Intensive glucose control in critically ill adults: a protocol for a systematic review and individual patient data meta-analysis / Controle intensivo da glicose em adultos em estado grave: um protocolo de revisão sistemática e metanálise de dados individuais de pacientes

ABSTRACT Objective: The optimal target for blood glucose concentration in critically ill patients is unclear. We will perform a systematic review and meta-analysis with aggregated and individual patient data from randomized controlled trials, comparing intensive glucose control with liberal glucose control in critically ill adults. Data sources: MEDLINE®, Embase, the Cochrane Central Register of Clinical Trials, and clinical trials registries (World Health Organization, clinical trials.gov). The authors of eligible trials will be invited to provide individual patient data. Published trial-level data from eligible trials that are not at high risk of bias will be included in an aggregated data meta-analysis if individual patient data are not available. Methods: Inclusion criteria: randomized controlled trials that recruited adult patients, targeting a blood glucose of ≤ 120mg/dL (≤ 6.6mmol/L) compared to a higher blood glucose concentration target using intravenous insulin in both groups. Excluded studies: those with an upper limit blood glucose target in the intervention group of > 120mg/dL (> 6.6mmol/L), or where intensive glucose control was only performed in the intraoperative period, and those where loss to follow-up exceeded 10% by hospital discharge. Primary endpoint: In-hospital mortality during index hospital admission. Secondary endpoints: mortality and survival at other timepoints, duration of invasive mechanical ventilation, vasoactive agents, and renal replacement therapy. A random effect Bayesian meta-analysis and hierarchical Bayesian models for individual patient data will be used. Discussion: This systematic review with aggregate and individual patient data will address the clinical question, 'what is the best blood glucose target for critically ill patients overall?' Protocol version 0.4 - 06/26/2023 PROSPERO registration: CRD42021278869

RESUMO Objetivo: Não está claro qual é a meta ideal de concentração de glicose no sangue em pacientes em estado grave. Realizaremos uma revisão sistemática e uma metanálise com dados agregados e de pacientes individuais de estudos controlados e randomizados, comparando o controle intensivo da glicose com o controle liberal da glicose em adultos em estado grave. Fontes de dados: MEDLINE®, Embase, Cochrane Central Register of Clinical Trials e registros de ensaios clínicos (Organização Mundial da Saúde, clinical trials.gov). Os autores dos estudos qualificados serão convidados a fornecer dados individuais de pacientes. Os dados publicados em nível de ensaio qualificado que não apresentem alto risco de viés serão incluídos em uma metanálise de dados agregados se os dados individuais de pacientes não estiverem disponíveis. Métodos: Critérios de inclusão: ensaios clínicos controlados e randomizados que recrutaram pacientes adultos, com meta de glicemia ≤ 120mg/dL (≤ 6,6mmol/L) comparada a uma meta de concentração de glicemia mais alta com insulina intravenosa em ambos os grupos. Estudos excluídos: aqueles com meta de glicemia no limite superior no grupo de intervenção > 120mg/dL (> 6,6mmol/L), ou em que o controle intensivo de glicose foi realizado apenas no período intraoperatório, e aqueles em que a perda de seguimento excedeu 10% até a alta hospitalar. Desfecho primário: Mortalidade intra-hospitalar durante a admissão hospitalar. Desfechos secundários: Mortalidade e sobrevida em outros momentos, duração da ventilação mecânica invasiva, agentes vasoativos e terapia de substituição renal. Utilizaremos metanálise bayesiana de efeito randômico e modelos bayesianos hierárquicos para dados individuais de pacientes. Discussão: Essa revisão sistemática com dados agregados e de pacientes individuais abordará a questão clínica: Qual é a melhor meta de glicose no sangue de pacientes graves em geral? Protocolo versão 0.4 - 26/06/2023 Registro PROSPERO: CRD42021278869

Intensive glucose control in critically ill adults: a protocol for a systematic review and individual patient data meta-analysis.

