Avoidance of red blood cell transfusion in an extremely preterm infant given recombinant human erythropoietin therapy

To avoid red blood cell (RBC) transfusions, recombinant human erythropoietin (rHuEPO) was given to an infant born at a gestation of 26 weeks and a birthweight of 830 g to parents who were Jehovah's Witnesses. The infant had hyaline membrane disease and required 52 days of assisted ventilation and 19 days of oxygen therapy. He received theophylline therapy for 61 days for recurrent apnoea and bradycardia. He developed bilateral intraventricular haemorrhage (IVH) and left-sided periventricular leucomalacia (PVL). Intravenous rHuEPO was started on day 1 at 200 U/kg per day for 1 month followed by subcutaneous rHuEPO 400 U/kg three times a week for 6 more weeks, supplemented with Vitamin E, folic acid and iron. Blood sampling was kept to a minimum and non-invasive blood-gas monitoring was used consistently. Consequently, the estimated cumulative volume of blood loss from sampling was only 21 mL during his hospital stay. His haemoglobin (Hb) was 150 g / L at birth and this fell to below 100 g / L from day 25 onwards. His lowest leucocyte count was 3.6x10⁹/L. He was discharged on day 83 with a Hb of 95 g/L, Hct of 29%, reticulocyte count of 2.8% and weight of 2400 g. At a postnatal age of 3 months, he had a Hb of 113 g/L. At 6 months, investigations showed: Hb 121 g/L, haematocrit 33%, reticulocyte 1% and a weight of 4.4 kg. He was readmitted to hospital once for an episode of vomiting and follow up to date showed developmental delay. Concerns remained whether the withholding of RBC transfusion in the infant was related to his IVH, PVL, prolonged recurrent apnoea and bradycardia and poor weight gain. Although rHuEPO therapy shows promise in reducing the need for RBC transfusions, its overall efficacy and safety remain to be proven and its routine use in preterm infants has to be weighed up against the potential benefits and risks of RBC transfusions.     

Prediction of transfusions in extremely low-birthweight infants in the erythropoietin era

BACKGROUND: The purpose of the present paper was to detect the clinical factors most predictive of red blood cell (RBC) transfusion in extremely low-birthweight (ELBW) infants in the recombinant human erythropoietin era. METHODS: Between 1995 and 2000, 66 ELBW infants were admitted to a level III neonatal intensive care unit. Fifty-four of 66 infants were eligible for enrollment in the present study. Infants were treated with erythropoietin 200 IU/kg per dose s.c. twice a week with 4-6 mg/kg per day iron supplement. RESULTS: The mean gestational age and birthweight were 26.5 +/- 2.1 weeks and 776 +/- 134 g, respectively. Ten of 54 ELBW infants (18.5%) died during the first 21 days. Eight of 10 dead infants (80.0%) and 27 of 44 surviving infants (61.4%) received one or more RBC transfusions. The overall requirement for RBC transfusions in the surviving infants was 3.0 +/- 3.2 per infant/hospital course (range: 0-9) . There were significant differences in gestational weeks, birthweight, initial hemoglobin value, 5 min Apgar score, phlebotomy loss, phlebotomy loss/birthweight, duration of mechanical ventilation, duration of oxygen supplement, and incidence of both intraventricular hemorrhage and chronic lung disease between the transfused and non-transfused group. The predictive variables, initial hemoglobin level (odds ratio [OR] 2.61; 1 g/dL), birthweight (OR 3.00; 100 g), and gestational week (OR 1.89; 1 week), were found to be most predictive for transfusion on logistic regression analysis. CONCLUSION: ELBW infants are still the population at greatest risk for repeated blood transfusions after introduction of erythropoietin treatment. If labor develops, it is often impossible to extend the pregnancy period, therefore efforts should be made to increase hemoglobin level at birth.     

