Albumin: rationale, use and evidence

Albumin: rationale, use and evidence Michaël Chassé, MD, MSc, FRCPC Intensivist, CHU de Québec PhD Candidate, Epidemiology, uottawa Research Fellow, Clinical Epidemiology Program Ottawa Hospital Research Institute ORBCoN spring symposium Friday April 24, 2015

Acknowledgements Dr Lauralyn McIntyre who kindly provided some slides used in this presentation as well as some unpublished data. ORBCoN spring symposium committee for inviting me

Conflicts of Interest None BUT I admit I do use Albumin products sometimes

Apr-11 May-11 Jun-11 Jul-11 Aug-11 Sep-11 Oct-11 Nov-11 Dec-11 Jan-12 Feb-12 Mar-12 Apr-12 May-12 Jun-12 Jul-12 Aug-12 Sep-12 Oct-12 Nov-12 Dec-12 Jan-13 Feb-13 Mar-13 Apr-13 May-13 Jun-13 Jul-13 Aug-13 Sep-13 Oct-13 Nov-13 Dec-13 Jan-14 Feb-14 Mar-14 Apr-14 May-14 Jun-14 Jul-14 Aug-14 Sep-14 Number of albumin units transfused 1000 Use of Albumin in Ottawa 900 800 700 600 500 400 300 200 100 0 Month Albumin 25% 100mL Albumin 5% 250mL Albumin 5% 500 ml

Objectives for today Review the biological rationale for using Albumin; Review the clinical trial evidence that supports the use of Albumin ; Review the factors driving the increased usage of Albumin in Ontario.

What is albumin? A big protein 55-60% of serum protein 66.5 kda Synthesized by the liver In healthy subjects Responsible for 80% of oncotic pressure 60% of oncotic pressure direct osmotic effect 40% result of negative charge Br J Anaesth 2000; 85: 599 610

What are albumin s functions? Maintenance of colloid oncotic pressure Transport protein Binds drugs Biological Plausibility...Yes!! Clinically Relevant Improvements in Outcome? Binds inflammatory mediators Anti-oxidant effects Vascular permeability Vincent, JL Best Practise and Research Clinical Anesthesiology 2009; 23: 183-191

Why may we use Albumin? Plasma 3 L ISS 10 L IC 30 L Blood Cells 2 L Iso-oncotic colloid (4 5% albumin) Hyper-oncotic colloid (20-25% albumin) Jacob et al, Crit Care 2012; 16: R86; Jacob and Chappell 2013; 19 (4): 282-289

Albumin levels are decreased in the critically ill.. Although production is increased Increased degradation Increased losses Leak from capillaries Vincent, JL Best Practise and Research Clinical Anesthesiology 2009; 23: 183 191; Barle, H etal, Clin Sci (London); 2006; 110 : 93-99

Can albumin leak? Margarson and Soni, British Journal of Anaesthesia, 92 (6):821±6 (2004)

Are colloids better maintained in the intravascular space compared to crystalloids? RCT/Yr Population Fluid Comparators Ratio Colloid/Crystalloid SAFE/2004 Critically ill N = 6997 4% albumin vs normal saline 1:1.4 VISEP/2008 Severe Sepsis/Septic Shock N = 537 10% HES vs ringers lactate 1:1.4 McIntyre/2008 Septic Shock 10% HES vs 1:1.1 N = 40 0.9% saline McIntyre/2012 Septic Shock N = 50 5% albumin vs 0.9% saline 1:1.4 Perner/2012 Severe Sepsis and shock N = 800 6% HES (130/0.42) vs ringers acetate 1:1.1 Annane/2013 Critically ill N = 2857 Any colloid vs Any crystalloid 1:1.5 Gattinoni/2014 Severe Sepsis/Septic Shock 20% album + Crys Vs Crys 1:1.02

Impact of low albumin Prognostic value Low albumin is predictor of mortality in the general population And in critically ill patients Anaesthesia. 1998 Aug;53(8):755-61. J Clin Epidemiol. 1997 Jun;50(6):693-703.

