Ethical aspects of cardiopulmonary resuscitation in premature neonates: where do we stand?

Advances in diagnosis, techniques, therapeutic interventions, organisation of perinatal care, and socio-economic factors have all contributed to the survival after resuscitation and intensive care of neonates with extremely low birth weight and gestational age. While morbidity during the first years of life in those infants does not increase, at school age multiple dysfunctions may become apparent. What are the limits of intensive care for the newborn? Is it right to use extreme technical and economic measures for neonates with a borderline chance of survival? What is justifiable for the neonate, the family, the society and how does legislation interfere in a decision process which involves starting, stopping or continuing intensive care? A short historical overview for the care of the newborn is given, followed by the outcome after resuscitation and treatment of the very low birth weight infant. Published management strategies and recommendations are discussed.

Prediction of nosocomial sepsis in neonates by means of a computer-weighted bedside scoring system (NOSEP score)

OBJECTIVE: To develop an easy-to-use bedside scoring system, composed of clinical variables, hematologic variables, and risk factors of infection, to predict nosocomial sepsis in neonatal intensive care unit patients. SETTING: A neonatal intensive care unit in a university hospital, Antwerp, Belgium. PATIENTS: Over 2 yrs, we analyzed two groups of patients. First, we prospectively studied 104 episodes of presumed nosocomial sepsis in 80 neonates (derivation cohort), and then we retrospectively studied 50 episodes in 39 neonates (validation cohort). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We developed two versions of a scoring system to predict nosocomial sepsis in sick neonates. The first scoring system (NOSEP-1 score) was based on 15 clinical, 12 laboratory, and 17 historical variables potentially connected with infection; the second one (NOSEP-2 score) also included the culture results of central vascular catheters. Based on the odds ratios of all independent variables, an additive and weighted score was developed and validated in a cohort of 39 patients screened for nosocomial sepsis in the same center. The NOSEP-1 score consisted of three laboratory variables (C-reactive protein > or =14 mg/L, thrombocytopenia <150 x 10(9)/L, and neutrophil fraction >50%), one clinical factor (fever >38.2 degrees C [100.8 degrees F]), and one risk factor (parenteral nutrition for > or =14 days). The NOSEP-2 score consisted of the same variables plus catheter-hub and catheter insertion site colonization data. Receiver operating characteristic curve analysis demonstrated good predictor performance of the NOSEP-1 score (area under the curve [Az] = 0.82 +/- 0.04 [SEM]) and NOSEP-2 score (Az = 0.84 +/- 0.04, p < .05). We checked whether a complex computer-generated scoring system (CD-1 and CD-2 scores) based on the original numerical values of the items used in NOSEP-1 and NOSEP-2 would improve the prediction of nosocomial sepsis. The analysis showed the accuracy of bedside NOSEP-1 and NOSEP-2 scores to be comparable with the more cumbersome computer-generated CD-1 and CD-2 scores (receiver operating characteristic curve, Az: CD-1 score = 0.81 +/- 0.04, p = .69, and CD-2 score = 0.86 +/- 0.04, p = .96). Finally, in the validation cohort, we showed that the developed scoring system has a good prediction potential for nosocomial sepsis (Hosmer-Lemeshow goodness-of-fit test, chi2 [19] = 16.34, p > .75). CONCLUSIONS: The simple bedside scoring system NOSEP-1 composed of C-reactive protein, neutrophil fraction, thrombocytopenia, fever, and prolonged parenteral nutrition exposure provides a valuable tool for early identification of nosocomial sepsis. Its predictive power can be improved by adding central vascular catheter insertion site and hub colonization to the score.

Treatment of patent ductus arteriosus with ibuprofen.

AIM: To evaluate the efficiency and side effects of ibuprofen for the early treatment of patent ductus arteriosus (PDA) and compare it with indomethacin. METHODS: Forty preterm infants with gestational ages of less than 33 weeks, with respiratory distress syndrome (RDS) and echocardiographically confirmed PDA, were randomly assigned at days 2 to 3 of life to receive either intravenous indomethacin 3 x 0.2 mg/kg at 12 hour intervals or intravenous ibuprofen 1 x 10 mg/kg, followed by 5 mg/kg 24 and 48 hours later. RESULTS: PDA closed in 15 of 20 patients from the indomethacin group (75%) and in 16 of 20 (80%) from the ibuprofen group. Seven patients (three indomethacin, four ibuprofen) required a second treatment with indomethacin and in five (three in the indomethacin group and two in the ibuprofen group) the duct was ultimately ligated. Ibuprofen patients had a better urinary output and showed no increase in serum creatinine concentrations compared with the indomethacin group. Ibuprofen was not associated with any other side effect. CONCLUSIONS: Ibuprofen treatment seems to be as efficient as indomethacin in closing PDA on the third day of life in preterm infants with respiratory distress syndrome and seems to have fewer renal side effects.