重组人促红细胞生成素对早产儿贫血和细胞免疫功能的影响

目的　观察重组人促红细胞生成素 (rHu Epo)对早产儿贫血的预防和细胞免疫功能的影响。 方法　将 6 0例早产儿随机分为治疗组和对照组各 30例 ,治疗组用rHu Epo 6 0 0IU/kg ,隔日一次× 6周 ,加常规治疗[速力菲 8mg/ (kg·d) ,VitC 0 .1Bid ;VitE 10mg ,qd],对照组仅用常规治疗。两组同时监测红细胞计数 (RBC)、血红蛋白 (Hb)、网织红细胞 (Ret) )、血清铁和细胞免疫功能的变化。结果　疗程结束后治疗组Ret 2 .0 7% ,对照组 0 .80 9% ,两组Ret相差 10个百分点左右。治疗组血清铁 13μmol/L ,对照组 2 2 .13μmol/L ,P<0 .0 1。治疗组贫血发生率 3.3% ,对照组 6 3.4% ,P <0 .0 1,两组贫血症状有明显差异。结论　rHu Epo能预防早产儿贫血     

Erythropoietin in very preterm infants

Three neonates (a male and two females of gestational ages 27, 27 and 29 weeks with birthweight 985,660 and 1130 g), born to parents who are Jehovah's Witnesses, were admitted to our neonatal intensive care unit over a 2 month period in 1992. Human recombinant erythropoietin (rHuEpo, 200 u/kg sc. on alternate days for 6-8 weeks) was started early in conjunction with strict control of blood sampling in an attempt to avoid the need for blood transfusion. The lowest haemoglobin recorded was 95 g/L at 35 days of age in the first infant. The amount of blood withdrawn for sampling was 21.4 mL, 20.7 mL and 5.5 mL, respectively. All were discharged near their expected birthdate, never having received a blood transfusion in the Nursery. It is possible to manage sick, very preterm, very low birthweight neonates in a neonatal intensive care setting without the use of blood transfusions by the early use of rHuEpo in conjunction with strict control of blood sampling.     

Stepping up versus standard doses of erythropoietin in preterm infants: a randomized controlled trial

In this study, it is hypothesized that a planned increase in the dose of recombinant human erythropoietin (rh-EPO) can prevent transfusion in very low birth weight infants. Two different regimens of rh-EPO were administrated, one consisting in increasing dosage up to 5000 U/kg/wk, according to the individual reticulocytes response, and the second in a standard therapy of 1250 U/kg/wk. Fifty-one infants participated. Despite a significant higher reticulocytosis, the study was prematurely terminated due to the results of an interim analysis showing that transfusion was not avoided by increasing the rh-EPO. No significant differences were found between the two regimens concerning transfusion rate, volume transfused, gain in weight, and adverse effects. Progressive titration of rh-EPO to improve the biological response does not leave premature infants free of transfusion.     

Transfusion-associated fall in platelet count in very low birthweight infants

Abstract Thirty-three infants with a birthweight of less than 1500 g were investigated retrospectively for the incidence and aetiology of thrombocytopenia occurring during the first week of life. The platelet count fell below 100 × 10⁹/l in 16 infants (48%). There was a moderately strong inverse correlation between the platelet count at its nadir during the first week or the first value below 100 × 10⁹/l and the percentage of blood volume transfused prior to this ( r =−0.61; P < 0.0001). When the platelet count was expressed as a percentage of the initial count the correlation was −0.74 ( P < 0.0001). The results were not affected by the elimination of the 10 infants with clinical conditions regarded as a probable cause of thrombocytopenia. The fitted least-squares regression line suggests that a transfusion equal to 10% of the blood volume on average reduced the platelet count by 19 × 10⁹/l or by 7% in these very low birthweight infants during the first week of life.     

Empiric red cell transfusion in asymptomatic preterm infants

In a prospective randomized trial, asymptomatic very low-birth-weight infants in a neonatal intensive care unit were either electively transfused with red cells to maintain capillary haematocrit greater than 0.35 l/l (group 1; n = 9), or were not transfused (group 2; n= 10). Individuals from both groups were excluded if they subsequently received non-elective transfusions, necessitated by their clinical condition. Electively transfused infants gained weight more rapidly than their non-transfused counterparts, but the duration of hospitalization was not shortened. Criteria of morbidity, such as patent ductus murmurs, apnoea and failure to thrive, were similar in both groups. We conclude that in the absence of clinical indications, transfusion to achieve a haematocrit greater than 0.35 l/l as an empiric procedure, improves weight gain but the risks of transfusion are likely to outweigh the benefits.     

