic therapy should be informed considering local antimicrobial resistance patterns, and if available follow-on antibiotic therapy should be guided by the antibiotic susceptibility of cultured bacteria. Malaria is diagnosed by rapid diagnostic test or light microscopy of a peripheral blood smear. Antigen or antibody tests are available for specific virus infections such as dengue, influenza, or Ebola virus disease. In immunocompromised patients, coinfection with tuberculosis should be suspected. For the diagnosis of septic shock, clinical indicators of systemic tissue hypoperfusion should be assessed. It is insufficient to rely solely on the presence of arterial hypotension, as arterial hypotension can be a late event. Plasma lactate is an important indicator of tissue hypoperfusion with strong prognostic significance.

In this chapter, we outline important elements for the general supportive care for patients with sepsis in resource-limited settings. We discuss the use of corticosteroids, sedation, neuromuscular blocking agents, deep venous thrombosis (DVT) prophylaxis, gastric ulcer prevention, glucose control, enteral feeding, renal replacement therapy, and initial fluid resuscitation. Low-dose corticosteroids are recommended in septic patients with refractory shock, pending completion of current trials. Important issues around sedation include the availability of selected opiates and benzodiazepines, ways of administration, and availability of expertise and (human) resources essential for dosing and monitoring of sedation to care for mechanically ventilated patients with sepsis. Venous thromboembolism prophylaxis with proton-pump inhibitors and histamine-2 receptor antagonists is generally available for stress ulcer prophylaxis in resource-limited ICUs and can be delivered feasibly and safely. Critical illness-associated hyperglycemia is common, and short-acting insulin is widely available and inexpensive. However, stringent blood glucose control is not recommended, since this is dangerous in settings where continuous intravenous insulin with frequent monitoring is not feasible. Enteral feeding can be with hospital-prepared foods where commercial feeds are not available or expensive. Risk of aspiration pneumonia starts early in comatose non-intubated patients. Although not as effective as hemodialysis or hemofiltration methods, peritoneal dialysis is a feasible and cost-effective alternative for renal replacement therapy in very resource-limited settings. Initial fluid resuscitation in severe sepsis or septic shock should be more conservative in resource-limited settings where positive-pressure mechanical ventilation is not readily available.

In this chapter we discuss recommendations on the identification of patients with acute respiratory distress syndrome (ARDS), indications for mechanical ventilation, and strategies for lung-protective ventilation in resource-limited settings. Where blood gas analyzers are unavailable, it can be replaced by the plethysmographic oxygen saturation/fractional inspirational oxygen concentration (SpOFiO) gradient. Bedside lung ultrasound is a valuable diagnostic tool assessing pulmonary edema and other pathologies. A number of recommendations for safe and lung-protective mechanical ventilation in patients with sepsis and respiratory failure are provided. However, many of these have not been trialed specifically in resource-limited settings. These recommendations include an elevated head-of-bed position and a minimum level of positive end-expiratory pressure (PEEP) of 5 cm HO only to be in patients with moderate or severe ARDS. In addition, low FiO and low oxygenation goals are suggested, using PEEP/FiO tables. Recruitment maneuvers are indicated in refractory hypoxia, but require experienced staff. Low tidal volumes (5–7 ml/kg predicted body weight, avoiding >10 ml/kg) are recommended and if at all possible in combination with end-tidal carbon dioxide (CO) monitoring for recognition of dislodgement of the endotracheal tube and under- or overventilation. “Volume-controlled” modes could be safer than “pressure-controlled” modes, and we recommend to check regularly whether a patient tolerates a “support” mode; we also suggest to perform spontaneous breathing trials to timely identify patients who are ready for extubation, but also to plan extubating patients when sufficient staff is around to guarantee safe re-intubation.

