Christiane S. Hartog

Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis

BACKGROUND The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids. METHODS In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringers lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. RESULTS The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringers lactate. CONCLUSIONS The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473.)

Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations

RATIONALE Reducing the global burden of sepsis, a recognized global health challenge, requires comprehensive data on the incidence and mortality on a global scale. OBJECTIVES To estimate the worldwide incidence and mortality of sepsis and identify knowledge gaps based on available evidence from observational studies. METHODS We systematically searched 15 international citation databases for population-level estimates of sepsis incidence rates and fatality in adult populations using consensus criteria and published in the last 36 years. MEASUREMENTS AND MAIN RESULTS The search yielded 1,553 reports from 1979 to 2015, of which 45 met our criteria. A total of 27 studies from seven high-income countries provided data for metaanalysis. For these countries, the population incidence rate was 288 (95% confidence interval [CI], 215-386; τ = 0.55) for hospital-treated sepsis cases and 148 (95% CI, 98-226; τ = 0.99) for hospital-treated severe sepsis cases per 100,000 person-years. Restricted to the last decade, the incidence rate was 437 (95% CI, 334-571; τ = 0.38) for sepsis and 270 (95% CI, 176-412; τ = 0.60) for severe sepsis cases per 100,000 person-years. Hospital mortality was 17% for sepsis and 26% for severe sepsis during this period. There were no population-level sepsis incidence estimates from lower-income countries, which limits the prediction of global cases and deaths. However, a tentative extrapolation from high-income country data suggests global estimates of 31.5 million sepsis and 19.4 million severe sepsis cases, with potentially 5.3 million deaths annually. CONCLUSIONS Population-level epidemiologic data for sepsis are scarce and nonexistent for low- and middle-income countries. Our analyses underline the urgent need to implement global strategies to measure sepsis morbidity and mortality, particularly in low- and middle-income countries.

New Approaches to Sepsis: Molecular Diagnostics and Biomarkers

SUMMARY Sepsis is among the most common causes of death in hospitals. It arises from the host response to infection. Currently, diagnosis relies on nonspecific physiological criteria and culture-based pathogen detection. This results in diagnostic uncertainty, therapeutic delays, the mis- and overuse of antibiotics, and the failure to identify patients who might benefit from immunomodulatory therapies. There is a need for new sepsis biomarkers that can aid in therapeutic decision making and add information about screening, diagnosis, risk stratification, and monitoring of the response to therapy. The host response involves hundreds of mediators and single molecules, many of which have been proposed as biomarkers. It is, however, unlikely that one single biomarker is able to satisfy all the needs and expectations for sepsis research and management. Among biomarkers that are measurable by assays approved for clinical use, procalcitonin (PCT) has shown some usefulness as an infection marker and for antibiotic stewardship. Other possible new approaches consist of molecular strategies to improve pathogen detection and molecular diagnostics and prognostics based on transcriptomic, proteomic, or metabolic profiling. Novel approaches to sepsis promise to transform sepsis from a physiologic syndrome into a group of distinct biochemical disorders and help in the development of better diagnostic tools and effective adjunctive sepsis therapies.

A systematic review of third-generation hydroxyethyl starch (HES 130/0.4) in resuscitation: safety not adequately addressed.

BACKGROUND:Hydroxyethyl starches (HES) are widely used for intravascular volume therapy in surgical, emergency, and intensive care patients. There are safety concerns with regard to coagulopathy, renal failure, pruritus, tissue storage, and mortality. Third-generation HES 130/0.4 is considered to have an improved risk profile. A common rationale for the use of HES is the belief that 3 to 4 times more crystalloid than colloid volume is needed to achieve similar hemodynamic end points. Our goal was to assess whether published studies on HES 130/0.4 resuscitation are sufficiently well designed to draw conclusions about the safety of this compound. In addition, we wanted to assess crystalloid-to-colloid fluid ratios in studies with goal-directed fluid regimen. METHODS:Systematic review of randomized controlled trials in which HES 130/0.4 is used for resuscitation. RESULTS:We identified 56 randomized controlled trials (RCTs) with HES 130/0.4 in. acute hypovolemia, mainly from the elective surgical setting (n = 45). Surgical studies were small-sized (median 25 patients in the HES groups, range 10 to 90) and of short duration (median 12 hours, range 0.5 to 144 hours). The median cumulative HES dose was 2465 mL (range 328 to 6229 mL), corresponding to 35 mL/kg in a 70-kg patient, the daily dose limit being 50 mL/kg. End points mostly addressed variable surrogate outcomes. Sixty percent of control fluids were other HES solutions, gelatins, or dextran, which have a similar risk profile. Without exception, these studies were not designed for clinically important safety outcomes, primarily because they were too small, used mostly inadequate control fluids, and had inappropriately short observation periods. Therefore, and also because of heterogeneity of patient groups and outcome definitions, results from these studies cannot be pooled. These studies do not allow any conclusion about the safety of HES 130/0.4. There is a common belief that 3 to 4 times more crystalloid than colloid volume is necessary to achieve similar hemodynamic effects. We found a considerably lower ratio in surgical studies (mean 1.8, SD 0.1). CONCLUSIONS:In summary, the extent of fluid load reduction that can be achieved by HES 130/0.4 is overestimated. Use of older HES solutions may be associated with serious side effects, and clinicians should be aware that there is no convincing evidence that third-generation HES 130/0.4 is safe in surgical, emergency, or intensive care patients despite publication of numerous clinical studies.