OBJECTIVE: The optimal target for blood glucose concentration in critically ill patients is unclear. We will perform a systematic review and meta-analysis with aggregated and individual patient data from randomized controlled trials, comparing intensive glucose control with liberal glucose control in critically ill adults. DATA SOURCES: MEDLINE®, Embase, the Cochrane Central Register of Clinical Trials, and clinical trials registries (World Health Organization, clinical trials.gov). The authors of eligible trials will be invited to provide individual patient data. Published trial-level data from eligible trials that are not at high risk of bias will be included in an aggregated data meta-analysis if individual patient data are not available. METHODS: Inclusion criteria: randomized controlled trials that recruited adult patients, targeting a blood glucose of ≤ 120mg/dL (≤ 6.6mmol/L) compared to a higher blood glucose concentration target using intravenous insulin in both groups. Excluded studies: those with an upper limit blood glucose target in the intervention group of > 120mg/dL (> 6.6mmol/L), or where intensive glucose control was only performed in the intraoperative period, and those where loss to follow-up exceeded 10% by hospital discharge. PRIMARY ENDPOINT: In-hospital mortality during index hospital admission. Secondary endpoints: mortality and survival at other timepoints, duration of invasive mechanical ventilation, vasoactive agents, and renal replacement therapy. A random effect Bayesian meta-analysis and hierarchical Bayesian models for individual patient data will be used. DISCUSSION: This systematic review with aggregate and individual patient data will address the clinical question, 'what is the best blood glucose target for critically ill patients overall?'Protocol version 0.4 - 06/26/2023PROSPERO registration:CRD42021278869.

Hemoadsorption in the critically ill-Final results of the International CytoSorb Registry.

The aim of the current paper is to summarize the results of the International CytoSorb Registry. Data were collected on patients of the intensive care unit. The primary endpoint was actual in-hospital mortality compared to the mortality predicted by APACHE II score. The main secondary endpoints were SOFA scores, inflammatory biomarkers and overall evaluation of the general condition. 1434 patients were enrolled. Indications for hemoadsorption were sepsis/septic shock (N = 936); cardiac surgery perioperatively (N = 172); cardiac surgery postoperatively (N = 67) and "other" reasons (N = 259). APACHE-II-predicted mortality was 62.0±24.8%, whereas observed hospital mortality was 50.1%. Overall SOFA scores did not change but cardiovascular and pulmonary SOFA scores decreased by 0.4 [-0.5;-0.3] and -0.2 [-0.3;-0.2] points, respectively. Serum procalcitonin and C-reactive protein levels showed significant reduction: -15.4 [-19.6;-11.17] ng/mL; -17,52 [-70;44] mg/L, respectively. In the septic cohort PCT and IL-6 also showed significant reduction: -18.2 [-23.6;-12.8] ng/mL; -2.6 [-3.0;-2.2] pg/mL, respectively. Evaluation of the overall effect: minimal improvement (22%), much improvement (22%) and very much improvement (10%), no change observed (30%) and deterioration (4%). There was no significant difference in the primary outcome of mortality, but there were improvements in cardiovascular and pulmonary SOFA scores and a reduction in PCT, CRP and IL-6 levels. Trial registration: ClinicalTrials.gov Identifier: NCT02312024 (retrospectively registered).

Estimating extra length of stay due to healthcare-associated infections before and after implementation of a hospital-wide infection control program.

INTRODUCTION: Healthcare-associated infections (HAIs) are a major health concern and have substantial effects on morbidity and mortality and increase healthcare costs. We investigated the effect of a hospital-wide program for the prevention of HAIs on additional length of stay (LOS). METHODS: We analyzed data from a prospective, single-center, quasi-experimental study with two surveillance periods before and after implementation of an infection prevention intervention program. HAI diagnosis was made according to surveillance definition criteria established by the US Centers for Disease Control and Prevention. A multistate model was used to estimate additional LOS for patients with HAI in both surveillance periods. RESULTS: During the first and second periods, 1,568 and 2,336 HAIs were identified among 26,943 and 35,211 patients, respectively. For HAI patients exclusively treated in a general ward, additional LOS was 8.4 (95% confidence interval, CI: 6.8-10.0) days in the first period and 9.6 (95% CI: 8.3-11.0) days in the second period (p = 0.26). For HAI patients treated in both an intensive care unit (ICU) and a general ward, additional LOS was 8.1 (95% CI: 6.3-9.9) days in the first period to 7.3 (95% CI: 6.1-8.5) days in the second period (p = 0.47). CONCLUSIONS: Healthcare-associated infections prolong LOS. A hospital-wide infection control program did not alter the prolongation of LOS.

