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.

Microbiology and risk factors for catheter exit-site and -hub colonization in neonatal intensive care unit patients.

OBJECTIVE: To identify risk factors and describe the microbiology of catheter exit-site and hub colonization in neonates. DESIGN: During a period of 2 years, we prospectively investigated 14 risk factors for catheter exit-site and hub colonization in 862 central venous catheters in a cohort of 441 neonates. Cultures of the catheter exit-site and hub were obtained using semiquantitative techniques at time of catheter removal. SETTING: A neonatal intensive care unit at a university hospital. RESULTS: Catheter exit-site colonization was found in 7.2% and hub colonization in 5.3%. Coagulase-negative staphylococci were predominant at both sites. Pathogenic flora were found more frequently at the catheter hub (36% vs 14%; P<.05). Through logistic regression, factors associated with exit-site colonization were identified as umbilical insertion (odds ratio [OR], 8.1; 95% confidence interval [CI95], 2.35-27.6; P<.001), subclavian insertion (OR, 54.6; CI95, 12.2-244, P<.001), and colonization of the catheter hub (OR, 8.9; CI, 3.5-22.8; P<.001). Catheter-hub colonization was associated with total parenteral nutrition ([TPN] OR for each day of TPN, 1.056; CI95, 1.029-1.083; P<.001) and catheter exit-site colonization (OR, 6.11; CI95, 2.603-14.34; P<.001). No association was found between colonization at these sites and duration of catheterization and venue of insertion, physician's experience, postnatal age and patient's weight, ventilation, steroids or antibiotics, and catheter repositioning. CONCLUSION: These data support that colonization of the catheter exit-site is associated with the site of insertion and colonization of the catheter hub with the use of TPN. There is a very strong association between colonization at both catheter sites.

Risk factors for central vascular catheter-associated bloodstream infections among patients in a neonatal intensive care unit.

The aim of this study was to identify risk factors for catheter-associated bloodstream infection (CABSI) in neonates. We undertook a prospective investigation of the potential risk factors for CABSI (patient-related, treatment-related and catheter-related) in a neonatal intensive care unit (NICU) using univariate and multivariate techniques. We also investigated the relationship between catheter hub and catheter exit site colonization with CABSI.Thirty-five episodes of CABSI occurred in 862 central catheters over a period of 8028 catheter-days, with a cumulative incidence of 4.1/100 catheters and an incidence density of 4.4/1000 catheter days. Factors independently associated with CABSI were: catheter hub colonization (odds ratio [OR] = 44.1, 95% confidence interval [CI] = 14.5 to 134.4), exit site colonization (OR = 14.4, CI = 4.8 to 42.6), extremely low weight (< 1000 g) at time of catheter insertion (OR = 5.13, CI = 2.1 to 12.5), duration of parenteral nutrition (OR=1.04, CI=1.0 to 1.08) and catheter insertion after first week of life (OR = 2.7, CI = 1.1 to 6.7). In 15 (43%) out of the 35 CABSI episodes the catheter hub was colonized, in nine (26%) cases the catheter exit site was colonized and in three (9%) cases colonization was found at both sites. This prospective cohort study on CABSI in a NICU identified five risk factors of which two can be used for risk-stratified incidence density description (birthweight and time of catheter insertion). It also emphasized the importance of catheter exit site, hub colonization and exposure to parenteral nutrition in the pathogenesis of CABSI.

The addition of indomethacin to betamimetics for tocolysis: any benefit for the neonate?

OBJECTIVE: To study the influence on the neonate of indomethacin administered to the mother as an additional tocolytic. STUDY DESIGN: The neonatal outcome in 76 closely matched low birth weight infants was compared retrospectively: those whose mothers received indomethacin together with betamimetics formed the study group, those whose mothers received only betamimetics formed the control group. RESULTS: There was an increased incidence of respiratory distress syndrome (RDS) in the study group (97% versus 45%; P<0.001), an increased need for surfactant use (68% versus 26%; P<0.001) and increased ventilatory support, and an increased incidence of bronchopulmonary dysplasia (BPD) (47% versus 24%; P=0.03). Gestation could not be prolonged significantly by the addition of indomethacin. CONCLUSION: Indomethacin as an additional tocolytic agent was associated with an increased incidence of RDS, surfactant use and BPD but did not significantly prolong gestation.

