ICU或脓毒血症液体复苏

ICU 或脓毒血症液体复苏,白蛋白的使用,内容提要,前言,白蛋白: 在ICU和重症脓毒血症中使用理论基础,白蛋白: 对脓毒血症和重症脓毒血症死亡率影响,白蛋白: possible non-oncotic mechanisms,万汶: 对死亡率和肾功能影响,白蛋白: 脓毒血症推荐,HES, hydroxyethyl starch,Introduction to the ICU and sepsis,Specialist hospital wards providing intensive treatment and monitoring for patients who are critically ill or in an unstable condition,ICU,http:/www.nhs.uk/Conditions/Intensive-care/Pages/Introduction.aspx accessed December 2013,心肺骤停后,重症,外科术后,是一种危及生命的疾病是对感染损伤组织和器官的反应如不及时治疗,脓毒血症,是 ICU1主要的死亡原因之一每年全球患脓毒血症约有180万重症脓毒血症是ICU病死率二倍1,ICU, intensive care unit1. Adrie et al. J Crit Care 2005; 20: 4658. 2. Daniels. J Antimicrob Chemother 2011; 66 (Suppl 2): ii11ii233. Guidet et al. Crit Care 2007; 22: 197203,多脏衰,死亡,脓毒性休克,治疗费用高1,3脓毒症病人费用高于ICU病人二倍以上1,定义,Dellinger et al. Crit Care Med 2013; 41: 580637,Sepsis is a major healthcare problem in terms of resources and expenditure1,流行病学,SOAP, Sepsis Occurrence in Acutely Ill Patients; UK ICNARC, United Kingdom Intensive Care National Audit and Research Centre1. Daniels. J Antimicrob Chemother 2011; 66 (Suppl 2): ii11ii23; 2. Harrison et al. Crit Care 2006; 10: R42; 3. Vincent et al. Crit Care Med 2006; 34: 3443534. Kumar et al. Chest 2011; 140: 12231231.,Global sepsis incidence/year: 1.8 million1,USA:4 2007 = 343/100,000,*Studies used different definitions of severe sepsis,Europe (SOAP study):3 2002 = 30%,England, Wales and NI:22003 = 66/100,000,Severe sepsis incidence/rate*,USA:427.3%,Europe (SOAP study):336%,England & Wales (UK ICNARC):239.8%,Sepsis/severe sepsis mortality rate,Principles of severe sepsis management,HES, hydroxyethyl starch1. Dellinger et al. Crit Care Med 2013; 41: 580637; 2. Rivers et al. N Engl J Med 2001; 345: 13681377; 3. Boyd et al. Crit Care Med 2011; 39: 259265;4. Brunkhorst et al. N Engl J Med 2008; 358: 125139; 5. Perner et al. N Engl J Med 2012; 367: 124134; 6. Myburgh et al. N Engl J Med 2012; 367: 19011911,Fluid therapy is key Improve organ perfusion and oxygenationPrevent organ failure,Crystalloid with or without colloidNatural or synthetic colloid,Early goal-directed treatment widely advocated2Avoid over-resuscitation and positive fluid balance3Safety concerns with HES46,白蛋白: rationale for use in the ICU/severe sepsis,Hypo白蛋白aemia is significantly more common in non-surviving sepsis patients,OR, odds ratio; CI, confidence intervalArtero et al. J Crit Care 2010; 25: 276-281,Prospective study of 112 patients with severe sepsis or septic shockSerum 白蛋白 level is an independent predictor of mortality(non-conditional multivariate analysis adjusted OR 0.34; 95% CI 0.15, 0.76; p=0.009 per 10g/L increment in 白蛋白 level),Hospital survivors,Hospital non-survivors,10/65,17/47,OR 2.85 (95% CI 1.11, 7.33),p=0.026,185%,Hypo白蛋白aemia is an important risk factor for mortality,Hypo白蛋白aemia: a significant independent predictor of AKI, and death after AKI development,*Per 10 g/L decrement in serum 白蛋白AKI, acute kidney injury; CI, confidence interval; ICU, intensive care unit; OR, odds ratioWiedermann et al. Intensive Care Med 2010; 36: 16571665,Pooled estimate of OR:* 2.34 (95% CI: 1.74, 3.14),Pooled estimate of OR:* 2.47 (95% CI: 1.51, 4.05),Meta-analysis of 17 observational studies (totalling 3917 patients)Relationship between serum 白蛋白 and:,AKI incidencein surgical or ICU patients (6 studies)in other hospital settings (5 studies),Mortality in patients who developed AKI (6 studies),白蛋白: effects on mortality in sepsis and severe sepsis,白蛋白 vs saline in severe sepsis: SAFE study subgroup,ICU, intensive care unit; RCT, randomised controlled trial; RRT, renal replacement therapy; SAFE, Saline versus 白蛋白 Fluid Evaluation1. SAFE study investigators. Intensive Care Med 2011; 37: 8696. 