Methods

Design: Parallel group RCT

Country: The Netherlands

Multicentre study: Yes (two university hospitals: Academic Medical Center and Leiden University Medical Center)

Setting: Hospital

Follow‐up: 90 days

Unit of allocation: Patients

Unit of analysis: Patients

Participants

Inclusion criteria: Adults > 18 years undergoing valve surgery

Exclusion criteria: Those with a medical indication for leukocyte‐depleted erythrocytes or who had received blood transfusions within the previous three months

Patients enrolled: 496

Patients randomised: 474

Buffy coat‐depleted packed cells: 237

Leukocyte‐depleted erythrocytes (LDs): 237

Patients transfused: not clearly reported

Patients considered for the analysis: 474

Main characteristics of patients:

Age: Buffy coat‐depleted packed cells group = 66.6 ± 12.5 years; LD group = 65.3 ± 14.7 years

Percentage of men: Buffy coat‐depleted packed cells group = 57%; LD group = 52%

Percentage of erythrocyte transfusions more or equal to four: Buffy coat‐depleted packed cells group= 55.3%; LD group= 61.2%

Storage time of the units: Buffy coat‐depleted packed cells group = 19.7 ± 5.4 ; LD group = 17.4 ± 5

Percentage of use of aprotinin: Buffy coat‐depleted packed cells group = 37.1; LD group = 36.3

Interventions

1. Experimental: Leukocyte‐depleted erythrocytes (LDs) (pre‐storage leukoreduction).

2. Control: Buffy coat–depleted packed cells (PCs).

Co‐intervention:

1. Quote: "Not all patients underwent induced hypothermia (29° to 33°C). In one hospital, aprotinin was used in some patients; this hospital had a medium‐care ward. Prophylactic antibiotics were given to all patients for 48 hours." (Page 2756).

2. Quote: "Platelet concentrates were prepared from pooled buffy coats and were all leukocyte‐depleted by filtration (< 1 x 10⁶ leukocytes per product) before storage".

Outcomes

Primary:

1. Mortality at 90 days after surgery.

Secondary:

1. Incidence of in‐hospital mortality.

2. Causes of death.

3. Incidence of multiple organ dysfunction syndrome.

4. Infections during the hospital stay.

5. Duration of ICU stay.

6. Hospitalization.

Quote: "An independent safety committee monitored the interim results of the primary end point." (Page 2757).

Notes

Trial registration: Not reported

Funding: This study was financially supported by the Netherlands Heart Foundation (grant 98.183) (Page 2760)

Rol of sponsor: Not reported

A priori sample size estimation: Yes

Conducted: Between June 1999 and May 2001

Declared conflicts of interest: Not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "a straightforward randomizations was performed by using a fixed block size (n=24) to ensure a balance between the randomizations groups" (Page 2756).

Allocation concealment (selection bias)

Low risk

Quote: "...the technicians randomly assigned the patients by opening a sealed and numbered envelope." "In the hospital electronic information system, a code was used during the study period to hide the random assignment" (Page 2756).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The patients, surgeons, anaesthesiologists, and the trial coordinators were blinded to the random assignment, as the technicians placed uniform study labels on the description on the erythrocyte bags" (Page 2756).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The patients, surgeons, anesthesiologists, and the trial coordinators were blinded to the random assignment, as the technicians placed uniform study labels on the description on the erythrocyte bags. In the hospital electronic information system, a code was used during the study period to hide the random assignment" (Page 2756).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Loss after transfusion: 0.4% (2/474)

Loss after transfusion in prestorage by filtration of LDs (LDs): 0.8% (2/237)

Loss after transfusion in Buffy coat–depleted packed cells (PCs): 0% (0/237)

Loss after transfusion. Imbalance between comparison groups: 0.8%

Selective reporting (reporting bias)

Low risk

Comment: The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).

Other bias

Low risk

The study appears to be free of other sources of bias.

Methods

Design: Parallel group RCT

Country: USA

Multicentre study: Yes (three centre trial)

Setting: Hospital

Follow‐up: 2 to 12 months

Unit of allocation: Patients

Unit of analysis: Patients

Participants

Inclusion criteria:

• Undergoing coronary artery bypass grafting, cardiac valve replacement or a combination of the two.

Exclusion criteria: Not reported in the abstract

• Patients enrolled: Not clearly reported in the abstract.

• Patients randomised: 1226.

Prestorage leukoreduced RBC (LR‐RBCs): The number of patients is not clearly reported in the abstract.

Standard RBCs (S‐RBCs): The number of patients is not clearly reported in the abstract.

• Patients transfused: 562.

• Patients considered for the analysis: Not clearly reported in the abstract.

Main characteristics of patients:

"Groups were statistically equivalent demographically and by all Society of Thoracic Surgery risk criteria".

Interventions

1. Experimental: LR‐RBCs (pre‐storage leukoreduction).

2. Control: S‐RBCs.

Co‐intervention: not reported in the abstract

Outcomes

Primary:

1. Operative and postoperative mortality at 60 days after surgery.

Secondary: Not reported in the abstract.

