BMJ  2004;328:1281 (29 May), doi:10.1136/bmj.38103.735266.55 (published 13 May 2004)

Paper

Effects of transfusion with red cells filtered to remove leucocytes: randomised controlled trial in patients undergoing major surgery

¹ Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center and Sanquin Blood Supply, PO Box 9600, 2300 RC Leiden, Netherlands, ² Department of Surgery, Leiden University Medical Center, Leiden, ³ Department of Medical Decision Making, Leiden University Medical Center, Leiden, ⁴ Department of Medical Statistics, Leiden University, Leiden, ⁵ Medisch Spectrum Twente, PO Box 50000, 7500 KA Enschede, ⁶ St Joseph Ziekenhuis, P O Box 7777, 5500 MB Veldhoven, ⁷ St Antonius Ziekenhuis, PO Box 2500, 3430 EM Nieuwegein, ⁸ Albert Schweitzer, Locatie Dordwijk, PO Box 306, 3300 AH Dordrecht, ⁹ Reinier de Graaf Groep, PO Box 5011, 2600 GA Delft

Abstract

Objective To compare postoperative complications in patients undergoing major surgery who received non-filtered or filtered red blood cell transfusions.

Design Prospective, randomised, double blinded trial.

Setting 19 hospitals throughout the Netherlands (three university; 10 clinical; six general).

Participants 1051 evaluable patients: 79 patients with ruptured aneurysm, 412 patients undergoing elective surgery for aneurysm, and 560 undergoing gastrointestinal surgery.

Interventions The non-filtered products had the buffy coat removed and were plasma reduced. The filtered products had the buffy coat removed, were plasma reduced, and filtered before storage to remove leucocytes.

Main outcome measures Mortality and duration of stay in intensive care. Secondary end points were occurrence of multiorgan failure, infections, and length of hospital stay.

Results No significant differences were found in mortality (odds ratio for filtered v non-filtered 0.80, 95% confidence interval 0.53 to 1.21) and in mean stay in intensive care (- 0.4 day, - 1.6 to 0.6 day). In the filtered group the mean length of hospital stay was 2.4 days shorter (- 4.8 to 0.0 day; P = 0.050) and the incidence of multiorgan failure was 30% lower (odds ratio 0.70, 0.49 to 1.00; P = 0.050). There were no differences in rates of infection (0.98 (0.73 to 1.32).

Conclusion The use of filtered transfusions in some types of major surgery may reduce the length of hospital stay and the incidence of postoperative multiorgan failure.

Introduction

Red blood cell transfusions are indispensable in major surgery, but they still entail potential risks for morbidity and mortality. On the other hand, beneficial effects such as better survival of allografts in kidney transplantation¹ and improved survival in patients with HIV who receive transfusions² are attributed to the allogeneic leucocytes.

Five randomised studies investigated the incidence of postoperative infections after abdominal surgery by comparing outcome after transfusions of non-filtered red blood cells or red blood cells with leucocytes filtered out. Three of these trials^3-5 observed a reduction and two^{6 7} found a similar incidence of postoperative infections after filtered transfusions. The findings were also conflicting for other outcomes such as mortality. We investigated whether removal of allogeneic leucocytes reduces postoperative complications in patients undergoing major surgery.

Methods

On the basis of the results of a pilot study we assumed that at least 65% of the target population would be both evaluable and transfused and calculated that about 1250 patients had to be randomised.

Study design and participants
The primary outcome measures were mortality in hospital and duration of stay in intensive care. The secondary end points were incidence of multiorgan failure and postoperative infections and length of hospital stay.

Each of 19 hospitals was invited to assign patients for one or more of the three surgery groups: ruptured aortic aneurysm, elective non-ruptured aortic aneurysm surgery, and gastrointestinal oncology. We excluded patients who were aged under 18 years, had received transfusions in the three month before the date of randomisation, or had had a previous adverse reaction to blood transfusions or had specific indications for filtered transfusions.

