Timing of intraventricular haemorrhage.

The detection of the onset of intraventricular haemorrhage (IVH) during life is a necessary preliminary to understanding the cause of this condition. In 10 infants of very low birthweight treated with serial transfusions of adult blood the proportions of transfused cells circulating after each transfusion were compared with the proportion of transfused cells found in the intraventricular clot at necropsy. This allowed the timing of IVH to be restricted retrospectively to the period between consecutive blood transfusions. In addition, the proportional changes of transfused cells produced by infusion of a known red cell mass allow changes in the babies'' original red cell mass to be followed during life. A fall in this value occurred in 8 infants dying with IVH and was taken to indicate haemorrhage. Comparison of the two methods in 9 infants suggested that, while in some cases intraventricular bleeding occurs rapidly, in others it takes place over a period of time. The interval between birth and the onset of haemorrhage was directly proportional to the gestational age of the infant.     

Transfusion related morbidity in premature babies: Possible mechanisms and implications for practice

Many premature babies, especially those with a low birth weight are given multiple transfusions during their first few weeks of life. The major serious complications of prematurity include bronchopulmonary dysplasia, with lesser incidences of retinopathy of prematurity, intraventricular haemorrhage, and necrotising enterocolitis. Many studies have shown correlations between the receipt of blood transfusions and the development of these conditions, but little is known of the underlying pathophysiology of this relationship. Recent studies are beginning to provide some answers. This review examines recent findings with regard to the influence of preparation and storage of paediatric packed red blood cell units on heme, iron, and oxidative status of the units and relates these to the ability of the premature baby to deal with these changes following the receipt of blood transfusions. Paediatric packed red blood cell units are a potential source of heme, redox active iron and free radicals, and this increases with storage age. Haemolysis of transfused red blood cells may add further iron and cell free haemoglobin to the recipient baby. Premature babies, particularly those with low birth weight and gestational age appear to have little reserve to cope with any additional iron, heme and/or oxidative load. The consequences of these events are discussed with regard to their contribution to the major complications of prematurity and a novel hypothesis regarding transfusion-related morbidity in premature babies is presented. The review concludes with a discussion of potential means of limiting transfusion related iron/heme and oxidative load through the preparation and storage of packed red blood cell units and through modifications in clinical practice.     

超低出生体重儿红细胞输注的临床分析

探讨超低出生体重(ELBW)儿减少红细胞输注的可能性。方法对1989～1997年9年间256 例超低出生体重儿的红细胞输注进行临床分析。在此期间红细胞输注指征进行了3次制订,对检验样本的采 血量进行了严格的控制,部分病例应用了重组人促红细胞生成素治疗。结果1994年以后有1/4的ELBW儿 不需要输注红细胞,1989～1997年平均输血次数由7次降至2.7次(P＜0.01)。按出生体重累计红细胞输注 量由163.5mL/kg降至69.2mL/kg(P＜0.01),接受供血者人数由6.3人降至1.5人(P＜0.01)。红细胞输注 前的平均红细胞压积比,机械通气者由0.43降至0.34、自主呼吸者由0.41降至0.31。ELBW儿更加不成熟,平 均胎龄由27.4周减至26.0周,平均出生体重由833g降至741g。存活率仍达78％,住院时间没有延长,严重并 发症如视网膜病、动脉导管未闭、脑室出血的发生率没有增加。结论制订严格的红细胞输注指征有助于减少 输血次数和接受供血者人数,且患儿临床耐受良好。     

Continuous cerebral electrical impedance monitoring in sick preterm infants

Cerebral electrical impedance (dZ) and intra-arterial blood pressure were measured continuously during the first 48 h after birth in 26 sick ventilated preterm infants with a birth weight <1500 g. The aim was to establish whether any patterns of dZ_p or the variability of either blood pressure or dZ_p would allow identification of those infants who developed intraventricular haemorrhage (IVH), periventricular leucomalacia (PVL) or a poor neurological outcome. IVH and PVL were diagnosed by ultrasound image obtained every 6 h. Cerebral electrical impedance recordings were unsuitable for analysis in three patients and a further three died within 14 h of birth. In the remaining 20 patients, no step changes that may have been related to the onset of IVH or PVL were evident and whilst three patterns of dZ_p were identified, they were not useful in distinguishing between normal infants or those who developed IVH, PVL or had a poor neurological outcome. Using multiple linear regression, the coefficient of variation of dZ_p was significantly associated with both IVH and outcome, as was the coefficient of variation of blood pressure. Continuous measurement of cerebral electrical impedance, whilst technically feasible in sick preterm infants, was not found useful as a method of identifying those who developed IVH, PVL or had a poor neurological outcome.     

