Limits of viability: definition of the gray zone.

INTRODUCTION: As survival and long-term morbidity of very preterm infants have improved over the past decade, the limits of infant viability, the level of maturity below which survival and/or acceptable neurodevelopmental outcome are extremely unlikely, have also decreased. STUDY DESIGN: In an effort to define the current limits of infant viability, the data in the literature on survival and long-term neurodevelopmental outcome in very preterm neonates have been reviewed. RESULT: The gestational age and birth weight below which infants are too immature to survive, and thus provision of intensive care is unreasonable, appears to be at <23 weeks and <500 g, respectively. Infants born at > or =25 weeks' gestation and with a birth weight of > or =600 g are mature enough to warrant initiation of intensive care, as the majority of these patients survive, and at least 50% do so without severe long-term disabilities. Finally, for infants born between 23(0/7) and 24(6/7) weeks' gestation and with a birth weight of 500 to 599 g, survival and outcome are extremely uncertain. For these infants born in the so-called 'gray zone' of infant viability, the line between patient autonomy and medical futility is blurred, and medical decision-making becomes even more complex and needs to embrace careful consideration of several factors. These factors include appraisal of prenatal data and the information obtained during consultations with the parents before delivery; evaluation of the patient's gestational age, birth weight and clinical condition upon delivery; ongoing reassessment of the patient's response to resuscitation and intensive care and continued involvement of the parents in the decision-making process after delivery. CONCLUSION: Based on these findings an algorithm is offered for consideration for neonatologists managing infants born in the 'gray zone' of infant viability. However, caution must be exercised when one considers incorporating this guideline into clinical practice because the algorithm is based on the analysis of the findings in the literature and the authors' experience rather than direct evidence.

Management of hypotension and low systemic blood flow in the very low birth weight neonate during the first postnatal week.

Systemic hypotension during the first postnatal week is associated with increased mortality and morbidity in the very low birth weight (VLBW) neonate. Hypotension is generally defined as blood pressure below the fifth percentile of the gestational- and postnatal-age dependent blood pressure norms. Recent studies indicate that in most VLBW neonates, cerebral blood flow autoregulation is indeed lost when blood pressure reaches the fifth percentile. Treatment of the circulatory compromise should address the primary pathogenic factor(s) of the condition (hypovolemia, myocardial compromise, failure of vasoregulation or a combination of factors). Recent findings also suggest that vasopressor resistance can be treated with a brief course of low-dose hydrocortisone. However, due to the short- and potential long-term side effects of early hydrocortisone treatment, its use should be restricted to neonates with vasopressor-resistant hypotension. Finally, concomitant administration of hydrocortisone with indomethacin should be avoided due to the increased incidence of gastrointestinal perforations.

Concurrent use of indomethacin and dexamethasone increases the risk of spontaneous intestinal perforation in very low birth weight neonates.

BACKGROUND: Dexamethasone or indomethacin predisposes very low birth weight (VLBW) neonates to spontaneous intestinal perforation (SIP). However, no study has specifically investigated the role of the concurrent use of indomethacin and dexamethasone in SIP. OBJECTIVE: To test whether the concurrent use of indomethacin and dexamethasone increases the risk of SIP. METHODS: In this single center, retrospective, 2:1 matched, case-control study, the odds of SIP were assessed using univariate and multivariate logistic regression analysis in < or =14-day old VLBW infants. RESULTS: Sixteen VLBW infants with SIP were matched to 32 controls by birth weight. After adjusting for clinically relevant variables, patients who received > or =3 doses of indomethacin for ductal closure or intraventricular hemorrhage prophylaxis and > or =3 doses of low-dose dexamethasone (0.3 mg/kg cumulative dose over 3 days) for refractory hypotension during the first postnatal week, were 9.6 times more likely to develop SIP [95% CI 1.22, 75.71]. CONCLUSIONS: The combined use of indomethacin and dexamethasone increases the risk of SIP in VLBW neonates.

Prone positioning decreases cardiac output and increases systemic vascular resistance in neonates.

