Axel Nierhaus

Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock

Objective: There is ongoing debate about the efficacy of polyvalent immunoglobulins as adjunctive therapy for sepsis or septic shock. Two meta‐analyses by the Cochrane collaboration calculated a significant reduction in mortality. However, data of the largest study were missing in one, and a subset of four high‐quality studies failed to show an effect in the other. To broaden the database, we performed a meta‐analysis of all randomized controlled studies published so far. Data Source: MEDLINE, EMBASE, Cochrane Library of randomized trials, and personal files. Study Selection: Meta‐analysis of all published randomized controlled studies published on polyvalent immunoglobulins (Ig) for treatment of sepsis or septic shock in adults, children, or neonates. Data Extraction: Twenty‐seven trials with a total of 2,202 patients fulfilled the inclusion criteria. Data Synthesis: As the immunologic state of neonates is different than that of adults or older children, data were evaluated separately for each group. Fifteen trials on 1,492 adults could be included. The pooled effect on mortality was a relative risk of death (RR) of 0.79 (95% confidence interval [CI] 0.69–0.90, p <= .0003). There was a strong trend in favor of an immunoglobulin preparation enriched with IgA and IgM (IgGAM) (RR = 0.66, 95% CI 0.51–0.84, p <= .0009) compared with preparations containing only IgG (RR = 0.85, 95% CI 0.73–0.99, p <= .04). In 12 trials on 710 neonates, the pooled effect on mortality was 0.56 (95% CI 0.42–0.74, p <= .0001). There was also a positive although less pronounced trend favoring the effect of IgGAM (RR = 0.50, 95% CI 0.34–0.73, p <= .0003) compared with IgG (RR = 0.63, 95% CI 0.42–0.96, p <= .03). A sensitivity analysis selecting eight trials in adults and ten in neonates of highest methodological quality confirmed these results. Conclusions: Polyvalent immunoglobulins exert a significant effect on mortality in sepsis and septic shock, with a trend in favor of IgGAM.

Effect of Empirical Treatment With Moxifloxacin and Meropenem vs Meropenem on Sepsis-Related Organ Dysfunction in Patients With Severe Sepsis: A Randomized Trial

CONTEXT Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The role of empirical combination therapy comprising at least 2 antibiotics of different mechanisms remains controversial. OBJECTIVE To compare the effect of moxifloxacin and meropenem with the effect of meropenem alone on sepsis-related organ dysfunction. DESIGN, SETTING, AND PATIENTS A randomized, open-label, parallel-group trial of 600 patients who fulfilled criteria for severe sepsis or septic shock (n = 298 for monotherapy and n = 302 for combination therapy). The trial was performed at 44 intensive care units in Germany from October 16, 2007, to March 23, 2010. The number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group. INTERVENTIONS Intravenous meropenem (1 g every 8 hours) and moxifloxacin (400 mg every 24 hours) or meropenem alone. The intervention was recommended for 7 days and up to a maximum of 14 days after randomization or until discharge from the intensive care unit or death, whichever occurred first. MAIN OUTCOME MEASURE Degree of organ failure (mean of daily total Sequential Organ Failure Assessment [SOFA] scores over 14 days; score range: 0-24 points with higher scores indicating worse organ failure); secondary outcome: 28-day and 90-day all-cause mortality. Survivors were followed up for 90 days. RESULTS Among 551 evaluable patients, there was no statistically significant difference in mean SOFA score between the meropenem and moxifloxacin group (8.3 points; 95% CI, 7.8-8.8 points) and the meropenem alone group (7.9 points; 95% CI, 7.5-8.4 points) (P = .36). The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9%; 95% CI, 19.0%-29.4%) in the combination therapy group compared with 59 deaths (21.9%; 95% CI, 17.1%-27.4%) in the monotherapy group (P = .58). By day 90, there were 96 deaths (35.3%; 95% CI, 29.6%-41.3%) in the combination therapy group compared with 84 deaths (32.1%; 95% CI, 26.5%-38.1%) in the monotherapy group (P = .43). CONCLUSION Among adult patients with severe sepsis, treatment with combined meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00534287.

