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Background The impact of the permissive hypotension approach in clinically well infants on regional cerebral oxygen saturation (rScO(2)) and autoregulatory capacity (CAR) remains unknown. Methods Prospective cohort study of blinded rScO(2) measurements within a randomized controlled trial of management of hypotension (HIP trial) in extremely preterm infants. rScO(2), mean arterial blood pressure, duration of cerebral hypoxia, and transfer function (TF) gain inversely proportional to CAR, were compared between hypotensive infants randomized to receive dopamine or placebo and between hypotensive and non-hypotensive infants, and related to early intraventricular hemorrhage or death. Results In 89 potentially eligible HIP trial patients with rScO(2) measurements, the duration of cerebral hypoxia was significantly higher in 36 hypotensive compared to 53 non-hypotensive infants. In 29/36 hypotensive infants (mean GA 25 weeks, 69% males) receiving the study drug, no significant difference in rScO(2) was observed after dopamine (n = 13) compared to placebo (n = 16). Duration of cerebral hypoxia was associated with early intraventricular hemorrhage or death. Calculated TF gain (n = 49/89) was significantly higher reflecting decreased CAR in 16 hypotensive compared to 33 non-hypotensive infants. Conclusions Dopamine had no effect on rScO(2) compared to placebo in hypotensive infants. Hypotension and cerebral hypoxia are associated with early intraventricular hemorrhage or death. Impact Treatment of hypotension with dopamine in extremely preterm infants increases mean arterial blood pressure, but does not improve cerebral oxygenation. Hypotensive extremely preterm infants have increased duration of cerebral hypoxia and reduced cerebral autoregulatory capacity compared to non-hypotensive infants. Duration of cerebral hypoxia and hypotension are associated with early intraventricular hemorrhage or death in extremely preterm infants. Since systematic treatment of hypotension may not be associated with better outcomes, the diagnosis of cerebral hypoxia in hypotensive extremely preterm infants might guide treatment.

There are few published data regarding the circulatory effects of systemic epinephrine infusions in newborn subjects. We therefore instrumented six piglets aged 5 to 10 d while they were under pentobarbitone anesthesia for determination of cardiac output, left anterior descending coronary artery flow, systemic and pulmonary pressures, and mixed venous, arterial and coronary sinus gases. Systemic, coronary, and pulmonary vascular resistances, coronary oxygen consumption, and myocardial oxygen extraction ratio were calculated. Epinephrine was infused at doses from 0.2 to 3.2 μg/kg/min doubling at 15-min intervals, and measurements were taken after stability had been obtained. Cardiac output increased at the lowest dose investigated, i.e. 0.2 μg/kg/min, and progressively increased as the dose was advanced up to 1.6 μg/kg/min, decreasing significantly at 3.2 μg/kg/min. Blood pressure increased progressively, being significantly above baseline at 0.8, 1.6, and 3.2 μg/kg/min and having increased by approximately 81% at the highest dose investigated. Pulmonary arterial pressures were also increased at 1.6 and 3.2 μg/kg/min, but only by 35% at the highest dose of 3.2 μg/kg/min. Systemic and pulmonary vascular resistances both decreased at the three lower doses investigated and then began to increase progressively; however, the systemic vascular resistance increased to a significantly greater degree than pulmonary vascular resistance. Coronary oxygen consumption increased progressively as the epinephrine dose was increased; however, coronary blood flow and coronary oxygen delivery increased more than oxygen consumption, leading to a progressive reduction in myocardial oxygen extraction ratio and a progressive increase in coronary sinus oxygen content. Whole-body oxygen consumption was increased, but to a lesser extent than systemic oxygen transport. We conclude that, at low doses, epinephrine is a potent inotrope and a systemic and pulmonary vasodilator in the newborn piglet. With progressive increases in the dose, systemic vasoconstriction is significantly greater than pulmonary. Increasing cardiac oxygen demands are oversupplied by increases in coronary blood flow.

