Storage Time and After Transfusion Survival Omar Alsuhaibani Transfusion Medicine Fellow Journal Club May 18 th, 2010 May 18 th, 2010

Objectives  Storage lesion & relative background information  Previous study quick review  Ongoing study (ABLE)  Article review  Critical appraisal  Discussion & questions

Background Storage lesion is an amalgamation of reversible and irreversible changes that begin after 2 to 3 weeks of storage

Background  Storage lesion - loss of deformability - loss of deformability - morphologic changes - morphologic changes - depletion of ATP & 2,3-DPG - depletion of ATP & 2,3-DPG  These changes decrease O2 transporting capacity & impair capillary passage

“storage lesion”

42-Day Post-storage pRBC Characteristics after Resususpension in AS Vox Sang 1998;75: CharacteristicPre-storagePost-storage pH ATP (μmol/g Hb) DPG (μmol /g Hb) Potassium (mEq/L) Glucose (mg/dl) Plasma Hb (mg/dl) Hemolysis (%)

The effect of red-cell age on outcomes  Inverse association between changes in gastric intramucosal pH and the age of transfused blood for patients who received red cells stored for more than 15 days  evidence of splanchnic ischemia developed in patients given older blood Marik PE,. Effect of stored blood transfusion on oxygen delivery in patients with sepsis. JAMA 1993 Marik PE,. Effect of stored blood transfusion on oxygen delivery in patients with sepsis. JAMA 1993

Background  Previous studies have found suggestive evidence of various adverse consequences; - increased mortality - increased mortality - increased LOS - increased LOS - infectious complications - infectious complications - thrombosis - thrombosis - multiorgan failure - multiorgan failure  However, studies were criticized being small and failed to control important sources of error  No large RCT of fresh vs stored RBCs has been completed

Koch and colleagues  patients given red-cell transfusions during coronary-artery bypass grafting, heart-valve surgery, or both  between June 30, 1998, and January 30,  2872 patients received 8802 units of blood that had been stored for 14 days or less (“newer blood”),  3130 patients received 10,782 units of blood that had been stored for more than 14 days (“older blood”).

Koch and colleagues  median duration of storage was 11 days for newer blood and 20 days for older blood.  patients who were given older units had higher rates of in-hospital mortality (2.8% vs. 1.7%, P = 0.004), intubation beyond 72 hours (9.7% vs. 5.6%, P<0.001), renal failure (2.7% vs. 1.6%, P = 0.003), and sepsis or septicemia (4.0% vs. 2.8%, P = 0.01).  complications were more common in patients given older blood (25.9% vs. 22.4%, P = 0.001).  older blood was associated with an increase in the risk- adjusted rate of the composite outcome (P = 0.03).  at 1 year, mortality was significantly less in patients given newer blood (7.4% vs. 11.0%, P<0.001).

Koch and colleagues “ In patients undergoing cardiac surgery, transfusion of red cells that had been stored for more than 2 weeks was associated with a significantly increased risk of postoperative complications as well as reduced short-term and long-term survival.’

Ongoing study  Age of BLood Evaluation (ABLE) trial in the resuscitation of critically ill patients  Double blind randomised parallel trial  The transfusion of fresh leuko-reduced red cells (stored for less than 8 days) will lead to a 5% or greater improvement in 90 day all cause mortality and clinically important decreases in morbidity in a vulnerable population of critically ill patients.

ABLE - Inclusion criteria Patients who: 1. Have had a request for a first red cell unit transfusion in the Intensive Care Unit (ICU), and 2. Have an anticipated length of invasive and/or non-invasive continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BIPAP) mechanical ventilation of at least 48 hours once enrolled, as estimated by the attending physician Patients who: 1. Have had a request for a first red cell unit transfusion in the Intensive Care Unit (ICU), and 2. Have an anticipated length of invasive and/or non-invasive continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BIPAP) mechanical ventilation of at least 48 hours once enrolled, as estimated by the attending physician

ABLE – exclusion criteria - less than 16 years of age - previously enrolled in the ABLE study - already been transfused with red cells during the current hospitalisation - obvious terminal illness documented in the medical record with a life expectancy of less than 3 months - undergone routine cardiac surgical care - a decision to withdraw/withhold some critical care had been made - obviously brain dead - no red cells with a storage time of 7 days or less available in the blood bank that cannot be transported from the blood supplier - require more than 1 unit of uncross-matched red cells - less than 16 years of age - previously enrolled in the ABLE study - already been transfused with red cells during the current hospitalisation - obvious terminal illness documented in the medical record with a life expectancy of less than 3 months - undergone routine cardiac surgical care - a decision to withdraw/withhold some critical care had been made - obviously brain dead - no red cells with a storage time of 7 days or less available in the blood bank that cannot be transported from the blood supplier - require more than 1 unit of uncross-matched red cells - a known objection to blood transfusions - autologous blood donations - difficulties in securing blood products (rare blood groups), and who are difficult to match - a known objection to blood transfusions - autologous blood donations - difficulties in securing blood products (rare blood groups), and who are difficult to match

