Storage Time and Storage Time and After Transfusion After Transfusion

SurvivalSurvival

Omar AlsuhaibaniOmar AlsuhaibaniTransfusion Medicine FellowTransfusion Medicine Fellow

Journal ClubJournal Club May 18May 18thth, 2010, 2010

ObjectivesObjectives

Storage lesion & relative background Storage lesion & relative background informationinformation

Previous study quick reviewPrevious study quick review Ongoing study (ABLE)Ongoing study (ABLE) Article reviewArticle review Critical appraisalCritical appraisal Discussion & questions Discussion & questions

BackgroundBackground

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

BackgroundBackground

Storage lesionStorage 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 These changes decrease O2 transporting

capacity & impair capillary passagecapacity & impair capillary passage

““storage lesion”storage lesion”

““storage lesion”storage lesion”

42-Day Post-storage pRBC Characteristics after 42-Day Post-storage pRBC Characteristics after Resususpension in ASResususpension in AS

Vox Sang 1998;75:212-217Vox Sang 1998;75:212-217

CharacteristicCharacteristic Pre-storagePre-storage Post-storagePost-storage

pHpH 6.86.8 6.46.4

ATP (μmol/g Hb)ATP (μmol/g Hb) 4.14.1 2.92.9

DPG (μmol /g Hb)DPG (μmol /g Hb) 9.09.0 0.30.3

Potassium (mEq/L)Potassium (mEq/L) 2.42.4 6363

Glucose (mg/dl)Glucose (mg/dl) 608608 402402

Plasma Hb (mg/dl)Plasma Hb (mg/dl) 3939 372372

Hemolysis (%)Hemolysis (%) ---- 0.610.61

The effect of red-cell age on The effect of red-cell age on outcomesoutcomes

Inverse association between changes in Inverse association between changes in gastric intramucosal pH and the age of gastric intramucosal pH and the age of transfused blood for patients who received transfused blood for patients who received red cells stored for more than 15 daysred cells stored for more than 15 days

evidence of splanchnic ischemia evidence of splanchnic ischemia developed in patients given older blooddeveloped in patients given older blood

Marik PE,. Effect of stored blood transfusion on oxygen delivery in patients with sepsis. JAMA 1993Marik PE,. Effect of stored blood transfusion on oxygen delivery in patients with sepsis. JAMA 1993

Background Background Previous studies have found suggestive evidence of Previous studies have found suggestive evidence of

various adverse consequences;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 However, studies were criticized being small and failed

to control important sources of errorto control important sources of error No large RCT of fresh vs stored RBCs has been No large RCT of fresh vs stored RBCs has been

completed completed

Koch and colleagues - 2008 Koch and colleagues - 2008

patients given red-cell transfusions during patients given red-cell transfusions during coronary-artery bypass grafting, heart-valve coronary-artery bypass grafting, heart-valve surgery, or bothsurgery, or both

between June 30, 1998, and January 30, 2006.between June 30, 1998, and January 30, 2006. 2872 patients received 8802 units of blood that 2872 patients received 8802 units of blood that

had been stored for 14 days or less (“newer had been stored for 14 days or less (“newer blood”),blood”),

3130 patients received 10,782 units of blood that 3130 patients received 10,782 units of blood that had been stored for more than 14 days (“older had been stored for more than 14 days (“older blood”).blood”).

Koch and colleagues - 2008Koch and colleagues - 2008 median duration of storage was 11 days for newer blood median duration of storage was 11 days for newer blood

and 20 days for older blood.and 20 days for older blood. patients who were given older units had higher rates of patients who were given older units had higher rates of

in-hospital mortality (2.8% vs. 1.7%, P = 0.004), in-hospital mortality (2.8% vs. 1.7%, P = 0.004), intubation beyond 72 hours (9.7% vs. 5.6%, P<0.001), 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 renal failure (2.7% vs. 1.6%, P = 0.003), and sepsis or septicemia (4.0% vs. 2.8%, P = 0.01).septicemia (4.0% vs. 2.8%, P = 0.01).

complications were more common in patients given older complications were more common in patients given older blood (25.9% vs. 22.4%, P = 0.001). blood (25.9% vs. 22.4%, P = 0.001).

older blood was associated with an increase in the risk-older blood was associated with an increase in the risk-adjusted rate of the composite outcome (P = 0.03). adjusted rate of the composite outcome (P = 0.03).

at 1 year, mortality was significantly less in patients at 1 year, mortality was significantly less in patients given newer blood (7.4% vs. 11.0%, P<0.001).given newer blood (7.4% vs. 11.0%, P<0.001).

