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Fluids in Sepsis Evidence and Cost

Faculty of medicine, dentistry and health sciences. Fluids in Sepsis Evidence and Cost. Albert Farrugia PhD Megha Bansal M Econ. The Seventh Annual Southeastern Critical Care Summit February 21-22, 2013. Disclosures .

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Fluids in Sepsis Evidence and Cost

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  1. Faculty of medicine, dentistry and health sciences Fluids in SepsisEvidence and Cost Albert Farrugia PhD MeghaBansal M Econ The Seventh Annual Southeastern Critical Care Summit February 21-22, 2013

  2. Disclosures I provide services to the pharmaceutical and biotechnology industry, including the manufacturers of therapies described in this presentation, who are also major sponsors of this Summit

  3. Current concepts of fluid exchange Annu. Rev. Biomed. Eng. 2007. 9:121–67 J Physiol 557.3 (3004) p704

  4. Shock • Circulatory failure leading to inadequate perfusion and delivery of oxygen to vital organs • Blood Pressure is often used as an indirect estimator of tissue perfusion • Oxygen delivery is an interaction of Cardiac Output, Blood Volume, Systemic Vascular Resistance

  5. Shock States

  6. Severe Sepsis • Major cause of morbidity and mortality worldwide. • Leading cause of death in non-coronary ICU. • 11th leading cause of death overall. • More than 750,000 cases/Y of severe sepsis in US. • In the US, > 500 patients die of severe sepsis daily. • Consumes significant healthcare resources: • Survivors of sepsis : • ICU stay prolonged an additional 8 days. • Additional costs incurred were $40,890/ patient. • Estimated annual healthcare costs due to severe sepsis in U.S. exceed $16 billion.

  7. Definitions (ACCP/SCCM, 1991) • Systemic Inflamatory Response Syndrome (SIRS): The systemic inflammatory response to a variety of severe clinical insults (For example, infection). • Sepsis: The systemic inflammatory response to infection. • Known or suspected infection, plus • >2 SIRS Criteria. • Severe Sepsis: • Sepsis plus >1 organ dysfunction. • MODS. • Septic Shock. • Sepsis induced with hypotension despite adequate resuscitation • Perfusion abnormalities which may include, but are not limited to lactic acidosis, oliguria, or an acute alteration in mental status.

  8. Organ Ischemia in Sepsis Vasodilation leads to slow and sluggish organ perfusion pressure Some capillary beds perfuse normally Others are badly damaged and this leads to capillary leak, resulting in edematous tissues, tissue compression and prevention of oxygen exchange Due to venous stasis and activation of coagulation, small vessels become obstructed and blood flow stops

  9. Goals of Resuscitation • Rivers Study- Early Goal Directed Therapy in Sepsis and Septic Shock • Emergency department with severe sepsis or septic shock, randomized to goal directed protocol vs standard therapy prior to admission to ICU • Early goal directed therapy conferred lower APACHE scores, indicating less severe organ dysfunction Rivers et al NEJM 2001

  10. Fluid Resuscitation of Shock • Crystalloid Solutions • “Normal” saline • “Balanced” solutions • Ringers Lactate solution • Plasmalyte • Colloid Solutions • Hydroxyethyl Starch(es) • Blood products (albumin, RBC, plasma)

  11. Choices and decision making in medical care • Evidence • RCTs • Systematic reviews • Cost effectiveness • Total medical costs • Role of Decision Analysis

  12. An ideal resuscitative fluid would maintain intravascular volume without expanding the interstitial space. • Crystalloid solutions are universally used for initial volume resuscitation in sepsis and septic shock…... • Colloid solutions achieve hemodynamic goals more quickly than crystalloids with significantly less volume. • As sepsis proceeds,…..significant tissue accumulation of resuscitation fluid occurs, and this may result in adverse effects.. Which Fluids? Elsevier 2010

  13. Isotonic saline, when administered in large volumes, is associated with hyperchloremic acidosis; this may …be toxic. Selected StatementsI

  14. The Origins of 0.9% Saline Not a physiological fluid – based on a mistake by a physiologist called Hamburger in 1830s He thought concentration of salt in blood was 0.9% but it is nearer 0.6% 0.9% NaCl is not a maintenance fluid It has certain specific uses “One cannot fail to be impressed with the danger of the utter recklessness with which salt solution is frequently prescribed, particularly in the postoperative period…the disastrous role played by the salt solution is often lost in light of the serious conditions that call forth its use.” George H. Evans, JAMA 1911

  15. Hospital mortality associated with type of metabolic acidosis Gunnerson KJ, Saul M, He S, Kellum JA: CritCare 2006, 10:R22

  16. A & A October 2001 vol. 93 no. 4 811-816 Balanced Versus Saline-Based Solutions on Acid-Base and Electrolyte Status in Elderly Surgical Patients A & A October 2001 vol. 93 no. 4 811-816

  17. The administration of buffered fluids to adult patients during surgery is equally safe and effective as the administration of non-buffered saline-based fluids. The use of buffered fluids is associated with less metabolic derangement, in particular hyperchloraemia and metabolic acidosis. Larger studies are needed to assess robust outcomes such as mortality. But…….

