Sepsis Management in Low- and Middle-Income Countries: A Systematic Review

doi:10.21203/rs.3.rs-3789542/v1

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Sepsis Management in Low- and Middle-Income Countries: A Systematic Review

https://doi.org/10.21203/rs.3.rs-3789542/v1

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Background

Optimal sepsis management in low-resource settings is the subject of active debate. Given resource limitations, prevalent co-morbidities, and unique infectious epidemiology, resuscitation strategies conceived in resource-rich settings may be difficult to apply more broadly. Evidence from low- and middle-income country (LMIC) settings is disparate and frequently discordant. We sought to synthesize the available data.

Methods

A systematic search of sepsis resuscitation interventions in LMIC was performed in PubMed, EMBASE, Scopus, Global Health Library databases, and the gray literature in accordance with PRSIMA guidelines. Studies were included if they defined a fluid or antibiotic intervention and measured the effect on in-hospital mortality for patients with undifferentiated sepsis. Studies were categorized based on the volume of fluid administered and the time to antibiotic administration.

Results

The search yielded 22,088 unique articles, of which 26 studies, encompassing 15,667 patients met the inclusion and were included. Over half the studies (14/26) evaluated the effect of fluid administration on mortality and found a trend toward increased mortality when more than 2 L were administered in the first 6 hours, while 1–2 L was associated with reduced mortality. Among the 15 studies evaluating the impact of antibiotic timing, administration within 3 hours was associated with reduced likelihood of in-hospital mortality. However, there was wide heterogeneity across study methodologies, outcomes, and resource variation.

Conclusion

Synthesis of the available data suggests that a judicious fluid strategy (between 1 and 2 liters within the first 6 hours) and early antibiotic administration are the most appropriate strategies for undifferentiated sepsis. More research is needed, especially in rural low-resource settings where we found a dearth of available research.

LMIC

Infectious Disease

Sepsis

There are over 48 million cases of sepsis yearly worldwide, with a disproportionate mortality burden borne by low- and middle- income countries (LMIC), where 83–87% of annual sepsis deaths occur^1–3. Over the past two decades, sepsis care in high-income countries (HIC) has evolved dramatically, with the development of standardized and targeted interventions, known as “Early Goal-Directed Therapy” (EGDT) that are integrated into care via clinical pathways^{2, 4, 5}. The main components of EGDT include aggressive fluid resuscitation and broad-spectrum antibiotics, within hours of a sepsis diagnosis. Much of the evidence supporting EGDT is from HIC^{4, 5}.

The appropriateness of EGDT-based sepsis management in LMIC remains unclear^{3, 6, 7}. In contrast to HICs, where acute bacterial infections are the leading cause of sepsis⁸, fungal, viral and parasitic infections comprise a large proportion of all sepsis etiologies in LMIC⁹. Furthermore, providers in LMIC frequently have limited resources to monitor the impact of interventions and address iatrogenic complications- such as aggressive fluid resuscitation resulting in respiratory distress requiring positive-pressure ventilation^{7, 10, 11}. In addition, the hallmark of targeted management is frequent monitoring of laboratory markers and physiologic measurements (such as Central Venous Pressure (CVP)), which are unavailable or difficult to implement in resource-limited settings^{7, 10}.

The few studies that have evaluated EGDT in low-resource settings report conflicting results^11–14. ICU-based studies in Uganda and Tanzania demonstrated a mortality benefit for EGDT in patients with severe sepsis^{15, 16}, while randomized control trials of EGDT in Kenya^{13, 14} and Zambia^{11, 12} were terminated early due to increased mortality and respiratory complications among patients in the intervention arms. In the absence of clear, context-specific evidence, acute-care providers in LMIC have little basis for treatment decisions.

Here we synthesize the available literature on sepsis interventions in LMIC. Given the heterogeneity in the availability of monitoring and diagnostic tools in resource-limited settings, the focus is on widely available interventions. We summarize the evidence, identify research and management gaps, and highlight opportunities for improving clinical outcomes in critically-ill patients receiving sepsis management in low-resource settings.

Database search

We conducted a search of the Pubmed, Embase, Scopus, and Global Health Library databases, using validated LMIC and infectious disease keywords¹⁷ (S1), to identify studies published through October 2022. We further searched the non-indexed and gray literature using Google Advanced Search. Keywords were adapted to each database (S1). Studies were imported into the Covidence© platform for screening and adjudication. The search methodology and study selection were performed in accordance with PRISMA guidelines (Fig. 1; S2)¹⁸.