We assessed patients before, during, and after surgery. The postoperative situation was assessed with standardised queries, daily in intensive care and weekly on the ward until the last day in hospital. We defined multiorgan failure and postoperative infection according to standard criteria.^{8 9}

Transfusion products
Units of red blood cell concentrates with the buffy coat removed contained up to 8x10⁸ white blood cells/unit, whereas in red blood cells filtered before storage the maximum count was 10⁶ white blood cells/unit. Numbers of units that were transfused before, during, and after surgery were downloaded from the hospital blood transfusion service computer system. Patients who received products in violation of randomisation remained in the assigned arm for intention to treat analysis. We performed subgroup analysis of the transfused population, according to transfusion, to evaluate effects related to transfusion (leucocyte dose).

Results

Over 15 months, 1200 patients were randomised. 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 red blood cells 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.

Patients' characteristics
There were 1051 patients eligible for analyses (526 in the non-filtered group and 525 in the filtered arm): 79 acute aneurysm surgery, 412 elective aneurysm surgery, and 560 gastrointestinal oncological surgery. The characteristics of the patients are presented in table 1.

View this table: [in this window] [in a new window]   Table 1 Characteristics of study population according to allocation to transfusions with filtered or non-filtered red blood cells and analysed group

 

Number of transfusions
In the total transfused study population analysed according to intention to treat, 278 patients in the group randomised to non-filtered products and 267 patients in the group randomised to filtered products received transfusions. The median number (25th-75th centiles) of transfusions was lower than expected (1 unit (0-4 units)).

Primary end points
Mortality in hospital—Mortality in hospital was 10.3% (54 patients) in the non-filtered group and 8.4% (44 patients) in the filtered group (table 2). There was a significant reduction in mortality (0.47, 0.23 to 0.99) in favour of filtered products in the patients undergoing gastrointestinal surgery. Because this difference in mortality between 23 (non-filtered) v 11 patients (filtered) (8% v 4%) could have been caused by imbalanced randomisation with respect to age, sex, duration of surgery, number of blood transfusions, or type of surgery, we have described the gastrointestinal group in more detail in table 3.

View this table: [in this window] [in a new window]   Table 2 Intention to treat analyses of primary and secondary end points. Figures are totals in group (non-filtered; filtered) and odds ratios or differences in means (95% confidence intervals)

 

View this table: [in this window] [in a new window]   Table 3 Patients undergoing gastrointestinal surgery differentiated by sex, age, type of surgery, blood transfusion with filtered or non-filtered red blood cells, and duration of surgery according to survival

 

Stay in intensive care—There was no significant difference in stay in intensive care between the randomised groups, though in the filtered group patients stayed an average of 0.4 days less (- 1.6 to 0.6 days).

Secondary end points
Multiorgan failure—One hundred and sixty four patients experienced multiorgan failure (16% of the total study population). There was a significantly lower incidence in the filtered group. The overall mean odds ratio for incidence of multiorgan failure was 0.70 (0.49 to 0.99; P = 0.05).

Postoperative infections—The incidence of postoperative infections was similar in the two groups. The combined odds ratio for the three types of surgery was 0.98 (0.73 to 1.32).

Hospital stay—Patients randomised to filtered products stayed an average of 2.4 days less (4.8 to 0.0 day). The figure shows the length of stay in the total population and in those patients undergoing elective surgery for aneurysm.

View larger version (38K): [in this window] [in a new window]   Cumulative hospital discharges

 

Discussion

We hoped to provide decision makers with evidence regarding a universal leucocyte filtration programme. The study ended early because politicians decided to mandate universal leucocyte filtration of red blood cells in the Netherlands to reduce the risk of transmission of prions through non-filtered transfusions. However, this meant that we had to stop recruitment before we reached our planned study size.

Interpretation and context
We found no significant differences in the primary end points (mortality and stay in intensive care). With respect to secondary end points, we found a significant difference in the incidence of postoperative multiorgan failure in favour of filtered products. The incidences of postoperative infections were not significantly different between the two randomised groups. The mean hospital stay was 2.4 days shorter in the group randomised to filtered products.

