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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.

To determine whether deferred cord clamping (DCC) compared with early cord clamping (ECC) was associated with reduction in death and/or severe neurologic injury among twins born at30 weeks of gestation.We performed a retrospective cohort study including all liveborn twins of30 weeks admitted to a tertiary-level neonatal intensive care unit (NICU) in Canada between 2015 and 2018 using the Canadian Neonatal/Preterm Birth Network database. We compared DCC ≥30 seconds vs ECC30 seconds. Our primary outcome was a composite of death and/or severe neurologic injury (severe intraventricular hemorrhage grade III/IV and/or periventricular leukomalacia). Secondary outcomes included neonatal morbidity and health care utilization outcomes. We calculated aORs and β coefficients for categorical and continuous variables, along with 95% CI. Models were fitted with generalized estimated equations accounting for twin correlation.We included 1597 twins (DCC, 624 [39.1%]; ECC, 973 [60.9%]). Death/severe neurologic injury occurred in 17.8% (n = 111) of twins who received DCC and in 21.7% (n = 211) of those who received ECC. The rate of death/severe neurologic injury did not differ significantly between the DCC and ECC groups (aOR 1.07; 95% CI, 0.78-1.47). DCC was associated with reduced blood transfusions (adjusted β coefficient, -0.49; 95% CI, -0.86 to -0.12) and NICU length of stay (adjusted β coefficient, -4.17; 95% CI, -8.15 to -0.19).The primary composite outcome of death and/or severe neurologic injury did not differ between twins born at30 weeks of gestation who received DCC and those who received ECC, but DCC was associated with some benefits.

ObjectiveTo determine whether restricting the use of inotrope after diagnosis of low blood pressure (BP) in the first 72 hours of life affects survival without significant brain injury at 36 weeks of postmenstrual age (PMA) in infants born before 28 weeks of gestation.DesignDouble-blind, placebo-controlled randomised trial. Caregivers were masked to group assignment.Setting10 sites across Europe and Canada.ParticipantsInfants born before 28 weeks of gestation were eligible if they had an invasive mean BP less than their gestational age that persisted for ≥15 min in the first 72 hours of life and a cerebral ultrasound free of significant (≥ grade 3) intraventricular haemorrhage.InterventionParticipants were randomly assigned to saline bolus followed by either a dopamine infusion (standard management) or placebo (5% dextrose) infusion (restrictive management).Primary outcomeSurvival to 36 weeks of PMA without severe brain injury.ResultsThe trial terminated early due to significant enrolment issues (7.7% of planned recruitment). 58 infants were enrolled between February 2015 and September 2017. The two groups were well matched for baseline variables. In the standard group, 18/29 (62%) achieved the primary outcome compared with 20/29 (69%) in the restrictive group (p=0.58). Additional treatments for low BP were used less frequently in the standard arm (11/29 (38%) vs 19/29 (66%), p=0.038).ConclusionThough this study lacked power, we did not detect major differences in clinical outcomes between standard or restrictive approach to treatment. These results will inform future studies in this area.Trial registration numberNCT01482559, EudraCT 2010-023988-17.

Objective The aim was to compare survival of patients with septic shock receiving or not hydrocortisone (HC) and to analyze the hemodynamic response to HC. Study Design It is a retrospective study of 62 premature neonates with septic shock (confirmed bacteremia) and/or necrotizing enterocolitis (NEC) stage 2 and above receiving inotropes with or without HC. We analyzed survival and hemodynamic response to HC. Results Thirty-nine (63%) premature neonates received HC and were compared with 23 (37%) who only received inotropes. Vasoactive index score (VAI) decreased and blood pressure, urine output, and oxygen requirements improved significantly following HC. Despite receiving more inotropes (VAI of 33 [20–53] vs 10 [8–20], p Conclusion HC was used in infants with increased inotropic support. HC during septic shock was associated with similar survival from episode, but with decreased survival at 1-year postmenstrual age.

Aim This study evaluated the clinical and haemodynamic effects of norepinephrine infusion in preterm infants. Methods The effects of norepinephrine therapy for refractory hypotension were evaluated in preterm infants between April 2009 and April 2011 at the neonatal intensive care unit of Sainte-Justine Hospital, Montreal, Quebec. Changes in haemodynamics and clinical parameters were analysed eight hours before and eight hours after the start of norepinephrine infusion, and eight hours after its cessation. Results During the study, 30 preterm infants at a mean gestational age of 26.5 ± 2.6 weeks (median: 25.7, 23.4-34) and birthweight of 903 ± 437 g (median 827, 450-2550) received norepinephrine infusion for neonatal septic shock. After eight hours of treatment, mean blood pressure, urine output and FiO2 significantly improved. Eight hours after cessation of norepinephrine infusion, the number of patients treated with other inotropes decreased significantly, 24 patients (80%) had normal mean blood pressure and 27 patients (90%) had normal urine output. Conclusion Norepinephrine therapy could be considered to improve blood pressure and urine output during neonatal septic shock in preterm infants. Further studies are needed to prove the efficacy and safety of norepinephrine infusion in neonates.

BACKGROUND Extremely premature infants born OBJECTIVES To explore time-frequency relationships between cerebral oxygenation and peripheral oximetry. DESIGN/METHODS Near infrared spectroscopy cerebral regional haemoglobin oxygen saturation (CrSO2), preductal peripheral perfusion index (PI), heart rate (HR), capillary oxygen saturation (SpO2), and blood pressure (BP) were monitored in the first 72h of life. Patients were grouped in infants with PH and/or IVH (n=8) and controls (n=10). Signals were decomposed in wavelets allowing the analysis of localized variations of power. This approach allowed to quantify the common power and determine the duration of significant cross-correlation, phase and coherence between each pair of signals. Groups were compared with Wilcoxon tests. RESULTS Figure 1 shows an example of CrSO2 and PI, and their cross-correlation, phase (semblance) and coherence in a control (left column) and a PH-IVH patient (right column). Durations of significant cross-correlation between CrSO2 and HR (p CONCLUSION This study is the first to apply time-frequency analysis to simultaneous NIRS and preductal peripheral oximetry in extremely preterm infants early in life. Significantly lower durations of cross-correlation (CrSO2 with HR and SpO2), anti-phase (CrSO2, SpO2) and coherence (PI, BP) in PH-IVH patients may reflect early abnormal circulation. Our results show the potential of non-invasive monitoring to identify premature infants at-risk of early PH-IVH.

