Differences in Blood Pressure in Infants After General Anesthesia Compared to Awake Regional Anesthesia (GAS Study-A Prospective Randomized Trial).

BACKGROUND: The General Anesthesia compared to Spinal anesthesia (GAS) study is a prospective randomized, controlled, multisite, trial designed to assess the influence of general anesthesia (GA) on neurodevelopment at 5 years of age. A secondary aim obtained from the blood pressure data of the GAS trial is to compare rates of intraoperative hypotension after anesthesia and to identify risk factors for intraoperative hypotension. METHODS: A total of 722 infants ≤60 weeks postmenstrual age undergoing inguinal herniorrhaphy were randomized to either bupivacaine regional anesthesia (RA) or sevoflurane GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born at <26 weeks of gestation. Moderate hypotension was defined as mean arterial pressure measurement of <35 mm Hg. Any hypotension was defined as mean arterial pressure of <45 mm Hg. Epochs were defined as 5-minute measurement periods. The primary outcome was any measured hypotension <35 mm Hg from start of anesthesia to leaving the operating room. This analysis is reported primarily as intention to treat (ITT) and secondarily as per protocol. RESULTS: The relative risk of GA compared with RA predicting any measured hypotension of <35 mm Hg from the start of anesthesia to leaving the operating room was 2.8 (confidence interval [CI], 2.0-4.1; P < .001) by ITT analysis and 4.5 (CI, 2.7-7.4, P < .001) as per protocol analysis. In the GA group, 87% and 49%, and in the RA group, 41% and 16%, exhibited any or moderate hypotension by ITT, respectively. In multivariable modeling, group assignment (GA versus RA), weight at the time of surgery, and minimal intraoperative temperature were risk factors for hypotension. Interventions for hypotension occurred more commonly in the GA group compared with the RA group (relative risk, 2.8, 95% CI, 1.7-4.4 by ITT). CONCLUSIONS: RA reduces the incidence of hypotension and the chance of intervention to treat it compared with sevoflurane anesthesia in young infants undergoing inguinal hernia repair.

Hypoxic ischemic encephalopathy--what can we learn from humans?

Hypoxic ischemic encephalopathy (HIE) is a condition that occurs in both human newborns and foals. The condition is the subject of extensive current research in human infants, but there have been no direct studies of HIE in foals, and hence, knowledge of the condition has been extrapolated from studies in humans and other animal models. The purpose of this review article is to highlight the most up-to-date and relevant research in the human field, and discuss how this potentially might have an impact in the management of foals with HIE.

Abnormal white matter signal on MR imaging is related to abnormal tissue microstructure.

BACKGROUND AND PURPOSE: White matter signal-intensity abnormalities (WMSA) on MR imaging are related to adverse neurodevelopmental outcome in extremely preterm infants. Diffusion tensor imaging (DTI) may detect alterations in cerebral white matter microstructure and thus may help confirm the pathologic basis of WMSA. This study aimed to relate regional DTI measures with severity of WMSA in very preterm infants. MATERIALS AND METHODS: One hundred eleven preterm infants (birth weight, <1250 g and/or gestational age, <30 weeks) were scanned at term-equivalent age (1.5T). WMSA were classified as normal, focal, or extensive. Apparent diffusion coefficient (ADC), fractional anisotropy (FA), axial (lambda1), and radial ([lambda2 + lambda3]/2) diffusivity were calculated in 12 regions of interest placed in the bilateral posterior limbs of the internal capsule, frontal (superior and inferior), sensorimotor, and occipital (superior and inferior) white matter regions. Data were compared by using 1-way analysis of variance, with a Bonferroni correction for multiple comparisons. RESULTS: Thirty-nine infants had normal, 59 infants had focal, and 13 infants had extensive WMSA. Compared with infants with normal or focal WMSA, infants with extensive WMSA had significantly lower FA in the internal capsule (P < .001), right inferior frontal regions (P < .05), and right superior occipital regions (P = .01); and higher radial diffusivity in the right internal capsule (P = .005), bilateral sensorimotor (P < .05), and right superior occipital regions (P < .05). Compared with infants with normal WMSA, infants with extensive WMSA had significantly higher ADC in bilateral sensorimotor regions (P < .01) and right superior occipital regions (P = .01), and lower axial diffusivity in the bilateral sensorimotor regions (P < .05). CONCLUSIONS: There are significant region-specific changes in ADC, FA, radial diffusivity, and axial diffusivity in preterm infants with extensive WMSA. Altered radial diffusivity was most prominent. This implies that disrupted premyelinating oligodendroglia is the major correlate with extensive WMSA rather than axonal pathology.