Practice and perception—A nationwide survey of therapy habits in sepsis*

Objective:To simultaneously determine perceived vs. practiced adherence to recommended interventions for the treatment of severe sepsis or septic shock. Design:One-day cross-sectional survey. Setting:Representative sample of German intensive care units stratified by hospital size. Patients:Adult patients with severe sepsis or septic shock. Interventions:None. Measurements and Main Results:Practice recommendations were selected by German Sepsis Competence Network (SepNet) investigators. External intensivists visited intensive care units randomly chosen and asked the responsible intensive care unit director how often these recommendations were used. Responses “always” and “frequently” were combined to depict perceived adherence. Thereafter patient files were audited. Three hundred sixty-six patients on 214 intensive care units fulfilled the criteria and received full support. One hundred fifty-two patients had acute lung injury or acute respiratory distress syndrome. Low-tidal volume ventilation ≤6 mL/kg/predicted body weight was documented in 2.6% of these patients. A total of 17.1% patients had tidal volume between 6 and 8 mL/kg predicted body weight and 80.3% >8 mL/kg predicted body weight. Mean tidal volume was 10.0 ± 2.4 mL/kg predicted body weight. Perceived adherence to low-tidal volume ventilation was 79.9%. Euglycemia (4.4–6.1 mmol/L) was documented in 6.2% of 355 patients. A total of 33.8% of patients had blood glucose levels ≤8.3 mmol/L and 66.2% were hyperglycemic (blood glucose >8.3 mmol/L). Among 207 patients receiving insulin therapy, 1.9% were euglycemic, 20.8% had blood glucose levels ≤8.3 mmol/L, and 1.0% were hypoglycemic. Overall, mean maximal glucose level was 10.0 ± 3.6 mmol/L. Perceived adherence to strict glycemic control was 65.9%. Although perceived adherence to recommendations was higher in academic and larger hospitals, actual practice was not significantly influenced by hospital size or university affiliation. Conclusions:This representative survey shows that current therapy of severe sepsis in German intensive care units complies poorly with practice recommendations. Intensive care unit directors perceive adherence to be higher than it actually is. Implementation strategies involving all intensive care unit staff are needed to overcome this gap between current evidence-based knowledge, practice, and perception.

Effects of fluid resuscitation with synthetic colloids or crystalloids alone on shock reversal, fluid balance, and patient outcomes in patients with severe sepsis: A prospective sequential analysis*