A retrospective epidemiological study of bacterial meningitis in an urban area in Belgium.

UNLABELLED: In order to obtain epidemiological data on the incidence of bacterial meningitis (BM) before the systematic introduction of vaccination against Haemophilus influenzae type b, a retrospective study of 124 children with proven BM was performed in an urban area in Belgium. N. meningitidis was the most prevalent cause, followed by H. influenzae and S. pneumoniae. Over a period of 6 years the incidence of BM increased ten fold, mainly due to an increase in N. meningitidis. The median age of the children with BM was 17 months and 35% of those with H. influenzae were younger than 1 year. Significant risk factors for BM as a whole were: age under 1 year, male gender, non-Caucasian descent and winter time. These findings may have implications for future vaccination policy in Belgium. CONCLUSION: Future vaccination schemes in Belgium should take into account than N. meningitis was the prevalent cause of bacterial meningitis and that certain factors increase the risk for developing bacterial meningitis.

Stress responses to tilting and odor stimulus in preterm neonates after intrauterine conditions associated with chronic stress.

The effect of conditions linked with chronic intrauterine stress (CIUSTR) on the function of the autonomic nervous system (ANS) has not yet been evaluated systematically in premature neonates. We hypothesized that intrauterine stress deranges the function of the ANS as assessed by the clinical responses to certain stimuli. Twenty-one premature neonates who had suffered from CIUSTR, such as maternal smoking, maternal hypertension, and intrauterine growth retardation (STR Group), and 30 neonates who had not suffered from those intrauterine conditions were studied (C Group). They were exposed to a 10-s postural change test and a 10-s odor test. Heart rate, respiratory rate, and noninvasive blood pressure were measured at 15 s, 30 s, and at 1, 2, 3, 4, and 5 min after the test. The overall reaction pattern after the postural change test was mainly sympathetic, and was more pronounced in the STR Group. After the odor test, the overall response was parasympathetic but less pronounced in the STR Group. We, therefore, speculate that neonates who suffer from conditions known to be associated with CIUSTR exhibit a higher adrenergic state with little reserve to counteract stressful situations that may make them more vulnerable.

Anti-glomerular basement membrane glomerulopathy in a young child.

We report the youngest patient with anti-glomerular basement membrane disease described in the literature to date. Age-dependent expression of the target antigen in this auto-immune disease explains the low incidence in young children. Despite adequate immunosuppression, renal function did not recover in our patient.

Functional residual capacity in healthy preschool children.

The purpose of this study was to evaluate the feasibility of routine functional residual capacity (FRC) measurements in healthy preschool children aged 2.7-6.4 yrs. Furthermore, accuracy and reproducibility were investigated and normal values were collected. A mass-produced closed-circuit helium dilution device (rolling seal) was used. Selection of the 113 healthy children (from the 571 measured) was based on an extensive personal and family history questionnaire and on clinical examination before measurements were performed. With three successive attempts it was possible to achieve at least two reproducible measurements in 73% of the children (repeatability coefficient 95.3 mL). The main problems were leakage at the corner of the mouth and irregular breathing pattern. The mean time to perform a measurement was 113 s. Mean FRC was significantly higher in boys than in girls: 778 versus 739 mL for a body length of 110 cm (p<0.05). FRC correlated with height (H) (r=0.69), weight (W) (r=0.56), age (A) (r=0.62) and all three combined (r=0.70): FRC = -534.89 + 1.84 x W (kg) + 10.07 x H (cm) + 2.51 x A (months). When a power or exponential function was used to describe FRC as a function of height, the results were not superior to the linear regression (r=0.69): FRC (mL) = -766.2 + 13.8 x H (cm) (r=0.69) or FRC (L) = 0.620 x H (m)(2.03) (r=0.69) or FRC (mL)= 99.5 x e(0.018xH (cm)) (r=0.69). Among these, we recommend the power function because it will better fit broader height ranges. Reliable functional residual capacity measurements can be routinely performed in preschool children with a mass-produced device. Reference values were collected for children 95-125 cm in height.