All about what type of fluid to use Author/yr Fluids compared # Studies Perel, 2011 Colloids vs Crystalloids 56 Bunn, 2011 Colloid vs Colloid 72 Alderson 2009 Albumin vs no albumin 37 Cochrane 2010 HES vs other fluid 34 We still don t have a clear answer

Why albumin? CC BY-SA 3.0, James Heilman, MD Public domain licence, U.S. Army Institute of Surgical Research, Fort Sam Houston, Texas Michaël Chassé, MD, own work

Potential indications for Albumin Recommend Y/N/Consider Hypovolemic critically ill patient Trauma, no brain injury Traumatic brain injury ARDS Severe sepsis/septic shock Burns Paracentesis Hepatorenal syndrome/spont. Bact. Peritonitis Dialysis Plasma exchange Ovarian hyperstimulation syndrome

28 Day Mortality Albumin Saline RR and 95% CI Overall 726/3473 729/3460 0.99 (0.91 1.09) Trauma 81/596 59/590 1.36 (0.99 1.86) ARDS 24/61 28/66 0.93 (0.61 1.41) Severe sepsis 185/603 217/615 0.87 (0.74 1.02) Finfer et al, NEJM 2004; 350: 2247-2256

Predefined sub-group with severe sepsis n = 1218 Finfer, S et al, Intensive Care Medicine, 2011; 37(1) 86-96

SAFE Severe Sepsis: 28 day mortality No differences in other outcomes (renal, ventilation, LOS ).. sub group analysis and 25% of patients from SAFE not included Finfer, S et al, Intensive Care Medicine, 2011; 37(1) 86-96

Greatest trend toward possible benefit of albumin compared to crystalloid fluids remained in the septic shock group Relative Risk 0.91: (0.81 1.01) No signals for harm with albumin Patel et al, BMJ 2014, 349: g4850

Recent Albios trial Relative risk, 0.94; 95% CI, 0.85 to 1.05; P=0.39 Relative risk, 0.87; 95% CI, 0.77 to 0.99; P=0.03 for septic shock Albios investigators, N Engl J Med 2014; 370:1412-1421

What about guidelines? Weak recommendation, low quality = 2C Dellinger et al. Surviving sepsis campaign 2012

N = 460 GCS 3 12 and an abnormal CT scan Myburgh J et al, NEJM 2008; 357: 874-884

Survival in SAFE TBI sub-group Survival 28 Days Survival 24 Months 20.4% 33.2% Myburgh J et al, NEJM 2008; 357: 874-884

Albumin in ARDS: A systematic review and meta - analysis RCTs colloids vs crystalloids on mortality and oxygenation in adults with ARDS 4130 citations 3 trials included All albumin vs saline N = 206 patients studied Uhlig, C et al Crit Care, 2014; 18: R10

What about albumin for burns? Author/Year Sample Size Intervention Jelenko, 1978 14 Hypertonic crystalloid with 12.5 g/l albumin Goodwin, 1983 79 2.5% albumin in ringers lactate Greenhalgh, 1995 70 25% albumin for levels 25 35 g/l Comparison Ringers lactate Ringers lactate No albumin unless levels < 15 g/l Relative Risk of Death and 95% CIs 2.40 (1.11 5.19) Roberts, I et al, BMJ, 1998; 317 (7153): 235-240 Cooper, 2006 42 5% albumin with ringers lactate Ringers lactate Relative Risk of Death and 95% CIs 2.93 (1.28 6.72) Alderson, P et al, Cochrane Library, 2011 Issue 10

Potential indications for Albumin Recommend Y/N/Consider Hypovolemic critically ill patient No Trauma, no brain injury? Traumatic brain injury ARDS Severe sepsis/septic shock Burns No To improve FiO2 or fluid balance? Maybe??, not as initial Paracentesis Hepatorenal syndrome/spont. Bact. Peritonitis Dialysis Plasma exchange Ovarian hyperstimulation syndrome

Plasmapheresis Albumin usage will depend on the incidence in use of plasmapheresis From the Guidelines on the Use of Therapeutic Apheresis in Clinical Practice from the writing Committee of the American Society for Apheresis: use of plasma versus albumin 3-page table of indications (78) Balance between infectious risk (higher with plasma), risk of coagulopathy (less with plasma), etc Journal of Clinical Apheresis 28:145 284 (2013)

Spontaneous bacterial peritonitis N Engl J Med 1999; 341:403-409

Spontaneous bacterial peritonitis Given renal outcome benefits, albumin is also used in most hepatorenal studies Clin Gastroenterol Hepatol. 2013 Feb;11(2):123-30

Paracentesis To reduce risks of hypovolemia, and maybe mortality after high volume therapeutic paracentesis 2012 AASLD practice guidelines: 6-8 g/l if more than 5L removed (No GRADE) Hepatology. 2013;57(4):1651. Hepatology. 2012 Apr;55(4):1172-81.

Dialysis Often used as resuscitation fluid in hypotensive dialysis patient (prevent volume) 1 RCT Knoll et al. J Am Soc Nephrol. 2004 Feb;15(2):487-92.

Ovarian hyperstimulation syndrome Cochrane (prevention) 2002: Hum Reprod. 2002;17(12):3027.

Ovarian hyperstimulation syndrome RCT, Bellver et al. 2003 (prevention): Hum Reprod. 2003;18(11):2283.

