Effect of Fluid Resuscitation Strategies for Obese Patients with Sepsis and Septic Shock: A Systematic Review

Purpose As the Surviving Sepsis Campaign (2021) recommended, patients with sepsis should be given a liquid infusion of 30 ml/kg (ideal body weight). However, the strategy may result in insufficient resuscitation for obese patients with sepsis. Therefore, we conducted a systematic evaluation of the effectiveness of the initial resuscitation strategy in obese sepsis patients. Materials and methods A computer search of PubMed, Embase, Cochrane library, and other databases collected cohort studies from the beginning of the survey to December 2021 to include articles evaluating initial resuscitation strategies for sepsis-obese patients. Results Of the six studies included, five used ideal body weight infusion strategies, and three used actual body weight infusion strategies. Differences in fluid volume were observed between the two strategies, but no significant difference was observed in the mortality of obese sepsis patients. In addition, there may be an infusion strategy other than the above two infusion methods, and the safety and efficacy of the new infusion strategy are unclear. The obesity paradox has been observed in most infusion strategies. Conclusion The association between obesity and infusion strategy has rarely been investigated in patients with sepsis and septic shock, and the existing results are conflicting. The risk of bias in all included studies was moderate or high. Before providing broad recommendations on the optimal first resuscitation approach to lower the chance of mortality, further clinical trials, and prospective research need to be done.


Introduction
Over the past decades, the global prevalence of overweight and obesity increased steadily with the improvement of living standards and becoming a public health problem. According to the latest epidemiological studies, more than one-fifth (20.6%) of adolescents and one-third (38.9%) of adults suffer from obesity in the United States [1,2], while the prevalence of overweight, general obesity, and abdominal obesity were up to 38.80, 13.99, and 43.15% respectively in China [3]. It is well known that obesity is closely associated with the occurrence of diabetes, hyperlipidemia, cardiovascular and cerebrovascular diseases [4]. The previous 1 3 studies have demonstrated that obese patients were closely related to a higher incidence of surgical site infection [5], postpartum infection [6], or even COVID-19 [7]. In critical care settings, treating obese people has long been a concern.
The early fluid resuscitation strategy improves prognosis and reduces organ failure and mortality risk in patients with septic shock [8][9][10]. Despite SSC 2021(Surviving Sepsis Campaign) recommendations for standardized initial fluid resuscitation (30 ml/kg) [8], a few studies have shown that obese patients received lower relative fluid volume than nonobese patients [11]. The differences could originate from the infusion strategy. Determining whether the discrepancy will affect the prognosis of sepsis obese patients remains an open question. In addition, although it is known that obesity harms severe patients, there are many conflicting findings regarding the protection of obesity in patients with sepsis. This phenomenon is clinically known as the "obesity paradox" (lower mortality in obese people). The molecular mechanism underlying this paradox remains to be elucidated but likely results from different clinical factors and therapeutic interventions. It remains to be seen whether this phenomenon can be observed with the same infusion strategy.
Therefore, we conducted a systematic evaluation to explore the optimal fluid infusion strategy during initial resuscitation in obese patients with sepsis and whether the "obesity paradox" could be observed under the same infusion strategy.

Eligibility Criteria
The review question we tried to answer was: Does the initial infusion strategy according to SSC guidelines reduce mortality in obese sepsis patients? It was formulated in accordance with the PICOS (population, intervention, comparison, outcomes, and study type) criteria (Table 1). Studies were selected on the basis of the following criteria: (1) Observational studies or randomized controlled trials related to the use of crystalline or colloidal fluids for initial resuscitation in patients with obese sepsis or obese septic shock. (2) These studies classified the sepsis patients according to the basis of WHO (World Health Organization) obesity classification criteria; (3) IBW infusion strategy and non-IBW infusion strategy were used as the main comparison content. (4) Primary outcome measures report all-cause mortality or hemodynamics during hospitalization. Secondary outcome measures included length of ICU stay, endotracheal intubation, and other measures. We excluded reviews, letters, correspondence, editorials, and nonhuman studies, but the reference lists of these articles were searched to identify other potential studies.

Information Sources
The following electronic databases were assessed, covering studies published until December 2021: PubMed, Embase, Cochrane Library, OVID, China National Knowledge Infrastructure (CNKI), and Wanfang Database. No date or language restriction was used predefined while conducting this search.

Search Strategy
The terms 'obesity' and 'sepsis' were obtained during this search. No terms referring to interventions or controls were used to amplify our search strategy. In December 2021, database searches were performed using the terms 'overweight' or 'obesity' and 'sepsis' or 'Pyemia' and related terms to obtain the broadest possible results. Potentially eligible papers were searched by screening reference lists and grey literature.