Tracheostomy in the Intensive Care Unit : A Nationwide Survey

BACKGROUND: The indication, timing and technique of tracheostomy have changed over the last several years. We performed a survey to assess the current practice of tracheostomy in German intensive care units (ICUs). METHODS: A postal questionnaire was sent to the head physicians of 513 German ICUs, excluding pediatric ICUs. RESULTS: We obtained responses from 455 of the 513 ICUs (89%). In 90% of the ICUs, tracheostomies were performed during the first 14 d of mechanical ventilation. Eighty-six percent of the ICUs routinely performed percutaneous dilatational tracheostomy; the modified Ciaglia technique was the most popular percutaneous technique (69%). The majority (98%) of the percutaneous procedures were performed under bronchoscopic control. Surgical tracheostomy is usually performed in the operating room (72%) by a surgeon (61%), whereas percutaneous dilatational tracheostomies are usually performed at the patients bedside in the ICU (98%) by an intensivist (93%). Tracheostomized patients were followed up routinely in 26% of the ICUs, and in 45% of the ICUs there were guidelines regarding the indication, the timing and the technique of tracheostomy. CONCLUSION: Percutaneous dilatational tracheostomy is the procedure of choice for tracheostomy in critically ill patients in Germany. The modified Ciaglia technique is the preferred percutaneous technique, and nearly all physicians routinely use bronchoscopic guidance. Most tracheostomies are done during the second week of mechanical ventilation.

Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock: A Randomized Clinical Trial

IMPORTANCE High-dose intravenous administration of sodium selenite has been proposed to improve outcome in sepsis by attenuating oxidative stress. Procalcitonin-guided antimicrobial therapy may hasten the diagnosis of sepsis, but effect on outcome is unclear. OBJECTIVE To determine whether high-dose intravenous sodium selenite treatment and procalcitonin-guided anti-infectious therapy in patients with severe sepsis affect mortality. DESIGN, SETTING, AND PARTICIPANTS The Placebo-Controlled Trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT), a multicenter, randomized, clinical, 2 × 2 factorial trial performed in 33 intensive care units in Germany, was conducted from November 6, 2009, to June 6, 2013, including a 90-day follow-up period. INTERVENTIONS Patients were randomly assigned to receive an initial intravenous loading dose of sodium selenite, 1000 µg, followed by a continuous intravenous infusion of sodium selenite, 1000 µg, daily until discharge from the intensive care unit, but not longer than 21 days, or placebo. Patients also were randomized to receive anti-infectious therapy guided by a procalcitonin algorithm or without procalcitonin guidance. MAIN OUTCOMES AND MEASURES The primary end point was 28-day mortality. Secondary outcomes included 90-day all-cause mortality, intervention-free days, antimicrobial costs, antimicrobial-free days, and secondary infections. RESULTS Of 8174 eligible patients, 1089 patients (13.3%) with severe sepsis or septic shock were included in an intention-to-treat analysis comparing sodium selenite (543 patients [49.9%]) with placebo (546 [50.1%]) and procalcitonin guidance (552 [50.7%]) vs no procalcitonin guidance (537 [49.3%]). The 28-day mortality rate was 28.3% (95% CI, 24.5%-32.3%) in the sodium selenite group and 25.5% (95% CI, 21.8%-29.4%) (P = .30) in the placebo group. There was no significant difference in 28-day mortality between patients assigned to procalcitonin guidance (25.6% [95% CI, 22.0%-29.5%]) vs no procalcitonin guidance (28.2% [95% CI, 24.4%-32.2%]) (P = .34). Procalcitonin guidance did not affect frequency of diagnostic or therapeutic procedures but did result in a 4.5% reduction of antimicrobial exposure. CONCLUSIONS AND RELEVANCE Neither high-dose intravenous administration of sodium selenite nor anti-infectious therapy guided by a procalcitonin algorithm was associated with an improved outcome in patients with severe sepsis. These findings do not support administration of high-dose sodium selenite in these patients; the application of a procalcitonin-guided algorithm needs further evaluation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00832039.

Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial

Importance Adjunctive hydrocortisone therapy is suggested by the Surviving Sepsis Campaign in refractory septic shock only. The efficacy of hydrocortisone in patients with severe sepsis without shock remains controversial. Objective To determine whether hydrocortisone therapy in patients with severe sepsis prevents the development of septic shock. Design, Setting, and Participants Double-blind, randomized clinical trial conducted from January 13, 2009, to August 27, 2013, with a follow-up of 180 days until February 23, 2014. The trial was performed in 34 intermediate or intensive care units of university and community hospitals in Germany, and it included 380 adult patients with severe sepsis who were not in septic shock. Interventions Patients were randomly allocated 1:1 either to receive a continuous infusion of 200 mg of hydrocortisone for 5 days followed by dose tapering until day 11 (n = 190) or to receive placebo (n = 190). Main Outcomes and Measures The primary outcome was development of septic shock within 14 days. Secondary outcomes were time until septic shock, mortality in the intensive care unit or hospital, survival up to 180 days, and assessment of secondary infections, weaning failure, muscle weakness, and hyperglycemia (blood glucose level >150 mg/dL [to convert to millimoles per liter, multiply by 0.0555]). Results The intention-to-treat population consisted of 353 patients (64.9% male; mean [SD] age, 65.0 [14.4] years). Septic shock occurred in 36 of 170 patients (21.2%) in the hydrocortisone group and 39 of 170 patients (22.9%) in the placebo group (difference, -1.8%; 95% CI, -10.7% to 7.2%; P = .70). No significant differences were observed between the hydrocortisone and placebo groups for time until septic shock; mortality in the intensive care unit or in the hospital; or mortality at 28 days (15 of 171 patients [8.8%] vs 14 of 170 patients [8.2%], respectively; difference, 0.5%; 95% CI, -5.6% to 6.7%; P = .86), 90 days (34 of 171 patients [19.9%] vs 28 of 168 patients [16.7%]; difference, 3.2%; 95% CI, -5.1% to 11.4%; P = .44), and 180 days (45 of 168 patients [26.8%] vs 37 of 167 patients [22.2%], respectively; difference, 4.6%; 95% CI, -4.6% to 13.7%; P = .32). In the hydrocortisone vs placebo groups, 21.5% vs 16.9% had secondary infections, 8.6% vs 8.5% had weaning failure, 30.7% vs 23.8% had muscle weakness, and 90.9% vs 81.5% had hyperglycemia. Conclusions and Relevance Among adults with severe sepsis not in septic shock, use of hydrocortisone compared with placebo did not reduce the risk of septic shock within 14 days. These findings do not support the use of hydrocortisone in these patients. Trial Registration clinicaltrials.gov Identifier: NCT00670254.

Serum procalcitonin (PCT): a valuable biochemical parameter for the post-mortem diagnosis of sepsis

Abstract The aim of this prospective study was to investigate whether serum procalcitonin (PCT) can be used as a post-mortem marker of sepsis and to determine whether this biochemical parameter can be employed in the forensic elucidation of death due to sepsis. At least three blood samples were collected between 0.3 and 139 h post-mortem from sepsis-related fatalities (n = 8) and control individuals (n = 53, where death was due to various natural and unnatural causes). Additionally one ante-mortem blood sample was collected shortly before death from the patients in the sepsis group. In the sepsis group, serum PCT concentrations, determined by using an immunoluminometric assay, were elevated in all patients for the whole observation period, whereas in the control group serum PCT was not detectable in 94% of the cases. Measurement of PCT levels seems reasonable until at least approximately 140 h postmortem, depending on the ante-mortem levels. A linear regression model is presented that allows the serum PCT concentration of an individual at the time of death to be estimated on condition that at least two positive post-mortem PCT values have been determined. Ante-mortem PCT values correlated well with the predicted PCT values at the time of death in the sepsis group using the standardized PCT logarithms. According to the results of the present study, PCT is a valuable biochemical parameter for the post-mortem discrimination between sepsis and underlying non-septic causes of death.

