Andrew Rhodes, Laura E Evans, Waleed Alhazzani, Mitchell M Levy, Massimo Antonelli, Ricard Ferrer, Anand Kumar, Jonathan E Sevransky, Charles L Sprung, Mark E Nunnally, Bram Rochwerg, Gordon D Rubenfeld, Derek C Angus, Djillali Annane, Richard J Beale, Geoffrey J Bellinghan, Gordon R Bernard, Jean-Daniel Chiche, Craig Coopersmith, Daniel P De Backer, Craig J French, Seitaro Fujishima, Herwig Gerlach, Jorge Luis Hidalgo, Steven M Hollenberg, Alan E Jones, Dilip R Karnad, Ruth M Kleinpell, Younsuk Koh, Thiago Costa Lisboa, Flavia R Machado, John J Marini, John C Marshall, John E Mazuski, Lauralyn A McIntyre, Anthony S McLean, Sangeeta Mehta, Rui P Moreno, John Myburgh, Paolo Navalesi, Osamu Nishida, Tiffany M Osborn, Anders Perner, Colleen M Plunkett, Marco Ranieri, Christa A Schorr, Maureen A Seckel, Christopher W Seymour, Lisa Shieh, Khalid A Shukri, Steven Q Simpson, Mervyn Singer, B Taylor Thompson, Sean R Townsend, Thomas Van der Poll, Jean-Louis Vincent, W Joost Wiersinga, Janice L Zimmerman, R Phillip Dellinger
Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.
Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.1007/s00134-017-4683-6. Epub 2017 Jan 18.
Abstract/Text
OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012".
DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development.
METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable.
RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions.
CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.
日本版敗血症診療ガイドライン特別委員会 日本集中治療医学会：日本版敗血症診療ガイドライン2020、日本集中治療医学会雑誌、2021：28:S1-S411.
Jian Han, Hua-ping Liang
Clinical significance of scoring system for systemic inflammatory response syndrome.
Chin J Traumatol. 2006 Oct;9(5):316-20.
Abstract/Text
The concepts of systemic inflammatory response syndrome (SIRS) and scoring system were defined by the journal of Bone in 1992. SIRS was described as occurrence of two or more clinical criteria in four ones (fever or hypothermia, tachypnea, tachycardia, and leukocytosis). An early diagnosis and estimation of systemic inflammation in patients is helpful for treatment selection. This paper reviews the application of SIRS scoring system, which has been extensively validated for large groups of critical care patients with severe injury and critical surgical diseases. Recent studies have documented SIRS score as a significant predictive parameter of adverse outcome in critical care patients. Furthermore, some studies also give us a suggestion on how to reduce the overload systemic response.
Alan E Jones, James F Fiechtl, Michael D Brown, Jason J Ballew, Jeffrey A Kline
Procalcitonin test in the diagnosis of bacteremia: a meta-analysis.
Ann Emerg Med. 2007 Jul;50(1):34-41. doi: 10.1016/j.annemergmed.2006.10.020. Epub 2006 Dec 11.
Abstract/Text
STUDY OBJECTIVE: We seek to evaluate the diagnostic performance of the procalcitonin test for the diagnosis of bacteremia in the emergency department (ED) population.
METHODS: We conducted a search of MEDLINE, bibliographies of previous systemic reviews, and pertinent national meeting research abstracts. We included studies that assessed the diagnostic accuracy of procalcitonin for bacteremia, with blood culture as the reference standard. We included prospective investigations of adults and children with suspected infection studied in the ED or at admission. Two authors independently extracted data and assessed study quality; consensus was reached by conference. The analysis was based on the I2 statistic for heterogeneity, unweighted summary receiver-operating characteristic curve, and random-effects pooled sensitivity and specificity across studies using the same test threshold.
RESULTS: The search yielded 348 publications and 1 unpublished study. Seventeen studies met the inclusion criteria and provided a sample of 2,008 subjects. There was a substantial degree of inconsistency (I2=64%). The unweighted summary receiver-operating characteristic curve provided the best overall estimate of test performance, with an area under the curve of 0.84 (95% confidence interval [CI] 0.75 to 0.90). Sensitivity analysis based on study quality did not significantly change the results. Subgroup analysis including only studies that used a test threshold of 0.5 or 0.4 ng/mL yielded pooled estimates for sensitivity and specificity of 76% (95% CI 0.66 to 0.84) and 70% (95% CI 0.60 to 0.79), respectively.
CONCLUSION: We found the diagnostic performance of the procalcitonin test for identifying bacteremia in ED patients to be moderate. Future research designed to determine the utility of the procalcitonin test as a diagnostic tool used in isolation for detecting bacteremia in ambulatory patients is needed before widespread clinical use.
Bernard Uzzan, Régis Cohen, Patrick Nicolas, Michel Cucherat, Gérard-Yves Perret
Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis.
Crit Care Med. 2006 Jul;34(7):1996-2003. doi: 10.1097/01.CCM.0000226413.54364.36.
Abstract/Text
OBJECTIVE: To quantify the accuracy of serum procalcitonin as a diagnostic test for sepsis, severe sepsis, or septic shock in adults in intensive care units or after surgery or trauma, alone and compared with C-reactive protein. To draw and compare the summary receiver operating characteristics curves for procalcitonin and C-reactive protein from the literature.
DATA SOURCE: MEDLINE (keywords: procalcitonin, intensive care, sepsis, postoperative sepsis, trauma); screening of the literature.
STUDY SELECTION: Meta-analysis of all 49 published studies in medical, surgical, or polyvalent intensive care units or postoperative wards. Children, medical patients, and immunocompromised patients were excluded.
DATA EXTRACTION: Thirty-three studies fulfilled inclusion criteria (3,943 patients, 1,828 males, 922 females; mean age: 56.1 yrs; 1,825 patients with sepsis, severe sepsis, or septic shock; 1,545 with only systemic inflammatory response syndrome); eight studies could not be analyzed statistically. Global mortality rate was 29.3%.
DATA SYNTHESIS: Global odds ratios for diagnosis of infection complicated by systemic inflammation were 15.7 for the 25 studies (2,966 patients) using procalcitonin (95% confidence interval, 9.1-27.1) and 5.4 for the 15 studies (1,322 patients) using C-reactive protein (95% confidence interval, 3.2-9.2). The summary receiver operating characteristics curve for procalcitonin was better than for C-reactive protein. In the 15 studies using both markers, the Q* value (intersection of summary receiver operating characteristics curve with the diagonal line where sensitivity equals specificity) was significantly higher for procalcitonin than for C-reactive protein (0.78 vs. 0.71, p = .02), the former test showing better accuracy.
CONCLUSIONS: Procalcitonin represents a good biological diagnostic marker for sepsis, severe sepsis, or septic shock, difficult diagnoses in critically ill patients. Procalcitonin is superior to C-reactive protein. Procalcitonin should be included in diagnostic guidelines for sepsis and in clinical practice in intensive care units.
Benjamin M P Tang, Guy D Eslick, Jonathan C Craig, Anthony S McLean
Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis.
Lancet Infect Dis. 2007 Mar;7(3):210-7. doi: 10.1016/S1473-3099(07)70052-X.
Abstract/Text
Procalcitonin is widely reported as a useful biochemical marker to differentiate sepsis from other non-infectious causes of systemic inflammatory response syndrome. In this systematic review, we estimated the diagnostic accuracy of procalcitonin in sepsis diagnosis in critically ill patients. 18 studies were included in the review. Overall, the diagnostic performance of procalcitonin was low, with mean values of both sensitivity and specificity being 71% (95% CI 67-76) and an area under the summary receiver operator characteristic curve of 0.78 (95% CI 0.73-0.83). Studies were grouped into phase 2 studies (n=14) and phase 3 studies (n=4) by use of Sackett and Haynes' classification. Phase 2 studies had a low pooled diagnostic odds ratio of 7.79 (95% CI 5.86-10.35). Phase 3 studies showed significant heterogeneity because of variability in sample size (meta-regression coefficient -0.592, p=0.017), with diagnostic performance upwardly biased in smaller studies, but moving towards a null effect in larger studies. Procalcitonin cannot reliably differentiate sepsis from other non-infectious causes of systemic inflammatory response syndrome in critically ill adult patients. The findings from this study do not lend support to the widespread use of the procalcitonin test in critical care settings.
P Marín Reina, I Ruiz Alcántara, S Vidal Micó, J L López-Prats Lucea, V Modesto I Alapont
[Accuracy of the procalcitonin test in the diagnosis of occult bacteremia in paediatrics: a systematic review and meta-analysis].
An Pediatr (Barc). 2010 Jun;72(6):403-12. doi: 10.1016/j.anpedi.2010.03.004. Epub 2010 May 13.
Abstract/Text
OBJECTIVE: To evaluate the diagnostic accuracy of serum procalcitonin (PCT) to detect severe bacterial infection (SBI) in ambulatory children attended in the emergency room (ER) for fever without source (FWS).
MATERIAL AND METHODS: A search was made in MEDLINE, OVID and EMBASE (to January 2010). We searched for papers that evaluated the diagnostic accuracy of serum PCT to detect SBI in children that, being previously well, were seen in the ER for FWS. We rated the methodological quality of each paper using objective validity criteria (QUADAS, CASPE) and included only those with the maximum quality in the analysis. The statistical meta-analysis was performed using the software, Meta-DiSc 1.1.1 for Windows.
RESULTS: The search identified 115 papers. Only 6 studies (prospective observational and analytic cohorts) fitted the inclusion criteria, with a sample size of 1139 patients. The prevalence of SBI was between 12.8% and 29% with a weighted mean of 18%. The overall senstivity was 0.771 (95% CI=0.707-0.826), the overall specificity was 0.804 (95% CI=0.777-0.830), the overall positive likelihood ratio was 3.610 (95% CI=2.481-5.253) and the overall negative likelihood ratio was 0.218 (95% CI=0.106-0.446). The diagnostic OR was 18.922 (95% CI=10.076-35.534), the Area under the SROC curve was 0.8801 (95% CI=0.821-0.939), and the optimal diagnostic cut-off value was Q*=0.8106 (95% CI=0.7512-0.8699).
CONCLUSIONS: On the basis of our analysis, in children with FWS seen in the ER, the serum PCT test accurately identifies those that have a SBI. We cannot extrapolate these results to other types of patients.
Copyright 2009 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.