重组人红细胞生成素对于早产儿神经发育保护作用的Meta分析

目的 采用Meta分析方法评价重组人红细胞生成素（rhEPO）对早产儿神经发育的保护作用。方法制定原始文献的纳入标准、排除标准及检索策略,检索PubMed、EMBASE、Cochrane图书馆、中国期刊全文数据库、万方数据库、维普中文科技期刊数据库及中国生物医学文献数据库等,获得rhEPO对早产儿神经发育保护的RCT或半随机对照试验（quasi-RCT）文献。使用Jadad量表对纳入文献进行质量评价,采用RevMan 5.0软件进行Meta分析。以智力发育指数(MDI)、神经运动发育指数(PDI)、新生儿行为神经评估（NBNA）评分、严重神经系统后遗症（脑瘫、失明和听力受损）发生率以及严重早产儿视网膜病（ROP,≥3级）、严重脑室内出血（IVH,≥3级）、坏死性小肠结肠炎（NEC）和支气管肺发育不良（BPD）的发生率等作为观察指标,进行综合评估。结果 共检索到118篇文献,符合纳入标准的2篇RCT和3篇quasi-RCT文献（n=233）进入Meta分析,其中英文文献2篇,中文文献3篇。文献质量评价A级1篇,B级1篇,C级3篇。各研究间的基线水平有一定差异,出生体重、孕周、rhEPO剂量和治疗持续时间不尽相同。Meta分析结果显示,rhEPO治疗组MDI评分显著高于对照组（WMD=7.73,95%CI：3.45~12.01,P=0.000 4）;rhEPO治疗组PDI评分显著高于对照组（WMD=3.81,95%CI：0.59~7.02,P=0.02）;rhEPO治疗组NBNA评分显著高于对照组（WMD=1.95,95%CI：1.56~2.35,P＜0.000 01）。两组MDI评分<70发生率（OR= 0.70,95%CI:0.31～1.61）、PDI评分<70发生率（OR=2.46,95%CI:0.94～6.45）、脑瘫（OR=1.08,95%CI:0.39～2.99）、失明（OR=0.34,95%CI:0.01～8.56）和听力受损（OR=1.04,95%CI:0.06～17.15）的发生率差异均无统计学意义。两组严重ROP（OR=1.30,95%CI：0.50~3.43）、严重IVH（OR=2.91,95%CI:0.64～13.23）、NEC（OR=0.57,95%CI:0.13～2.54）和BPD（OR=1.06,95%CI:0.50～2.26）发生率的差异均无统计学意义。结论 应用rhEPO治疗可能改善早产儿神经系统预后,可能对于早产儿神经系统发育有保护作用,且不增加严重ROP的发生率。     

早期应用重组人促红细胞生成素对早产儿脑白质发育的影响

目的 应用磁共振弥散张量成像（DTI）的部分各项异性参数（FA）评价早期应用重组人促红细胞生成素（rhEPO）对早产儿脑白质发育的影响。方法 以81例胎龄≤ 32周、出生体重 < 1 500 g、生后24 h内住院的早产儿为研究对象,随机分为两组：rhEPO组（42例）使用rhEPO治疗,对照组（39例）使用等体积的生理盐水注射。2组均于纠正胎龄35~37周行头部MRI、DWI、DTI检查,并测定相同感兴趣区的部分各项异性参数（FA）。结果 两组早产儿颅内出血、脑室周围白质软化、局灶性脑白质损伤、广泛性脑白质损伤等发生率的差异无统计学意义（P > 0.05）。rhEPO组早产儿内囊后肢、胼胝体压部、额叶白质、枕叶白质FA值高于对照组（P < 0.05）,2组早产儿顶叶白质、丘脑、豆状核、尾状核FA值的差异无统计学意义（P > 0.05）。结论 早期应用重组人红细胞生成素对早产儿脑白质发育有神经保护作用。     