Sequential organ failure assessment score is an excellent operationalization of disease severity of adult patients with hospitalized community acquired pneumonia - results from the prospective observational PROGRESS study.

BACKGROUND: CAP (Community acquired pneumonia) is frequent, with a high mortality rate and a high burden on health care systems. Development of predictive biomarkers, new therapeutic concepts, and epidemiologic research require a valid, reproducible, and quantitative measure describing CAP severity. METHODS: Using time series data of 1532 patients enrolled in the PROGRESS study, we compared putative measures of CAP severity for their utility as an operationalization. Comparison was based on ability to correctly identify patients with an objectively severe state of disease (death or need for intensive care with at least one of the following: substantial respiratory support, treatment with catecholamines, or dialysis). We considered IDSA/ATS minor criteria, CRB-65, CURB-65, Halm criteria, qSOFA, PSI, SCAP, SIRS-Score, SMART-COP, and SOFA. RESULTS: SOFA significantly outperformed other scores in correctly identifying a severe state of disease at the day of enrollment (AUC = 0.948), mainly caused by higher discriminative power at higher score values. Runners-up were the sum of IDSA/ATS minor criteria (AUC = 0.916) and SCAP (AUC = 0.868). SOFA performed similarly well on subsequent study days (all AUC > 0.9) and across age groups. In univariate and multivariate analysis, age, sex, and pack-years significantly contributed to higher SOFA values whereas antibiosis before hospitalization predicted lower SOFA. CONCLUSIONS: SOFA score can serve as an excellent operationalization of CAP severity and is proposed as endpoint for biomarker and therapeutic studies. TRIAL REGISTRATION: clinicaltrials.gov NCT02782013 , May 25, 2016, retrospectively registered.

The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis - a secondary analysis of a large randomised controlled trial.

BACKGROUND: This study assessed the ability of mid-regional proadrenomedullin (MR-proADM) in comparison to conventional biomarkers (procalcitonin (PCT), lactate, C-reactive protein) and clinical scores to identify disease severity in patients with sepsis. METHODS: This is a secondary analysis of a randomised controlled trial in patients with severe sepsis or septic shock across 33 German intensive care units. The association between biomarkers and clinical scores with mortality was assessed by Cox regression analysis, area under the receiver operating characteristic and Kaplan-Meier curves. Patients were stratified into three severity groups (low, intermediate, high) for all biomarkers and scores based on cutoffs with either a 90% sensitivity or specificity. RESULTS: 1089 patients with a 28-day mortality rate of 26.9% were analysed. According to the Sepsis-3 definition, 41.2% and 58.8% fulfilled the criteria for sepsis and septic shock, with respective mortality rates of 20.0% and 32.1%. MR-proADM had the strongest association with mortality across all Sepsis-1 and Sepsis-3 subgroups and could facilitate a more accurate classification of low (e.g. MR-proADM vs. SOFA: N = 265 vs. 232; 9.8% vs. 13.8% mortality) and high (e.g. MR-proADM vs. SOFA: N = 161 vs. 155; 55.9% vs. 41.3% mortality) disease severity. Patients with decreasing PCT concentrations of either ≥ 20% (baseline to day 1) or ≥ 50% (baseline to day 4) but continuously high MR-proADM concentrations had a significantly increased mortality risk (HR (95% CI): 19.1 (8.0-45.9) and 43.1 (10.1-184.0)). CONCLUSIONS: MR-proADM identifies disease severity and treatment response more accurately than established biomarkers and scores, adding additional information to facilitate rapid clinical decision-making and improve personalised sepsis treatment.