Zhangbin Yu, Jiebo Liu, Qing Sun, Yufang Qiu, Shuping Han, Xirong Guo
The accuracy of the procalcitonin test for the diagnosis of neonatal sepsis: a meta-analysis.
Scand J Infect Dis. 2010 Oct;42(10):723-33. doi: 10.3109/00365548.2010.489906.
Abstract/Text
A meta-analysis was performed to assess the accuracy of the procalcitonin (PCT) test for diagnosing neonatal sepsis. The major databases, MEDLINE, EMBASE and the Cochrane Library were searched for studies published between January 1996 and May 2009 that evaluated PCT as a diagnostic marker for neonatal sepsis and provided sufficient data to calculate sensitivity and specificity. Twenty-two studies were included in the analysis. Trials that evaluated the PCT test for the diagnosis of early-onset neonatal sepsis at different time points (birth, 0-12 h, 12-24 h, and 24-48 h) and late-onset neonatal sepsis (LONS) all showed moderate accuracy (Q* = 0.79, 0.86, 0.81, 0.82, and 0.77, respectively). The PCT test was more accurate than the C-reactive protein (CRP) test for the diagnosis of LONS. A sensitivity analysis found that differences in PCT assay producer, gestational age and severity of sepsis in the study population may partially explain the between-studies heterogeneity. The PCT test showed moderate accuracy in diagnosing neonatal sepsis, regardless of differences in diagnostic criteria and time points for testing. For the diagnosis of LONS, the PCT test showed better accuracy than the CRP test. PCT is a valuable additional tool for the diagnosis of neonatal sepsis.
S M Pasha, F A Klok, J D Snoep, I C M Mos, R J Goekoop, M A Rodger, M V Huisman
Safety of excluding acute pulmonary embolism based on an unlikely clinical probability by the Wells rule and normal D-dimer concentration: a meta-analysis.
Thromb Res. 2010 Apr;125(4):e123-7. doi: 10.1016/j.thromres.2009.11.009. Epub 2009 Nov 26.
Abstract/Text
INTRODUCTION: The Wells clinical decision rule (CDR) and D-dimer tests can be used to exclude pulmonary embolism (PE). We performed a meta-analysis to determine the negative predictive value (NPV) of an "unlikely" CDR (METHODS: Prospective studies that withheld anti-coagulant treatment from patients with clinically suspected PE and an "unlikely" CDR in combination with a normal D-dimer concentration without performing further tests were searched for in Medline, Cochrane and Embase. Primary endpoints were the recurrence rate of venous thromboembolism (VTE) and PE-related mortality during 3-months follow-up.
RESULTS: Four studies including 1660 consecutive patients were identified. The pooled incidence of VTE after initial exclusion of acute PE based on an "unlikely" CDR and normal D-dimer was 0.34% (95%CI 0.036-0.96%), resulting in a NPV of 99.7% (95%CI: 99.0-99.9%, random effects-model). The risk for PE related mortality was very low: 1/1660 patients had fatal PE (0.06%, 95%CI 0.0017-0.46%).
CONCLUSION: Acute PE can be safely excluded in patients with clinically suspected acute PE who have an "unlikely" probability and a negative D-dimer test and anticoagulant treatment can be withheld. There is no need for additional radiological tests in these patients to rule out PE.
(c) 2009 Elsevier Ltd. All rights reserved.
Marc Carrier, Marc Righini, Reza Karami Djurabi, Menno V Huisman, Arnaud Perrier, Philip S Wells, Marc Rodger, Walter A Wuillemin, Grégoire Le Gal
VIDAS D-dimer in combination with clinical pre-test probability to rule out pulmonary embolism. A systematic review of management outcome studies.
Thromb Haemost. 2009 May;101(5):886-92.
Abstract/Text
Clinical outcome studies have shown that it is safe to withhold anticoagulant therapy in patients with suspected pulmonary embolism (PE) who have a negative D-dimer result and a low pretest probability (PTP) either using a PTP model or clinical gestalt. It was the objective of the present study to assess the safety of the combination of a negative VIDAS D-dimer result in combination with a non-high PTP using the Wells or Geneva models to exclude PE. A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews. Seven studies (6 prospective management studies and 1 randomised controlled trial) reporting failure rates at three months were included in the analysis. Non-high PTP was defined as "unlikely" using the Wells' model, or "low/intermediate" PTP using either the Geneva score, the Revised Geneva Score, or clinical gestalt. Two reviewers independently extracted data onto standardised forms. A total of 5,622 patients with low/intermediate or unlikely PTP were assessed using the VIDAS D-dimer. PE was ruled out by a negative D-dimer test in 2,248 (40%, 95% confidence intervals [CI] 38.7 to 41.3%) of them. The three-month thromboembolic risk in patients left untreated on the basis of a low/intermediate or unlikely PTP and a negative D-dimer test was 3/2,166 (0.14%, 95% CI 0.05 to 0.41%). In conclusion, the combination of a negative VIDAS D-dimer result and a non-high PTP effectively and safely excludes PE in an important proportion of outpatients with suspected PE.
Jodi B Segal, John Eng, Leonardo J Tamariz, Eric B Bass
Review of the evidence on diagnosis of deep venous thrombosis and pulmonary embolism.
Ann Fam Med. 2007 Jan-Feb;5(1):63-73. doi: 10.1370/afm.648.
Abstract/Text
PURPOSE: This review summarizes the evidence regarding the efficacy of techniques for diagnosis of deep venous thrombosis (DVT) and pulmonary embolism.
METHODS: We searched for studies using MEDLINE, MICROMEDEX, the Cochrane Controlled Trials Register, and the Cochrane Database of Systematic Reviews through June 2006. We reviewed randomized controlled trials, systematic reviews of trials, and observational studies if no trials were available. Paired reviewers assessed the quality of each included article and abstracted the data into summary tables. Heterogeneity in study designs precluded mathematical combination of the results of the primary literature.
RESULTS: Our review found 22 relevant systematic reviews and 36 primary studies. The evidence strongly supports the use of clinical prediction rules, particularly the Wells model, for establishing the pretest probability of DVT or pulmonary embolism in a patient before ordering more definitive testing. Fifteen studies support that when a D-dimer assay is negative and a clinical prediction rule suggests a low probability of DVT or pulmonary embolism, the negative predictive value is high enough to justify foregoing imaging studies in many patients. The evidence in 5 systematic reviews regarding the use of D-dimer, in isolation, is strong and demonstrates sensitivities of the enzyme-linked immunosorbent assay (ELISA) and quantitative rapid ELISA, pooled across studies, of approximately 95%. Eight systematic reviews found that the sensitivity and specificity of ultrasonography for diagnosis of DVT vary by vein; ultrasonography performs best for diagnosis of symptomatic, proximal vein thrombosis, with pooled sensitivities of 89% to 96%. The sensitivity of single-detector helical computed tomography for diagnosis of pulmonary embolism varied widely across studies and was below 90% in 4 of 9 studies; more studies are needed to determine the sensitivity of multidetector scanners.
CONCLUSIONS: While the strength of the evidence varies across questions, it is generally strong.
Andrew Rhodes, Rebecca J Cusack, Philip J Newman, R Michael Grounds, E David Bennett
A randomised, controlled trial of the pulmonary artery catheter in critically ill patients.
Intensive Care Med. 2002 Mar;28(3):256-64. doi: 10.1007/s00134-002-1206-9. Epub 2002 Feb 13.
Abstract/Text
OBJECTIVE: To compare the survival and clinical outcomes of critically ill patients treated with the use of a pulmonary artery catheter (PAC) to those treated without the use of a PAC.
DESIGN: Prospective, randomised, controlled, clinical trial from October 1997 to February 1999.
SETTING: Adult intensive care unit at a large teaching hospital.
PATIENTS: Two hundred one critically ill patients were randomised either to a PAC group ( n=95) or the control group ( n=106). One patient in the control group was withdrawn from the study and five patients in the PAC group did not receive a PAC. All participants were available for follow-up.
INTERVENTIONS: Participants were assigned to be managed either with the use of a PAC (PAC group) or without the use of a PAC (control group).
MAIN OUTCOME MEASURES: Survival to 28 days, intensive care and hospital length of stay and organ dysfunction were compared on an intention-to-treat basis and also on a subgroup basis for those participants who successfully received a PAC. RESULTS There was no significant difference in mortality between the PAC group [46/95 (47.9%)] and the control group [50/106 (47.6)] (95% confidence intervals for the difference -13 to 14%, p>0.99). The mortality for participants who had management decisions based on information derived from a PAC was 41/91 (45%, 95% confidence intervals -11 to 16%, p=0.77). The PAC group had significantly more fluids in the first 24 h (4953 (3140, 7000) versus 4292 (2535, 6049) ml) and an increased incidence of renal failure (35 versus 20% of patients at day 3 post randomisation p<0.05) and thrombocytopenia ( p<0.03).
CONCLUSIONS: These results suggest that the PAC is not associated with an increased mortality.
James Dean Sandham, Russell Douglas Hull, Rollin Frederick Brant, Linda Knox, Graham Frederick Pineo, Christopher J Doig, Denny P Laporta, Sidney Viner, Louise Passerini, Hugh Devitt, Ann Kirby, Michael Jacka, Canadian Critical Care Clinical Trials Group
A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients.
N Engl J Med. 2003 Jan 2;348(1):5-14. doi: 10.1056/NEJMoa021108.
Abstract/Text
BACKGROUND: Some observational studies suggest that the use of pulmonary-artery catheters to guide therapy is associated with increased mortality.
METHODS: We performed a randomized trial comparing goal-directed therapy guided by a pulmonary-artery catheter with standard care without the use of a pulmonary-artery catheter. The subjects were high-risk patients 60 years of age or older, with American Society of Anesthesiologists (ASA) class III or IV risk, who were scheduled for urgent or elective major surgery, followed by a stay in an intensive care unit. Outcomes were adjudicated by observers who were unaware of the treatment-group assignments. The primary outcome was in-hospital mortality from any cause.