Neonatal jaundice in 'healthy' very low birthweight infants

The daily bilirubin levels during the first week of life in 94 premature very low birthweight (VLBW, < 1500g) relatively 'healthy' infants were determined. Mean daily bilirubin values peaked on the fourth day of life at 188.1 μmol/l (s.e.m. = 5.3). Twenty-eight infants developed hyperbilirubinaemia (bilirubin > 260 μmol/l), at which time they were exposed to phototherapy. When individual peak bilirubin values were evaluated, the overall peak value was 213.9 μmol/l (s.e.m. = 5.1) occurring at 4.81 days (s.e.m. = 0.11), although the value is most likely an underestimate, since the 28 pre-phototherapy values were not truly peak values. Seventy-six (81%) infants experienced bilirubin levels > 170 μmol/l. The method of delivery apparently had no impact on the bilirubin levels.
All the infants remained well and progressed satisfactorily.'Healthy' VLBW infants experience a much greater incidence and severity of neonatal jaundice than mature infants with the same clinical status.     

Effect of hemoglobin on transfusion and neonatal adaptation in extremely low-birthweight infants

Background: The aim of the present paper was to investigate the effect of initial hemoglobin level on red blood cell transfusion and neonatal adaptation in extremely low-birthweight (ELBW) infants.
Methods: Subjects consisted of 54 ELBW infants admitted to level III neonatal intensive care unit between 1995 and 2000, and divided into two groups based on hemoglobin level at birth. High hemoglobin was defined as hemoglobin ≥15.0 g/dL.
Results: There were no significant differences in gestational age and birthweight between the high hemoglobin group ( n  = 28) and low hemoglobin group ( n  = 26). The high hemoglobin group had decreased probability of requiring red blood cell transfusion ( P  < 0.05) and number of red blood cell transfusions ( P  < 0.05). Mortality rate in the low hemoglobin group was significantly higher compared with the high hemoglobin group ( P  = 0.03). In the high hemoglobin group, blood pressures during the first 24 h were significantly higher ( P  < 0.05) and the risk of intraventricular hemorrhage was significantly lower ( P  = 0.04) compared with the low hemoglobin group. The predictive variables, initial hemoglobin level (odds ratio 1.93 [decrease by 1 g/dL]) and intraventricular hemorrhage ≥III (odds ratio 21.76 [positive]) were found to be most predictive for death on logistic regression.
Conclusion: High hemoglobin level at birth is associated with a significantly reduced requirement for red blood cell transfusion and might contribute to stabilization of blood pressure, and thus reduce mortality and the risk of severe intraventricular hemorrhage.     

How appropriate are commercially available human milk fortifiers?

A preliminary investigation was made into the effectiveness of two breastmilk fortifiers on the Australian market (FM-85 [Nestle, Vevey, Switzerland] and Enfamil Human Milk Fortifier [EHMF; Mead Johnson, Evansville, IN, USA]). Infants < 1800 g and < 34 weeks gestation at birth, who were receiving breast milk, were randomized to receive either of the fortifiers (n= 14 for FM-85, n= 10 for EHMF), until a weight of 2 kg was reached. Infants not receiving breast milk (n= 9) were fed a preterm formula (Prenan, Nestlé). The two fortifier groups were similar in most parameters examined: (i) weight gain (17.9 ± 3.0 vs 17.4 ± 3.5g/kg per day); (ii) head circumference growth (1.02 ± 0.28 vs 1.03 ± 0.25 cm/week); (iii) arm muscle area growth (32.6 ± 20.0 vs 33.5 ± 13.7 mm²/week); (iv) arm fat area growth (14.3 ± 6.1 vs 14.0 ± 8.7 mm²/week); (v) plasma calcium (2.52 ± 0.08 vs 2.58 ± 0.15 mmol/L); (vi) plasma phosphate (2.02 ± 0.21 vs 2.13 ± 0.32 mmol/L); (vii) plasma copper (5.28 ± 2.83 vs 5.66 ± 3.07 pmol/L); and (vii) plasma zinc (13.3 ± 5.5 vs 15.8 ± 9.2 μmol/L). The FM-85 group had a higher alkaline phosphatase level (355 ± 110 vs 231 ± 70 iu/L) than the EHMF group; however, no values were outside the normal range. The Prenan group had a higher rate of weight gain (23.6 ± 3.3 g/kg per day) and higher arm fat area growth rate (25.2 ± 7.6 mm²/week) than the fortifier groups, while all other parameters were similar. The incidence of feed intolerance was considered high in both fortifier groups. The addition of many of the components of breastmilk fortifiers has not been well validated and it is proposed that a simplified fortifier composed of protein and phosphate may be better tolerated and equally effective at optimizing growth and bone mineralization. The specific needs of extremely low birthweight infants (>1000 g) have not been addressed.     

