Surgical Infection Society Research Priorities: A Narrative Review of Fourteen Years of Progress

Abstract

Background:

In 2006, the Surgical Infection Society (SIS) utilized a modified Delphi approach to define 15 specific priority research questions that remained unanswered in the field of surgical infections. The aim of the current study was to evaluate the scientific progress achieved during the ensuing period in answering each of the 15 research questions and to determine if additional research in these fields is warranted.

Methods:

For each of the questions, a literature search using the National Center for Biotechnology Information (NCBI) was performed by the Scientific Studies Committee of the SIS to identify studies that attempted to address each of the defined questions. This literature was analyzed and summarized. The data on each question were evaluated by a surgical infections expert to determine if the question was answered definitively or remains unanswered.

Results:

All 15 priority research questions were studied in the last 14 years; six questions (40%) were definitively answered and 9 questions (60%) remain unanswered in whole or in part, mainly because of the low quality of the studies available on this topic. Several of the 9 unanswered questions were deemed to remain research priorities in 2020 and warrant further investigation. These included, for example, the role of empiric antimicrobial agents in nosocomial infections, the use of inotropes/vasopressors versus volume loading to raise the mean arterial pressure, and the role of increased antimicrobial dosing and frequency in the obese patient.

Conclusions:

Several surgical infection-related research questions prioritized in 2006 remain unanswered. Further high-quality research is required to provide a definitive answer to many of these priority knowledge gaps. An updated research agenda by the SIS is warranted at this time to define research priorities for the future.

In 2006, leading experts in the Surgical Infection Society (SIS) proposed a research agenda based on areas of defined importance in which there were clear knowledge gaps [1]. The priority research agenda was developed using a modified Delphi process to attain consensus among more than 60 experts to determine the most important questions on which to focus future research efforts. The report identified common themes—optimal antimicrobial use, prevention of surgical site infections (SSIs), and treatment of sepsis and septic shock. Areas of long-standing debate (hypertonic saline for resuscitation and the role of fever suppression) were identified as enduring questions that still required answers.

The SIS, through its Scientific Studies Committee (SIS-SCC) believes there to be value in reviewing our previous research agenda, evaluating the progress to date, and using this knowledge to define and focus our future research priorities in the current resource-constrained environment. In this narrative review, a concise summary of the relevant literature is presented to determine if each research question has been studied sufficiently and answered.

Materials and Methods

Using the framework of the research agenda published in 2006, current members of the SIS-SSC reviewed the current literature available to address each question. First, literature published up to May 2020 was searched to identify all English-language studies that attempted to address each of the defined questions (National Center for Biotechnology Information [NCBI]; https://www.ncbi.nlm.nih.gov). Search terms were derived from each specific question. The search was not limited to any specific study design to ensure an important study was not omitted inadvertently. Second, relevant literature was analyzed and summarized critically by one of the co-authors. Third, the evidence published to date for each question was evaluated to determine if the question was answered definitively or remains unanswered. Finally, all co-authors evaluated, in a blinded fashion, the summarized literature review and assessed whether the question had been answered. Each question was deemed to be either (1) answered definitively or (2) not yet answered, either fully or in part, and in need of further study. Disagreements were reviewed and resolved by one or more of the co-authors to achieve consensus. Priority questions below are listed verbatim from the 2006 report. The results of this analysis are summarized in Table 1.

Table 1.

Current Status of 2006 Research Agenda Priorities

Rank	Question	Category	Sufficient data to answer question?	Answer to question
1	Does strict glycemic control compared with standard care reduce the risk of surgical site infection in patients undergoing abdominal surgery?	Prevention of SSI	Yes	Tight glycemic control reduces the risk of SSI
2	Does a fixed short term of antimicrobial therapy (e.g., 5 d) in patients with intra-abdominal infections affect the risk of microbiological or clinical cure compared with patients receiving therapy for a duration determined by clinical parameters (resolution of temperature and WBC)?	Intra-abdominal infection	Yes	Short course antimicrobial therapy is equally effective
3	Is there any difference in antimicrobial resistance, ICU length of stay, and mortality rate in patients with suspected nosocomial infections who receive early, empiric antimicrobial therapy compared with an approach where antimicrobial is withheld until culture data are available?	Nosocomial infection	No	Requires further study
4	Will control of blood glucose in the high normal range (100–150 mg/dL) in infected surgical ICU patients achieve equivalent reduction in deaths compared with intensive insulin therapy to maintain blood glucose between 80–110 mg/dL?	Sepsis/septic shock	Yes	No mortality benefit with IIT vs. conventional therapy
5	Is there any survival benefit to raising blood pressure pharmacologically in adult patients with septic shock with inotropes/vasopressors compared with volume loading and tolerance of lower MAP?	Sepsis/septic shock	No	Requires further study
6	Does avoidance of systemic hypothermia and increased arterial oxygenation in the early post-operative period reduce the risk of surgical site infections compared with standard care?	Prevention of SSI	No	Requires further study
7	Does resuscitation with hypertonic saline reduce the incidence of organ dysfunction, nosocomial infection, or death in patients with septic or traumatic shock?	Sepsis/septic shock	Yes	No benefit with HTS resuscitation
8	Does routine antimicrobial prophylaxis with a 2–4-wk course of a carbapenem compared with placebo affect the risk of infected necrotizing pancreatitis, need for operative intervention, antimicrobial resistance, or death among those admitted with severe necrotizing pancreatitis?	Pancreatitis	Yes	No benefit with carbapenem prophylaxis
9	Is there a difference in the rate of SSIs, non-union, cost, or antimicrobial resistance in patients with open fractures treated with 24 vs. 72 h of antimicrobial prophylaxis? Separate strata for heavily contaminated wounds where 72 h would be compared with 7 d	Prevention of SSI	No	Requires further study
10	Does antioxidant therapy improve the morality rate or reduce subsequent organ dysfunction compared with placebo in patients with sepsis?	Sepsis/septic shock	No	Requires further study
11	Does an increase in antimicrobial dose or frequency reduce the incidence of SSIs or cure rates (for pharmacokinetics established infections) in the obese patient?	Antimicrobial pharmacokinetics	No	Requires further study
12	Is there any difference in ventilator days, ICU length of stay (LOS), cost, antimicrobial resistance, mortality rate, and clinical or microbiologic cure rates in patients with ventilator-associated pneumonia (VAP) receiving seven vs. 14 d of antimicrobial therapy?	Ventilator-associated pneumonia	Yes	No difference between 7 and 14 d of antimicrobial therapy.
13	Does rotation of empiric antimicrobial regimens in the ICU affect clinical cure rates or the emergence of resistant organisms compared with standard practice? If so, what is the optimal interval?	Nosocomial infection	No	Requires further study
14	Does routine fever suppression affect clinical or microbiologic cure rates in septic surgical patients?	Sepsis/septic shock	No	Requires further study
15	Is there any difference in cost, sensitivity, and specificity of BAL, mini-BAL, sputum sample, CXR and chest CT as diagnostic tests in those with suspected VAP?	Ventilator-associated pneumonia	No	Requires further study