Twenty healthy preterm infants of less than 34 wk gestation were studied with continuous recordings, commencing within 8 h of birth, for up to 1 wk of age to determine the usual time course of the appearance of apnea and to classify apnea types. Airway occlusion studies were also performed on a regular basis to determine whether apneic spells were preceded or followed by a reduction in central respiratory drive. Apneic spells of greater than 15 s duration accompanied by hypoxia or bradycardia occurred in all infants before 24 h of age. The frequency of apneic spells was highest in the first 24 h after birth with a mean frequency of 0.9/h and gradually reduced thereafter, falling to 0.2/h by 5 d of age (p less than 0.01). Apneic spells were more likely to be obstructive in the first 2 d of life than thereafter (p less than 0.05). Central apnea was proportionately significantly less frequent during this time period. Reduced respiratory drive, as demonstrated by airway occlusion pressures, was associated with more frequent apnea and was evident at the first occlusion study, which frequently preceded the first significant apnea.

The relationship between periodic breathing and idiopathic apnea of prematurity was investigated. We recorded respiratory impedance, heart rate, pulse oximetry and end-tidal COz from 68 untreated infants of less than or equal to 34 wk gestation with a diagnosis of idiopathic apnea of prematurity. Mean birth wt was 1476 g (SD 420) and mean gestational age was 29.9 wk (SD 2.6). Apneas of more than 15 s duration that were associated with hypoxemia or bradycardia were identified by semiauto- mated analysis of computerized records. A total of 1116 significant apneic spells were identified, only one of which occurred during an epoch of periodic breathing, five others occurred within 2 min of the end of an epoch of periodic breathing. Less than 0.6% of significant apneic spells occur within 2 min of periodic breathing. In all of the 12 infants that were monitored starting in the first 12 h or life, significant apneic spells were identified before 36 h of age and no precipitating factors were identified. Periodic breathing did not occur during the first 48 h of life, a finding that supports the concept that the peripheral che- moreceptor is inactive in the first 48 h of life. Periodic breathing in the premature infant is not a precursor to significant apnea. (Pediatr Res 27: 118-121, 1990)

The pulmonary vasculature of newborns with persistent pulmonary hypertension is characterized by active vasoconstriction and vascular remodeling. It has been suggested that endothelin-1 (ET-1), a potent vasoconstrictor and growth promoter, may be involved in the pathogenesis of persistent pulmonary hypertension of the newborn. To determine whether treatment with an ET(A) receptor antagonist can reverse pulmonary hypertension in the neonate, 1-d-old piglets were exposed to hypoxia for 3 d to induce pulmonary hypertension and then treated for the remainder of the 14 d with an orally active, nonpeptidic ET(A) antagonist (TBC3711, 22 mg x kg(-1) x d(-1)). At the end of the exposure, Hb, pulmonary artery pressure, right ventricle to left ventricle plus septum weight ratio, percentage wall thickness, ET-1 circulating levels, perfusion pressure, and dilator response to the nitric oxide (NO) donor, SIN-1 (3-morpholinosydnonimine-N-ethylcarbamide) in isolated perfused lungs were determined. Exhaled NO and hemodynamic variables were also examined in an intact anesthetized animal preparation that had undergone the same treatment. By 3 d of exposure to hypoxia, piglets had already developed significant pulmonary hypertension as estimated by their pulmonary artery pressure (24.0 +/- 1.3 mm Hg versus 14.2 +/- 3.4 mm Hg) and percentage wall thickness (26.6 +/- 5.9% versus 18.7 +/- 2.4% for vessels 0-30 microm). Whereas further exposure to hypoxia for 14 d did not enhance the increase in pulmonary artery pressure and percentage wall thickness, it did augment the right ventricle to left ventricle plus septum weight ratio (0.71 +/- 0.09 versus 0.35 +/- 0.01). ET-1 circulating levels were increased only when exposure to hypoxia was prolonged to 14 d (5.1 +/- 2.4 pg/mL versus 1.0 +/- 0.4 pg/mL). Treatment with TBC3711 from d 3 to d 14, once pulmonary hypertensive changes were established and while hypoxic exposure persisted, caused significant reduction in the right ventricle to left ventricle plus septum weight ratio (0.60 +/- 0.06), pulmonary artery pressure (20.0 +/- 4.8 mm Hg), and percentage wall thickness (18.5 +/- 3.3%) and restored the dilator response to the NO donor SIN-1. Prolonged hypoxia markedly reduced exhaled NO concentrations (0.3 +/- 0.6 ppb), although treatment of hypoxic animals with TBC3711 restored the concentration of exhaled NO (4.4 +/- 2.8 ppb) to the level of normoxic controls (4.9 +/- 3.0 ppb). Lastly, treatment with TBC3711 increased ET-1 circulating levels in both the normoxic (5.4 +/- 2.8 pg/mL) and hypoxic (13.0 +/- 6.3 pg/mL) groups. In conclusion, the specific ET(A) receptor antagonist, TBC3711, can significantly ameliorate the morphologic changes encountered in hypoxia-induced pulmonary hypertension in the newborn piglet and may improve the dilator response to NO.

