Prompt care for patients with sepsis is often hampered in LRS by the heterogeneity of sepsis, a limited understanding of its relevant symptoms, and the relative lack of advanced diagnostics, all leading to an increased risk of death. ^, Continuous monitoring systems and biomarker testing, for example, venous lactate, are typically limited in availability. Clinical prognostic tools, such as the National Early Warning Score (NEWS) and its derivatives, may serve as valuable adjuncts in the absence of advanced diagnostics. However, their performance in LRS appears to be less sensitive and specific compared with studies in high-resource settings (HRS). ^, Locally-validated tools, such as the Universal Vital Assessment score, appear to outperform NEWS in predictive accuracy in studies conducted in sub-Saharan Africa, presumably resulting from their validation using local cohorts rather than patients in North America and Europe. ^, Lastly, purely clinical signs, such as somnolence, decreasing urine output, and poor capillary refill time, are reasonable surrogates for tissue perfusion and may identify patients with suspected sepsis sufficiently well to trigger intervention ( Table 1 ).

Rapid, active empiric antimicrobial therapy is one of the cornerstones of effective sepsis care. Mortality in HRS increases by 7% to 10% with each hour of delay in antibiotic therapy in patients with septic shock. Although less marked, delayed antibiotics due to delays in sepsis recognition over 6 hours are still linked to increased mortality in hemodynamically-stable patients. Data from LRS are limited, but it is reasonable to assume that similar delays will have comparable, if not greater, impacts on outcomes.

Severe malaria can present as sepsis in endemic regions, with a high rate of bacterial coinfection (10%). and often coexists (10%) with bacterial infections. Malaria diagnosis requires either microscopy by an experienced expert or newer methods such as rapid antigen testing and polymerase chain reaction, may be limited by lower sensitivity or increased cost, respectively. In patients with suspected sepsis in a malaria-endemic region, empiric antimalarial treatment is recommended when malaria cannot be rapidly excluded. Intravenous artesunate is the preferred therapy; alternatives include intramuscular artemether or IV quinine. Oral regimens, such as artemether-lumefantrine, may serve as temporizing options.

Antimicrobial resistance (AMR) is highly prevalent in many LRS, with an estimated 1.27 million deaths attributed to bacterial AMR alone in 2019. In some regions, greater than 75% of Escherichia coli and Klebsiella pneumoniae clinical isolates are resistant to third-generation cephalosporins, and from 7% to 36% of hospitalized patients in a multinational cohort in Bangladesh, Botswana, Chile, Guatemala, India, and Kenya were found to be colonized with carbapenem-resistant Enterobacterales. This high rate of resistance leads to inadequate empiric therapy or, alternatively, overuse of highly broad-spectrum agents. However, routine diagnostics are often limited in these settings, and many hospitals lack regular, updated cumulative antibiograms to guide empiric therapy. ^,

Rapid, effective source control is as critical to sepsis care as antibiotics, but its availability depends on resources such as surgical capacity, anesthesia, blood banks, and postoperative care. Observational studies from HRS describe that early source control within 6 hours of presentation is associated with reduced mortality. ^, Unfortunately, the Lancet Commission on Global Surgery reported in 2015 that an estimated 5 billion people worldwide lacked timely access to safe, affordable surgical and anesthetic care. In practice, this leads to delays in source control, higher rates of uncontrolled intra-abdominal infection, and ultimately worse sepsis outcomes. Progress has been limited in achieving the goals of the Lancet Commission, in part due to health system disruptions during the COVID-19 pandemic. Improving triage pathways, decentralizing basic emergency surgical capability, scaling up anesthesia and surgical workforces, and ensuring perioperative and postoperative infection control are critical steps to reduce sepsis mortality from surgically treatable causes. ^,,,

In HRS, volume resuscitation with isotonic fluids has been associated with improved outcomes in observational studies, with 30 mL/kg of a balanced crystalloid solution (eg, lactated Ringer’s) recommended by current guidelines. The precise volume of fluid to administer remains unclear when evaluated in clinical trials, however, with more restrictive fluid volumes of less than 1.5 L showing equivalent outcomes as larger volumes. ^,

These findings, however, may not necessarily apply to LRS. The FEAST trial, evaluating the role of fluid therapy in African children with severe infections, showed an increase in 48-hour mortality in participants randomized to rapid bolus resuscitation (albumin or normal saline) versus maintenance fluids in settings without ready access to advanced respiratory or critical care support. This highlighted that aggressive early boluses could be harmful where downstream supportive care (oxygen, ventilation, and transfusion) is limited. It is important to observe, however, that the excess mortality in these children appeared to be related to cardiovascular collapse rather than directly due to hypervolemia, that is, pulmonary or cerebral edema. This suggests that the harm from fluid therapy in the LRS context may not solely be due to volume overload but possibly related to reperfusion injury following delayed rather than early resuscitation. This phenomenon does not appear to be confined to children; subsequent studies in adults in Africa have shown similar lack of benefit and possible harm with early fluid resuscitation for sepsis. ^,