BAL = bronchoalveolar lavage; CT = computed tomography; CXR = chest radiography; ICU = intensive care unit; IIT = intensive insulin therapy; SSI = surgical site infection; VAP = ventilator-associated pneumonia.

Results

Priority 1. Does strict glycemic control compared with standard care reduce the risk of surgical site infection in patients undergoing abdominal surgery?

Several studies have demonstrated a clear association between hyperglycemia and SSI in patients undergoing abdominal surgery [2 –8]. The first large randomized controlled trial (RCT) examining tight glycemic control (TGC) (target blood glucose [BG] range 80–110 mg/dL) demonstrated a significant reduction in deaths [9]. This was followed by the NICE-SUGAR trial, which compared TGC (target BG range 81–108 mg/dL) with conventional therapy [10]. Although the NICE-SUGAR study included a substantial proportion of post-operative patients, it did not report on SSI as an outcome in either arm. A single-center RCT of 61 surgical patients both with and without diabetes mellitus in an intensive care unit (ICU) setting showed a marked decrease in SSI with TGC (target glucose range 80–120 mg/dL) from 30% to 7%, but there were significantly more hypoglycemic events in the strict-control group [13]. A larger single-center RCT of 447 surgical patients who underwent hepatobiliary–pancreatic surgery also showed a decrease in SSI with TGC (80–110 mg/dL) from 9.8% to 4.1% (p = 0.028)[14]. A meta-analysis of 15 RCTs in 2,836 surgical patients demonstrated a significant benefit in reducing SSI with a TGC protocol compared with a conventional protocol [15]. The summary estimate showed a significant benefit for TGC compared with a conventional glucose control protocol in reducing SSI (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.29–0.64; p < 0.001). A significantly higher risk of hypoglycemic events was noted for the intensive-control group compared with the conventional group (OR 5.55, 95% CI 2.58–11.96), with no higher risk of death (OR 0.74, 95% CI 0.45–1.23)

Summary: Tight glucose control reduces the risk of SSI in patients undergoing abdominal surgery.

Priority 2. Does a fixed, short term of antimicrobial therapy (e.g., five days) in patients with intra-abdominal infections affect the risk of microbiological or clinical cure compared with patients receiving therapy for a duration determined by clinical parameters (resolution of temperature and white blood cell [WBC] count)?

Since the publication of the SIS research agenda in 2006 [1], complicated intra-abdominal infection (cIAI) has continued to contribute to the global burden of disease in general and surgery patients specifically. The literature suggests that the morbidity rate ranges from 5% in otherwise healthy patients to 50% in high-risk patients or those with critical illness [17,18]. Despite the SIS guideline recommendation for a short duration of antibiotics [19], most physicians continue to treat patients beyond the resolution of signs of infection (e.g., WBC count, fever, abdominal tenderness, ileus), often for as long as 14 days after source control [20 –22]. In 2015, the STOP-IT trial led by members of the SIS answered this exact question [23]. The study randomized 518 patients who had undergone adequate source control of a cIAI to receive antibiotics until two days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group) or to receive a fixed course of antibiotics (experimental group) for 4 ± 1 calendar days. The control group received on average 8 days of antibiotics. The experimental group received on average 4 days of antibiotics (Table 2). The incidence of the primary outcome, a composite incidence of SSI, recurrent IAI, and death, was not different between groups (21.8% versus 22.3%; p = 0.92) (Table 2). As a result, the authors concluded that 4 days of antibiotics is sufficient to treat patients with cIAI after adequate source control. Subsequent post-hoc analyses confirmed that, even in the subsets of patients presenting with sepsis or fungal abdominal infections or those whose source control was exclusively percutaneous, a short-term course of antibiotics was sufficient [24 –26]. However, the mean Acute Physiology and Chronic Health Evaluation (APACHE) II score in this trial was relatively low at 10.1; and thus, the results may not be generalizable to patients presenting with septic shock.

Table 2.

Primary and Major Secondary Outcomes in STOP-IT Trial

Outcome measure	Control group (N = 260)	Experimental group (N = 257)	P
Composite outcome (SSI, recurrent abdominal infections, death) (%)	22.3	21.8	0.92
SSI (%)	8.8	6.6	0.43
Recurrent abdominal infections (%)	13.8	15.6	0.67
Death (30 d) (%)	0.8	1.2	0.99
Duration of therapy for index infection (d)	8.0	4.0	< 0.001
Antimicrobial-free days	21	25	< 0.001

SSI = surgical site infection. Data abstracted from reference 23.

Summary: A short course of antibiotics is effective in patients with cIAI after obtaining source control.

Priority 3. Is there any difference in antimicrobial resistance, intensive care unit length of stay, or mortality rate in patients with suspected nosocomial infections who receive early, empiric antimicrobial therapy compared with an approach where antimicrobial is withheld until culture data are available?

The literature regarding the use of empiric antimicrobial agents specifically in patients with suspected nosocomial infections is limited. However, examining the evidence regarding the use of empiric antibiotics in patients with sepsis may provide guidance. A prospective study of 356 patients with sepsis by Barie et al. demonstrated that delayed antibiotic administration was an independent predictor of death (OR 1.02; 95% CI 1.003–1.038/30 min delay) [27]. Similarly, Kumar et al. reported that every hour of delay in antibiotic administration in septic shock decreased survival by 7.6% [28]. Additional studies of early antibiotic administration reported a similar impact on death [29,30]. Based on the results of these studies, the Surviving Sepsis Campaign (SSC) guidelines strongly recommended administration of empiric antibiotics as soon as possible in patients with sepsis or septic shock [31].