RESULTS: Of 3803 eligible patients, 1994 (52.4 percent) underwent randomization. The base-line characteristics of the two treatment groups were similar. A total of 77 of 997 patients who underwent surgery without the use of a pulmonary-artery catheter (7.7 percent) died in the hospital, as compared with 78 of 997 patients in whom a pulmonary-artery catheter was used (7.8 percent)--a difference of 0.1 percentage point (95 percent confidence interval, -2.3 to 2.5). There was a higher rate of pulmonary embolism in the catheter group than in the standard-care group (8 events vs. 0 events, P=0.004). The survival rates at 6 months among patients in the standard-care and catheter groups were 88.1 and 87.4 percent, respectively (difference, -0.7 percentage point [95 percent confidence interval, -3.6 to 2.2]; negative survival differences favor standard care); at 12 months, the rates were 83.9 and 83.0 percent, respectively (difference, -0.9 percentage point [95 percent confidence interval, -4.3 to 2.4]). The median hospital stay was 10 days in each group.
CONCLUSIONS: We found no benefit to therapy directed by pulmonary-artery catheter over standard care in elderly, high-risk surgical patients requiring intensive care.
Copyright 2003 Massachusetts Medical Society
Christian Richard, Josiane Warszawski, Nadia Anguel, Nicolas Deye, Alain Combes, Didier Barnoud, Thierry Boulain, Yannick Lefort, Muriel Fartoukh, Frederic Baud, Alexandre Boyer, Laurent Brochard, Jean-Louis Teboul, French Pulmonary Artery Catheter Study Group
Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial.
JAMA. 2003 Nov 26;290(20):2713-20. doi: 10.1001/jama.290.20.2713.
Abstract/Text
CONTEXT: Many physicians believe that the pulmonary artery catheter (PAC) is useful for the diagnosis and treatment of cardiopulmonary disturbances; however, observational studies suggest that its use may be harmful.
OBJECTIVE: To determine the effects on outcome of the early use of a PAC in patients with shock mainly of septic origin, acute respiratory distress syndrome (ARDS), or both.
DESIGN, SETTING, AND PATIENTS: A multicenter randomized controlled study of 676 patients aged 18 years or older who fulfilled the standard criteria for shock, ARDS, or both conducted in 36 intensive care units in France from January 30, 1999, to June 29, 2001.
INTERVENTION: Patients were randomly assigned to either receive a PAC (n = 335) or not (n = 341). The treatment was left to the discretion of each individual physician.
MAIN OUTCOME MEASURES: The primary end point was mortality at 28 days. The principal secondary end points were day 14 and 90 mortality; day 14 organ system, renal support, and vasoactive agents-free days; hospital, intensive care unit, and mechanical ventilation-free days at day 28.
RESULTS: The 2 groups were similar at baseline. There were no significant differences in mortality with or without the PAC at day 14: 49.9% vs 51.3% (mortality relative risk [RR], 0.97; 95% confidence interval [CI], 0.84-1.13; P =.70); day 28: 59.4% vs 61.0% (RR, 0.97; 95% CI, 0.86-1.10; P =.67); or day 90: 70.7% vs 72.0% (RR, 0.98; 95% CI, 0.89-1.08; P =.71). At day 14, the mean (SD) number of days free of organ system failures with or without the PAC (2.3 [3.6] vs 2.4 [3.5]), renal support (7.4 [6.0] vs 7.5 [5.9]), and vasoactive agents (3.8 [4.8] vs 3.9 [4.9]) did not differ. At day 28, mean (SD) days in hospital with or without the PAC (0.9 [3.6] vs 0.9 [3.3]), in the intensive care unit (3.4 [6.8] vs 3.3 [6.9]), or mechanical ventilation use (5.2 [8.5] vs 5.0 [8.5]) did not differ.
CONCLUSION: Clinical management involving the early use of a PAC in patients with shock, ARDS, or both did not significantly affect mortality and morbidity.
Sheila Harvey, David A Harrison, Mervyn Singer, Joanne Ashcroft, Carys M Jones, Diana Elbourne, William Brampton, Dewi Williams, Duncan Young, Kathryn Rowan, PAC-Man study collaboration
Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled trial.
Lancet. 2005 Aug 6-12;366(9484):472-7. doi: 10.1016/S0140-6736(05)67061-4.
Abstract/Text
BACKGROUND: Over the past 30 years the pulmonary artery catheter (PAC) has become a widely used haemodynamic monitoring device in the management of critically ill patients, though doubts exist about its safety. Our aim was, therefore, to ascertain whether hospital mortality is reduced in critically ill patients when they are managed with a PAC.
METHODS: We did a randomised controlled trial to which we enrolled 1041 patients from 65 UK intensive care units. We assigned individuals to management with (n=519) or without (n=522) a PAC. The timing of insertion and subsequent clinical management were at the discretion of the treating clinician. Intensive care units decided a priori to have the option of using an alternative cardiac output-monitoring device in control patients.
FINDINGS: 1014 patients were eligible for analysis. We noted no difference in hospital mortality between patients managed with or without a PAC (68% [346 of 506] vs 66% [333 of 507], p=0.39; adjusted hazard ratio 1.09, 95% CI 0.94-1.27). We noted complications associated with insertion of a PAC in 46 of 486 individuals in whom the device was placed, none of which was fatal.
INTERPRETATION: Our findings indicate no clear evidence of benefit or harm by managing critically ill patients with a PAC. Efficacy studies are needed to ascertain whether management protocols involving PAC use can result in improved outcomes in specific groups if these devices are not to become a redundant technology.
Yasser Sakr, Jean-Louis Vincent, Konrad Reinhart, Didier Payen, Christian J Wiedermann, Durk F Zandstra, Charles L Sprung, Sepsis Occurrence in Acutely Ill Patients Investigators
Use of the pulmonary artery catheter is not associated with worse outcome in the ICU.
Chest. 2005 Oct;128(4):2722-31. doi: 10.1378/chest.128.4.2722.
Abstract/Text
STUDY OBJECTIVES: In critically ill patients, the impact of pulmonary artery catheter (PAC) use on outcome is debatable. We investigated the epidemiology of PAC use in European ICUs and its relation to outcome.
DESIGN: International cohort, observational study.
SETTING: One hundred ninety-eight European ICUs participating in the Sepsis Occurrence in Acutely Ill Patients Study.
PATIENTS: All 3,147 adult patients admitted to one of the participating ICUs between May 1, 2002, and May 15, 2002.
INTERVENTIONS: None.
MEASUREMENTS AND RESULTS: Patients were classified according to whether or not they had a PAC at any time during their ICU stay, and were followed up until death, hospital discharge, or for 60 days. Propensity score case matching was performed, and matched pairs were examined for baseline characteristics and outcome. Of 3,147 patients, 481 patients (15.3%) had a PAC. Patients with a PAC were older, had a higher incidence of heart failure, a lower incidence of cancer, and were more commonly surgical admissions. Fluid balance was comparable between the two groups. ICU and hospital mortality rates were higher in patients with a PAC (28.1% vs 16.8% and 32.5% vs 22.5%, respectively; p < 0.001). However, PAC use was not an independent risk factor for 60-day mortality in multivariate analysis, and in 453 propensity-matched pairs ICU and hospital mortality rates were comparable between groups (26.7% vs 26.3% and 31.4% vs 32.8%, p = not significant). Survival to 60 days was similar between the two matched groups (log rank = 0.02; p = 0.894).
CONCLUSIONS: This observational study suggests that PAC use is not associated with increased mortality in this heterogeneous population.
Sanderland T Gurgel, Paulo do Nascimento
Maintaining tissue perfusion in high-risk surgical patients: a systematic review of randomized clinical trials.
Anesth Analg. 2011 Jun;112(6):1384-91. doi: 10.1213/ANE.0b013e3182055384. Epub 2010 Dec 14.
Abstract/Text
BACKGROUND: Surgical patients with limited organic reserve are considered high-risk patients and have an increased perioperative mortality. For this reason, they need a more rigorous perioperative protocol of hemodynamic control to prevent tissue hypoperfusion. In this study, we systematically reviewed the randomized controlled clinical trials that used a hemodynamic protocol to maintain adequate tissue perfusion in the high-risk surgical patient.
METHODS: We searched MEDLINE, Embase, LILACS, and Cochrane databases to identify randomized controlled clinical studies of surgical patients studied using a perioperative hemodynamic protocol of tissue perfusion aiming to reduce mortality and morbidity; the latter characterized at least one dysfunctional organ in the postoperative period. Pooled odds ratio (POR) and 95% confidence interval (CI) were calculated for categorical outcomes.
RESULTS: Thirty-two clinical trials were selected, comprising 5056 high-risk surgical patients. Global meta-analysis showed a significant reduction in mortality rate (POR: 0.67; 95% CI: 0.55-0.82; P < 0.001) and in postoperative organ dysfunction incidence (POR: 0.62; 95% CI: 0.55-0.70; P < 0.00,001) when a hemodynamic protocol was used to maintain tissue perfusion. When the mortality rate was >20% in the control group, the use of a hemodynamic protocol to maintain tissue optimization resulted in a further reduction in mortality (POR: 0.32; 95% CI: 0.21-0.47; P < 0.00,001). Monitoring cardiac output with a pulmonary artery catheter and increasing oxygen transport and/or decreasing consumption also significantly reduced mortality (POR: 0.67; 95% CI: 0.54-0.84; P < 0.001 and POR: 0.71; 95% CI: 0.57-0.88; P < 0.05, respectively). Therapy directed at increasing mixed or central venous oxygen saturation did not significantly reduce mortality (POR: 0.68; 95% CI: 0.22-2.10; P > 0.05). The only study using lactate as a marker of tissue perfusion failed to demonstrate a statistically significant reduction in mortality (OR: 0.33; 95% CI: 0.07-1.65; P > 0.05).
CONCLUSIONS: In high-risk surgical patients, the use of a hemodynamic protocol to maintain tissue perfusion decreased mortality and postoperative organ failure. Monitoring cardiac output calculating oxygen transport and consumption helped to guide therapy. Additional randomized controlled clinical studies are necessary to analyze the value of monitoring mixed or central venous oxygen saturation and lactate in high-risk surgical patients.
B A Mizock, J L Falk
Lactic acidosis in critical illness.
Crit Care Med. 1992 Jan;20(1):80-93.
Abstract/Text
PURPOSE: This article reviews the current body of knowledge regarding lactic acidosis in critically ill patients. The classification of disordered lactate metabolism and its pathogenesis are examined. The utility of lactate as a metabolic monitor of shock is examined and current therapeutic strategies in the treatment of patients suffering from lactic acidosis are extensively reviewed. The paper is designed to integrate basic concepts with a current approach to lactate in critical illness that the clinician can use at the bedside.