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.

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.

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.

Clinical experience with ceftriaxone treatment in the neonate.

The safety of ceftriaxone has been evaluated in 80 neonates who were treated empirically for suspected infection with either ceftriaxone and ampicillin (group A, age 0-72 h) or ceftriaxone and vancomycin (group B, age greater than 72 h). Within 48 h after birth 2 group A patients died from sepsis (Haemophilus influenzae, Streptococcus pneumoniae, 1 case each); 1 group B patient died from sepsis (Pseudomonas aeruginosa). All bacterial isolates from group A patients were susceptible to ceftriaxone, but in 4 of the 8 group B patients with positive cultures a change in antibiotic therapy was required. Eosinophilia, thrombocytosis and an increase in serum alkaline phosphatases were observed in a limited number of patients during and after discontinuation of treatment. Direct hyperbilirubinemia ( > 2 mg/dl) occurred in 2 cases during treatment. Gallbladder sludge was sonographically diagnosed in 6 patients, but disappeared within 2 weeks after detection. One neonate had exanthema. Nurses rated ease of administration as very good. Ceftriaxone appears to be an interesting alternative in the empiric antibiotic treatment in the early neonatal period.

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.

The use of intravenously administered immunoglobulins in the prevention of severe infection in very low birth weight neonates.

In a randomized prospective study in 116 selected neonates with very low birth weight, the effect of standard doses of intravenously administered immunoglobulins (IVIG) on the occurrence of severe infections was studied. No difference in infection rate or severity of infection could be observed between the treated neonates and the control group. The lack of effect could not be explained by an insufficient increase in the IgG serum levels, or inversely, by high immunosuppressive IgG levels. It is concluded that in very low birth weight neonates the administration of IVIG, under the conditions used in this investigation, does not protect against severe infection.

Intracardiac thrombus formation with rapidly progressive heart failure in the neonate: treatment with tissue type plasminogen activator.

A newborn is described in whom the use of a central venous line was complicated by septicaemia and by intracardiac thrombus formation with tricuspid valve insufficiency and heart failure. Besides antibiotics, treatment consisted of tissue type plasminogen activator (tPA) for three days. This treatment resulted in the disappearance of the thrombus and the tricuspid insufficiency. No adverse effects were noted. Treatment with tPA should be considered in intracardiac thrombus formation with rapidly progressive heart failure in the neonate.

Idiopathic arterial calcification of infancy.

We describe two twin sisters in whom calcification of different arteries was detected in the first weeks of life. Transient renal insufficiency, arterial hypertension, and skeletal abnormalities were also observed. One child had anasarca and heart decompensation at birth. Prenatal infarction of one kidney had occurred in the same infant. A kidney biopsy showed calcium deposits in all the layers of the arteries. Most findings in these patients are compatible with idiopathic arterial calcification of infancy (IACI). Investigation of calcium and phosphorus metabolism revealed spontaneously receding hypercalciuria, increased intraerythrocytic calcium levels, and transient X-ray abnormalities of the long bones. Treatment initially consisted of biphosphonate and later, the calcium antagonist flunarizin. A progressive diminution of the arterial calcification was observed in the course of both treatments.

Idiopathic cerebral arterial infarction with paucity of symptoms in the full-term neonate.

Two full-term neonates, one with convulsions and intermittent generalized hypotonia and one with poor sucking, temperature instability, and lethargy, are reported. CT scan findings suggested cerebral arterial infarction. Arteriography revealed occlusion of the middle cerebral artery, unilaterally in the first and bilaterally in the second patient. The evolution of the infarct could be followed on serial CT scans. No predisposing factors during pregnancy or delivery were found, and serious neurologic deficits developed in both children. These cases demonstrate that, even in full-term neonates with discrete or moderate neurologic symptoms and born after normal pregnancy and delivery, the possibility of vasoocclusive brain infarction should be considered. The diagnosis is suggested by imaging techniques, of which CT scanning seems to have the greatest value at present. This technique also permits the follow-up of the lesions. The prognosis for neurologic development appears to be variable: minor neurologic deficits as well as unexplained spastic hemiplegia in older children may be the consequence of inapparent cerebral arterial infarction in the neonatal period.