Austrian Society for Blood Transfusion and Regenerative Medicine. Klagenfurt - May 2015

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1 Restrictive & Liberal Red Cell Transfusion Strategies in Adult Patients Reconciling Clinical Data with Best Practice Austrian Society for Blood Transfusion and Regenerative Medicine ÖGBT Klagenfurt - May 2015 Marek Mirski MD, PhD Thomas & Dorothy Tung Professor Chief Neuroanesthesiology [ ] Director Neurosciences Critical Care Units [ ] Professor Anesthesiology, Neurology, Neurosurgery Johns Hopkins Medicine

2 Disclosures - No Industry Conflicts I am very satisfied after a wonderful luncheon I am very happy to be here with my International Clinical & Scientific Colleagues

3 Restrictive Transfusion Guideline There is general agreement that RBC transfusion is typically not indicated for hemoglobin (Hb) levels of > 10 g/dl and that transfusion of RBCs should be considered when Hb is < 7 to 8 g/dl depending on patient characteristics. The decision to transfuse RBCs should be based on a clinical assessment of the patient that weighs the risks associated with transfusion against the anticipated benefit. American Association of Blood Banks (AABB)

4 Restrictive Transfusion Guideline There is general agreement that RBC transfusion is typically not indicated for hemoglobin (Hb) levels of > 10 g/dl and that transfusion of RBCs should be considered when Hb is < 7 to 8 g/dl depending on patient characteristics. The decision to transfuse RBCs should be based on a clinical assessment of the patient that weighs the risks associated with transfusion against the anticipated benefit. American Association of Blood Banks (AABB)

5 Blood Transfusion Issues - More Than Simply Hgb Neuro Physiological Benefits? - Cerebral & spinal cord O 2 delivery - Diminished ischemia - Improved neurological outcomes Define Stable Patient? - Small hemorrhage? - Coagulopathy? Cardiac Benefits? - Coronary O 2 delivery - Diminished ischemia - Stable post-op? Neuro-functional Outcome? - Post-op geriatric - Acute rehabilitation Transfusion Risks? - Multiple organ dysfunction/failure (MOD/F) - Increased infection risk - Increased mortality

6 -The 2nd Austrian Benchmark Study: Blood Use in Elective Surgery - Results and Practice Change Since 2007 Nadir Hb in patients who received transfusions (denoted by TX ) and those who did not (denoted by non TX ). In THR and TKR, the second study showed higher nadir Hb in patients who received transfusions and lower values in patients who did not receive transfusions. In CABG, all patients presented with lower nadir Hb in the second study. ( ) First study; ( ) second study. Discussion: Larger lost RBC volume, lower preoperative and postoperative nadir Hb levels, and female sex were the main independent predictors of transfusion. The multivariate models generally had high predictive values, accounting for more than 70% of the variation in transfusion rates. Likewise, independent significant predictors of the higher relative volume of transfused RBCs included higher relative lost RBC volume, lower preoperative and postoperative nadir Hb, and female sex when all procedures were considered. Gombotz H, Rehak PH, Shander A, Hofmann A. Transfusion 2014;54,

7 Murphy et. al. Crit Care Med 2013;41, RBC Transfusion - Results and Practice Change

8 - EVIDENCE BASED MEDICINE Era of Databases & Correlations Be Careful What & HowYou Read The Literature! Since > 450 PubMed articles on Restrictive Transfusion

9 - Efficacy of Transfused RBC - Important RBC storage lesion - depletion of 2,3 diphosphoglycerate (DPG) Level is inversely proportional to the affinity of hemoglobin for oxygen 1 Left-shifting the Hb disassociation curve may theoretically impair tissue delivery of oxygen Ample clinical data - correction of anemia in both stable and critically ill patients provides an acute increase in oxygen delivery and functional organ tissue benefit following RBC transfusion 2,3 This effect also appears independent of the storage duration of the transfused red cells 2-4. It has been demonstrated that Hb oxygen affinity is affected also by temperature, ph, and base excess, and it is the local in vivo environment with respect to these variables that may reduce the impact of the decreased 2,3-DPG Chaplin H Jr, et. al. Current status of red-cell preservation and availability in relation to the developing national blood policy. N Engl J Med. 1974;291(2): Weiskopf RB, et. al. Fresh blood and aged stored blood are equally efficacious in immediately reversing anemia-induced brain oxygenation deficits in humans. Anesthesiology 2006;104(5): Walsh T, et. al. Does the storage time of transfused red blood cells influence regional or global indexes of tissue oxygenation in anemic critically ill patients? Crit Care Med 2004; 32(2): Roberson RS, et. al. Impact of transfusion of autologous 7- versus 42-day-old AS-3 red blood cells on tissue oxygenation and the microcirculation in healthy volunteers. Trans 2012;52(11):