Background Nitric oxide (NO) is a major endogenous regulator of vascular tone. Inhaled nitric oxide (iNO) gas has been investigated as treatment for persistent pulmonary hypertension of the newborn. Objectives To determine whether treatment of hypoxaemic term and near-term newborn infants with iNO improves oxygenation and reduces rate of death and use of extracorporeal membrane oxygenation (ECMO), or affects long-term neurodevelopmental outcomes. Search methods We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1), MEDLINE via PubMed (1966 to January 2016), Embase (1980 to January 2016) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to January 2016). We searched clinical trials databases, conference proceedings and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We contacted the principal investigators of studies published as abstracts to ascertain the necessary information. Selection criteria Randomised studies of iNO in term and near-term infants with hypoxic respiratory failure, with clinically relevant outcomes, including death, use of ECMO and oxygenation. Data collection and analysis We analysed trial reports to assess methodological quality using the criteria of the Cochrane Neonatal Review Group. We tabulated mortality, oxygenation, short-term clinical outcomes (particularly use of ECMO) and long-term developmental outcomes. Statistics: For categorical outcomes, we calculated typical estimates for risk ratios and risk differences. For continuous variables, we calculated typical estimates for weighted mean differences. We used 95% confidence intervals and assumed a fixed-effect model for meta-analysis. Main results We found 17 eligible randomised controlled studies that included term and near-term infants with hypoxia. Ten trials compared iNO versus control (placebo or standard care without iNO) in infants with moderate or severe severity of illness scores (Ninos 1996; Roberts 1996; Wessel 1996; Davidson 1997; Ninos 1997; Mercier 1998; Christou 2000; Clark 2000; INNOVO 2007; Liu 2008). Mercier 1998 compared iNO versus control but allowed back-up treatment with iNO for infants who continued to satisfy the same criteria for severity of illness after two hours. This trial enrolled both preterm and term infants but reported most results separately for the two groups. Ninos 1997 studied only infants with congenital diaphragmatic hernia. One trial compared iNO versus high-frequency ventilation (Kinsella 1997). Six trials enrolled infants with moderate severity of illness scores (oxygenation index (OI) or alveolar-arterial oxygen difference (A-aDO2)) and randomised them to immediate iNO treatment or iNO treatment only after deterioration to more severe criteria (Barefield 1996; Day 1996; Sadiq 1998; Cornfield 1999; Konduri 2004; Gonzalez 2010). Inhaled nitric oxide appears to have improved outcomes in hypoxaemic term and near-term infants by reducing the incidence of the combined endpoint of death or use of ECMO (high-quality evidence). This reduction was due to a reduction in use of ECMO (with number needed to treat for an additional beneficial outcome (NNTB) of 5.3); mortality was not affected. Oxygenation was improved in approximately 50% of infants receiving iNO. The OI was decreased by a (weighted) mean of 15.1 within 30 to 60 minutes after the start of therapy, and partial pressure of arterial oxygen (PaO2) was increased by a mean of 53 mmHg. Whether infants had clear echocardiographic evidence of persistent pulmonary hypertension of the newborn (PPHN) did not appear to affect response to iNO. Outcomes of infants with diaphragmatic hernia were not improved; outcomes were slightly, but not significantly, worse with iNO (moderate-quality evidence). Infants who received iNO at less severe criteria did not have better clinical outcomes than those who were enrolled but received treatment only if their condition deteriorated. Fewer of the babies who received iNO early satisfied late treatment criteria, showing that earlier iNO reduced progression of the disease but did not further decrease mortality nor the need for ECMO (moderate-quality evidence). Incidence of disability, incidence of deafness and infant development scores were all similar between tested survivors who received iNO and those who did not. Authors' conclusions Inhaled nitric oxide is effective at an initial concentration of 20 ppm for term and near-term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia.

Endotracheal intubation, a common procedure in newborn care, is associated with pain and cardiorespiratory instability. The use of premedication reduces the adverse physiological responses of bradycardia, systemic hypertension, intracranial hypertension and hypoxia. Perhaps more importantly, premedication decreases the pain and discomfort associated with the procedure. All newborn infants, therefore, should receive analgesic premedication for endotracheal intubation except in emergency situations. Based on current evidence, an optimal protocol for premedication is to administer a vagolytic (intravenous [IV] atropine 20 μg/kg), a rapid-acting analgesic (IV fentanyl 3 μg/kg to 5 μg/kg; slow infusion) and a short-duration muscle relaxant (IV succinylcholine 2 mg/kg). Intubations should be performed or supervised by trained staff, with close monitoring of the infant throughout.

A large proportion of very preterm infants receive treatment for hypotension. The definition of hypotension is unclear, and, currently, there is no evidence that treating it improves outcomes or, indeed, which treatment to choose among the available alternatives. Assessment of circulatory adequacy of the preterm infant requires a careful clinical assessment and may also require ancillary investigations. The most commonly used interventions, fluid boluses and dopamine, are problematic: fluid boluses are statistically associated with worse clinical outcomes and may not even increase blood pressure, whereas dopamine increases blood pressure mostly by causing vasoconstriction and may decrease perfusion. For neither intervention is there any reliable data showing clinical benefit. Prospective trials of intervention for hypotension and circulatory compromise are urgently required.

Introduction: Many practitioners routinely treat infants whose mean arterial blood pressure in mm Hg is less than their gestational age in weeks (GA). Objective: To assess the effectiveness of utilising a combined approach of clinical signs, metabolic acidosis and absolute blood pressure (BP) values when deciding to treat hypotension in the extremely low birthweight (ELBW) infant. Methods: Retrospective cohort study of all live born ELBW infants admitted to our neonatal intensive care unit over a 4-year period. Patients were grouped as either normotensive (BP never less than GA), hypotensive and not treated (BP,GA but signs of good perfusion; we termed this permissive hypotension) and hypotensive treated (BP,GA with signs of poor perfusion). Results: 118 patients were admitted during this period. Blood pressure data were available on 108 patients. 53% of patients were hypotensive (mean BP in mm Hg less than GA in weeks). Treated patients had lower birth weight and GA, and significantly lower blood pressure at 6, 12, 18 and 24 h. Normotensive patients and patients designated as having permissive hypotension had similar outcomes. Mean blood pressure in the permissive group increased from 26 mm Hg at 6 h to 31 mm Hg at 24 h. In a logistic regression model, treated hypotension is independently associated with mortality, odds ratio 8.0 (95% CI 2.3 to 28, p,0.001). Conclusions: Blood pressure spontaneously improves in ELBW infants during the first 24 h. Infants hypotensive on GA criteria but with clinical evidence of good perfusion had as good an outcome as normotensive patients. Treated low blood pressure was associated with adverse outcome.

Methylxanthine therapy is commonly used for apnea of prematurity but in the absence of adequate data on its efficacy and safety. It is uncertain whether methylxanthines have long-term effects on neurodevelopment and growth.We randomly assigned 2006 infants with birth weights of 500 to 1250 g to receive either caffeine or placebo until therapy for apnea of prematurity was no longer needed. The primary outcome was a composite of death, cerebral palsy, cognitive delay (defined as a Mental Development Index score of85 on the Bayley Scales of Infant Development), deafness, or blindness at a corrected age of 18 to 21 months.Of the 937 infants assigned to caffeine for whom adequate data on the primary outcome were available, 377 (40.2%) died or survived with a neurodevelopmental disability, as compared with 431 of the 932 infants (46.2%) assigned to placebo for whom adequate data on the primary outcome were available (odds ratio adjusted for center, 0.77; 95% confidence interval [CI], 0.64 to 0.93; P=0.008). Treatment with caffeine as compared with placebo reduced the incidence of cerebral palsy (4.4% vs. 7.3%; adjusted odds ratio, 0.58; 95% CI, 0.39 to 0.87; P=0.009) and of cognitive delay (33.8% vs. 38.3%; adjusted odds ratio, 0.81; 95% CI, 0.66 to 0.99; P=0.04). The rates of death, deafness, and blindness and the mean percentiles for height, weight, and head circumference at follow-up did not differ significantly between the two groups.Caffeine therapy for apnea of prematurity improves the rate of survival without neurodevelopmental disability at 18 to 21 months in infants with very low birth weight. (ClinicalTrials.gov number, NCT00182312 [ClinicalTrials.gov].).

The objective of the study was to determine whether administering doxapram by infusion to the very low birthweight infant, prior to extubation during the first 3 weeks of life, would increase the incidence of successful extubation. The study patients, 56 infants of less than 1251 g birthweight and less than 30 weeks' gestation, were entered in the first 3 weeks of life when lung disease had started to improve. A randomized blinded trial was performed, with infants receiving 3.5 mg kg -1 doxapram bolus, followed by an infusion at I mg kg -1 h -1 , or placebo. Weaning from positive pressure ventilation was standardized and extubation occurred after a 12 h trial of an intermittent mandatory ventilation (IMV) rate of 6 breaths min -1 , if PCO 2 7.26, and FiO 2 55 mmHg), excessive oxygen requirement (FiO 2 > 0.8) or frequent apnoea (more than three in 12 h, or more than two requiring face mask IMV in 24 h). No difference was noted in the frequency of successful extubation between the groups. Fifteen infants in each group were successfully extubated before the 10th day of the study. In conclusion, when given in accordance with this protocol doxapram does not increase the likelihood of successful extubation in the very low birthweight infant. Increasing successful extubations in this group of infants will require other strategies.

