Sepsis and Septic Shock in Low- and Middle-Income Countries

Abstract

Background:

The greatest burden of sepsis- and septic shock-related morbidity and mortality is in low- and middle-income countries (LMICs). Accurate tracking of incidence and outcomes of patients in LMICs with sepsis has been limited by changing definitions, lack of diagnosis coding and health records, and deficits in personnel. Improving sepsis care in LMICs requires studying outcomes prospectively so that setting appropriate definitions, scoring systems, and treatment guidelines can be created. Our goal is to review the burden of sepsis and septic shock in LMICs, the evolution and applicability of definitions to LMICs, and management.

Methods:

The literature was searched through PubMed using a Boolean approach and the following terms: sepsis, septic shock, low- and middle-income countries. Articles were read by the authors and relevant information was abstracted and included with citations to create a narrative review.

Results:

The estimated worldwide incidence of sepsis admissions is 31.5 million cases per year leading to 5.3 million deaths. The World Health Organization (WHO) has urged LMICs to establish sepsis prevalence and outcomes. Most authors and societies involved in creating sepsis and septic shock definitions have been from high-income countries (HICs). Applicability of sepsis definitions in LMICs is uncertain. Quick-Sequential Organ Failure Assessment (qSOFA) and universal vital assessment (UVA) are useful screening and triage tools in LMICs because they can be done at the bedside. The key tenets of management of sepsis and septic shock in LMICs include early fluid resuscitation and antibiotic therapy coupled with source control when there is a surgical process. Surgical causes of sepsis should be identified rapidly. Scaling up surgical capacity in LMICs is an important step to improve source control of sepsis.

Conclusion:

Management guidelines specific to LMICs for sepsis and septic shock need to be refined further and studied prospectively. Improving access to surgery will improve outcomes of surgical cases of sepsis.

The majority of worldwide sepsis- and septic shock-related morbidity and mortality occurs in low- and middle- income countries (LMICs) [1,2]. Sepsis and septic shock definitions were revised in 2016. Sepsis is defined as a dysregulated host response to infection leading to life-threatening organ dysfunction, whereas septic shock is an advanced illness resulting in substantial circulatory, metabolic, and cellular dysfunction [3]. Although a common illness state, the study of sepsis has been difficult because of multiple revisions in case definitions over nearly three decades and the complex characteristics of the syndrome itself.

In LMICs tracking sepsis and septic shock incidence and outcomes has been even more challenging because of resource limitations in personnel and technology that limit data collection. Additionally, the Global Burden of Disease taxonomy, created by the World Health Organization (WHO) and World Bank, does not consider sepsis an individual diagnosis beyond the neonatal period and categorizes infections separately [4]. To improve sepsis care in LMICs requires defining the disease clearly and making it a priority in international registries as its own entity so that outcomes can be tracked and assessed at intervals. This can also lead to streamlining management and using limited resources more efficiently. This review aims to characterize the burden of sepsis and septic shock in LMICs, summarize and contextualize the progression of sepsis definitions as they apply in LMICs, and highlight key aspects of diagnosis and management.

Methodology

The authors initially searched PubMed using a Boolean approach and the following terms: sepsis, septic shock, low- and middle-income countries. We then used these terms to perform a Medline search utilizing the National Library of Medicine's Medical Subject Headings to avoid using “ahead of print” citations or any publications prior to 1966 that might have been found through the PubMed search. Literature was read by the authors and relevant information was abstracted and included with citations to create a narrative review. Cross referencing was then done to augment our literature search by hand searching the references of each publication. We excluded case reports and publications written in non-English languages.

Burden of the Disease and Why It Needs to Be Defined in LMICs

Because of data limitations it is not possible to quantify the burden of sepsis and septic shock in LMICs accurately. However, estimates can be formed from the minimal literature that does exist and by extrapolating from data from high-income countries (HICs). The most robust source on the topic is a systematic review by Fleischmann et al. [1] that searched 15 databases to define sepsis incidence and fatality rates in adults. Although the data obtained were mostly from HICs they provided global estimates on the incidence of sepsis admissions to be 31.5 million cases per year leading to 5.3 million deaths [1]. Despite doing this extrapolation one of the authors' main conclusions is the “urgent need” to measure sepsis-related mortality and morbidity in LMICs. Rudd et al. [5] believe these extrapolations underestimate the burden of sepsis in LMICs because infectious diseases as a whole are more common in LMICs. In HICs, sepsis and septic shock incidences are recorded by reviewing electronic health records (EHR) for International Classification of Disease (ICD) codes. The WHO has recently encouraged all countries, including LMICs, to increase use of the ICD system to “establish the prevalence and profile of sepsis” [6]. However, development of EHRs in LMICs will likely remain a major challenge because of technologic and economic constraints.