Intraventricular haemorrhage and the renin-angiotensin-aldosterone system in very low birthweight infants

Blood volume, plasma renin activity (PRA) and urine aldosterone excretion (UAE) were measured in ten very low birthweight infants who had a Grade 3 or 4 intraventricular haemorrhage (IVH) during the first 2 days after birth. Mean (range) birthweight was 950 (630-1500) g and gestational age was 27 (23-31) weeks. Nine infants were receiving assisted ventilation and one was breathing spontaneously. Eight IVH occurred on the first postnatal day and two on the second; seven were symptomatic and three asymptomatic. PRA was significantly higher than control values on Day 1 only; median 244 (range 91-654) ng/ml per h vs. 64 (4-259) ng/ml per h (P less than 0.01). Infants with symptomatic IVH in the preceding 8 h (n = 6) all had PRA greater than 300 ng/ml per h; none of these infants had received transfusions or volume expansion between IVH and PRA measurement. PRA was less than 100 ng/ml per h in the three infants with asymptomatic IVH and one infant with greater than 24 h interval between IVH and PRA measurement; three of these four had received transfusions prior to PRA measurement. UAE was not significantly different from control values on either Day 1 or Day 2. Blood volume at 22 +/- 3 h postnatal age ranged from 75 to 107 ml/kg. There was an inverse logarithmic correlation between PRA and blood volume (r = 0.883; P less than 0.005), with PRA values exceeding 300 ng/ml per h when blood volume was less than 90 ml/kg. UAE did not correlate with either PRA or blood volume.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low levels of plasminogen in cerebrospinal fluid after intraventricular haemorrhage: a limiting factor for clot lysis?

The aim of this study was to measure plasminogen in the cerebrospinal fluid (CSF) of control neonates with no infection or haemorrhage and in infants who had suffered intraventricular haemorrhage (IVH). A chromogenic substrate method was used. The 16 reference infants had a median CSF plasminogen level of 0.74% of that of normal adult plasma (range 0.17-1.1%). The 11 infants with IVH had a median CSF plasminogen level of 0.55% of normal adult plasma (range 0-4.4%). Six of the IVH infants went on to develop permanent hydrocephalus despite the use of intraventricular plasminogen activators. Endogenous fibrinolysis and the potential for fibrinolytic treatment in the CSF may be limited by low concentrations of plasminogen, and administration of recombinant plasminogen may assist attempts to clear intraventricular blood clots. Cerebrospinal fluid, hydrocephalus, intraventricular haemorrhage, newborn infant, plasminogen
A Whitelaw, Department of Paediatrics, Aker University Hospital, 0514 Oslo, Norway     

Unilateral posthaemorrhagic hydrocephalus in the neonatal period or later in infancy

Five infants who developed unilateral hydrocephalus associated with antenatal or perinatal intraventricular haemorrhage (IVH) in the neonatal period or later in infancy are reported. Unilateral hydrocephalus occurred following discharge home in four of our five cases, two of whom had been treated during the neonatal period with either serial lumbar punctures or punctures from a Rickham reservoir. An obstruction at the level of the foramen of Monro following a large subependymal matrix bleed appeared to be the underlying aetiology. These data suggest that infants who suffer a predominantly unilateral IVH, with or without parenchymal involvement, can subsequently develop unilateral hydrocephalus. Cranial ultrasound examinations should be repeated at regular intervals during the first year of life, as unilateral hydrocephalus can still develop after a period of apparent stabilization.     

Spontaneous intraventricular haemorrhage in utero

The authors report three cases of unexplained prenatal intraventricular haemorrhage (IVH) in three term infants. In the first two cases the suspected diagnosis of prenatal IVH was made a few hours after delivery, in accordance with the ultrasonographic feature of clots in the ventricles, whereas in the third case prenatal ultrasonography was suggestive of hydrocephalus with intraventricular clots.Abbreviations IVH intraventricular haemorrhage - SEH subependymal haemorrhage - CT computed tomography - US ultrasonography     

Sustained hematological consequences in the first week of neonatal life secondary to placental dysfunction