DATA SOURCES: Comprehensive review of the available, basic science, medical, surgical, and critical care literature.
CONCLUSIONS: The severity of lactic acidosis in critically ill patients correlates with overall oxygen debt and survival. Lactate determinations may be useful as an ongoing monitor of perfusion as resuscitation proceeds. Therapy of critically ill patients with lactic acidosis is designed to maximize oxygen delivery in order to reduce tissue hypoxia by increasing cardiac index, while maintaining hemoglobin concentration. Buffering agents have not been shown to materially affect outcome from lactic acidosis caused by shock. The benefits of other specific therapies designed to reduce the severity of lactic acidosis remain unproven.
Alan E Jones, Nathan I Shapiro, Stephen Trzeciak, Ryan C Arnold, Heather A Claremont, Jeffrey A Kline, Emergency Medicine Shock Research Network (EMShockNet) Investigators
Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial.
JAMA. 2010 Feb 24;303(8):739-46. doi: 10.1001/jama.2010.158.
Abstract/Text
CONTEXT: Goal-directed resuscitation for severe sepsis and septic shock has been reported to reduce mortality when applied in the emergency department.
OBJECTIVE: To test the hypothesis of noninferiority between lactate clearance and central venous oxygen saturation (ScvO2) as goals of early sepsis resuscitation.
DESIGN, SETTING, AND PATIENTS: Multicenter randomized, noninferiority trial involving patients with severe sepsis and evidence of hypoperfusion or septic shock who were admitted to the emergency department from January 2007 to January 2009 at 1 of 3 participating US urban hospitals.
INTERVENTIONS: We randomly assigned patients to 1 of 2 resuscitation protocols. The ScvO2 group was resuscitated to normalize central venous pressure, mean arterial pressure, and ScvO2 of at least 70%; and the lactate clearance group was resuscitated to normalize central venous pressure, mean arterial pressure, and lactate clearance of at least 10%. The study protocol was continued until all goals were achieved or for up to 6 hours. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment.
MAIN OUTCOME MEASURE: The primary outcome was absolute in-hospital mortality rate; the noninferiority threshold was set at Delta equal to -10%.
RESULTS: Of the 300 patients enrolled, 150 were assigned to each group and patients were well matched by demographic, comorbidities, and physiological features. There were no differences in treatments administered during the initial 72 hours of hospitalization. Thirty-four patients (23%) in the ScvO2 group died while in the hospital (95% confidence interval [CI], 17%-30%) compared with 25 (17%; 95% CI, 11%-24%) in the lactate clearance group. This observed difference between mortality rates did not reach the predefined -10% threshold (intent-to-treat analysis: 95% CI for the 6% difference, -3% to 15%). There were no differences in treatment-related adverse events between the groups.
CONCLUSION: Among patients with septic shock who were treated to normalize central venous and mean arterial pressure, additional management to normalize lactate clearance compared with management to normalize ScvO2 did not result in significantly different in-hospital mortality.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00372502.
Mark E Mikkelsen, Andrea N Miltiades, David F Gaieski, Munish Goyal, Barry D Fuchs, Chirag V Shah, Scarlett L Bellamy, Jason D Christie
Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock.
Crit Care Med. 2009 May;37(5):1670-7. doi: 10.1097/CCM.0b013e31819fcf68.
Abstract/Text
PRINCIPLE: Serum lactate is a potentially useful biomarker to risk-stratify patients with severe sepsis; however, it is plausible that elevated serum lactate is simply a manifestation of clinically apparent organ dysfunction and/or shock (i.e., refractory hypotension).
OBJECTIVE: To test whether the association between initial serum lactate level and mortality in patients presenting to the emergency department (ED) with severe sepsis is independent of organ dysfunction and shock.
DESIGN: Single-center cohort study. The primary outcome was 28-day mortality and the risk factor variable was initial venous lactate (mmol/L), categorized as low (< 2), intermediate (2-3.9), or high (> or = 4). Potential covariates included age, sex, race, acute and chronic organ dysfunction, severity of illness, and initiation of early goal-directed therapy. Multivariable logistic regression analyses were stratified on the presence or absence of shock.
SETTING: The ED of an academic tertiary care center from 2005 to 2007.
PATIENTS: Eight hundred thirty adults admitted with severe sepsis in the ED.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Mortality at 28 days was 22.9% and median serum lactate was 2.9 mmol/L. Intermediate (odds ratio [OR] = 2.05, p = 0.024) and high serum lactate levels (OR = 4.87, p < 0.001) were associated with mortality in the nonshock subgroup. In the shock subgroup, intermediate (OR = 3.27, p = 0.022) and high serum lactate levels (OR = 4.87, p = 0.001) were also associated with mortality. After adjusting for potential confounders, intermediate and high serum lactate levels remained significantly associated with mortality within shock and nonshock strata.
CONCLUSIONS: Initial serum lactate was associated with mortality independent of clinically apparent organ dysfunction and shock in patients admitted to the ED with severe sepsis. Both intermediate and high serum lactate levels were independently associated with mortality.
Pablo Perel, Ian Roberts
Colloids versus crystalloids for fluid resuscitation in critically ill patients.
Cochrane Database Syst Rev. 2011 Mar 16;(3):CD000567. doi: 10.1002/14651858.CD000567.pub4. Epub 2011 Mar 16.
Abstract/Text
BACKGROUND: Colloid solutions are widely used in fluid resuscitation of critically ill patients. There are several choices of colloid and there is ongoing debate about the relative effectiveness of colloids compared to crystalloid fluids.
OBJECTIVES: To assess the effects of colloids compared to crystalloids for fluid resuscitation in critically ill patients.
SEARCH STRATEGY: We searched the Cochrane Injuries Group Specialised Register, CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED), ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S), and The Controlled Trials metaRegister (www.controlled-trials.com). Reference lists of relevant studies and review articles were searched for further trials. The searches were last updated in September 2008.
SELECTION CRITERIA: Randomised controlled trials (RCTs) of colloids compared to crystalloids, in patients requiring volume replacement. We excluded cross-over trials and trials in pregnant women and neonates.
DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and rated quality of allocation concealment. We analysed trials with a 'double-intervention', such as those comparing colloid in hypertonic crystalloid to isotonic crystalloid, separately. We stratified the analysis according to colloid type and quality of allocation concealment.
MAIN RESULTS: We identified 65 eligible trials; 56 of these presented mortality data.Colloids compared to crystalloidsAlbumin or plasma protein fraction - 23 trials reported data on mortality, including a total of 7754 patients. The pooled relative risk (RR) from these trials was 1.01 (95% confidence interval (95% CI) 0.92 to 1.10). When we excluded the trial with poor quality allocation concealment, pooled RR was 1.00 (95% CI 0.91 to 1.09). Hydroxyethyl starch - 17 trials compared hydroxyethyl starch with crystalloids, n = 1172 patients. The pooled RR was 1.18 (95% CI 0.96 to 1.44). Modified gelatin - 11 trials compared modified gelatin with crystalloid, n = 506 patients. The pooled RR was 0.91 (95% CI 0.49 to 1.72). (When the trials by Boldt et al were removed from the three preceding analyses, the results were unchanged.) Dextran - nine trials compared dextran with a crystalloid, n = 834 patients. The pooled RR was 1.24 (95% CI 0.94 to 1.65).Colloids in hypertonic crystalloid compared to isotonic crystalloidEight trials compared dextran in hypertonic crystalloid with isotonic crystalloid, including 1283 randomised participants. Pooled RR was 0.88 (95% CI 0.74 to 1.05).
AUTHORS' CONCLUSIONS: There is no evidence from RCTs that resuscitation with colloids reduces the risk of death, compared to resuscitation with crystalloids, in patients with trauma, burns or following surgery. As colloids are not associated with an improvement in survival, and as they are more expensive than crystalloids, it is hard to see how their continued use in these patients can be justified outside the context of RCTs.
Simon Finfer, Rinaldo Bellomo, Neil Boyce, Julie French, John Myburgh, Robyn Norton, SAFE Study Investigators
A comparison of albumin and saline for fluid resuscitation in the intensive care unit.
N Engl J Med. 2004 May 27;350(22):2247-56. doi: 10.1056/NEJMoa040232.
Abstract/Text
BACKGROUND: It remains uncertain whether the choice of resuscitation fluid for patients in intensive care units (ICUs) affects survival. We conducted a multicenter, randomized, double-blind trial to compare the effect of fluid resuscitation with albumin or saline on mortality in a heterogeneous population of patients in the ICU.
METHODS: We randomly assigned patients who had been admitted to the ICU to receive either 4 percent albumin or normal saline for intravascular-fluid resuscitation during the next 28 days. The primary outcome measure was death from any cause during the 28-day period after randomization.
RESULTS: Of the 6997 patients who underwent randomization, 3497 were assigned to receive albumin and 3500 to receive saline; the two groups had similar baseline characteristics. There were 726 deaths in the albumin group, as compared with 729 deaths in the saline group (relative risk of death, 0.99; 95 percent confidence interval, 0.91 to 1.09; P=0.87). The proportion of patients with new single-organ and multiple-organ failure was similar in the two groups (P=0.85). There were no significant differences between the groups in the mean (+/-SD) numbers of days spent in the ICU (6.5+/-6.6 in the albumin group and 6.2+/-6.2 in the saline group, P=0.44), days spent in the hospital (15.3+/-9.6 and 15.6+/-9.6, respectively; P=0.30), days of mechanical ventilation (4.5+/-6.1 and 4.3+/-5.7, respectively; P=0.74), or days of renal-replacement therapy (0.5+/-2.3 and 0.4+/-2.0, respectively; P=0.41).
CONCLUSIONS: In patients in the ICU, use of either 4 percent albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days.