Inhaled nitric oxide has been reported to act as a specific pulmonary vasodilator. We used the newborn piglet to create acute hypoxic pulmonary hypertension and examined the effect of inhaled nitric oxide in this model. Six newborn piglets were instrumented in order to measure cardiac index, pulmonary arterial pressure, and systemic arterial pressure. Pulmonary hypertension was induced by reducing the fraction of inspired oxygen to 0.12 to 0.14. With hypoxia (arterial oxygen saturation between 35 and 45%), pulmonary arterial pressure increased by 48% (p < 0.01), pulmonary vascular resistance increased by 74% (p < 0.01), and both systemic arterial pressure and systemic vascular resistance decreased by 38 and 31%, respectively (p < 0.01). The animals were then giving varying concentrations of inhaled nitric oxide between 5 and 80 parts per million in random order. All concentrations of nitric oxide were associated with a rapid decrease in pulmonary arterial pressure and pulmonary vascular resistance (p < 0.001). Cardiac index increased (p < 0.001) and systemic vascular resistance significantly decreased (p = 0.01) with all doses of inhaled nitric oxide. The ratio of pulmonary to systemic vascular resistance decreased with all levels of inhaled nitric oxide (p < 0.001). For all of the above observations there was no significant difference noted between the varying doses of nitric oxide. The time course of the pulmonary arterial pressure response to nitric oxide was approximately twice as fast as that seen with the inhalation of 100% oxygen (10, 50, 90% responses of 4.1, 8.8, 88.6 versus 6.7, 51.9, 197 s, respectively; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Background: The CAP trial enrolled 2006 infants with birth weights 500-1250 g who were randomly assigned to caffeine therapy or placebo for apnea of prematurity (N Engl J Med 2006; 354: 2112 and 2007; 357:1893). Objective: To reassess CAP trial participants at 5 years. Design and methods: The main outcome at 5 years was a composite of death or survival with disability in one of 6 domains including neuromotor function, cognition, behaviour, and general health. Standardized tests included the Gross Motor Function Classification System (GMFCS), the Wechsler Preschool and Primary Scale of Intelligence, and the Child Behavior Checklist Parent Form. Results: A total of 1932 children were eligible for the present study. Vital status was ascertained for 1810 children (94%). Adequate data for the composite outcome of death or disability were available for 1641 children (85%). Table 1 shows the results for the composite outcome and for 5 of its components. Conclusions: Observed rates of functional outcomes at 5 years still favoured caffeine therapy for apnea of prematurity over placebo treatment. However, cognitive impairment was no longer reduced in caffeine-treated infants.

Sodium deficiency is associated with decreased muscle growth and protein synthesis. We investigated the influence of diet-induced sodium deficiency on the rate and extent of compensatory growth of the right lung after left pneumonectomy in young rats of 83 ± 1 g body weight. Starting 1 wk before surgery, all rats were fed a diet deficient only in sodium (2-9 µmol Na+/g of food) ad libitum. Sodium-deficient rats were supplied with distilled water, whereas sodium-replete controls were supplied water containing 37 mM NaCl. After 7 d on the experimental diets, both groups were divided and subjected either to sham thoracotomy (Sham) or to left pneumonectomy (PNX). Somatic growth and both normal and compensatory growth of the lungs were assessed 3, 4, and 7 d later. Sodium-deficient animals grew more slowly than control animals. In control PNX rats, right lung weight to body weight ratio (LW/BW) increased to equal that of the combined LW/BW in control Shams by postoperative d 4, and remained at the Sham combined LW/BW value on postoperative d 7. Compensatory lung growth was less rapid in sodium-deficient PNX animals. At postoperative d 4, right LW/BW was low relative to combined LW/BW of sodium-deficient Shams. This ratio approached but did not reach the sodium-deficient Sham combined LW/BW value by d 7. Sodium deficiency thus reduced the rate of compensatory growth of the right lung. RNA/g dry tissue and RNA/DNA were low in sodium-deficient lungs relative to control at d 0 and 7 but during the rapid phase of compensatory growth (d 3 and 4), both groups responded with a 20% increase in tissue RNA concentration. Similar protein/DNA ratios between PNX and Sham-operated animals in both sodium-deficient and control groups, along with elevated total DNA content in the right lung of both PNX groups, suggest that the compensatory growth was hyperplastic rather than hypertrophic. Our study demonstrates that diet-induced sodium deficiency decreases somatic growth and slows the compensatory growth of the right lung after PNX.