To this point sepsis has not received the level of coverage and research funding that cardiovascular and oncologic disease has. This is because of a combination of factors including substantially lower potential for development of lucrative pharmaceutical therapies. It is then useful to compare sepsis incidence and mortality with other disease processes that are already well defined and accepted to be major threats to longevity, cause substantial morbidity, and consume large amounts of healthcare resources. The incidence of sepsis requiring admission is now similar to myocardial infarction (MI) in HICs. Worldwide, lessons can also be learned from the successes that have been established through monitoring for MIs aggressively and diligently. Large diverse databases have demonstrated reductions in the MI incidence and fatality [7]. By establishing accurate data, risk factors such as elevated low-density lipoprotein and blood pressure were targeted for improvement [7]. Primary prevention schemes also exist for sepsis and could lead to a decrease in incidence in LMICs. Defining the sepsis burden and risk factors for sepsis admissions in LMICs could lead to targeted improvements in primary prevention strategies such as vaccination programs, malaria prophylaxis, and human immunodeficiency virus (HIV) testing. Improving access to quality diabetes management may lead to decreased infection rates and in turn progression to sepsis. Establishing LMIC-focused risk profiles and appropriate diagnostic procedures to identify those with sepsis could result in earlier detection and improve outcomes. However, to establish these risk factors and markers we need to monitor and establish population-based data on sepsis in LMICs.

Evolution of the Definitions of Sepsis and Septic Shock: Applicability in LMICs

There have been substantial alterations in the definitions of sepsis and septic shock since the original concepts were published in 1992 to standardize terminology so that treatment strategies could be evaluated consistently [8,9]. Refer to Table 1 for a description of the evolution of sepsis definitions. With recent improvements in understanding of pathobiology, sepsis is no longer viewed as involving inflammatory excess only as it was previously. Sepsis can create both proinflammatory and anti-inflammatory processes and responses. In 2016 a task force re-defined sepsis definitions and criteria and titled this Sepsis-3. In this most recent paradigm sepsis is defined as life-threatening organ dysfunction caused by dysregulated response to infection and objectively defined as an increase in the Sequential Organ Failure Assessment (SOFA) score of two points or more with confirmed infection. Severe sepsis was eliminated as a distinct entity and septic shock was defined as a subset of sepsis in which there exists substantial circulatory, metabolic, or cellular derangements. Clinically, septic shock is categorized objectively as sepsis that requires vasopressors to achieve a mean arterial pressure (MAP) >65 mm or presence of a lactate level >2 mmol/L without hypovolemia [3].

Table 1.

Evolution of Sepsis and Septic Shock Definitions

	Term	Definition	Countries represented among authors
American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference (1991) [8]	SIRS	Systemic inflammatory response to a variety of insults manifested by two or more of the following:	United States
		1. Temperature >30°C or <39°C
		2. Heart rate >90 bpm
		3. Respiratory rate >20 breaths/min
		4. WBC count >12,000/cu mm, <4,000/mm³, or >10% immature band forms
	Sepsis	Systemic response to infection manifested by two or more of the SIRS conditions.
	Severe sepsis	Sepsis associated with organ dysfunction, hypoperfusion, or hypertension.
	Septic shock	Sepsis-induced hypotension that does not resolve despite adequate fluid resuscitation plus perfusion abnormalities that can include lactic acidosis, oliguria, or acute alterations in mental status.
SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions (2001) [9]	Sepsis	Infection, documented or suspected, and some of the following:	United States, Canada, United Kingdom, Belgium, The Netherlands
		- General parameters
		- Inflammatory parameters
		- Hemodynamic parameters
		- Organ dysfunction parameters
		- Tissue perfusion parameters
The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) (2016) [3]	Sepsis	Life-threatening organ dysfunction caused by a dysregulated host response to infection	United Kingdom, United States, France, Germany, Australia, Canada, The Netherlands, Belgium
	Organ dysfunction and SOFA	An acute change in total SOFA score ≥2 points consequent to the infection.
		SOFA score assigns points based on values relating to:
		- Respiration (Pao₂/Fio₂)
		- Coagulation (platelet count)
		- Liver (bilirubin)
		- Central nervous system (Glasgow Coma Scale)
		- Renal (creatinine and urine output)
	Septic shock	Sepsis with persistent hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and serum lactate level >2 mmol/L despite adequate volume resuscitation
	qSOFA	Tool for bedside identification of patients with suspected infection likely to have a prolonged ICU stay
		- Respiratory rate ≥22 breaths/min
		- Altered mentation
		- Systolic blood pressure ≤100 mm Hg