Background Nitric oxide is a major endogenous regulator of vascular tone. Inhaled nitric oxide gas has been investigated as a treatment for persistent pulmonary hypertension of the newborn. Objectives To determine whether treatment of hypoxaemic term and near-term newborn infants with inhaled nitric oxide (iNO) improves oxygenation and reduces the rates of death, the requirement for extracorporeal membrane oxygenation (ECMO), or affects long term neurodevelopmental outcomes. Search strategy Electronic and hand searching of pediatric/neonatal literature and personal data files. In addition we contacted the principal investigators of articles which have been published as abstracts to ascertain the necessary information. Selection criteria Randomized and quasi-randomized studies of inhaled nitric oxide in term and near term infants with hypoxic respiratory failure. Clinically relevant outcomes, including death, requirement for ECMO, and oxygenation. Data collection and analysis Trial reports were analysed for methodologic quality using the criteria of the Cochrane Neonatal Review Group. Results of mortality, oxygenation, short term clinical outcomes (particularly need for ECMO), and long term developmental outcomes were tabulated. Statistics: For categorical outcomes, typical estimates for relative risk and risk difference were calculated. For continuous variables, typical estimates for weighted mean difference were calculated. 95% confidence intervals were used. A fixed effect model was assumed for meta-analysis. Main results Fourteen eligible randomized controlled studies were found in term and near term infants with hypoxia. Seven of the trials compared iNO to control (placebo or standard care without iNO) in infants with moderate or severe severity of illness scores. Four of the trials compared iNO to control, but allowed back up treatment with iNO if the infants continued to satisfy the same criteria for severity of illness after a defined period of time. Two trials enrolled infants with moderate severity of illness score (OI or AaDO2) and randomized to immediate iNO treatment or iNO treatment only if they deteriorated to more severe criteria. One trial studied only infants with congenital diaphragmatic hernia (Ninos 1997) , and one trial enrolled both preterm and term infants (Mercier 1998), but reported the majority of the results separately for the two groups. Inhaled nitric oxide appears to improve outcome in hypoxaemic term and near term infants by reducing the incidence of the combined endpoint of death or need for ECMO. The reduction seems to be entirely a reduction in need for ECMO; mortality is not reduced. Oxygenation improves in approximately 50% of infants receiving nitric oxide. The Oxygenation Index decreases by a (weighted) mean of 15.1 within 30 to 60 minutes after commencing therapy and PaO2 increases by a mean of 53 mmHg. Whether infants have clear echocardiographic evidence of persistent pulmonary hypertension of the newborn (PPHN) or not does not appear to affect outcome. The outcome of infants with diaphragmatic hernia was not improved; indeed there is a suggestion that outcome was slightly worsened. The incidence of disability, incidence of deafness and infant development scores are all similar between tested survivors who received nitric oxide or not. Authors' conclusions On the evidence presently available, it appears reasonable to use inhaled nitric oxide in an initial concentration of 20 ppm for term and near term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia. Plain language summary Inhaled nitric oxide is safe and can help some full term babies suffering respiratory failure who have not responded to the usual methods of support. Inhaled nitric oxide can help some full term babies suffering respiratory failure who have not responded to the usual methods of support. Trials have shown that inhaled nitric oxide can increase the levels of oxygen in babies' blood and reduce the need for extracorporeal membrane oxygenation (ECMO), a highly technical and invasive therapy. Unfortunately, these benefits of inhaled nitric oxide care not seen in babies whose respiratory failure is due to a diaphragmatic hernia. Inhaled nitric oxide has not shown any short or longer term adverse effects.

The diagnosis and management of hypotension in the very low birth weight (VLBW) is a controversial area. To establish if there is any consensus in the diagnostic criteria and therapeutic interventions in the hypotensive VLBW among neonatologists in Canada. A postal questionnaire was sent to neonatologists in all level II and III neonatal intensive care units throughout Canada. In total, 120 questionnaires were sent. Ninety-five completed questionnaires were returned. Seventy-six percent of respondents work in units where at least 50 VLBWs and 43% where at least 100 VLBWs are cared for annually. Fifty-seven percent of the respondents have at least 10 years experience as practicing neonatologists. 25.8% rely on blood pressure values alone when intervening, the most common being a blood pressure less than gestational age in weeks. Ninety-seven percent of respondents commence therapy with a fluid bolus. Normal saline is the predominant volume administered (95%). Dopamine remains the pressor of choice. Great variation exists in starting doses and total amount administered. Similar variation exists with epinephrine, with tenfold differences in starting doses (0.01–0.1 mcg/kg/min) and tenfold differences in maximum dose (0.4–4 mc/kg/min) administered. Steroid doses used ranged from 0.1 mg/kg/dose of hydrocortisone to 5 mg/kg/dose. Bicarbonate is rarely used. Three predominant therapeutic regimes exist. These include (i) volume followed by dopamine then a steroid (32%), (ii) volume, dopamine, dobutamine (29%), (iii) volume, dopamine, epinephrine (22%). This is the first large study of practices among neonatologists addressing hypotension in the VLBW infant. There is wide variation in practice, which is a reflection of the lack of good evidence currently available for this very common problem.

To determine the relationship between respiratory patterns and acid gastro-esophageal reflux (g-e reflux) prior to discharge of the formerly preterm infant.Forty-five infants of32 weeks' gestation were studied at an average postmenstrual age of 37.2 weeks (SD 3.5). Following informed parental consent, a 12-hour multichannel recording including esophageal pH was obtained. Apneas of greater than 10 seconds were recorded, as well as the occurrence of bradycardia or desaturation.Acid g-e reflux (pH4.0) occurred at least once in all of the infants; prevalence was between1% and 41% of the 12-hour record (median 4.6%, interquartile range 0.5% to 9%). The number of reflux episodes ranged from 1 to 143 (median 23). The number of apneas (10 seconds duration) ranged from 0 to 71, median 6. There was no correlation between apnea frequency or severity and reflux frequency or duration. There was no difference in apnea frequencies between the 5 minutes after the start of a reflux episode and the 5 minutes prior to each episode.Acid g-e reflux in the formerly preterm infant at discharge is frequent and may be prolonged; there is no association between reflux and apnea.

