Fluid resuscitation in the ICU/sepsis. The use of albumin

Transcription

1 Fluid resuscitation in the ICU/sepsis The use of albumin

2 Overview Introduction to the ICU and sepsis Albumin: rationale for use in the ICU and severe sepsis Albumin: effects on mortality in sepsis and severe sepsis Albumin: possible non-oncotic mechanisms HES: effects on mortality and kidney function Albumin: sepsis recommendations HES, hydroxyethyl starch

3 Introduction to the ICU and sepsis

4 Intensive care unit Specialist hospital wards providing intensive treatment and monitoring for patients who are critically ill or in an unstable condition After surgery Following an accident Severe illness [accessed December 2013]

5 Sepsis A life-threatening condition Response to infection injures tissues and organs Without prompt treatment Septic shock Multiple organ failure Death A leading cause of death in ICU million cases of severe sepsis globally each year 2 Severe sepsis doubles the mortality rate of ICU patients 1 High costs of care 1,3 Sepsis more than doubles the mean cost of care per ICU patient 1 ICU, intensive care unit 1. Adrie et al. J Crit Care 2005; 20: Daniels. J Antimicrob Chemother 2011; 66 (Suppl 2): ii11 ii23 3. Guidet et al. Crit Care 2007; 22:

6 Definitions Sepsis infection plus systemic manifestations of infection Severe sepsis sepsis associated with organ dysfunction or tissue hypoperfusion Septic shock sepsis induced hypotension despite fluid resuscitation Dellinger et al. Crit Care Med 2013; 41:

7 Epidemiology Global sepsis incidence/year: 1.8 million 1 Severe sepsis incidence/rate* Sepsis/severe sepsis mortality rate England, Wales and NI: = 66/100,000 England & Wales (UK ICNARC): % Europe (SOAP study): = 30% Europe (SOAP study): 3 36% USA: = 343/100,000 USA: % Sepsis is a major healthcare problem in terms of resources and expenditure 1 *Studies used different definitions of severe sepsis SOAP, Sepsis Occurrence in Acutely Ill Patients; UK ICNARC, United Kingdom Intensive Care National Audit and Research Centre 1. Daniels. J Antimicrob Chemother 2011; 66 (Suppl 2): ii11 ii23; 2. Harrison et al. Crit Care 2006; 10: R42; 3. Vincent et al. Crit Care Med 2006; 34: Kumar et al. Chest 2011; 140:

8 Principles of severe sepsis management Initial resuscitation and infection issues 1 Haemodynamic support and adjunctive therapy 1 Other supportive therapy 1 Fluid therapy is key Improve organ perfusion and oxygenation Prevent organ failure Crystalloid with or without colloid Natural or synthetic colloid Early goal-directed treatment widely advocated 2 Avoid over-resuscitation and positive fluid balance 3 Safety concerns with HES 4 6 HES, hydroxyethyl starch 1. Dellinger et al. Crit Care Med 2013; 41: ; 2. Rivers et al. N Engl J Med 2001; 345: ; 3. Boyd et al. Crit Care Med 2011; 39: ; 4. Brunkhorst et al. N Engl J Med 2008; 358: ; 5. Perner et al. N Engl J Med 2012; 367: ; 6. Myburgh et al. N Engl J Med 2012; 367:

9 Albumin: rationale for use in the ICU/ severe sepsis

10 Patients with albumin <20g/L (%) Hypoalbuminaemia is significantly more common in non-surviving sepsis patients /65 survivors OR 2.85 (95% CI 1.11, 7.33) p= % 17/47 Category Hospital 1 Category Hospital non- 2 survivors Prospective study of 112 patients with severe sepsis or septic shock Serum albumin 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 albumin level) Hypoalbuminaemia is an important risk factor for mortality OR, odds ratio; CI, confidence interval Artero et al. J Crit Care 2010; 25:

11 Hypoalbuminaemia: a significant independent predictor of AKI, and death after AKI development Meta-analysis of 17 observational studies (totalling 3917 patients) Relationship between serum albumin and: AKI incidence in surgical or ICU patients (6 studies) in other hospital settings (5 studies) Mortality in patients who developed AKI (6 studies) Pooled estimate of OR:* 2.34 (95% CI: 1.74, 3.14) Pooled estimate of OR:* 2.47 (95% CI: 1.51, 4.05) *Per 10 g/l decrement in serum albumin AKI, acute kidney injury; CI, confidence interval; ICU, intensive care unit; OR, odds ratio Wiedermann et al. Intensive Care Med 2010; 36:

12 Albumin: effects on mortality in sepsis and severe sepsis

13 Aim Albumin vs saline in severe sepsis: SAFE study subgroup Compare the effect of albumin vs saline on mortality and organ function in patients with severe sepsis 1 Study design Pre-defined subgroup analysis of a RCT conducted in 16 ICUs 1 Comparison 4% albumin (N=603) 1 Saline (N=615) 1 Patient population Primary endpoint Secondary endpoints Severe sepsis 1 All-cause mortality within 28 days of randomisation 1 Length of ICU or hospital stay, duration of mechanical ventilation or RRT 2 ICU, intensive care unit; RCT, randomised controlled trial; RRT, renal replacement therapy; SAFE, Saline versus Albumin Fluid Evaluation 1. SAFE study investigators. Intensive Care Med 2011; 37: SAFE study investigators. N Engl J Med 2004; 350:

14 28-day mortality (%) SAFE: albumin reduces the risk of mortality compared with saline in patients with severe sepsis OR 0.87 (95% CI 0.74, 1.02) p=0.09 Total severe sepsis unadjusted patient group (N=1218) OR 0.71 (95% CI 0.52, 0.97) p=0.03 Multivariate adjusted analysis group (N=919)* CI, confidence interval; OR, odds ratio; SAFE, Saline versus Albumin Fluid Evaluation *Multivariate analysis after adjustment for baseline characteristics, in patients with complete baseline data SAFE Study Investigators. Intensive Care Med 2011; 37: % (RR) 29% (RR) Saline Albumin

15 SAFE study subgroup: albumin vs saline in volume expansion Albumin may have produced greater intravascular volume expansion than saline, demonstrated by reduced heart rate and increased venous pressure Patients who received albumin experienced: Lower heart rate on days 1 (p=0.002) and 3 (p=0.03) 1 Higher CVP on days 1 3 (p<0.005 for each day) CVP, central venous pressure; SAFE, Saline versus Albumin Fluid Evaluation SAFE study investigators. Intensive Care Med 2011; 37: 86 96

16 Cost-effectiveness of albumin: SAFE study subgroup French cohort of >11,000 sepsis/septic shock patients 1 Application of the mortality reduction rate observed in the SAFE study 2 Albumin deemed to be cost-effective intervention in patients with sepsis SAFE, Saline versus Albumin Fluid Evaluation 1. Guidet et al. Crit Care 2007; 22: ; 2. SAFE study investigators. N Engl J Med 2004; 350:

17 Delaney et al. meta-analysis: albumin significantly lowers risk of mortality vs other fluids in sepsis Aim Study design Included studies Patient population Compare mortality in sepsis following resuscitation with albumin versus other fluids Meta-analysis 17 RCTs Comparison of 4%, 4.5%, 5% or 20% albumin with control (saline, Ringer s lactate, HES or gelatin) N=1977 Sepsis (8 studies) Sepsis as a subgroup (9 studies) HES, hydroxyethyl starch; RCT, randomised controlled trial Delaney et al. Crit Care Med 2011; 39:

18 Mortality* (%) Albumin reduces the risk of mortality vs control in sepsis OR 0.82 (95% CI 0.67, 1.00) p= Category 1 Category 2 Control (saline, Ringer s lactate, HES or gelatin) Albumin *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:

19 Wiedermann et al. meta-analysis: relationship between hyperoncotic albumin and AKI Aim Compare the effects of hyperoncotic albumin or HES on AKI Study design Meta-analysis of RCTs Studies included Patient population Primary endpoint Secondary endpoint Evaluated AKI following infusion of hyperoncotic colloid vs control (crystalloid, 4 5% hypo-oncotic albumin or no fluid): 20 25% albumin (7 studies) 10% HES (4 studies) N=1220 Surgery (3 studies), ascites (4 studies) or spontaneous bacterial peritonitis (2 studies) Severe sepsis or septic shock (1 study) Early septic shock (1 study) Does hyperoncotic albumin or HES increase AKI risk vs control? Mortality AKI, acute kidney injury; HES, hydroxyethyl starch; RCT, randomised controlled trial Wiedermann et al. Crit Care 2010; 14: R191

20 Pooled incidence of AKI (%) Pooled mortality (%) Hyperoncotic albumin significantly decreases risk of AKI and mortality vs control 20 OR 0.24 (95% CI 0.12, 0.48) p< OR 0.52 (95% CI 0.28, 0.95) p= Control Albumin 0 Control Albumin Control* Albumin Control* Albumin *Crystalloid, 4 5% hypo-oncotic albumin or no fluid; CI, confidence interval; OR, odds ratio Wiedermann et al. Crit Care 2010; 14: R191

21 Outlook: albumin in sepsis trials EARSS 1 (NCT ) Multicentre RCT 20% albumin vs saline in septic shock 800 patients in France Primary outcomes: 28-day mortality Publication expected Preliminary results: no significant difference in mortality; no evidence of renal dysfunction with albumin 2 ALBIOS 3 (NCT ) Multicentre RCT 20% albumin vs crystalloid in sepsis or septic shock 1800 patients in Italy Primary outcomes: mortality at 28 and 90 days Publication expected RCT, randomised controlled trial 1. EARSS study record. Available at [accessed December 2013]; 2. Charpentier & Mira. Intensive Care Med 2011; 37 Suppl 1: S115; 3. ALBIOS study record. Available at [accessed December 2013]

22 Albumin: possible non-oncotic mechanisms accountable for the benefit in sepsis

23 Benefit of albumin in sepsis: possible non-oncotic mechanisms Antioxidant Increased plasma thiols 1 Anti-inflammatory activity Influences cytokine activity 2 Protects glycocalyx 3 Nitric oxide modulator 4 Endotoxin binding 5 Drug binding and altered pharmacodynamics 6 Antibiotics A range of other drugs 1. Quinlan et al. Clin Sci (Colch) 1998; 95: ; 2. Nathan et al. J Cell Biol 1993; 122: ; 3. Jacob et al. Transplantation 2009; 87: ; 4. Chen et al. Scand J Gastroenterol 2009; 44: Jürgens et al. J Endotoxin Res 2002; 8: ; 6. Evans. Aliment Pharmacol Ther 2002; 16 (Suppl. 5): 6 11

24 Thiols (μm) Plasma concentration Albumin (g/l) Antioxidant activity of albumin in sepsis 20% albumin infusion 28 patients with sepsis 6 healthy subjects (control) ** ** ** # ** Serum albumin increased Despite vascular leak * * Antioxidant thiols increased ** ** *p<0.01 vs pre-albumin administration; **p<0.001 vs pre-albumin administration; #p<0.001 vs 5 min post-albumin administration Quinlan et al. Clin Sci (Lond) 1998; 95: pre 5 min 4 h Control (N=6) Septic (N=28)