2. SAFE study investigators. N Engl J Med 2004; 350: 22472256,CI, confidence interval; OR, odds ratio; SAFE, Saline versus 白蛋白 Fluid Evaluation*Multivariate analysis after adjustment for baseline characteristics, in patients with complete baseline dataSAFE Study Investigators. Intensive Care Med 2011; 37: 8696,SAFE: 白蛋白 reduces the risk of mortality compared with saline in patients with severe sepsis,Total severe sepsis patient group (N=1218),Multivariate analysis group (N=919)*,OR 0.71 (95% CI 0.52, 0.97),p=0.03,OR 0.87 (95% CI 0.74, 1.02),p=0.09,13%(RR),29%(RR),SAFE study subgroup: 白蛋白 vs saline in volume expansion,CVP, central venous pressure; SAFE, Saline versus 白蛋白 Fluid EvaluationSAFE study investigators. Intensive Care Med 2011; 37: 8696,白蛋白 may have produced greater intravascular volume expansion than saline, demonstrated by reduced heart rate and increased venous pressure,Patients who received 白蛋白 experienced:Lower heart rate on days 1 (p=0.002) and 3 (p=0.03)1Higher CVP on days 13 (p11,000 sepsis/septic shock patients1,白蛋白 deemed to be cost-effective intervention in patients with sepsis,Delaney et al. meta-analysis: 白蛋白 significantly lowers risk of mortality vs other fluids in sepsis,HES, hydroxyethyl starch; RCT, randomised controlled trialDelaney et al. Crit Care Med 2011; 39: 386391,白蛋白 reduces the risk of mortality vs control in sepsis,*Duration of follow-up varied between studies; hospital/ICU discharge in 14 studies, 28 days in 2 studies and 30 days in a single study; CI, confidence interval; OR, odds ratio; Delaney et al. Crit Care Med 2011; 39: 386391,OR 0.82 (95% CI 0.67, 1.00),p=0.047,白蛋白,Control(saline, Ringers lactate, HES or gelatin),Wiedermann et al. meta-analysis: relationship between hyperoncotic 白蛋白 and AKI,AKI, acute kidney injury; HES, hydroxyethyl starch; RCT, randomised controlled trialWiedermann et al. Crit Care 2010; 14: R191,Hyperoncotic 白蛋白 significantly decreases risk of AKI and mortality vs control,*Crystalloid, 45% hypo-oncotic 白蛋白 or no fluid; CI, confidence interval; OR, odds ratioWiedermann et al. Crit Care 2010; 14: R191,OR 0.24 (95% CI 0.12, 0.48),p0.0001,Control*,白蛋白,白蛋白,Control*,Outlook: 白蛋白 in sepsis trials,ALBIOS3 (NCT00707122)Multicentre RCT20% 白蛋白 vs crystalloid in sepsis or septic shock1800 patients in ItalyPrimary outcomes: mortality at 28 and 90 days,RCT, randomised controlled trial1. EARSS study record. Available at /show/NCT00327704 accessed December 2013; 2. Charpentier 3. ALBIOS study record. Available at /show/NCT00707122 accessed December 2013,EARSS1 (NCT00327704)Multicentre RCT20% 白蛋白 vs saline in septic shock800 patients in FrancePrimary outcomes: 28-day mortality,Publication expected 20132014,Publication expected 20132014Preliminary results: no significant difference in mortality; no evidence of renal dysfunction with 白蛋白2,白蛋白: possible non-oncotic mechanisms accountable for the benefit in sepsis,Benefit of 白蛋白 in sepsis: possible non-oncotic mechanisms,1. Quinlan et al. Clin Sci (Colch) 1998; 95: 459465; 2. Nathan et al. J Cell Biol 1993; 122: 243256; 3. Jacob et al. Transplantation 2009; 87: 956965; 4. Chen et al. Scand J Gastroenterol 2009; 44: 619625. 