Koch and colleagues - 2008Koch and colleagues - 2008

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

Ongoing studyOngoing study

Age of BLood Evaluation (ABLE) trial in the Age of BLood Evaluation (ABLE) trial in the resuscitation of critically ill patients resuscitation of critically ill patients

Double blind randomised parallel trialDouble blind randomised parallel trial The transfusion of fresh leuko-reduced red cells The transfusion of fresh leuko-reduced red cells

(stored for less than 8 days) will lead to a 5% or (stored for less than 8 days) will lead to a 5% or greater improvement in 90 day all cause greater improvement in 90 day all cause mortality and clinically important decreases in mortality and clinically important decreases in morbidity in a vulnerable population of critically ill morbidity in a vulnerable population of critically ill patients. patients.

ABLE - Inclusion criteria ABLE - Inclusion criteria

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

ABLE – exclusion criteria ABLE – exclusion criteria - less than 16 years of age - less than 16 years of age

- previously enrolled in the ABLE study - previously enrolled in the ABLE study - already been transfused with red cells during the current - already been transfused with red cells during the current hospitalisation hospitalisation - obvious terminal illness documented in the medical record with a - obvious terminal illness documented in the medical record with a life expectancy of less than 3 months life expectancy of less than 3 months - undergone routine cardiac surgical care - undergone routine cardiac surgical care - a decision to withdraw/withhold some critical care had been made - a decision to withdraw/withhold some critical care had been made - obviously brain dead - obviously brain dead - no red cells with a storage time of 7 days or less available in the - 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 blood bank that cannot be transported from the blood supplier - require more than 1 unit of uncross-matched red cells - require more than 1 unit of uncross-matched red cells

- a known objection to blood transfusions - a known objection to blood transfusions - autologous blood donations - autologous blood donations - difficulties in securing blood products (rare blood groups), and who - difficulties in securing blood products (rare blood groups), and who are difficult to match are difficult to match

ABLEABLE Primary outcome:Primary outcome: 90-day all cause mortality. 90-day all cause mortality. Secondary outcomes:Secondary outcomes: 1. Other mortality rates and survival times as measured at ICU 1. Other mortality rates and survival times as measured at ICU

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

IsIs

likelike ?! ?!

Study design & methodsStudy design & methods

a large, retrospective cohort study using a a large, retrospective cohort study using a population-based database of blood population-based database of blood transfusion recipientstransfusion recipients

all recipients of at least one RBC all recipients of at least one RBC transfusion in Sweden and Denmark transfusion in Sweden and Denmark between 1995 and 2002, as recorded in between 1995 and 2002, as recorded in the Scandinavian Donations and the Scandinavian Donations and Transfusions (SCANDAT) database.Transfusions (SCANDAT) database.

Study design & methodsStudy design & methods

Component production and transfusion practice Component production and transfusion practice follow very similar national guidelinesfollow very similar national guidelines

Maximum storage time for RBCs in SAGM Maximum storage time for RBCs in SAGM solution has been 42 days in Sweden and 35 solution has been 42 days in Sweden and 35 days in Denmarkdays in Denmark

Units that were leuko-reduced through filtering or Units that were leuko-reduced through filtering or other means were used to a varying but other means were used to a varying but generally increasing extent throughout the entire generally increasing extent throughout the entire study periodstudy period

Study design & methodsStudy design & methods Swedish and Danish databases were merged to Swedish and Danish databases were merged to

form the Scandinavian Donations and form the Scandinavian Donations and Transfusions (SCANDAT) databaseTransfusions (SCANDAT) database

The investigation was limited to patients aged 15 The investigation was limited to patients aged 15 to 90 years with known blood type, who had not to 90 years with known blood type, who had not received any transfusions in the 2 years received any transfusions in the 2 years preceding the index transfusionpreceding the index transfusion

Transfusions were grouped into episodes Transfusions were grouped into episodes containing an exposure period and a follow-up containing an exposure period and a follow-up period, both of which were varied to assess period, both of which were varied to assess short- and long-term survival in relation to RBC short- and long-term survival in relation to RBC storage time.storage time.

Study design & methodsStudy design & methods

Exclusions :Exclusions : autologous unitsautologous units ABO-nonidentical unitsABO-nonidentical units units from unknown donorsunits from unknown donors units of unknown storage time that were units of unknown storage time that were

transfused during the exposure periodtransfused during the exposure period

Study design & methodsStudy design & methods

Short-term survival was assessed using a 1-day Short-term survival was assessed using a 1-day exposure period and an overlapping 7-day exposure period and an overlapping 7-day follow-up period (i.e., from Day 1 through Day 7)follow-up period (i.e., from Day 1 through Day 7)

Long-term survival was assessed using a 7-day Long-term survival was assessed using a 7-day exposure period with follow-up from Day 8 exposure period with follow-up from Day 8 through Day 730 (i.e., 2 years). through Day 730 (i.e., 2 years).

