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CORRESPONDENCE The purported deleterious effect of transfusion-related
immunomodulation (TRIM) on postoperative infection and its prevention by leukoreduction of transfused blood are a matter of great controversy among transfusion medicine specialists. In a recent review on this
issue,1 Vamvakas and Blajchman pointed out that current evidence supporting a beneficial effect of leukoreduction is
inconclusive because randomized-controlled trials (RCTs) have produced
contradictory findings. But a 10% increase in the risk of
postoperative infection associated with transfusion of nonleukoreduced
allogeneic blood could have passed undetected in some RCTs, and an
unaffordable large number of patients should be enrolled in future
trials in order to detect such a small effect. Because postoperative
infection is a frequent, serious, and expensive complication of
surgery, even a 10% decrease in its incidence would result in a public health benefit so large that regulatory agencies may decide to implement universal leukoreduction without waiting for the results of
further trials. This may be a sound precautionary measure, provided
that TRIM would really play a role in postoperative infection. Allogeneic blood transfusion impairs T-cell-mediated immunoresponse,
as measured by a decreased antigen-driven lymphoblastic transformation
and natural killer activity.2 This is consistent with the
protective effect that blood transfusion has on renal allografts, which
is the only TRIM effect that has been unequivocally demonstrated at the
clinical level. But at the present state of knowledge, it is hard to
believe in a connection between impaired T-cell function and the
postoperative events attributed to allogeneic blood transfusion. The
latter includes surgical infections (wound, intra-abdominal abcesses,
fistulization, mediastinitis), nosocomial infections (pneumonia,
urinary tract), and other postoperative complications such as leakage
from bowel anastomoses, aortocoronary suture dehiscence, and multiorgan
failure. Each of these events has been found in some of the RCTs
reviewed by Vamvakas and Blajchman to occur more frequently in the
patients transfused with regular allogeneic red blood cells (RBCs) than
in recipients of leukoreduced or autologous blood. Therefore, the
question arises as to whether transfusion of leukoreduced or autologous
blood might have been a surrogate for another mechanism by which blood
transfusion could actually propitiate the above-mentioned postoperative complications. In the RCT by Heiss et al,3 patients in the autologous
transfusion arm had deposited 2 units of blood 10 and 7 days before surgery, whereas those in the allogeneic blood arm received standard blood bank RBCs (storage time not stated). In the study by Houbiers et
al,4 patients in the leukoreduced blood arm were
transfused with laboratory-filtered RBCs that were 2-3 days old, while
patients in the control arm received regular, stored RBCs (storage time not stated). In the RCTs by Jensen et al5 and Tarter et
al,6 patients in the leukoreduced arm received RBCs that
were passed through a bedside filter, whereas control patients were
transfused with conventional, unfiltered RBCs (storage times not
mentioned). And van de Watering et al,7 who compared
buffy-coat-depleted RBCs, fresh-filtered units, and stored-filtered
units, stated that transfused blood was between 7 and 21 days old,
without further specification by study arm. Because it is common
practice to select RBC units stored for a short period for bedside
filtration, whereas units closer to expiration date are selected for
regular transfusion, it is plausible that leukoreduced or autologous
blood may have been a surrogate for fresher blood in all the above RCTs. Longer storage of transfused RBCs has been associated with higher
incidence of postoperative infection after resection of rectal
cancer8 or coronary artery bypass surgery,9
as well as with poorer outcomes in critically ill
patients.10,11 The deleterious effect of stored blood may
be due to accumulation upon storage of leukocyte-derived inflammation
mediators, which could be prevented by prestorage leukoreduction, or to
depleted levels of 2,3-diphosphoglycerate and decreased deformability
of stored RBCs, both impairing oxygen delivery to the tissues. Both healing of surgical anastomoses and defense mechanisms against infection in wounds are critically dependent on an adequate oxygen supply.12,13 Rigid RBCs produce capillary slugging and
occlusion, leading to local ischemia14 and poor delivery
of prophylactic antibiotics. In the gut, this may further lead to
bacterial translocation, a process that plays an important role in the
development of multiorgan failure.14 Although transfused
RBCs recover their normal function after 12-24 hours, the first few
hours after tissue contamination by bacteria are critical for wound
infection to be established.12 These observations suggest
a biologically plausible alternative to TRIM for the postoperative
complications attributed to allogeneic transfusion. Needless to say,
such mechanism would not be influenced by prestorage leukoreduction. A reanalysis of the raw data of published RCTs, as the one proposed by
Vamvakas and Blajchman,1 including the length of storage
of transfused RBCs, if available, could provide insight on the
existence of explanations other than TRIM for the observed beneficial
effects of leukoreduced or autologous blood transfusion. Otherwise,
further studies aimed at clarifying this point are needed before
universal leukoreduction is accepted as a worthy health intervention.