OBJECTIVE: To evaluate the cardiovascular response to short-term prone positioning in neonates. STUDY DESIGN: In this prospective study, we continuously monitored heart rate (HR), stroke volume (SV) and cardiac output (CO) by electrical velocimetry in hemodynamically stable neonates in each of the following positions for 10 min: supine, prone and back-to-supine position. Skin blood flow (SBF) was also continuously assessed on the forehead or foot using Laser Doppler technology. Systemic vascular resistance (SVR) index was calculated as mean blood pressure (BP)/CO. Data were analyzed using repeated measures analysis of variance. RESULTS: Thirty neonates (gestational age: 35±4 weeks; postmenstrual age: 36±3 weeks) were enrolled. HR did not change in response to positioning. However, in prone position, SV, CO and SBF decreased and SVR index increased from 1.5±0.3 to 1.3±0.3 ml kg(-1) (mean ±s.d., P<0.01), 206±44 to 180±41 ml kg(-1) min(-1) (P<0.01), 0.54±0.30 to 0.44±0.29 perfusion units (P<0.01) and 0.25±0.06 to 0.30±0.07 mm Hg ml(-1) kg(-1) min(-1) (P<0.01), respectively. After placing the infants back-to-supine position, SV, CO, SBF and SVR index returned to baseline. The above pattern of cardiovascular changes was consistent in vast majority of the studied neonates. CONCLUSIONS: Short-term prone positioning is associated with decreased SV, CO and SBF and increased calculated SVR index.

The p15 matrix protein of moloney murine leukemia virus is a phosphotyrosine protein.

Retroviruses have been etiologically implicated with leukemia in humans and animals. Understanding the virus life cycle, the proteins and enzymes involved in its replication, is essential for developing potent anti-viral drugs. Phosphorylation of retroviral proteins may alter their shape in such a way as to increase or inhibit their biological activities and thus influence the replication and pathogenic potential of the retroviruses. In our previous work, we demonstrated that non-cytotoxic doses of tyrphostins (protein tyrosine kinase blockers) inhibit moloney murine leukemia virus (Mo-MuLV) replication in acutely and chronically infected cells. In an attempt to understand their mode of action as anti-MoMuLV drugs, we examined the possibility that a viral protein is phosphorylated in tyrosine. Indeed, in our present work, we show that the p15 matrix protein (MA) of Mo-MuLV is a phosphotyrosine protein and is the only viral protein which is phosphorylated on tyrosine. Moreover, treatment of Mo-MuLV/NIH/3T3 chronically infected cells with tyrphostin AG-555 specifically inhibits the synthesis of p15 and other viral proteins but does not affect the synthesis of cellular proteins. Our results suggest that tyrosine phosphorylation of p15 MA protein may play a pivotal role in Mo-MuLV replication.

DNA binding properties of the zinc-bound and zinc-free HIV nucleocapsid protein: supercoiled DNA unwinding and DNA-protein cleavable complex formation.

The HIV nucleocapsid (NC) protein contains, as those of other retroviruses, two Cys-His arrays which function as zinc finger binding domains. The nucleic acid binding properties of retroviral NC have been previously demonstrated. In this study, we characterized the DNA binding ability of the zinc-bound and zinc-free forms of HIV NC. We found that in addition to binding single-stranded DNA, both forms bind and unwind supercoiled plasmid DNA. The binding ability of the zinc-bound form was higher than the zinc-free form. In addition we showed the formation of NC protein-DNA cleavable complex which is the result of a presumably covalent bond formed between the protein and the phosphate moiety of the DNA backbone. The NC unwinding activity and the protein-DNA cleavable complex formation resembles the first step of the relaxing mechanism of DNA topoisomerase. Our results shed light on the possibility of a novel physiological function for the HIV NC protein in the viral life cycle.

Tyrphostin AG-555 inhibits early and late stages of Moloney murine leukemia virus replication cycle.

We have previously shown that certain tyrphostin derivatives, known as protein tyrosine blockers, inhibited Moloney murine leukemia virus (Mo-MuLV) replication in acutely and chronically infected NIH/3T3 cells, without affecting cell viability or growth. In our present work, we examined the stages in the viral life cycle that are affected by tyrphostin AG-555. We found that this drug inhibited the integration of the viral DNA into the host genome in acutely infected cells. This compound also reduced the level of viral RNA and specifically inhibited viral protein synthesis in NIH/3T3/Mo-MuLV chronically infected cells while no effect on the cellular beta-actin was observed. Since tyrphostin AG-555 inhibited both the early stages (integration process) and the late stages (viral protein synthesis) in the virus life cycle, it offers a potential advantage over other compounds which affect only one stage in the viral life cycle. Therefore, tyrphostin AG-555 may be considered as a potent antiretroviral drug.

Dopamine and natriuresis. Mechanism of action and developmental aspects.