  18. But……. Association of a chloride-restrictive (vs chloride-liberal) intravenous fluid strategy with AKI in critically ill patients Fluids used : 2008 Cl- = 120 – 150 mmol/l 2009 Cl- = 19 – 109 mmol/l JAMA. 308(15):1566-1572, October 17, 2012. DOI: 10.1001/jama.2012.13356

  19. Albumin is safe, although its cost-effectiveness has not been established, nor is there evidence of efficacy in sepsis. Selected StatementsII

  20. The role of albumin as a resuscitation fluid for patients with sepsis: A systematic review and meta-analysis Crit Care Med 2011 Vol. 39, No. 2, 386-91

  21. Albumin can ameliorate the disturbed microcirculatory effects of sepsis Albumin decreases neutrophil activation induced by fluid infusion, crystalloinds and synthetic colloids increase it. Rhee P, et al. Crit Care Med 2000; 28(1): 74-78. Albumin reduces TNF induced endothelial activation. Nohe et al Intensive Care Med 1999; 25: 1381-1385; Zhang et al Cardiovasc Res. 2002 Sep;55(4):820-9 Albumin solution reverses the LPS induced albumin leakage across vessel walls. Powers KA, et al. Crit Care Med 2003; 31: 2355-63 ;Anning PB et Intensive Care Med. 2004 Oct;30(10):1944-9 Albumin infusion results in sustained thiol levels in septic patients. Quinlan G, et al. ClinSci1998; 95: 459-65.

  22. Microcirculatory perfusion in sepsisPotentially impairing factors Spronk et al Critical Care 2004, 8:462-468

  23. Albumin is retained intravascularly… Fluid Therapy in Septic Patients …and expands plasma volume Ernest et al Critical Care Medicine:Volume 27(1)January 1999 pp 46-50 SAFE investigators Int Care Med 2011, 37 (1), 86-96

  24. RCTs - Albumin versus saline Sepsis and Septic Shock

  25. The power and the glory Theoretical Effect of a Drug for Septic Shock on All-Cause Mortality at 28 Days, According to Revised Estimates of Residual Attributable Mortality. Wenzel RP, Edmond MB N Engl J Med. 2012 May 31; 366(22):2122-4

  26. Albumin vs saline Sepsis and Septic ShockMortality All 0.83 p=0.011

  27. Systematic review of resuscitation of children with severe infection and shock ] Trials of albumin in malaria Akech et al BMJ. 2010; 341: c4416

  28. Mortality after fluid bolus in African children with severe infection - The FEAST Trial N Engl J Med. 2011 Jun 30;364(26):2483-95

  29. HES formulations are widely used for fluid resuscitation in sepsis. Older, high molecular weight compounds should be avoided because of problems with coagulation and accumulation, particularly with renal failure. Selected StatementsIII

  30. HES in sepsis – MA and RCTs

  31. HES and renal probleamsEarly MAs • “Studies including sepsis patients revealed that HES treated individuals had a 55% increased risk of developing kidney failure and a 59% increased risk of requiring dialysis.” • “There is insufficient clinical evidence to suggest that 6%130/0.4’s favourable pharmacokinetics compared to older HES products result in improved kidney outcomes.” Dart et al Cochrane Reports 2009 • “The use of HES for acute volume resuscitation of critically ill patients, and in particular those with severe sepsis and septic shock, appeared to be associated with increased use of renal replacement therapy. “ • “We do not recommend the routine use of starches for acute volume resuscitation in critically ill patients, particularly patients with severe sepsis or septic shock.” Zarychanskiet al Open Medicine 2009

  32. Mortality following HES resuscitation Zarychanski et al Open Medicine 2009;3(4):e196–209

  33. Renal outcomes (RRT) following HES resuscitation Zarychanski et al Open Medicine 2009;3(4):e196–209

  34. Crystalloids Morbidity Associated with severe Sepsis CRYSTMASstudy Adult patients with severe sepsis Crit Care. 2012 May 24;16(3):R94.