A novel quantitative simple brain metric using MR imaging for preterm infants.

BACKGROUND AND PURPOSE: The application of volumetric techniques to preterm infants has revealed brain volume reductions. Such quantitative data are not available in routine neonatal radiologic care. The objective of this study was to develop simple brain metrics to compare brain size in preterm and term infants and to correlate these metrics with brain volumes from volumetric MR imaging techniques. MATERIALS AND METHODS: MR images from 189 preterm infants <30 weeks' gestational age or <1250 g birthweight scanned at term-equivalent age and 36 term infants were studied. Fifteen tissue and fluid measures were systematically evaluated on 4 selected sections. The results were correlated with total brain, gray matter, white matter, and CSF volumes. RESULTS: The mean bifrontal, biparietal, and transverse cerebellar diameters were reduced (-11.6%, 95% confidence interval [CI], -13.8% to -9.3%; -12%, 95% CI, -14% to -9.8%; and -8.7%, 95% CI, -10.5% to -7% respectively) and the mean left ventricle diameter was increased (+22.3%, 95% CI, 2.9%-41.6%) in preterm infants (P < .01). Strong correlations were found between the bifrontal and biparietal measures with total brain tissue volume, whereas the size of the ventricles and the interhemispheric measure correlated with CSF volume. Intraobserver reliability was high (intraclass correlation coefficients [ICC], >0.7), where interobserver agreement was acceptable for tissue measures (ICC, >0.6) but lower for fluid measures (ICC, <0.4). CONCLUSIONS: Simple brain metrics at term-equivalent age showed smaller brain diameters and increased ventricle size in preterm infants compared with full-term infants. These measures represent a reliable and easily applicable method to quantify brain growth and assess brain atrophy in this at-risk population.

I.V. acetaminophen pharmacokinetics in neonates after multiple doses.

BACKGROUND: Pharmacokinetics of an i.v. prodrug of acetaminophen (propacetamol) in neonates after repeat dosing are reported, with scant data for i.v. acetaminophen formulation. METHODS: Neonates from an intensive care unit received 6-hourly prn i.v. acetaminophen dosed according to postmenstrual age (PMA): 28-32 weeks, 10 mg kg(-1); 32-36 weeks, 12.5 mg kg(-1); and > or =36 weeks, 15 mg kg(-1). A maximum of five blood samples for assay and liver function tests (LFTs) were collected. A one-compartment linear disposition model (zero-order input; first-order elimination) was used to describe time-concentration profiles using population modelling (NONMEM). RESULTS: Fifty neonates, median (range) PMA 38.6 (32-45) weeks, mean (SD) weight 2.9 (0.7) kg, received a mean of 15 doses over a median 4 days with 189 serum acetaminophen and 231 LFT measurements. Standardized population parameter estimates for a term neonate were clearance (CL) 5.24 (CV 30.5%) litre h(-1) 70 kg(-1) and volume of distribution (V) 76 (29.6%) litre 70 kg(-1). CL increased with PMA from 4.4 litre h(-1) 70 kg(-1) at 34 weeks to 6.3 litre h(-1) 70 kg(-1) at 46 weeks. The presence of unconjugated hyperbilirubinaemia was associated with reduced CL: 150 micromol litre(-1) associated with 40% CL reduction. Acetaminophen concentrations between 10 and 23 mg litre(-1) at steady state are predicted after 15 mg kg(-1) 6-hourly for a neonate of PMA 40 weeks. Hepatic enzyme analysis of daily samples changed significantly for one patient whose alanine aminotransferase concentration tripled. CONCLUSIONS: The parameter estimates are similar to those described for propacetamol. There was no evidence of hepatotoxicity. Unconjugated hyperbilirubinaemia impacts upon CL, dictating dose reduction.