The present paper summarizes our studies on the mechanisms of the dopamine induced changes in renal macro- and microcirculation as well as in proximal and distal tubular sodium handling which contributes to the natriuresis induced by the drug. Some aspects of the physiological role of locally generated dopamine in regulating sodium excretion are also reviewed. Finally, by describing the cardiovascular, renal and hormonal effects of dopamine in the preterm human neonate, some of the developmental aspects of the renal effects of the drug are also discussed.

The significance of L-amino acid decarboxylase and DARPP-32 in the kidney.

This study examines the role of endogenous dopamine (DA) for the regulation of renal tubular sodium (Na) transport. The enzyme L-amino acid decarboxylase (L-AADC) that converts L-dopa to DA has been localized to the proximal tubule cells with immunocytochemistry. Locally formed DA will inhibit the activity of Na-K-ATPase, the enzyme that yields energy to active Na transport. The effect is of physiological importance during high salt diet. The phosphoprotein DARPP-32, a DA1 receptor associated third messenger is abundant in the medullary thick ascending limb of Henle (mTAL). DARPP-32 is phosphorylated after activation of DA1 receptors. DARPP-32 is in its phosphorylated form a potent phosphatase inhibitor. Activation of the DA1 receptor in mTAL with the DA1 agonist SKF 82526 causes dose-dependent inhibition of Na-K-ATPase activity. The effect involves activation of cAMP protein kinase. It is likely that this effect is potentiated by DARPP-32.

Developmental changes in erythrocyte Na(+),K(+)-ATPase subunit abundance and enzyme activity in neonates.

AIM: To study the relation between erythrocyte Na(+),K(+)-ATPase subunit isoform composition, Na(+),K(+)-ATPase activity, and cation pump function in preterm and term neonates. DESIGN: Erythrocyte Na(+),K(+)-ATPase subunit isoform abundance, Na(+),K(+)-ATPase activity, and cation pump function were studied in blood samples obtained from 56 preterm neonates of 28-32 weeks gestation (group 1), 58 preterm neonates of 33-36 weeks gestation (group 2), and 122 term neonates (group 3) during the first two postnatal days. RESULTS: alpha(1) isoform abundance was higher and beta(2) isoform abundance was lower in group 1 than in group 3 (p = 0.0002). alpha(2) and beta(1) isoform abundance did not change with maturation and there was no evidence for the presence of the alpha(3) isoform. Gestational age was inversely related to Na(+), K(+)-ATPase activity (p = 0.0001) and directly related to intracellular Na(+) concentration (p = 0.0025). CONCLUSIONS: Expression of the alpha(1) and beta(2) Na(+),K(+)-ATPase subunit isoforms is developmentally regulated. The increased abundance of alpha(1) isoforms of immature neonates translates to increased ATPase activity. The lower intracellular Na(+) concentration of immature neonates suggests that their erythrocyte Na(+),K(+)-ATPase cation pump function may also be increased.

Meningitis in a newborn infant with urosepsis, negative blood cultures and initially normal cerebrospinal fluid findings.

This case presentation supports the observation that initial cerebrospinal fluid findings can be normal in newborn infants with sepsis syndrome who then develop evidence for meningeal involvement. Therefore, if initial lumbar puncture results are negative, a repeat lumbar puncture is recommended to look for meningitis in newborns that are critically ill with sepsis syndrome.

Use of high-frequency jet ventilation in neonates with hypoxemia refractory to high-frequency oscillatory ventilation.

OBJECTIVE: To describe the response to high-frequency jet ventilation in infants with hypoxemic respiratory failure unresponsive to high-frequency oscillatory ventilation. METHODS: This was a retrospective analysis of chart records on demographics, ventilator settings, blood gas analysis and calculated oxygenation index prior to and during the first 7 days of high-frequency jet ventilation in ten consecutive infants. RESULTS: Before the initiation of high-frequency jet ventilation, the ventilatory mean airway pressure (MAP; cmH2O), fraction of inspired oxygen (FiO2) and oxygenation index on high-frequency oscillatory ventilation were 14.3 +/- 1.3, 0.97 +/- 0.02 and 29 +/- 5, respectively. Three hours after the initiation of high-frequency jet ventilation, the oxygenation index improved to 18 +/- 4 (p < 0.001) and the improvement was sustained during the study period. By 6 h of high-frequency jet ventilation, the FiO2 decreased to 0.62 +/- 0.09 (p < 0.01) and, by 1-3 h of ventilation, the MAP decreased to 10.9 +/- 1.3 (p < 0.01). The improvement in FiO2 persisted for 7 days while, although the MAP remained lower throughout the study, the improvement in MAP failed to reach statistical significance after 72 h. No significant changes in pH, pCO2, or pO2 before or during high-frequency jet ventilation were noted. CONCLUSION: High-frequency jet ventilation improves hypoxemic respiratory failure unresponsive to high-frequency oscillatory ventilation in infants. These findings suggest that not all high-frequency ventilatory devices yield the same clinical results.