Study selection

Duplicates were removed using the Covidence© platform. Titles were screened independently and only included if they pertained to the management or treatment of adults (age ≥ 18 years) with sepsis in LMIC. Country-specific income classifications were applied as defined by the World Bank for fiscal year 2022¹⁹. Each abstract was screened by two independent reviewers, studies were excluded if they were review articles, case reports, vaccine trials, simulation studies, or descriptive or epidemiological studies without a clinical intervention. Given the heterogeneity in the availability of diagnostic and monitoring tools, only studies measuring the effect of fluid and/or antibiotic administration were included. Studies focused on specific pathogens or infectious diagnoses were excluded. We further excluded studies that did not report in-hospital mortality. Studies conducted in both LMIC and high-income settings were included only if data from LMIC could be disaggregated. Disagreements between screeners were adjudicated by a third independent reviewer. Relevant studies then underwent full-text review with data abstraction by two independent reviewers.

Data Extraction and Analysis

Data on the volume, type, and rate of intravenous fluids administered and the timing of antibiotic delivery were extracted into excel from the selected studies and analyzed. Analyses were limited to the volume of fluids delivered within 6 hours of presentation where available, as this has been associated with sepsis survival⁵. In studies reporting only total volume of intravenous fluids delivered, we used the average weight of adults in the given country or region to estimate weight-based fluid administration²⁰. Given inconsistent reporting of antibiotic type and regional and temporal differences in antibiotic availability, we focused on time to antibiotic delivery. Only participants with known vital status at end of follow-up for the primary outcome were included. The primary outcome of interest was the odds-ratio of in-hospital mortality. Where this metric was unavailable, the first reported mortality outcome was evaluated and odds ratios were calculated using the available data. Given differences in reported covariates and adjustment for confounders, crude odds ratios were reported. A significance threshold of p < 0.05 was applied throughout the analysis. Where key data were missing or discordant, we attempted to contact the study’s authors for clarification.

The quality of each study was assessed independently by four authors, with discrepancies adjudicated by consensus. For observational studies, quality was assessed using a modified Newcastle-Ottawa scale²¹. For clinical trials, quality was assessed using the Cochrane Risk of Bias Tool²².

The database search identified a total of 22,088 unique articles (Fig. 1), of which 26 studies were included in the review (Table 1). The publication dates of the included studies ranged from 2007 to 2022. Only two studies were published prior to 2010, and eighteen were published in 2016 or later.

Of the 26 studies, seven were conducted in sub-Saharan Africa, nine in Latin America and the Caribbean, six in East Asia and the Pacific, and four in the Middle East. The majority of the studies were conducted in upper-middle-income settings (15 of 26; 58%). Across the studies, a total of 15,650 patients were included (Table 1), of whom 3,198 (20%) were in lower-middle-income or low-income countries. Eighteen of the 24 observational studies were considered high quality (Newcastle-Ottawa score of ≥ 7). The two randomized control trials^{11, 12} had low total risk of bias (Table 1).