Two large retrospective studies published in 2017, with 35,000 and 49,331 patients, reported significant increases in the mortality rate in patients with sepsis for each hour of delay in antibiotic administration, with the highest risk of death seen with delayed antibiotics in those patients with septic shock [32,33]. However, important limitations of these studies have led to debate regarding the SSC recommendations. Most studies were retrospective, and as a result, the independent contribution of factors such as concomitant treatments within sepsis bundles and appropriateness of antibiotic choices and source control are difficult to elucidate without a prospective study design. Most notably, though, the majority of patients included in the above studies had septic shock; and thus, extrapolation of these results to patients with sepsis but without shock is difficult without additional evidence to support this practice [27 –30].

With respect to surgical infections, Hranjec et al. evaluated the impact of antibiotics in a prospective before–after cohort study of 1,483 patients admitted to a surgical ICU. Initiation of antibiotics when objective evidence of infection had been obtained (“conservative” approach) was associated with a lower mortality rate, greater likelihood of initiation of an appropriate therapeutic regimen, and a shorter mean duration of therapy compared with an “aggressive” approach of empiric antibiotic initiation on the basis of suspicion alone [34]. There was no difference in terms of hospital or ICU length of stay (LOS) with the “aggressive” versus “conservative” initiation of antibiotics in patients admitted to the ICU with sepsis.

The first RCT of early antibiotics for sepsis, the PHANTASi trial, evaluated the effects of initiating the first dose of antibiotic in the ambulance versus in the emergency department (ED) [35]. The early intervention group received an antibiotic 96 min sooner on average than the usual care group; however, there was no mortality benefit. A multicenter prospective trial of 2,454 patients also demonstrated no difference in the mortality rate using antibiotics in the first hour or within 3 h in the ED [36]. Two systematic reviews and a meta-analysis also demonstrated no impact on the mortality rate for each hour of delay in treatment [37] and no difference in deaths between patients receiving antibiotics in the immediate (0–1 h) versus early (>1 h–3 h) periods, including subgroup analysis of patients with septic shock [38]. Despite this evidence, the latest update of the SSC guidelines in 2018 suggested a 1-h bundle to initiate treatment as early as possible for all patients suspected of having sepsis, including those with nosocomial infections [39]. This bundle has been challenged and debated [40 –42], and more recently, the Infectious Diseases Society of America (IDSA) recommended that early antibiotic administration be reserved for patients in septic shock (for which the evidence is greatest) and to use caution in patients with suspected sepsis without shock until the diagnosis is confirmed [43].

Early administration of antibiotics may benefit some patients; for others, there is a potential for harm. Fewer than 60% of patients admitted to the ICU for suspected sepsis are confirmed to have an infection; only a subset of those patients have a bacterial infection [44 –50]. Uninfected patients and patients with viral or fungal infections are subjected to antibacterial-related risks without benefit. Early administration also encourages overuse of antibiotics [51], which leads to increased rates of Clostridioides difficile infection, more antibiotic resistance, and disruption of the gut microbiome [52 –54]. There are no high-quality studies examining the effect of empiric therapy of nosocomial infections compared with antibiotic initiated after culture and susceptibility test results are available.

Summary: Early empiric antibiotic administration reduces the mortality rate in patients with septic shock. In contrast, in patients without shock or with a lower probability of infection, delaying antibiotics until definite evidence of an infection is available is a reasonable approach. Due to limited studies, the effect of empiric therapy of nosocomial infections on antibiotic resistance, ICU length of stay, and death remains unanswered.

Priority 4. Will control of blood glucose in the high normal range (100–150 mg/dL) in infected surgical intensive care unit patients achieve equivalent reduction in the mortality rate compared with intensive insulin therapy to maintain blood glucose between 80 and 110 mg/dL?

The RCT of TGC (BG range 80–110 mg/dL) in the surgical ICU in 1,548 patients conducted by Van den Berghe et al. identified a significant reduction in both morbidity and death; however, patients with sepsis were not analyzed separately [9]. A nearly identical study performed in 1,200 medical ICU patients by the same group failed to identify the same mortality benefit [55]. The multi-center VISEP trial by Brunkhorst et al. evaluated TGC (goal BG: 80–110 mg/dL) versus conventional therapy (goal BG:180–200 mg/dL) in patients with sepsis. In their mixed medical/surgical cohort of 537 patients, no differences in the mortality rate were identified at 28 or 90 days [56].

The similar COIITSS trial, a multicenter RCT that evaluated TGC (goal BG 80–110 mg/dL) versus conventional therapy (local preference) in 509 critically ill medical and surgical patients with sepsis, likewise did not demonstrate a mortality benefit with TGC [57]. Neither the VISEP nor the COIITSS trial evaluated surgical patients as a specific subgroup. Finally, the NICE-SUGAR trial is the largest study of TGC (goal BG 81–108 mg/dL) versus conventional (goal BG <180 mg/dL) therapy in the literature (6,104 patients). The authors saw a lower overall mortality rate at 90 days with conventional therapy. Interestingly, whereas this study also was performed in a mixed medical/surgical cohort, those patients who had an operative indication for admission (2,232 patients) also had more deaths with TGC (OR 1.31; 95% CI 1.07–1.61). They found no differences in the mortality rate for the subgroup with severe sepsis [10].

A meta-analysis of 26 RCTs, which contained the NICE-SUGAR trial data, evaluating TGC compared with conventional therapy among critically ill patients demonstrated that patients admitted to a surgical ICU had a mortality benefit with TGC (relative risk [RR] 0.63; 95% CI 0.44–0.91) [58]. The different targets of TGC (BG ≤6.1 mmol/L versus ≤8.3 mmol/L) did not influence either deaths or the risk of hypoglycemia. However, the studies included in the surgical ICU portion of this meta-analysis did not include patients with active infection as a specific subgroup or specifically studied a group of non-infected patients.