Copyright 2004 Massachusetts Medical Society
Laura Evans, Andrew Rhodes, Waleed Alhazzani, Massimo Antonelli, Craig M Coopersmith, Craig French, Flávia R Machado, Lauralyn Mcintyre, Marlies Ostermann, Hallie C Prescott, Christa Schorr, Steven Simpson, W Joost Wiersinga, Fayez Alshamsi, Derek C Angus, Yaseen Arabi, Luciano Azevedo, Richard Beale, Gregory Beilman, Emilie Belley-Cote, Lisa Burry, Maurizio Cecconi, John Centofanti, Angel Coz Yataco, Jan De Waele, R Phillip Dellinger, Kent Doi, Bin Du, Elisa Estenssoro, Ricard Ferrer, Charles Gomersall, Carol Hodgson, Morten Hylander Møller, Theodore Iwashyna, Shevin Jacob, Ruth Kleinpell, Michael Klompas, Younsuck Koh, Anand Kumar, Arthur Kwizera, Suzana Lobo, Henry Masur, Steven McGloughlin, Sangeeta Mehta, Yatin Mehta, Mervyn Mer, Mark Nunnally, Simon Oczkowski, Tiffany Osborn, Elizabeth Papathanassoglou, Anders Perner, Michael Puskarich, Jason Roberts, William Schweickert, Maureen Seckel, Jonathan Sevransky, Charles L Sprung, Tobias Welte, Janice Zimmerman, Mitchell Levy
Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.
Intensive Care Med. 2021 Nov;47(11):1181-1247. doi: 10.1007/s00134-021-06506-y. Epub 2021 Oct 2.
Abstract/Text
E Rivers, B Nguyen, S Havstad, J Ressler, A Muzzin, B Knoblich, E Peterson, M Tomlanovich, Early Goal-Directed Therapy Collaborative Group
Early goal-directed therapy in the treatment of severe sepsis and septic shock.
N Engl J Med. 2001 Nov 8;345(19):1368-77. doi: 10.1056/NEJMoa010307.
Abstract/Text
BACKGROUND: Goal-directed therapy has been used for severe sepsis and septic shock in the intensive care unit. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand. The purpose of this study was to evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit.
METHODS: We randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were obtained serially for 72 hours and compared between the study groups.
RESULTS: Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133 to standard therapy; there were no significant differences between the groups with respect to base-line characteristics. In-hospital mortality was 30.5 percent in the group assigned to early goal-directed therapy, as compared with 46.5 percent in the group assigned to standard therapy (P = 0.009). During the interval from 7 to 72 hours, the patients assigned to early goal-directed therapy had a significantly higher mean (+/-SD) central venous oxygen saturation (70.4+/-10.7 percent vs. 65.3+/-11.4 percent), a lower lactate concentration (3.0+/-4.4 vs. 3.9+/-4.4 mmol per liter), a lower base deficit (2.0+/-6.6 vs. 5.1+/-6.7 mmol per liter), and a higher pH (7.40+/-0.12 vs. 7.36+/-0.12) than the patients assigned to standard therapy (P < or = 0.02 for all comparisons). During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to early goal-directed therapy than in those assigned to standard therapy (13.0+/-6.3 vs. 15.9+/-6.4, P < 0.001).
CONCLUSIONS: Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.
日本集中治療医学会・日本救急医学会合同作成：日本版敗血症診療ガイドライン2016、日救急医会誌. 2017; 28:S1-S4.
Daniel De Backer, Patrick Biston, Jacques Devriendt, Christian Madl, Didier Chochrad, Cesar Aldecoa, Alexandre Brasseur, Pierre Defrance, Philippe Gottignies, Jean-Louis Vincent, SOAP II Investigators
Comparison of dopamine and norepinephrine in the treatment of shock.
N Engl J Med. 2010 Mar 4;362(9):779-89. doi: 10.1056/NEJMoa0907118.
Abstract/Text
BACKGROUND: Both dopamine and norepinephrine are recommended as first-line vasopressor agents in the treatment of shock. There is a continuing controversy about whether one agent is superior to the other.
METHODS: In this multicenter, randomized trial, we assigned patients with shock to receive either dopamine or norepinephrine as first-line vasopressor therapy to restore and maintain blood pressure. When blood pressure could not be maintained with a dose of 20 microg per kilogram of body weight per minute for dopamine or a dose of 0.19 microg per kilogram per minute for norepinephrine, open-label norepinephrine, epinephrine, or vasopressin could be added. The primary outcome was the rate of death at 28 days after randomization; secondary end points included the number of days without need for organ support and the occurrence of adverse events.
RESULTS: The trial included 1679 patients, of whom 858 were assigned to dopamine and 821 to norepinephrine. The baseline characteristics of the groups were similar. There was no significant between-group difference in the rate of death at 28 days (52.5% in the dopamine group and 48.5% in the norepinephrine group; odds ratio with dopamine, 1.17; 95% confidence interval, 0.97 to 1.42; P=0.10). However, there were more arrhythmic events among the patients treated with dopamine than among those treated with norepinephrine (207 events [24.1%] vs. 102 events [12.4%], P<0.001). A subgroup analysis showed that dopamine, as compared with norepinephrine, was associated with an increased rate of death at 28 days among the 280 patients with cardiogenic shock but not among the 1044 patients with septic shock or the 263 with hypovolemic shock (P=0.03 for cardiogenic shock, P=0.19 for septic shock, and P=0.84 for hypovolemic shock, in Kaplan-Meier analyses).
CONCLUSIONS: Although there was no significant difference in the rate of death between patients with shock who were treated with dopamine as the first-line vasopressor agent and those who were treated with norepinephrine, the use of dopamine was associated with a greater number of adverse events. (ClinicalTrials.gov number, NCT00314704.)
2010 Massachusetts Medical Society
Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. The Veterans Administration Systemic Sepsis Cooperative Study Group.
N Engl J Med. 1987 Sep 10;317(11):659-65. doi: 10.1056/NEJM198709103171102.
Abstract/Text
We conducted a multicenter randomized, double-blind, placebo-controlled trial of early short-term, high-dose methylprednisolone sodium succinate in 223 patients with clinical signs of systemic sepsis and a normal sensorium (112 received glucocorticoid and 111 placebo). Patients also received antibiotics and intravenous fluids. Glucocorticoid or placebo was administered intravenously by a bolus (30 mg per kilogram of body weight over 15 minutes) followed by infusion of 5 mg per kilogram per hour for nine hours. The average time between the diagnosis of sepsis and infusion was 2.8 hours. The principal end point was 14-day mortality, which was similar in the placebo (22 percent) and glucocorticoid (21 percent) groups (P = 0.97). Mortality was also not significantly different between those receiving placebo and those receiving glucocorticoid in subgroups with evidence of sepsis (21 vs. 19 percent), gram-negative bacteremia (27 vs. 7 percent), gram-positive bacteremia (18 vs. 26 percent), or all gram-negative infections (25 vs. 17 percent). Resolution of secondary infection within 14 days was significantly higher in patients receiving placebo (12 of 23) than in those receiving glucocorticoid (3 of 16) (P = 0.03), but mortality rates were similar in both treatment groups for those with unresolved infection (36 vs. 31 percent). We conclude that early high-dose glucocorticoid therapy does not reduce mortality significantly in patients with systemic sepsis who have a normal sensorium, and therefore should not be used as adjunctive therapy.
R C Bone, C J Fisher, T P Clemmer, G J Slotman, C A Metz, R A Balk
A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock.
N Engl J Med. 1987 Sep 10;317(11):653-8. doi: 10.1056/NEJM198709103171101.
Abstract/Text
The use of high-dose corticosteroids in the treatment of severe sepsis and septic shock remains controversial. Our study was designed as a prospective, randomized, double-blind, placebo-controlled trial of high-dose methylprednisolone sodium succinate for severe sepsis and septic shock. Diagnosis was based on the clinical suspicion of infection plus the presence of fever or hypothermia (rectal temperature greater than 38.3 degrees C [101 degrees F] or less than 35.6 degrees C [96 degrees F]), tachypnea (greater than 20 breaths per minute), tachycardia (greater than 90 beats per minute), and the presence of one of the following indications of organ dysfunction: a change in mental status, hypoxemia, elevated lactate levels, or oliguria. Three hundred eighty-two patients were enrolled. Treatment--either methylprednisolone sodium succinate (30 mg per kilogram of body weight) or placebo--was given in four infusions, starting within two hours of diagnosis. No significant differences were found in the prevention of shock, the reversal of shock, or overall mortality. In the subgroup of patients with elevated serum creatinine levels (greater than 2 mg per deciliter) at enrollment, mortality at 14 days was significantly increased among those receiving methylprednisolone (46 of 78 [59 percent] vs. 17 of 58 [29 percent] among those receiving placebo; P less than 0.01). Among patients treated with methylprednisolone, significantly more deaths were related to secondary infection. We conclude that the use of high-dose corticosteroids provides no benefit in the treatment of severe sepsis and septic shock.
John L Moran, Petra L Graham, Sue Rockliff, Andrew D Bersten
Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective.
Crit Care. 2010;14(4):R134. doi: 10.1186/cc9182. Epub 2010 Jul 13.
Abstract/Text
INTRODUCTION: Current low (stress) dose corticosteroid regimens may have therapeutic advantage in severe sepsis and septic shock despite conflicting results from two landmark randomised controlled trials (RCT). We systematically reviewed the efficacy of corticosteroid therapy in severe sepsis and septic shock.
METHODS: RCTs were identified (1950-September 2008) by multiple data-base electronic search (MEDLINE via OVID, OVID PreMedline, OVID Embase, Cochrane Central Register of Controlled trials, Cochrane database of systematic reviews, Health Technology Assessment Database and Database of Abstracts of Reviews of Effects) and hand search of references, reviews and scientific society proceedings. Three investigators independently assessed trial inclusion and data extraction into standardised forms; differences resolved by consensus.
RESULTS: Corticosteroid efficacy, compared with control, for hospital-mortality, proportion of patients experiencing shock-resolution, and infective and non-infective complications was assessed using Bayesian random-effects models; expressed as odds ratio (OR, (95% credible-interval)). Bayesian outcome probabilities were calculated as the probability (P) that OR ≥1. Fourteen RCTs were identified. High-dose (>1000 mg hydrocortisone (equivalent) per day) corticosteroid trials were associated with a null (n = 5; OR 0.91(0.31-1.25)) or higher (n = 4, OR 1.46(0.73-2.16), outlier excluded) mortality probability (P = 42.0% and 89.3%, respectively). Low-dose trials (<1000 mg hydrocortisone per day) were associated with a lower (n = 9, OR 0.80(0.40-1.39); n = 8 OR 0.71(0.37-1.10), outlier excluded) mortality probability (20.4% and 5.8%, respectively). OR for shock-resolution was increased in the low dose trials (n = 7; OR 1.20(1.07-4.55); P = 98.2%). Patient responsiveness to corticotrophin stimulation was non-determinant. A high probability of risk-related treatment efficacy (decrease in log-odds mortality with increased control arm risk) was identified by metaregression in the low dose trials (n = 9, slope coefficient -0.49(-1.14, 0.27); P = 92.2%). Odds of complications were not increased with corticosteroids.