Postnatal thyroid hormones for preterm infants with transient hypothyroxinaemia.

BACKGROUND: Extremely premature infants are at risk of transient hypothyroxinaemia in the first weeks after birth. These low thyroid hormone levels are associated with an increased incidence of neonatal morbidity, mortality and longer term developmental impairments. Thyroid hormone therapy might prevent these problems. OBJECTIVES: To determine the evidence for thyroid hormone therapy in preterm infants with transient hypothyroxinaemia (low thyroid hormone level, normal TSH) for improvement of neonatal outcomes and neurodevelopment. SEARCH STRATEGY: Searches were performed of The Cochrane Central Register of Controlled (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966 - March 2006), PREMEDLINE (March 2006), EMBASE (1980 - March 2006), previous reviews including cross references, abstracts and conference proceedings, supplemented by requests to expert informants. SELECTION CRITERIA: Trials enrolling preterm infants with transient hypothyroxinaemia (low thyroid hormone level, normal TSH level) in the neonatal period, using random or quasi-random patient allocation to thyroid hormone therapy compared to control (placebo or no treatment). DATA COLLECTION AND ANALYSIS: Independent assessment of trial quality and data extraction by each review author. Synthesis of data using relative risk (RR) and weighted mean difference (WMD) using standard methods of the Cochrane Collaboration and its Neonatal Review Group. MAIN RESULTS: Only one study was eligible. Chowdhry (1984) enrolled 23 infants < 1250 g and 25 - 28 weeks gestation with transient hypothyroxinaemia (serum total T4

Postnatal thyroid hormones for respiratory distress syndrome in preterm infants.

BACKGROUND: Preterm infants with respiratory distress syndrome are at increased risk of adverse neonatal and developmental outcomes. In animal research, thyroid hormones stimulate surfactant production and reduce the incidence and severity of respiratory distress when given antenatally. OBJECTIVES: To determine whether thyroid hormone therapy used postnatally in preterm infants with suspected respiratory distress syndrome results in clinically important improvements in respiratory morbidity and subsequent improvements in neonatal and long term outcomes. SEARCH STRATEGY: Searches were performed of The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966 - March 2006), PREMEDLINE (March 2006), EMBASE (1980 - March 2006), previous reviews including cross references, abstracts and conference proceedings, supplemented by requests to expert informants. SELECTION CRITERIA: Trials that enrolled preterm infants with suspected respiratory distress syndrome and allocated infants thyroid hormone treatment compared to control commenced in the first 48 hours after birth. DATA COLLECTION AND ANALYSIS: Independent assessment of trial quality and data extraction by each author. Synthesis of data using relative risk (RR) and weighted mean difference (WMD) using standard methods of the Cochrane Collaboration and its Neonatal Review Group. MAIN RESULTS: Two studies enrolled preterm infants with respiratory distress. Amato (1988) allocated infants to L-thyroxine 50 mug/dose at 1 and at 24 hours or no treatment. Amato (1989) allocated infants to L-triiodothyronine 50 mug/day in two divided doses for two days or no treatment. Both studies had methodological concerns including quasi-random methods of patient allocation, no blinding of treatment or measurement and substantial post allocation losses. Neither study reported any significant benefits in neonatal morbidity or mortality from use of thyroid hormones. Meta-analysis of two studies (80 infants) found no significant difference in mortality to discharge (typical RR 1.00, 95% CI 0.47, 2.14). Amato 1988 reported no significant difference in use of mechanical ventilation (RR 0.64, 95% CI 0.38, 1.09). No significant effects were found in use of mechanical ventilation, duration of mechanical ventilation, air leak, CLD at 28 days in survivors, patent ductus arteriosus, intraventricular haemorrhage or necrotising enterocolitis. Neurodevelopment was not reported. AUTHORS' CONCLUSIONS: There is no evidence from controlled clinical trials that postnatal thyroid hormone treatment reduces the severity of respiratory distress syndrome, neonatal morbidity or mortality in preterm infants with respiratory distress syndrome.