Notes

Trial registration: Not reported in the abstract

Funding: Not reported in the abstract

Role of sponsor: Not reported in the abstract

A priori sample size estimation: Not reported in the abstract

Conducted: Not reported in the abstract

Declared conflicts of interest: "No relevant conflicts of interest to declare" (reported in the abstract)

Other relevant information: All study characteristics were obtained from the abstract. We tried to contact two trial authors by email, but no response has not yet been obtained

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "patients (undergoing coronary artery bypass grafting, cardiac valve replacement, or a combination of the two) were pre‐operatively randomised to receive either LR‐ or S‐RBCs (Abstract).

Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Allocation concealment (selection bias)

Unclear risk

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "Patients and clinicians were blinded as to product type" (Abstract).

The blinding methods are not clearly reported.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Patients and clinicians were blinded as to product type" (Abstract).

Comments: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

"562 patients (45.8%) were transfused: 304 received LR‐RBCs and 258 S‐RBCs" (Abstract)

Loss after transfusion: Not reported in the abstract

Loss after transfusion LR group: Not reported in the abstract

Loss after transfusion Control group: Not reported in the abstract

Loss after transfusion. Imbalance between comparison groups: Not reported in the abstract.

Comment: Insufficient reporting of attrition/exclusions to permit judgement of ‘low risk’ or ‘high risk’ (e.g. number randomised not stated, no reasons for missing data provided).

Selective reporting (reporting bias)

Unclear risk

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’ (Abstract data).

Other bias

High risk

Design bias: 1226 patients randomised; only 562 (45.8) were transfused.

Methods

Design: Parallel group RCT

Country: USA

Multicentre study: Yes (11 academic medical centres)

Setting: Hospital

Follow‐up: 12 months

Unit of allocation: Patients

Unit of analysis: Patients

Participants

Inclusion criteria:

Those 14 years of older, with confirmed HIV infection and documented CMV infection (by chart or antibody testing), Karnofsky performance score of ≥ 40, expected survival of more than 1 month, symptomatic anaemia requiring red blood concentrates transfusion and no received transfusions within 72 hours of enrolment.

Exclusion criteria:

Those with a surgical reason for transfusion, a priori history for transfusion, renal failure requiring dialysis, thrombocytopenic purpura, used intravenous immunoglobulin within 6 weeks of entry or those that had started new antiretroviral drugs or systematic immunomodulators within 2 weeks of entry.

• Patients enrolled: 531.

• Patients randomised: 531.

Leukoreduced red blood concentrates transfusion: 265

Unmodified red blood concentrates transfusion: 266

• Patients transfused: 521.

• Patients considered for the analysis: 470.

Main characteristics of patients:

Age: Leukoreduced group = 38.3 ± 8.2 years; Unmodified group = 38.4 ± 8.3 years

Percentage of men: Leukoreduced group = 79%; Unmodified group = 79%

Percentage of antiretroviral therapy‐potent combination: Leukoreduced group = 27%; Unmodified group = 22%

Karnofsky score: Leukoreduced group = 71.4 ± 13.2; Unmodified group = 70.9 ± 12.8

CD4 cells/μL, median: Leukoreduced group = 16 (3 to 71.5); Unmodified group = 12.5(4 to 76)

Interventions

1. Experimental: Leukoreduced RBC transfusion (pre‐storage leukoreduction)

2. Control: Unmodified RBC transfusion.

Cointervention: Leukoreduced platelets if was required.

Outcomes

1. Primary (changed 3 months after beginning of study):

   1. Survival. "...additional resources were obtained to increase accrual to 640 and change the primary clinical end point to survival" (Page 1594).

2. Secondary:

   1. Time to death.

   2. First serious HIV‐related complication (including specific AIDS‐defining conditions and serious bacterial infections associated with median survival times of < 1 year or an acute mortality > 5%).

   3. Time to new or progressive CMV end organ disease.

   4. Plasma HIV RNA and CMV DNA levels.

   5. Lymphocyte subset markers.

   6. Change in cytokine and lymphocyte activation markers.

Notes

Trial registration: Not reported

Funding: This study was financially supported by Roche Molecular systems and National Heart, Lung and Blood Institute (contract RR00046) (Page 1600).

Role of sponsor: Reagents: Funding/Support: Reagents for detection and quantitation of CMVDNA by polymerase chain reaction were contributed by Roche Molecular Systems (Alameda,Calif). Support provided by National Heart was not detailed

A priori sample size estimation: Yes

Conducted: July 1995 through June 1999

Declared conflicts of interest: Trial authors received research funding from Roche

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The study was a randomised, double blind, comparative study" (Page 1593).

Quote: "Treatment allocation was made centrally by the study coordinating center, using stratified permuted blocks with dynamic balancing within each center" (Page 1593).

Allocation concealment (selection bias)

Low risk

Quote: "Treatment allocation was made centrally by the study coordinating center, using stratified permuted blocks with dynamic balancing within each center" (Page 1593).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The participants, investigators, study coordinators, and persons having any contact with the patients were blinded to study treatment assignments. Blood bank technical staff who prepared the blood products were aware of the treatment assignments" (Page 1593).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The participants, investigators, study coordinators, and persons having any contact with the patients were blinded to study treatment assignments. Blood bank technical staff who prepared the blood products were aware of the treatment assignments" (Page 1593).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Loss after transfusion: 9.8% (51/521)

Loss after transfusion LR group: 10.8 (28/259)

Loss after transfusion Control group: 8.8% (23/262)

Imbalance between comparison groups: 2%

Selective reporting (reporting bias)

Low risk

Comment: The study protocol is available and all of the study's pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way.