Although we found no significant benefit of filtered products on mortality in hospital in the total population, we did see an effect in the subgroup of patients undergoing gastrointestinal surgery. We excluded an apparent imbalance in randomisation (which could have caused this difference) by showing that with respect to relevant risk factors the distribution of randomised gastrointestinal patient to non-filtered and filtered products was balanced (see bmj.com). This observation is in agreement with the outcomes of a recent randomised controlled trial in cardiac surgery¹⁰ and of the Canadian registration study.¹¹

We found no evidence to support the use of filtered products to prevent infection in patients undergoing major surgery. In our three previous studies that compared filtered products with red blood cells with the buffy coat removed (the standard Dutch product), we found a reduction in postoperative infections only in patients undergoing cardiac surgery who had received more than 3 units.^{6 10 12} Others reported a correlation between the number of blood transfusions and multiorgan failure.¹² In our previous (multicentre) non-cardiac surgery study⁶ and in the present study only a relatively small number of patients received 4 or more units.

Economic evaluation
Another benefit of filtered products in our study, besides a reduced incidence of multiorgan failure, was a reduction in mean length of hospital stay. The reduction in hospital stay was partly due to fewer patients who received filtered products who stayed for more than 90 days in hospital (10 non-filtered v 1 filtered). The reduction in hospital stay was present in all subgroups and most pronounced in the patients undergoing elective surgery for aneurysm who received transfusions. The two Canadian intervention studies also showed a reduction in hospital stay.^{11 13} Reduction in hospital stay supports the general leucocyte reduction of red blood cells by filtration. If we extrapolate the benefit of filtrated products to the Dutch healthcare system, with 16 300 aneurysm and gastrointestinal procedures a year, a mean reduction of 2.4 days in hospital would reduce the national hospital costs by 29.5m/year (£19.6m, $35.0m). In the Netherlands the annual cost of universal leucocyte depletion of red blood cells is about 20m (assuming filtration costs of 40/unit). The reduced mean hospital stay associated with filtered products could, to a large extent, compensate the extra cost of filtration in the Netherlands. In other countries where standard whole blood transfusion has been compared with filtered red blood cells, implementation of filtration seems to be cost neutral or cost saving in some settings.^{14 15}

What is already known on this topic Reduction of leucocytes in red blood cell concentrates by filtration results in less alloimmunisation in patients receiving transfusions and transplants In patients undergoing cardiac surgery and transfused with at least 4 units the use of filtered red blood cells reduces postoperative infections and mortality The use of filtered red blood cells has also been shown to reduce postoperative infections in patients undergoing colorectal surgery What this study adds The use of filtered red blood cells results in a shorter stay in hospital and a lower incidence of multiorgan failure in patients undergoing major vascular or oncological surgery Mortality was lower in the subgroup of patients undergoing gastrointestinal oncological surgery

Conclusions
Although we had to stop recruiting patients before we reached the desired study size, results for some end points had reached significance. Leucocyte reduced transfusions in this group of patients undergoing major surgery significantly reduced the incidence of multiorgan failure and length of hospital stay. Our results also contribute to the discussion of the cost effectiveness of using filtered red blood cells.

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This is the abridged version of an article that was posted on bmj.com on 13 May 2004: http://bmj.com/cgi/doi/10.1136/bmj.38103.735266.55

We thank the following members of the Tactics trial group for their participation (see bmj.com for a full list), the contributors from the Sanquin Blood Bank, the research nurses, and members of the data monitoring safety committee of Tactics.

Contributors: See bmj.com

Funding: Health Insurance Board (College voor Zorgverzekeringen (project OG99/023), the Netherlands. The National Sanquin Blood Banks produced blood products under study and reimbursed the difference in costs.

Competing interests: None declared.

Ethical approval: The protocol was first approved by the ethics committee of the Medical Spectrum Twente recognised by Dutch Central Council for Medical Research (CCMO) and subsequently endorsed by all ethics committees of the other participating hospitals.

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(Accepted 18 March 2004)

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