CONCLUSIONS: Although a null effect for mortality treatment efficacy of low dose corticosteroid therapy in severe sepsis and septic shock was not excluded, there remained a high probability of treatment efficacy, more so with outlier exclusion. Similarly, although a null effect was not excluded, advantageous effects of low dose steroids had a high probability of dependence upon patient underlying risk. Low dose steroid efficacy was not demonstrated in corticotrophin non-responders. Further large-scale trials appear mandated.
Djillali Annane, Virginie Maxime, Fidaa Ibrahim, Jean Claude Alvarez, Emuri Abe, Philippe Boudou
Diagnosis of adrenal insufficiency in severe sepsis and septic shock.
Am J Respir Crit Care Med. 2006 Dec 15;174(12):1319-26. doi: 10.1164/rccm.200509-1369OC. Epub 2006 Sep 14.
Abstract/Text
RATIONALE: Diagnosis of adrenal insufficiency in critically ill patients has relied on random or cosyntropin-stimulated cortisol levels, and has not been corroborated by a more accurate diagnostic standard.
OBJECTIVE: We used the overnight metyrapone stimulation test to investigate the diagnostic value of the standard cosyntropin stimulation test, and the prevalence of sepsis-associated adrenal insufficiency.
METHODS: This was an inception cohort study.
MEASUREMENTS AND RESULTS: In two consecutive septic cohorts (n = 61 and n = 40), in 44 patients without sepsis and in 32 healthy volunteers, we measured (1) serum cortisol before and after cosyntropin stimulation, albumin, and corticosteroid-binding globulin levels, and (2) serum corticotropin, cortisol, and 11beta-deoxycortisol levels before and after an overnight metyrapone stimulation. Adrenal insufficiency was defined by postmetyrapone serum 11beta-deoxycortisol levels below 7 microg/dl. More patients with sepsis (31/61 [59% of original cohort with sepsis] and 24/40 [60% of validation cohort with sepsis]) met criteria for adrenal insufficiency than patients without sepsis (3/44; 7%) (p < 0.001 for both comparisons). Baseline cortisol (< 10 microg/dl), Delta cortisol (< 9 microg/dl), and free cortisol (< 2 microg/dl) had a positive likelihood ratio equal to infinity, 8.46 (95% confidence interval, 1.19-60.25), and 9.50 (95% confidence interval, 1.05-9.54), respectively. The best predictor of adrenal insufficiency (as defined by metyrapone testing) was baseline cortisol of 10 microg/dl or less or Delta cortisol of less than 9 microg/dl. The best predictors of normal adrenal response were cosyntropin-stimulated cortisol of 44 microg/dl or greater and Delta cortisol of 16.8 microg/dl or greater.
CONCLUSIONS: In sepsis, adrenal insufficiency is likely when baseline cortisol levels are less than 10 microg/dl or delta cortisol is less than 9 microg/dl, and unlikely when cosyntropin-stimulated cortisol level is 44 microg/dl or greater or Delta cortisol is 16.8 microg/dl or greater.
Paul E Marik, Stephen M Pastores, Djillali Annane, G Umberto Meduri, Charles L Sprung, Wiebke Arlt, Didier Keh, Josef Briegel, Albertus Beishuizen, Ioanna Dimopoulou, Stylianos Tsagarakis, Mervyn Singer, George P Chrousos, Gary Zaloga, Faran Bokhari, Michael Vogeser, American College of Critical Care Medicine
Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine.
Crit Care Med. 2008 Jun;36(6):1937-49. doi: 10.1097/CCM.0b013e31817603ba.
Abstract/Text
OBJECTIVE: To develop consensus statements for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients.
PARTICIPANTS: A multidisciplinary, multispecialty task force of experts in critical care medicine was convened from the membership of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. In addition, international experts in endocrinology were invited to participate.
DESIGN/METHODS: The task force members reviewed published literature and provided expert opinion from which the consensus was derived. The consensus statements were developed using a modified Delphi methodology. The strength of each recommendation was quantified using the Modified GRADE system, which classifies recommendations as strong (grade 1) or weak (grade 2) and the quality of evidence as high (grade A), moderate (grade B), or low (grade C) based on factors that include the study design, the consistency of the results, and the directness of the evidence.
RESULTS: The task force coined the term critical illness-related corticosteroid insufficiency to describe the dysfunction of the hypothalamic-pituitary-adrenal axis that occurs during critical illness. Critical illness-related corticosteroid insufficiency is caused by adrenal insufficiency together with tissue corticosteroid resistance and is characterized by an exaggerated and protracted proinflammatory response. Critical illness-related corticosteroid insufficiency should be suspected in hypotensive patients who have responded poorly to fluids and vasopressor agents, particularly in the setting of sepsis. At this time, the diagnosis of tissue corticosteroid resistance remains problematic. Adrenal insufficiency in critically ill patients is best made by a delta total serum cortisol of < 9 microg/dL after adrenocorticotrophic hormone (250 microg) administration or a random total cortisol of < 10 microg/dL. The benefit of treatment with glucocorticoids at this time seems to be limited to patients with vasopressor-dependent septic shock and patients with early severe acute respiratory distress syndrome (PaO2/FiO2 of < 200 and within 14 days of onset). The adrenocorticotrophic hormone stimulation test should not be used to identify those patients with septic shock or acute respiratory distress syndrome who should receive glucocorticoids. Hydrocortisone in a dose of 200 mg/day in four divided doses or as a continuous infusion in a dose of 240 mg/day (10 mg/hr) for > or = 7 days is recommended for septic shock. Methylprednisolone in a dose of 1 mg x kg(-1) x day(-1) for > or = 14 days is recommended in patients with severe early acute respiratory distress syndrome. Glucocorticoids should be weaned and not stopped abruptly. Reinstitution of treatment should be considered with recurrence of signs of sepsis, hypotension, or worsening oxygenation. Dexamethasone is not recommended to treat critical illness-related corticosteroid insufficiency. The role of glucocorticoids in the management of patients with community-acquired pneumonia, liver failure, pancreatitis, those undergoing cardiac surgery, and other groups of critically ill patients requires further investigation.
CONCLUSION: Evidence-linked consensus statements with regard to the diagnosis and management of corticosteroid deficiency in critically ill patients have been developed by a multidisciplinary, multispecialty task force.
Anand Kumar, Paul Ellis, Yaseen Arabi, Dan Roberts, Bruce Light, Joseph E Parrillo, Peter Dodek, Gordon Wood, Aseem Kumar, David Simon, Cheryl Peters, Muhammad Ahsan, Dan Chateau, Cooperative Antimicrobial Therapy of Septic Shock Database Research Group
Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock.
Chest. 2009 Nov;136(5):1237-48. doi: 10.1378/chest.09-0087. Epub 2009 Aug 20.
Abstract/Text
OBJECTIVE: Our goal was to determine the impact of the initiation of inappropriate antimicrobial therapy on survival to hospital discharge of patients with septic shock.
METHODS: The appropriateness of initial antimicrobial therapy, the clinical infection site, and relevant pathogens were retrospectively determined for 5,715 patients with septic shock in three countries.
RESULTS: Therapy with appropriate antimicrobial agents was initiated in 80.1% of cases. Overall, the survival rate was 43.7%. There were marked differences in the distribution of comorbidities, clinical infections, and pathogens in patients who received appropriate and inappropriate initial antimicrobial therapy (p < 0.0001 for each). The survival rates after appropriate and inappropriate initial therapy were 52.0% and 10.3%, respectively (odds ratio [OR], 9.45; 95% CI, 7.74 to 11.54; p < 0.0001). Similar differences in survival were seen in all major epidemiologic, clinical, and organism subgroups. The decrease in survival with inappropriate initial therapy ranged from 2.3-fold for pneumococcal infection to 17.6-fold with primary bacteremia. After adjustment for acute physiology and chronic health evaluation II score, comorbidities, hospital site, and other potential risk factors, the inappropriateness of initial antimicrobial therapy remained most highly associated with risk of death (OR, 8.99; 95% CI, 6.60 to 12.23).
CONCLUSIONS: Inappropriate initial antimicrobial therapy for septic shock occurs in about 20% of patients and is associated with a fivefold reduction in survival. Efforts to increase the frequency of the appropriateness of initial antimicrobial therapy must be central to efforts to reduce the mortality of patients with septic shock.
Anand Kumar, Nasia Safdar, Shravan Kethireddy, Dan Chateau
A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: a meta-analytic/meta-regression study.
Crit Care Med. 2010 Aug;38(8):1651-64. doi: 10.1097/CCM.0b013e3181e96b91.
Abstract/Text
OBJECTIVE: To assess whether a potential benefit with combination antibiotic therapy is restricted to the most critically ill subset of patients, particularly those with septic shock.
DATA SOURCES: OVID MEDLINE (1950-October 2009), EMBASE (1980-October 2009), the Cochrane Central Register of Controlled Trials (to third quarter 2009), the ClinicalTrial.gov database, and the SCOPUS database.
STUDY SELECTION: Randomized or observational studies of antimicrobial therapy of serious bacterial infections potentially associated with sepsis or septic shock. Fifty studies met entry criteria.
DATA EXTRACTION: Study design, mortality/clinical response, and other variables were extracted independently by two reviewers. When possible, study datasets were split into mutually exclusive groups with and without shock or critical illness.
DATA SYNTHESIS: Although a pooled odds ratio indicated no overall mortality/clinical response benefit with combination therapy (odds ratio, 0.856; 95% confidence interval, 0.71-1.03; p = .0943; I = 45.1%), stratification of datasets by monotherapy mortality risk demonstrated substantial benefit in the most severely ill subset (monotherapy risk of death >25%; odds ratio of death, 0.51; 95% confidence interval, 0.41-0.64; I = 8.6%). Of those datasets that could be stratified by the presence of shock/critical illness, the more severely ill group consistently demonstrated increased efficacy of a combination therapy strategy (odds ratio, 0.49; 95% confidence interval, 0.35-0.70; p < .0001; I = 0%). An increased risk of death was found in low-risk patients (risk of death CONCLUSION: Combination antibiotic therapy improves survival and clinical response of high-risk, life-threatening infections, particularly those associated with septic shock but may be detrimental to low-risk patients.