Other bias

Low risk

Comment: The study appears to be free of other sources of bias.

Methods

Design: Parallel group RCT

Country: Italy

Multicentre study: No

Setting: Hospital

Follow‐up: Not clearly reported, outcomes were measured up to 1 hour after blood transfusion

Unit of allocation: Patients

Unit of analysis: Patients

Participants

Inclusion criteria: Adult patients admitted to ICU of the AOU Ospedali Riuniti of Ancona with sepsis, severe sepsis or septic shock as diagnosed according to standard criteria and requiring blood transfusion for haemoglobin (Hb) levels of less than 8 g/dL or as indicated by the attending physician in accordance with the local hospital guidelines.

Exclusion criteria: Aged < 18 years, previous blood transfusions during ICU stay, previous history of coagulation disorders, cardiogenic or hemorrhagic shock, pregnancy and factors impeding the sublingual microcirculation evaluation (oral surgery and maxillofacial trauma)

• Patients enrolled: 20

• Patients randomised: 20

Leukodepleted RBC transfusion: 10

Non‐leukodepleted RBC transfusion: 10

• Patients transfused: 20

• Patients considered for the analysis: 20

Main characteristics of patients:

Age: Non‐leukodepleted group = 70 (65 to 72) years; leukodepleted group = 74 (64 to 79) years

Percentage of men: Non‐leukodepleted group = 50%; leukodepleted group = 70%

Interventions

1. Experimental: Leukodepleted RBC transfusion: leukoreduction was performed by a blood bank physician using the filter Sepacell RZ‐200 (Fenwal, Inc., Lake Zurich, IL, USA) within a maximum of 5 days after donor blood withdrawal (post‐storage leukoreduction).

2. Control: Non‐leukodepleted RBC transfusion.

Cointervention: Related to sepsis treatment (fluid therapy, vasopressors and inotropic agents, antibiotics, etc.)

Outcomes

1. Primary:

   1. Microcirculatory Flow Index (MFI) before and after blood transfusion.

2. Secondary:

   1. Peripheral tissue oxygen saturation (StO2).

   2. Tissue Hb index (THI).

   3. Vascular lumen perfused boundary region (PBR).

   4. Glycocalyx damage markers.

Notes

Trial Registration: NCT01584999

Funding: Not reported

Role of sponsor: Not reported

A priori sample size estimation: Yes

Conducted: February 2011 and 2012

Declared conflicts of interest: One trial author "CI is the inventor of Sidestream Dark Field imaging technology" technique used to measure the outcomes, this author "holds shares in MicroVision Medical and was a consultant for this company more than four years ago but has had no further contact with the company since then. He declares that he has no other competing interests in this field other than his commitment to promoting the importance of the microcirculation during patient care and no other relationships or activities that could appear to have influenced the submitted work. HV holds the position of chief scientific officer in GlycoCheck BV. The other authors declare that they have no competing interests".

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported.

Allocation concealment (selection bias)

Low risk

"Blood product randomization was performed through sealed envelopes by a physician at the blood bank" (Page 2).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"a physician at the blood bank blindly provided the blood bags to the ICU; neither the attending physician nor the investigators nor the patients were aware of the type of RBCs transfused" (Page 2).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"a physician at the blood bank blindly provided the blood bags to the ICU; neither the attending physician nor the investigators nor the patients were aware of the type of RBCs transfused" (Page 2).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: All patients transfused were analysed.

Patients lost to follow‐up: None.

Selective reporting (reporting bias)

Low risk

Comment: The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified.

Other bias

Low risk

—

Methods

Design: Parallel group RCT

Country: Denmark

Multicentre study: Yes (2 university departments of colorectal surgery; page 844).

Setting: Hospital

Follow‐up: 30 days after surgery

Unit of allocation: Patients

Unit of analysis: Patients

Participants

Inclusion criteria: Patients admitted for elective colorectal surgery

Exclusion criteria: < 18 years of age, need for emergency surgery, or immunosuppressive treatment, except steroids

• Patients enrolled: 589

• Patients randomised: 589

Leucocyte‐depleted red cells group: 290

Buffy‐coat‐poor red cells group: 299

• Patients transfused: 260

• Patients considered for the analysis: 586

Main characteristics of patients:

Age = Median (range): Leucocyte‐depleted red cells group = 69 (35 to 89) years; Buffy‐coat‐poor red cells group = 68 (29 to 92) years

Percentage of men: Leucocyte‐depleted red cells group = 50%; buffy‐coat‐poor red cells group = 48%

Number of procedures: Sigmoid resection: Leucocyte‐depleted red cells group = 11; Buffy‐coat‐poor red cells group = 19

Blood loss = Median (range): Leucocyte‐depleted red cells group = 715 (50 to 3500) mL; Buffy‐coat‐poor red cells group = 805 (10 to 4300) mL.

Interventions

1. Leucocyte‐depleted red cells group (the timing of leukoreduction is not reported).

2. Buffy‐coat‐poor red cells group.

Cointervention:

Quote: "All patients received an intravenous dose of cefuroxime 3 g and metronidazole 1.5 g after induction of anaesthesia" (Page 842).

Outcomes

This RCT did not specify by primary or secondary outcomes.