25 Treatment example: volume resuscitation of septic shock goal MAP >65 mmhg 1. Normal saline and albumin Start with up to 30 ml/kg (2L) normal saline over 30 min Add up to 60 g albumin over 3 h if MAP remains <70 mmhg 2. Noradrenaline, balanced crystalloid and albumin MAP titration to >65 mmhg with noradrenalin starting at 0.01 µg/kg/min Addition of balanced crystalloid boluses if fluid-responsive Addition of g albumin if plasma albumin levels <3 g/dl and LV function not depressed Start dobutamine at 2.5 µg/kg/min if LV function normal/depressed MAP, mean arterial pressure; LV, left ventricular Wiedermann CJ. Available at [Accessed January 2014]

26 HES, hydroxyethyl starch HES: effects on mortality, kidney function and bleeding evidence from recent landmark trials and meta-analyses

27 HES 130/0.42 vs Ringer s acetate (6S study): safety and efficacy in severe sepsis? Aim Evaluate safety of HES 130/0.42* vs Ringer s acetate in severe sepsis Study design Multicentre, parallel group, blinded, randomised Comparison 6% HES 130/0.42 (N=398) Ringer s acetate (N=400) Maximum daily dose: 33 ml/kg ideal body-weight/day Patients 18 years Severe sepsis within previous 24 hours Required fluid resuscitation in the ICU Primary endpoint Death or end-stage kidney failure (dependence on dialysis), 90 days post-randomisation Secondary Development of AKI in the ICU within 90 days post-randomisation (RRT endpoints or in renal SOFA score from 2 at randomisation to 3) Doubling of plasma creatinine level in the ICU post-randomisation *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-specified 6S, Scandinavian Starch for Severe Sepsis/Septic Shock; AKI, acute kidney injury; HES, hydroxyethyl starch; ICU, intensive care unit; SOFA, sequential organ failure Perner et al. N Engl J Med 2012; 367:

28 90-day mortality (%) Patients requiring RRT (%) HES 130/0.42 significantly increases risk of mortality and RRT vs Ringer s acetate in severe sepsis RR 1.17 (95% CI 1.01, 1.36) p= % RR 1.35 (95% CI 1.01, 1.80) p= % Ringer's Ringer s acetate (N=400) acetate HES 130/0.42 HES (N=398) 130/ Ringer's Ringer s acetate (N=400) acetate HES 130/0.42 (N=398) HES 130/0.42 CI, confidence interval; HES, hydroxyethyl starch; RR, relative risk Perner et al. N Engl J Med 2012; 367:

29 Patients with bleeding (%) HES 130/0.42 significantly increases risk of bleeding vs Ringer s acetate in severe sepsis Post-hoc analysis of 6S trial database (study population 798 ICU patients with severe sepsis) 30 RR 1.55 (95% CI 1.16, 2.08) Risk factors at baseline for bleeding (multivariate analysis) p= % Variable Assignment to HES 130/0.42 Odds ratio (95% CI) 1.80 (1.25, 2.60) p value Admitted to university hospital 1.49 (1.03, 2.17) Ringer's acetate (N=400) Ringer s acetate HES 130/0.42 (N=398) HES 130/0.42 Surgery prior to ICU admission 1.93 (1.31, 2.81) CI, confidence interval; HES, hydroxyethyl starch; ICU, intensive care unit; RR, relative risk Haase et al. Intensive Care Med 2013; 39:

30 HES 130/0.4 vs saline (CHEST study): safety and efficacy in the ICU? Aim Evaluate safety of HES 130/0.42* vs saline in ICU patients Study design Multicentre, parallel group, blinded, randomised Comparison 6% HES 130/0.4 (N=3315) 0.9% saline (N=3336) Maximum daily dose: 50 ml/kg body-weight/day However, the mean daily dose was 526 ml, substantially < max Patients 18 years Required fluid resuscitation in the ICU Heterogenous; patients with sepsis at baseline: HES 130/0.4 (N=979), saline (N=958) Primary endpoint Death at 90 days post-randomisation Secondary endpoints Incidence of AKI (5-category RIFLE criteria) Use of RRT Duration of RRT and mechanical ventilation Specified new organ failures Cause-specific mortality 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 therapy Myburgh et al. N Engl J Med 2012; 367: Within 90 days postrandomisation

31 90-day mortality (%) Trend to higher mortality with HES 130/0.4 vs saline in the ICU 1 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, However, a non-statistically significant increase in mortality at day 90 was observed with HES 130/0.4 compared with saline 1 0 Saline (N=3336) Saline HES 130/0.4 (N=3315) HES 130/0.4 CI, confidence interval; HES, hydroxyethyl starch; RR, relative risk 1. Myburgh et al. N Engl J Med 2012; 367: ; 2. Perner et al. N Engl J Med 2012; 367:

32 Incidence of RRT (%) HES 130/0.4 significantly increases risk of RRT vs saline in the ICU RR 1.21 (95% CI 1.00, 1.45) p= % Saline (N=3375) HES 130/0.4 (N=3352) Saline HES 130/0.4 Within 90 days post-randomisation. CI, confidence interval; HES, hydroxyethyl starch; RR, relative risk; RRT, renal replacement therapy Myburgh et al. N Engl J Med 2012; 367:

33 Serum creatinine (µmol/l) Creatinine levels* revealed significantly higher risk of injury and failure in the HES 130/0.4 group No. at risk HES Saline P= Baseline Study day HES Saline Serum creatinine levels were significantly increased and urine output was significantly decreased in the HES 130/0.4 group compared with the saline group Relative risks of meeting criteria for kidney dysfunction or injury were higher in the HES 130/0.4 group *Post hoc analysis. HES, hydroxyethyl starch Myburgh et al. N Engl J Med 2012; 367:

34 Meta-analyses of HES 130/ in patients with sepsis: Haase et al. Systematic review with meta-analysis and trial sequential analysis of 9 RCTs (3456 ICU patients with sepsis) HES 130/ vs crystalloids or albumin Outcome # of studies # of patients Mortality* Requirement for RRT Requirement for RBC transfusion Severe adverse events *In pre-defined analysis of trials with low risk of bias Favours HES Favours control Risk ratio (95% CI) 1.11 (1.00, 1.23) 1.36 (1.08, 1.72) 1.29 (1.13, 1.48) 1.30 (1.02, 1.67) HES 130/ increases mortality, requirement for RRT and blood transfusions, and incidence of SAEs (vs control fluids) in ICU patients with sepsis 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 event Haase et al. BMJ 2013; 346: f839

35 Meta-analyses of HES 130/ in patients with sepsis: Patel et al. Meta-analysis of 6 RCTs (3033 ICU patients with severe sepsis) HES 130/ vs non-hes fluids* Outcome # of studies # of patients Mortality at 90 days Requirement for RRT Risk ratio (95% CI) 1.13 (1.02, 1.25) 1.42 (1.09, 1.86) Requirement for allogeneic transfusion Favours HES Favours control 1.21 (1.08, 1.36) Use of HES 130/ was associated with increased mortality, and requirement for RRT and allogeneic transfusions (compared with non-hes fluids) in patients with severe sepsis * 20% albumin, 0.9% NaCl or Ringer s acetate CI, confidence interval; HES, hydroxyethyl starch; ICU, intensive care unit; RCT, randomised controlled trial; RRT, renal replacement therapy Patel et al. Intensive Care Med. 2013; 39:

36 Meta-analysis of HES as a class in critical illness: Zarychanski et al. 38 RCTs (10,978 ICU patients) Any HES vs crystalloids, albumin or gelatin Endpoints mortality and acute kidney injury Outcome # of studies # of patients Mortality* 28 10,290 Requirement for RRT Acute renal failure Risk ratio (95%CI) 1.09 (1.02, 1.17) 1.32 (1.15, 1.50) 1.27 (1.09, 1.47) Favours HES Favours control HES use was associated with a significant increased risk of mortality and acute kidney injury in critically ill patients *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 therapy Zarychanski et al. JAMA 2013; 309:

37 Mortality (%) Meta-analysis of HES 130/ in critical illness: Wiedermann et al. 15 RCTs (8580 patients in different settings*) HES 130/ vs crystalloids or albumin Endpoint mortality RR 1.10 (95% CI 1.02, 1.19) p= Control HES 130/0.4 or 0.42 * Including acute illness, major surgery, trauma and severe sepsis/septic shock CI, confidence interval; HES, hydroxyethyl starch; RCT, randomised controlled trial; RR, relative risk Wiedermann and Joannidis. Swiss Med Wkly 2013; 143: w13747

38 Mortality (%) Incidence of RRT (%) Meta-analyses of HES 130/ in critical illness: Gattas et al RCTs (10,391 ICU patients) HES 130/ vs control fluids Endpoints mortality and incidence of RRT RR 1.08 (95% CI 1.00, 1.17) p= RR 1.25 (95% CI 1.08, 1.44) p= % (RR) Control HES 130/0.4 or Control HES 130/0.4 or 0.42 CI, confidence interval; HES, hydroxyethyl starch; ICU, intensive care unit; RCT, randomised controlled trial; RR, relative risk Gattas et al. Intensive Care Med 2013; 39:

39 Hyperoncotic HES: does it contribute to AKI? Aim Compare the effects of hyperoncotic albumin or HES on AKI Study design Meta-analysis of RCTs Studies included Patient population Primary endpoint Secondary endpoint Evaluated AKI following infusion of hyperoncotic colloid vs control (crystalloid, 4 5% hypo-oncotic albumin or no fluid): 20 25% albumin (7 studies) 10% HES (4 studies) N=1220 Surgery (3 studies), ascites (4 studies) or spontaneous bacterial peritonitis (2 studies) Severe sepsis or septic shock (1 study) Early septic shock (1 study) Does hyperoncotic albumin or HES increase AKI risk vs control? Mortality AKI, acute kidney injury; HES, hydroxyethyl starch Wiedermann et al. Crit Care 2010; 14: R191

40 Pooled incidence of AKI (%) Pooled mortality (%) Hyperoncotic HES significantly increases risk of AKI and mortality vs control 35 OR 1.92 (95% CI 1.31, 2.81) 40 OR 1.41 (95% CI 1.01, 1.96) 30 p< p= Control Control* HES HES 0 Control Control* HES HES *Crystalloid, 4 5% hypo-oncotic albumin or no fluid; AKI, acute kidney injury; CI, confidence interval; HES, hydroxyethyl starch; OR, odds ratio Wiedermann et al. Crit Care 2010; 14: R191

41 HES safety concerns and recommendations: EMA Recommendations of the EMA PRAC on the use of HES-containing solutions endorsed by the CMDh, representing EU member states 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 should not be used for more than 24 hours and patients kidney function should be monitored after HES administration HES solutions may continue to be used in patients to treat hypovolaemia, where treatment with crystalloids alone are not considered to be sufficient CMDh, Coordination Group for Mutual Recognition and Decentralised Procedures Human; EMA, European Medicines Agency; PRAC, Pharmacovigilance Risk Assessment Committee Hydroxyethyl-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: [accessed December 2013]