There is growing recognition that the timing, volume, and context (patient population, baseline anemia or malaria, and availability of ventilatory support, among others) matter greatly in LRS. Although guidelines continue to recommend volume resuscitation for patients with sepsis in LRS, cautious, physiology-guided initial resuscitation (administering small boluses and closely reassessing the response) is recommended, along with earlier consideration of vasopressors when available. Particular caution is advised regarding large, repeated boluses late in the disease course when critical care support is limited. In the absence of advanced monitoring or lactate testing, responses to fluid resuscitation may be monitored using decreases in heart rate, increases in systolic blood pressure may be used as surrogates for improvement in intravascular volume status. Changes in pulse pressure and systolic arterial pressure through a brachial cuff can be used to assess a fluid-induced increase in cardiac output, although all these methods are limited. ^, Decreases in capillary refill time with resuscitation have been validated as equivalent to, if not superior to, lactate-guided measures.

In LRS, the choice of vasopressors must weigh drug availability, nursing ratios, monitoring capacity, and the logistics of safe peripheral infusion. Guidelines recommend norepinephrine as the first-line vasopressor for septic shock, but norepinephrine infusion requires medications, reliable IV access, monitoring, and often central venous access. Where central access or pumps are unavailable, well-structured protocols for short-term peripheral norepinephrine infusion (peripheral lines, protocolized site checks, short durations, and early plan for escalation) have shown low-complication rates and can be lifesaving. ^,

If norepinephrine is not available, epinephrine is an acceptable alternative, particularly in children. ^, Although dopamine has been shown to have higher adverse effects in randomized trials (such as higher risks of arrythmia), randomized trials have not shown a clear difference in mortality between norepinephrine and dopamine, and dopamine is presumably superior to no vasopressor support in the absence of other agents. ^,

Oxygen is the most commonly required form of organ support in sepsis, spanning modalities from nasal cannula and simple masks to noninvasive ventilation (NIV) and mechanical ventilation. Oxygen availability became a critical scarce resource in many regions, including parts of the United States, during the COVID-19 pandemic. ^, In many regions, oxygen supply is chronically unreliable; in a survey across 39 low- and middle-income countries, only 24.5% of primary, 52.4% of secondary, and 66.8% of tertiary facilities reported reliable oxygen availability, with inadequate levels of availability of critical equipment such as cylinders, concentrators, delivery devices, and monitoring equipment such as pulse oximetry. Limited oxygen availability in LRS may lead to the need to triage, resulting in restricted access for vulnerable patients. Oxygen concentrators can expand access but require reliable power sources. ^, Solar-powered systems and low-pressure storage mechanisms have shown promise as a way to improve access to oxygen therapy in LRS, particularly when electricity is unreliable. ^,,

Basic monitoring with pulse oximetry may be unavailable or unreliable in LRS, with equipment reliability, batteries, maintenance, and staff training serving as barriers. ^, Clinical signs such as tachypnea, tachycardia, or cyanosis may be helpful in the absence of oximetry but tend to be evident only in severe illness, and reliance on such markers will likely lead to delays in treatment. ^,, (63) Interventions to strengthen oxygen systems, such as routine pulse oximetry, reliable supplies, and maintenance programs have demonstrably reduced pediatric pneumonia mortality and improved quality of care. ^, Nonetheless, significant gaps in access persist. Advanced respiratory support remains out of reach for many facilities, leaving a substantial unmet need.

Advanced extracorporeal support for patients with sepsis includes renal replacement therapy for acute kidney injury, extracorporeal membrane oxygenation (ECMO) for refractory respiratory or cardiac failure, and durable mechanical cardiac support. Acute kidney injury (AKI) is common in sepsis, but a substantial proportion of patients who meet indications for dialysis in LRS never receive it due to lack of equipment or trained staff, consumable costs, or inability to pay. Peritoneal dialysis may be a feasible, lower-resource alternative in many settings and has been promoted by international nephrology bodies as part of a pragmatic strategy.

ECMO and other high-cost extracorporeal supports are largely absent outside high-income regions because of cost, staff, and volume requirements; targeted regionalization and careful case selection are the realistic near-term models where these technologies exist. In Africa, there are only 5 centers registered with the Extracorporeal Life Support Organization, despite the continent containing over 16% of the world’s population. Before and during the COVID-19 pandemic, new ECMO centers established in South Africa, India, and the Middle East have reported mortality rates higher than, but comparable to, those in higher-resource settings. However, access to these centers remains limited by distance and capacity. ^,, These limited extracorporeal options mean that clinicians must prioritize early prevention, basic organ support, and timely transfer when appropriate.