The alternative would be the implementation of a very expensive
intervention that may eventually prove to be useless.
Arturo Pereira
References
1.
Vamvakas EC, Blajchman MA.
Deleterious clinical effects of transfusion-associated immunomodulation: fact or fiction?
Blood.
2001;97:1180-1195
2.
Innerhofer P, Luz G, Spötl L, et al.
Immunological changes after transfusion of autologous or allogeneic buffy coat-poor versus white cell-reduced blood to patients undergoing arthroplasty, I: proliferative T-cell responses and the balance of helper and suppressor T-cells.
Transfusion.
1999;39:1089-1096[CrossRef][Medline]
[Order article via Infotrieve].
3.
Heiss MM, Mempel W, Jauch K-W, et al.
Beneficial effect of autologous blood transfusion on infectious complications after colorectal cancer surgery.
Lancet.
1993;342:1328-1333[CrossRef][Medline]
[Order article via Infotrieve].
4.
Houbiers JGA, Brand A, van de Watering LMG, et al.
Randomized controlled trial comparing transfusion of leukocyte-depleted or buffy-coat-depleted blood in surgery for colorectal cancer.
Lancet.
1994;344:573-578[CrossRef][Medline]
[Order article via Infotrieve].
5.
Jensen LS, Kissmeyer-Nielsen P, Wolf B, Qvist N.
Randomized comparison of leukocyte-depleted versus buffy-coat-poor blood transfusion and complications after colorectal surgery.
Lancet.
1996;348:841-845[CrossRef][Medline]
[Order article via Infotrieve].
6.
Tarter PI, Mohandas K, Azar P, Endres J, Kaplan J, Spivack M.
Randomized trial comparing packed red cell blood transfusion with and without leukocyte depletion for gastrointestinal surgery.
Am J Surg.
1998;176:462-466[CrossRef][Medline]
[Order article via Infotrieve].
7.
Van de Watering LMG, Hermans Jo, Houbiers JGA, et al.
Beneficial effect of leukocyte depletion of transfused blood on postoperative complications in patients undergoing cardiac surgery: a randomized controlled trial.
Circulation.
1998;97:562-568
8.
Mynster T, Nielsen HJ.
The impact of storage time of transfused blood on postoperative infectius complications in rectal cancer surgery.
Scand J Gastroenterol.
2000;35:212-217[CrossRef][Medline]
[Order article via Infotrieve].
9.
Vamvakas EC, Carven JH.
Transfusion and postoperative pneumonia in coronary artery bypass graft surgery: effect of the length of storage of transfused red cells.
Transfusion.
1999;39:701-710[CrossRef][Medline]
[Order article via Infotrieve].
10.
Purdy FR, Tweeddale MG, Merrick PM.
Association of mortality with age of blood transfused in septic ICU patients.
Can J Anaesth.
1997;44:1256-1261[Medline]
[Order article via Infotrieve].
11.
Zallen G, Offner PJ, Moore EE, et al.
Age of transfused blood is an independent risk factor for postinjury multiple organ failure.
Am J Surg.
1999;178:570-572[CrossRef][Medline]
[Order article via Infotrieve].
12.
Greiff R, Akça O, Horn E-P, et al.
Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection.
New Engl J Med.
2000;342:161-167
13.
Hamzaoglu I, Karahasanoglu T, Ayadin S, et al.
The effect of hyperbaric oxygen on normal and ischemic colon anastomoses.
Am J Surg.
1998;176:458-461[CrossRef][Medline]
[Order article via Infotrieve].
14.
Bone RC, Marik PE, Sibbald WJ.
Effect of stored-blood transfusion on oxygen delivery in patients with sepsis.
JAMA.
1993;269:3024-3029
Pereira proposes that the apparent association between
allogeneic blood transfusion (ABT) and postoperative infection,
reported by some of the randomized controlled trials (RCTs) reviewed in our recent article,1 might have been due to the
transfusion of fresher units to patients who received either white-cell
(WBC)-reduced or autologous (as compared with non-WBC-reduced) red
blood cells (RBCs) in those studies. We agree that (1) alternative
mechanisms exist that might explain the apparent association between
ABT and postoperative infection and (2) definitive evidence justifying the implementation of universal WBC reduction for the prevention of the
purported deleterious clinical effects of transfusion-related immunomodulation (TRIM) has not been presented. But universal, prestorage WBC reduction likely will be implemented soon,2 despite the absence of such definitive evidence. Thus, the
implementation of universal WBC reduction will preclude the undertaking
of further RCTs investigating TRIM effects mediated by allogeneic WBCs.