Distribution of plasma Vitamin E levels in supplemented very low birthweight infants

Abstract The distribution of plasma Vitamin E (VE) was determined in 25 very low birthweight (VLBW) infants who were supplemented with 100 mg/kg per day of α-tocopherol acetate, given intragastrically. Their mean birthweight was 917 g and mean gestational age was 28 weeks. Mean plasma VE levels after 1 and 6 weeks' supplementation were 2.7 mg/dL (s.e.m. = 1.0) and 6.4 mg/dL (s.e.m. = 1.4), respectively (the difference was not significant). There was wide variability in plasma VE levels in these infants despite being on an identical dose of tocopherol. Plasma VE was < 0.5 mg/dL in 12% of samples, 0.5–3.0 mg/dL in 32%, 3.1–5.0 mg/dL in 18%, and 5.1–20 mg/dL in 38%. Fifteen of the 25 infants had at least one level in the range which has been associated with an increased incidence of septicaemia and necrotizing enterocolitis (> 5.0 mg/dL).
These data suggest that if a policy of VE supplementation for VLBW infants is chosen, monitoring of plasma VE levels appears necessary so that the dosage can be adjusted in order to maintain plasma VE within the optimal range. This study's dosage regimen of supplementing infants with 100 mg/kg per day of VE was associated with a high incidence of elevated plasma VE levels and it is concluded that it is not advisable to use such large doses of VE in the premature newborn.     

Nasal continuous positive airway pressure and outcomes of preterm infants

OBJECTIVES: To document the effects of changing to a primarily nasal continuous positive airway pressure (CPAP)-based system of respiratory support on respiratory and non-respiratory outcomes in preterm infants. METHODOLOGY: Outcomes in two groups of preterm infants with a birthweight of 1000-1499 g were compared retrospectively over a 5-year period before (period I; n = 57) and after (period II; n = 59) the introduction of a primarily nasal CPAP-based approach to respiratory support, modelled closely on that used at the New York Presbyterian Hospital (Columbia University), formally known as the Columbia-Presbyterian Medical Center, in New York. RESULTS: From period I to period II, there was a decline in the number of infants ventilated (65 vs 14%, respectively) and receiving surfactant (40 vs 12%, respectively) and in the median days of ventilation (6 vs 2, respectively) and oxygen (4 vs 2, respectively). There were decreases in chronic lung disease (CLD) at 28 days (11 vs 0%, respectively), death or CLD at 28 days (16 vs 3%, respectively), the use of pressor support (34 vs 7%, respectively), the incidence of necrotizing enterocolitis (11 vs 0%, respectively), time to reach full oral feeds (17.3 vs 13.2 days, respectively), discharge weight (2569 vs 2314 g, respectively) and average length of stay (61 vs 52.9 days, respectively). There were no differences in neurosonographic or other morbidity outcomes. CONCLUSIONS: A CPAP-based approach to respiratory support of the preterm infant may decrease the invasiveness and duration of respiratory support and may decrease respiratory and some non-respiratory adverse outcomes without an associated increase in neurosonographic or other morbidity outcomes. Further prospective trials are warranted.     