Does targeted neonatal echocardiography affect hemodynamics and cerebral oxygenation in extremely preterm infants?

OBJECTIVE: To investigate the effect of targeted neonatal echocardiography (TnEcho) on heart rate, arterial oxygen saturation (SPO2), cerebral regional oxygen saturation (CrSO2) and cerebral fractional oxygen extraction (CFOE) in extremely preterm infants during the first 3 postnatal days. STUDY DESIGN: s a nested study in a prospective observational study, we acquired continuous data on heart rate, SPO2, CrSO2 and CFOE. Data averaged for the duration of TnEcho study were compared with the data collected during a baseline period immediately before the start of echocardiography. The duration of the baseline and study periods was the same. TnEcho evaluation included assessment of preload, afterload, contractility, left and right ventricular output, patent ductus arteriosus and foramen ovale. RESULT: We analyzed 138 data pairs before and during TnEcho in 22 extremely preterm infants (gestational age 25.9 ± 1.2 weeks; range 23 to 27). There was no significant difference in heart rate between baseline and TnEcho period. There was a statistical, but clinically negligible, difference between baseline and TnEcho in SPO2 (median (quartile) 91.4% (88.9, 94.2) vs 91.3% (88.9, 94), P = 0.048), CrSO2 (76.8% (70.7, 81.5) vs 74.9% (69.5, 80.1), P<0.0001) and CFOE (15.8% (9.8, 23.6) vs 17.5% (11.3, 24.7), P<0.0001). The changes in the parameters monitored were similar in preterm infants who developed peri/intraventricular hemorrhage and in those who did not. CONCLUSION: Although there were statistically significant changes in SPO2, CrSO2 and CFOE, the alterations were minimal and unlikely of clinical relevance. Thus, cerebral hemodynamics and systemic and cerebral oxygenation are not perturbed during TnEcho and the procedure is well tolerated by the extremely preterm infants during the postnatal transitional period.

The use of mobile robotic telemedicine technology in the neonatal intensive care unit.

OBJECTIVE: To describe the use of a wireless, mobile, robotic telecommunications system in the Neonatal Intensive Care Unit (NICU). STUDY DESIGN: In this prospective study utilizing 304 patient encounters on 46 preterm and term neonates in a level IIIa NICU, a bedside neonatologist ('on-site neonatologist'; ONSN) and a neonatologist at a distant location ('off-site neonatologist'; OFFSN) evaluated selected demographic information, laboratory data and clinical and radiological findings of the subjects. The OFFSN used a commercial wireless, mobile, robotic telecommunications system controlled from a remote site. The two physicians were blinded to each other's findings and agreement rates of the evaluations between the ONSN and the OFFSN were compared using kappa statistics. Agreement rates between two ONSNs using the same protocol with 39 patient encounters served as the reference standard. The dependability and timeliness of data transmission were also assessed. RESULT: Excellent or intermediate-to-good agreements were noted for all but a few physical examination assessments between both the ONSN and OFFSN and the two ONSNs. Poor agreements were found for certain physical examination parameters (breath-, heart- and bowel-sounds and capillary refill time) with or without the use of telemedicine. The median duration of the encounters by the ONSN and OFFSN and the two ONSNs was similar. Five encounters were excluded from the analysis because of technical difficulties. No complications associated with the use of the mobile robot were noted. CONCLUSION: Our findings indicate that the use of mobile robotic telemedicine technology is feasible for neonates in the NICU.

A meta-analysis of dopamine use in hypotensive preterm infants: blood pressure and cerebral hemodynamics.