Randomized Controlled Trial of Nasal Synchronized Intermittent Mandatory Ventilation after Extubation of Very Low Birth Weight Infants

Response to Inhaled Nitric Oxide in the Newborn; Prospective Comparison of Standard and Very Low Dose

Association between Apnea Free Days and Findings on Objective Recordings prior to Discharge

Lack of Association between Pre-Discharge Apnea and Acid G-E Reflux in Formerly Preterm Infants

Current neonatal delivery room (DR) resuscitation teaching includes the use of chest compressions and/or intratracheal epinephrine (CPR) for infants with a heart rate 750 gm birthweight. Methods: We evaluated the outcome of all inborn infants whose birthweights (BW) were 750gm(15/98). Surviving infants were followed up to 36 months adjusted age (AA) using standardized neurodevelopmental (ND) assessments including the Amiel-Tison Neurologic Screen and the Gesell Developmental Screening Inventory. Results: Overall, 21 infants required CPR in the DR, of whom 13 were < 750 gm. Three infants, all < 750 gm, have normal neurodevelopmental outcome at 6, 19,& 26 months AA. These preliminary results indicate that intact survival is possible for infants of < 750 gm BW following CPR in the DR as defined above. Further information is required regarding the indications for CPR, the use of the individual components(compressions and epinephrine) and the duration of CPR from retrospective and prospective evaluation of larger data sets. In addition, we require more complete neurodevelopmental follow-up in order to develop recommendations for the use of CPR in the DR resuscitation of the < 1000 gm birthweight infant. Table

The Cumulative Sum Technique and the Introduction of an Extremely Low Birthweight Protocol. † 996

Decision making for infants presenting with HLHS is complex and inhibited by an absence of comparative studies. Transplantation has a high success rate and good functional long term outcome, carries the unknown risks of long term immunosuppression and is limited by donor availability. The “Norwood” : procedure has an improving survival rate in experienced hands, but also carries unknown long term risks particularly neurodevelopmental outcome. Decision analysis has been developed as a way of making complex decisions using the best available information and should be ideally suited to this situation. Methods: A literature search for the latest information on survival rates was performed in September 1997. The initial values entered into the model were: survival of stage 1 Norwood, 85%; survival of stage 2, 95%; and of stage 3, 90%. Transplant availability 30% in the first month of life and 40% of the remaining infants in the next 5 months; immediate survival, 85% and 5 y survival, 90% of immediate survivors. Variations in the values assigned to the parameters were examined to determine the effects of improving donor availability or improving surgical results. A combined approach was also evaluated in which infants would be listed for transplant at birth and undergo a stage 1 Norwood procedure at 1 month of age if they have not received a transplant by this time; infants would then remain on the transplant list until 6 months at which time a stage 2 procedure is performed and the infant taken off the transplant list. Results: With the staged surgical repair approach alone the model gave a 5 y survival rate of 52% similar to the best recently reported results of 58% (Bove and Lloyd 1996). For infants placed on a transplant list alone, the model calculates 26% 5 y survival. The combined approach using the same parameters gives an expected 5 y survival of 61%. If donor availability improves, so that 80% of infants could be transplanted before 6 months, the 5 y survival of transplantation improves to 56% and survival rate of the combined approach improves to 67%. Improvements in Norwood results to a feasible maximum 5 y survival of 66% also improved the outcome of infants assigned to the combination protocol to 71% 5 y survival. Discussion. The combined approach performed best in this analysis, a result which was quite robust to changes in the assumptions underlying the model. Such an approach is currently offered in few centers. Long term neurodevelopmental follow up is essential for further improvements in decision making.