重组人类促红细胞生成素预防极低出生体重儿贫血的研究

目的　评价重组人类促红细胞生成素 (rhu EPO)在相同剂量下不同应用频度对预防极低出生体重儿(VLBWI)贫血的效果。方法　将东南大学附属徐州医院儿科 2 0 0 1年 9月至 2 0 0 3年 9月收治的 2 2例VLBWI随机分成两组 ,均在出生第 8天开始予rhu EPO ,每周 75 0IU/kg ,共 6周。Ⅰ组 (12例 )每周 3次给药 ;Ⅱ组 (10例 )每周 1次给药。另设未予rhu EPO的 12例VLBWI作为对照组 (Ⅲ组 )。动态观察血红蛋白、红细胞计数、红细胞压积比等。结果　 (1) 3组患儿在出生第 2 8天血红蛋白值的差异均有统计学意义 (P <0 0 1) ,出生第 6 4天的差异有统计学意义 (P <0 0 1) ,但Ⅰ、Ⅱ组间 P =0 0 5 2。 (2 ) 3组患儿在出生第 2 8天红细胞计数的差异均有统计学意义(P <0 0 1) ,出生第 6 4天的差异有统计学意义 (P <0 0 1) ,但Ⅰ、Ⅱ组间P =0 0 74。 (3) 3组患儿在出生第 2 8天红细胞压积比的差异有统计学意义 (P <0 0 1) ,但Ⅰ、Ⅱ组间P =0 14 0 ,出生第 6 4天的差异有统计学意义 (P <0 0 1) ,但Ⅰ、Ⅱ组间P =0 195。结论　在rhu EPO相同的每周总量下 ,每周 3次给药比每周 1次给药能明显提高VLBWI的血红蛋白及红细胞计数     

Oral iron supplementation in preterm infants treated with erythropoietin

BACKGROUND: It is not known whether a moderate dose of oral iron supplementation would further enhance erythropoiesis in recombinant human erythropoietin (EPO)-treated very low-birthweight (VLBW) infants. METHODS: In total, 24 preterm infants with birthweights 750-1499 g were enrolled at the age of 14-28 days to receive 400 IU/kg per week EPO subcutaneously for 8 weeks. The infants were randomly allocated either to receive oral iron supplementation 4 mg/kg per day or to serve as controls. RESULTS: Hemoglobin and the absolute reticulocyte count in the iron supplementation and the control groups remained identical throughout the study period, whereas serum ferritin was significantly lower in the control group at study exit and follow up. Rates of treatment success (no need for transfusion and hemoglobin never below 8 g/dL) also did not differ between the groups. CONCLUSIONS: In this study we did not find a clear advantage in a moderate dose of oral iron supplementation on erythropoiesis in EPO-treated VLBW infants. Whether a higher dose would lead to enhanced erythropoiesis remains to be answered.     

重组人促红细胞生成素对极低出生体重儿神经智能发育的影响

目的 评估早期给予重组人促红细胞生成素（rhEPO）对极低出生体重儿（VLBWI）神经智能发育的临床疗效。方法 选取VLBWI 78例,根据患儿父母的选择分为rhEPO治疗组（n=35）与对照组（n=43）。治疗组生后4~5 h内给予rhEPO（250 IU/kg,每周3次,连用4周）。纠正胎龄40周时行新生儿神经行为检测（NBNA）,纠正胎龄3月、6月、12月时进行Gesell发育量表评估,并比较纠正胎龄6月时脑干诱发电位（ABR）及头颅B超的异常率。结果 治疗组纠正胎龄40周的NBNA评分高于对照组（P<0.05）。治疗组纠正胎龄3月时的适应能力优于对照组,纠正胎龄6月时的大运动、适应能力、社交能力优于对照组,纠正胎龄12月时的大运动、适应能力、精细动作、社交能力、语言明显优于对照组,差异均具有统计学意义（均P<0.05）。治疗组纠正胎龄6月时的ABR异常率、头颅B超异常率明显低于对照组（P<0.05）。结论 早期rhEPO治疗可以促进VLBWI神经系统症状早期恢复,改善患儿的认知、运动及语言能力,对神经系统具有一定的保护作用。