Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study.

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Methodology:

• Prospective multicentre observational study analysing a sub-cohort of the NECTARINE trial.
• The NECTARINE (NEonate and Children audiT of Anaesthesia pRactice IN Europe) trial recruited patients up to 60 weeks postmenstrual age undergoing anaesthesia for surgical and diagnostic procedures in 165 centres in 31 European countries in 2016-2017. The NECTARINE trial included 5609 patients undergoing 6542 procedures. This sub-cohort receiving peri-operative red blood cell transfusions included 447 procedures (406 patients).
• 7% of patients were younger than 37 weeks postmenstrual age at the time of their procedure and 47.7% (213 patients) were born prematurely.
• The primary endpoint was the haemoglobin level triggering a transfusion in neonates in 3 groups; week 1 of life, week 2 of life and week 3 and older. Secondary endpoints included transfusion volumes, delta haemoglobin (pre-procedure Hb subtracting the transfusion triggering Hb, or the drop in Hb before a decision to transfuse) and 30-day and 90-day morbidity and mortality.
• RBC transfusions in the 447 procedures were triggered by: intra-operative anaemia (218 procedures), cardiovascular instability (113 procedures) or a combination of both factors (116 procedures).
• 2% of the procedures were non-cardiac surgery (52.3% visceral surgery and 10.2 neurosurgery). 30.4% were cardiac surgery and 1.3% were cardiac catheterization and 2% non-cardiac interventional catheterization. 7.4% had cyanotic congenital heart disease.

Results:

• Transfusion triggering thresholds for Hb were week 1 of life: 9.6 g/dl [8.7 to 10.9], week 2 of life: 9.6 g/dl [7.7 to 10.4] and week 3 of life and above: 8.0 g/dl [7.3 to 9] (median and IQR)
• The median pre-procedure Hb level, the delta Hb and the transfusion volume for the three groups were:
  • Week 1: 13.9 [12 to 16] g/dl and 2.4 [0.8 to 5.3] and 16.7 [12.8 to 21.5] ml/kg
  • Week 2: 12.6 [10.6 to 14.6] g/dl and 1.3 [0.1 to 4.2] and 20.0 [12.5 to 30.2] ml/kg
  • Week 3 and above: 10.4 [9.1 to 11.8] g/dl and 1.6 [0.0 to 3.2] and 17.1 [10.9 to 26.4] ml/kg
• The study showed a 30-day morbidity rate of 47.8% (194/406) and a 90-day mortality rate of 11.3% (46/406). For comparison, the overall morbidity and mortality rate of the NECTARINE trial was 13.5% (708/5609) and 2.0% (103/5609) respectively.
  • Week 1 of life had an overall morbidity rate of 59% (46/78) and mortality rate of 12.8% (10/78).
  • Week 2 of life had the highest morbidity and mortality rate. Morbidity rate: 63.6% (28/44). Mortality rate: 15.9% (7/44)
  • Week 3 of life and above had the lowest morbidity and mortality rate, however still much higher than the overall NECTARINE mortality. Morbidity rate: 42.3% (120/284). Mortality rate: 10.2% (29/284).
• The article goes on to discuss the large variability in transfusion triggering Hb thresholds and the potential causes of the almost four-fold increase in morbidity and the up to five-fold increase in mortality compared to the patients who were not transfused.
  • Transfusion-triggering Hb thresholds are lower in this study than the existing guidelines (see the below for data from the Australian National Blood Authority).
  • The authors discuss tests and parameters that may be used to guide transfusion, such as point-of-care testing, reduced global O₂ delivery, high oxygen consumption, use of NIRS and lactate. They suggest that by using some of these parameters one might consider transfusing some children well before the lower limits of recommended Hb levels are reached.
  • In addition, they state that in the absence of impaired tissue oxygenation and haemodynamic instability, an infant or neonate is unlikely to need RBC transfusion, even when presenting with Hb levels below the recommended thresholds.
• Regarding the mortality and morbidity levels, the authors state that this shows that neonates and small infants receiving peri-operative RBC transfusions are at an increased risk of morbidity and mortality compared with older children. Neonates receiving RBC transfusion in their 2 weeks of life have the highest morbidity and mortality in this trial. This group also contains the highest number of neonates with young gestational age, the highest proportion of cardiac surgery and had the highest transfusion volumes. These patients are likely to be more vulnerable and might have shown increased morbidity and mortality irrespective of RBC transfusion.
• As a reference I would like to include the Australian National Blood Authority’s Patient Management guide to transfusion of preterm infants:
  • Postnatal week 1: 100-130 g/L, week 2: 85-125 g/L, week 3: 70-110 g/L (These are consistent with other guidelines in this area).

My personal thoughts on this trial:

• The NECTARINE trial is impressive!
• I think it is good to review the literature on transfusion thresholds and how to optimise transfusion strategies including transfusion thresholds for the individual patient you are currently treating. This appears to be particularly important in the premature and neonatal patient population.
• Despite RBC transfusions having a range of potentially adverse events, I disagree with the statement in the article “An important finding of this study is that peri-operative RBC transfusions is associated with increased morbidity and mortality and should be administered judiciously”. I do agree with the “administered judiciously” part, however I disagree with the “peri-operative RBC transfusions is associated with increased morbidity and mortality”. I would state that it is not possible to prove causality between RBC transfusion and morbidity and mortality in this population. It is very likely that these children have underlying health conditions that lead to the RBC transfusion and that these underlying health conditions themselves carry a direct increased risk of morbidity and mortality. The authors do acknowledge this in the article.
• The patient population with the highest rate of morbidity and mortality in this trial is the population I personally have the highest respect for. They have a small blood volume, their pathology is so serious that they undergo surgery despite clear knowledge of their vulnerability and they may be more difficult to monitor, with ETCO₂ and NIBP in particular showing a wide range of variability in the smallest children. Even small amounts of sudden blood loss will cause a degree of instability in some of these children. This article confirms that this patient population should command the maximum amount of respect.

Reviewed by Dr Jon Salicath