SIRS = systemic inflammatory response syndrome; WBC = white blood count; SOFA = Sequential Organ Failure Assessment Score; Pao₂/Fio₂ = partial pressure of oxygen, alveolar/fraction of inspired oxygen; qSOFA = Quick Sequential Organ Failure Assessment Score; MAP = mean arterial pressure; ICU = intensive care unit.

It is unclear whether definitions and diagnostic criteria for sepsis and septic shock are useful in LMICs. The majority of the authors of the publications that resulted from the sepsis consensus conferences in 1991, 2001, and 2016, were from HICs whereas sepsis incidence and mortality are likely a greater burden in LMICs [1]. Under-representation of LMICs in authorship and consensus conferences is presumably related to a number of factors: lack of participation of individuals from LMICs in critical care societies on higher income continents, limited establishment and reach of medical and surgical societies in LMICs, and less resources for travel among other factors. Additionally, with LMICs having much less well-defined data on sepsis incidence and outcomes, this further inhibits participation in international consensus conferences [1,10].

Because LMICs have not been able to contribute substantially to creating and honing the criteria and definitions of sepsis and septic shock, these criteria and definitions are not as useful or applicable in these settings. The sepsis definition created in the 1990s centered around systemic inflammatory response (SIRS) criteria that are readily obtainable in most lower resource settings if laboratory capabilities for performing white blood cell (WBC) count are available. Establishing a diagnosis of septic shock in LMICs, however, is more challenging. Septic shock diagnosis requires hypotension despite adequate fluid resuscitation with perfusion abnormalities manifested by elevated lactic acid, oliguria, and altered mental status. “Adequate fluid resuscitation” was not well defined at the time of these initial definitions and in lower resource settings this is likely to lead to wide ranges of interpretations. Measuring perfusion abnormalities requires hourly urine output monitoring through a bladder catheter or serial lactic acid measurements, both unlikely to be readily available in LMICs, especially lactic acid measurements [11].

Contemporarily in Sepsis-3, sepsis was defined as an increase in the SOFA score of two or more points with confirmed infection. Unfortunately, the early studies that validated the SOFA system were based on data from HICs. A multicenter prospective study of more than 1,000 patients that identified SOFA as useful in describing the degree of organ dysfunction and failure by Vincent et al. [12] was based on data gathered from 40 intensive care units (ICUs), all from 16 HICs. This affirms that there is a cycle in which clinical experience and data from HICs creates scoring systems that are then subsequently used to form definitions at consensus conferences comprising members and societies from only HICs. The SOFA score involves partial pressure of oxygen, alveolar/fraction of inspired oxygen (Pao₂/Fio₂) ratio, Glasgow Coma Scale (GCS), MAP and vasopressor requirements, liver function, platelet count, and creatinine. Measuring Pao₂/Fio₂ ratio requires arterial blood gas analysis, which is not readily available in many hospitals in LMICs [11]. Regularly following some of the other laboratory parameters of SOFA may also be difficult in LMICs. The Sepsis-3 definition is then likely not of substantial utility in LMICs in improving communication between providers about individual patients, guiding development of locally deliverable treatment protocols, and recording of accurate registries of cases for research and quality improvement.