ABLE  Primary outcome: 90-day all cause mortality. 90-day all cause mortality.  Secondary outcomes: 1. Other mortality rates and survival times as measured at ICU discharge, hospital discharge, 28 days and 6 months post-discharge 2. Number of cases of multiple organ dysfunction syndrome (MODS), highest number of organ failures per patient, MODS score and time to development of MODS as measured while in the ICU 3. Serious nosocomial infections including: 3.1. Nosocomial pneumonia 3.2. Deep tissue infections (e.g. peritonitis, mediastinitis) 3.3. Bacteraemia from organisms not considered normal skin flora and judged important enough to treat by the attending team, as measured while in the ICU 4. Adverse events and transfusion reactions as measured while in ICU 5. Length of stay (ICU and hospital) 6. Length of time requiring respiratory, haemodynamic and renal support as measured while in ICU 1. Other mortality rates and survival times as measured at ICU discharge, hospital discharge, 28 days and 6 months post-discharge 2. Number of cases of multiple organ dysfunction syndrome (MODS), highest number of organ failures per patient, MODS score and time to development of MODS as measured while in the ICU 3. Serious nosocomial infections including: 3.1. Nosocomial pneumonia 3.2. Deep tissue infections (e.g. peritonitis, mediastinitis) 3.3. Bacteraemia from organisms not considered normal skin flora and judged important enough to treat by the attending team, as measured while in the ICU 4. Adverse events and transfusion reactions as measured while in ICU 5. Length of stay (ICU and hospital) 6. Length of time requiring respiratory, haemodynamic and renal support as measured while in ICU

Is Is like ?! like ?!

Study design & methods  a large, retrospective cohort study using a population-based database of blood transfusion recipients  all recipients of at least one RBC transfusion in Sweden and Denmark between 1995 and 2002, as recorded in the Scandinavian Donations and Transfusions (SCANDAT) database.

Study design & methods  Component production and transfusion practice follow very similar national guidelines  Maximum storage time for RBCs in SAGM solution has been 42 days in Sweden and 35 days in Denmark  Units that were leuko-reduced through filtering or other means were used to a varying but generally increasing extent throughout the entire study period

Study design & methods  Swedish and Danish databases were merged to form the Scandinavian Donations and Transfusions (SCANDAT) database  The investigation was limited to patients aged 15 to 90 years with known blood type, who had not received any transfusions in the 2 years preceding the index transfusion  Transfusions were grouped into episodes containing an exposure period and a follow-up period, both of which were varied to assess short- and long-term survival in relation to RBC storage time.

Study design & methods Exclusions : Exclusions :  autologous units  ABO-nonidentical units  units from unknown donors  units of unknown storage time that were transfused during the exposure period

Study design & methods  Short-term survival was assessed using a 1-day exposure period and an overlapping 7-day follow-up period (i.e., from Day 1 through Day 7)  Long-term survival was assessed using a 7-day exposure period with follow-up from Day 8 through Day 730 (i.e., 2 years).  Follow-up was terminated upon death, emigration, or end of registration in the SCANDAT database (December 31,2002)

Study design & methods  exposure categories were 0-9, 10-19, , or days old  mixed category, with recipients of multiple units that fell into more than one age class  freshly prepared units used for special indications e.g. when units are prepared for patients with irregular RBC antibodies, recipients of 10- to 19-day-old units were used as the reference group

Statistical Analysis   The relative risks of death, expressed as hazard ratios, were estimated using Cox proportional hazards regression   Six indication groups were established according to a sequential algorithm: 1) trauma 2) nontrauma, cardiovascular surgery; 3) nontrauma, noncardiovascular surgery for malignant Disease 4) nontrauma, noncardiovascular, nonmalignancy, major surgery 5) other care for hematologic malignancy 6) other hospital care.

Statistical Analysis   All variables were treated as categorical except age, calendar period, and number of RBC transfusions   Possible statistical interactions between the main exposure and country, sex, age, calendar time, and number of transfusions were explored with likelihood ratio tests   All p values were two-sided.

Statistical Analysis   The proportional hazards assumption was evaluated using Schoenfeld residuals from the main models   All statistical analyses were conducted using computer software   Since some patients experienced more than one transfusion episode, robust variance estimates were used

Results  After various exclusions, 404,959 transfusion episodes remained for analysis.  The 7-day risk of death was similar in all exposure groups,  a tendency for a higher risk emerged among recipients of blood stored for 30 to 42 days (hazard ratio, 1.05; 95% confidence interval [CI], ), compared to recipients of blood stored for 10 to 19 days.  With 2-year follow-up, this excess remained at the same level (hazard ratio, 1.05; 95% CI, ).  No dose response pattern was revealed and no differential effect was seen when the analyses were restricted to recipients of leuko-reduced units only.

Conclusions  This large study showed a 5% excess mortality confined exclusively to recipients of RBCs stored for 30 days or more.  The observed excess in this group, which remained constant across follow-up but attained significance only in the long-term follow-up, seemed more compatible with a higher baseline risk among the recipients of the very oldest units than with an actual deleterious effect of the old units per se.

Conclusions  Confounding may have inflated any true effect of older RBCs, and the true effect, if any, in the combined Swedish and Danish transfusion recipient population is likely to be less than what was observed in this investigation  The excess seems more compatible with recently published review articles that have concluded that the evidence supporting an association between longer storage and adverse clinical outcomes is scarce.

Critical Appraisal  Study design  Follow-up  Very large sample  A key strength of this study is the unbiased exposure and outcome ascertainment  Study by definition was retrospective but all data were collected prospectively

Critical Appraisal  The confidence in causal inference based on observational study results is limited, despite tight adjustments for the majority of previously implicated confounding factors  Therefore, we need more convincing evidence RCTs

Critical Appraisal  Great impact on the cost of blood production  Finally, would the results of this study change my transfusion practice?

Thank you