Recommendations for hemodynamic assessment and support in sepsis and septic shock in resource-limited settings are largely lacking. In this chapter, we reviewed the literature and provided recommendations regarding hemodynamic assessment and support, taking into consideration aspects of efficacy and effectiveness, availability and feasibility, and affordability and safety. We suggest using capillary refill time, skin mottling scores, and skin temperature gradients and suggest passive leg raise test to guide fluid resuscitation. We recommend crystalloid solutions as the initial fluid of choice and recommend initial fluid resuscitation with 30 ml/kg in the first 3 h but with extreme caution in settings where there is lack of mechanical ventilation. Patients with severe malaria or severe dengue without hypotension should not receive fluid bolus therapy. We recommend against early start of vasopressors and suggest starting a vasopressor in patients with persistent hypotension after initial fluid resuscitation with at least 30 ml/kg, but earlier when there is lack of access to mechanical ventilation, and recommend using norepinephrine (noradrenaline) as first-line vasopressor. We suggest in patients with suspected bacterial sepsis starting an inotrope with persistence of plasma lactate >2 mmol/l or persistence of skin mottling or prolonged capillary refill time when plasma lactate cannot be measured and only after initial fluid resuscitation. We suggest the use of dobutamine as first-line inotrope, recommend administering vasopressors through a central venous line, and suggest administering vasopressors and inotropes via a central venous line using a syringe or infusion pump when available.

Recommendations on the management of infections in patients with sepsis and septic shock are mainly derived from studies on bacterial sepsis in high-income settings and are not necessarily applicable elsewhere due to differences in etiology and diagnostic or treatment capacity. In this chapter, we provide recommendations on infection management in resource-limited ICUs, taking into account relevant contextual factors such as the availability, affordability, and feasibility of interventions.

We empirical antibiotic therapy in patients with sepsis should cover all expected pathogens and likely resistance patterns, based on locally acquired epidemiological data as large regional variations exist. Limited availability of certain classes of antibiotics can complicate implementation of this. We that research groups in collaboration with stakeholders provide microbiological data from sentinel sites throughout resource-limited settings to guide local empirical antibiotic choices.

There is weak evidence from resource-limited settings suggesting timely administration of antibiotics is beneficial. Observational data suggest that, in many resource-limited settings, the administration of antibiotics to most patients within 1 h of sepsis or septic shock recognition is feasible. Therefore, given biological plausibility and evidence from resource-rich settings, w appropriate antibiotics should be given within the first hour following sepsis or septic shock recognition. In resource-limited settings, microbiological laboratory facilities are often restricted, but there was evidence from these settings that taking blood cultures was associated with improved outcome in sepsis and septic shock and with improved appropriateness of antibiotics. We that blood cultures should be taken before the administration of antibiotics in locations where this is possible. Ideally, two sets of blood cultures should be obtained, although the additional yield has not been assessed in resource-limited settings. It is realized that in many hospitals, routine blood culture is unfeasible and expanding microbiological laboratory capacity could improve care.

Identification of an infection source and source control are additional challenges in resource-limited settings and are affected by the facilities available. There was weak evidence of reasonable sensitivity of both chest radiography and ultrasound in the diagnosis of abdominal hollow viscus perforation (mainly studied in typhoid or tuberculosis) and abscesses in melioidosis. We found weak evidence that timely surgery was beneficial in typhoidal gastrointestinal perforations. Because of lack of published evidence, we do not provide specific recommendations on the use of chest radiography or ultrasound in resource-limited settings. We that source control is carried out within 12 h of admission to hospital, except in the specific case of pancreatic necrosis, where there is evidence from resource-rich settings that delay in surgical intervention may be beneficial.