The Sepsis-3 definitions also proposed a simpler bedside tool that may be useful in LMICs. The Quick-Sequential Organ Failure Assessment (qSOFA) is a rapid tool comprising three clinically obtainable data points: respiratory rate, mentation, and systolic blood pressure (Table 2). Scoring two or more points identifies “patients as more likely to have poor outcomes typical of sepsis” [3]. The qSOFA does not define sepsis but is a screening tool that requires only clinical assessment to identify and triage patients with organ dysfunction caused by a dysregulated host response to infection, and those subsequently at increased risk for adverse outcomes that may need more in-depth evaluations and treatments [3,13]. A recent retrospective cohort study found qSOFA and modified qSOFA (adding 1 point for age >50 years) to be predictive of mortality from sepsis [13]. The qSOFA was also found to have higher predictive validity than SIRS for mortality and organ dysfunction in patients with suspected infection in an emergency department [14]. However, another recent study by Williams et al. [15] that enrolled almost 9,000 patients in an emergency department with suspected infection showed qSOFA to have high specificity (96%) but poor sensitivity (30%) for predicting organ dysfunction. This sensitivity was much poorer than that for SIRS (72%) [15]. Limited work has been done to evaluate the validity of qSOFA and other scoring systems in LMICs. A recent retrospective analysis of nine studies that occurred across 10 LMICs showed positive qSOFA criteria to be associated with increased risk of death in patients with suspected infection. This was also shown with SIRS but less strongly [16]. Increasing qSOFA score was also associated with increased risk of death but this was not the case with SIRS. Huson et al. [17] reviewed more than 300 patients admitted to a limited-resource hospital in Gabon with fever or hypothermia. They found a positive qSOFA score was an accurate hospital mortality predictor for patients with bacterial infections, malaria, and tuberculosis [17]. It is important that a scoring system in LMICs is useful and accurate for a wider range of presentations beyond the common bacterial infections that are the majority of causes of sepsis in HICs. Malaria, HIV/AIDS, tuberculosis, and typhoid are among such presentations that occur more commonly in LMICs than HICs. Huson et al. [18] also showed similar utility of qSOFA in predicting mortality in a prospective study of 458 patients with suspected infection in Lilongwe, Malawi. The universal vital assessment (UVA) score was created from retrospective cohort data from sub-Saharan hospitals and requires no laboratory data. It also is the only sepsis scoring system that assigns points for HIV status and has outperformed the Modified Early Warning Score (MEWS), SIRS, and qSOFA in predicting mortality in patients with suspected infection [19].

Table 2.

Bedside Scoring Systems for Sepsis in LMICs

	Study population	Study location	Findings
qSOFA in LMICs	343 patients with suspected infection	Hospital with limited supportive care facilities in Gabon	qSOFA ≥2 had sensitivity of 87% and specificity of 75% for predicting in-hospital mortality for patients with both suspected bacterial infection and malaria
	458 patients with suspected infection	Kamuzu Central Hospital, Lilongwe, Malawi	qSOFA ≥2 had sensitivity of 72% and specificity of 68% for predicting in-hospital mortality for patients with suspected infection
	6,569 patients with suspected infection	Retrospective secondary analysis of patient cohorts in Bangladesh, Haiti, India, Indonesia, Myanmar, Rwanda, Sierra Leone, Sri Lanka, Thailand, and Vietnam	qSOFA had superior predictive validity to SIRS for both identification of sepsis and in-hospital mortality
UVA	277 patients visiting the ED	Albert Schweitzer Hospital, Lambaréné, Gabon	UVA had the greatest predictive power of in-hospital mortality (sensitivity 91% and specificity 78%), followed by qSOFA (sensitivity 55%, specificity 82%), whereas SIRS and MEWS had lower predictive ability

LMICs = qSOFA = Quick Sequential Organ Failure Assessment Score; UVA = universal vital assessment; ED = emergency department; SIRS = systemic inflammorty response syndrome; MEWS = Modified Early Warning Score.

Diagnosis of Infectious Etiologies in LMICs

Definitive diagnosis of causative organisms with microbiologic identification is important in understanding global sepsis burdens and to enhance care across all settings. Confirming infection in HICs remains difficult and almost 50% of patients have been shown to present with culture-negative sepsis in a recent epidemiologic study [20]. In LMICs there are obstacles to achieving organism-specific data because microbiology laboratories are often limited in equipment and personnel. Obtaining culture specimens is also limited by lack of consumable collection containers or devices, phlebotomists, and technicians. A review from facilities in Haiti and Rwanda associated with Partners in Health identified some of the key laboratory deficits and ways to address them. It was found that microbiologic capabilities were often not related to local disease burdens and that hospitals that were deemed to be able to provide “basic” laboratory services were not providing any “essential” services for microbiologic or pathologic diagnoses [21]. In LMICs frequently only national or reference laboratories are capable of performing essential microbiology testing. Training laboratory technicians and leadership is often severely lacking in LMICs as well. Partners in Health along with the Haitian organization Zanmi Lasante have undertaken a long-term project to bolster laboratory capabilities by first building a large regional reference laboratory, improving the equipment supply chain, and providing training programs [21]. This approach may serve as a model for other LMICs to improve microbiologic laboratory capacity and quality, however, it is uncertain if the economic resources will be available widely to many LMICs.