Summary: Although there have been no randomized trials of TGC within the range of 100–150 mg/dL in a purely surgical ICU population, the evidence overall suggests that using TGC to achieve a narrow, targeted BG goal is not beneficial in surgical patients with sepsis.

Priority 5. Is there any survival benefit to raising blood pressure pharmacologically in adult patients with septic shock with inotropes/vasopressors compared with volume loading and tolerance of lower mean arterial pressure?

Different iterations of this question exist within the critical care literature. In regard to higher versus lower mean arterial pressure (MAP), two RCTs have evaluated higher MAPs (either 80–85 mm Hg or 75–80 mm Hg) compared with lower MAPs (65–70 mm Hg or 60–65 mm Hg) [59 –61]. Neither study showed a benefit for higher MAPs in these settings. Several retrospective studies suggested that fluid overloading is associated with more deaths [62 –64]. Currently, there is a trial that is evaluating restrictive fluid administration with early use of vasopressors to maintain MAP >65 mm Hg compared with usual care [65]. However, no studies have evaluated directly the survival benefit from avoidance or reduction of inotropes by volume loading in order to maintain or tolerate a lower MAP.

Summary: There is insufficient evidence to provide a definite answer to this question. Neither excessive use of inotropes nor excessive volume loading is associated with a survival benefit. A safe lower MAP goal has yet to be established, but pharmacologic elevation of MAP for an extended time period appears non-beneficial.

Priority 6. Does avoidance of systemic hypothermia and increased arterial oxygenation in the early post-operative period reduce the risk of surgical site infections compared with standard care?

Systemic hypothermia

Normothermia has been recommended as a quality performance measure and often is included in SSI reduction bundles. These recommendations stem from two RCTs involving intra-operative warming. The first trial, in patients undergoing colorectal surgery, found a greater risk of SSI in patients not actively warmed, as well as a longer LOS [66]. The second trial examined the effect of hypothermia in patients undergoing clean surgery (breast, varicose vein, or hernia) and found significantly more SSIs in the non-warmed group [67].

Most subsequent studies on this topic have been retrospective and have explored different definitions of hypothermia, some as an attempt to define rules for temperature control that are most important for reducing the risk of SSI. For example, a retrospective case-control study of 1,300 patients with SSI found no association with intra-operative hypothermia using three metrics: End-of-case temperature, intra-operative nadir, and degree/duration of hypothermia (^oC*h < 36°C) [68]. Similarly, no association was found for patients undergoing segmental colectomy [69], ventral hernia repair [70], or orthopedic surgery [71] using several different definitions of hypothermia. A recent meta-analysis that included six cohort studies and two RCTs also indicated no association between peri-operative hypothermia and SSI [72].

Conversely, retrospective studies looking at more severe degrees of hypothermia (< 35°C) do suggest a higher risk of SSI in trauma patients undergoing laparotomy [73], patients receiving hyperthermic intra-peritoneal chemotherapy (HIPEC) [74], and patients having gastrointestinal surgery lasting longer than 3 h [75]. However, safety concerns about forced-air warming have been raised recently, including a potentially higher risk for SSI attributable to disruption of clean laminar air flow and direct contamination by air that blows from the warming equipment [76] or aerosolizes bacteria from the floor.

Summary: There is no definite answer about the impact of hypothermia on the risk of SSI. Determination is limited by the ambiguity of definitions and lack of clarity about when it is during the peri-operative period that normothermia is most important. A consensus definition of normothermia targets would make prospective research on this topic more feasible.

Increased arterial oxygenation

The RCTs examining the effect of peri-operative hyperoxia on SSI risk suggest that there is no risk reduction attending the use of supplemental O₂. The 2009 PROXI trial, a double-blind RCT in which patients undergoing abdominal surgery received F_IO₂ 0.8 or 0.3 during surgery and for 2 h thereafter, found no difference in the rate of SSI or pulmonary complications at 14 d [77]. These findings were consistent in a subgroup analysis of obese patients (body mass index [BMI] >30 kg/m²) [78]. Long-term follow-up demonstrated a higher risk of death with hyper-oxygenation, particularly in patients undergoing cancer surgery [79]. Additional large multicenter RCTs demonstrated no difference in SSI for patients undergoing abdominal, gynecologic, or breast surgery [80] or colorectal surgery [81] who were treated with F_IO₂ 0.8 versus 0.3. Similarly, no difference in SSI was found for women receiving F_IO₂ 0.8 versus 0.3 after cesarean delivery [82] nor for morbidly obese patients undergoing bariatric surgery [83].

By contrast, a 2009 meta-analysis of RCTs demonstrated a reduction in SSI with the use of F_IO₂ 0.8 in the peri-operative period. This effect was greater for patients undergoing colorectal procedures [84]. Various RCTs also have shown lower SSI rates with supplemental O₂ or hyper-oxygenation for patients undergoing lower limb revascularization [85], open appendectomy [86], open surgery for perforated peptic ulcer [87], or surgery for acute sigmoid diverticulitis [88]. However, the integrity of the data in these last two studies has been called into question because of possible statistical errors and plagiarism [89].

Summary: There is insufficient evidence to provide a definite answer to this question. In general, use of F_IO₂ 0.8 in the peri-operative period does not reduce the risk of SSI. However, patients undergoing certain types of procedures, including colorectal or emergency surgery, may benefit from this intervention.

Priority 7. Does resuscitation with hypertonic saline reduce the incidence of organ dysfunction, nosocomial infection, or death in patients with septic or traumatic shock?

Hypertonic Saline in Trauma

Studies examining the efficacy of hypertonic saline (HTS) in hypotensive trauma patients can be categorized by the setting (pre-hospital versus hospital-based) and treatment (with or without dextran) arms. In 2009, a systematic review and meta-analysis of pre-hospital and hospital-based studies was unable to draw any definitive conclusion about the impact of HTS [90].

In 2011, a multicenter double-blind RCT of HTS (initial resuscitation fluid, 250 mL of either 7.5% saline per 6% dextran 70 (hypertonic saline/dextran; HSD), 7.5% saline (hypertonic saline; HS), or 0.9% saline (normal [physiologic] saline; NS) in hypotensive trauma patients in the pre-hospital setting was stopped early after obtaining 23% of the proposed sample size because of the Data Safety Monitoring Board recommendations concerning futility and potential safety concerns. [91]. In this study, 895 patients were randomized and included for analysis, which demonstrated no differences in 6-hour or 28-day survival or acute respiratory distress syndrome (ARDS)-free 28-day survival. Similar conclusions were drawn by two additional systematic reviews and meta-analyses of studies examining the impact of HTS in hypotensive trauma patients in both pre-hospital and hospital settings [92,93].