Table 1. Included studies: study location, population, and quality metric.
							Study Quality*
Author	Citation #	Year	Journal	Country	Income Designation	Study Type	Selection	Comparability	Outcome	Total
Amir A	23	2016	J Crit Care	Uganda	Low Income	Observational	4	1	3	8
Amir A	24	2017	J Crit Care	Uganda	Low Income	Observational	4	2	2	8
Andrews B	12	2014	Crit Care Med	Zambia	Lower Middle	Clinical Trial	Low	High	Low	Low
Andrews B	11	2017	JAMA	Zambia	Lower Middle	Clinical Trial	Low	High	Low	Low
Arulappen A	43	2022	Antibiotics	Malaysia	Upper Middle	Observational	3	2	3	8
Ascuntar J	41	2020	Journal of Intensive Care	Colombia	Upper Middle	Observational	4	2	3	9
Bhikoo R	24	2017	S Afr Med J	South Africa	Upper Middle	Observational	3	0	3	6
Bumanglag N	33	2019	Crit Care Expl	Phillipines	Lower Middle	Observational	3	2	3	8
Castaño P	42	2019	Trop Med Int Health	Colombia	Upper Middle	Observational	4	2	3	9
Conde K	29	2013	PLoS One	Brazil	Upper Middle	Observational	2	2	3	7
El Khuri C	36	2018	Emerg Med Int	Lebanon	Upper Middle	Pre-Post	3	2	3	8
Espinosa-Almanza C	34	2019	Rev Bras Ter Intensiva	Colombia	Upper Middle	Observational	4	2	3	9
Jacob S	31	2009	PLoS One	Uganda	Low	Observational	4	0	3	7
Jacob S	15	2012	Crit Care Med	Uganda	Low	Pre-Post	3	2	3	8
Jalili M	36	2013	Acta Med Iran	Iran	Upper Middle	Observational	3	0	2	5
Li Z	30	2013	Chin Med J	China	Upper Middle	Pre-Post	3	0	3	6
Machado F	27	2017	Crit Care	Brazil	Upper Middle	Observational	3	2	3	8
Nakornchai T	38	2014	J Med Assoc Thai	Thailand	Upper Middle	Observational	3	1	2	6
Noritomi D	28	2013	Intensive Care Med	Brazil	Upper Middle	Pre-Post	3	2	3	8
Papali A	25	2017	J Crit Care	Haiti	Low	Observational	4	2	3	9
Papali A	35	2017	J Crit Care	Haiti	Low	Pre-Post	3	0	3	6
Sanguanwit P	44	2022	Int J of Emerg Medicine	Thailand	Upper Middle	Observational	3	2	3	8
Savran Y	39	2016	Acta Medica Mediterr	Turkey	Upper Middle	Observational	3	2	3	8
Siddiqui S	32	2009	J Ayub Med Coll Abbottabad	Pakistan	Lower Middle	Observational	4	1	3	8
Tan I	40	2019	Phillipine J Int Med	Phillipines	Lower Middle	Observational	4	0	2	6
Yokota P	37	2014	PLoS One	Brazil	Upper Middle	Observational	2	2	3	7
		*Measured using the Newcastle-Ottawa Scale for assessing quality of observational studies, and Cochrane Risk of Bias tool for randomized control trials.

Intravenous Fluids

Fourteen studies were included in the analysis of the impact of intravenous fluids on mortality (Fig. 2, S3 Table )1^{1, 12, 23–35}. The type of fluid administered was specified as crystalloid in seven studies and was unspecified in seven. Twelve were observational studies and two were randomized controlled trials. Twelve studies reported fluid resuscitation at 6 hours, while two reported other fluid endpoints (4³² and 24³⁵ hours).

Three studies reported significantly lower mortality with more aggressive fluid resuscitation (OR 0.50, 95% CI 0.36–0.69; OR 0.33, 95% CI 0.11–0.95; OR 0.45, 95% CI 0.31–0.63)^{26, 28, 33} while two studies found increased mortality in the intervention arm which included more aggressive fluid administration than the other studies (OR 1.88, 95% CI 1.07–3.30; OR 4.80, 95% CI 1.94–11.89)^{12, 32} (Fig. 2). The remaining nine studies did not find a significant association between more aggressive fluid strategies and in-hospital mortality.

Among the three studies in which the intervention consisted of 30 mL/kg of fluid resuscitation while the control arm delivered less than 20 mL/kg of fluid, two (66%) demonstrated significantly reduced mortality (OR 0.50, 95% CI 0.36–0.69; OR 0.33, 95% CI 0.11–0.95)^{26, 33}, and no studies found an increase in mortality (Fig. 2, S3 Table). Among studies where the intervention and control arms delivered over 40 mL/kg and over 20ml/kg respectively, all studies demonstrated greater odds of mortality in the intervention arm, with one study finding a statistically significant difference (OR 1.88, 95% CI 1.07–3.30)¹². Finally, among the two studies in which both the intervention and control arm delivered less than 20ml/kg of fluid, no mortality benefit was seen^{23, 31, 32}, with one study showing increased mortality in the intervention arm (OR 4.80 CI 1.94–11.89)³².