Establishing an objective, culture-based diagnosis of infection in a surgical patient is even more difficult in LMIC settings. Surgical patients who present to the hospital with a focal anatomic infectious process (i.e., acute appendicitis, cholecystitis, soft tissue infections) may not be diagnosed via standard microbiologic assessments of blood, urine, or sputum as is more common in non-surgical sepsis. This is also the case for most post-operative infections. Most intra-abdominal infectious surgical processes in HICs are now diagnosed by a combination of advanced imaging, most often computed tomography (CT) scan with intravenous contrast, and emergency clinician and surgical consultation. It is the authors' opinion and observation that the advanced imaging findings play the largest role in establishing the diagnosis and usually precede the evaluation by the surgical consultant. Advanced imaging is obtained in 15% to 45% of presentations to emergency departments in HICs [22,23]. In LMICs CT scanners are often not available and if they are the scans cannot necessarily be obtained as rapidly or widely and not always with intravenous contrast. Although 100% of HICs have at least one CT scanner per one million people, this is the case for less than 15% of LMICs [24].

With less availability of imaging, establishing a surgical diagnosis requires greater clinical acumen through more detailed gathering of a history of present illness and a thorough physical examination. It is common in tertiary LMIC hospitals for a surgical resident to be assigned to the emergency department to see all patients with abdominal pain or other surgical problems. This allows them to refine their skills in history taking and in mastering the many physical findings associated with each surgical problem. Unfortunately, in LMICs attending surgeons and surgical trainees who have developed these skills are not widely available in the many non-tertiary settings to which large numbers of patients with surgical sepsis present. Although LMICs comprise 48% of the world's population, only 19% of surgeons work in LMICs. The differences in surgeon density between LMICs and HICs make the disparities appear even more stark with a rate of 0.7 surgeons per 100,000 population in LMICs compared with 57 per 100,000 in HICs [25]. This dearth of trained surgeons in LMICs greatly compromises ability to diagnose and intervene in cases of surgical sepsis.

Disseminating training and use of point of care ultrasound may be more feasible in LMICs than pursuing acquisition of large numbers of CT scanners as has been done in HICs. Point of care ultrasound (POCUS) has been used successfully in LMICs to diagnose numerous infectious and surgical processes that can progress to sepsis and septic shock. These include but are not limited to filariasis, Chagas disease, ascaris infection, echinococcal cysts, intra-abdominal and soft tissue abscesses, intussusception, splenic tuberculosis, and more straightforward entities such as acute appendicitis, acute cholecystitis, and bowel obstruction [26]. Liver abscesses are more common in LMICs and POCUS is a preferred approach for diagnosis and treatment because the patient can receive simultaneous aspiration and drainage guided by the ultrasound. Point of care ultrasound has also been used to guide fluid resuscitation in patients with abdominal sepsis in LMICs. Inferior vena cava collapsibility to follow hemodynamic response to fluid therapy has been described as an approach to guide decision making as to when to proceed to the operating room for laparotomy [27]. Point of care ultrasound is portable, non-invasive, repeatable, and less expensive than other advanced forms of radiologic imaging, and hopefully in the future can be delivered even at district levels in LMICs.

Management of Sepsis and Septic Shock-Fluid Resuscitation, Antibiotic Agents, Surgical Source Control

The most recent guidelines from the Surviving Sepsis Campaign (SSC) provide graded recommendations for the management of sepsis [28]. The authors termed these recommendations as international guidelines, however, among the 51 medical centers involved only three were from LMICs. Two were from Brazil and one from Belize, both considered higher middle-income countries. Despite this the recommendations warrant review for applicability in managing sepsis in LMICs. For the initial resuscitation of the patient with sepsis with hypoperfusion 30 mL/kg of crystalloid fluid over the first three hours of presentation is suggested based on data from goal-directed therapy trials [29,30]. Although some evidence exists that fluid resuscitation strategies derived from HICs may lead to worse outcomes in LMICs in children and adults it is beyond the scope of this review to sort out all of the arguments or limitations of particular quantities [31,32].