Study Selection
Yijun Zhang and Minjie Wang searched independently, according to predefined inclusion and exclusion criteria. Duplicate literature deletion, title, and abstract screening for relevance were done using NoteExpress software (3.5.0.9054). Then, the full text was acquired to determine inclusion eligibility eventually. Disagreements were resolved by consensus-based discussion or by a third reviewer's opinion.

Data Extraction and Quality Assessment
Two reviewers (Yijun Zhang and Minjie wang) independently extracted data from each study using the extract table template. The extracted data were as follows: author information, year of publication, study type, BMI categories studied, sample size, the definition of sepsis, and outcomes. The primary outcome was the mortality of obese sepsis patients. Secondary outcomes included hospital length of

Data Synthesis and Analysis
Given the significant methodological and statistical differences between studies, combining data using meta-analysis techniques were considered inappropriate. This article reviews the literature on the effect of initial fluid resuscitation infusion on mortality in obese and overweight sepsis patients. A synthesis of narratives is presented.

Literature Search
Overall, we identified 40 records and included six original articles after eliminating duplicate and unqualified headlines. Figure 1 shows a detailed flow chart of the screening process.

General Characteristics of the Studies
From the time of publication, four of the included studies were published in the last 3 years. Geographically, four studies were performed in America and one in Europe. A multicenter study involving the United States, Canada, Saudi, and Arabia. All subjects were age 18 or older. The majority of studies were retrospective, and only one study was prospective. The primary characteristics of the six included studies are described in Table 2.

IBW Infusion Strategy
Of these, five studies used the IBW (ideal body weight) infusion strategy, with case fatality rates that ranged from 8 to 30.9%. After adjusting for population, condition, and treatment-related variables, Taylor et al. [12] found that the mortality rate of obese patients using the IBW infusion strategy was 16.1%. Ward and Kuttab et al. observed similar results [13,14]. In the study of Antal, only 49.3% of patients met SSC requirements when the initial resuscitation dose was administered in the first 3 h according to local guidelines, while fluid volume increased significantly in each group after subsequent dose adjustment, and all-cause mortality remained at 30.9% [15]. Kaseer et al. [16] found that severe sepsis progressed to septic shock in 18% of patients using the IBW infusion strategy and without the use of vasopressor. The above patients were reported as obese, with a mortality rate of 8%.

ABW Infusion Strategy
ABW (actual body weight) infusion strategy was used in three studies, and the mortality associated with this infusion strategy varied widely. Taylor

Other Strategies
Taylor et al. [12] adjusted the initial resuscitation fluid volume according to the recommended drug dose, and the fluid volume was between IBW and ABW. The mortality rate of the population using this infusion strategy was 15.3%.

Obesity Paradox
The retrospective analyses of an extensive American multicenter database reported by Taylor et al. reported. After adjusting for population, condition, and treatment-related variables, there was no significant difference in mortality between obese and non-obese patients with sepsis [12]. In another study, compared with regular patients, obese patients with septic shock had lower crude mortality (odds ratio (OR) 0.80, 95% confidence interval (95% CI) 0.66-0.97). Mortality was not statistically significant between the two groups after combining sepsis intervention and baseline characteristic multivariate logistic regression analysis [17]. However, Kuttab et al. discussed sepsis obesity in their subgroup and showed that the mortality rate of obese patients was lower than that of non-obese sepsis patients [14]. Most studies have observed an "obesity paradox" phenomenon, irrespective of differential baseline levels of obese patients.

Risk of Bias Assessment and Grade Profile Evidence
The details about the risk of bias were respectively shown in Table 3. ROBINS-I scale was used to evaluate literature quality. Two studies were classified as having a high risk of bias for included cohort studies. Kaseer et al. [16] could not determine whether the baseline results were reliable because they did not specify the infusion method or duration. Meanwhile, Kuttab et al. [14] did not report fluid data for obese patients, so we categorize them as high risk through discussion.

Discussion
This systematic review of observational studies assessed the effect in initial resuscitation effects of ABW compared to IBW in obese patients with sepsis. A total of six studies were included, and the results varied widely across studies, making it impossible to make a solid conclusion. The results  Table 3 The risk of bias assessment of included cohort studies by using the ROBINS-I tool of observational studies are subject to different factors and must be interpreted cautiously. In all studies, the risk of bias is moderate to high.