Hyperoxaluria with hyperglycoluria not due to alanine:glyoxylate aminotransferase defect: a novel type of primary hyperoxaluria.

Considering the clinical heterogeneity of primary hyperoxaluria type I (PH1) and the fact that in many instances this diagnosis was made without enzymatic and immunohistochemical investigation, other disturbances of oxalate metabolism than those presently known can be expected in PH1. Using a gaschromatographic/mass spectrometric method that allows quantification of these acids, hyperoxaluria and hyperglycoluria was found repeatedly in two unrelated patients. The hyperoxaluria was unresponsive to pyridoxine. There was no nephrocalcinosis or urolithiasis. In the liver biopsy normal AGT activity and normal localization of this enzyme in the peroxisome was found. In one patient abnormal Km and maximal activity and mozaicism of AGT were excluded. Hyperoxaluria and hyperglycoluria were also found in other family members, suggesting autosomal dominant transmission. Although the underlying defect leading to hyperoxaluria and hyperglycoluria could not be identified in these patients, it is probable that they represent a separate type of primary hyperoxaluria.

Stress responses in preterm neonates after normal and at-risk pregnancies.

OBJECTIVE: To evaluate the autonomic response in preterm neonates born after an at-risk pregnancy. METHODOLOGY: Twenty-one preterm neonates (gestational age; GA) 29-37 weeks; bodyweight (BW): 720-2113 g; postnatal age: 2-126 days), born after at-risk pregnancies (stressed (STR) group), were compared to 30 preterm neonates (GA: 26-36 weeks; BW: 813-2380 g: postnatal age: 2-86 days) without any intrauterine risk factor (C group). A 10 s pain stimulus was given on the forefoot and heart rate, respiratory rate and blood pressure were measured at 15 and 30 s, at 1, 2, 3, 4 and 5 min. After 10 s ocular compression six cardiac variables were recorded. RESULTS: After the pain stimulus the STR-group had a significant increase of heart rate at 15 s and an increase of diastolic blood pressure at 30 s. In the C group a significant increase of heart rate at 15 s was recorded. For the respiratory rate both groups showed an initial depression (significant at 15 s in the C group) followed by an increase. The time to react to the ocular compression was significantly shorter in the STR-group than in the C-group and thus more parasympathetic. CONCLUSIONS: We hypothesize that the different sympathetic and parasympathetic reaction patterns of the vital parameters to triggers in the STR-group are due to chronic stress, pointing to an altered maturation of the two components of the autonomic nervous system after chronic intrauterine stress (CIUSTR).

Ontogeny of epinephrine, norepinephrine, dopamine-beta-hydroxylase, and chromogranin A in the adrenal gland of pigs.

OBJECTIVE: To obtain data on the ontogeny of catecholamines and other chromaffin vesicle components, which could serve as a basis for the study of their role during fetal life in normal and pathologic conditions. DESIGN: Epinephrine, norepinephrine, dopamine-beta-hydroxylase, and chromogranin A contents were measured in the porcine adrenal gland during various stages of gestation. ANIMALS: 934 porcine fetuses representing 22 gestational ages between 43 and 108 days. PROCEDURE: Total homogenates of adrenal glands were extracted and contents of different neurochemical markers were measured, using high-performance liquid chromatography, immunoassays, and western blotting. Immunohistochemical studies also were performed. RESULTS: Epinephrine and norepinephrine contents as a function of gestational age can be represented by a sigmoidal curve. Norepinephrine content rises early in gestation, whereas epinephrine content increases later. Maximal increase was significantly higher for epinephrine content. A progressive appearance of separate epinephrine- and norepinephrine-storing cells was documented. Dopamine-beta-hydroxylase content as a function of gestational age can be adequately represented by a parabolic curve. No quantitative changes in chromogranin A concentration were observed, but western blotting revealed qualitative changes with progressing gestational age. CONCLUSIONS: Important changes occur in catecholamine formation around day 60 of gestation. The sharp increase in epinephrine/norepinephrine contents and the appearance of separate epinephrine- and norepinephrine-storing cells may be related to the progressive splanchnic innervation of the adrenal gland. The presence of chromogranin A early in gestation may indicate its necessity for catecholamine storage.