The practice of mouth-to-mouth resuscitation was the first natural experiment using hypoxic gas mixtures for resuscitation. Although supplemental oxygen is now the standard during neonatal resuscitation, this practice has never been validated in prospective controlled trials. Neonatal resuscitation is primarily directed toward establishing early lung aeration and maintaining lung volume during expiration to overcome the initial vagal and hypoxic bradycardia. It remains unclear whether supplemental oxygen facilitates this process or contributes to potential hypoxia/reoxygenation injury, inhibition of breathing, and possible aggravation of atelectasis by the attenuation of nitrogen splinting. Accumulating evidence over the last decade has challenged clinicians to reconsider the optimal oxygen concentration for resuscitation of the newborn term infant. A critical review of 6 randomized trials that compared the use of room air (RA) and 100% oxygen reported that RA was associated with a significant lowering of mortality rate from 13% to 8% ( P = .0021), with a typical odds ratio (OR) of 0.57 (95% confidence interval [CI]: 0.42–0.78); however, no difference was observed for infants with a 1-minute Apgar score of 1000gm) revealed a greater reduction in mortality rate in the RA group, from 35% in the 100% O2 group to 21% in the RA group (typical OR: 0.51 [95% CI: … Address correspondence to Neil Finer, MD, UCSD Medical Center, 402 W Dickinson St, MPF Building, Suite 1-140, San Diego, CA 92103-8774. E-mail: nfiner{at}ucsd.edu

Apnea commonly occurs in preterm infants and may persist beyond term. We prospectively investigated the relationship between apnea that persisted beyond 35 weeks post-conceptional age and subsequent neurodevelopment in early childhood. Between January, 1990-November, 1993, we performed predischarge respiratory recordings, using 24-hr, 4-channel pneumography, at 35 weeks or more of postconceptional age in 164 infants (birth weight

Objective: Temporal effects of prolonged hypoxaemia and reoxygenation, on the systemic pulmonary and mesenteric circulations in newborn piglets, were investigated. Methods: Two groups [control ( n =5), hypoxaemic ( n =7)] of 1–3 day old anaesthetised piglets were instrumented with ultrasound flow probes placed to measure cardiac, hepatic arterial flow and portal venous flow indices, and catheters inserted for measurements of systemic and pulmonary arterial pressures. Hypoxaemia with arterial oxygen saturation 40–50% was maintained for 3 h, followed by reoxygenation with 100% inspired oxygen. Results: Cardiac index was transiently elevated at 30–60 min of hypoxaemia (23% increase from baseline 158±39 ml/kg/min), along with increases in stroke volume but not heart rate. A significant decrease in systemic vascular resistance after 30 min of hypoxaemia was followed by hypotension at 180 min of hypoxaemia. Progressive pulmonary hypertension with significant vasoconstriction was found after 30 min of hypoxaemia. The hypoxaemic mesenteric vasoconstriction was transient with a 37% decrease in portal venous flow index at 15 min of hypoxaemia (29±12 vs. 46±18 ml/kg/min of baseline, p

The incidence of complications was recorded for 269 consecutive neonatal endotracheal intubations after instituting a routine policy of premedication. Two hundred and fifty-three of the intubations were premedicated with a combination of atropine, fentanyl and succinylcholine, 194 were without incident, 28 required two attempts, 22 required more than two attempts, and 9 required a second attempt with a smaller endotracheal tube. All infants were successfully intubated. We conclude that a policy of routine neonatal premedication for intubation is safe, feasible, and humane.

Objective: To determine the effects of a continuous epinephrine infusion on renal and mesenteric blood flow in both healthy newborn piglets and animals subjected to hemorrhagic shock. Methods: Superior mesenteric artery (SMA) and left renal artery ultrasonic flow probes were implanted into 16 1- to 3-day-old piglets. Two days later, the effects of epinephrine on SMA and renal blood flow, mean arterial pressure (MAP) and central venous pressure were measured in conscious, non-sedated normovolemic piglets. Epinephrine doses of 0.2, 0.4, 0.8, 1.6 and 3.2 µg/kg·min were used in random order. Piglets were subsequently hemorrhaged (20 ml/kg) to mild hypotension and again received epinephrine infusion in the same doses. Results: Doses of epinephrine less than 3.2 µg/kg·min had no significant effects on renal or mesenteric arterial flow. At 3.2 µg/kg·min of epinephrine during normovolemia, there was a significant decrease in SMA blood flow (34% [SD 42], p < 0.05) and increase in SMA vascular resistance (147% [SD 114], p < 0.05). Similar results were shown during hypovolemia, SMA flow decreased by 32% (SD 33), and SMA vascular resistance increased by 220.3% (SD 177). At 3.2 µg/kg·min renal artery flow decreased by 43% (SD 21) during normovolemia and a similar decrease occurred during hypovolemia, 37% (SD 31). Renal vascular resistance increased by about 200% at this dose (normovolemia 211% [SD 185], hypovolemia 186% [SD 150], p < 0.01). Low-to-moderate dose epinephrine caused no significant change in SMA or renal blood flow. During hypovolemia low dose epinephrine infusion was associated with a trend to increased SMA blood flow. Conclusion: Low-dose epinephrine does not cause vasoconstriction in the renal or mesenteric circulations during normovolemia or hypovolemia. High doses of epinephrine above 1.6 µg/kg·min may cause renal or mesenteric ischemia, in either the normovolemic or hypovolemic neonate.

Nitric oxide given as an inhalation (INO) is a novel selective pulmonary vasodilator without effects on the systemic circulation. Preliminary observations indicated that INO treatment was associated with improvements in oxygenation in near-term newborn infants with hypoxic respiratory failure and persistent pulmonary hypertension of the newborn (PPHN). Subsequently, at least eight prospective randomized controlled trials evaluating the use of INO in the near-term neonate with hypoxic respiratory failure have been presented or published. A meta-analysis of these trials has provided evidence that INO improves the PaO 2 in the INO-treated infants by 52.8 mm Hg (weighted mean difference) compared with controls (95% CI, 38.2, 67.4), and significantly decreases the oxygenation index by 16.9 compared with controls (95% CI, −22.2, −11.6). The incidence of death or need for ECMO is significantly reduced by treatment with INO, relative risk 0.71 compared to control (95% CI, 0.57, 0.87), with the majority of the improvement observed in the reduction in the need for ECMO. A single study of infants with congenital diaphragmatic hernia (CDH) did not show a benefit for early INO therapy, with treated infants having a greater requirement for ECMO ( P =.043). At present, there are no long-term evaluations of infants who have received INO as part of these prospective trials. INO improves oxygenation and reduces the need for ECMO in the near-term hypoxic neonate, but further research is required to evaluate the ultimate safety and benefit of this therapy.

OBJECTIVE To determine the effects of stimulation of vascular dopaminergic receptor subtype 1 (dopamine-1) receptors in the renal and mesenteric vascular beds of a neonatal model. DESIGN Prospective, unblinded, dose-response evaluation in an awake animal. SETTING University research laboratory. SUBJECTS Thirty newborn piglets, obtained and instrumented at 1 to 3 days of age and studied 48 hrs later. INTERVENTIONS Animals were chronically instrumented with transit time ultrasound flow probes around the left renal and superior mesenteric arteries. They were then intravenously infused with either dopamine (2 to 32 micrograms/kg/min) or fenoldopam (1 to 100 micrograms/kg/min), which is a selective agonist of the dopamine-1 receptor. MEASUREMENTS AND MAIN RESULTS Blood pressure was only significantly increased by the highest infusion rate of dopamine (32 micrograms/kg/min), from a mean of 78 mm Hg at baseline to 87 mm Hg. Mesenteric and renal vascular resistances were unchanged by dopamine at any dose. Dopamine at 32 micrograms/kg/min decreased renal blood flow by 16.6 +/- 19.6 (SD) % and increased renal vascular resistance by 39.6 +/- 41.1% (p < .05). Mesenteric blood flow increased by 15% at 32 micrograms/kg/min (p < .05) but mesenteric vascular resistance was not affected by dopamine. Fenoldopam reduced blood pressure at infusion rates of 5, 10, and 100 micrograms/kg/min. Fenoldopam had no effect on renal vascular resistance at any dose. Fenoldopam reduced mesenteric vascular resistance at 5 micrograms/kg/min and at all higher doses. CONCLUSIONS These data demonstrate the absence of dopaminergic receptor-mediated vasodilation in the porcine neonatal renal vascular bed. In the mesenteric artery, dopamine-1 receptor-mediated vasodilation may be obtained. Dopamine itself, probably because of stimulation of other receptors, causes renal artery vasoconstriction and does not increase superior mesenteric artery blood flow.