Survival Benefits of IBW and ABW
The SSC 2021 guidelines recommend using at least 30 mL/ kg (IBW) of crystalloid during initial fluid resuscitation. This initial recovery of fixed volume is based on observational evidence [18]. In the PROCESS [19], ARISE [20], and PROMISE [21] trials, the average amount of fluid received before randomization was also in the 30 mL/kg range, leading the guidelines to conclude that such infusion doses were generally accepted in the clinic [22]. However, the guidelines of the SSC do not deal with the obese population. It is worth noting that the obese population adopted distinct infusion strategies that may differ both in IBW and ABW. For different infusion strategies, the amount of fluid obtained could vary greatly. In an observational study of fluid resuscitation in burn patients, the fluid volume of the obese patients with ABW was compared to that of the normal-weight patients, showing a significant reduction. Moreover, obese patients received more fluid after adjusting the infusion strategy to IBW [23]. Arabi et al. [17] exclusively investigated different intervention results of obese sepsis patients and found that the obese and morbidly obese groups received fewer fluids in the initial resuscitation stage. Many studies [15][16][17]24] have mentioned the difference in fluid infusion between obese and non-obese patients. In the first 12 h after confirmation of severe sepsis, the non-IBW group received a higher amount of fluid, with 13% of patients requiring mechanical ventilation initiation versus 2% in the IBW group. This difference may be due to pulmonary edema caused by excessive resuscitation. Additionally, fluid boluses could lead to a positive fluid balance and excess fluid in the interstitial space [25,26], resulting in tissue edema, decreased oxygen delivery, and increased mortality [27][28][29]. The effect of this fluid difference is the source of debate over IBW and ABW infusion strategies.
After comparing IBW and non-IBW infusion strategies in obese sepsis patients, Kaseer et al. found that mortality was 8% in the IBW group and 4% in the non-IBW group [16]. On the contrary, Antal et al. found that patients' hemodynamic indicators improved after adjusting the infusion strategy to IBW [15]. We reason that these seemingly conflictive results might be due to the following reasons. The minimal small sample size in some studies may have contributed to the result. Complications may occur around initial fluid recovery, and these factors were not considered in current studies. Another possibility is that patients with fewer physical disorders themselves receive less fluid than regular patients. However, from a clinical point of view, the risk of fluid insufficiency in initial resuscitation is significant. The SSC recommended infusion dose may not be the optimal infusion strategy, but there is no evidence of higher quality that has shown that ABW is more effective than IBW. In addition, Taylor et al. [12] propose a new management strategy and found the method has potential survival benefits in obese patients. The adjusted body weight dose for obese patients will mean a lower fluid volume than the traditional actual body weight dose but a higher fluid volume than the ideal body weight dose. The strategy showed a survival benefit of fluid administration based on weight adjustment compared with the ideal weight administration strategy (OR 0.29, 95% CI 0.11-0.79). This suggests that better infusion strategies may exist for obese sepsis patients. However, the safety and effectiveness of this infusion strategy are still unknown and need to be validated.
Future studies or guidelines need to define more significant differences in the amount of fluid needed for resuscitation in different populations and establish methods for assessing the volume needs of obese patients, taking into account differences in body mass index in these patients.

Is there an"Obesity Paradox" in Obese Sepsis
Patients?
At least 25% of adults admitted to ICU in a developed country have an overweight, obese, or morbidly obese body mass index. Although there is much evidence that obesity reduces overall life expectancy, most observational studies show that absolute mortality is 5-15% lower in obese patients than in normal-weight patients [30]. Higher metabolic levels, activation of the renin-angiotensin system, and the inability of adipose tissue to produce immunomodulatory molecules may account for the survival advantage [31]. There is much evidence that overweight and obesity may have a protective effect on patients with sepsis, but morbid obesity is not included [32][33][34][35]. Better ICU survival has been observed in overweight/obese patients compared to those who are underweight, have a normal weight, or are morbidly obese. The "obesity paradox" results remain inconsistent and contradictory in our systematic review. Although the balance of the infusion strategy baseline has been controlled, there may be several reasons to account for this discrepancy. The leading causes may be methodological problems, including selection bias in patients with sepsis, analysis of uncontrolled confounding factors such as smoking, potential site, type of infection, nutritional status, treatment style, race, etc. In addition, the small sample size is also a factor.

Future Directions
The limitations of the current literature suggest the need for studies to provide a high level of evidence on infusion strategies and doses for initial resuscitation in obese patients with septic shock and to clarify their status in treating obesity in this particular population. Given the growing number of obese people and the specificity of this population, evaluation of infusion strategies, comorbidities, and costs in normal-weight patients cannot be assumed to apply to obese people.

Conclusions
In patients with sepsis and septic shock, the relationship between obesity and infusion strategy has only occasionally been researched, and the available data are contradictory. The risk of bias in all included studies was moderate or high. In conclusion, more clinical trials and prospective studies should be conducted before making general recommendations about the best initial resuscitation strategy to reduce the risk of death.