Prophylactic postnatal thyroid hormones for prevention of morbidity and mortality in preterm infants.

BACKGROUND: Observational studies have shown an association between transiently low thyroid hormone levels in preterm infants in the first weeks of life (transient hypothyroxinaemia) and abnormal neurodevelopmental outcome. Thyroid hormone replacement might prevent this. OBJECTIVES: To determine whether prophylactic thyroid hormones given to preterm infants without congenital hypothyroidism result in clinically important changes in neonatal and long term outcomes. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966 - March 2006), EMBASE, PREMEDLINE, and searches of abstracts of conference proceedings, citations of published articles and expert informants. SELECTION CRITERIA: All trials using random or quasi-random patient allocation in which prophylactic thyroid hormone treatment was compared to control in premature infants. DATA COLLECTION AND ANALYSIS: Assessment of trial quality, data extraction and synthesis of data, using relative risk (RR) and weighted mean difference (WMD), were performed using standard methods of the Cochrane Collaboration and its Neonatal Review Group. MAIN RESULTS: Four studies enrolling 318 infants were included. All studies enrolled preterm infants on the basis of gestational age criteria. All studies commenced treatment in the first 48 hours, but used different regimens, dose and durations of treatment. All four studies used thyroxine (T4). Valerio 2004 incorporated one arm with an early short course of T3, then T4 for 6 weeks. Only two studies with neurodevelopmental follow-up were of good methodology (van Wassenaer 1997; Vanhole 1997). All studies were small with the largest (van Wassenaer 1997) enrolling 200 infants.No significant difference was found in neonatal morbidity, mortality or neurodevelopmental outcome in infants who received thyroid hormones compared to control. van Wassenaer 1997 reported no significant difference in abnormal mental development at 6, 12, 24 months (RR 0.67, 95% CI 0.28, 1.56) or five years (RR 0.66, 95% CI 0.22, 1.99) or cerebral palsy assessed at five years (RR 0.72, 95% CI 0.28, 1.84). Meta-analysis of two studies (van Wassenaer 1997, Vanhole 1997) found no significant difference in the Bayley MDI (WMD -1.14, 95% CI -5.46, 3.19) and PDI (WMD 0.22, 95% CI -4.80, 5.24) at 7 - 12 months. van Wassenaer 1997 reported no significant difference in the Bayley MDI (MD -3.50, 95% CI -11.21, 4.21) and PDI (MD 3.10, 95% CI -3.31, 9.51) at 24 months, IQ scores at 5 years (MD -2.10, 95% CI -7.91, 3.71) and children in special schooling at 10 years (RR 0.88, 95% CI 0.43, 1.83). Meta-analysis of all four trials found no significant difference in mortality to discharge (typical RR 0.76, 95% CI 0.46 to 1.24). van Wassenaer 1997 reported no significant difference in death or cerebral palsy at five years (RR 0.70, 95% CI 0.43 to 1.14). No significant differences were reported for neonatal morbidities, including the need for mechanical ventilation, duration of mechanical ventilation, air leak, CLD in survivors at 28 days or 36 weeks, intraventricular haemorrhage, severe intraventricular haemorrhage, periventricular leucomalacia, patent ductus arteriosus, sepsis, necrotising enterocolitis or retinopathy of prematurity. AUTHORS' CONCLUSIONS: This review does not support the use of prophylactic thyroid hormones in preterm infants to reduce neonatal mortality, neonatal morbidity or improve neurodevelopmental outcomes. An adequately powered clinical trial of thyroid hormone supplementation with the goal of preventing the postnatal nadir of thyroid hormone levels seen in very preterm infants is required.