To determine the hemodynamic responses to dopamine and epinephrine infusions in newborn piglets during normoxia and hypoxia.Prospective, randomized, blind cross-over study.Newborn piglets (n = 7).Animals were acutely instrumented for measurements of cardiac output, pulmonary and systemic pressures, carotid and coronary artery blood flow, and coronary artery oxygen consumption. Dopamine at infusion rates of 2 to 16 micrograms/kg/min and epinephrine 0.2 to 1.6 micrograms/kg/min were administered during normoxia. Six piglets were similarly prepared and were then made hypoxic to an arterial O2 saturation of 45% to 50%. Epinephrine at infusion rates of 0.2 to 3.2 micrograms/kg/min and dopamine at rates of 2 to 32 micrograms/kg/min were administered in random order during hypoxia.During normoxia, cardiac output increased similarly with both drugs and was significantly increased byor = 0.2 micrograms/kg/min of epinephrine and significantly increased by 8 or 16 micrograms/kg/min of dopamine. Mean arterial blood pressure was not affected by dopamine but was significantly increased by epinephrine at a rate of 1.6 micrograms/kg/min. The relative effects of the drugs on pulmonary and systemic vascular resistance differed, the pulmonary/systemic vascular resistance ratio was reduced at the higher doses of epinephrine (i.e., 0.8 and 1.6 micrograms/kg/min) and was unaffected by dopamine. Coronary artery oxygen consumption and coronary blood flow increased significantly with both medications at rates0.4 and 4 micrograms/kg/min, respectively. Increases of both variables were greater with epinephrine than with dopamine. Myocardial extraction ratio was unaffected by dopamine and reduced at 0.2 and 1.6 micrograms/kg/min of epinephrine. Hypoxia caused significant increases in cardiac index, systemic blood pressure, pulmonary arterial pressure, carotid artery blood flow, coronary artery blood flow, coronary oxygen consumption, coronary oxygen extraction ratio, and the pulmonary/systemic vascular resistance ratio. Mean systemic arterial blood pressure increased significantly with 1.6 and 3.2 micrograms/kg/min of epinephrine, but was not significantly affected by dopamine at any infusion rate. Cardiac index was not affected significantly by either of the medications. Thus, there was a significant increase in the calculated systemic vascular resistance index with the highest dose of epinephrine, in contrast to the slight, statistically significant, decrease in calculated systemic vascular resistance index with the highest dose of dopamine. Epinephrine significantly reduced pulmonary arterial pressures at 0.2, 0.4, and 0.8 microgram/kg/min. Dopamine had no effect on this variable. The pulmonary/systemic vascular resistance ratio was significantly reduced by epinephrine at doses of 0.2 and 3.2 micrograms/kg/min, whereas the highest dose of dopamine caused a significant increase in the pulmonary/systemic vascular resistance ratio.Epinephrine infusion during normoxia increases systemic pressure more than pulmonary arterial pressure at dosesor = 8 micrograms/kg/min, and furthermore, produces a more appropriate hemodynamic profile in the presence of hypoxic pulmonary hypertension than dopamine infusion, in the acutely operated anesthetized piglet.

Adult intraabdominal surgery performed with the minimal-access technique has created a revolution in surgery. This technique has remained largely unused for pediatric surgical procedures because of concerns regarding its safety and efficacy. Presently, intraabdominal insufflation of CO 2 is the preliminary step to performing minimal access surgery. In this study, an animal model was developed to determine the effects of intraabdominal CO 2 insufflation in the infant. Eight piglets (4 to 6 kg; 14 to 19 days of age) were instrumented under fentanyl anesthesia to allow measurement of arterial blood pressure (BP), central venous pressure (CVP), heart rate (HR), cardiac index (CI), inferior vena cava pressure (IVCp), inferior vena cava flow (IVCf), mediastinal pressure (Mp), partial pressure of CO 2 (Paco 2 ), and minute ventilation (V E ) at baseline and during 1 hour of CO 2 insufflation to a pressure of 15 mm Hg and again when ventilation was increased to control Paco 2 levels. Continuous recording of data allowed time-course analysis of 15-minute blocks to determine the rate of change of measured variables. A second group of 6 piglets (4 to 6 kg) underwent the same instrumentation, but their baseline values were compared with those during N 2 O insufflation to isolate the effects of increased intraabdominal pressure. During CO 2 insufflation alone, Paco 2 increased by 31% ( P 2 absorption from the peritoneal cavity because V E was unchanged. CO 2 insufflation alone was associated with increases of 10% in CI ( P = .02), 29% in CVP ( P = .01), and 17% in BP ( P 2 was controlled by increased ventilation, there was no significant change in CI, increases of 7% in SVR ( P = .02), 57% in CVP ( P = .001), and 7% in BP ( P = .01), and a 22% decrease in IVCf ( P = .04). N 2 O insufflation resulted in no significant change in CI, increases of 22% in SVR ( P = .01), 35% in CVP ( P = .01), and 16% in BP ( P = .005), and a 25% decrease in IVCf ( P = .02). CO 2 insufflation is associated with significant CO 2 absorption and increased myocardial work in the piglet model.

Do extremely immature preterm infants with blood pressure which is believed to be low have reduced systemic perfusion, reduced cerebral oxygen delivery, increased cerebral injury, an increase in acute complications of prematurity and an increase in long-term disability? If so, below what value of blood pressure do these adverse outcomes increase? These unanswered questions are of vital importance; extremely preterm infants have high rates of developmental delay and disability, blood pressures are often numerically very low and many preterm infants receive treatments which are potentially toxic with the goal of increasing their blood pressure. Unfortunately, it is not at all clear whether the common treatments for low blood pressure improve systemic flow or cerebral perfusion, or among the available options, which treatments are effective? The reason for this poverty of information is the lack of adequate trials. There are no controlled studies of hypotension therapy in the preterm newborn which include an untreated group, so changes in systemic perfusion or indirect measures of cerebral blood flow cannot necessarily be ascribed to the intervention. In addition, the small number of comparative trials that have been performed have all been vastly underpowered, and have concentrated on short-term physiological end points, usually blood pressure.1 One study which compared the effects of dopamine and epinephrine on indices of cerebral perfusion showed an increase of about 20% in cerebral blood volume after 2 h of treatment, in association with about a 50% increase in mean blood pressure, with no difference between the groups2; there was …

Persistent pulmonary hypertension of the newborn may occur with perinatal asphyxia, either because of direct effects of hypoxia/ischemia on pulmonary arterial function or indirectly because both are associated with meconium aspiration syndrome or perinatal sepsis/pneumonia. Therapies for persistent pulmonary hypertension of the newborn have the potential to affect cerebral function and cerebral perfusion in infants with hypoxic ischemic encephalopathy. Our literature review concludes that hyperventilation should be avoided, bicarbonate therapy is unproven, and hypoxia and hyperoxia should both be avoided. Nitric oxide improves pulmonary artery pressure and systemic perfusion. The effects of inotropic agents on cerebral perfusion or outcomes are uncertain.