Hospital-related cost of sepsis: A systematic review.

OBJECTIVES: This article systematically reviews research on the costs of sepsis and, as a secondary aim, evaluates the quality of economic evaluations reported in peer-reviewed journals. METHODS: We systematically searched the MEDLINE, National Health Service (Abstracts of Reviews of Effects, Economic Evaluation and Health Technology Assessment), Cost-effectiveness Analysis Registry and Web of Knowledge databases for studies published between January 2005 and June 2015. We selected original articles that provided cost and cost-effectiveness analyses, defined sepsis and described their cost calculation method. Only studies that considered index admissions and re-admissions in the first 30 days were published in peer-reviewed journals and used standard treatments were considered. All costs were adjusted to 2014 US dollars. Medians and interquartile ranges (IQRs) for various costs of sepsis were calculated. The quality of economic studies was assessed using the Drummond 10-item checklist. RESULTS: Overall, 37 studies met our eligibility criteria. The median of the mean hospital-wide cost of sepsis per patient was $32,421 (IQR $20,745-$40,835), and the median of the mean ICU cost of sepsis per patient was $27,461 (IQR $16,007-$31,251). Overall, the quality of economic studies was low. CONCLUSIONS: Estimates of the hospital-related costs of sepsis varied considerably across the included studies depending on the method used for cost calculation, the type of sepsis and the population that was examined. A standard model for conducting cost improve the quality of studies on the costs of sepsis.

C-Terminal Alpha-1 Antitrypsin Peptide: A New Sepsis Biomarker with Immunomodulatory Function.

Systemic inflammatory response syndrome (SIRS) is a life threatening condition and the leading cause of death in intensive care units. Although single aspects of pathophysiology have been described in detail, numerous unknown mediators contribute to the progression of this complex disease. The aim of this study was to elucidate the pathophysiological role of CAAP48, a C-terminal alpha-1 antitrypsin fragment, that we found to be elevated in septic patients and to apply this peptide as diagnostic marker for infectious and noninfectious etiologies of SIRS. Incubation of human polymorphonuclear neutrophils with synthetic CAAP48, the SNP-variant CAAP47, and several control peptides revealed intense neutrophil activation, induction of neutrophil chemotaxis, reduction of neutrophil viability, and release of cytokines. We determined the abundance of CAAP48 in patients with severe sepsis, severe SIRS of noninfectious origin, and viral infection. CAAP48 levels were 3-4-fold higher in patients with sepsis compared to SIRS of noninfectious origin and allowed discrimination of those patients with high sensitivity and specificity. Our results suggest that CAAP48 is a promising discriminatory sepsis biomarker with immunomodulatory functions, particularly on human neutrophils, supporting its important role in the host response and pathophysiology of sepsis.

Extra length of stay and costs because of health care-associated infections at a German university hospital.

BACKGROUND: Health care-associated infections (HAIs) can be associated with increased health care costs. We examined extra length of hospital stay (LOS) and associated per diem costs attributable to HAIs in a large academic medical center. METHODS: Data for analysis were acquired in a preinterventional phase of a prospective cohort study (ALERTS) conducted over 12 months in 27 general and 4 intensive care units at Jena University Hospital. HAIs were identified among patients hospitalized for ≥48 hours with at least 1 risk factor for HAI and new antimicrobial therapy; the diagnosis was confirmed by U.S. Centers for Disease Control and Prevention criteria. Extra LOS was estimated by multistate modeling, and associated extra costs were based on average per diem costs for clinical units sampled. RESULTS: Of a total of 22,613 patients hospitalized for ≥48 hours, 893 (3.95%) experienced 1,212 episodes of HAI during 12 months. The associated mean extra LOS ± SEM in general units was 8.45 ± 0.80 days per case and 8.09 ± 0.91 days for patients treated in both general and intensive care units. Additional costs attributable to HAIs were €5,823-€11,840 ($7,453-$15,155) per infected patient. CONCLUSION: HAIs generated substantial extra costs by prolonging hospitalization. Potential clinical and financial savings may be realized by implementing effective infection prevention programs.