OBJECTIVE: To evaluate the relationship between umbilical artery end diastolic velocity in growth restricted fetuses and neonatal hematologic parameters. STUDY DESIGN: Growth restricted fetuses were studied with ultrasound and Doppler evaluations. Neonates were analyzed in two groups based on umbilical artery Doppler status: positive end-diastolic velocities (PEDV) and absent or reversed end-diastolic velocities (AEDV). At birth and throughout the first week of life, groups were compared for anemia and thrombocytopenia; transfusion of red blood cells, platelets, and fresh frozen plasma; and intraventricular hemorrhage (IVH). RESULTS: Seventy-three neonates met inclusion criteria, 38 with PEDV, 35 with AEDV. Those with AEDV were delivered 3 weeks earlier, were 450 g smaller, had lower cord arterial pH values, and greater cord artery base deficits (p<0.05, respectively). AEDV neonates were twice as likely to be anemic and thrombocytopenic at birth and remain so during the first week, requiring more red blood cell and platelet transfusions. There was no difference in occurrence of severe IVH between groups. CONCLUSION: Hematological alterations associated with intrauterine growth restriction appear to continue into the first week of neonatal life. These are proportional to the degree of placental dysfunction and are predicted by fetal Doppler status. SUMMARY: Abnormal development of the placental vascular tree is the primary step in a cascade of fetal compromises leading to intrauterine growth restriction (IUGR). Doppler ultrasound evaluation of fetal and placental blood flows provides a non-invasive assessment of the fetal condition which reflects the impact of placental vascular abnormalities. The degree of placental dysfunction determines the severity of fetal disease, which can affect many fetal organ systems. In addition to disturbances in placental respiratory function, abnormal umbilical artery Doppler status is also indicative of hematologic abnormalities during fetal life and at birth. Neonates who had more severe placental dysfunction, as depicted by absent umbilical artery end diastolic velocity, were more likely to be anemic and thrombocytopenic at birth and remain so during the first week of life, and required more transfusions than those with positive end diastolic velocities. The severity of hematologic alterations during the first week of life in growth restricted neonates was proportional to and predicted by the antenatal umbilical artery end diastolic velocity Doppler status.     

Comparing alloimmunization in preterm infants after transfusion of fresh unmodified versus stored leukocyte-reduced red blood cells.

PURPOSE: To compare the occurrence of red blood cell (RBC), platelet (PLT), and white blood cell (WBC) antibodies in preterm infants after transfusions. METHODS: A randomized, blinded trial was conducted in which preterm infants were transfused either with stored RBCs, prepared by prestorage leukocyte reduction and transfused throughout 42 days of storage to limit donor exposure (n = 18), or with fresh RBCs prepared without leukocyte reduction and transfused within 7 days after collection from as many donors as needed to guarantee freshness (n = 17). Nontransfused preterm infants of comparable birth weight were control subjects (n = 11). RESULTS: No RBC antibodies were detected in serial blood samples taken during the first 6 months of life. Similarly, no definite WBC antibodies were found, although weak reactivity was detected transiently in sera from two infants. Accordingly, RBC and WBC antibody production did not differ among groups. In all, 11% of the transfused the infants exhibited platelet antibodies: 14% of the infants given stored leukocyte-reduced RBCs and 7% of the infants given fresh nonleukocyte-reduced RBCs (difference not statistically significant). CONCLUSIONS: Preterm infants rarely produce antibodies to blood cell antigens after RBC transfusions, regardless of whether the exposure is to fresh unmodified RBCs from several donors or to stored leukocyte-reduced RBCs from a limited number of donors. Therefore, efforts to limit donor exposures or to remove WBCs from blood components cannot be justified simply for purposes of preventing alloimmunization in neonates.     

Endogenous fibrinolysis in neonatal cerebrospinal fluid

Although many infants with intraventricular haemorrhage (IVH) recover without hydrocephalus, little is known about how blood is cleared from the CSF pathways. Fibrinolytic activity was measured by the fibrin plate method in CSF from 11 normal infants and 17 infants with IVH. Normal CSF showed no fibrinolytic activity. All the samples taken less than 17 days from diagnosis of IVH samples taken between 17 and 60 days of IVH showed fibrinolytic activity. In 1 infant where 14 serial samples were taken, there was no detectable fibrinolysis up to 16 days after IVH but from 19 to 52 days there was definite fibrinolytic activity. Delayed endogenous fibrinolysis in the CSF is common after IVH but may, in some cases, be insufficient to prevent hydrocephalus.     

Serial measurements of cerebral blood flow velocity in preterm infants during the first 72 hours of life

Serial measurements of cerebral blood flow velocity (CBFV) were made in 29 preterm infants, using continuous wave Doppler ultrasound. CBFV was measured in both anterior cerebral arteries and quantitative measurements of CBFV were determined using the area under the velocity curve. In all ventilated infants, CBFV increased significantly during the first 6 hours of life and continued to increase until 16 hours of age. Thereafter, CBFV remained relatively constant. This increase in CBFV was primarily the result of increased diastolic flow. Three infants who had evidence of intraventricular haemorrhage on cranial ultrasound, had similar CBFV compared with the infants with no evidence of haemorrhage. Two infants died and both demonstrated areas of periventricular leukomalacia at autopsy. These infants had a prolonged period of low CBFV. These measurements provide normal data for ventilated, preterm infants. As previously suggested in term infants, the initial rise in CBFV may be secondary to closure of the ductus although a generalized decrease in peripheral vascular resistance could also be a contributing factor. Fluctuations in CBFV rather than individual readings are probably more important in the genesis of IVH. An episode of significantly reduced CBFV is a poor prognostic sign.     