Clinical defense response to cold and noise in preterm neonates after intrauterine conditions associated with chronic stress.

Threatening stimuli may trigger abnormal reaction patterns in animals and infants. We investigated whether chronic intrauterine stress influenced these reactions. The autonomic defense response to cold and noise in 21 preterm newborns who had suffered from chronic intrauterine stress, such as maternal smoking, maternal hypertension, and intrauterine growth retardation (STR-group) was compared with the response in 30 preterm newborns without such condition (C-group). An ice cube was applied to the forehead and a 90 dB bleeptone was presented to the ears. After the cold test the heart rate, systolic, diastolic, and mean blood pressure increased in both groups, but to a lesser extent in the STR-group: the heart rate increased more at 2 minutes in the C-group (p = 0.009), and the systolic blood pressure was higher in the C-group at 30 seconds (p = 0.007). The respiratory rate decreased in both groups. After the auditory stimulus, no significant difference in response between the two groups was seen for any of the parameters. The number of arousals between the two groups was similar for both tests; they uniformly resulted in increased heart and respiratory rates. The classic passive defense response was not observed in either group of preterm newborns. The observed reaction could be defined as a combination of a sympathetic, active fight-or-flight reaction and a parasympathetic passive freezing, or paralysis, reaction. The latter was less pronounced in the C-group. This may point to a change in the maturation of the autonomic nervous system after chronic intrauterine stress. It is speculated that this could make these infants more vulnerable in stressful situations.

Low thyroxinaemia occurs in the majority of very preterm newborns.

UNLABELLED: Transient hypothyroxinaemia with normal thyroid stimulating hormone (TSH) levels is a well-known condition in preterm neonates and is generally assumed to be a harmless epiphenomenon of prematurity. This assumption is, however, based on studies that included very few neonates with a gestational age (GA) below 30 weeks. We therefore measured serum free thyroxine (FT4) and serum TSH on days 1 and 14 in 263 neonates with a GA between 26 and 41 weeks. In 13 infants (5%), transient hypothyroidism (low FT4 and TSH >20 mU/l on day 14) was found. In the remaining 250 patients FT4 on days 1 and 14 but not TSH correlated positively with GA. In neonates with a GA of 35-41 weeks, FT4 increased postnatally to levels within or above the normal adult range. In contrast, in the very preterm group (26-31 weeks) the already low FT4 levels declined to values significantly below the range observed in term neonates. A significant proportion of these neonates had FT4 levels within the hypothyroid range. There was no difference in thyroid function between neonates treated with povidone-iodine or chlorhexidine. CONCLUSION: Very preterm neonates have FT4 levels on day 14 that are much lower than is generally assumed while TSH remains in the normal range. We therefore propose to measure FT4 in all preterms with a GA below 33 weeks, during the 2nd week of life.

Umbilical cord dopamine beta-hydroxylase, chromogranin A and met-enkephalin after conditions associated with chronic intrauterine stress.

OBJECTIVE: To evaluate whether the markers of autonomic nervous system activity, dopamine beta-hydroxylase (DBH), chromogranin A (CGA) and met-enkephalin (E), are different in cord blood from neonates born after conditions associated with chronic intrauterine stress (CIUS) as compared to neonates born after a normal pregnancy. STUDY DESIGN: 61 newborns (median BW 2,840 g, range 617-4270 g) born after a pregnancy complicated by maternal hypertension, maternal smoking, maternal diabetes mellitus or intrauterine growth retardation (STR group) were compared with 88 neonates (median BW 2,910 g, range 4,00-4,370 g) who had not suffered from such intrauterine conditions. DBH, CGA and E were measured in the cord blood of both groups. RESULTS: When both groups were taken together, high DBH values were best related to maternal smoking (p = 0.004) and low E levels to maternal diabetes (p = 0.02). Within the STR group, high DBH values were best related with all conditions linked with CIUS (p = 0.008), E levels were best linked with the combination of intrauterine growth retardation (positive correlation) and maternal diabetes (negative correlation) (p = 0.03). For CGA there was only a weak positive relation with maternal smoking (p = 0.3). CONCLUSION: Certain intrauterine conditions associated with CIUS, especially maternal smoking, may lead to alterations of the autonomic nervous system as revealed by some of its markers in cord blood of neonates. This may be important in the pathogenesis of certain conditions after birth, such as the sudden infant death syndrome.