5. Jrgens et al. J Endotoxin Res 2002; 8: 115126; 6. Evans. Aliment Pharmacol Ther 2002; 16 (Suppl. 5): 611,Antioxidant activity of 白蛋白 in sepsis,*p0.01 vs pre-白蛋白 administration; *p0.001 vs pre-白蛋白 administration;#p65 mmHg,MAP, mean arterial pressure; LV, left ventricular Wiedermann CJ. Available at /posters/browse/summary/1094955 Accessed January 2014,2. Noradrenaline, balanced crystalloid and 白蛋白MAP titration to 65 mmHg with noradrenalin starting at 0.01 g/kg/minAddition of balanced crystalloid boluses if fluid-responsiveAddition of 4060 g 白蛋白 if plasma 白蛋白 levels 3 g/dL and LV function not depressedStart dobutamine at 2.5 g/kg/min if LV function normal/depressed,1. Normal saline and 白蛋白Start with up to 30 mL/kg (2L) normal saline over 30 minAdd up to 60 g 白蛋白 over 3 h if MAP remains 70 mmHg,HES: effects on mortality, kidney function and bleeding evidence from recent landmark trials and meta-analyses,HES, hydroxyethyl starch,HES 130/0.42 vs Ringers acetate (6S study): safety and efficacy in severe sepsis?,*Title of paper states 130/0.4, but the HES studied was 130/0.42. Lower than maximum daily dose of HES recommended by the manufacturer (50 mL/kg). A number of other endpoints were pre-specified6S, Scandinavian Starch for Severe Sepsis/Septic Shock; AKI, acute kidney injury; HES, hydroxyethyl starch; ICU, intensive care unit; SOFA, sequential organ failurePerner et al. N Engl J Med 2012; 367: 124134,HES 130/0.42 significantly increases risk of mortality and RRT vs Ringers acetate in severe sepsis,CI, confidence interval; HES, hydroxyethyl starch; RR, relative riskPerner et al. N Engl J Med 2012; 367: 124134,RR 1.17 (95% CI 1.01, 1.36),17%,p=0.03,Ringers acetate,HES 130/0.42,Ringers acetate,HES 130/0.42,HES 130/0.42 significantly increases risk of bleeding vs Ringers acetate in severe sepsis,CI, confidence interval; HES, hydroxyethyl starch; ICU, intensive care unit; RR, relative riskHaase et al. Intensive Care Med 2013; 39: 21262134,Ringers acetate,HES 130/0.42,Post-hoc analysis of 6S trial database (study population 798 ICU patients with severe sepsis),Patients with bleeding (%),HES 130/0.4 vs saline (CHEST study): safety and efficacy in the ICU?,AKI, acute kidney injury; CHEST, Crystalloid versus Hydroxyethyl Starch Trial; HES, hydroxyethyl starch; ICU, intensive care unit; RIFLE, risk, injury, failure, loss and end-stage kidney injury; RRT, renal replacement therapyMyburgh et al. N Engl J Med 2012; 367: 19011911,Within 90 days post-randomisation,Trend to higher mortality with HES 130/0.4 vs saline in the ICU1,CI, confidence interval; HES, hydroxyethyl starch; RR, relative risk1. Myburgh et al. N Engl J Med 2012; 367: 19011911; 2. Perner et al. N Engl J Med 2012; 367: 124134,RR 1.06 (95% CI 0.96, 1.18),p=0.26,Rate of death was lower than expected due to patient exclusions, and substantially lower than that observed in similar studies (e.g. 6S study)1,2However, a non-statistically significant increase in mortality at day 90 was observed with HES 130/0.4 compared with saline1,HES 130/0.4,Saline,HES 130/0.4 significantly increases risk of RRT vs saline in the ICU,Within 90 days post-randomisation. CI, confidence interval; HES, hydroxyethyl starch; RR, relative risk; RRT, renal replacement therapyMyburgh et al. N Engl J Med 2012; 367: 19011911,RR 1.21 (95% CI 1.00, 1.45),21%,p=0.04,Saline,HES 130/0.4,Creatinine