Krischan D Sjauw, Annemarie E Engström, Marije M Vis, René J van der Schaaf, Jan Baan, Karel T Koch, Robbert J de Winter, Jan J Piek, Jan G P Tijssen, José P S Henriques
A systematic review and meta-analysis of intra-aortic balloon pump therapy in ST-elevation myocardial infarction: should we change the guidelines?
Eur Heart J. 2009 Feb;30(4):459-68. doi: 10.1093/eurheartj/ehn602. Epub 2009 Jan 23.
Abstract/Text
Aims Intra-aortic balloon counterpulsation (IABP) in ST-segment elevation myocardial infarction (STEMI) with cardiogenic shock is strongly recommended (class IB) in the current guidelines. We performed meta-analyses to evaluate the evidence for IABP in STEMI with and without cardiogenic shock. Methods and results Medical literature databases were scrutinized to identify randomized trials comparing IABP with no IABP in STEMI. In absence of randomized trials, cohort studies of IABP in STEMI with cardiogenic shock were identified. Two separate meta-analyses were performed respectively. The first meta-analysis included seven randomized trials (n = 1009) of STEMI. IABP showed neither a 30-day survival benefit nor improved left ventricular ejection fraction, while being associated with significantly higher stroke and bleeding rates. The second meta-analysis included nine cohorts of STEMI patients with cardiogenic shock (n = 10529). In patients treated with thrombolysis, IABP was associated with an 18% [95% confidence interval (CI), 16-20%; P < 0.0001] decrease in 30 day mortality, albeit with significantly higher revascularization rates compared to patients without support. Contrariwise, in patients treated with primary percutaneous coronary intervention, IABP was associated with a 6% (95% CI, 3-10%; P < 0.0008) increase in 30 day mortality. Conclusion The pooled randomized data do not support IABP in patients with high-risk STEMI. The meta-analysis of cohort studies in the setting of STEMI complicated by cardiogenic shock supported IABP therapy adjunctive to thrombolysis. In contrast, the observational data did not support IABP therapy adjunctive to primary PCI. All available observational data concerning IABP therapy in the setting of cardiogenic shock is importantly hampered by bias and confounding. There is insufficient evidence endorsing the current guideline recommendation for the use of IABP therapy in the setting of STEMI complicated by cardiogenic shock. Our meta-analyses challenge the current guideline recommendations.
Roland Prondzinsky, Henning Lemm, Michael Swyter, Nikolas Wegener, Susanne Unverzagt, Justin M Carter, Martin Russ, Axel Schlitt, Ute Buerke, Arnd Christoph, Hendrik Schmidt, Matthias Winkler, Joachim Thiery, Karl Werdan, Michael Buerke
Intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized IABP SHOCK Trial for attenuation of multiorgan dysfunction syndrome.
Crit Care Med. 2010 Jan;38(1):152-60. doi: 10.1097/CCM.0b013e3181b78671.
Abstract/Text
OBJECTIVE: Patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction with cardiogenic shock (CS) are often treated with intra-aortic balloon pump counterpulsation (IABP), even though the evidence to support this is limited. We determined whether IABP as an addition to PCI-centered therapy ameliorates multiorgan dysfunction syndrome (MODS) in patients with acute myocardial infarction complicated by CS.
DESIGN: A prospective, randomized, controlled, open-label clinical trial recruiting patients between March 2003 and June 2004 (ClinicalTrials.gov ID NCT00469248).
SETTING: Tertiary care university hospital.
PATIENTS AND INTERVENTIONS: Forty-five consecutive patients with AMI and CS undergoing PCI were randomized to treatment with or without IABP.
MEASUREMENTS AND MAIN RESULTS: Acute Physiology and Chronic Health Evaluation (APACHE) II scores (primary outcome measure), hemodynamic values, inflammatory markers, and plasma brain natriuretic peptide (BNP) levels (secondary outcomes) were collected over 4 days from randomization. The prospective hypothesis was that adding IABP therapy to "standard care" would improve CS-triggered MODS. The addition of IABP to standard therapy did not result in a significant improvement in MODS (measured by serial APACHE II scoring over 4 days). IABP use had no significant effect on cardiac index or systemic inflammatory activation, although BNP levels were significantly lower in IABP-treated patients. Initial and serial APACHE II scoring correlated with mortality better than cardiac index, systemic inflammatory state, and BNP levels in this group of patients. Nonsurvivors had significantly higher initial APACHE II scores (29.9 +/- 2.88) than survivors (18.1 +/- 1.66, p < .05). Nevertheless, discrepancies among patients within the groups cannot be ruled out and might interfere with our results.
CONCLUSIONS: In this randomized trial addressing addition of IABP in CS patients, mechanical support was associated only with modest effects on reduction of APACHE II score as a marker of severity of disease, improvement of cardiac index, reduction of inflammatory state, or reduction of BNP biomarker status compared with medical therapy alone. However, the limitations of our present trial preclude any definitive conclusion, but request for a larger prospective, randomized, multicentered trial with mortality as primary end point.
Amol Bahekar, Mukesh Singh, Sarabjeet Singh, Rohit Bhuriya, Khraisat Ahmad, Sandeep Khosla, Rohit Arora
Cardiovascular outcomes using intra-aortic balloon pump in high-risk acute myocardial infarction with or without cardiogenic shock: a meta-analysis.
J Cardiovasc Pharmacol Ther. 2012 Mar;17(1):44-56. doi: 10.1177/1074248410395019. Epub 2011 Feb 18.
Abstract/Text
BACKGROUND: Intra-aortic balloon pump (IABP) has been widely used ever since it was first developed in 1962 and became part of clinical practice in 1968. It is used to treat patients with complications of acute myocardial infarction (AMI) such as cardiogenic shock, refractory left ventricular failure, and for high-risk patients undergoing angioplasty and coronary artery bypass grafting. However, current literature demonstrates a significant variance in terms of indications for using IABP and its outcomes. The aim of this study is to review the existing literature to analyze whether the use of IABP offers any cardiovascular benefit to the patients with AMI and the complications associated with the use of IABP. Material and
METHODS: A systematic review of literature identified 16 studies. We analyzed the primary endpoint (in-hospital mortality, reinfarction, recurrent ischemia) and secondary endpoint (incidence of moderate and severe bleeding during hospitalization at 7 days). We estimated the proportion of between-study inconsistency (heterogeneity) due to true differences between studies (rather than differences due to random error or chance) using the I2 statistic. Mantel-Haenszel fixed-effect model was used to calculate the combined relative risks (RRs) when studies were homogenous, and the random effect model was used when studies were heterogenic. A 2-sided α error <.05 was considered statistically significant.
RESULTS: Meta-analysis revealed that in-hospital mortality of patients with AMI with and without cardiogenic shock did not differ between IABP group as compared to no IABP group (RR: 1.11; confidence interval [CI]: 0.69-1.78; P = .67). However, analysis of patients with AMI with cardiogenic shock showed statistically significant improvement in mortality (RR: 0.72; CI: 0.60-0.86; P < .0004). There was no significant reduction in the rate of reinfarction (RR: 0.81; CI: 0.30-2.17; P = .67) or recurrent ischemia (RR: 0.78; CI: 0.34-1.78; P = .55) using IABP. Intra-aortic balloon pump was found to significantly increase the risk of moderate bleeding (RR: 1.71; CI: 1.03-2.85; P = .04) and major bleeding (RR: 4.01; CI: 2.66-6.06; P < .0001).
CONCLUSION: The present meta-analysis suggests that patients with high-risk AMI without cardiogenic shock do not seem to benefit from the use of IABP as measured by in-hospital mortality, rate of reinfarction, and recurrent angina. However, in patients with AMI with cardiogenic shock (systolic blood pressure [SBP] < 90), there was significant reduction in mortality using IABP. The use of IABP is associated with increase in the rate of both moderate and severe bleeding.
Paul A Carless, David A Henry, Jeffrey L Carson, Paul Pc Hebert, Brian McClelland, Katharine Ker
Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion.
Cochrane Database Syst Rev. 2010 Oct 6;(10):CD002042. doi: 10.1002/14651858.CD002042.pub2. Epub 2010 Oct 6.
Abstract/Text
BACKGROUND: Most clinical practice guidelines recommend restrictive red cell transfusion practices, with the goal of minimising exposure to allogeneic blood (from an unrelated donor). The purpose of this review is to compare clinical outcomes in patients randomised to restrictive versus liberal transfusion thresholds (triggers).
OBJECTIVES: To examine the evidence for the effect of transfusion thresholds on the use of allogeneic and/or autologous blood, and the evidence for any effect on clinical outcomes.
SEARCH STRATEGY: Trials were identified by: computer searches of the Cochrane Central Register of Controlled Trials (the Cochrane Library Issue 3, 2009), OVID MEDLINE (1966 to August 2009), Current Contents (1993 to November 2004), and the Web of Science (2004 to August 2009). References in identified trials and review articles were checked and experts contacted to identify any additional trials.
SELECTION CRITERIA: Controlled trials in which patients were randomised to an intervention group or to a control group. Trials were included where intervention groups were assigned on the basis of a clear transfusion 'trigger', described as a haemoglobin (Hb) or haematocrit (Hct) level below which an RBC transfusion was to be administered.
DATA COLLECTION AND ANALYSIS: Relative risks of requiring allogeneic blood transfusion, transfused blood volumes and other clinical outcomes were pooled across trials, using a random effects model. The risk of bias was assessed.
MAIN RESULTS: Seventeen trials involving a total of 3746 patients were identified. Restrictive transfusion strategies reduced the risk of receiving a red blood cell (RBC) transfusion by a relative 37% (RR=0.63; 95% CI 0.54 to 0.74). This equates to an average absolute risk reduction (ARR) of 33% (95% CI 21% to 45%). The volume of RBCs transfused was reduced on average by 0.75 units (95% CI 0.20 to 1.30 units). However, heterogeneity between trials was statistically significant (P<0.001; I²≥74%) for these outcomes. Restrictive transfusion strategies did not appear to impact on the rate of adverse events compared to liberal transfusion strategies (i.e. mortality, cardiac events, myocardial infarction, stroke, pneumonia and thromboembolism). Restrictive transfusion strategies were associated with a statistically significant reduction in the rates of infection (RR=0.76; 95% CI 0.60 to 0.97). The use of restrictive transfusion strategies did not reduce hospital or intensive care length of stay.