It does seem prudent, however, for emergency departments in LMICs to have protocols suggesting a set quantity of fluid based on weight and presence of hypoperfusion. Providing no fluid resuscitation is most likely to result in end organ dysfunction, end organ damage, and markedly higher rates of mortality in patients presenting with sepsis or septic shock. Presence of hypoperfusion could be based on bedside physical examination assessing mottling, capillary refill, extremity temperature, qSOFA scoring, and initial hourly urine output. A recent multicenter trial in Brazil showed improved organ function at 72 hours in patients with sepsis resuscitated while guided by capillary refill time (CRT) compared with lactic acid levels [33]. Mean arterial pressure is the driving pressure for organ perfusion and the SSC recommends maintaining a MAP of 65 mm or greater. Whereas dynamic monitoring is preferable to static measurements, invasive arterial lines and other devices are often not available in LMIC ICUs and rarely available in emergency departments. A survey last decade showed that implementation of SSC bundles was only possible in less than 2% of settings according to providers who responded [34]. Much like how POCUS may be a more cost effective and widely deliverable strategy in LMICs, further research into the utility and accuracy of findings such as CRT to guide sepsis resuscitation is warranted.

The WHO first published the Integrated Management of Adult Illness (IMAI) District Clinician Manual in 2011, which contains criteria and guidelines for sepsis in LMICs [35]. The IMAI guidelines specifically stress hypotension and respiratory distress as the most important markers of organ dysfunction in sepsis. Modified sepsis criteria are proposed that substitute systolic blood pressure <100 mm for WBC count in the SIRS portion of the original sepsis criteria. In contrast to the approach from the SSC the IMAI guidelines suggest a more conservative fluid approach of 1 mL/kg per hour intravenously or orally. This takes into account concern for negative effects of excess fluid on lung function as well as the heterogeneity of sepsis etiologies in LMICs and their associated variation in fluid requirements for resuscitation. However, the IMAI guidelines were created mostly by expert consensus because limited evidence existed at this time in LMICs. Recently data have emerged from LMICs on these IMAI guidelines. A before and after study of patients in Kenya presenting to a teaching hospital with sepsis, almost half of whom were HIV positive, had improved lactic acid clearance when IMAI guidelines were followed compared to usual care [36]. Mortality was not improved, however, in adults with septic shock in Uganda who received IMAI guided fluid resuscitation [37].

Broad-spectrum antibiotic agents should be started as early as possible upon recognition of sepsis or septic shock. More than one antibiotic agent may be needed to achieve coverage of resistant gram-positive organisms such as methicillin-resistant Staphylococcus aureus, numerous possible gram-negative organisms, and occasionally vancomycin-resistant enterococci (VRE). Methicillin-resistant Staphylococcus aureus (MRSA) and VRE as sources of sepsis are more common in patients who have indwelling devices or who have recently been in hospitals or care facilities. It is a misconception that LMICs have lower rates of antimicrobial-resistant (AMR) organisms. For example, investigations have shown MRSA to account for at least 20% of Staphylococcus aureus in all WHO regions and upwards of 80% in East African countries [38 –40].

Antimicrobial coverage for patients in LMICs presenting with sepsis are even more challenging as fungal organisms, malaria, tuberculosis, and HIV/AIDS-related infections are common among many other entities. Antibiotic availability is often limited and heterogeneous for non-AMR and especially AMR organisms in LMICs because of high costs and supply limitations. Additionally, patients in LMICs are often required to pre-pay out of pocket to access medications and cannot afford antibiotics. Despite these issues, antibiotic use in LMICs increased by 114% from 2000 to 2015, a greater increase than in HICs [41]. Use of commonly reserved broad-spectrum antibiotic agents for complex resistant organisms including glycylcyclines, oxazolidinones, carbapenems, and polymyxins also increased markedly both in LMICs and HICs [40]. We suggest early administration of antibiotic agents for patients with likely sepsis or septic shock, however, we do not believe the SSC recommendation of giving the antibiotic agents within one hour of sepsis recognition is the safest approach in LMICs [28]. Such time to therapy recommendations will likely lead to increased use of antibiotic agents in LMICs, possibly in cases in which they are not indicated such as in patients with fungal or parasitic etiologies of their sepsis state. Additionally, antibiotic stewardship based on culture data is less common in LMICs that also may lead to initially unindicated antibiotic agents being used for lengthy periods.