In insulin-secreting β-cells, depolarization-response coupling is dependent upon the operation of function of ion selective channels. In response to glucose, a depolarization of the cell membrane results from ATP-sensitive K+ (KATP) channel closure. This in turn generates openings from voltage-dependent Ca2+ channels, and the appearance of action potentials associated with the accelerated influx of Ca2+. The subsequent rise in cytosolic Ca2+ then leads to insulin release. Diazoxide is an agonist of KATP channels and thus inhibits the release of insulin in normal β-cells. In persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) gene variations in the subunits of KATP channels have been linked to the disease. In our studies, we have investigated the functional properties of β-cells isolated from 29 patients with PHHI following pancreatectomy. 5/29 patients were from families with a previous history of PHHI, and 28/29 patients had a severe form of the disease that was either unresponsive or incompletely responsive to medical therapy with either diazoxide or somatostatin, used in combination with an elevated glucose infusion rate. In 8/29 subjects defects in the SUR1 gene have been identified. Studies of ion channel function and cytosolic Ca2+ signalling events were performed on isolated β-cells using patch-clamp techniques and cell microfluorimetry proceedures, respectively. The results of these experiments were correlated to insulin secretion studies in vitro and in vivo. These investigations revealed that loss of KATP channel function prevails inβ-cells isolated from PHHI patients. In many cases there was a direct correlation between defects in KATP channel activity and a spontaneous depolarisation of the cell membrane, leading to the appearance of action potentials. This inappropriate influx of Ca2+ is suggested to underpin the uncontrolled release of insulin from PHHI β-cells and is supported by[1] direct measurements of Ca2+-dependent exocytosis (through capacitance changes in isolated cells) and [2] by showing that removal of external Ca2+ or the addition of Ni2+ to the isolated cells, both lowers cytosolic Ca2+ levels and inhibits insulin secretion. These novel studies of isolated β-cells from patients with neonatal hyperinsulinsm [1] document the condition as a novel ion channel disorder and[2] provide important clues to the development of new lines of medical therapy with which to treat this condition.

Lung Lavage with KL4 Surfactant in a Neonatal Model of Meconium Aspiration; The Importance of Peep. † 960

We investigated the effects of clinically comparable doses of ibuprofen and indomethacin on renal, gastrointestinal and cerebral perfusion in newborn piglets, and hypothesized that ibuprofen would have less effect on regional circulations. Methods: Fentanyl anesthetized 1 to 3 day old piglets were instrumented with a pulmonary artery catheter, a femoral arterial catheter and a carotid arterial catheter advanced into the left ventricle for administration of microspheres. Animals were randomly assigned to receive ibuprofen (20 mg/kg, n = 8), indomethacin (0.3 mg/kg, n = 7) or vehicle (n = 6). Fluorescent microspheres were injected prior to and at 20, 40, 60, 90 and 120 minutes after drug administration. Regional blood flow and vascular resistance were calculated; relative resistance at the indicated times was calculated from resistance values prior to drug injection. Results: Heart rate, blood pressure, cardiac output, and systemic and pulmonary vascular resistances were not affected by the drugs. Blood gases were also unaffected by either drug or vehicle. Baseline blood flows were: kidney cortex= 464 (SD 29); duodenum/jejunum = 155 (SD 32); ileum = 108 (SD 22); colon = 109 (SD 14.7); cerebral cortex = 91 (SD 17); brainstem = 71 (SD 12) [all mL/min/100g tissue].

Early intravenous dexamethasone (dex) for the prevention of BPD in surfactant treated babies with RDS. 1138

Predischarge Respiratory Recordings in Premature Infants; Influence of Gestational Age, Postconceptional Age, BPD, and Intubation on Apnea Frequency and Type † 1755