Assessment of the impact of the removal of cerebrospinal fluid on cerebral tissue volumes by advanced volumetric 3D-MRI in posthaemorrhagic hydrocephalus in a premature infant.

Current clinical practice in the premature infant with posthaemorrhagic ventricular dilatation (PHVD) includes drainage of cerebrospinal fluid (CSF). This case study used advanced volumetric three dimensional magnetic resonance imaging to document the impact of CSF removal on the volume of regional brain tissues in a premature infant with PHVD. The removal of a large volume of CSF was associated with an identical reduction in CSF volume, but more dramatically with a significant increase in the regional volumes of cortical grey matter and myelinated white matter. The alterations in cerebral cortical grey matter and myelinated white matter volumes may provide insight into the established association of PHVD with deficits in cognitive and motor functions.

Pre-eclampsia: a predisposing factor for neonatal venous sinus thrombosis?

Neonatal venous sinus thrombosis is a well-recognized, but infrequently diagnosed, cause of neonatal encephalopathy. Previous reports have tended to omit reference to the importance of maternal factors in predisposing the infant to this condition. This report, in which eight patients with neonatal venous sinus thrombosis are presented, will reveal a strong association between pre-eclampsia, prothrombotic disorders, and neonatal venous sinus thrombosis. Contrary to previously published reports, there is a high likelihood of neurodevelopmental residua after this condition.

Where patients with cancer die in South Australia, 1990-1999: a population-based review.

OBJECTIVE: To determine the place of death of South Australians who die of cancer. DESIGN: A population-based, cross-sectional study of data from the South Australian Cancer Registry. PARTICIPANTS: 29,230 patients with cancer dying in 1990-1999. MAIN OUTCOME MEASURES: Place of death; patient demography; year of death; survival from diagnosis; and type of cancer. RESULTS: 25.0% of patients died in a metropolitan public hospital, 19.9% in a hospice, 16.9% in a country hospital, 15.8% at a private residence, 12.7% in a metropolitan private hospital, and 9.7% in a nursing home. Although the change in place of death was not marked, multivariate logistic regression showed a secular trend away from metropolitan public hospitals towards metropolitan private hospitals and, in 1998-1999, towards nursing homes. Patients dying of cancer in a metropolitan public hospital were more likely to be younger, males, born outside Australia, and residents of lower socioeconomic areas of Adelaide. They were also more likely to have died within three months of diagnosis, and to have a haematological malignancy or a cancer of the upper digestive tract, lung or female breast. In contrast, patients dying at a private residence tended to be under 70 years and comprise longer-term survivors. Country residents were less likely than Adelaide residents to die in a hospice. CONCLUSION: The proportion of patients dying in different settings have health service implications. The relatively low use of hospice facilities by country patients may reflect differences in access to hospice facilities.

Model-based inversion of speckle interferometer fringe patterns.

Micrometer-scale rigid-body translations are determined fromelectronic speckle interferometric fringe patterns. An iterativeminimum error procedure employs the relative fringe order of pickedpositions of fringe maxima and minima within a single interferogram tocalculate the displacement field directly. The method does notcalculate the displacement at a single point but relies on theassumption that the character, but not the magnitudes or directions, ofthe displacements over the viewing area of the interferogram isknown. That is, a model of the displacements exists. Onperfect, noise-free forward modeled fringe patterns calculated for an 8.0-mum displacement, the phase error is less than 2 x10(-6) fringe orders (1.3 x 10(-5) rad)and probably results only from numerical noise in the inversion. Onreal fringe patterns obtained in electronic speckle interferometricexperiments, mean phase errors are generally less than 5 x10(-5) fringe orders (3.2 x 10(-4)rad), suggesting that the technique is robust despite errorsresulting from speckle noise, lack of accuracy in positioning ofexperimental components, and image-distortion corrections.

Optimization of fringe pattern calculation with direct correlations in speckle interferometry.