1. Abdominal wound infection: Accumulation of pus with spontaneous discharge or requiring surgical drainage.

2. Deep surgical infection: Intraabdominal abscess or septicaemia.

3. Pneumonia: Fever and infiltrate on chest radiography.

4. Surgical complications: Anastomotic leakage, abdominal wound dehiscence, intra‐abdominal bleeding and ileus.

5. Operation‐related mortality: Death during hospital stay or within 30 days after surgery.

Notes

Trial Registration: Not reported.

Funding: Not reported.

Role of sponsor: Not stated.

A priori sample size estimation: Yes.

Conducted: Between January 1992 and January 1995.

Declared conflicts of interest: Not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "were randomly allocated using sealed envelopes to receive either..." (Page 841).

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Allocation concealment (selection bias)

Unclear risk

Quote: "were randomly allocated using sealed envelopes to receive either..." (Page 841) Use of opaque envelopes is not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Physicians who were blinded to the transfusion protocol performed follow‐up examinations..." (Page 842).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: All patients transfused were analysed. (Page 842).

Selective reporting (reporting bias)

Low risk

Comment: The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified.

Other bias

Unclear risk

Comment: Sample size estimation took into account loss to follow‐up due to no transfusion.

Methods

Design: Parallel group RCT

Country: France

Multicentre study: No

Setting: Hospital

Follow‐up: 6 months

Unit of allocation: Patients

Unit of analysis: Patients

Participants

Inclusion criteria: "Patients included in the trial were more than 18 years of age and of both sexes and were to undergo surgery for cancer...with a transfusion‐during‐surgery (TdS) risk greater than 30 percent".

Exclusion criteria: "Patients were not eligible for inclusion if they presented contraindications to the use of UN‐RBCs or presented any RBC antibodies and/or anti‐HLA and/or antigranulocyte alloimmunization" (page 1692).

• Patients enrolled: 161

• Patients randomised: 37

Unmodified RBCs (UN‐RBC): 19

Leukoreduced RBCs (LR‐RBC): 18

• Patients transfused: 36

• Patients considered for the analysis: 35

Main characteristics of patients:

Age = Median (range): Unmodified RBCs group = 56 (40 to 73) years; Leukoreduced RBCs group= 54 (37 to 65) years

Percentage of men: Unmodified RBCs group = 33%; Leukoreduced RBCs group = 47%

Tumour location: Pelvis: Unmodified RBCs group = 11; Leukoreduced RBCs group = 8. Head and neck: Unmodified RBCs group = 6; Leukoreduced RBCs group = 7. Miscellaneous: Unmodified RBCs group = 1; Leukoreduced RBCs group = 2

Blood loss = Median (range): Unmodified RBCs group = 1500 (300 to 3650) mL; Leukoreduced RBCs group = 1325 (300 to 6800) mL

Interventions

1. Unmodified RBCs.

2. Leukoreduced RBCs (post‐storage leukoreduction).

Cointervention: Two patients (11%) in the unmodified RBCs group and three patients (18%) received fresh‐frozen plasma. None of the patients received platelet concentrate.

Outcomes

"The main endpoint of the study was to compare immune status in both treatment groups" (page 1692). This was measured through surrogate variables (i.e. microchimerism, peripheral blood cell counts and cytokine production capacity). However, other outcomes were described: "In addition to immune status, other factors compared between the two groups were survival and incidence of nosocomial infection" (page 1694).

Notes

Trial registration: ClinicalTrials database NCT00180869

Funding: "grants from the French Association for Cancer Research (L'Association pour la Recherche sur le Cancer [9653]) and the French Association for Blood Transfusion Research (L'Association pour la Recherche enTransfusion [081997])" (page 1691)

Role of sponsor: Not stated

A priori sample size estimation: Yes

Conducted: between 15 September 1997 and 28 February 1998

Declared conflicts of interest: Not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomization was performed centrally by computer in the Gustave Roussy Cancer Institute Biostatistics Unit after the investigator had sent a fax indicating the minimization factors of the patient" (page 1693).

Allocation concealment (selection bias)

Unclear risk

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Patients and surgeons were not blinded of the treatment allocation" (page 1693).

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "Patients and surgeons were not blinded of the treatment allocation" (page 1693).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

36 patients were transfused: 18 received unmodified RBCs (UN‐RBC) and 18 received Leukoreduced RBCs (LR‐RBC).

Loss after transfusion: 2.77% (1/36).

Loss after transfusion LR group: 1 died during surgery.

Loss after transfusion Control group: None.

Loss after transfusion. Imbalance between comparison groups: 5%.

Selective reporting (reporting bias)

Unclear risk

Survival after perioperative transfusion is reported in Figure 2. However, number of death is not clearly reported.

Other bias

Unclear risk

Comment: Sample size estimate was calculated based on Th2 polarization. It is unclear what dropout rate was considered in the sample size estimation of 75 participants.

Methods

Design: Parallel group RCT

Country: USA

Multicentre study: No

Setting: Hospital

Follow‐up: 28 days after randomisation

Unit of allocation: Patients

Unit of analysis: Patients

Participants

Inclusion criteria: Age of above 17 years and red cell transfusion within 24 hours of injury

Exclusion criteria: Those with an anticipated survival of less than 48 hours, active infection at presentation, receipt of blood products for the current injury before randomisation, individuals with blood group AB Rh negative or B Rh negative, patients with clinically significant red cell alloantibodies requiring an antiglobulin crossmatch, recipients with prior requirements for irradiation, leukoreduction, od CMV protection, subjects enrolled in a concurrent study of pre‐hospital hypertonic saline resuscitation or incarcerated subjects.