Decreased serum concentrations of sphingosine-1-phosphate in sepsis

IntroductionSphingosine-1-phosphate (S1P) is a signaling lipid that regulates pathophysiological processes involved in sepsis progression, including endothelial permeability, cytokine release, and vascular tone. The aim of this study was to investigate whether serum-S1P concentrations are associated with disease severity in patients with sepsis.MethodsThis single-center prospective-observational study includes 100 patients with systemic inflammatory response syndrome (SIRS) plus infection (n = 40), severe sepsis (n = 30), or septic shock (n = 30) and 214 healthy blood donors as controls. Serum-S1P was measured by mass spectrometry. Blood parameters, including C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), lactate, and white blood cells (WBCs), were determined by routine assays. The Sequential Organ Failure Assessment (SOFA) score was generated and used to evaluate disease severity.ResultsSerum-S1P concentrations were lower in patients than in controls (P < 0.01), and the greatest difference was between the control and the septic shock groups (P < 0.01). Serum-S1P levels were inversely correlated with disease severity as determined by the SOFA score (P < 0.01) as well as with IL-6, PCT, CRP, creatinine, lactate, and fluid balance. A receiver operating characteristic analysis for the presence or absence of septic shock revealed equally high sensitivity and specificity for S1P compared with the SOFA score. In a multivariate logistic regression model calculated for prediction of septic shock, S1P emerged as the strongest predictor (P < 0.001).ConclusionsIn patients with sepsis, serum-S1P levels are dramatically decreased and are inversely associated with disease severity. Since S1P is a potent regulator of endothelial integrity, low S1P levels may contribute to capillary leakage, impaired tissue perfusion, and organ failure in sepsis.

Revisiting the white blood cell count: immature granulocytes count as a diagnostic marker to discriminate between SIRS and sepsis--a prospective, observational study.

BackgroundSepsis is a serious disease condition and a major cause of intensive care unit (ICU) admission. Its diagnosis in critically ill patients is complicated. To diagnose an infection rapidly, and to accurately differentiate systemic inflammatory response syndrome (SIRS) from sepsis, is challenging yet early diagnosis is vital for early induction of an appropriate therapy. The aim of this study was to evaluate whether the immature granulocyte (IG) count is a useful early diagnostic marker of sepsis compared to other markers. Therefore, a total of 70 consecutive surgical intensive care patients were assessed. IGs were measured from whole blood samples using an automated analyzer. C-reactive protein (CRP), lipopolysaccharide binding protein (LBP) and interleukin-6 (IL-6) concentrations were also determined. The observation period was a maximum of 21 days and ended with the patients’ discharge from ICU or death. Receiver operating characteristic (ROC) analyses were conducted and area under the curve (AUC) was calculated to determine sensitivities and specificities for the parameters.ResultsWe found that the IG count significantly discriminates between infected and non-infected patients (P < 0.0001) with a sensitivity of 89.2% and a specificity of 76.4%, particularly within the first 48 hours after SIRS onset. Regarding the discriminative power for infection, the IG count was more indicative than other clinical parameters such as CRP, LBP and IL-6, which had a sensitivity of less than 68%. Additionally, the highest diagnostic odds ratio (DOR) with 26.7 was calculated for the IG count within the first 48 hours. During the course of the disease ROC curve analyses showed a superior positive predictive value of the IG count compared to the other measured parameters during the first five days following the fulfillment of SIRS criteria. However, the number of IGs was not correlated with ICU mortality.ConclusionsThe total number of IG in peripheral blood from ICU patients is a good marker to discriminate infected and non-infected patients very early during SIRS. However, the IG count is not suitable as a prognostic marker for mortality. Routine and serial measurement of IGs may provide new possibilities for rapid screening of SIRS patients on ICU with suspected infections.