OBJECTIVES To determine whether maximal inspiratory force predicts successful neonatal extubation, and whether aminophylline affects maximal inspiratory force or the success rate of extubation. DESIGN Double-blind, prospective, randomized, placebo-controlled trial. SETTING Tertiary level neonatal intensive care unit. PATIENTS A total of 20 ventilated, preterm, newborn infants: birth weight < 2.5 kg; gestation < 35 wks. INTERVENTIONS Intravenous aminophylline 4 mg/kg bolus followed by 2.5 mg/kg every 6 hrs x three doses, then 1.5 mg/kg every 6 hrs; or placebo. Drug administration began when infants were receiving an FIO2 of < 0.4 and were progressively weaning from assisted mechanical ventilation. A standardized weaning protocol was instituted, and patients were extubated when they were able to tolerate a mechanical ventilatory rate of < 5 cycles/min. MEASUREMENTS AND MAIN RESULTS Occlusion pressures, including maximal inspiratory force, were measured before aminophylline and daily until endotracheal extubation. Arterial blood gases were measured every 3 hrs, and 24-hr cardiac and respiratory recordings were performed postextubation. Three of ten aminophylline-treated patients failed extubation compared with two of ten placebo infants (p = nonsignificant). Mean apnea frequency postextubation was 0.02/hr in the aminophylline group compared with 0.3/hr in the placebo group (p < .05). Aminophylline had no effect on successful extubation or on maximal inspiratory force. Maximal inspiratory force was not correlated with the success of extubation. Apnea frequency postextubation was significantly reduced by aminophylline. CONCLUSIONS Aminophylline is an effective prophylaxis for postextubation apnea in the preterm infant but does not affect maximal inspiratory force or increase the success rate of extubation in this patient population.

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.

To describe the various anesthetic techniques used for surgical closure of PDA in premature infants at the Montreal Children's Hospital and assess their impact on postoperative outcome.The charts of all preterms who underwent PDA ligation during a 21-month period were reviewed for preoperative status, intraoperative anesthetic management and postoperative outcome. We determined the associations between independent variables and two postoperative outcome variables: unstable postoperative respiratory course (UPRC) and hypotension.The mean weight at surgery of the 33 infants was 1.031±0.29 kg. All infants, but one, received intraoperative opioids. Eight patients presented UPRC. Mean fentanyl doses were 5.3±2.6 mcg kg(-1) for patients with UPRC vs 22.6±16.6 mcg kg(-1) for patients without UPRC (P=0.004). Applying the receiver-operator characteristic curve (ROC), 10.5 mcg kg(-1) of fentanyl was established as the dose that discriminated and identified patients who experienced UPRC. The postnatal and postmenstrual age of the patient, birthweight, current weight, ventilator settings preoperatively, previous courses of indomethacin, sex and preoperative creatinine, were not correlated with the dose of fentanyl equivalent used. Logistic regression did not show a relationship between any of the previously mentioned factors and receiving a fentanyl equivalent of10.5 mcg kg(-1). The only factor associated with the total fentanyl equivalent dose (as a continuous variable) or receiving10.5 mcg kg(-1) (as a dichotomous variable) was the identity of the anesthetist involved, P0.001.We conclude that the use of at least 10.5 mcg kg(-1) of fentanyl equivalent as a component of the anesthetic regimen for surgical closure of a PDA in premature infants, avoids an unstable postoperative respiratory course.

any very preterm infants require assisted ventilation. After resolution of their initial pulmonary dysfunction, when extubated they are at risk of failure due to poor respiratory drive, atelectasis, residual pulmonary function abnormalities, or intercurrent illness. Keeping such infants extubated will decrease lung injury and improve long-term pulmonary and perhaps even neurologic outcomes. On the other hand, if failure of extubation could be accurately predicted, then extubation could be deferred and the trauma of reintubation after a brief failed extubation, with increased work of breathing, hypoventilation, and respiratory acidosis, could be avoided.

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)

OBJECTIVE. Our goal was to determine whether, for preterm newborn infants with respiratory disease, inhaled nitric oxide reduced the rates of death, bronchopulmonary dysplasia, intracranial hemorrhage, or neurodevelopmental disability. METHODS. We searched Medline, Embase, Healthstar, and the Cochrane Central Register of Controlled Trials using the search terms “nitric oxide,” “clinical trial,” and “newborn” and covering 1985–2006. We also searched abstracts of the Pediatric Academic Societies. RESULTS. Eleven randomized, controlled trials of inhaled nitric oxide therapy for preterm infants were found. The trials were grouped into 3 categories according to the entry criteria, that is, entry in the first 3 days of life on the basis of oxygenation criteria (early rescue), enrollment after 3 days on the basis of elevated risk of bronchopulmonary dysplasia, and routine use for intubated preterm infants. Early rescue treatment based on oxygenation criteria did not seem to affect mortality or bronchopulmonary dysplasia rates. Routine use for intubated preterm infants showed a barely significant reduction in the incidence of the combined outcome of death or bronchopulmonary dysplasia (relative risk [RR]: 0.91 [95% confidence limits (CLs): 0.84, 0.99]). Later treatment based on the risk of bronchopulmonary dysplasia showed no significant effect on this outcome. Early rescue treatment showed a trend toward increased incidence of severe intracranial hemorrhage, whereas routine use for intubated preterm infants seemed to show a reduction in the incidence of either severe intracranial hemorrhage or periventricular leukomalacia (RR: 0.70 [95% CLs: 0.53, 0.91]). CONCLUSIONS. Inhaled nitric oxide as rescue therapy for very ill preterm infants undergoing ventilation does not seem to be effective and may increase severe intracranial hemorrhage. Later use of inhaled nitric oxide to prevent bronchopulmonary dysplasia does not seem to be effective. Early routine use of inhaled nitric oxide for mildly sick, preterm infants seems to decrease the risk of serious brain injury and may improve rates of survival without bronchopulmonary dysplasia.

Background: Endotracheal intubation in the neonate is painful and is associated with adverse physiological effects. Some premedication regimens have been shown to reduce these effects, but the optimal regimen is not yet determined. Method: Data on semi-elective intubations were prospectively collected in the neonatal intensive care unit over a six month period. Patients received 20 μg/kg atropine, 200 μg/kg mivacurium (a non-depolarising muscle relaxant) followed by 5 μg/kg fentanyl. Results: Thirty three patients were electively intubated during this time period. The primary reason for intubation was surfactant administration (53%). Median (range) birth weight, gestational age, and age at intubation were 1360 g (675–4200), 29 weeks (25–38), and 33 hours (1–624) respectively. Twenty two of the infants were intubated on the first attempt. Median duration from initial insertion of the laryngoscope to successful intubation was 60 seconds (15 seconds to 20 minutes). In 18 cases, the first attempt was by a trainee with no previous successful intubation experience, 10 of whom intubated within two attempts. Muscle relaxation occurred at a mean (SD) of 94 (51) seconds, and mean (range) time to return of spontaneous movements was 937 seconds (480–1800). Intubation conditions were scored as excellent using a validated intubation scale. Conclusion: Effective analgesia can be administered and intubation performed with some brief desaturations, even when junior personnel are being taught their first intubation. In this first report of mivacurium for intubation in the newborn, effective bag and mask ventilation was easily achieved during muscle relaxation and was associated with excellent intubation conditions, permitting a high success rate for inexperienced personnel.

The objective of this study was to determine the dose–response effects of epinephrine, given by systemic intravenous infusion to the halothane-anesthetized newborn piglet, on renal blood flow, mean arterial blood pressure, and renal vascular resistance. Seven newborn piglets were acutely instrumented. A transit-time ultrasound flow probe was placed around the renal artery and a femoral arterial catheter was placed for blood pressure monitoring. Epinephrine was infused in doubling doses from 0.2 to 3.2 μg∙kg−1∙min−1. Mean arterial blood pressure increased from 54 mmHg (1 mmHg = 133.3 Pa) to an average of 96 mmHg at 3.2 μg∙kg−1∙min−1 of epinephrine. Renal blood flow increased from 165 mL∙min−1∙100 g−1 at baseline to 185 mL∙min−1∙100 g−1 at a dose of 0.2 μg∙kg−1∙min−1 and increased further at 0.4 and 0.8 μg∙kg−1∙min−1 to reach 261 mL∙min−1∙100 g−1. Renal blood flow began to fall at a dose of 3.2 μg∙kg−1∙min−1, remaining however, significantly above baseline (211 mL∙min−1∙100 g−1). Consequently, calculated renal vascular resistance fell as the dose was increased from 0.2 to 0.8 μg∙kg−1∙min−1 and then rose again at 1.6 and 3.2 μg∙kg−1∙min−1, being significantly above baseline at 3.2 μg∙kg−1∙min−1. These results demonstrate that epinephrine when given by systemic infusion to the halothane-anesthetized newborn pig is a renal vasodilator at low doses and causes renal vasoconstriction at moderate to high doses. Renal blood flow remained above baseline at all doses tested, and thus, within the dosage range tested, epinephrine infusion should not cause renal ischemia.Key words: epinephrine, kidney blood flow, piglet, renal vascular resistance.