T lymphocyte subpopulations in high-risk infants: influence of age and blood transfusions

Methodology was established to analyze T lymphocytes and T cell subsets with monoclonal antibodies on microsamples of blood obtained by heel puncture in infants. Results in 39 high-risk infants indicated that during the early neonatal period they had a higher percentage of T4-bearing cells and a lower percentage of T8 antigen-positive cells as compared with adults. These values progressively approached adult values, and at 3 to 7 months the T cell subsets and the T4/T8 ratios were within the adult range. A significant inverse relationship was noted between the number of blood transfusions given to the infants between 2 and 12 weeks of age and the corresponding T4/T8 ratio. These findings suggest that interpretation of T cell subsets in frequently transfused infants should take into consideration not only the age of the infant but also the possible influence of transfusions per se on the distribution of T cell subsets in the peripheral blood.     

Strict guideline reduces the need for RBC transfusions in premature infants

The aim of this study was to verify if the adoption of a strict guideline would reduce the need for red blood cell transfusions in the first 28 days of life in very low birth weight preterm infants. Retrospective study of two cohorts of very low birth weight infants transfused according to neonatologist decision (Period 1) or according to a strict guideline for erythrocytes transfusion (Period 2). Clinical and hematological data of 80 premature infants transfused in both periods of the study were obtained by chart review. During the first 28 days of life, 45 (62.5%) of 72 premature infants born in the Period 1, and 44 (55.7%) of 79 newborns born in Period 2 received at least one erythrocyte transfusion; p = 0.40. Among patients transfused, the median number of transfusions was four per infant transfused (range: 1-13; mean: 4.6 +/- 3.2) in Period 1 and 3 (range: 1-18; mean: 4.0 +/- 3.5) in Period 2; p = 0.26. The median volume of erythrocytes administered per infant transfused in Period 1 was 40 ml kg(-1) (range: 10-170; mean: 48.8 +/- 38.3) and in Period 2 was 30 ml kg(-1) (range: 10-225; mean: 43.4 +/- 40.4), p = 0.41. Multiple linear regression analysis, after adjusting for birth weight, clinical risk index for babies, blood loss and days of ventilation, showed that the adoption of the strict guideline reduced the volume of erythrocytes transfused in 15.91 ml kg(-1) per infant transfused (95% CI: -24.69-7.14) p < 0.001. The adoption of a strict guideline reduced the need for red blood cells transfusions in very low birth weight infants.     

Serial Measurements of Cerebral Blood Flow Velocity in Preterm Infants during the First 72 Hours of Life

ABSTRACT. Serial measurements of cerebral blood flow velocity (CBFV) were made in 29 preterm infants, using continuous wave Doppler ultrasound. CBFV was measured in both anterior cerebral arteries and quantitative measurements of CBFV were determined using the area under the velocity curve. In all ventilated infants, CBFV increased significantly during the first 6 hours of life and continued to increase until 16 hours of age. Thereafter, CBFV remained relatively constant. This increase in CBFV was primarily the result of increased diastolic flow. Three infants who had evidence of intraventricular haemorrhage on cranial ultrasound, had similar CBFV compared with the infants with no evidence of haemorrhage. Two infants died and both demonstrated areas of periventricular leukomalacia at autopsy. These infants had a prolonged period of low CBFV. These measurements provide normal data for ventilated, preterm infants. As previously suggested in term infants, the initial rise in CBFV may be secondary to closure of the ductus although a generalized decrease in peripheral vascular resistance could also be a contributing factor. Fluctuations in CBFV rather than individual readings are probably more important in the genesis of IVH. An episode of significantly reduced CBFV is a poor prognostic sign.     

Clinical events relating to intraventricular haemorrhage in the newborn.

Continuous measurements of arterial pressures, heart rates, respiratory movements, and respiratory rates were made from birth in 44 infants at risk from intraventricular haemorrhage (IVH). 17 babies died with IVH, in 10 of whom the event was timed objectively. Events in these babies were compared with survivors of similar birthweights, gestational ages, severity of birth asphyxia, and severity of hyaline membrane disease (HMD). IVH followed severe HMD and was associated with cessation of the babies' own respiratory efforts while on a ventilator and also with characteristic cardiorespiratory events. The minimum arterial pressure before IVH was lower than in comparable babies who survived. It is suggested that fluctuations of systemic blood pressure from initial low levels may be important in the pathogenesis of IVH. It is possible that changes in cerebral blood flow are of even greater significance.     