levels* revealed significantly higher risk of injury and failure in the HES 130/0.4 group,*Post hoc analysis. HES, hydroxyethyl starchMyburgh et al. N Engl J Med 2012; 367: 19011911,Serum creatinine levels were significantly increased and urine output was significantly decreased in the HES 130/0.4 group compared with the saline groupRelative risks of meeting criteria for kidney dysfunction or injury were higher in the HES 130/0.4 group,120,Serum creatinine (mol/L),110,100,90,0,Baseline,0,1,2,3,4,5,6,Study day,32603283,21972253,28992916,21112196,15761614,12381291,9981026,851857,No. at riskHESSaline,P=0.004,Meta-analyses of HES 130/0.380.45 in patients with sepsis: Haase et al.,HES 130/0.380.45 increases mortality, requirement for RRT and blood transfusions, and incidence of SAEs (vs control fluids) in ICU patients with sepsis,Systematic review with meta-analysis and trial sequential analysis of 9 RCTs (3456 ICU patients with sepsis)HES 130/0.380.45 vs crystalloids or 白蛋白,CI, confidence interval; ICU, intensive care unit; HES, hydroxyethyl starch; RBC, red blood cell; RCT, randomised controlled trial; RRT, renal replacement therapy; SAE, serious adverse eventHaase et al. BMJ 2013; 346: f839,Favours HES,Favours control,*In pre-defined analysis of trials with low risk of bias,Meta-analyses of HES 130/0.40.42 in patients with sepsis: Patel et al.,Use of HES 130/0.40.42 was associated with increased mortality, and requirement for RRT and allogeneic transfusions (compared with non-HES fluids) in patients with severe sepsis,Meta-analysis of 6 RCTs (3033 ICU patients with severe sepsis)HES 130/0.40.42 vs non-HES fluids*,* 20% 白蛋白, 0.9% NaCl or Ringers acetateCI, confidence interval; HES, hydroxyethyl starch; ICU, intensive care unit; RCT, randomised controlled trial; RRT, renal replacement therapyPatel et al. Intensive Care Med. 2013; 39: 811822,Favours HES,Favours control,Meta-analysis of HES as a class in critical illness: Zarychanski et al.,*Excluding studies carried out by Boldt et al. (owing to a high risk of inaccurate or fraudulent data) CI, confidence interval; HES, hydroxyethyl starch; ICU, intensive care unit; RCT, randomised controlled trial; RRT, renal replacement therapyZarychanski et al. JAMA 2013; 309: 678688,Favours control,Favours HES,38 RCTs (10,978 ICU patients)Any HES vs crystalloids, 白蛋白 or gelatinEndpoints mortality and acute kidney injury,HES use was associated with a significant increased risk of mortalityand acute kidney injury in critically ill patients,Meta-analysis of HES 130/0.40.42 in critical illness: Wiedermann et al.,Control,HES130/0.4 or 0.42,Mortality (%),RR 1.10 (95% CI 1.02, 1.19),p=0.018,15 RCTs (8580 patients in different settings*) HES 130/0.40.42 vs crystalloids or 白蛋白Endpoint mortality,* Including acute illness, major surgery, trauma and severe sepsis/septic shockCI, confidence interval; HES, hydroxyethyl starch; RCT, randomised controlled trial; RR, relative riskWiedermann and Joannidis. Swiss Med Wkly 2013; 143: w13747,Meta-analyses of HES 130/0.40.42 in criticalillness: Gattas et al.,Control,HES 130/0.4 or 0.42,Mortality (%),RR 1.08 (95% CI 1.00, 1.17),p=0.7,Incidence of RRT (%),RR 1.25 (95% CI 1.08, 1.44),p=0.81,25%(RR),35 RCTs (10,391 ICU patients)HES 130/0.40.42 vs control fluidsEndpoints mortality and incidence of RRT,Control,HES 130/0.4 or 0.42,CI, confidence interval; HES, hydroxyethyl starch; ICU, intensive care