BACKGROUND Indomethacin therapy for closure of patent ductus arteriosus frequently causes oliguria, and occasionally more serious renal dysfunction. Low dose dopamine has been suggested as a means for preventing this side effect. OBJECTIVES PRIMARY OBJECTIVE To determine whether dopamine therapy may prevent indomethacin-mediated deterioration in renal function in the preterm newborn infant without serious adverse effects. SECONDARY OBJECTIVE To assess the effects of dopamine on the above variables in two subgroups: (1) patients given indomethacin as prophylaxis of intraventricular hemorrhage, and (2) patients given indomethacin as treatment of patent ductus arteriosus SEARCH STRATEGY Standard methods of the Cochrane Neonatal Review Group (CNRG) were used. We searched MEDLINE (1966-2001) using PubMed as the search engine, EMBASE (1974-2001) and the Cochrane Controlled Trials Register (CCTR) from the Cochrane Library (Issue 3, 2001). In addition we contacted the principal investigators if necessary to ascertain the required information. SELECTION CRITERIA Randomized or quasi-randomized studies of the effects of dopamine on urine output, glomerular filtration rate, fluid balance or incidence of renal failure, in preterm newborn infants receiving indomethacin. The comparison group should have received no dopamine. DATA COLLECTION AND ANALYSIS We used the standard methods of the Cochrane Collaboration and those of the CNRG. The primary outcomes of interest were: mortality before discharge; intraventricular hemorrhage, grade three or four; cystic periventricular leukomalacia; renal failure (either oliguria, defined as a urine output less than 1 ml/kg/hour or an elevation in creatinine by more than 40 micromoles/L); failure to close the ductus arteriosus; need for surgical PDA ligation. For categorical outcomes, we calculated typical estimates for relative risk and risk difference. For continuous outcomes the weighted mean difference (WMD) was calculated. Fixed effect models were assumed for meta-analysis. MAIN RESULTS Three studies were found (total number randomized patients, 75) which fulfilled the entry criteria for this review. All were single center trials which enrolled NICU patients receiving indomethacin for symptomatic patent ductus arteriosus. There are no (or only partial) results for effects of dopamine on several of the primary outcomes, including death before discharge, serious intraventricular hemorrhage, cystic periventricular leukomalacia, or renal failure. There has been inadequate investigation of the effects of dopamine on cerebral perfusion or cardiac output, or GI complications, or endocrine toxicity. Dopamine improved urine output [WMD 0.68 ml/kg/hour (95% CI 0.22, 1.44)], but there was no evidence of effect on serum creatinine (WMD 2.04 micromoles/liter, CI -17.90, 21.97) or the incidence of oliguria (urine output < 1 ml/kg/hour) (RR 0.73, CI 0.35, 1.54). There was no evidence of effect of dopamine on the frequency of failure to close the ductus arteriosus (RR 1.11, CI 0.56, 2.19). REVIEWER'S CONCLUSIONS There is no evidence from randomized trials to support the use of dopamine to prevent renal dysfunction in indomethacin-treated preterm infants.

Objective. Carnitine is thought to be a conditionally essential biological cofactor for premature infants. A preliminary study suggested that carnitine could significantly reduce apnea of prematurity. The objective of this study was to evaluate critically the role of carnitine in idiopathic apnea of prematurity and to determine whether the use of carnitine would facilitate discontinuation of mechanical ventilatory support, shorten the duration of ventilatory support, and reduce the amount of time that such infants are exposed to both mechanical ventilation and oxygen. We also wanted to determine the effects of supplemental carnitine on weight gain, time to regain birth weight, time to achieve full enteral feedings, and length of hospital stay. Methods. A prospective, randomized, blinded trial was conducted on 44 preterm infants who were from the same neonatal intensive care unit and who were ≤32 weeks’ gestational age with a postnatal age Results. There were no significant differences between the 2 groups in the occurrence of apnea as detected by cardiorespiratorygram or nursing observation. There were no significant differences between the groups in regard to total days on ventilator, days of nasal continuous positive airway pressure, time to regain birth weight, time to reach enteral feedings of 120 mL/kg/d, discharge weight, adjusted age at discharge, need for oxygen at 28 days’ and 36 weeks’ adjusted age, or length of stay. The plasma carnitine level was a median of 15.5 μmol/L (range: 7.6–30.5) for the placebo infants compared with a median of 195.3 μmol/L (range: 71.7–343.6) for the carnitine infants. Conclusions. In this blinded, randomized, placebo-controlled study, we found that infants who received supplemental carnitine did not demonstrate any reduction in apnea of prematurity, ventilator or nasal continuous positive airway pressure days, or the need for supplemental oxygen therapy. Although carnitine may be of significant nutritional benefit for very low birth weight infants, our study does not support its use to reduce apnea of prematurity or decrease dependence on mechanical ventilation.

Since its first appearance, the Pediatric Advanced Life Support (PALS) course has recommended a minimum dose of atropine of 0.1 mg regardless of the body weight of the child. The most recent update of PALS, after the extensive International Liaison Committee on Resuscitation (ILCOR) process, designed to develop the evidence base of resuscitation recommendations, still contains this same recommendation.1 This recommendation is frequently quoted by pediatric residents fresh from their PALS courses; I have often been informed that a lower dose causes “paradoxical bradycardia.” Indeed, the computerized printouts for resuscitation drugs and doses from our hospital information system are based on the PALS guidelines and give the same recommended dose. Thus, if the computerized printout were to be followed, a 2-kg infant would receive 0.1 instead of 0.04 mg of atropine. If the indication persisted and a second dose were to be given, potentially lethal overdosage could occur. This minimum dose is widely repeated. The 12th edition of The Harriet Lane Handbook 2 states that the preanesthesia dose (30–60 minutes before operation) for a child is “0.01 mg/kg/dose SC/IV/IM, max. dose: 0.4 mg/dose; min. dose: 0.1 mg/dose; may repeat Q4–6 hr” and for “Cardiopulmonary resuscitation (see remarks): Child,” the recommended dose is “0.02 mg/kg/dose IV Q5 min × 2–3 doses PRN; min. dose: 0.1 mg”; the remarks to which the authors refer included: “Doses < 0.1 mg have … Address correspondence to Keith J. Barrington, MB, ChB, Division of Neonatology, Saint Justine University Hospital Center, 3175 Cote St Catherine, Montreal, Quebec, Canada H3T 1C5. E-mail: keith.barrington{at}umontreal.ca