Two further systematic reviews, focused on the impact of pre-hospital HTS for hypotensive trauma patients, were published in 2017. One included five trials: Four administered a fixed 250-mL dose of 7.5% NaCl, and a single trial administered 300 mL in the pre-hospital setting [94]. Control solutions included 0.9 % NaCl (two studies) and Ringer's lactate (two studies), and one study used Ringer's acetate as the control. Studies that included a colloid as part of the intervention were excluded. Meta-analysis of the five studies (1,162 patients) demonstrated no significant differences in deaths or other secondary outcomes (LOS, multiple organ dysfunction score, disability, neurologic outcomes). The second review included nine trials (3,490 patients) in the systematic review and six trials in the meta-analysis in which administration of a colloid in conjunction with HTS was considered [95]. Consistent with previous studies, this meta-analysis demonstrated no significant benefit from HTS with or without dextran on deaths or secondary outcomes (adverse events, infections, multiple organ dysfunction syndrome [MODS], and hospital LOS) for resuscitation of hypotensive trauma patients in the pre-hospital setting.

Summary: There is no benefit from HTS on the mortality rate or other secondary outcomes in either the pre-hospital or hospital setting, with or without colloid administration, in the resuscitation of hypotensive trauma patients.

HTS in sepsis

In an open-label, two-by-two factorial, multicenter, double-blind RCT (HYPERS2S), 442 patients aged ≥18 y with septic shock received mechanical ventilation either with F_IO₂ 1.0 (hyperoxia) or F_IO₂ set to target an arterial hemoglobin oxygen saturation (SHbO₂) of 88%–95% (normoxia) during the first 24 h; patients also received either 280-mL boluses of 3.0% NaCl or 0.9% NaCl for fluid resuscitation during the first 72 hours [96]. The primary endpoint was death by 28 days post-randomization. A series of 223 patients were assigned to normoxia whereas 219 received hyperoxia; 224 were assigned to isotonic saline versus 218 assigned to HTS. The trial was stopped prematurely for safety reasons. In the HTS group, 89 (42%) of 214 patients died vs. 81 (37%) of the 220 patients in the isotonic group (hazard ratio [HR] 1.19; 95% CI 0.88–1.61; p = 0.25). There was no difference in the likelihood of serious adverse events in the groups (p = 0.23).

Summary: In patients with septic shock, resuscitation with HTS does not improve survival.

Priority 8. Does routine antimicrobial prophylaxis with a two- to four-week course of a carbapenem compared with placebo affect the risk of infected necrotizing pancreatitis, need for operative intervention, antimicrobial resistance, and death among those admitted with severe necrotizing pancreatitis?

Among hundreds of beta-lactam compounds, carbapenems possess the widest spectrum against gram-positive and gram-negative bacteria with a relative resistance to hydrolysis from common beta-lactamases; consequently, they are highly effective in the treatment of cIAIs [97]. In 2006, at the time of definition of the SIS research agenda, it was logical to ask if these antibiotics could prevent deterioration in patients with necrotizing pancreatitis (NP) given those drugs reported ability to penetrate peri-pancreatic tissue [98]. Since then, several RCTs have been performed, including a high-quality double-blind, placebo-controlled RCT with strong participation by SIS members [98]. This study, as well as others, revealed that prophylactic carbapenems do not provide any benefit in NP [99]. Interestingly, meropenem induces dysbiosis with changes in epithelial barrier function and modifications in the activity of Toll-like receptor–2-positive cells, increasing intestinal inflammation, and accelerating bacterial translocation and occurrence of more deaths in animal models of acute pancreatitis [100]. Thus not surprisingly; recent RCTs demonstrated that carbapenem prophylaxis in NP can, paradoxically, be harmful [101] and promote the harboring of multi–drug-resistant (MDR) organisms and fungi in pancreatic tissue [102]. Nevertheless, whether there exists an ideal prophylactic agent in sterile NP remains unresolved; hence studies using these same agents (either alone or in combination with other compounds) continue to be published, with mixed results [99]. Favorable clinical outcomes reported in some trials may be the result of patient selection in the study population with the use of biomarkers such as procalcitonin (PCT) and C-reactive protein (CRP) or particular trial design parameters (timing, doses, associated therapies). Improved resuscitation and supportive care of these patients over time, as well as a sequential (step-up) multi-disciplinary approach for source control, thereby avoiding the highly morbid open pancreatic necrosectomy, may also confound recent results [103,104].

Summary: Non-selective antimicrobial prophylaxis with a carbapenem does not provide any benefit with respect to need for operative interventions, appearance of antimicrobial resistance, or death among patients with severe NP.

Priority 9. Is there a difference in the rate of surgical site infections, non-union, cost, or antimicrobial resistance in patients with open fractures treated with 24 versus 72 hours of antimicrobial prophylaxis? Separate strata for heavily contaminated wounds where 72 hours would be compared with 7 days.

Close to the time of publication of the Delphi consensus survey [1], an SIS guideline was published with recommendations for prophylactic antibiotic use in open fractures [105]. Evidence supported the use of short-course, first-generation cephalosporins in combination with modern orthopedic techniques (and damage control principles) to reduce the risk of infection and other sequelae in the treatment of low-energy (i.e., Gustilo-Anderson Grade I) injuries [106]. However, a lack of high-quality RCTs precluded further recommendations for the treatment of more severe (Grade II–III) open orthopedic injuries. Most clinical reports have been anecdotal, poorly designed, or underpowered.