Objective:To assess shock reversal and required fluid volumes in patients with septic shock. Design:Prospective before and after study comparing three different treatment periods. Setting:Fifty-bed single-center surgical intensive care unit. Patients:Consecutive patients with severe sepsis. Interventions:Fluid therapy directed at preset hemodynamic goals with hydroxyethyl starch (predominantly 6% hydroxyethyl starch 130/0.4) in the first period, 4% gelatin in the second period, and only crystalloids in the third period. Measurements and Main Results:Main outcome was time to shock reversal (serum lactate <2.2 mmol/L and discontinuation of vasopressor use). Hemodynamic goals were mean arterial pressure >70 mm Hg; ScvO2 <70%; central venous pressure >8 mm Hg. Safety outcomes were acute kidney injury defined by Risk, Injury, Failure, Loss, and End-stage kidney disease criteria and new need for renal replacement therapy. Hemodynamic measures, serum lactate, and creatinine were comparable at baseline in all study periods (hydroxyethyl starch n = 360, gelatin n = 352, only crystalloids n = 334). Severity scores, hospital length of stay, and intensive care unit or hospital mortality did not differ significantly among groups. All groups showed similar time to shock reversal. More fluid was needed over the first 4 days in the crystalloid group (fluid ratios 1.4:1 [crystalloids to hydroxyethyl starch] and 1.1:1 [crystalloids to gelatin]). After day 5, fluid balance was more negative in the crystalloid group. Hydroxyethyl starch and gelatin were independent risk factors for acute kidney injury (odds ratio, 95% confidence interval 2.55, 1.76–3.69 and 1.85, 1.31–2.62, respectively). Patients receiving synthetic colloids received significantly more allogeneic blood products. Conclusions:Shock reversal was achieved equally fast with synthetic colloids or crystalloids. Use of colloids resulted in only marginally lower required volumes of resuscitation fluid. Both low molecular weight hydroxyethyl starch and gelatin may impair renal function.

Renal effects of synthetic colloids and crystalloids in patients with severe sepsis: a prospective sequential comparison.

Objectives: Hydroxyethyl starch 200 is associated with renal impairment in sepsis, but hydroxyethyl starch 130/0.4 and gelatin are considered to be less harmful. We hypothesized that fluid therapy with only crystalloids would decrease the incidence of acute kidney injury. Design: Prospective sequential comparison during intensive care unit stay. Setting: Surgical intensive care unit. Patients: Patients with severe sepsis. Interventions: Changes in standard fluid therapy, with predominantly 6% hydroxyethyl starch from January 2005 to June 2005, 4% gelatin from January 2006 to June 2006, and only crystalloids from September 2008 to June 2009. Measurements and Main Results: Acute kidney injury was defined by the presence of at least one RIFLE class; 118 patients received hydroxyethyl starch, 87 patients received gelatin, 141 patients received only crystalloids. Baseline serum creatinine values were similar. Patients received median cumulative doses of 46 (interquartile range, 18–92) mL/kg hydroxyethyl starch and 43 (interquartile range, 18–76) mL/kg gelatin. Total median fluid amounts were 649 (interquartile range, 275–1098) mL/kg in the hydroxyethyl starch group, 525 (237–868) mL/kg in the gelatin group, and 355 (173–911) mL/kg in the crystalloid group. The difference was statistically significant for hydroxyethyl starch after adjustment for multiple testing. Mean daily fluid intake and fluid balance were higher on days 0 and 1 in the crystalloid group. Acute kidney injury occurred in 70% of patients receiving hydroxyethyl starch (adjusted p = .002) and in 68% of patients receiving gelatin (adjusted p = .025) vs. 47% patients receiving crystalloids. Need for renal replacement therapy tended to be higher in the hydroxyethyl starch group (34%; adjusted p = .086) and in the gelatin group (34%; adjusted p = .162) in comparison to the crystalloid group (20%). Intensive care unit and hospital mortality were similar in each group (hydroxyethyl starch: 35% and 43%; gelatin: 26% and 31%; crystalloids: 30% and 37%). Conclusion: Fluid resuscitation with only crystalloids was equally effective, resulted in a more positive fluid balance only on the first 2 days, and was associated with a lesser incidence of acute kidney injury.

The efficacy and safety of colloid resuscitation in the critically ill.