10 - Efficacy of Transfused RBC Recent (<10 days) vs. Old Blood (>21 days) Between-Group Differences in 7-Day Change in MODS. Steiner ME et al. Effects of Red-Cell Storage Duration on Patients Undergoing Cardiac Surgery. N Eng J Med 2015;372:

11 - Efficacy of Transfused RBC - Primary and Secondary Outcomes. Conclusions The duration of red-cell storage was not associated with significant differences in the change in MODS. We did not find that the transfusion of red cells stored for 10 days or less was superior to the transfusion of red cells stored for 21 days or more among patients 12 years of age or older who were undergoing complex cardiac surgery Steiner ME et al. Effects of Red-Cell Storage Duration on Patients Undergoing Cardiac SurgeryN Engl J Med 2015;372:

12 To the OR & ICU patient at the bedside different clinical settings: i. Stable ICU ii. Post-operative iii. Recenthemorrhage iv. Under-resuscitated v. Ongoing hemorrhage vi. Patient with severe organ dysfunction vii. Patient with ischemia Strong emphasis that Restrictive Transfusion Practice is Beneficial Liberal Transfusion is Thereby Harmful

13 - Transfusion in Critical Care Anemia & Cardiac Disease Retrospective: 4,470 critically ill patients Patients who died in ICU: lower hemoglobin Patients w/ anemia, APACHE II score > 20, and a cardiac diagnosis - significantly lower mortality rate following 1-6 PRBC 55% - no transfusions 32-35% - 1 to 6 units Increasing Hgb in anemic cardiac patients - improved survival (OR = 0.80 for each 10 g/l increase, p = 0.012) Conclusion: anemia increases the risk of death in critically ill patients with cardiac disease. Blood transfusions appear to decrease this risk Hébert PC, et. al. Does transfusion practice affect mortality in critically ill patients? Transfusion Requirements in Critical Care (TRICC) Investigators and the Canadian Critical Care Trials Group. Am J Respir Crit Care Med May;155(5):

14 - Liberal vs Restrictive Transfusion in Surgery - Anemia in Critical Illness vs Perioperative Period TRICC Trial critically ill patients Restrictive group: transfusion for Hgb <7 Liberal group: transfusion for Hgb <10 Primary Outcome: 30-day mortality 30-day mortality was no different Hospital mortality less (p=0.05) 60-day mortality: no difference ICU mortality: no difference Restrictive mortality less, only if Arbitrary Sub-group analysis: < 55 yrs, APACHE <20 & no cardiac disease Alternative Conclusion: Conclusion: A restrictive No strategy difference of red-cell amongst transfusion treatmentis groups. at least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients, with the possible exception of patients with acute myocardial infarction and unstable angina. Hébert PC, et. al. Multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med Feb 11;340(6):409-17