Follow-up was terminated upon death, Follow-up was terminated upon death, emigration, or end of registration in the emigration, or end of registration in the SCANDAT database (December 31,2002)SCANDAT database (December 31,2002)

Study design & methodsStudy design & methods

exposure categories were 0-9, 10-19, 20-exposure categories were 0-9, 10-19, 20-29, or 30-42 days old29, or 30-42 days old

mixed category, with recipients of multiple mixed category, with recipients of multiple units that fell into more than one age classunits that fell into more than one age class

freshly prepared units used for special freshly prepared units used for special indications e.g. when units are prepared indications e.g. when units are prepared for patients with irregular RBC antibodies, for patients with irregular RBC antibodies, recipients of 10- to 19-day-old units were recipients of 10- to 19-day-old units were used as the reference groupused as the reference group

Statistical AnalysisStatistical 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 AnalysisStatistical 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 AnalysisStatistical 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 Results After various exclusions, 404,959 transfusion episodes After various exclusions, 404,959 transfusion episodes

remained for analysis.remained for analysis. The 7-day risk of death was similar in all exposure The 7-day risk of death was similar in all exposure

groups, groups, a tendency for a higher risk emerged among recipients a tendency for a higher risk emerged among recipients

of blood stored for 30 to 42 days (hazard ratio, 1.05; of blood stored for 30 to 42 days (hazard ratio, 1.05; 95% confidence interval [CI], 0.97-1.12), compared to 95% confidence interval [CI], 0.97-1.12), compared to recipients of blood stored for 10 to 19 days. recipients of blood stored for 10 to 19 days.

With 2-year follow-up, this excess remained at the same With 2-year follow-up, this excess remained at the same level (hazard ratio, 1.05; 95% CI, 1.02-1.08).level (hazard ratio, 1.05; 95% CI, 1.02-1.08).

No dose response pattern was revealed and no No dose response pattern was revealed and no differential effect was seen when the analyses were differential effect was seen when the analyses were restricted to recipients of leuko-reduced units only.restricted to recipients of leuko-reduced units only.

ConclusionsConclusions

This large study showed a 5% excess mortality This large study showed a 5% excess mortality confined exclusively to recipients of RBCs stored confined exclusively to recipients of RBCs stored for 30 days or more.for 30 days or more.

The observed excess in this group, which The observed excess in this group, which remained constant across follow-up but attained remained constant across follow-up but attained significance only in the long-term follow-up, significance only in the long-term follow-up, seemed more compatible with a higher baseline seemed more compatible with a higher baseline risk among the recipients of the very oldest units risk among the recipients of the very oldest units than with an actual deleterious effect of the old than with an actual deleterious effect of the old units per se.units per se.

ConclusionsConclusions

Confounding may have inflated any true effect of Confounding may have inflated any true effect of older RBCs, and the true effect, if any, in the older RBCs, and the true effect, if any, in the combined Swedish and Danish transfusion combined Swedish and Danish transfusion recipient population is likely to be less than what recipient population is likely to be less than what was observed in this investigationwas observed in this investigation

The excess seems more compatible with The excess seems more compatible with recently published review articles that have recently published review articles that have concluded that the evidence supporting an concluded that the evidence supporting an association between longer storage and adverse association between longer storage and adverse clinical outcomes is scarce.clinical outcomes is scarce.

Critical AppraisalCritical Appraisal

Study designStudy design Follow-up Follow-up Very large sampleVery large sample A key strength of this study is the A key strength of this study is the

unbiased exposure and outcome unbiased exposure and outcome ascertainmentascertainment

Study by definition was retrospective but Study by definition was retrospective but all data were collected prospectively all data were collected prospectively

Critical AppraisalCritical Appraisal

The confidence in causal inference based The confidence in causal inference based on observational study results is limited, on observational study results is limited, despite tight adjustments for the majority despite tight adjustments for the majority of previously implicated confounding of previously implicated confounding factorsfactors

Therefore, we need more convincing Therefore, we need more convincing evidence RCTsevidence RCTs

Critical AppraisalCritical Appraisal

Great impact on the cost of blood Great impact on the cost of blood productionproduction

Finally , would the results of this study Finally , would the results of this study change my transfusion practice?change my transfusion practice?

Thank youThank you