  35. Following the CRYSTMAS study (Crit Care. 2012 May 24;16(3):R94.) Approved Product Information for VoluvenTime to Renal Replacement Therapy “The number of subjects undergoing RRT was 21 vs 11 for the 90 day observation period and 17 vs 8 for the first 7 days of treatment. Mean Duration of RRT was 9.1 days in the Voluven arm vs 4.3 days in the saline arm. Kaplan-Meir curves for time to RRT showed a trend against Voluven.” VoluvenPI included by FDA

  36. “6S” study N Engl J Med. 2012 Jul 12;367(2):124-34.

  37. “6S” study “….patients with severe sepsis who received fluid resuscitation with HES 130/0.4, as compared with those who received Ringer’s acetate, had a higher risk of death at 90 days, were more likely to receive renal-replacement therapy, and had fewer days alive without renal-replacement therapy and fewer days alive out of the hospital.” N Engl J Med. 2012 Jul 12;367(2):124-34.

  38. CHEST STUDY N Engl J Med. 2012 Nov 15;367(20):1901-11.

  39. CHEST STUDY N Engl J Med. 2012 Nov 15;367(20):1901-11. “…does not provide evidence that resuscitation with 6% HES (130/0.4), as compared with saline, in the ICU provides any clinical benefit to the patient. Indeed, the use of HES resulted in an increased rate of renal replacement therapy. Thus, the selection of resuscitation fluid in critically ill patients requires careful consideration of its safety, its potential effect on patient-centered outcomes, and its cost.”

  40. The FIRST trial - Distribution of renal outcomes in blunt and penetrating trauma by fluid group Br. J. Anaesth. (2011) 107 (5): 693-702.

  41. Hot off the press • Three new meta analyses published on HES in the week beginning 18 February 2013 • Intensive Care Med. 2013 Feb 14. [Epub ahead of print], GattasDJ, Dan A, Myburgh J, Billot L, Lo S, Finfer S; CHEST Management Committee. • BMJ. 2013 Feb 15;346:f839. doi: 10.1136/bmj.f839. HaaseN, Perner A, Hennings LI, Siegemund M, Lauridsen B, Wetterslev M, Wetterslev J. • JAMA. 2013 Feb 20;309(7):678-88. doi: 10.1001/jama.2013.430. ZarychanskiR, Abou-Setta AM, Turgeon AF, Houston BL, McIntyre L, Marshall JC, Fergusson DA. • All HES products increase mortality and the need for RRT • Previous favorable risk/efficacy profile totally dependent on Boldt studies (retracted) “

  42. JAMA Editorial February 20, 2013 “….the harms of hydroxyethyl starch most likely outweigh the benefits and suggest that these products should not be used for acute volume resuscitation of critically ill patients.”

  43. Indirect comparisons Networkmeta-analysis / mixed treatment comparisons Treatment A (crystalloid) Treatment B (albumin) Treatment C (HES) • Evidence from head to head comparison trials is often limited or unavailable • Using evidence from A vs B and A vs C trials to draw conclusions about the effect of B relative to C • Itallows all evidence to be combined in a single analysis • Inference based on more evidence can (usually) provide more precision • Treatments can be ranked • Better informed decisions 43

  44. Network MA for studies in sepsisSearch strategy 6 5 1 1 Bansal et al 2013

  45. Network MA for studies in sepsisRanking probabilities of competing fluid treatments Bansal et al 2013

  46. No Money…… “Dear Chief Secretary, I'm afraid to tell you there's no money left” Outgoing Labour Chief Secretary to the UK Treasury Liam Byrne note to his successor in the incoming Coalition government 2010

  47. Decision tree to assess cost-effectiveness Fluids in sepsis

  48. Results of cost-effectiveness analysis * Years saved/lost compared to crystalloid.

  49. Summary/Conclusions Sepsis results in lowered tissue perfusion and can manifest shock requiring volume replenishment A variety of fluids for the treatment of sepsis have been proposed Evidence continues to accrue that colloids are required after initial crystalloid infusion Physiological indications that balanced crystalloids are preferable have not been confirmed in clinical trials in patients Albumin has been shown to improve outcomes in septic patients HES has been shown to increase mortality an cause renal damage Employing network meta-analysis and decision modeling allows direct comparison between fluid therapies In decision-making, a focus on total, long term costs needs to supersede short term considerations of individual interventions

  50. Money again “and you pays your money, and you makes your choice” Mark Twain in Huckleberry Finn

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