When stratified by region, one study conducted in sub-Saharan Africa demonstrated statistically significant reduction in mortality with moderate fluid resuscitation (≥ 30mL/kg vs < 30mL/kg) (OR 0.33, 95% CI 0.11–0.95)²⁶, while one study demonstrated a significant increase in mortality with an aggressive fluid resuscitation strategy (57.7 mL/kg vs 32.9 mL/kg) (OR 1.88, 95% CI 1.07–3.30)¹². In Latin America and the Caribbean, one study demonstrated significant reduction in mortality with moderate fluid resuscitation (≥ 20mL/kg to < 20mL/kg) (OR 0.45, CI 0.31–0.63)²⁸. Of studies in Asia, one study showed significant reduction in mortality with moderate fluid resuscitation (35.4mL/kg vs 17.7 mL/kg) (OR 0.50, 95% CI 0.36–0.69), while another demonstrated an increase in mortality associated with minimal fluid resuscitation (≥ 17.3 mL/kg compared to < 17.3 mL/kg) (OR 4.80 CI 1.94–11.89)³².

Time to Antibiotic Administration

Fifteen studies were included in the analysis of time to antibiotic delivery on mortality (Fig. 3, S1 Table )2^{4, 25, 27, 28, 30–32, 36–44}. Among these studies, only two specified the type of antibiotic delivered. Among 13 studies evaluating antibiotic delivery within 1–3 hours, 8 showed significant mortality reduction (61.5%)^{27, 28, 32, 36, 37, 39, 40, 43}. Notably, in two studies in which antibiotics were delivered after 3 hours, neither found a mortality benefit to earlier administration^{23, 25}. The effect of early antibiotics on mortality was observed across regions (Fig. 3).

Intervention Bundles

Six studies were included in the analysis of the impact of combined intervention bundles, including both fluids and antibiotics, on sepsis mortality^{11, 12, 15, 30, 35, 45}. Three studies demonstrated a significant reduction in mortality^{15, 30, 45}, while one study reported increased mortality with the implementation of the full intervention bundle¹² (S3 Table). Among the studies reporting lower mortality with intervention bundles, Jacob et al (2012) delivered 1L bolus (16.5 ml/kg) in the intervention arm and titrated further resuscitation based on systolic blood pressure¹⁵, Li et al (2013) delivered 20 ml/kg of crystalloid³⁰, and El Khuri et al (2019) delivered between 1L (17 ml/kg) and 2L (35 ml/kg)⁴⁵. In the two studies where initial (< 1 hr) control arm fluid resuscitation was reported^{15, 30}, both administered less than 20mL/kg. In the study reporting increased mortality with intervention bundles, Andrews et al (2017), both the intervention and control groups received more than 30 ml/kg of fluid resuscitation¹².

Across the included studies, all sites delivered antibiotics within 3 hours. However, there was heterogeneity in antibiotic administration in the control groups: all three studies demonstrating a significant mortality benefit with bundle administration reported more rapid antibiotic delivery in the intervention arm^{15, 30, 45} while the study demonstrating increased mortality with bundle administration reported no significant difference in time to antibiotic administration¹² (S3 Table).

Overall our review found that early antibiotic administration (within 3 hours) and moderate fluid resuscitation (30 mL/kg in 6 hours). Combined, these strategies demonstrated a reduction in mortality across healthcare settings on three continents.

There is substantial evidence that early administration of broad-spectrum antibiotics reduced sepsis mortality. Our review did not provide enough data on a specific type or combination of antibiotics to make a recommendation. Most studies used the descriptor “broad-spectrum” antibiotics. We recommend the use of broad-spectrum antibiotics based on local availability, cost, and resistance patterns, as outlined in the World Health Organization’s (WHO) prescribing guide for LMIC^{5, 46}. Interestingly, none of the included studies reported empiric treatment of malaria or tuberculosis, two common etiologies of global sepsis mortality^{2, 9}.