Nevertheless, several papers have shown that protocolized antibiotic prophylaxis of open long-bone fractures, regardless of grade or site, can reduce the risk of infection, decrease variation in practice, and diminish prolonged and unnecessary antibiotic administration [106 –108]. A recent comprehensive review summarized the findings of more than 220 publications and 100 practice patterns [109]. Despite repeated demonstration of better clinical outcomes with the application of protocolized care (i.e., early [< 3 hours] administration of antibiotic from the time of injury), single-agent gram-positive prophylaxis <24 hours duration for Gustilo-Anderson I and II fractures; single agent broad-spectrum coverage (usually a third-generation cephalosporin) for ≤3 days for Gustilo-Anderson Grade III fractures; and early excisional debridement (< 6 hours after injury) of heavily contaminated wounds, with external fracture stabilization, vascularized soft tissue coverage (if necessary) and staged reconstruction, these protocols have been slow to gain acceptance [110 –112]. Skepticism is related not only to the aforementioned poor quality of the supporting evidence, but also to fear of serious complications that may trigger litigation. The increasing prevalence of high-velocity gunshot fractures with associated soft-tissue destruction may define a separate high-risk category not described by the Gustilo-Anderson system [113] and may require further research and re-evaluation of the current paradigm [114].

Summary: Protocolized care as described above improves clinical outcomes in open fractures, but low-quality evidence continues to hinder universal application by specialty surgeons.

Priority 10. Does antioxidant therapy improve the mortality rate or reduce subsequent organ dysfunction compared with placebo in patients with sepsis?

Antioxidant therapy has been proposed as a down-regulator of the inflammation associated with sepsis. Selenium, which is depleted in critically ill patients, is a cofactor for many anti-oxidant enzymes. Whereas several earlier studies demonstrated a decrease in the mortality rate with selenium supplementation in patients with sepsis, recent RCTs have not reproduced those results. For example, the 2007 Selenium in Intensive Care (SIC) trial showed a trend toward fewer deaths in patients with severe sepsis by post-hoc analysis [115]. However, a subsequent RCT of high-dose selenium administration in patients with sepsis demonstrated no difference in the 28-d mortality rate [116]. In addition, a large multicenter 2 × 2 factorial trial of selenium administration and PCT-guided anti-infective therapy in patients with severe sepsis showed no survival benefit (28-day death) for patients who received selenium [117].

Vitamin C plays a role in the scavenging of reactive oxygen species, the synthesis of catecholamines and vasopressin, and several immune-regulatory functions [118,119]. A Phase 1 RCT of vitamin C given to 24 patients with severe sepsis demonstrated a rapid reduction in the Sequential Organ Failure Assessment (SOFA) score, as well as reduced concentrations of CRP and PCT [120]. Another RCT of vitamin C treatment in patients with septic shock demonstrated a lower vasopressor dose and duration and a significant decrease in the 28-day mortality rate [121]. Vitamin C also was studied retrospectively by Marik et al. in 2017 [122]. Vitamin C in conjunction with hydrocortisone and thiamine in patients with sepsis was associated with a marked reduction in the mortality rate, shorter duration of vasopressor use, lower rates of acute kidney injury, and a more rapid reduction in SOFA scores [122].

However, two recent RCTs demonstrated no improvement for patients with sepsis treated with parenteral vitamin C. In the CITRIS-ALI study, a double-blind, multi-center RCT, vitamin C did not improve organ dysfunction scores or lead to changes in inflammation biomarkers for patients with sepsis or ARDS [123]. Similarly, the VITAMINS RCT, in which vitamin C combined with hydrocortisone and thiamine was compared with hydrocortisone alone, demonstrated no improvement in the mortality rate or vasopressor-free time with vitamin C [124].

Summary: There is insufficient evidence to provide an answer to this question. Selenium administration does not reduce the mortality rate for patients with sepsis. Selenium's role as an antioxidant is dependent on glutathione peroxidase. Unfortunately, all studies of selenium to date have failed to include glutathione supplements, and no study of glutathione has addressed selenium. Future studies should consider repletion of both selenium and glutathione to answer this question definitively. Vitamin C, administered independently of steroid therapy, is not beneficial for patients with sepsis. Further work is needed to understand the potential synergistic effects of vitamin C in patients with sepsis.

Priority 11. Does an increase in antimicrobial dose or frequency reduce the incidence of surgical site infections or cure rates (for pharmacokinetics-established infections) in the obese patient?

Although there are limited data, an increased dose of antibiotic, based on the patient's body mass, appears to be necessary in obesity. Falagas et al. summarized in 2010 the existing pharmacologic data regarding the distribution of antibiotics in patients of various body masses [125]. They concluded that “available data support the notion that antimicrobial agents, such as several β-lactams, vancomycin, fluoroquinolones, macrolides, linezolid, sulfonamides, and fluconazole, which are approved as flat dosing regimens, should be given in higher doses to patients with large body size to better attain pharmacodynamic targets,” although prophylaxis was not discussed specifically. A single-center study by Polso et al. showed that weight-based dosing optimized serum concentrations of a variety of antibiotics [126]. No data exist to support the idea that weight-based dosing reduces the risk of SSI. Indeed, a single-center trial of 3 g versus 2 g of cefazolin prophylaxis in morbidly obese women undergoing cesarean section showed no effect on the SSI rate [127].

Summary: There is insufficient evidence to provide an answer to this question.

Priority 12. Is there any difference in ventilator days, intensive care unit length of stay, cost, antimicrobial resistance, mortality rate, or clinical or microbiologic cure rates in patients with ventilator-associated pneumonia receiving 7 versus 14 days of antimicrobial therapy?

Notwithstanding the compound nature of the question and the fact that definitions for pneumonia have changed during the last decade (with dubious applicability to critically ill surgical patients) [128,129] and continue to differ from study to study, answers to some of these questions have become available. Moreover, the emergence of antibiotic stewardship [130] in the last few years has been accompanied by additional germane questions that have been addressed in the interim, notably regarding the propriety and effectiveness of antibiotic de-escalation (ADE) for the management of ventilator-associated pneumonia (VAP) in critically ill/injured surgical patients [131,132]. On balance, short-course therapy and ADE (which may abet short-course therapy) appear to be safe and effective.