AUTHORS' CONCLUSIONS: The existing evidence supports the use of restrictive transfusion triggers in patients who are free of serious cardiac disease. The effects of conservative transfusion triggers on functional status, morbidity and mortality, particularly in patients with cardiac disease, need to be tested in further large clinical trials. In countries with inadequate screening of donor blood, the data may constitute a stronger basis for avoiding transfusion with allogeneic red cells.
CRASH-2 trial collaborators, Haleema Shakur, Ian Roberts, Raúl Bautista, José Caballero, Tim Coats, Yashbir Dewan, Hesham El-Sayed, Tamar Gogichaishvili, Sanjay Gupta, Jorge Herrera, Beverley Hunt, Pius Iribhogbe, Mario Izurieta, Hussein Khamis, Edward Komolafe, María-Acelia Marrero, Jorge Mejía-Mantilla, Jaime Miranda, Carlos Morales, Oluwole Olaomi, Fatos Olldashi, Pablo Perel, Richard Peto, P V Ramana, R R Ravi, Surakrant Yutthakasemsunt
Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.
Lancet. 2010 Jul 3;376(9734):23-32. doi: 10.1016/S0140-6736(10)60835-5. Epub 2010 Jun 14.
Abstract/Text
BACKGROUND: Tranexamic acid can reduce bleeding in patients undergoing elective surgery. We assessed the effects of early administration of a short course of tranexamic acid on death, vascular occlusive events, and the receipt of blood transfusion in trauma patients.
METHODS: This randomised controlled trial was undertaken in 274 hospitals in 40 countries. 20 211 adult trauma patients with, or at risk of, significant bleeding were randomly assigned within 8 h of injury to either tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Randomisation was balanced by centre, with an allocation sequence based on a block size of eight, generated with a computer random number generator. Both participants and study staff (site investigators and trial coordinating centre staff) were masked to treatment allocation. The primary outcome was death in hospital within 4 weeks of injury, and was described with the following categories: bleeding, vascular occlusion (myocardial infarction, stroke and pulmonary embolism), multiorgan failure, head injury, and other. All analyses were by intention to treat. This study is registered as ISRCTN86750102, Clinicaltrials.govNCT00375258, and South African Clinical Trial RegisterDOH-27-0607-1919.
FINDINGS: 10 096 patients were allocated to tranexamic acid and 10 115 to placebo, of whom 10 060 and 10 067, respectively, were analysed. All-cause mortality was significantly reduced with tranexamic acid (1463 [14.5%] tranexamic acid group vs 1613 [16.0%] placebo group; relative risk 0.91, 95% CI 0.85-0.97; p=0.0035). The risk of death due to bleeding was significantly reduced (489 [4.9%] vs 574 [5.7%]; relative risk 0.85, 95% CI 0.76-0.96; p=0.0077).
INTERPRETATION: Tranexamic acid safely reduced the risk of death in bleeding trauma patients in this study. On the basis of these results, tranexamic acid should be considered for use in bleeding trauma patients.
FUNDING: UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation.
Copyright 2010 Elsevier Ltd. All rights reserved.
CRASH-2 collaborators, Ian Roberts, Haleema Shakur, Adefemi Afolabi, Karim Brohi, Tim Coats, Yashbir Dewan, Satoshi Gando, Gordon Guyatt, B J Hunt, Carlos Morales, Pablo Perel, David Prieto-Merino, Tom Woolley
The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.
Lancet. 2011 Mar 26;377(9771):1096-101, 1101.e1-2. doi: 10.1016/S0140-6736(11)60278-X.
Abstract/Text
BACKGROUND: The aim of the CRASH-2 trial was to assess the effects of early administration of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage. Tranexamic acid significantly reduced all-cause mortality. Because tranexamic acid is thought to exert its effect through inhibition of fibrinolysis, we undertook exploratory analyses of its effect on death due to bleeding.
METHODS: The CRASH-2 trial was undertaken in 274 hospitals in 40 countries. 20,211 adult trauma patients with, or at risk of, significant bleeding were randomly assigned within 8 h of injury to either tranexamic acid (loading dose 1 g over 10 min followed by infusion of 1 g over 8 h) or placebo. Patients were randomly assigned by selection of the lowest numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Both participants and study staff (site investigators and trial coordinating centre staff ) were masked to treatment allocation. We examined the effect of tranexamic acid on death due to bleeding according to time to treatment, severity of haemorrhage as assessed by systolic blood pressure, Glasgow coma score (GCS), and type of injury. All analyses were by intention to treat. The trial is registered as ISRCTN86750102, ClinicalTrials.gov NCT00375258, and South African Clinical Trial Register/Department of Health DOH-27-0607-1919.
FINDINGS: 10,096 patients were allocated to tranexamic acid and 10,115 to placebo, of whom 10,060 and 10,067, respectively, were analysed. 1063 deaths (35%) were due to bleeding. We recorded strong evidence that the effect of tranexamic acid on death due to bleeding varied according to the time from injury to treatment (test for interaction p<0.0001). Early treatment (≤1 h from injury) significantly reduced the risk of death due to bleeding (198/3747 [5.3%] events in tranexamic acid group vs 286/3704 [7.7%] in placebo group; relative risk [RR] 0.68, 95% CI 0.57-0.82; p<0.0001). Treatment given between 1 and 3 h also reduced the risk of death due to bleeding (147/3037 [4.8%] vs 184/2996 [6.1%]; RR 0.79, 0.64-0.97; p=0.03). Treatment given after 3 h seemed to increase the risk of death due to bleeding (144/3272 [4.4%] vs 103/3362 [3.1%]; RR 1.44, 1.12-1.84; p=0.004). We recorded no evidence that the effect of tranexamic acid on death due to bleeding varied by systolic blood pressure, Glasgow coma score, or type of injury.
INTERPRETATION: Tranexamic acid should be given as early as possible to bleeding trauma patients. For trauma patients admitted late after injury, tranexamic acid is less effective and could be harmful.
FUNDING: UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Rolf Rossaint, Bertil Bouillon, Vladimir Cerny, Timothy J Coats, Jacques Duranteau, Enrique Fernández-Mondéjar, Beverley J Hunt, Radko Komadina, Giuseppe Nardi, Edmund Neugebauer, Yves Ozier, Louis Riddez, Arthur Schultz, Philip F Stahel, Jean-Louis Vincent, Donat R Spahn, Task Force for Advanced Bleeding Care in Trauma
Management of bleeding following major trauma: an updated European guideline.
Crit Care. 2010;14(2):R52. doi: 10.1186/cc8943. Epub 2010 Apr 6.
Abstract/Text
INTRODUCTION: Evidence-based recommendations are needed to guide the acute management of the bleeding trauma patient, which when implemented may improve patient outcomes.
METHODS: The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with the aim of developing a guideline for the management of bleeding following severe injury. This document presents an updated version of the guideline published by the group in 2007. Recommendations were formulated using a nominal group process, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence and based on a systematic review of published literature.
RESULTS: Key changes encompassed in this version of the guideline include new recommendations on coagulation support and monitoring and the appropriate use of local haemostatic measures, tourniquets, calcium and desmopressin in the bleeding trauma patient. The remaining recommendations have been reevaluated and graded based on literature published since the last edition of the guideline. Consideration was also given to changes in clinical practice that have taken place during this time period as a result of both new evidence and changes in the general availability of relevant agents and technologies.
CONCLUSIONS: This guideline provides an evidence-based multidisciplinary approach to the management of critically injured bleeding trauma patients.
Phillip Lieberman, Richard A Nicklas, Christopher Randolph, John Oppenheimer, David Bernstein, Jonathan Bernstein, Anne Ellis, David B K Golden, Paul Greenberger, Steven Kemp, David Khan, Dennis Ledford, Jay Lieberman, Dean Metcalfe, Anna Nowak-Wegrzyn, Scott Sicherer, Dana Wallace, Joann Blessing-Moore, David Lang, Jay M Portnoy, Diane Schuller, Sheldon Spector, Stephen A Tilles
Anaphylaxis--a practice parameter update 2015.
Ann Allergy Asthma Immunol. 2015 Nov;115(5):341-84. doi: 10.1016/j.anai.2015.07.019.
Abstract/Text
P Korenblat, M J Lundie, R E Dankner, J H Day
A retrospective study of epinephrine administration for anaphylaxis: how many doses are needed?
Allergy Asthma Proc. 1999 Nov-Dec;20(6):383-6.
Abstract/Text
The precise amount of epinephrine needed to reverse severe symptomatology due to an anaphylactic reaction is unknown. We tried to determine how frequently more than one injection of epinephrine is required to treat an anaphylactic reaction. A retrospective review of patient charts with anaphylactic reactions requiring epinephrine, in response to inhalant allergen and hymenoptera venom immunotherapy as well as live hymenoptera stings, examined type of reaction; number, doses, and timing of epinephrine administered; and ancillary treatment. A total of 105 anaphylactic reaction events of varying severity (Ring's classification) were recorded (54--Grade I, 29--Grade II, 18--Grade III, 0--Grade IV, 4--unknown). The median epinephrine dose administered was 0.3 cc (range 0.1 to 0.8 cc, 1:1000). The timing of the first epinephrine injection was < or = 5 minutes in 27, 6-10 minutes in 13, 11-30 minutes in 16, < or = 30 minutes in 32, 31-60 minutes in 12, and > 60 minutes in five epinephrine treated patients. Overall, 38 patients (35.5%; CI95, 26.4-44.6%) required > 1 epinephrine injection. Of these, 11 experienced Grade I (11/54-20.3%; CI95, 9.6-31.0%), 12--Grade II (12/29-41.5%, CI95, 23.5-59.3%), and 13--Grade III (13/18-72.2%, CI95, 51.5-92.9%); reactivity was unknown in 2 patients. Forty-four patients also received an antihistamine, 10 received corticosteroids, and 30 received both medications and/or other ancillary therapy. A significant number of patients (> 35%) with anaphylactic reactions received greater than one epinephrine dose to manage events for the three classes of severity. Patients at risk for anaphylaxis and their caregivers need to recognize that more than one dose of epinephrine may be required for treatment of anaphylaxis.