During the initial care period in which fluid resuscitation and antibiotic therapy are started identification of surgical sources of sepsis or septic shock is crucial. Operating room staff and anesthesiology can then prepare for the case to expedite the process of source control. The most common diagnoses that require surgical source control both in LMICs and HICs include appendicitis, cholecystitis, intestinal perforation, intestinal ischemia, sigmoid volvulus, abscess, an infected indwelling device, and necrotizing soft tissue infection. The approaches used most commonly to treat these conditions involve laparotomy, incision and drainage, and debridement.

The SSC guidelines from 2017 recommend achieving source control as soon as “medically and logistically practical” but do not specify a time to therapy goal (Table 3). Retrospective studies of patients with gastrointestinal perforations and necrotizing soft tissues infections suggest that mortality is reduced if source control is achieved within six to 12 hours of presentation [42 –44]. Most of the time to therapy studies for source control have been done in higher income settings and rarely include important outcomes other than mortality such as rates of organ dysfunction or failure, length of hospital stay, and need for the ICU. Obstacles that can delay surgical source control are numerous in LMICs: limited radiologic imaging, lack of operating rooms or equipment, lack of anesthesia and surgical staff, and distance to a referral facility where these are available. In 2015 Meara et al. [45] reviewed the deficits in surgical care in LMICs and how to scale-up delivery of essential services. The authors define the bellwether procedures as laparotomy, cesarean delivery, and washout of open fracture. The ability to deliver these procedures indicates that a hospital or system can provide other important procedures [45]. The goal is for there to be access to these bellwether procedures within two hours for 80% of the population worldwide by 2030. Improving delivery of bellwether procedures is entirely applicable to improving sepsis care in LMIC as the resources to achieve those procedures would facilitate the ability to address the majority of etiologies of sepsis for which timely delivery of surgical source control is needed. Collaboration between those studying and working to improve surgical source control of sepsis in LMICs and larger groups such as the Lancet Commission on Global Surgery should be thus encouraged.

Table 3.

Surgical Procedures for Source Control of Sepsis

Incision and drainage of abscess

Debridement of necrotizing soft tissue infection

Removal of indwelling device or hardware

Appendectomy

Cholecystectomy

Intestinal repair or resection

Conclusion

Improving the care of patients with sepsis and septic shock in LMICs requires a multidisciplinary approach. Collaborations are needed between HICs and LMICs and governments and ministries of health within HICs will have to invest substantial personnel and other resources to create an infrastructure that allows for wider and more timely delivery of care for septic patients. Although the deficits in infrastructure in LMICs required to provide sepsis care are numerous there remain some high-yield means to potentially improve care rapidly. Training community health workers, general practitioners, nurses, and surgeons in the fundamentals of fluid resuscitation, selective but early use of antibiotic agents, and surgical source control could likely decrease morbidity and mortality from sepsis and septic shock substantially in LMICs. It is also important that we either define how well sepsis definitions, scoring systems, and protocols derived mostly from HICs can be applied in LMICs or we must continue to hone definitions and protocols derived from LMICs. Sepsis-3 elements including qSOFA need to be evaluated prospectively in large numbers of patients in LMICs. Modified sepsis guidelines and bundles scaled to available resources in LMICs that have been shown to be effective in smaller studies should be further studied in other LMICs [46].

“Counting sepsis” also needs to improve substantially so that we can define and quantify the burden in LMICs so that training and resource allocation can be bolstered [5]. It is unclear whether this is best accomplished by following WHO recommendations to increase use of ICD documentation, further formalizing sepsis definitions in LMICs, dedicated personnel to maintain registries, or through greater availability of technology and data collection systems. Last, the recent increasing enthusiasm of a number of international organizations for scaling up surgical delivery in LMICs to more widely provide bellwether surgical procedures aligns well with other initiatives to improve sepsis care.

Footnotes

Funding Information

No funding was provided for this project.

Author Disclosure Statement

No competing financial interests exist.

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