In a 2015 Cochrane review [133], Pugh at al. identified six trials that included 1,088 participants. Surgical patients comprised 402/888 subjects (45.7%) from the four studies where the proportion could be determined. The authors noted “substantial variation” in definitions, interventions, and reported outcomes. For patients with VAP, a short course (7 or 8 days) of antibiotic compared with a long course (10–15 days) increased 25-day antibiotic-free days (mean difference 4.02 days; 95% CI 2.26–5.78 days). The risk of VAP recurrence caused by an MDR organism also was reduced (OR 0.44; 95% CI 0.21–0.95), albeit in just one study of only 110 participants. For cases of VAP attributable specifically to non-fermenting gram-negative bacilli, (NFGNB; Acinetobacter spp., Pseudomonas spp., Stenotrophomonas maltophilia) recurrence (determined from two studies enrolling 176 participants) was greater among patients who received short-course therapy (OR 2.18; 95% CI 1.14–4.16). Mortality outcomes were not significantly different (Table 3).

Table 3.

Stratified Outcomes after Short- versus Prolonged-Course Antibiotics for Ventilator-Associated Pneumonia: Systematic Review and Meta-Analysis

Subgroup	Odds ratio (95% confidence interval)	Evidence quality
Death
Overall	1.18 (0.77–1.80)	Moderate
NFGNB	0.95 (0.39–2.27)	Low
MRSA	1.28 (0.32–5.09)	Moderate
Recurrence of pneumonia
Overall	1.41 (0.94–2.12)	Low
NFGNB	2.18 (1.14–4.16)	Moderate
MRSA	1.56 (0.12–19.61)	Moderate

MRSA = methicillin-resistant Staphylococcus aureus; NFGNB = Non-fermenting gram-negative bacilli. Abstracted from reference 133.

Subsequent to the Cochrane review, Klompas et al. [134] randomized 1,290 patients (524 [40.6%] of whom were surgical patients) for possible VAP requiring daily minimum positive end-expiratory pressure of ≤5 cm H₂O and F_IO₂ ≤ 0.40 for at least 3 days. Among enrollees, 259 were treated for 1–3 days and 1,031 were treated for >3 days. There were no significant differences between groups in time to extubation alive (HR 1.16; 95% CI 0.98–1.36) for short- versus long-course treatment; or for death while being ventilated mechanically (HR 0.82; 95% CI 0.55–1.220), time to hospital discharge alive (HR 1.07; 95% CI 0.91–1.26), or in-hospital death (HR 0.99; 95% CI 0.75–1.31). Three sensitivity analyses using propensity scoring (surgical population 39.9%) mirrored the primary analysis.

Summary: On balance, short-course therapy of VAP appears to be safe and effective.

Priority 13. Does rotation of empiric antimicrobial regimens in the intensive care unit affect clinical cure rates or the emergence of resistant organisms compared with standard practice? If so, what is the optimal interval?

No high-quality study exists that compels the implementation of antibiotic rotation tactics [135]. To date, no RCT compares rotation and standard practice, although a single RCT comparing two rotation regimens, cycling and mixing [136], failed to demonstrate a difference [137]. Nonetheless, the lack of heterogeneity in antibiotic use in the ICU is believed to be associated with the development of antibiotic resistance. Multiple studies, either of retrospective or before–after designs, yielded conflicting results [138 –140]. Mathematical modeling of bacterial resistance suggests that combination therapy is most effective, regardless of rotational tactic [141,142].

Summary: No definite answer exists for the effectiveness of antibiotic rotation in reducing the emergence of MDR organisms.

Priority 14. Does routine fever suppression affect clinical or microbiologic cure rates in septic surgical patients?

Fever, a common feature of sepsis, has long been considered to be a protective physiologic host defense mechanism. Fever augments inflammatory responses, increases immune cell function [143], decreases bacterial and viral load [144], and enhances the activity of antimicrobial agents [145], ultimately leading to infection resolution. Despite this protective effect, fever frequently is treated to reduce patient discomfort and physiologic cardiorespiratory stress.

Two observational studies demonstrated that fever among infected ICU patients was associated with a lower mortality rate [146,147], and pharmacologic antipyresis was accompanied by a higher mortality rate in sepsis [147]. Similarly, an observational study of 2,225 patients with sepsis or septic shock showed that fever measured in the ED was strongly associated with a lower mortality rate and shorter hospital LOS [148]. Likewise, a retrospective study of 1,264 patients demonstrated that in patients with sepsis, a maximum temperature of 38.3°C to 39.4°C was associated with a reduced mortality rate but that pharmacologic antipyresis had no benefit [149].

The mode of fever management in patients with sepsis, pharmacologic antipyresis versus external cooling, may have differential effects on the mortality rate. An RCT evaluating the impact of fever management in patients with septic shock assigned 200 patients to external cooling for 48 hours versus no fever suppression. External cooling significantly decreased the vasopressor requirement and lowered the 14-day mortality rate (but no difference in mortality at ICU or hospital discharge) [150]. However, there were several limitations: The study was open label, there was no limitation on fever management beyond 48 hours, and baseline vasopressor doses were higher in the control group. In a post-hoc analysis, antipyresis with external cooling was the primary mediator of decreased early death [151].

A second RCT (HEAT) randomized 691 ICU patients T ≥ 38°C and suspected infection to fever suppression by intravenous acetaminophen versus placebo [152]. There were no differences in ICU-free days, or 28-day or 90-day deaths and thus no benefit from fever suppression with acetaminophen in patients with infection. The findings of the HEAT trial are supported by two systematic reviews and meta-analyses of sepsis patients that showed that antipyretic therapy (physical cooling or pharmacologic antipyresis) did not decrease the mortality rate [153,154].

Summary: There is insufficient evidence to provide a definitive answer to this question. Routine pharmacologic antipyresis in patients with sepsis does not improve survival and, indeed, may increase the mortality rate. By contrast, there is some evidence to support external cooling that warrants further study to confirm whether fever suppression using this method has a beneficial impact on clinical outcomes or microbiologic cure rates in surgical patients with sepsis.

Priority 15. Is there any difference in cost, sensitivity, and specificity of bronchoalveolar lavage (BAL), mini-BAL, sputum sample, chest radiography (CXR), or chest computed tomography (CT) as diagnostic tests in those with suspected VAP?

Nosocomial pneumonia is a leading cause of surgical complications, and patients with VAP are at greater risk for further organ dysfunction, prolonged ICU LOS, and death [155], not to mention the tremendous consumption of resources that could be applied elsewhere [156]. The increasing prevalence of MDR organisms as the cause of VAP, combined with engendered delays in antibiotic initiation and treatment failures related to inappropriate antibiotic use remain major concerns [1].