Stress disorders following prolonged critical illness in survivors of severe sepsis.

OBJECTIVES: To examine the frequency of acute stress disorder and posttraumatic stress disorder in chronically critically ill patients with a specific focus on severe sepsis, to classify different courses of stress disorders from 4 weeks to 6 months after transfer from acute care hospital to postacute rehabilitation, and to identify patients at risk by examining the relationship between clinical, demographic, and psychological variables and stress disorder symptoms. DESIGN: Prospective longitudinal cohort study, three assessment times within 4 weeks, 3 months, and 6 months after transfer to postacute rehabilitation. SETTING: Patients were consecutively enrolled in a large rehabilitation hospital (Clinic Bavaria, Kreischa, Germany) admitted for ventilator weaning from acute care hospitals. PATIENTS: We included 90 patients with admission diagnosis critical illness polyneuropathy or critical illness myopathy with or without severe sepsis, age between 18 and 70 years with a length of ICU stay greater than 5 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acute stress disorder and posttraumatic stress disorder were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, criteria by a trained and experienced clinical psychologist using a semistructured clinical interview for Diagnostic and Statistical Manual of Mental Disorders. We further administered the Acute Stress Disorder Scale and the Posttraumatic Symptom Scale-10 to assess symptoms of acute stress disorder and posttraumatic stress disorder. Three percent of the patients had an acute stress disorder diagnosis 4 weeks after transfer to postacute rehabilitation. Posttraumatic stress disorder was found in 7% of the patients at 3-month follow-up and in 12% after 6 months, respectively. Eighteen percent of the patients showed a delayed onset of posttraumatic stress disorder. Sepsis turned out to be a significant predictor of posttraumatic stress disorder symptoms at 3-month follow-up. CONCLUSIONS: A regular screening of post-ICU patients after discharge from hospital should be an integral part of aftercare management. The underlying mechanisms of severe sepsis in the development of posttraumatic stress disorder need further examination.

Sepsis survivors monitoring and coordination in outpatient health care (SMOOTH): study protocol for a randomized controlled trial.

BACKGROUND: Sepsis sequelae include critical illness polyneuropathy, myopathy, wasting, neurocognitive deficits, post-traumatic stress disorder, depression and chronic pain. Little is known howlong-term sequelae following hospital discharge are treated. The aim of our study is to determine the effect of a primary care-based, long-term program on health-related quality of life in sepsis survivors. METHODS/DESIGN: In a two-armed randomized multicenter interventional study, patients after sepsis (n = 290) will be assessed at 6, 12 and 24 months. Patients are eligible if severe sepsis or septic shock (ICD-10), at least two criteria of systemic inflammatory response syndrome (SIRS), at least one organ dysfunction and sufficient cognitive capacity are present. The intervention comprises 1) discharge management, 2) training of general practitioners and patients in evidence-based care for sepsis sequelae and 3) telephone monitoring of patients. At six months, we expect an improved primary outcome (health-related quality of life/SF-36) and improved secondary outcomes such as costs, mortality, clinical-, psycho-social- and process-of-care measures in the intervention group compared to the control group. DISCUSSION: This study evaluates a primary care-based, long-term program for patients after severe sepsis. Study results may add evidence for improved sepsis care management. General practitioners may contribute efficiently to sepsis aftercare. TRIAL REGISTRATION: U1111-1119-6345. DRKS00000741, CCT-NAPN-20875 (25 February 2011).

Targeted metabolomics for discrimination of systemic inflammatory disorders in critically ill patients.