Combination antimicrobial therapy increases healthcare costs and toxicity. Current SSC guidelines only recommend combination therapy in specific situations, such as when the chances of multidrug resistance are high. Evidence in multidrug-resistant or extensively drug-resistant bacteria was confined to studies of infection, where combination therapy was beneficial. Where the chances of multidrug resistance are high, combination antibiotics should be considered. Choice of combination therapy should be guided by local epidemiology and known effective combinations. Antimicrobial therapy should be de-escalated whenever possible. It is recognized that without microbiological information, de-escalation is difficult. The use of biomarkers such as procalcitonin to guide de-escalation of antimicrobial therapy is promising but needs further assessment in resource-limited settings before a recommendation can be made.

In conclusion, large variations in disease etiology and high rates of antimicrobial resistance combined with restricted choice of antibiotics and limited microbiological data pose significant challenges in the management of septic patients in resource-limited settings. Increased use of combination therapy and broad-spectrum antibiotic risks increases antimicrobial resistance. Enhanced surveillance necessitates better collaboration between stakeholders and improved microbiological facilities, which in turn requires significant investment. However, newer technologies which negate the need for specialist staff and equipment may become more available. This would not only improve the management of individual patients but, by providing high-quality epidemiological data, may help combat the global threat of antimicrobial resistance.

This chapter summarizes recommendations on important aspects of the management of patients with severe malaria and severe dengue. Severe falciparum malaria requires rapid parasitological diagnosis by microscopy or rapid diagnostic test (RCT) and prompt initiation of parenteral artesunate. Fluid bolus therapy should be avoided in patients without hypotensive shock, and we suggest initial (24 h) crystalloid fluid therapy of 2–4 mL/kg/h, which may subsequently be reduced to 1 mL/kg/h in patients receiving additional fluids, e.g., through enteral tube feeding. In the minority of those patients presenting with hypotensive shock, we suggest fluid bolus therapy (30 mL/kg) with an isotonic crystalloid and early initiation of vasopressor support. Enteral feeding in non-intubated adult patients with cerebral malaria can start after 60 h, to avoid aspiration pneumonia. There are insufficient data to suggest this in pediatric cerebral malaria.

The diagnosis of severe dengue is commonly with a combined dengue antigen (NS1) and antibody RDT. No antiviral treatment is currently available. Dengue shock results from capillary leakage, although hemorrhage or depression of myocardial contractility can contribute. The World Health Organization guidelines recommend restoration of the circulation guided by pulse pressure, capillary refill time, hematocrit, and urine output. Large (>15 mL/kg) rapid (<30 min) fluid boluses should be avoided, but prompt fluid administration with crystalloids is essential and should be restricted as soon as the critical phase is over to avoid pulmonary edema. Corticosteroids are not recommended, neither is platelet transfusion for thrombocytopenia in the absence of active bleeding or other risk factors.

This chapter provides recommendations on the management of pediatric sepsis in intensive care units (ICUs) in resource-limited settings. Rapidly identification of severe sepsis through a combination of danger signs of end-organ dysfunction or impaired circulation is vital to improve outcome. Better scoring systems for risk stratification tailored for resource-poor settings are needed. Rapid vascular access is critical, and we suggest that in children with septic shock, the placement of an intraosseous line should be considered for vascular access rapidly after an attempt for intravenous access fails. We recommend a careful and individualized approach to fluid administration. For children with severe acute malnutrition without signs of severe shock, we suggest careful administration of intravenous fluids at an initial rate of 10–15 mL/kg/h (no fluid boluses). For well-nourished children who show signs of severely impaired circulation, we careful administration of 10–15 mL/kg of crystalloids over 30–60 min. We recommend incorporation of protocols for timely antibiotic administration, oxygen and respiratory support, and fluid management. We recommend blood transfusion in children with severe anemia and malaria only if there are signs such as respiratory distress or shock or with a hemoglobin concentration below 4 g/dL, requiring rapid transfusion. Children in resource-limited settings with severe respiratory distress and hypoxemia from sepsis could benefit from bubble continuous positive airway pressure (CPAP). Finally, we recommend using a tidal volume of 5–8 mL/kg predicted body weight in all mechanically ventilated children with sepsis-induced lung injury.