• Patients enrolled: 1864

• Patients randomised: 1864

Standard transfusion: 935

Leukoreduced transfusion: 929

• Patients transfused: 515

• Patients considered for the analysis: 324

Main characteristics of patients included in full analysis.

Age: Standard group = 42.1 ± 18 years; Leukoreduced group = 42.3 ± 19 years

Percentage of men: Standard group = 69%; Leukoreduced group = 66%

Percentage of penetrating injury mechanism: Standard group = 18%; Leukoreduced group = 19%

Injury Severity Score: Standard group = 25.5 ± 11; Leukoreduced group = 23.9 ± 11

Interventions

1. Leukoreduced transfusion: Prestorage‐Leucoreduced RBC (pre‐storage leukoreduction).

2. Standard transfusion: Non Prestorage‐Leucoreduced RBC (standard units).

Cointerventions: "All patients received apheresis platelets when platelets were required" (Page 343).

Outcomes

1. Primary:

   1. Infection within 28 days of randomisation.

2. Secondary:

   1. Resource use: ventilator days, lengths of hospital stay and length of ICU.

   2. Degree of multiple organ dysfunction.

   3. Mortality.

Note: TRALI was assessed by Watkins 2008 as a secondary analysis.

Notes

Trial registration: www.clinicaltrials.gov, August 23, 2005. Registration No.: NCT00135291

Funding: National Institutes of Health (NIH)

Role of sponsor: The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review or approval of the manuscript.

A priori sample size estimation: Yes

Conducted: Between 3 February 2003 and 30 August 2004.

Declared conflicts of interest: Not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The hospital‐based transfusion support service performed the randomization in a 1:1 ratio, using a permuted block scheme (block size of six)" (Page 344).

Allocation concealment (selection bias)

Low risk

Quote: "Using preprinted sealed opaque envelopes containing the study identification number and randomization arm (listed as arm 1 or arm 2) to conceal allocation" (Page 344).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Before unit issue, the transfusion service added a Food and Drug Admnistration approved study label to blind the leukoreduction process; the transfusion report accompanying the red cell unit was also blinded" (Page 343).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Before unit issue, the transfusion service added a Food and Drug Admnistration approved study label to blind the leukoreduction process; the transfusion report accompanying the red cell unit was also blinded" (Page 343).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Loss after transfusion: 5% (16/324).

Loss after transfusion LR group: 7% (11/156).

Loss after transfusion Control group: 3% (5/168).

Imbalance between comparison groups: 4%.

Selective reporting (reporting bias)

Low risk

Comments: The study protocol is available and all of the study's pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way.

Other bias

Low risk

Comment: The study appears to be free of other sources of bias.

Methods

Design: Parallel group RCT

Country: USA

Multicentre study: No

Setting: Hospital

Follow‐up: 1 year

Unit of allocation: Patients

Unit of analysis: Patients

Participants

Inclusion criteria: All potential cadaver renal allograft recipients

Exclusion criteria: Not clearly reported

• Patients enrolled: 126

• Patients randomised: 107

PRBCs group: 42

Leukocyte poor red cells group: 45

Mixed group: 20

• Patients transfused: 107

• Patients considered for the analysis: 107

Main characteristics of patients included in full analysis were not fully stated:

Quote: "there were no significant differences between transfusion groups in terms of demographic factors, including number of transfusions, age, race, sex, degree of HLA match, number of diabetics or the use of ATG posttransplant" (Page 117).

Interventions

1. PRBCs group: PRBCs.

2. Leukocyte poor red cells group: Leukocyte poor red cell (the timing of leukoreduction is not reported).

Cointerventions: "All transplant recipients received conventional maintenance immunosuppressive therapy with azathioprine and prednisone, and antithymocyte globulin (ATG) and/or bolus methylprednisolone was used for the treatment of rejection episodes" (Page 117).

Outcomes

This RCT did not specify by primary or secondary outcomes.

1. Panel reactive antibody (PRA) levels: percent of panel cells showing at least 20% lysis with patients' serum, regardless of serum dilution, as determined by the antiglobulin modification.

2. Allograft and patient survival.

Notes

Trial registration: Not reported.

Funding: National Kidney Foundation of North Carolina

Role of sponsor: Not stated

A priori sample size estimation: No

Conducted: Between September 1980 and June 1982

Declared conflicts of interest: Not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "...after obtaining informed consent, patients were randomly assigned to receive" (Page 116).

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Allocation concealment (selection bias)

Unclear risk

Quote: "...after obtaining informed consent, patients were randomly assigned to receive..." (Page 116).

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Selective reporting (reporting bias)

High risk

Comment: The study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Other bias

High risk

Design bias.

Methods

Design: Parallel group RCT

Country: USA

Multicentre study: No

Setting: Hospital

Follow‐up: Unclear. Quote: "Patients were followed up daily in the hospital until discharge (...) and contacted by phone following discharge to elicit possible symptoms of infection".