We also agree with Pereira that further research into these questions is necessary, and we present 2 clinical research designs that could, in
an era of universal WBC reduction, (1) establish the existence of a
deleterious TRIM effect of allogeneic WBCs and (2) bolster (or refute)
the possibility of an alternative mechanism for the association between
ABT and postoperative infection proposed by Pereira. In our review,1 we demonstrated that the available RCTs
reporting on an association between ABT and postoperative infection produced discordant findings, which are impossible to reconcile by a
meta-analysis of the published results. But a meta-analysis of the raw
patient data Alternatively, the risk of postoperative infection could be compared
between patients transfused before or after the implementation of
universal WBC reduction.5 Such observational comparisons should present data on the length of storage of the transfused blood
components to investigate the 3 hypotheses presented in Table
1. As suggested by Pereira and,
previously, by us,6,7 the transfusion of stored, rigid
RBCs depleted of nitric oxide (NO) could impede blood flow to the
viscera (through vascular obstruction and/or vasoconstriction),
predisposing to ischemia and thus, perhaps, infection. Relevantly, both
we6 and others8 have reported that increased
length of storage of (non-WBC-reduced) transfused RBCs is associated
with an increased risk of postoperative infection. This relationship
could be due to ischemia, secondary to the presence in the circulation
of old, rigid RBCs (as Pereira indicates) or to biologic response
modifiers, released from deteriorating WBCs and accumulating in the
supernatant fluid of cellular blood components in a time-dependent
manner during storage.9 If either of these 2 hypotheses
were to be confirmed, a longer storage time of (non-WBC-reduced)
transfused RBCs would be associated with an increased risk of
postoperative infection. Therefore, as suggested by Pereira, the length
of storage of the transfused RBCs should be investigated as a possible
explanation for the disagreements among the available RCTs in any
future IPD meta-analysis of these studies.
It is possible that future research will not corroborate the reported association6,8 between increased length of storage of the transfused blood components and an increased risk of postoperative infection. If the TRIM effects were mediated by immunologically active, intact allogeneic WBCs,1 fresher (as opposed to older) blood components would be associated with an increased risk of infection. Table 1 presents 3 mechanisms that may underlie an association of ABT with postoperative infection as mutually exclusive hypotheses and shows the expected results from future observational comparisons of patients transfused before or after the implementation of universal WBC reduction, in the event that these 3 hypotheses were indeed mutually exclusive and only 1 of them was correct.
Eleftherios C. Vamvakas and Morris
A. Blajchman
References 1. Vamvakas EC, Blajchman MA. Deleterious clinical effects of transfusion-associated immunomodulation: fact or fiction? Blood. 2001;97:1180-1195. 2. Department of Health and Human Services. How should the government respond to the current public debate over leukoreduction? volume II. Transcript of the January 26, 2001, meeting of the Advisory Committee on Blood Safety and Availability. http://dhhs.gov/bloodsafety/transcripts/20010126.html. Accessed on April 10, 2001. 3. Blajchman MA. Allogeneic blood transfusions, immunomodulation and postoperative bacterial infection: do we have the answers yet? Transfusion. 1997;37:121-125[CrossRef][Medline] [Order article via Infotrieve]. 4. Vamvakas EC, Blajchman MA. A proposal for an individual patient data based meta-analysis of randomized controlled trials of allogeneic transfusion and postoperative bacterial infection. Transf Med Rev. 1997;11:180-194[CrossRef][Medline] [Order article via Infotrieve]. 5. Vamvakas EC, Dzik WH, Blajchman MA. Deleterious effects of transfusion-associated immunomodulation: appraisal of the evidence and recommendations for prevention. In: Vamvakas EC, Blajchman MA, eds. Immunomodulatory effects of blood transfusion. Bethesda, MD: AABB Press; 1999:253-285. 6. Vamvakas EC, Carven JH. Transfusion and postoperative pneumonia in coronary artery bypass graft surgery: effect of the length of storage of transfused red cells. Transfusion. 1999;39:701-710. 7. Vamvakas EC, Blajchman MA. Prestorage versus poststorage white cell reduction for the prevention of the deleterious immunomodulatory effects of allogeneic blood transfusion. Transf Med Rev. 2000;14:23-33[CrossRef][Medline] [Order article via Infotrieve]. 8. Mynster T, Nielsen HJ. The impact of storage time of transfused blood on postoperative infectious complications in rectal cancer surgery: Danish RANX05 Colorectal Cancer Study Group. Scand J Gastroenterol. 2000;35:212-217. 9. Nielsen HJ, Reimert CM, Pedersen AN, et al. Time-dependent, spontaneous release of white cell- and platelet-derived bioactive substances from stored human blood. Transfusion. 1996;36:960-965[CrossRef][Medline] [Order article via Infotrieve].   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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often referred to as meta-analysis of individual-patient
data (IPD)
