Xenon offers stable haemodynamics independent of induced hypothermia after hypoxia-ischaemia in newborn pigs.

PURPOSE: To assess the effect of 18 hour (h) 50% xenon (Xe) inhalation at normothermia (NT, 38.5°C) or hypothermia (HT, 33.5°C) on mean arterial blood pressure (MABP), inotropic support and heart rate (HR) following an induced perinatal global hypoxic-ischaemic insult (HI) in newborn pigs. METHODS: Newborn pigs ventilated under inhalational anaesthesia, following a 45 min HI (inhaled oxygen fraction reduced until amplitude integrated electroencephalogram was less than 7 µV), were randomised to three Xe (n = 45) (50% Xe 18 h with NT, HT 12 h or HT 24 h) or three non-Xe groups (n = 53) (0% Xe with NT, HT 12 h or HT 24 h) under otherwise identical conditions. We measured MABP and HR every minute. Hypotension (MABP <40 mmHg) was treated sequentially with 2 × 10 mL/kg saline, dopamine, norepinephrine and hydrocortisone if required. RESULTS: Xe maintained higher MABP during HT (5.1 mmHg, 95% CI 2.34, 7.89), rewarming (10.1 mmHg, 95% CI 6.26, 13.95) and after cessation (4.1 mmHg, 95% CI 0.37, 7.84) independent of HT, inotropic support and acidosis. Xe reduced the duration of inotropic support by 12.6 h (95% CI 5.5, 19.73). Inotropic support decreased the HR reduction induced by HT from 9 to 5 bpm/°C during cooling and from 10-7 to 4-3 bpm/°C during rewarming. There was no interaction between Xe, HT, inotropic support and acidosis. Xe during HT cleared lactate faster; 3 h post-HI median (IQR) values of (Xe HT) 2.8 mmol/L (0.9, 3.1) vs. (HT) 5.9 mmol/L (2.5, 7.9), p = 0.0004. CONCLUSION: Xe maintained stable blood pressure, thereby reducing the inotropic support requirements during and after administration independently of induced HT-current neonatal encephalopathy treatment. Xe may offer haemodynamic benefits in clinical neuroprotection studies.

Randomized clinical trial of prevention of hydrocephalus after intraventricular hemorrhage in preterm infants: brain-washing versus tapping fluid.

OBJECTIVE: Hydrocephalus is a serious complication of intraventricular hemorrhage in preterm infants, with adverse consequences from permanent ventriculoperitoneal shunt dependence. The development of hydrocephalus takes several weeks, but no clinical intervention has been shown to reduce shunt surgery in such infants. The aim of this study was to test a new treatment intended to prevent hydrocephalus and shunt dependence after intraventricular hemorrhage. METHODS: We randomly assigned 70 preterm infants who had gestational ages of 24 to 34 weeks and were progressively enlarging their cerebral ventricles after intraventricular hemorrhage to either (1) drainage, irrigation, and fibrinolytic therapy to wash out blood and cytokines or (2) tapping of cerebrospinal fluid by reservoir as required to control excessive expansion and signs of pressure (standard treatment). We evaluated outcomes at 6 months of age or hospital discharge (if later). RESULTS: Of 34 infants who were assigned to drainage, irrigation, and fibrinolytic therapy, 2 died and 13 underwent shunt surgery (dead or shunt: 44%). Of 36 infants who were assigned to standard therapy, 5 died and 14 underwent shunt surgery (dead or shunt: 50%). This difference was not significant. Twelve (35%) of 34 infants who received drainage, irrigation, and fibrinolytic therapy had secondary intraventricular hemorrhage compared with 3 (8%) of 36 in the standard group. Secondary intraventricular hemorrhage was associated with an increased risk for subsequent shunt surgery and more blood transfusions. CONCLUSIONS: Despite its logical basis and encouraging pilot data, drainage, irrigation, and fibrinolytic therapy did not reduce shunt surgery or death when tested in a multicenter, randomized trial. Secondary intraventricular hemorrhage is a major factor that counteracts any possible therapeutic effect from washing out old blood.

A neonatal piglet model of intraventricular hemorrhage and posthemorrhagic ventricular dilation.