Unit of allocation: Patients

Unit of analysis: Patients

Participants

Inclusion criteria: Those scheduled for inpatient gastrointestinal surgery under general anaesthesia

Exclusion criteria: Not clearly reported

• Patients enrolled: 224

• Patients randomised: 224

Filtered group: 106

Unfiltered group: 118

• Patients transfused: 59

• Patients considered for the analysis: 221

Main characteristics of patients:

Age (Unclear if median or mean): Filtered group = 54 years; Unfiltered group = 50 years

Percentage of men: Filtered group = 49%; Unfiltered group = 50%

Hematocrit (Unclear if median or mean): Filtered group = 38; Unfiltered group = 37

Percentage of hypertension: Filtered group = 14%; Unfiltered group = 10%

Percentage of diagnosis of malignancy: Filtered group = 38%; Unfiltered group = 38%

Interventions

1. Filtered group: Leukocyte‐filtered RBCs (the timing of leukoreduction is not reported).

2. Unfiltered group: PRBCs.

Cointerventions: "Preoperative preparation included intravenous antibiotics for all patients and bowel cleansing with Golytely for patients in whom transection of the colon or rectum was anticipated" (Page 463)

Outcomes

This RCT did not specify by primary or secondary outcomes.

1. Postoperative infectious complications: abdominal wound infections, urinary tract infections, Pneumonia, intra‐abdominal collections.

2. Length of stay

3. Hospital charges.

Notes

Trial Registration: Not reported.

Funding: Pall Corporation, Gel Cove, NY

Role of sponsor: Not stated.

A priori sample size estimation: Unclear. Trial authors reported the criteria for sample size calculation, including a 60% of dropout rate ("40% of gastrointestinal surgery patients at our institution receive blood transfusions"). The software or method for sample size calculation is not reported. Using the ARCSINUS approximation, and using the same criteria reported by authors, 174 subjects are necessary in first group and 174 in the second to find as statistically significant a proportion difference, expected to be of 0.2 in group 1 and 0.05 in group 2, with an anticipated drop‐out rate of 60%. The study included 224 participants (118 and 106 patients in each group), 59 were transfused (26%) and 50 participants received allogeneic RBC transfusions.

Conducted: Between 1 August 1993 and 31 January 1994

Declared conflicts of interest: Not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were randomly allocated by the study personnel in the blood bank" (Page 463).

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Allocation concealment (selection bias)

Unclear risk

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: all patients transfused were analysed (Page 842).

Selective reporting (reporting bias)

High risk

This RCT did not report mortality.

Comment: The study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Other bias

High risk

Design bias.

Sample size bias. Trial authors reported the criteria for sample size calculation, including a 60% of dropout rate ("40% of gastrointestinal surgery patients at our institution receive blood transfusions"). The software or method for sample size calculation is not reported. Using the ARCSINUS approximation, and using the same criteria reported by the study authors, 174 subjects are necessary in first group and 174 in the second to find as statistically significant a proportion difference, expected to be of 0.2 in group 1 and 0.05 in group 2, with an anticipated drop‐out rate of 60%. The study included 224 participants (118 and 106 patients respectively), 59 were transfused (26%) and 50 participants received allogeneic RBC transfusions.

Methods

Design: Parallel group RCT

Country: Denmark

Multicentre study: No

Setting: Hospital

Follow‐up: 30 days

Unit of allocation: Patients

Unit of analysis: Patients

Participants

Inclusion criteria: Patients admitted —acute and elective— to the Department of Colorectal surgery, undergoing open colorectal surgery

Exclusion criteria: Those receiving blood transfusions within the final 3 months prior to surgery and those below 18 years

• Patients enrolled: 279

• Patients randomised: 279

Leukocyte‐depleted erythrocyte suspensions group (LD‐SAGM): 139 patients

Buffycoat‐depleted group: 140 patients

• Patients transfused: 125 (112 to the allocated group)

• Patients considered for the analysis: 279

Main characteristics of patients:

Age: Median/range: Leukocyte‐depleted erythrocyte group = 71 (66 to 77) years; Leukocyte‐depleted erythrocyte = 73 (62 to 79) years

Percentage of men: LD‐SAGM group = 51%; Non‐leukocyte‐depleted erythrocyte suspensions (SAGM) group = 60%

Number of malignant colorectal disease: LD‐SAGM group = 37; SAGM group = 56

Hemoglobin: Median/range: LD‐SAGM group = 12.6 (10.6 to 14.2) g/dL; SAGM group = 12.4 (11.1 to 13.9) g/dL

Interventions

1. Experimental: LD‐SAGM (pre‐storage leukoreduction).

2. Control: SAGM.

Cointervention: "all patients received perioperative prophylactic antibiotics intravenously (3 g ampicillin or 3 g cefuroxim and 1.5 g metronidazol)" (Page 149).

Platelet transfusion as co‐intervention was not reported

Outcomes

This RCT did not specify by primary or secondary outcomes.

1. Posooerative infectious complications: Abdominal wound infection, intra‐abdominal abscess, septicaemia, pneumonia.

2. Non‐infectious surgical complications: Anastomosis leakage, wound rupture, intra‐abdominal bleeding, acute myocardial infarction, deep vein thrombosis, pulmonary embolism, cerebral ischaemic stroke, death.