A direct correlation technique is used to calculate correlation fringe patterns from consecutive speckle patterns acquired with a dual-beam electronic speckle interferometer. Although more calculations are required than in standard image differencing routines, an advantage of the method is that the illumination over the surface of the object need not be uniform. In the method, Pearson's coefficient of correlation between the intensities within a set of adjacent pixels is calculated. This has the added advantage of being directly related to the theoretical phase-dependent correlation. A mapping of this measure of correlation results in the correlation fringe pattern. Laboratory tests were carried out with in-plane translations ranging from 5 to 45 mum. The correlation calculations were carried out by using cells (square sets of pixels) in the raw speckle images with dimensions ranging from 2 pixels x 2 pixels to 19 pixels x 19 pixels. Both cell dimension and translation magnitude dependent decorrelation effects influence the quality of the correlation fringe patterns.

Identification and characterization of a soluble c-kit receptor produced by human hematopoietic cell lines.

Stem cell factor (SCF) triggers cell growth by binding to cell surface c-kit receptors. Soluble forms of several cytokine receptors have been described and may play a role in the modulation of cytokine activity in vivo. For these reasons, we investigated whether human hematopoietic cells produce soluble c-kit receptors. The human leukemia cell lines OCIM1 and MO7e display approximately 80,000 and approximately 35,000 high-affinity cell surface c-kit receptors, respectively. Soluble c-kit receptors were detected by enzyme immunoassay in OCIM1 and MO7e culture supernatants. We determined the molecular weight and binding affinity of soluble c-kit receptor produced by OCIM1 cells, soluble c-kit receptor purified from human serum, and recombinant soluble c-kit receptor expressed in CHO cells. The three soluble c-kit receptors each have a molecular weight of 98 kD. Quantitative binding experiments with 125I-SCF indicate that the soluble c-kit receptors obtained from human serum or OCIM1 cells have binding affinities for SCF of approximately 200 to 300 pmol/L, in contrast to the recombinant form, which has a binding affinity of approximately 1.5 nmol/L. All three forms of the soluble c-kit receptor were able to compete with c-kit receptors on OCIM1 cells for 125I-SCF binding. Thus human hematopoietic cells can produce a soluble form of the c-kit receptor that retains high-affinity SCF binding activity. We speculate that the soluble c-kit receptor may bind SCF and function as a receptor antagonist in vivo.

Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6.

The Axl receptor tyrosine kinase was identified as a protein encoded by a transforming gene from primary human myeloid leukaemia cells by DNA-mediated transformation of NIH 3T3 cells. Axl is the founding member of a family of related receptors that includes Eyk, encoded by a chicken proto-oncogene originally described as a retroviral transforming gene, and c-Mer, encoded by a human proto-oncogene expressed in neoplastic B- and T-cell lines. The transforming activity of Axl demonstrates that the receptor can drive cellular proliferation. The function of Axl in non-transformed cells and tissues is unknown, but may involve the stimulation of cell proliferation in response to an appropriate signal, namely a ligand that activates the receptor. We report here the purification of an Axl stimulatory factor, and its identification as the product of growth-arrest-specific gene 6 (ref. 6). This is, to our knowledge, the first description of a ligand for the Axl family of receptors.

B61 is a ligand for the ECK receptor protein-tyrosine kinase.

A protein ligand for the ECK receptor protein-tyrosine kinase has been isolated by using the extracellular domain (ECK-X) of the receptor as an affinity reagent. Initially, concentrated cell culture supernatants were screened for receptor binding activity using immobilized ECK-X in a surface plasmon resonance detection system. Subsequently, supernatants from selected cell lines were fractionated directly by receptor affinity chromatography, resulting in the single-step purification of B61, a protein previously identified as the product of an early response gene induced by tumour necrosis factor-alpha. We report here that recombinant B61 induces autophosphorylation of ECK in intact cells, consistent with B61 being an authentic ligand for ECK. ECK is a member of a large orphan receptor protein-tyrosine kinase family headed by EPH, and we suggest that ligands for other members of this family will be related to B61, and can be isolated in the same way.