OBJECTIVE: Dopamine administration results in variable effects on blood pressure in hypotensive preterm infants. The clinical benefits of dopamine administration in increasing cerebral blood flow (CBF) and reducing adverse neurological outcomes in hypotensive preterm neonates are unclear. The objective of this study was to examine the efficacy of dopamine for treatment of hypotension and investigate the changes in cerebral hemodynamics and central nervous system injury in hypotensive preterm infants following dopamine administration. STUDY DESIGN: Standard meta-analytic techniques, including random and fixed effects models, were used to calculate combined effect size correlations and significance levels. RESULT: Random effects meta-analysis found that dopamine increases mean arterial blood pressure (12 studies; N=163; r=0.88, 95% confidence interval (CI)=0.76 to 0.94) and systolic blood pressure (8 studies; N=142; r=0.81, 95% CI=0.42 to 0.94). For the increase in blood pressure, dopamine administration was associated with a significantly greater overall efficacy than dobutamine (seven studies; N=251; r=0.26; 95% CI=0.20 to 0.32), colloid (two studies; N=67; r=0.60; 95% CI=0.41 to 0.74) and hydrocortisone (one study; N=28; r=0.40; 95% CI=0.034 to 0.67). CBF increased following dopamine administration (five studies; N=75; r=0.36; 95% CI=-0.059 to 0.67) and the increase in CBF was greater in hypotensive than normotensive preterm infants (eight studies; N=153; r=0.16; 95% CI=-0.0080 to 0.32). There were no statistically significant differences in adverse neurological outcome between dopamine and dobutamine (three studies; N=118; r=-0.13; 95% CI=-0.31 to 0.059), epinephrine (two studies; N=46; r=0.06; 95% CI=-0.23 to 0.34), colloid (two studies; N=80; r=0.0070; 95% CI=-0.218 to 0.23) or hydrocortisone administration (one study; N=40; r=-0.10; 95% CI=-0.40 to 0.22). CONCLUSION: Dopamine administration increases mean and systolic blood pressure in hypotensive preterm infants, and is more effective than dobutamine, colloid or hydrocortisone alone. Dopamine administration is associated with increased CBF, with greater increases in CBF in hypotensive than in normotensive preterm infants. Dopamine is not associated with a greater incidence of adverse effects than other therapies used to treat hypotension.

Hydrocortisone for hypotension and vasopressor dependence in preterm neonates: a meta-analysis.

BACKGROUND: A full consensus has not been reached about the hemodynamic efficacy of hydrocortisone administration in hypotensive and vasopressor-dependent preterm neonates. OBJECTIVE: To examine the efficacy of hydrocortisone for treatment of hypotension and reduction of vasopressor requirements in preterm infants. METHOD: Standard meta-analytic techniques, including random and fixed effects models, were used to calculate combined effect size correlations and significance levels. RESULT: Random effects meta-analysis showed that hydrocortisone increases blood pressure (seven studies; N=144; r=0.71, 95%CI=0.18 to 0.92) and reduces vasopressor requirement (five studies; N=93; r=0.74, 95%CI=0.0084 to 0.96). The number of new or unretrieved studies averaging null results required to increase the overall p to 0.05 is k=78 for blood pressure increase and k=47 for vasopressor requirement reduction. CONCLUSION: The effects of hydrocortisone on increasing blood pressure and decreasing vasopressor requirements in preterm infants are robust with a large tolerance for future null results. Actual clinical benefits of increasing blood pressure and decreasing vasopressor requirements, however, remain unknown. Long-term sequelae of hydrocortisone administration have yet to be fully elucidated.

Hemodynamic monitoring in neonates: advances and challenges.

Continuous, reliable and real-time assessment of major determinants of cardiovascular function in preterm and term neonates has long been an elusive aim in neonatal medicine. Accordingly, aside from continuous assessment of heart rate, blood pressure and arterial oxygen saturation, bedside monitoring of major determinants of cardiovascular function of significant clinical relevance such as cardiac output, systemic vascular resistance, organ blood flow distribution and tissue oxygen delivery and coupling has only recently become available. Without obtaining reliable information on the changes in and interactions among these parameters in the neonatal patient population during postnatal transition and later in the neonatal period, development of effective and less harmful treatment approaches to cardiovascular compromise is not possible. This paper briefly reviews the recent advances in our understanding of developmental cardiovascular physiology and discusses the methods of bedside assessment of cardiovascular function in general and organ perfusion, tissue oxygen delivery and brain function in particular in preterm and term neonates. The importance of real-time data collection and the need for meticulous validation of the methods recently introduced in the assessment of neonatal cardiovascular function such as echocardiography, electrical impedance cardiometry, near infrared spectroscopy, visible light and laser-Doppler technology are emphasized. A clear understanding of the accuracy, feasibility, reliability and limitations of these methods through thorough validation will result in the most appropriate usage of these methods in clinical research and patient care.