Dear Editor

The paper by Wardle et al brings the interesting concept of use of peripheral fractional oxygen extraction to guide the blood transfusion in preterm infants in clinical practice[1]. The clinical dilemma of deciding when to and when not to transfuse preterm neonates is always a major topic of debate amongst professionals involved in caring preterm neonates. There is a great deal of variation amongst Neonatologists about the cut off of hemoglobin or hematocrit levels to be used for transfusions in preterm babies. There are not many randomised studies in literature to address this issue, and of the few we know, they have either methodological limitations or are not published in their full form [2,3,4,5,6]. Therefore, as Wardle et al state, there is no doubt that we need more studies to produce evidence-based guidelines for blood transfusion in preterm neonates[1]. These studies should not only look at number of transfusions, acute mortality and morbidity but also developmental outcomes at 2-3 years of age. Can a more serious consideration of physiologic basis assist us in deciding us about when to transfuse? These might have postulated benefits in terms of oxygen delivery to the tissues[7].

The risks and benefits of transfusion include those of maintaining a high or low hemoglobin and some additional risks and benefits of the transfusion itself. A high hemoglobin level, maintained by frequent transfusion, enhances arterial oxygen content and oxygen transport to the tissues. But this is usually far in excess of need, and so oxygen delivery (equal to oxygen uptake or consumption) is not limited by hemoglobin content. However, in chronic ischemic or hypoxic hypoxia, where oxygen delivery may be limited by oxygen transport, a high hemoglobin may be required to maintain oxygen delivery to the tissues. Expected consequences of chronic anemic hypoxia might be thought to be poor growth or impaired neurodevelopmental outcome. On the other hand, if allowing the hemoglobin to fall to lower levels has no critical or limiting effects on oxygen delivery, growth and development will continue unimpaired without the potential adverse effects of blood transfusion, such as transfusion-borne infection or iron overload. Even further complicating these physiologic considerations is the decrease in oxygen affinity of hemoglobin with postnatal age, which increases the ability of the blood to deliver oxygen, and the effect of transfusion of adult hemoglobin, which enhances this effect.

While reading the paper by Wardle et al raised several questions in my mind.
(1) In the abstract of article it is stated that the primary outcome measures were number of transfusion received, rate of weight gain, and postmenstrual age at discharge. In contradiction to this in the main methodology details of article authors state single primary outcome measure as, “number of transfusions received after randomization”, and all other were secondary outcome measures.
(2) The first criterion stated in Group 1 (Conventional Group) for transfusion, “ transfused at Hb of 140g/L if inspired oxygen concentration >0.35 or mean airway pressure >6 cm of water” appears liberal.
(3) It is stated that one of the transfusion criterion set for Group 2 (NIRS Group), “ transfused at FOE >0.47”. In “blinding” paragraph it is stated that, “forearm FOE measurements were made on all infants in both groups, these results were only available to researchers and not to the clinical team”. This statement implies that clinicians were not aware or notified of the FOE values even in “NIRS Group”.
(4) The frequency of Hb measurement by authors is described as, “daily in first week of monitoring, then about 4 times a week until the infant was 30 weeks postconceptional age, and then about twice a week”. Going through the paper it is evident that these infants were enrolled in to study when they were not ventilated or ventilated with FIO2 <_40 and="and" the="the" postnatal="postnatal" median="median" age="age" at="at" randomization="randomization" was="was" _5days.="_5days." taking="taking" these="these" two="two" facts="facts" in="in" to="to" account="account" i="i" think="think" frequency="frequency" of="of" hb="hb" monitoring="monitoring" during="during" study="study" very="very" frequent="frequent" contributing="contributing" excess="excess" iatrogenic="iatrogenic" blood="blood" loss.br="loss.br"> (5) In the footnote of Table 1, it is mentioned that the results are given as “median (range)”. For example, birthweight in grams in NIRS group 1200 (range1004-1373). The reader will interpret this as the baby in this group with lowest weight at 1004 gram. But as you go through the table later it is mentioned that 9 infants were £ 1000 gram. It is left to the poor reader to make a serious thoughtful effort to interpret this “range” in reality means ‘interquartile range”.
(6) In discussion authors state that many infants in NIRS group were transfused on by clinicians because of low Hb or clinical symptoms, even though FOE was not >0.47. Authors state that these clinical symptoms could have been due to clinical reasons other than anemia such as infection. It would have been useful if authors had given us some data about infection rate differences in two groups knowing that this is a prospective study.

References

(1) Wardle SP, Garr R, Yoxall CW, Weindling AM. A pilot randomised controlled trial of peripheral fractional oxygen extraction to guide blood transfusions in preterm infants. Arch Dis Child Fetal Neonatal Ed 2002; 86:F22-27.

(2) Blank JP, Sheagren TG, Vajaria J, Mangurten HH, Benawra RS, Puppala BL. The role of RBC transfusion in the premature infant. Am.J.Dis.Child. 1984; 138:831-833.

(3) Ransome OJ, Moosa EA, Mothebe FM, Spector I. Are regular 'top-up' transfusions necessary in otherwise well, growing premature infants? S Afr Med J. 1989; 75:165-166.

(4) Connelly RJ, Stone SH, Whyte RK. Early vs. late red cell transfusion in low birth weight infants. Pediatr Res 1998; 43: 170A.

(5) Bell EF, Strauss RG, Widness JA, Mahoney LT, Mock DM, Seward VJ, et al. Choice of hematocrit threshold for erythrocyte transfusion in preterm infants. Pediatric Res.2000; 47:389A.

(6) Bifano EM, Bode MM, D’Eugenio DB. Prospective randomized trial of high vs. low hematocrit in ELBW Infants: One-year growth and neurodevelopmental outcome. Pediatr Res 2002; 51:325A.

(7) Andersen C. Critical haemoglobin thresholds in premature infants. Arch Dis Child Fetal Neonatal Ed. 2001; 84:F146-148.