42 HES safety concerns and recommendations: EMA Assessment by the PRAC on the benefits and risks of HES products Selected instructions and precautions to be included in the SmPC of HES products Use of HES should be restricted to the lowest possible dose, with a maximum daily dose of 30 ml/kg the initial phase of volume resuscitation, with a maximum time interval of 24 hours Use of HES is not recommended in patients undergoing cardiac surgery in association with CPB (owing to risk of excessive bleeding) for use in children Other 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 CPB, cardiopulmonary bypass; EMA, European Medicines Agency; HES, hydroxyethyl starch; PRAC, Pharmacovigilance Risk Assessment Committee; SmPC, Summary of Product Characteristics Assessment report for solutions for infusion containing hydroxyethyl starch. Available at: [accessed December 2013]

43 HES safety concerns and recommendations: EMA PRAC assessment on the benefits and risks of HES products 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 patients PRAC assessment: given the study limitations (HES only constituted part of the colloid arm, administration protocol deviations), CRISTAL findings did not refute 6S/VISEP results BaSES randomised study comparing HES vs Ringer s lactate No increase in mortality and AKI associated with HES in patients with sepsis PRAC assessment: given the limited number of patients in study, findings need further confirmation RaFTinG prospective clinical registry of fluid therapy use in Germany No increased risk of mortality in ICU patients receiving colloids (or HES) compared to crystalloids PRAC assessment: only limited conclusions can be made from this observational study as it is not possible to exclude treatment bias or difference in baseline characteristics between treatment groups 6S, Scandinavian Starch for Severe Sepsis/Septic Shock; AKI, acute kidney injury; BaSES, Basel Starch Evaluation in Sepsis; CRISTAL, Therapy in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill; EMA, European Medicines Agency; HES, hydroxyethyl starch; ICU, intensive care unit; PRAC, Pharmacovigilance Risk Assessment Committee; RaFTinG, Rational Fluid Therapy in Germany; RCT, randomised controlled trial; VISEP, Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis Assessment report for solutions for infusion containing hydroxyethyl starch. Available at: [accessed December 2013]

44 Comparison of albumin vs HES Parameter HES 1 Albumin 2 Indication Hypovolaemia due to acute blood loss (only when crystalloids are considered insufficient for volume replacement) Contraindications Critically ill Sepsis Burns Renal impairment Severe coagulopathy Not recommended Cardiac surgery Children Surgery and trauma Administration Lowest possible dose Maximum use up to 24 h Maximum dose 10 ml/kg Long-term monitoring Renal function to be monitored for at least 90 days after administration Hypovolaemia (EU) (>10 additional indications are licensed in US and ROW) Prior allergic reaction to albumin Dose according to patient s individual requirement No maximum time restriction No maximum dose restriction Not necessary HES, hydroxyethyl starch; ROW, rest of world 1. Assessment report for solutions for infusion containing hydroxyethyl starch. Available at: [accessed December 2013]. 2. Alburex 5 Summary of Product Characteristics. Available at: [accessed December 2013]

45 Albumin: sepsis recommendations

46 ESICM: Sepsis Recommendations 2012 We recommend not to use HES with molecular weight 200 kda and/or degree of substitution >0.4 in patients with severe sepsis (grade 1B) We suggest that HES 130/0.4 be used in severe sepsis and other ICU patients with increased risk for AKI* or bleeding only in the context of clinical trials rather than in routine clinical practice (grade 2C) We suggest that albumin may be included in the resuscitation of severe sepsis patients (grade 2B) *Older age, cardiovascular surgery, sepsis, contrast nephropathy; AKI, acute kidney injury; HES, hydroxyethyl starch Grading: 1 = strong recommendation; 2 = weak recommendation; B = moderate quality of evidence; C = low quality of evidence ESICM, European Society of Intensive Care Medicine Reinhart et al. Intensive Care Med 2012; 38:

47 Surviving Sepsis Campaign: recommendations for severe sepsis and septic shock Crystalloids for initial fluid resuscitation in patients with severe sepsis or septic shock (grade 1B) Albumin for fluid resuscitation in patients with severe sepsis or septic shock requiring substantial amounts of crystalloids (grade 2C) Recommend against the use of HES in patients with severe sepsis or septic shock (grade 1B) HES, hydroxyethyl starch Grading: 1 = strong recommendation; 2 = weak recommendation; A = high quality of evidence; B = moderate quality of evidence ; C = low quality of evidence (based on 2012 Surviving Sepsis Campaign guidelines) Dellinger et al. Crit Care Med 2013; 41:

48 Albumin: Summary: colloids in sepsis Mortality Evidence for survival benefit vs other colloids 1,2 Kidney function Neutral effect on renal and other organ function 2,3 Potential non-oncotic benefits 4 9 Guidelines May be included in the resuscitation of severe sepsis patients Delaney et al. Crit Care Med 2011; 39: ; 2. SAFE study investigators. Intensive Care Med 2011; 37: 86 96; 3. Wiedermann et al. Crit Care 2010; 14: R191; 4. Quinlan et al. Clin Sci (Colch) 1998; 95: ; 5. Nathan et al. J Cell Biol 1993; 122: ; 6. Jacob et al. Transplantation 2009; 87: ; 7. Chen et al. Scand J Gastroenterol 2009; 44: ; 8. Jürgens et al. J Endotoxin Res 2002; 8: ; 9.Evans. Aliment Pharmacol Ther 2002; 16 (Suppl. 5): 6 11; 10. Reinhart et al. Intensive Care Med 2012; 38:

49 HES: Summary: colloids in sepsis Mortality Significantly risk of mortality vs control 1,2 Significantly risk of death vs control in sepsis/severe sepsis 3,4 Significantly risk of mortality vs control in the ICU 5,6 Kidney function Significantly risk of AKI vs control 1 Significantly risk of RRT vs control in sepsis/severe sepsis 3,4 Significantly risk of RRT vs control in the ICU 5,6 Guidelines HES 200 kda/>0.4 not recommended for severe sepsis 7 HES 130/0.4 should only be used within the setting of a clinical trial in severe sepsis and ICU patients with increased risk of AKI or bleeding 7 AKI, acute kidney injury; HES, hydroxyethyl starch; ICU, intensive care unit; RRT, renal replacement therapy 1. Wiedermann et al. Crit Care 2010; 14: R191; 2. Wiedermann and Joannidis. Swiss Med Wkly 2013; 143: w Haase et al. BMJ 2013; 346: f839; 4. Patel et al. Intensive Care Med. 2013; 39: ; 5. Zarychanski et al. JAMA 2013; 309: ; 6. Gattas et al. Intensive Care Med. 2013; 39: ; 7. Reinhart et al. Intensive Care Med 2012; 38:

50 References (A-D) Adrie C et al. Epidemiology and economic evaluation of severe sepsis in France: age, severity, infection site, and place of acquisition (community, hospital, or intensive care unit) as determinants of workload and cost. J Crit Care 2005; 20: ALBIOS study record. Available at [accessed December 2013] Artero A et al. Prognostic factors of mortality in patients with community-acquired bloodstream infection with severe sepsis and septic shock. J Crit Care 2010; 25: Assessment report for solutions for infusion containing hydroxyethyl starch. Available at: pdf [accessed December 2013] Boyd JH et al. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med 2011; 39: Blanco J et al. Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multicentre study. Crit Care 2008; 12: R158 Brunkhorst FM et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358: Charpentier J, Mira J-P. Efficacy and tolerance of hyperoncotic albumin administration in septic shock patients: the EARSS study. Intens Care Med 2011; 37 Suppl 1: S115 Chen T-A et al. Effect of intravenous albumin on endotoxin removal, cytokines, and nitric oxide production in patients with cirrhosis and spontaneous bacterial peritonitis. Scand J Gastroenterol 2009; 44: Daniels R. Surviving the first hours in sepsis: getting the basics right (an intensivist's perspective). J Antimicrob Chemother 2011; 66 (Suppl 2): ii11 ii23

51 References (D-H) Delaney AP et al. The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and metaanalysis. Crit Care Med 2011; 39: Dellinger RP et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: Crit Care Med 2013; 41: EARSS study record. Available at [accessed December 2013] Evans. Review article: albumin as a drug--biological effects of albumin unrelated to oncotic pressure. Aliment Pharmacol Ther 2002; 16 (Suppl. 5): 6 11 FDA Safety Communication: Boxed Warning on increased mortality and severe renal injury, and additional warning on risk of bleeding, for use of hydroxyethyl starch solutions in some settings. Available at: [accessed December 2013] Gattas DJ et al. Fluid resuscitation with 6 % hydroxyethyl starch (130/0.4 and 130/0.42) in acutely ill patients: systematic review of effects on mortality and treatment with renal replacement therapy. Intensive Care Med. 2013; 39: Guideline on core SmPC for human albumin solution. Available at [accessed December 2013] Guidet B et al. The COASST study: cost-effectiveness of albumin in severe sepsis and septic shock. Crit Care 2007; 22: Haase N et al. Hydroxyethyl starch 130/ versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis. BMJ 2013; 346: f839 Harrison DA et al. The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Crit Care 2006; 10: R42 [accessed December 2013]

52 References (H-S) Hydroxyethyl-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: WC0b01ac058004d5c1 [accessed December 2013] Jacob M et al. Albumin augmentation improves condition of guinea pig hearts after 4 hr of cold ischemia. Transplantation 2009; 87: Jürgens G et al. Investigation into the interaction of recombinant human serum albumin with Re-lipopolysaccharide and lipid A. J Endotoxin Res 2002; 8: Kumar G et al. Nationwide Trends of Severe Sepsis in the 21st Century ( ) Chest 2011; 140: Myburgh JA et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012; 367: Nathan C et al. Albumin inhibits neutrophil spreading and hydrogen peroxide release by blocking the shedding of CD43 (sialophorin, leukosialin). J Cell Biol 1993; 122: Patel A et al. Randomised trials of 6 % tetrastarch (hydroxyethyl starch 130/0.4 or 0.42) for severe sepsis reporting mortality: systematic review and meta-analysis. Intensive Care Med. 2013; 39: Perner A et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012; 367: Quinlan GL et al. Administration of albumin to patients with sepsis syndrome: a possible beneficial role in plasma thiol repletion. Clin Sci (Colch) 1998; 95: Reinhart K et al. Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients. Intensive Care Med 2012; 38: Rivers E et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345: SAFE study investigators. Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med 2011; 37: 86 96

53 References (S-Z) SAFE study investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350: Vincent JL et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006; 34: Wiedermann CJ et al. Hyperoncotic colloids and acute kidney injury: a meta-analysis of randomized trials. Crit Care 2010; 14: R191 Wiedermann CJ et al. Hypoalbuminemia and acute kidney injury: a meta-analysis of observational clinical studies. Intensive Care Med 2010; 36: Wiedermann CJ and Joannidis M. Increased mortality after infusion of modern hydroxyethyl starch. Swiss Med Wkly 2013; 143: w13747 Zarychanski R et al. Association of Hydroxyethyl Starch Administration With Mortality and Acute Kidney Injury in Critically Ill Patients Requiring Volume Resuscitation. JAMA 2013; 309:

54 Prescribing information: Human Albumin 20% Behring Name: Human Albumin 20% Behring, low salt, Solution for infusion. Qualitative and quantitative composition: Active ingredients: Solution containing 200 g/l of total protein of which at least 96% is human albumin. 50 ml contain at least 9.6 g of human albumin. The solution is hyperoncotic. Other ingredients: Sodium ions, Caprylate, N- acetyl-d,l-tryptophan, Chloride ions, HCl or NaOH (in small amounts for ph adjustment), Water for injections. Therapeutic indications: Increase in oncotic pressure in case of oncotic deficiency; diluted as a 4 5% solution for iso-oncotic volume replacement with long-term effect; therapy of albumin deficiency. Contraindications: Hypersensitivity to albumin preparations or to any of the excipients of the product. Special warnings and precautions for use: Suspicion of allergic or anaphylactic type reactions (reaction like an allergic shock) requires immediate discontinuation of the injection. In case of shock, standard medical treatment for shock should be implemented. Albumin should be used with caution in conditions where hypervolaemia (oversized blood volume) and its consequences or haemodilution (dilution of the blood) could represent a special risk for the patient. Examples of such conditions are: Decompensated cardiac insufficiency (severe heart muscle deficiency), hypertension (increased blood pressure), oesophageal varices (disease of the gullet vessels), pulmonary oedema, haemorrhagic diathesis (increased tendency to bleeding), severe anaemia (severe red blood cell deficiency), renal and post-renal anuria (kidney failure). The colloid-osmotic effect of human albumin 200 or 250 g/l is approximately four times that of blood plasma. Therefore, when highly concentrated albumin is administered, care must be taken to assure adequate hydration (fluid supply) of the patient. Patients should be monitored carefully to guard against circulatory overload or hyperhydration (increased volume of total body water) g/l human albumin solutions are relatively low in electrolytes compared to the g/l human albumin solutions. When albumin is given, the electrolyte status of the patient should be monitored and appropriate steps taken to restore or maintain the electrolyte balance. Albumin solutions must not be diluted with water for injections as this may cause haemolysis (destruction of red cells) in recipients. If comparatively large volumes are to be replaced, controls of coagulation and haematocrit are necessary. Care must be taken to ensure adequate substitution of other blood constituents (coagulation factors, electrolytes, platelets and erythrocytes). Hypervolaemia may occur if the dosage and rate of infusion are not adjusted to the patients circulatory situation. At the firstclinical signs of cardiovascular overload (headache, dyspnoea [difficulty in breathing], jugular vein congestion), or increased blood pressure, raised venous pressure or pulmonary oedema, the infusion is to be stopped immediately. Human Albumin 20% Behring, low salt contains 125 mmol sodium per 1000 ml. To be taken into consideration by patients on a controlled sodium diet. Pregnancy and lactation: The safety of Human Albumin 20% Behring, low salt, for use in human pregnancy has not been established in controlled clinical trials. However, clinical experience with albumin suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected, particularly since human albumin is a normal constituent of human blood. No animal reproduction studies have been conducted with Human Albumin 20% Behring, low salt. Experimental animal studies are insufficient to assess the safety with respect to reproduction, development of the embryo or foetus, the course of gestation and peri- and postnatal development. Virus safety: When medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. These include careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, and the testing of each donation and pools of plasma for signs of virus/infections. Manufacturers of these products also include steps in the processing of the blood or plasma that can inactivate or remove viruses. Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot be totally excluded. This also applies to any unknown or emerging viruses or other types of infections. There are no reports of virus infections with albumin manufactured to European Pharmacopoeia specifications by established processes. It is strongly recommended that every time you receive a dose of Human Albumin 20% Behring, low salt, the name and batch number of the product are recorded in order to maintain a record of the batches used. Interactions with other medicinal products and other forms of interactions: No specific interactions of human albumin with other medicinal products are known. Incompatibilities: Human Albumin 20% Behring, low salt, must not be mixed with other medicinal products (except the recommended diluents), whole blood and packed red cells. Undesirable effects: The following adverse reactions are based on post marketing experience and were observed very rarely (<1 / 10,000 including reported single cases): General disorders and administration site conditions: Chills, fever, nausea, vomiting, headache, malaise and flush. Immune system disorders: Hypersensitivity reactions or allergic-anaphylactic reactions such as rash, itching, urticaria, dyspnoea, tachycardia, bradycardia, hypotension. These reactions might in single cases be reaching as far as life-threatening shock. Mild reactions normally disappear rapidly after the infusion rate has been slowed down or the infusion stopped. In case of severe reactions (e.g. anaphylactic shock) the infusion has to be stopped immediately and appropriate treatment instituted. Prescription status: Prescription-only drug. Name and address of the Manufacturer and Marketing Authorisation Holder: CSL Behring GmbH, Emil-von-Behring-Str. 76, D Marburg. Date of revision of the text: March 2008.