Clinical features of critically ill patients with Shiga toxin-induced hemolytic uremic syndrome.

Objective:In Spring 2011, an unprecedented outbreak of Shiga toxin–producing Escherichia coli serotype O104:H4–associated hemolytic uremic syndrome occurred in Northern Germany. The aim of this study was to describe the clinical characteristics, treatments, and outcomes of critically ill patients with Shiga toxin–producing E. coli–associated hemolytic uremic syndrome during this outbreak. Design, Setting, and Patients:Multicenter, retrospective, observational study of critically ill adult patients with Shiga toxin–producing E. coli–associated hemolytic uremic syndrome in six hospitals in Hamburg, Germany, between May 2011 and August 2011. Measurements and Main Results:During the study period, 106 patients with Shiga toxin–producing E. coli–associated hemolytic uremic syndrome were admitted to eight ICUs. The median age was 40 years (range, 18–83) with a female:male ratio of 3:1. The median time from onset of clinical symptoms to hospital admission was 3 days and from hospital to ICU admission an additional 3 days. A total of 101 patients (95.3%) had acute renal failure and 78 (73.6%) required renal replacement therapy. Intubation and mechanical ventilation were required in 38 patients (35.8%) and noninvasive ventilation was required in 17 patients (16.0%). The median duration of invasive ventilation was 7 days (range, 1–32 days) and the median ICU stay was 10 days (range, 1–45 days). Fifty-one patients (48.1%) developed sepsis; of these 51 patients, 27 (25.4%) developed septic shock. Seventy patients (66.0%) developed severe neurological symptoms. Ninety-seven patients (91.5%) were treated with plasma exchange and 50 patients (47.2%) received eculizumab (monoclonal anti-C5 antibody). The mortality rate was 4.7%. Mild residual neurological symptoms were present in 21.7% of patients at ICU discharge, and no patient required renal replacement therapy 6 months after ICU admission. Conclusions:During the 2011 Shiga toxin–producing E. coli–associated hemolytic uremic syndrome outbreak in Germany, critical illness developed rapidly after hospital admission, often in young women. The infection was associated with severe neurological and renal symptoms, requiring mechanical ventilation and renal replacement therapy in a substantial proportion of patients. Overall, recovery was much better than expected.

Use of a Weighted, Automated Analysis of the Differential Blood Count to Differentiate Sepsis from Non-Infectious Systemic Inflammation: The Intensive Care Infection Score (ICIS)

INTRODUCTION Rapid and accurate diagnosis and immediate treatment of sepsis are of crucial importance. However, differentiating sepsis from Systemic Inflammatory Response Syndrome (SIRS) is a difficult challenge. Many diagnostic approaches based on clinical chemistry surrogate markers have not improved the situation. MATERIAL AND METHODS The ICIS score was established in a cohort of 70 consecutive patients with SIRS. The score includes five parameters involved in the early innate immune response: mature neutrophils count, immature neutrophils count, antibody-secreting cells count, detection of neutrophils and monocytes/macrophages activation. The score can be provided in real-time without sample preparation and is independent from inter-observer variability. RESULTS Each ICIS score parameter itself is highly correlated with the occurrence of infection. A mean ICIS value of < 5 (lower cut-off level) indicated the absence of infection whereas the score did not fall below a value of 6 in infected patients throughout the observation time. The area under curve to detect infection for ICIS was found to be highest compared to CRP, LBP, EPO, IL-6 and TNF-α (AUC=0.851, P < 0.0001). CONCLUSION Cut-off values for ICIS as a marker of infection were defined by this pilot study. The superior discriminative power of ICIS compared to CRP, LBP, EPO, IL-6 and TNF-α is underlined by its high positive and negative predictive value, particularly within the first 48 hours (PPV=79.7%, NPV=74.5%). The ICIS score provides promising potential for reliably and swiftly discriminating sepsis from SIRS in the first critical hours.