15 Table 1. Large Prospective Randomized Clinical Trials on Transfusion Triggers Clinical Trial Patient Population Restrictive Strategy (Hb Trigger -Target) Liberal Strategy (Hb Trigger -Target) Reduction in Blood Utilization Primary Outcome Event Restrictive (Incidence) Liberal (Incidence) P Hebert, et al, (n=838) Critically ill (adults) 7 to 8.5 g/dl 10 to 10.7 g/dl 54% less RBC units transfused 30-day mortality 18.7% 23.3% 0.11 Composite endpoint 11% 10% 0.85 Hajjar, et al, Cardiac 58% less RBC 8 to 9.1 g/dl surgery 10 to 10.5 g/dl units (n=502) (Adults) transfused 30-day mortality Cardiogenic Shock ARDS Acute renal injury requiring dialysis 6% 9% 2% 4% 5% 6% 1% 5% Carson, et al (n=2,016) Femur fracture (Elderly adults) 8.0 to 9.5 g/dl 10.0 to 11.0 g/dl 65% less RBC units transfused Composite endpoint 60-day mortality 60-day Inability to walk 34.7% 28.1% 6.6% 35.2% 27.6% 7.6% NS NS NS Villanueva, et al, (n=921) Gastrointestin al bleeding (Adults) 7 to 9.2 g/dl 9 to 10.1 g/dl 59% less RBC units transfused 45-day all-cause mortality 5% 9% 0.02 Mirski MA, Frank SM, Kor DJ, Holmes DR Jr. The Spectrum of Restrictive and Liberal Red Cell Transfusion Strategies in Adult Patients Reconciling Clinical Data with Best Practice. Critical Care 2015;19:

16 - Correlation Between Transfusion & Adverse Effects - Data emanate - observational datasets Linked RBC transfusion with the risk for suppressive immunomodulation nosocomial infections ischemic complications acute kidney injury amongst others Important! Trials on restrictive transfusion - documented the relative tolerance of lower hemoglobin levels in discrete patient cohorts Very same studies have largely failed to show actual physiological benefit over more liberal RBC transfusion practices. Aggregate of observational data do raise concern regarding these potential associations Pervasive risk for uncontrolled or unmeasured bias and confounding errors of analysis Observations may drive clinical impressions and protocols, but research by association must be interpreted with great caution In many cases, transfusion as a specific intervention merely serves as a marker for increased disease complexity.

17 - Transfusion in Critical Care - Anemia & Trauma Patients Review of 203 trauma patients in TRICC Trial: Primary endpoint: 30-day mortality No Difference Liberal vs Restrictive Also No - Increase MOD Change ICU or hospital LOS 30 or 60-day mortality No difference in infection rates

18 Table 2. Strength of Association Between Red Cell Transfusion and Purported Clinical Adverse Effects Adverse Effect Multi-System Organ Dysfunction Nosocomial Infection Allergic or Immuno-modulation, Tumor Promotion Showing Correlating Effect Highest Level Clinical Studies Ref Observational Studies 10,11 Observational & Retrospective Studies Observational & Retrospective Studies 10, Pulmonary Edema Level I RCT 1, 6 Pulmonary [Non-Edema] incl. ARDS Acute Kidney Injury Myocardial Ischemia Cerebral Ischemia Shock Cardiac Arrest Bleeding/Coagulopathy Observational Studies 10, 16 Observational & Retrospective Studies 17, 18 Prospective Cohort 19, 20 Observational & Retrospective Studies 9, 19, 21 Observational Study 10 Prospective Cohorts 19, 20 Observational Study 10 Highest Level Study Reflects the rank order of scientific merit typically afforded to studies based on trial design. Highest to lowest: Prospective, randomized, clinical trial (RCT), Prospective subset analyses of randomized studies, Non-randomized Controlled Trials, Observational Case Series including prospective and retrospective cohort analysis, and consecutive and non-consecutive case series. ARDS acute respiratory distress syndrome. Mirski MA, Frank SM, Kor DJ, Holmes DR Jr. The Spectrum of Restrictive and Liberal Red Cell Transfusion Strategies in Adult Patients Reconciling Clinical Data with Best Practice. Crit Care 2015;19:

19 Table 2. Strength of Association Between Red Cell Transfusion and Purported Clinical Adverse Effects Adverse Effect Multi-System Organ Dysfunction Nosocomial Infection Allergic or Immuno-modulation, Tumor Promotion Showing Correlating Effect Highest Level Clinical Studies Ref Showing No Correlation Ref Observational Studies 10,11 Level I RCT 1 Observational & Retrospective Studies Observational & Retrospective Studies 10, 12 Level I RCT (2), RCT (1), RCT Meta-Analysis 2, 3, 6, Level I RCT (2) 6 Pulmonary Edema Level I RCT 1, 6 Level I RCT (3), RCT Meta-Analysis 3, 5, 6, 8 Pulmonary [Non-Edema] incl. ARDS Acute Kidney Injury Myocardial Ischemia Cerebral Ischemia Shock Cardiac Arrest Bleeding/Coagulopathy Observational Studies 10, 16 Level I RCT (3), RCT (1) 2, 3, 5, 6 Observational & Retrospective Studies 17, 18 Level I RCT (2), RCT (1) 2, 3, 6 Prospective Cohort 19, 20 Level I RCT (4), RCT (1) 1-3, 5, 6 Observational & Retrospective Studies 9, 19, 21 Level I RCT (3), RCT (1), RCT Meta-Analysis 2, 3, 5, 6, 8 Observational Study 10 Level I RCT 1, 3 Prospective Cohorts 19, 20 Level I RCT 1, 3, 5 Observational Study 10 Level I RCT 3 Highest Level Study Reflects the rank order of scientific merit typically afforded to studies based on trial design. Highest to lowest: Prospective, randomized, clinical trial (RCT), Prospective subset analyses of randomized studies, Non-randomized Controlled Trials, Observational Case Series including prospective and retrospective cohort analysis, and consecutive and non-consecutive case series. ARDS acute respiratory distress syndrome. Mirski MA, Frank SM, Kor DJ, Holmes DR Jr. The Spectrum of Restrictive and Liberal Red Cell Transfusion Strategies in Adult Patients Reconciling Clinical Data with Best Practice Crit Care 2015;19:

20 From: Red Blood Cell Transfusion: A Clinical Practice Guideline From the AABB* Ann Intern Med. 2012;157(1): doi: / Adverse effects of RBC transfusion contrasted with other risks. Risk is depicted on a logarithmic scale. Shaded bars represent the risk per RBC unit transfused, and unshaded bars represent the risk for fatality per person per year for various life events.

21 - RBC Transfusion - Peri-operative & Critical Care Anemia & Consequence in: Cardiac Disease Neurological Injury Peri-Operative Resuscitation Post-Operative Rehabilitation & Recovery

22 - RBC Transfusion - Cardiac Disease

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24 - RBC Transfusion - Cardiac Disease Hemoglobin as Fixed Variable Not Transfusion Corresponding Ischemia Rates: 39.1% % % %

25 - Transfusion & TBI - 76 Patients in TRICC Trial Restrictive (Hgb 7-9) vs Liberal (10-12) Results - 30-day all-cause mortality rates: Restrictive group - 17% Liberal group - 13% No change MOF Same ICU & hospital LOS Conclusion: We were unable to detect significant improvements in mortality with a liberal as compared to restrictive transfusion strategy in critically ill trauma victims with moderate to severe head injury. McIntyre LA, Fergusson DA, Hutchison JS, Pagliarello G, Marshall JC, Yetisir E, Hare GM, Hébert PC. Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury. Neurocrit Care. 2006;5(1):4-9.

26 - Transfusion & TBI patients Restrictive (Hgb > 7) vs Liberal (>10) With or without EPO Results - 6- month neuro outcome scores: No difference between all 4 groups Range Hgb 9-12 both groups. Increase thrombotic risk in Hbg >10 Group

27 - Transfusion & TBI -

28 - Hemoglobin & SAH Cerebral Metabolism 20 SAH patients retrospective study Monitoring ICP, PbtO 2, microdialysis Hgb < 9g/dL correlated with: Lower PbtO 2 [19.9 vs 27.2] (p=0.02) Increased LPR: 36 vs 29 (p=0.16) Increased brain hypoxia: 52% vs 21% (p<0.01) Conclusion: A Hgb concentration <9 g/dl is associated with an increased incidence of brain hypoxia and cell energy dysfunction in patients with poor-grade subarachnoid hemorrhage. Oddo M, et. al. Hemoglobin Concentration and Cerebral Metabolism in Patients With Aneurysmal Subarachnoid Hemorrhage. Stroke 2009;40:

29 - Transfusion Following SAH 103 SAH patients; logistic regression Higher Hgb correlated with - Improved overall outcome (MRS) at 14d & 3 mo Reduced angiographic vasospasm Reduced risk of vasospasm induced infarction Conclusion: We found that SAH patients with higher initial and mean Hgb values had improved outcomes. Higher Hgb in SAH patients may be beneficial.and may warrant further study Naidech AM, et. al. Higher hemoglobin is associated with less cerebral infarction, poor outcome, and death after subarachnoid hemorrhage. Neurosurgery Oct;59(4): Naidech AM, et. al. Higher hemoglobin is associated with improved outcome after subarachnoid hemorrhage. Crit Care Med Oct;35(10):

30 - Transfusion Following ICH - Five hundred forty-six consecutive subjects were identified from an ongoing single-center, prospective cohort study of non-traumatic ICH over a 6-year period. Anemia of 546 patients (26%) on admission PRBC transfusion patients (18%) during 1 st 5 day Univariate 30-day mortality [anemia, age, glucose, anticoagulation, GCS, hematoma volume, hematoma location, IVH, and DNR] : transfusion improved survival at 30 days (odds ratio: 2.76; 95%, ; P =.002) Conclusion: PRBC transfusion was associated with improved outcome in these patients.

31 RBC Transfusion During Active Hemorrhage Death was due to unsuccessfully controlled bleeding in 3 patients (0.7%) in the restrictive-strategy group and in 14 patients (3.1%) in the liberal-strategy group (P=0.01). Villanueva C et al. N Engl J Med 2013;368:11-21.

32 Effects of Intravenous Fluid Restriction on Postoperative Complications Brandstrup B, et. al., Danish Study Group on Perioperative Fluid Therapy. OBJECTIVE: To investigate the effect of a restricted intravenous fluid regimen versus a standard regimen on complications after colorectal resection. SUMMARY BACKGROUND DATA: Associations between postoperative weight gain and poor survival as well as fluid overload and complications have been shown. METHODS: We did a randomized observer-blinded multicenter trial. After informed consent was obtained, 172 patients were allocated to either a restricted or a standard intraoperative and postoperative intravenous fluid regimen. The restricted regimen aimed at maintaining preoperative body weight; the standard regimen resembled everyday practice. The primary outcome measures were complications; the secondary measures were death and adverse effects. RESULTS: The restricted intravenous fluid regimen significantly reduced postoperative complications both by intention-to-treat (33% versus 51%, P = 0.013) and per-protocol (30% versus 56%, P = 0.003) analyses. The numbers of both cardiopulmonary (7% versus 24%, P = 0.007) and tissue-healing complications (16% versus 31%, P = 0.04) were significantly reduced. No patients died in the restricted group compared with 4 deaths in the standard group (0% versus 4.7%, P = 0.12). No harmful adverse effects were observed. CONCLUSION: The restricted perioperative intravenous fluid regimen aiming at unchanged body weight reduces complications after elective colorectal resection

33 Independent risk factor poor outcome - Anemia in the Elderly - increased mortality, functional dependence, impaired cognition, re-admission to the hospital, and falls 1-3 Prospective study (1,156 patients >65 yr-old) - evaluated in 6 basic and 8 instrumental activities of daily living (IADLs): Anemia (Hb<12.0 g/dl) - poorer performance and strength 4. Following orthopedic surgery - functional rehabilitation & recovery are impaired and the duration of rehabilitation prolonged in patients with anemia (Hb < 10 g/dl) 5 Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) trial - liberal transfusion strategy offered no benefit in terms of reducing mortality or the ability to ambulate (10 feet or across the room) without assistance 6. Primary functional outcome of walking (using the investigators criteria) may not, however, be a robust test of endurance. 1. Balducci L. Anemia, fatigue and aging. Transfus Clin Biol 2010;17(5-6): Terekeci HM, et. al. Relationship between anaemia and cognitive functions in elderly people. Eur J Intern Med 2010;21(2): Chaves PH, et al. What constitutes normal hemoglobin concentration in community dwelling disabled older women?j Am Ger Soc 2004;52(11): Penninx BW, et. al. Anemia is associated with disability and decreased physical performance and muscle strength in the elderly. J Am Geriatr Soc 2004;52(6): Foss NB, et. al. Anaemia impedes functional mobility after hip fracture surgery. Age Ageing 2008;37(2): Carson JL,et. al. FOCUS Investigators. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med 2011;365(26):