Evidence-based guidelines from high income settings promote early and aggressive fluid resuscitation with at least 30 mL/kg in 6 hours, without clear stipulations for preventing over resuscitation^{5, 47}, based on the universal availability of positive pressure ventilation and vital sign monitoring⁷. When evaluating the amount of fluid resuscitation provided for sepsis care in LMIC, we observed a “goldilocks” effect, where both overly-aggressive resuscitation (> 40 ml/kg in 6 hours)^{11, 12} and insufficient resuscitation (< 20 ml/kg in 6 hours)³² appeared to be associated with increased mortality. In LMIC settings, ventilators and monitors are not frequently available, and thus over-resuscitation is as deadly as under-resuscitation⁴⁸. Additionally, the study setting appeared to modify the effect of fluids on mortality. All of the studies that demonstrated a significant reduction in mortality with fluid administration strategies were in urban, tertiary care hospitals in Upper Middle-Income Countries (Lebanon, South Africa, Brazil, and China)^{26, 28, 30, 45}. Study location can have a dramatic influence on the effectiveness of resuscitation. The prevalence of comorbid illness, including HIV, TB, and malnutrition, and the lack of ventilators, pulse oximetry, and nursing staff to adequately monitor over-resuscitation in lowest-resource settings may explain some of this variation^{12, 23}. In keeping with recommendations from the African Federation for Emergency Medicine⁴⁹ and the WHO Integrated Management of Adult Illness²⁴ guidelines, we recommend pairing fluid resuscitation with frequent monitoring for signs of fluid overload.

The majority of the included studies were rated “high quality and “low” risk of bias but this should be taken within context. Although each individual study may be well designed, the heterogeneity between studies limits meaningful inference about the measured interventions, making a metanalysis not feasible. Given the disparate nature of practice environments in low-resource settings, even if studies are well designed, if they are measuring different populations one cannot easily combine their data to draw broad conclusions.

Practice considerations

What does this mean if you are developing a sepsis management protocol for your institution? A one-size-fits-all approach is not supported by the existing literature. Care guidelines should be locally-tailored based on the clinical infrastructure, and availability of monitoring and respiratory resources^{3, 7, 48, 50}. For example, in rural low-resource environments with no ventilator support, empiric fluid resuscitation should be more slowly administered. Local stakeholder engagement is key when developing context-specific guidelines, including those knowledgeable on current antibiotic resistance patterns and the provision of definitive care. All management guidelines should deliver feasible strategies that cover the core tenets of sepsis management, early diagnosis, continuous monitoring, resuscitation, and definitive care⁷.

Limitations of the study and the available evidence

The heterogeneity of study sites, sepsis intervention strategies, outcome metrics, and timeframe for outcome measurement made meta-analysis unfeasible. Secondly, many of the available studies are observational in nature, and, as a result, are subject to confounding by factors including patient comorbidities, type of infection, and severity of illness. As more aggressive fluid resuscitation is likely administered to more severely ill patients, we believe the bias in the observed mortality difference between moderate and little fluid resuscitation would be toward the null. However, this confounding by indication may be at play in comparing the aggressive versus moderate fluid volumes delivered. Interestingly, the only study that demonstrated an increased risk of mortality with bundle implementation reported multivariable adjusted results, adjusting for baseline Simplified Acute Physiology Score, with preserved effect¹². Thirdly, many studies used set volume fluid strategies while others used weight-based resuscitation. To allow for comparisons between studies we assumed country-average body weights that may not be representative of a particular study location or critically-ill patients. Additionally, we cannot exclude differential recognition of sepsis and the impact on deployment of interventions. Some of the observed differences in mortality may be due to earlier recognition of infection rather than an impact of the intervention(s) themselves. Finally, this review was limited to the English language literature.

While resource limitations and co-morbidities prevalent in low-resource environments makes fluid over-resuscitation dangerous, this should not imply that the basics of sepsis care do not apply in LMIC. Current data supports adhering to the central tenets of early antibiotics and fluid resuscitation. We found that a moderate fluid resuscitation strategy coupled with early antibiotic administration is appropriate for treating sepsis in these settings. This is also in keeping with current international sepsis care guidelines^{5, 47}. There is a need for more data, and better cohesion among studies conducted to develop sepsis guidelines informed by the underlying regional epidemiology, co-morbidities, and resource availability.

Funding

There was no funding contributions for this study.

Completing Interest Declaration

There are no competing interests by any authors.

Author Contribution

BH, AJ, and GL are responsible for the primary design of the study. Four authors, AJ, GL, TL, and OV are responsible for screening studies, primary data extraction, analysis and quality interpretation. NA, AR, KL, and PC contributed to article review and data extraction. All authors approved the final version of the article for submission and agree to be personally responsible for their individual contributions.

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No competing interests reported.

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Sepsis Management in Low- and Middle-Income Countries: A Systematic Review

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