Intra-arterial blood pressure reference ranges, death and morbidity in very low birthweight infants during the first seven days of life

OBJECTIVES: We aimed to: (1) assess the association of average, low, high and variable mean blood pressure (mbp) on death and the common morbidities of very low birthweight infants, and in doing so, (2) to derive representative reference ranges for mbp in very low birthweight infants. STUDY DESIGN: This five year retrospective study assessed 1 min computer recordings of intra-arterial mbp in 232 very low birthweight infants over the first 7 days of life in a tertiary NICU. Four measures of mbp were assessed: average, variability, maximum (per time period), and percentage of time with a mean blood pressure less than the infant's gestation. Correlation was made with death and the development of intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL) and retinopathy of prematurity (ROP). RESULTS: The mbp increased with increasing birthweight and postnatal age (though with a slight decrease on days 6 and 7). Birthweight, gestation and colloid support (adjusted for birthweight and gestation) were the only factors significantly associated with mbp. IVH was predominantly associated with a low and variable mbp on the day IVH was noted or the day before. PVL and ROP were not associated with blood pressure. CONCLUSIONS: These reference ranges include more infants and data than previously published and relate mbp in this cohort to morbidity and mortality. They could assist clinicians in judging appropriate mbp for birthweight.     

Developmental and neurological progress of preterm infants with intraventricular haemorrhage and ventricular dilatation.

A prospective neurological and developmental assessment was completed at ages 6, 9, and 12 months on 39 preterm infants under 34 weeks'' gestation. In the newborn period each infant had an assessment of gestation and sequential neurological and ultrasound examinations and was placed in one of three groups: intraventricular haemorrhage (IVH) (n = 14), IVH followed by ventricular dilatation (n = 11), and control infants with no evidence of IVH (n = 14). When corrected for prematurity the Griffiths''s developmental quotients (DQs) were normal at 6, 9, and 12 months for every infant except one aged 12 months. In contrast, the uncorrected DQs at 12 months were under 80 in only one of the 14 preterm infants without haemorrhage, compared with 2 of the 14 with IVH, and with 7 of the 9 with IVH and dilatation. There was also a higher incidence of neurological abnormality at each follow-up age in the infants with IVH plus ventricular dilatation, compared with those with IVH alone, or with infants without IVH. Similar differences were also demonstrated in 5 milestones reflecting gross motor, fine motor, and social or verbal development in the three groups at 6, 9, and 12 months. The neurological and developmental deficits seemed to relate more closely to the presence of post-haemorrhagic ventricular dilatation than to the size of the initial haemorrhage itself. These results may have important implications for therapeutic intervention in the management of newborn infants with IVH and ventricular dilatation.     

Perfusion monitoring and intraventricular hemorrhage in preterm infants

Cardiovascular instability in preterm infants during the early postnatal period correlates with the development of intraventricular hemorrhage (IVH). Due to the correlation between hypotension and fluctuation of blood pressure, treatment was targeted specifically at hypotension to prevent IVH, but this was not successful. Recently, several novel perfusion markers have been found to be correlated with the development of IVH, and they are of current interest in cardiovascular management. In this review, the correlation between IVH and conventional, as well as novel, perfusion markers is examined.     

Haemodynamic effects of differing blood transfusion rates in infants less than 1500 g

Objective : To investigate whether the haemodynamic effects of the standard 2-3 h blood transfusion increases the risk for intraventricular haemorrhage (IVH) and patent ductus arteriosus (PDA) in very low birthweight infants.
Methodology : In a randomized controlled study, haemodynamic changes using slow and rapid transfusion were compared. Twenty-seven very low birthweight infants were divided between 12 h ( n = 14) and 3 h ( n = 13) transfusion groups. Blood pressure, ejection fraction (EF), anterior cerebral artery pulsatility index (Pl), blood gases, serum electrolytes and haematocrit were measured pre- and post-transfusion. Infectious status was also monitored.
Results : Blood pressure (48.1/25.5 vs 55.7/30.2 mmHg) and EF (0.68 vs 0.73) increased significantly during rapid transfusion ( P >0.01) but remained stable with slow transfusion. Serum potassium, base excess and incidence of infection did not increase in either group.
Conclusions : Slow transfusion causes less haemodynamic disturbance than rapid transfusion, thereby preventing the potential risk for IVH and PDA.