Intratracheal dead space wash out (ITDSWO) has been developed as a method for reducing the effective dead space and has been studied in a number of low volume lung disease models. A study in preterm human neonates with hyaline membrane disease showed effective ventilation at lower airway pressures when ITDSWO was administered using a multiluminal endotracheal tube. Some models have however suggested that gas trapping may occur. We wished to determine whether ITDSWO with a multiluminal tube would be effective in a severe inhomogeneous lung disease model where elevated PaCO2 may be problematic and dead space washout would be potentially advantageous. Methods: Newborn piglets were instrumented under fentanyl anesthesia with arterial and pulmonary artery catheters. Assisted ventilation with a neonatal ventilator was commenced and after stability was assured, meconium was instilled as a 30% slurry in saline in a dose of 3 mL/kg followed after 20 minutes by a further 3 mL/kg. The animals were then monitored until PaO2 was less than 140 mmHg in an FiO2 of 1.0. At this time sequential 20 minute periods with and without extra flow delivered near the tip of the ETT via integral extra lumens built into the wall of the tube was commenced. No other changes in ventilation were permitted. Blood gas changes, airway pressures, and hemodynamics were monitored. In 4 animals flow was administered at 250 mL/min of gas with the same FiO2 as the main inspired gases, In 1animal a flow of 2 litres/min was used. Results: We confirmed that flow was being delivered to the tip of the endotracheal tube using end-tidal CO2 monitoring. There were no effects of the flow on cardiac output, pulmonary artery pressure or mean airway pressure. PaCO2 did not change when the extra flow was added. PaCO2 without flow = 42.3 (SD 9.3) mmHg, with flow = 42.8 (SD 10.7) mmHg. There were no effects on oxygenation; PaO2 with flow = 122 (SD 86) mmHg, without flow = 121(SD 86) mmHg. In the animal that received a flow of 2 litres/min PaCO2 increased during ITDSWO by 4 to 6 mmHg. Conclusion: In this lung disease model, which has airway obstruction and gas trapping as a prominent pathological feature, ITDSWO using the above methodology is ineffective possibly because of retardation of expiration and increased gas trapping. ITDSWO for meconium aspiration may require even lower flows or a different methodology such as the reverse thrust catheter.

Respiratory alkalosis (RA) continues to be used as a therapy for persistent pulmonary hypertension of the newborn. Hypothesis: Prolonged alkalosis has adverse effects on hemodynamic variables, furthermore, it can exacerbate hypoxic induced pulmonary vasoconstriction. Method: 2 groups (control n=5, and hypocapnic alkalosis, n=6) of 1-3 d old fentanyl anesthetized, vecuronium paralyzed piglets (mean weight 1.69 ± 0.11 kg) were instrumented with an arterial catheter and a flow directed thermodilution catheter to measure cardiac index (Q), mean systemic (SAP) and pulmonary (PAP) arterial pressure. Baseline values were recorded. Alveolar hypoxia was then induced to arterial O2 sats of 50-60% for 15 minutes. RA (pH 7.55-7.60) was then achieved and continued for 240 minutes by hyperventilation in the RA group, and final values were recorded. Inspired CO2 was used with hyperventilation in the control group to maintain PaCO2 35-45 mmHg and pH 7.35-7.45. Hypoxia was induced again at 15 and 240 minutes. Pulmonary and systemic vascular resistance (PVR and SVR) and stroke volume (SV) were calculated. Results: Prolonged alkalosis leads to a statistically significant 18% fall in SAP (ANOVA, p

Partial Liquid Ventilation (PLV) and Conventional Gas Ventilation(GV) : Histopathologic differences in newborn piglet lungs in a Meconium Aspiration Syndrome (MAS) model 1591

Objective: To determine the dose related effects of continuous epinephrine (Epi) infusion on renal and mesenteric blood flow in both healthy and shocked newborn piglets. Methods: Superior mesenteric artery(SMA) and left renal artery (RA) ultrasonic flow probes were implanted into 16, 1-3 day old piglets. 2 d later, the effects of Epi on SMA and RA flow (f), mean arterial pressure (MAP) and CVP were measured in awake animals. Vascular resistances (vr) were calculated. Epi doses of 0.2, 0.4, 0.8, 1.6 and 3.2μg/kg/min were infused in random order for 20 minutes, with 15 minute recovery periods. Piglets were then hemorrhaged to mild hypotension (20 ml/kg) and Epi was repeated. Results: Percentage change from baseline is shown, Mean (SD).*=p

EFFECTS OF PROLONGED DOBUTAMINE INFUSION ON SYSTEMIC, PULMONARY, RENAL AND MESENTERIC HEMODYNAMICS IN THE AWAKE PIGLET. 134