Notes

Trial registration: Not reported

Funding: Not reported

Role of sponsor: Not reported

A priori sample size estimation: Yes (but not fulfilled)

Conducted: Between May 1997 and November 1999

Declared conflicts of interest: Not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were allocated in the blood bank to receive either..." Page 148.

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Allocation concealment (selection bias)

Unclear risk

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The blood units were supplied by the blood bank, and all units were blinded. White labels were placed on the unit product code numbers, but bar code labels were intact, ensuring safe handling" (Page 149).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Surgeons who were blinded to the transfusion protocol performed the follow‐up examinations" (Page 149).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Loss after transfusion: 10.4% (13/125).

Loss after transfusion LR group: 12.7 % (7/55).

Loss after transfusion Control group: 8.5% (6/70).

Imbalance between comparison groups: 4.2%.

Selective reporting (reporting bias)

Low risk

The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified.

Other bias

High risk

Sample size bias. "Discontinued study due to large exclusions than expected, as well as higher rates of infection, insufficient sample size" (Page 149).

The estimation of sample size bias considered 10% of random error and did not reported it.

Design bias.

Industry bias: Unclear.

Methods

Design: Parallel group RCT

Country: The Netherlands

Multicentre study: No

Setting: Hospital

Follow‐up: 60 days after surgery

Unit of allocation: Patients

Unit of analysis: Patients

Participants

Inclusion criteria: Adults patients undergoing Coronary Artery Bypass grafting (CAGB) surgery, cardiac valve surgery or a combination of both, who had not received blood within the last 6 months.

Exclusion criteria: None clearly reported

• Patients enrolled: 944

• Patients randomised: 914

Packed cells without buffy coat: 306

Fresh‐filtered units: 305

Stored‐filtered units: 303

• Patients transfused: 866

• Patients considered for the analysis: 914

Main characteristics of patients:

Age: Standard packed cells without buffy coat group = 64.4 ± 9.5 years; Fresh‐filtered units group = 62.9 ± 9.8 years. Stored‐filtered units group = 63.3 ± 9.1 years

Percentage of men: Standard packed cells without buffy coat group = 72%; Fresh‐filtered units group = 74%. SF group = 68%

Percentage of history of myocardial infarction: Standard packed cells without buffy coat group = 50.3%; Fresh‐filtered units group = 44.6%. Stored‐filtered units group = 46.4%

Preoperative Hb: Standard packed cells without buffy coat group = 8.8 ± 0.9 mmol/L; Fresh‐filtered units group = 8.9 ± 0.9 mmol/L. Stored‐filtered units group = 8.8 ± 0.9 mmol/L

Postoperative Hb: Standard packed cells without buffy coat group = 6.6 ± 0.7 mmol/L; Fresh‐filtered units group = 6.6 ± 0.7 mmol/L. Stored‐filtered units group = 6.5 ± 0.7 mmol/L

Interventions

1. PC trial arm: Standard packed cells without buffy coat.

2. FF trial arm: Fresh‐filtered units (pre‐storage leukoreduction).

3. SF trial arm: Stored‐filtered units (post‐storage leukoreduction).

Cointervention: Quote: "Antibiotic prophylaxis was given for 24 hours with CABG and for 48 hours with valve or combined surgery" (Page 563).

Outcomes

1. Primary:

   1. Incidence of postoperative infections.

   2. HLA antibody formation.

2. Secondary:

   1. Duration of hospitalisations.

   2. Postoperative mortality within 60 days.

   3. Other postoperative complications.

Notes

Trial registration: Not reported

Funding: NPBI bv, Emmer‐Compascuum, The Netherlands

Role of sponsor: Not reported

A priori sample size estimation: unclear. Trial authors reported the only two criteria for sample size calculation (the proportion expected in each group). The dropout rate expected is not reported.

Conducted: Between March 1992 and August 1994

Declared conflicts of interest: Not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "patients were, by means of a randomizations list at the hospital transfusion service, randomly allocated..." (Page 563).

Allocation concealment (selection bias)

Unclear risk

Comment: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "The surgeons and anesthetists were blind to the randomizations result" (Page 563).

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "The surgeons and anesthetists were blind to the randomization result" (Page 563).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: All patients transfused were analysed (Page 567).

Selective reporting (reporting bias)

Low risk

The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified.

Other bias

Low risk

Methods

Design: Parallel group RCT

Country: The Netherlands

Multicentre: Yes, 19 hospitals (3 university, 10 clinical, 6 general)

Setting: Hospital

Follow‐up: 15 months

Unit of allocation: Patients

Unit of analysis: Patients

Participants

Inclusion criteria: Patients with ruptured aortic aneurysm elective non‐ruptured AA surgery or gastrointestinal oncology)

Exclusion criteria: Those aged under 18 years, had received transfusions in the three month before the date of randomisation, or had a previous adverse reaction to blood transfusions or had a specific indications for filtered products.