55 Prescribing information: Albumin (Human) USP, 20%, Albuminar -20 Active substance: Albumin (Human) 20%, Albuminar -20 is a sterile aqueous solution of albumin obtained from adult human venous plasma. Each 100 ml contains 20 g serum albumin Excipients: Sodiumacetyltryptophanate, sodium caprylate. Prescription-only medicine. Pharmaceutical form: Solution for infusion. Therapeutic indications: Emergency treatment of shock and other conditions requiring urgent restoration of blood volume. Treatment of burns to prevent marked haemoconcentration and maintain electrolyte balance. Hypoproteinaemia, with or without oedema. Posology and method of administration: Albuminar -20 may be given intravenously undiluted or diluted with normal saline or 5% dextrose. 250 ml / litre is approximately isotonic and iso-osmotic with citrated plasma. In patients with normal blood volume, the infusion rate of undiluted solution should be slow enough (1 ml / min) to prevent too rapid expansion of plasma volume. In shock, the dose and duration of therapy are based on the patient s responsiveness. The initial dose may be followed by additional albumin within minutes if necessary. In the treatment of burns, suggested therapy during the first 24 hours includes administration of large volumes of crystalloid solution. Thereafter more albumin and less crystalloid solution are required to prevent haemoconcentration and maintain electrolyte balance. In Hypoproteinemia, 250 to 350 ml may be required to reduce oedema and normalise serum protein levels. Since blood volume in such patients is usually normal, doses over 100 ml should not be given faster than 100 ml in 30 to 45 minutes. If slower administration is desired, mix 200 ml with 300 ml of 10% dextrose solution and administer by continuous drip at 100 ml / hour. Contraindications: Albuminar -20 may be contraindicated in patients with severe anaemia, cardiac failure or a history of allergy to human albumin. Special warnings and precautions for use: Infusion of protein containing solutions excessively or inappropriately diluted with hypotonic solutions may cause severe haemolysis and acute renal failure. Do not use if solution is turbid. Since this product contains no preservative, do not begin administration more than 4 hours after opening. If dehydration is present, administer additional fluids concomitantly or subsequently. Administration of large quantities of albumin should be supplemented with or replaced by packed red blood cells to combat the subsequent relative anaemia. The quick blood pressure response which may follow rapid administration of concentrated albumin necessitates careful observation. Albuminar -20 should be administered with caution to patients with low cardiac reserve or no albumin deficiency because of the risk of circulatory compromise. In hypertension, a slower administration rate is desired. If anaphylactic or severe anaphylactoid reactions occur, discontinue infusion immediately. Infusion rates and the patient s clinical state should be monitored closely during infusion. Safety and effectiveness in paediatric patients have not been established. Viral safety: The risk of transmission of pathogenic agents by products manufactured from human blood is reduced by screening plasma donors, testing for virus infections, and inactivating and/or removing certain viruses during manufacture. Despite this, the risk of transmission of infectious agents, including those not yet known or identified, cannot be totally eliminated. Based on effective donor screening andproduct manufacturing processes, the risk of transmission of viral diseases or Creutzfeldt-Jakob disease is extremely remote. Pregnancy and lactation: It is not known whether Albuminar causes foetal harm when administered to pregnant women or affects reproduction capacity. Albuminar -20 should be given during pregnancy only if clearly needed. Undesirable effects: The incidence of untoward reactions to Albuminar -20 is low. There are reports of sometimes severe anaphylaxis and of hypersensitivity reactions (including urticaria, skin rash, pruritus, oedema, erythema, hypotension and bronchospasm). Nausea, vomiting, increased salivation, chills and febrile reactions have also been reported. Pack sizes: 50 ml vials containing 10 g albumin, 100 ml vials containing 20 g albumin. Marketing authorisation holder: CSL Behring LLC, Kankakee, IL USA. Date of revision of the text: August 2010.

56 Prescribing information: Alburex 20 Name: Alburex 20, 200 g/l, solution for infusion. Qualitative and quantitative composition: Alburex 20 is a solution containing 200 g/l of total human plasma protein of which at least 96% is human albumin. Alburex 20 is hyperoncotic to normal plasma. Pharmaceutical form: Solution for infusion. Therapeutic indications: Restoration and maintenance of circulating blood volume where volume deficiency has been demonstrated and use of a colloid is appropriate. The choice of albumin rather than artificial colloid will depend on the clinical situation of the individual patient, based on official recommendations. Contraindications: Hypersensitivity to albumin preparations or to any of the excipients. Special warnings and precautions for use: Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the infusion. In case of shock, standard medical treatment for shock should be implemented. Albumin should be used with caution in conditions where hypervolaemia and its consequences or haemodilution could represent a special risk for the patient. Examples of such conditions are: decompensated cardiac insufficiency, hypertension, oesophageal varices, pulmonary oedema, haemorrhagic diathesis, severe anaemia, renal and post-renal anuria. The colloid-osmotic effect of human albumin 200 g/l is approximately four times that of blood plasma. Therefore, when concentrated albumin is administered, care must be taken to assure adequate hydration of the patient. Patients should be monitored carefully to guard against circulatory overload and hyperhydration. Albumin solutions must not be diluted with water for injections as this may cause haemolysis in recipients. Hypervolaemia may occur if the dosage and infusion rate are not adjusted to the patient s circulatory situation. At the first clinical signs of cardiovascular overload (headache, dyspnoea, jugular vein congestion), or increased blood pressure, raised venous pressure and pulmonary oedema, the infusion is to be stopped immediately and the patient s haemodynamic parameters carefully monitored. Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation / removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens. There are no reports of proven virus transmissions with albumin manufactured to European Pharmacopoeia specifications by established processes. It is strongly recommended that every time that Alburex 20 is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product. Pregnancy and lactation: The safety of Alburex 20 for use in human pregnancy has not been established in controlled clinical trials. However, clinical experience with albumin suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected. Undesirable effects: Mild reactions such as flush, urticaria, fever and nausea occur rarely. These reactions normally disappear rapidly when the infusion rate is slowed down or the infusion is stopped. Very rarely, severe reactions such as shock may occur. In these cases, the infusion should be stopped immediately and an appropriate treatment should be initiated. Manufacturer: CSL Behring AG, Wankdorfstrasse 10, 3000 Bern 22. Date of revision of the text: November 2009.