Congenital streptococcal toxic shock syndrome with absence of antibodies against streptococcal pyrogenic exotoxins.

Congenital infection with group A beta-hemolytic streptococcus was complicated by toxic shock syndrome in a neonate. We hypothesize that the severity of the clinical syndrome was related to the streptococcal pyrogenic exotoxin in the absence of corresponding antibodies. The outcome may have been favorably influenced by the antibodies to streptococcal pyrogenic exotoxin present in the immunoglobulins given as treatment.

Aspirin versus indomethacin treatment of patent ductus arteriosus in preterm infants with respiratory distress syndrome.

Indomethacin (Indo) is commonly used for treatment of patent ductus arteriosus (PDA) but has renal failure as a main side effect. Aspirin (ASA) is an alternative, but there are no controlled trials on its efficacy. We randomly assigned 75 premature infants suffering from respiratory distress syndrome (RDS) (mean gestational age: 29.6 +/- 2.5 wk, mean birth weight: 1295 +/- 464 g) (+/- SD) and on artificial ventilation at the start of the study (mean: 3.4 d of life), to either Indo (3 x 0.2 mg/kg/12 h) or ASA (4 x 15 mg/kg/6 h). PDA and degree of shunting were evaluated by echocardio-Doppler; side effects were carefully recorded. PDA closed in 35/38 patients from the Indo group (92%) and in 16/37 patients from the ASA group (43%) (p < 0.0001). Nineteen patients needed further treatment with Indo or surgery (17 in the ASA group and 2 in the Indo group). The only side effect observed was a decrease of uresis in the Indo group during 4 d post treatment (p < 0.01). Closing of PDA was positively correlated with gestational age, but not with time of starting Indo/ASA or grade of shunting. We conclude that ASA is not as effective in closing PDA as Indo, but has no adverse effect on uresis.

Inadequate intravenous feeding in sick neonates: a retrospective study.

It is a common experience that during intravenous feeding (IVF) in neonates the administered amounts do not always meet the recommendations. In an attempt to quantify these deficits and to determine the causes we studied the data of 2 comparable groups of neonates admitted to a neonatal intensive care unit (NICU). In Group 1 (N = 107; gestational age 25-42 weeks; birth weight 690-5920 g) the minimum recommended intake of energy (70 kCal/kg/d) and of aminoacids (2.5g/kg/d) was not met in 17% and in 71% respectively. The main causes of inadequate intake were believed to be the nearly exclusive use of peripheral venous access, and the restriction in glucose and/or lipid administration because of extreme prematurity and/or severe illness. In Group 2 (N = 99; gestational age 24-42 weeks; birth weight 670-4300 g), where these causes were corrected, 11% and 54% of the patients still received an insufficient amount of energy and amino acids respectively. It can be concluded that in the daily practice in a NICU, even in optimal conditions and following the recent recommendations for IVF, a considerable proportion of preterm neonates do not receive the minimal recommended amount of energy and aminoacids.

Urinary excretion of purine and pyrimidine metabolites in the neonate.

Random urine samples from 614 neonates were screened for metabolites of purine and pyrimidine metabolism using an adapted column chromatographic method. A restricted number of metabolites and a number of unidentified peaks appeared on the chromatograms. No inborn errors of this metabolism were found. The chromatograms were identical in term and in premature or dysmature neonates, except for the presence of more unidentified peaks in the latter group. The pattern was not influenced by the type of feeding or i.v. nutrition. Metabolites of different medications were identified. One female neonate with an increased excretion of uracil was shown to be heterozygous for ornithine carbamyl transferase deficiency.

Protein restriction in chronic renal failure.

The aim of the study was to investigate the effect of a protein restricted diet on renal function and growth of children with chronic renal failure. In a multicentre prospective study 56 children (aged 2-18 years) with chronic renal failure were randomly assigned to the protein restricted (0.8-1.1 g/kg/day) or the control group. All children were followed up by the same paediatrician and dietitian. After a follow up period of three years there was no significant difference in glomerular filtration rate between children on a protein restricted diet and children of the control group. There was no significant difference in weight with respect to height and height SD score between the protein restricted and the control group. Compliance with the protein restricted diet, as indicated by the prospective diet diaries and the serum urea:creatinine ratio, was good. This study shows that children with chronic renal failure do not benefit from a protein restricted diet.