34 - Anemia in the Elderly - Liberal versus restrictive blood transfusion strategy: 3-year survival and cause of death results from the FOCUS randomized controlled trial. Figure 2 Long-term survival with liberal versus restrictive transfusion strategies Jeffrey L Carson, et. al. Liberal versus restrictive blood transfusion strategy: 3-year survival and cause of death results from the FOCUS randomised controlled trial. The Lancet, Volume 385, Issue 9974, 2015,

35 - Research Initiatives - At an academic level, a multidisciplinary think tank from the US National Heart, Lung, and Blood Institute (NHLBI) convened in 2011 and agreed to 10 transfusionrelated concepts deemed most important to examine in the near term and included among them were multiple trials evaluating RBC transfusion trigger strategies to improve overall outcome. Specific recommendations included the need for three adult trials designed to validate the following primary hypotheses: Higher Hb levels resulting from a liberal transfusion strategy during cardiopulmonary bypass surgery will lead to lower incidence of 30-day all-cause mortality; In patients with acute coronary syndrome or coronary artery disease undergoing cardiac catheterization, a liberal transfusion strategy will be associated with a lower incidence of composite outcome of all-cause mortality at 30 days; In hemodynamically stable patients in the ICU, with a history of ischemic heart disease, multiple organ dysfunction scores will be improved by maintaining the hemoglobin greater than 10 g/dl.

36 AABB Clinical Guideline - Restrictive transfusion strategy (7-8 g/dl) in hospitalized, stable patients. No recommendation during active hemorrhage No recommendation during peri-operative period No recommendation - for or against a liberal or restrictive transfusion strategy for hospitalized patients with acute coronary syndrome or neurological patients.

37 Summary Restrictive therapy - tolerated in low complexity ICU or nonhemorrhagic surgical patients Liberal therapy not worse than restrictive by trial evidence Optimal homeostasis Suggest Hgb higher ( ) when risk ischemia for Cardiac & Neuro Balance between blood product & crystalloid Maintenance of adequate BP (perfusion) is equally vital

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41 - Transfusion Following TBI Cerebral Oxygenation 30 TBI patients; randomization to Hgb 8, 9, or 10 Each group transfused if Hgb < threshold Monitored brain ph, Pbto 2, L/P ratio Transfusion at each level increased Pbto 2 No change in L/R ration or brain ph Conclusion: Transfusion of packed red blood cells acutely results in improved brain tissue oxygen without appreciable effect on cerebral metabolism Zygun DA, Nortje J, Hutchinson PJ, Timofeev I, Menon DK, Gupta AK. The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury. Crit Care Med Mar;37(3):

42 - Transfusion Following SAH Increase in Brain Oxygen 8 SAH patients w/ O 15 PET, Tx 1 u PRBC Transfusion correlated with - 15% rise in Hgb 18% rise in DO 2 Global CBF unchanged Reduced O 2 extraction Conclusion: Transfusion of red blood cells to anemic patients with subarachnoid hemorrhage resulted in a significant rise in cerebral DO 2 without lowering global CBF. Dhar R, Zazulia AR, Videen TO, Zipfel GJ, Derdeyn CP, Diringer MN. Red blood cell transfusion increases cerebral oxygen delivery in anemic patients with subarachnoid hemorrhage. Stroke Sep;40(9): Epub 2009 Jul 23.

43 - Transfusion Following SAH 421 SAH patients; logistic regression Transfusion correlated with - Medical complications 46% in patients receiving PRBC 30% in non-prbc transfused patients Infections rate higher CNS & systemic Mechanical ventilation Reduced O 2 extraction But not mortality or outcome Conclusion: These data suggest that RBCTs are associated with medical complications after SAH. However, the data do not infer causation... Alternative Conclusion: PRBC - a marker for more complex patients. Levine J, Kofke A, Cen L, Chen Z, Faerber J, Elliott JP, Winn HR, Le Roux P. Red blood cell transfusion is associated with infection and extracerebral complications after subarachnoid hemorrhage. Neurosurgery Feb;66(2):312-8.