• Patients enrolled: 1200

• Patients randomised: 1200

Non‐filtered products: 605

Filtered products: 595

• Patients transfused: 494

• Patients considered for the analysis: 1051

Main characteristics of patients allocated to groups (transfused+non‐transfused):

Age: Non‐filtered group = 67 ± 11 years; Filtered group = 66 ± 11.5 years

Percentage of men: Non‐filtered group = 69%; Filtered group = 68%

Percentage of patients transfused: Non‐filtered group = 53%; Filtered group = 51%

Duration of surgery: Non‐filtered group = 210 min; Filtered group = 205 min

Interventions

1. Experimental group: Filtered RBC transfusions (pre‐storage leukoreduction).

2. Control group: Non‐filtered RBC transfusions. (buffy coat removed and were plasma reduced).

Outcomes

Primary:

1. Mortality and duration of stay in intensive care.

Secondary:

1. Multi‐organ failure.

2. Infections.

3. Length of hospital stay.

Notes

Trial registration: www.clinicaltrials.gov, 23 August 2005. Registration No.: NCT00135291

Funding: Health insurance Board, the Netherlands, The National Sanquin Bllod banks.

Role of sponsor: Not reported

A priori sample size estimation: Yes

Conducted: Since June 2000 until December 2001

Declared conflicts of interest: Yes

Note: 22 patients because of administrative and logistic errors. The intake of patients in the study had to be stopped at the end of 2001 because of the implementation of universal leucocyte depletion of RBCs in The Netherlands. This measure was taken by the Dutch Ministry of Health in an effort to reduce the risk of possible transmission of variant Creutzfeldt‐Jacob disease in non‐filtered transfusions.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "randomisation was performed either by telephone (central registration of randomisation) or by opening numbered and sealed envelopes at the hospital blood transfusion services. The transfusion service ensured that the released RBCs appeared identical" (Page 2).

Allocation concealment (selection bias)

Low risk

Quote: "randomisation was performed either by telephone (central registration of randomisation) or by opening numbered and sealed envelopes at the hospital blood transfusion services. The transfusion service ensured that the released RBCs appeared identical" (Page 2).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Neither the identity of the patient nor the randomisation group was stored in the main database. The actual randomisation was provided to the statistician only at the final analysis. (Page 2).

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "During the study, protocol violations were reported monthly to the national trial office. Patients who received products in violation of randomisation remained in the assigned arm for intention to treat analysis." (Page 2).

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss after transfusion: 9.35% (51/545).

Loss after transfusion filtered RBC transfusions: 11% (30/267).

Loss after transfusion non‐filtered RBC transfusions: 7.5% (21/278).

Imbalance between comparison groups: 3.5%.

Comment: Missing outcome data are balanced in numbers across study groups. However, reasons for missing outcome data are likely to be related to true outcome (Protocol violations).

Selective reporting (reporting bias)

Low risk

The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified.

Other bias

High risk

Design bias.

Methods

Design: Parallel group RCT

Country: UK

Multicentre study: No

Setting: Hospital

Follow‐up: 3 months after discharge

Unit of allocation: Patients

Unit of analysis: Patients

Participants

Inclusion criteria: Patients admitted for elective coronary artery bypass grafting or aortic or mitral valve replacement, either singly or in combination

Exclusion criteria: Those with a history of recurrent infections, had a current blood disorder, were taking steroid or other immunosuppressive drugs or received transfusions within the past 12 months

• Patients enrolled: 597

• Patients randomised: 597

Plasma reduced group: 198 patients

Buffy coat‐depleted group: 204 patients

WBC filtered group: 195 patients

• Patients transfused: 509

• Patients considered for the analysis: 597

Main characteristics of patients (included non‐transfused):

Age: Plasma reduced group = 62.2 ± 9.1 years; Buffy coat‐depleted group = 62.4 ± 8.1 years. WBC filtered group = 61.7 ± 8.6 years

Gender ratio (men to women): Plasma reduced group = 2.9; Buffy coat‐depleted group = 2.6; WBC filtered group= 2.9

Preoperative Hb in g/dL: Plasma reduced group = 14.2 ± 1.2; Buffy coat‐depleted group = 14.1 ± 1.2. WBC filtered group = 14.2 ± 1.2

Discharge Hb in g/dL: Plasma reduced group = 11.3 ± 0.9; Buffy coat‐depleted group = 11.3 ± 1. WBC filtered group = 11.1 ± 0.9

Interventions

1. Plasma reduced.

2. Buffy coat‐depleted.

3. WBC filtered (pre‐storage leukoreduction).

Outcomes

Primary

1. Events coded as hospital acquired infection.

Secondary:

• 1. Length of hospital stay.

  2. Postoperative fever.

  3. Use of antibiotics in hospital.

  4. Evidence of infection after discharge from hospital.

Notes

Trial registration: Not reported

Funding: This study was supported in part by a grant from the Northern and Yorkshire R & D directorate of the National Health Service

Role of sponsor: Not reported

A priori sample size estimation: Yes

Conducted: Not reported

Declared conflicts of interest: Not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were randomly assigned to receive, in the event of a transfusion, PR, BCD, or WCF blood" (Page 1128).

Allocation concealment (selection bias)

Unclear risk

Quote: "Randomization by sealed envelopes was carried out in the hospital blood transfusion department at the time of the admission clinic" (Page 1128). Use of opaque envelopes is not reported.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "The surgical staff were not blinded as to the blood component given, but were unaware of the randomization when the first decision to transfuse was made" (Page 1128).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: Collection and review of data to determine postoperative infections and other variables were carried out without knowledge of the randomization or type of blood given" (Page 1128).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: All patients transfused were analysed.

Selective reporting (reporting bias)

Low risk

The study protocol is unavailable but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).

Other bias

Low risk

Comment: The study appears to be free of other sources of bias.