OBJECT: The combination of intraventricular hemorrhage (IVH) and posthemorrhagic ventricular dilation (PHVD) remains an important cause of disability in children surviving prematurity. Currently, there is no clear agreement on the management of neonatal IVH, apart from the eventual insertion of a shunt to control PHVD. Cerebrospinal fluid (CSF) shunts are associated with a relatively high complication rate in this population. The development of new treatment options requires greater understanding of the pathophysiological mechanisms of IVH and PHVD, as well as an opportunity to monitor closely their effects on the immature brain. The authors have developed a neonatal large animal model of IVH with long-term survival, allowing the full development of PHVD. METHODS: Fourteen piglets that were 3 to 24 hours old were randomized to receive slow injections of autologous blood, autologous blood with elevated hematocrit, or artificial CSF after induction of general anesthesia. A fourth group served as controls. All animals underwent surgery to form an artificial fontanelle at the bregma. Physiological parameters, including intracranial pressure and electroencephalography, were monitored during injection. RESULTS: Serial cranial ultrasonography studies performed during the 23- to 44-day survival period demonstrated progressive ventricular dilation in the animals injected with blood. Ventricular volumes, measured with image analysis software, confirmed the highest dilation after injection of blood with an elevated hematocrit. Histological evaluation showed fibrosis in the basal subarachnoid space of hydrocephalic piglets. CONCLUSIONS: This piglet model closely replicates human neonatal IVH and PHVD. It allows detailed physiological and ultrasonographic monitoring over a prolonged survival period. It is suitable for evaluation of noninvasive as well as surgical options in the management of IVH and PHVD.

Non-protein-bound iron in brain interstitium of newborn pigs after hypoxia.

Oxidative damage is implied in perinatal hypoxic-ischemic brain injury, most importantly in white matter. Nonprotein-bound iron (NPBI) catalyzes the formation of toxic hydroxyl radicals. We measured the extracellular level of NPBI through microdialysis in the cortex, striatum, and periventricular white matter before, during and after severe hypoxia in newborn pigs. NPBI was analyzed by a new spectrophotometric method in which ferrous iron is chelated by bathophenanthroline. NPBI was present in all brain areas under baseline conditions and increased in white matter from 0.97 (0.69) to 2.75 (1.85) micromol/l (not corrected for recovery rate) during early reoxygenation. NPBI may contribute to oxidative injury after perinatal hypoxic insults.

Phase 1 trial of prevention of hydrocephalus after intraventricular hemorrhage in newborn infants by drainage, irrigation, and fibrinolytic therapy.

OBJECTIVE: Treatment of posthemorrhagic ventricular dilation in premature infants is fraught with failures and complications. We have piloted a new treatment aimed at removing intraventricular blood and the cytokines associated with hydrocephalus. METHODS: Twenty-four infants were enrolled with ventricular width enlarged to 4 mm over the 97th centile after a large intraventricular hemorrhage. Sixteen had parenchymal brain lesions before treatment. Median gestation was 28 weeks, and birth weight was 1150 g. At a median postnatal age of 17 days, 2 ventricular catheters (1 right frontal, 1 left occipital) were inserted with 13 infants also having a reservoir frontally. Tissue plasminogen activator 0.5 mg/kg was given intraventricularly 8 hours before the ventricles were irrigated with artificial cerebrospinal fluid at 20 mL/h for a median of 72 hours. RESULTS: Seventeen of 23 survivors (74%) did not require a ventriculoperitoneal shunt. One infant (of 23 weeks' gestation) died. Two infants developed reservoir-associated infection, and 2 infants had a second intraventricular hemorrhage. Of the 19 survivors aged >12 months postterm, 8 were normal, 7 (37%) had single disability, and 4 (21%) had multiple disabilities. CONCLUSIONS: Shunt surgery was reduced compared with historical controls with similar treatment criteria. Mortality and single and multiple disability rates all showed downward trends. Reducing pressure, free iron, and proinflammatory and profibrotic cytokines may reduce periventricular brain damage and permanent hydrocephalus. Additional advances will require a controlled trial and better knowledge of the mechanisms of hydrocephalus.