There is no consensus definition of VAP owing to the lack of specificity that arises from clinical overlap with other conditions such as atelectasis, pulmonary contusion, and ARDS [155]. Neither improved imaging technology, nor diagnostic tests, nor changed clinical criteria have improved diagnostic accuracy. Paradoxically, new concepts such as “ventilator-associated events” (VAE) have added to the confusion. Two recent guidelines, one from the IDSA and the American Thoracic Society [157] and the other from a Eurocentric international group [158], have attempted to resolve these issues. However, a definitive diagnostic method for VAP remains elusive, considering differences between these documents with respect to the timing and invasiveness of sputum sampling. However, the importance of a deep-tissue protected-specimen microbiologic culture when positive is strongly recognized. The benefit for an individual patient may not be obvious, but in ICUs plagued by MDR organisms, the overall information obtained from cultures will offset any cost incurred, as it supports a data-driven antibiotic stewardship approach [159]. This includes a better implementation of empiric treatment with coverage based on local antibiograms and treatment regimens that allow rapid de-escalation when possible. The question of timing of initiation of empiric treatment remains controversial and has not been answered meaningfully by any diagnostic modality. These documents include other recommendations such as limited duration of antibiotic treatment and recognizing the emergent role of biomarkers such as PCT to guide duration of treatment and are an invitation for future research and discussion.

Summary: There is insufficient evidence to provide an answer to this question. The most accurate diagnostic method for VAP has yet to be determined. Differences in cost, sensitivity, and specificity of specimen collection techniques are irrelevant until a consensus definition is reached.

Discussion

In this update, we reviewed the current literature on topics of defined priority with knowledge gaps as set forth in 2006 by the SIS. A review of the previous research agenda was warranted to determine if progress had been made in addressing these knowledge gaps and whether the defined research priorities required further study. Our review indicates that progress has been made in several key areas. Although some questions were not answered directly in surgical patients per se, because designing trials specific to surgical patients has unique challenges, including recruitment of appropriate patients and controls, standardization of treatment, and suitable treatment blinding, high-quality data can reasonably be extrapolated to our patients in many instances. Many key questions in surgical infections remain unanswered either because the required study has not been conducted or the quality of current evidence is low. The major reasons for poor evidence quality include heterogeneity of study populations, poor study designs, inconsistent definitions, heterogeneity of treatment protocols, confounding within treatment bundles, and variable outcomes across studies.

In parallel, and as part of the renewal of the Delphi process to define a contemporary surgical infections research agenda, the SIS-SSC asked these same questions using different methods. Whereas the present analysis was performed by one SIS-SSC member for each question, and conclusions were based on a detailed literature review, Delaplain et al. [160] asked respondents to a new 2020 Delphi survey to offer opinions on the 15 questions reviewed here from 2006. Each respondent was asked whether the question was answered or still requires study and also whether the question was still considered important. Some differences between the present study and that of Delaplain et al. were noted. There was concordance on the question of adequacy for 12 of the 15 questions, four of which were in the affirmative and eight in refutation (Table 4). Discrepancies manifested for questions 6 (hypothermia/hyperoxia) (answered affirmatively by Delaplain et al.), 7 (HTS resuscitation), and 12 (duration of therapy for VAP) (answered affirmatively herein).

Table 4.

Comparison of Present Study with Analysis of Delaplain et al. [160]

	Question Answered Adequately
Question/synopsis	Present Study	Delaplain et al.
1. Glycemic control/SSI abdominal surgery	Yes	Yes
2. Brief antibiotic/cIAI	Yes	Yes
3. Early empiric antibiotic/sepsis	No	No
4. Glycemic control/ICU infection	Yes	Yes
5. Vasopressors vs. volume loading/shock	No	No
6. Hypothermia/hyperoxia	No	Yes
7. Hypertonic saline	Yes	No
8. Antibiotic prophylaxis/severe pancreatitis	Yes	Yes
9. Antibiotic prophylaxis/open fractures	No	No
10. Antioxidants for sepsis	No	No
11. More antibiotic/obesity	No	No
12. Antibiotic duration/VAP	Yes	No
13. Antibiotic rotation	No	No
14. Routine fever suppression	No	No
15. Optimum diagnostic test/VAP	No	No

cIAI = complicated intra-abdominal infection. ICU = intensive care unit. SSI = surgical site infection. VAP = ventilator-associated pneumonia.

Of interest, Delaplain et al. found that eight questions remaining unanswered still are considered important/very important today [160] but by a larger percentage of respondents than they were initially [1], indicating that these questions are not “going away.” Also of note, of the four questions considered to be answered adequately by both analyses (1, 2, 4, and 8) (Table 4), one (2) was considered still important/very important despite ostensibly adequate data. This underscores the derivation/meaning of “expertise” as highlighted by Delaplain et al. [160], in that expertise does not derive solely from knowledge of applicable Class I data. It also is possible that respondents may have conflated two considerations, specifically “this question is important to the SIS as a society” with “this question is important for the betterment of patient care.” It also will be interesting to determine whether the unanswered questions that have not “gone away” will retain sufficient priority in the next Delphi iteration to determine the future research agenda in surgical infections.

Limitations include the study selection and reporting biases inherent in narrative reviews. Inadvertent omission of important studies also may have occurred. Assessment of whether the question has been answered definitively also is subject to bias, although we believe that the authors, as members of the SIS-SCC, were a representative sampling of experts in the field of surgical infections and thus qualified to make this determination.

This update highlights areas where robust, high-quality data still are needed to inform and optimize the clinical care of surgical patients. We strongly recommend that research efforts be directed toward advancing knowledge where substantial gaps or controversies continue to exist. Further clinical trials are justified to resolve these questions and will have to address limitations of previous work in order to advance the care of patients with surgical infections. Furthermore, it now is time to replicate the Delphi survey of the SIS members to develop a revised research agenda to guide future surgical trials, a project that currently is in progress through the SIS-SSC.

Footnotes

Funding Information

There are no funding sources to disclose for this article.

Author Disclosure Statement

The authors of this article have no financial disclosures or conflict of interest related to this project.

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