unit; RCT, randomised controlled trial; RR, relative riskGattas et al. Intensive Care Med 2013; 39: 558568,Hyperoncotic HES: does it contribute to AKI?,AKI, acute kidney injury; HES, hydroxyethyl starchWiedermann et al. Crit Care 2010; 14: R191,Hyperoncotic HES significantly increases risk of AKI and mortality vs control,*Crystalloid, 45% hypo-oncotic 白蛋白 or no fluid; AKI, acute kidney injury; CI, confidence interval; HES, hydroxyethyl starch; OR, odds ratioWiedermann et al. Crit Care 2010; 14: R191,OR 1.92(95% CI 1.31, 2.81),p0.0008,HES,Control*,HES,Control*,HES safety concerns and recommendations: EMA,Recommendations of the EMA PRAC on the use of HES-containing solutionsendorsed by the CMDh, representing EU member states,HES solutions should not be used for more than 24 hours and patients kidney function should be monitored after HES administration,CMDh, Coordination Group for Mutual Recognition and Decentralised Procedures Human; EMA, European Medicines Agency; PRAC, Pharmacovigilance Risk Assessment CommitteeHydroxyethyl-starch solutions (HES) should no longer be used in patients with sepsis or burn injuries or in critically ill patients CMDh endorses PRAC recommendations. Available at: http:/www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/10/news_detail_001930.jsp&mid=WC0b01ac058004d5c1 accessed December 2013,HES solutions must no longer be used to treat patients with sepsis or burn injuries, or critically ill patients, because of an increased risk of kidney injury and mortality,HES solutions may continue to be used in patients to treat hypovolaemia, where treatment with crystalloids alone are not considered to be sufficient,HES safety concerns and recommendations: EMA,Selected instructions and precautions to be included in the SmPC of HES products,CPB, cardiopulmonary bypass; EMA, European Medicines Agency; HES, hydroxyethyl starch; PRAC, Pharmacovigilance Risk Assessment Committee; SmPC, Summary of Product CharacteristicsAssessment report for solutions for infusion containing hydroxyethyl starch. Available at: http:/www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Hydroxyethyl_starch-containing_medicines_107/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500154254.pdf accessed December 2013,Assessment by the PRAC on the benefits and risks of HES products,Use of HES should be restricted to the lowest possible dose, with a maximum daily dose of 30 mL/kgthe initial phase of volume resuscitation, with a maximum time interval of 24 hoursUse of HES is not recommended in patients undergoing cardiac surgery in association with CPB (owing to risk of excessive bleeding)for use in childrenOther available options should be considered for patients undergoing surgery or trauma (owing to lack of robust long-term safety data on HES use)Renal function of patients to be monitored for 90 days following HES administration,HES safety concerns and recommendations: EMA,Studies presented in support of HES:CRISTAL RCT comparing colloid vs crystalloid for fluid resuscitation No risk of mortality associated with use of HES in ICU patientsPRAC assessment: given the study limitations (HES only constituted part of the colloid arm, administration protocol deviations), CRISTAL findings did not refute 6S/VISEP resultsBaSES randomised study comparing HES vs Ringers lactateNo increase in mortality and AKI associated with HES in patients with sepsisPRAC assessmen