Despite evidence from clinical studies and meta-analyses that resuscitation with colloids or crystalloids is equally effective in critically ill patients, and despite reports from high-quality clinical trials and meta-analyses regarding nephrotoxic effects, increased risk of bleeding, and a trend toward higher mortality in these patients after the use of hydroxyethyl starch (HES) solutions, colloids remain popular and the use of HES solutions is increasing worldwide.We investigated the major rationales for colloid use, namely that colloids are more effective plasma expanders than crystalloids, that synthetic colloids are as safe as albumin, that HES solutions have the best risk/benefit profile among the synthetic colloids, and that the third-generation HES 130/0.4 has fewer adverse effects than older starches.Evidence from clinical studies shows that comparable resuscitation is achieved with considerably less crystalloid volumes than frequently suggested, namely, <2-fold the volume of colloids.Albumin is safe in intensive care unit patients except in patients with closed head injury. All synthetic colloids, namely, dextran, gelatin, and HES have dose-related side effects, which are coagulopathy, renal failure, and tissue storage. In patients with severe sepsis, higher doses of HES may be associated with excess mortality. The assumption that third-generation HES 130/0.4 has fewer adverse effects is yet unproven. Clinical trials on HES 130/0.4 have notable shortcomings. Mostly, they were not performed in intensive care unit or emergency department patients, had short observation periods of 24 to 48 hours, used cumulative doses below 1 daily dose limit (50 mL/kg), and used unsuitable control fluids such as other HES solutions or gelatins.In conclusion, the preferred use of colloidal solutions for resuscitation of patients with acute hypovolemia is based on rationales that are not supported by clinical evidence. Synthetic colloids are not superior in critically ill adults and children but must be considered harmful depending on the cumulative dose administered. Safe threshold doses need to be determined in studies in high-risk patients and observation periods of 90 days. Such studies on HES 130/0.4 are still lacking despite its widespread and increasing use. Because there are safer and equally effective alternatives in the form of crystalloids, use of synthetic colloids should be avoided except in the context of clinical studies.

Guidelines for Family-Centered Care in the Neonatal, Pediatric, and Adult ICU.

Objective: To provide clinicians with evidence-based strategies to optimize the support of the family of critically ill patients in the ICU. Methods: We used the Council of Medical Specialty Societies principles for the development of clinical guidelines as the framework for guideline development. We assembled an international multidisciplinary team of 29 members with expertise in guideline development, evidence analysis, and family-centered care to revise the 2007 Clinical Practice Guidelines for support of the family in the patient-centered ICU. We conducted a scoping review of qualitative research that explored family-centered care in the ICU. Thematic analyses were conducted to support Population, Intervention, Comparison, Outcome question development. Patients and families validated the importance of interventions and outcomes. We then conducted a systematic review using the Grading of Recommendations, Assessment, Development and Evaluations methodology to make recommendations for practice. Recommendations were subjected to electronic voting with pre-established voting thresholds. No industry funding was associated with the guideline development. Results: The scoping review yielded 683 qualitative studies; 228 were used for thematic analysis and Population, Intervention, Comparison, Outcome question development. The systematic review search yielded 4,158 reports after deduplication and 76 additional studies were added from alerts and hand searches; 238 studies met inclusion criteria. We made 23 recommendations from moderate, low, and very low level of evidence on the topics of: communication with family members, family presence, family support, consultations and ICU team members, and operational and environmental issues. We provide recommendations for future research and work-tools to support translation of the recommendations into practice. Conclusions: These guidelines identify the evidence base for best practices for family-centered care in the ICU. All recommendations were weak, highlighting the relative nascency of this field of research and the importance of future research to identify the most effective interventions to improve this important aspect of ICU care.

The effect of selenium therapy on mortality in patients with sepsis syndrome: a systematic review and meta-analysis of randomized controlled trials.

Background:Patients with sepsis syndrome commonly have low serum selenium levels. Several randomized controlled trials have examined the efficacy of selenium supplementation on mortality in patients with sepsis. Objective:To determine the efficacy and safety of high-dose selenium supplementation compared to placebo for the reduction of mortality in patients with sepsis. Sources of Data:We searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, SciFinder, and Clinicaltrials.gov. Selection Criteria:Randomized controlled parallel group trials comparing selenium supplementation in doses greater than daily requirement to placebo on the outcome of mortality in patients with sepsis syndrome. Data Collection and Analysis:Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. The primary outcome was mortality; secondary outcomes were ICU length of stay, nosocomial pneumonia, and adverse events. Trial authors were contacted for additional or clarifying information. Results:Nine trials enrolling a total of 792 patients were included. Selenium supplementation in comparison to placebo was associated with lower mortality (odds ratio, 0.73; 95% CI, 0.54, 0.98; p = 0.03; I2 = 0%). Among patients receiving and not receiving selenium, there was no difference in ICU length of stay (mean difference, 2.03; 95% CI, –0.51, 4.56; p = 0.12; I2 = 0%) or nosocomial pneumonia (odds ratio, 0.83; 95% CI, 0.28, 2.49; p = 0.74; I2 = 56%). Significant heterogeneity among trials in adverse event reporting precluded pooling of results. Conclusions:In patients with sepsis, selenium supplementation at doses higher than daily requirement may reduce mortality. We observed no impact of selenium on ICU length of stay or risk of nosocomial pneumonia.