The occurrence of systemic inflammatory response syndrome (SIRS) remains a major problem in intensive care units with high morbidity and mortality. The differentiation between noninfectious and infectious etiologies of this disorder is challenging in routine clinical practice. Many biomarkers have been suggested for this purpose; however, sensitivity and specificity even of high-ranking biomarkers remain insufficient. Recently, metabolic profiling has attracted interest for biomarker discovery. The objective of this study was to identify metabolic biomarkers for differentiation of SIRS/sepsis. A total of 186 meta-bolites comprising six analyte classes were determined in 143 patients (74 SIRS, 69 sepsis) by LC-MS/MS. Two markers (C10:1 and PCaaC32:0) revealed significantly higher concentrations in sepsis. A classification model comprising these markers resulted in 80% and 70% correct classifications in a training set and a test set, respectively.This study demonstrates that acylcarnitines and glycerophosphatidylcholines may be helpful for differentiation of infectious from noninfectious systemic inflammation due to their significantly higher concentration in sepsis patients. Considering the well known pathophysiological relevance of lipid induction by bacterial components, metabolites as identified in this study are promising biomarker candidates in the differential diagnosis of SIRS and sepsis.

Mass spectometry-based protein patterns in the diagnosis of sepsis/systemic inflammatory response syndrome.

Early differential diagnosis of systemic inflammatory reactions in critically ill patients is essential for timely implementation of lifesaving therapies. Despite many efforts made, reliable biomarkers to discriminate between infectious and noninfectious causes of systemic inflammatory response syndrome (SIRS) are currently not available. Recent advances in mass spectrometry-based methods have raised hopes that identification of spectral patterns from serum/plasma samples can be instrumental in this context. We compared protein expression patterns from patients with SIRS of infectious and noninfectious origin. Plasma samples from 166 patients obtained under rigorously standardized preanalytical conditions were applied to Q10 and CM10 ProteinChips. Protein profiles were used to train and develop decision tree classification algorithms. Discriminatory peaks were isolated and identified. Classification trees distinguished patients with noninfectious SIRS with organ dysfunction following open heart surgery using cardiopulmonary bypass from those with severe sepsis or septic shock with distinct sensitivities and specificities. Results were validated in a blinded test set in two independent experiments and in a second independently collected test set. Discriminatory peaks at 13.8 and 55.7 kd were identified as transthyretin and α1-antitrypsin; the third protein at m/z 4,798 was assigned to a proteolytic fragment of α1-antitrypsin. Taken together, our data demonstrate that plasma protein profiling allows reproducible discrimination between patients with infectious and noninfectious SIRS with high sensitivity and specificity. However, rigorous standardization as well as considering drug-related interferences is essential when interpreting protein profiling studies. Identification of discriminatory proteins suggests a direct link between infectious-related protease activity and a sepsis-specific diagnostic pattern for discrimination of patients with SIRS.

Acute renal failure in patients with severe sepsis and septic shock--a significant independent risk factor for mortality: results from the German Prevalence Study.

BACKGROUND: Sound data about the prevalence of acute renal failure (ARF) among patients with severe sepsis and septic shock are lacking. Further, it is not known whether ARF is an independent risk factor for mortality in septic patients or merely an indicator of disease severity. METHODS: A prospective cross-sectional one-day prevalence study was carried out in a representative sample of German ICUs, divided into five strata (< 200 beds; 201-400 beds; 401-600 beds; > 600 beds; university hospitals). 3877 patients were screened of whom 415 had severe sepsis and septic shock. RESULTS: Fourteen patients (3.4%) had chronic dialysis-dependent RF and were excluded from analysis. Of the remaining 401 patients, 166 (41.4%) had ARF, as defined by a rise in creatinine above twice the upper limit of normal and/or a drop in urine output to < 0.5 ml/kg bodyweight. Median APACHE II score was 22 in patients with ARF and 16 in patients without ARF (p< 0.0001). Patients with severe sepsis/septic shock had an overall hospital mortality of 55.2%. Hospital mortality in patients with ARF was 67.3% and without ARF 42.8% (p< 0.0001). After adjustment for APACHE II score and age, ARF remained a significant independent risk factor for death [odds ratio (OR) 2.11, 95% confidence interval (CI) 1.27-3.52]. Mortality in septic patients was not associated with pre-existing, non-dialysis-dependent chronic kidney disease, whereas in dialysis-dependent patients with sepsis mortality increased to 86%. CONCLUSION: In this representative survey in patients with severe sepsis/septic shock, prevalence of ARF is high with 41.4%. ARF represents a significant independent risk factor for mortality in these patients.