Potential indications for Albumin Recommend Y/N/Consider Hypovolemic critically ill patient No Trauma, no brain injury? Traumatic brain injury ARDS Severe sepsis/septic shock Burns Paracentesis Hepatorenal syndrome/spont. Bact. Peritonitis No To improve FiO2 or fluid balance? Maybe? Seems safe?, not as initial Consider Consider/Yes Dialysis? Plasma exchange Ovarian hyperstimulation syndrome Alb vs Plasma?? (Conflicting)

Increased use in Albumin?

Why albumin? Public domain licence, U.S. Army Institute of Surgical Research, Fort Sam Houston, Texas

Finfer, S et al, Intensive Care Medicine, 2011; 37(1) 86-96

Albios investigators, N Engl J Med 2014; 370:1412-1421

Fluid balance Finfer, S et al, Intensive Care Medicine, 2011; 37(1) 86-96

Albumin use Australia, New Zealand, Canada Jones et al, Anesth and Inten Care; 38(2), March 2010 Roberts, BMJ, 1999; 318: 1214 5% = red bar 25% = blue bar Data courtesy of Canadian Blood Services

What people say they do? International early septic shock resuscitation survey of 1097 ED and ICU physicians Jan/14 Type of Colloid Fluid 100 90 80 70 60 50 40 30 20 10 0 6% 4-5% albumin 20-25% albumin 1% 1% Hydroxyethyl Starch Rarely/Never Sometimes Often/Always McIntyre et al, unpublished data

Typical resuscitation fluid by specialty 5% Albumin, 11% Plasmalyte, 15% Typical Fluid Use by ICU 'often/always' Normal Saline, 28% Typical Fluid Use by ED 'often/always' Ringer's, 81% Ringer's, 35% Plasmalyte, 3% 5% Albumin, 0% Normal Saline, 84% McIntyre et al, unpublished data

Number of albumin units transfused Preliminary exploratory data Apr-11 May-11 Jun-11 Jul-11 Aug-11 Sep-11 Oct-11 Nov-11 Dec-11 Jan-12 Feb-12 Mar-12 Apr-12 May-12 Jun-12 Jul-12 Aug-12 Sep-12 Oct-12 Nov-12 Dec-12 Jan-13 Feb-13 Mar-13 Apr-13 May-13 Jun-13 Jul-13 Aug-13 Sep-13 Oct-13 Nov-13 Dec-13 Jan-14 Feb-14 Mar-14 Apr-14 May-14 Jun-14 Jul-14 Aug-14 Sep-14 1000 Use of Albumin in Ottawa 900 800 700 600 500 400 300 200 100 0 Month Albumin 25% 100mL Albumin 5% 250mL Albumin 5% 500 ml Michaël Chassé, for the ORBCON project, et al. Unpublished data

How fast is the increase? Albumin 25% 100 ml Additional 7.5 more units per month, p<0.0001 for linear trend Michaël Chassé, for the ORBCON project, et al. Unpublished data

How fast is the increase? Alb 5% 250 ml Alb 5% 500 ml Additional 4.5 more units per month, p<0.0001 for linear trend Michaël Chassé, for the ORBCON project, et al. Unpublished data

Hypotheses? Decreased synthetic colloid use?

Units transfused Apr-11 Can it be explained by decreased use in synthetic colloids? May-11 Jun-11 Jul-11 Aug-11 Sep-11 Oct-11 Nov-11 Dec-11 Jan-12 Feb-12 Mar-12 Apr-12 May-12 Jun-12 Jul-12 Aug-12 Sep-12 Oct-12 Nov-12 Dec-12 Jan-13 Feb-13 Mar-13 Apr-13 May-13 Jun-13 Jul-13 Aug-13 Sep-13 Oct-13 Nov-13 Dec-13 Jan-14 Feb-14 Mar-14 Apr-14 May-14 Jun-14 Jul-14 Aug-14 Sep-14 25 Use of synthetic colloids 20 15 10 5 0 Pentaspan 250mL Pentaspan 500 ml Voluven 250 ml Voluven 500 ml Includes only units transfused following an order What about cardiac bypass circuit priming? Michaël Chassé, for the ORBCON project, et al. Unpublished data

Albumin and procedural codes (CCI) Among all procedures performed on patients receiving albumin: 1LZ37LAGB = use cardiac bypass circuit (6.96%) 1KR58LA = vein retrieval (for CABG) (3.78%) 1IJ76LAXXQ = CABG (3.3%) 1HV90LAXXL = Aortic valve surgery (1.91%) Top 2 procedures performed: 1GZ31CAND = Mechanical ventilation (15.21%) 1IS53GRLF = Central line (11.0%) *** Not at the patient level (yet) ***

Hypotheses? Decreased synthetic colloid use? Preliminary data suggests unlikely in clinic. Needs confirmation (especially in cardiac surgery). Timing with new evidence?

Number of albumin units transfused Preliminary exploratory data Apr-11 May-11 Jun-11 Jul-11 Aug-11 Sep-11 Oct-11 Nov-11 Dec-11 Jan-12 Feb-12 Mar-12 Apr-12 May-12 Jun-12 Jul-12 Aug-12 Sep-12 Oct-12 Nov-12 Dec-12 Jan-13 Feb-13 Mar-13 Apr-13 May-13 Jun-13 Jul-13 Aug-13 Sep-13 Oct-13 Nov-13 Dec-13 Jan-14 Feb-14 Mar-14 Apr-14 May-14 Jun-14 Jul-14 Aug-14 Sep-14 1000 Use of Albumin in Ottawa ALBIOS abstract ALBIOS abstract 900 800 700 600 500 400 300 200 100 0 Month Albumin 25% 100mL Albumin 5% 250mL Albumin 5% 500 ml Michaël Chassé, for the ORBCON project, et al. Unpublished data

Number of albumin units transfused Preliminary exploratory data Apr-11 May-11 Jun-11 Jul-11 Aug-11 Sep-11 Oct-11 Nov-11 Dec-11 Jan-12 Feb-12 Mar-12 Apr-12 May-12 Jun-12 Jul-12 Aug-12 Sep-12 Oct-12 Nov-12 Dec-12 Jan-13 Feb-13 Mar-13 Apr-13 May-13 Jun-13 Jul-13 Aug-13 Sep-13 Oct-13 Nov-13 Dec-13 Jan-14 Feb-14 Mar-14 Apr-14 May-14 Jun-14 Jul-14 Aug-14 Sep-14 1000 FEAST trial Use of Albumin in Ottawa 900 800 700 600 500 400 300 200 100 0 Month Albumin 25% 100mL Albumin 5% 250mL Albumin 5% 500 ml Michaël Chassé, for the ORBCON project, et al. Unpublished data

Number of albumin units transfused Preliminary exploratory data Apr-11 May-11 Jun-11 Jul-11 Aug-11 Sep-11 Oct-11 Nov-11 Dec-11 Jan-12 Feb-12 Mar-12 Apr-12 May-12 Jun-12 Jul-12 Aug-12 Sep-12 Oct-12 Nov-12 Dec-12 Jan-13 Feb-13 Mar-13 Apr-13 May-13 Jun-13 Jul-13 Aug-13 Sep-13 Oct-13 Nov-13 Dec-13 Jan-14 Feb-14 Mar-14 Apr-14 May-14 Jun-14 Jul-14 Aug-14 Sep-14 1000 900 Use of Albumin in Ottawa SCC guidelines 800 700 600 500 400 300 200 100 0 Month Albumin 25% 100mL Albumin 5% 250mL Albumin 5% 500 ml Michaël Chassé, for the ORBCON project, et al. Unpublished data

Hypotheses? Decreased synthetic colloid use? Preliminary data suggests unlikely. Needs confirmation (especially in cardiac surgery). Timing with new evidence in favor of albumin? Not much very recent, no evidence Timing with restrictive fluid trials? No clinical rationale for FEAST Needs better description of patients to associated with trial publication (surgical? Sepsis? Cardiac Surgery?) Timing with resuscitation guidelines? Trend started before

No answer Need better description of Albumin use Ongoing ORBCON proof of concept Ottawa, Hamilton and London Additional surveys to understand reasons? Observational studies? Cost-benefit analysis? How appropriate is the use of Albumin? Maybe it is?

Apr-11 Jun-11 Aug-11 Oct-11 Dec-11 Feb-12 Apr-12 Jun-12 Aug-12 Oct-12 Dec-12 Feb-13 Apr-13 Jun-13 Aug-13 Oct-13 Dec-13 Feb-14 Apr-14 Jun-14 Aug-14 Apr-11 Jun-11 Aug-11 Oct-11 Dec-11 Feb-12 Apr-12 Jun-12 Aug-12 Oct-12 Dec-12 Feb-13 Apr-13 Jun-13 Aug-13 Oct-13 Dec-13 Feb-14 Apr-14 Jun-14 Aug-14 Thank you! 25 20 1000 900 800 700 600 500 400 300 200 100 0 15 10 5 0 Pentaspan 250mL Pentaspan 500 ml Voluven 250 ml Voluven 500 ml Month Albumin 25% 100mL Albumin 5% 250mL Albumin 5% 500 ml 5% Albumin, 11% Plasmalyte, 15% Normal Saline, 28% Ringer's, 81%