Objective. There is little information on the response to very low doses of inhaled nitric oxide (iNO) in hypoxic near-term infants. The potential toxicities of iNO are dose related; thus, the ability to use lower doses safely and effectively may be advantageous. We hypothesized that there is no difference in the acute improvement in oxygenation between treatment with inhaled nitric oxide at 1 to 2 parts per million (ppm) or 10 to 20 ppm. Methods. We randomized near-term and term infants with hypoxic respiratory failure with oxygenation indices (OIs) of ≥10 and Pao2 Results. Thirty minutes after the study gas was initiated, Pao2 increased significantly overall in the low-dose (90.7 ± 41 torr to 166.8 ± 95.6 torr) and high-dose (76.2 ± 32.7 torr to 198.7 ± 142.8 torr) groups; the maximal increase was seen in the infants who initially were treated with 10 ppm. The OI also decreased significantly overall and also was significant in the high-dose group (21.0 ± 13.7 to 11.4 ± 10.4; low-dose: 18.3 ± 7.1 to 13.2 ± 12.3). There was a nonsignificant fall of Paco2 with iNO treatment (low dose 35 ± 7.3 to 30 ± 8.5 torr vs high dose 35.2 ± 9.9 to 32.4 ± 10.7 torr). A sustained response (ie, maintaining a Pao2 and OI gain greater than 20% for the duration of the study gas administration) was greater in the high-dose group (53.3% vs 30.0%). In addition, dose increases were required more often in the low-dose group than in the high-dose group (80.0% vs 57.1%). Among patients who did not respond to the initial iNO dose, 100.0% and 83.3% responded at higher doses of iNO for the low- and high-dose groups, respectively. There were no differences for death, need for extracorporeal membrane oxygenation, or other outcomes between the groups. Conclusions. We did not find any significant difference in response to low- versus high-dose iNO. An initial exposure to low-dose iNO does not compromise the response to higher doses if required and may result in less toxicity.

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.

Objective. To determine whether noninvasive, nasal synchronized intermittent mandatory ventilation (nSIMV) improves the likelihood that very low birth weight infants will be successfully extubated. Methods. Infants of 70; Fio2 >0.7; or severe recurrent apnea (>2 apneas requiring intermittent positive-pressure ventilation in 24 hours or >6 apneas >20 seconds per day). The study ended after 72 hours postextubation or when infants satisfied failure criteria. A sample size of 54 was determined by power analysis. Results. Mean birth weight (831 standard deviation [SD]: 193 g) and gestation (26.3 SD: 1.8 weeks) did not differ between groups. Mean age at extubation was 7.6 (SD: 9.7) days, range 1 to 40 days. The nSIMV group had a lower incidence of failed extubation 4/27 compared with the continuous positive airway pressure group, 12/27. This was attributable to both a decreased incidence of apnea and a decreased incidence of hypercarbia. There was no increase in the incidence of abdominal distension or feeding intolerance. Discussion. nSIMV is effective in preventing extubation failure in very low birth weight infants in the first 72 hours after extubation. Noninvasive ventilation may have other roles in the care of the very low birth weight infant.

To determine the effects of therapy with inhaled nitric oxide (NO) gas and partial or complete blockade of endogenous NO synthesis with N(omega)nitro-L-arginine (L-NA) on the hemodynamic responses to group B streptococci infusion in newborn piglets.Randomized, acute intervention study.Animal research laboratory.Twenty-five anesthetized piglets younger than 3 days of age divided into five groups.Heat-killed group B streptococci (GBS) were infused systemically until a 50% increase in pulmonary artery pressure (PAP) was obtained, and the infusion was continued for another 2 hrs. The five groups were designed as follows: group 1, sepsis control: continuous GBS infusion, with two brief trials (10 mins) of inhaled NO given after the initial development of pulmonary hypertension and again 2 hrs later; group 2, continuous inhaled NO: NO was given at 40 ppm for 2 hrs during GBS infusion; group 3, high-dose L-NA pretreatment: 10 mg/kg L-NA bolus followed by 1 mg/kg/min before, and continuing throughout, GBS infusion; group 4, high-dose L-NA: same dose as in group 3, but given after the start of the GBS infusion with continuous inhaled NO at 40 ppm; and group 5, low-dose L-NA: 3 mg/kg bolus given after start of GBS infusion with continuous inhaled NO at 40 ppm.The sepsis controls, group 1, had an increase in PAP, which took 15-45 mins to develop, from a mean of 3.4 (SD 0.7) to 5.9 (1.9) kPa (p.05), at which time the cardiac index had decreased from 169 (28) to 146 (46) mL/kg/min (p.05). Brief inhaled NO during the early phase decreased PAP to normal. Two hours later, PAP had increased to 6.1 (0.2) kPa and cardiac index had decreased to 88 (31) mL/kg/min. Inhaled NO after 2 hrs decreased PAP to 3.2 (0.5) kPa and increased cardiac index to 106 (44) ml/kg/min (p.05). Continuous inhaled NO (group 2) ameliorated the deterioration in cardiac index, which at 2 hrs was 140 (30) mL/kg/min (significantly greater than in the sepsis controls) (p.05). The L-NA-pretreated animals (group 3) had a greater increase in PAP and pulmonary vascular resistance index when GBS infusion was started. PAP increased from 3.0 (0.7) to 7.3 (1.5) kPa within 15 mins, and cardiac index simultaneously decreased to 68 (20) mL/kg/min. Cardiac index subsequently rapidly deteriorated to 48 (21) mL/kg/min, and only one of five animals survived for 2 hrs. Group 4 animals also developed a rapid deterioration in cardiac output, and only two of five survived for 2 hrs. Group 5 animals had results indistinguishable from group 2 animals.Pulmonary hypertension and shock resulting from GBS infusion in newborn piglets are much worse if endogenous NO production is completely inhibited. Continuous inhaled NO with or without low-dose L-NA inhibits the decrease in cardiac output.

OBJECTIVE: To examine the hemodynamic effects of magnesium sulfate (MgSO4) in a neonatal model of meconium aspiration syndrome. DESIGN: A prospective animal study. PATIENTS AND PARTICIPANTS:Eight anesthetized neonatal piglets. METHODS: Animals were instrumented under fentanyl anesthesia for the determination of pulmonary and systemic blood pressures and cardiac index. A model of meconium aspiration was produced by instilling 6 to 7 ml of 20% fresh human meconium in normal saline down the endotracheal tube, resulting in hypoxemia (mean arterial O2 saturation 73 SD, 10%), respiratory acidosis (mean pH 7.08, SD 0.04; PACO2 89, SD 2 torr), and pulmonary arterial hypertension (mean pulmonary artery pressure 52 SD, 5 mm Hg). A total of four aliquots of MgSO4 (25 mg/kg equivalent to 0.1 mM/kg of magnesium) were administered intravenously to five animals (total of 100 mg/kg MgSO4). Three animals served as controls and did not receive MgSO4. RESULTS: Each dose of MgSO4 was associated with a transient decrease in heart rate, cardiac index, pulmonary and systemic arterial pressures, and SAO2, followed by a partial gradual recovery of all these variables within 2 to 3 minutes. According to measurements taken after MgSO4 therapy, there was a significant decrease in arterial saturations (from 73 SD (10%) to 63 SD (13%); p < 0.05), mean systemic blood pressure (from 77 SD (16 mm Hg) to 74 SD (15 mm Hg); p < 0.05) and pulmonary artery pressure (to 52 SD (5 mm Hg); p < 0.05). The ratio between pulmonary and systemic vascular resistance was not significantly affected by MgSO4 therapy. There were no changes in the control animals. CONCLUSION: The administration of magnesium sulfate is associated with increased hypoxemia in this model of meconium aspiration syndrome, probably because of worsening ventilation perfusion mismatch. These data do not provide any physiological support for the use of MgSO4 in the neonate with meconium aspiration and pulmonary hypertension and suggest that this agent should be used cautiously, if at all, in such situations.

Objective: To test the hypothesis that prolonged alkalosis decreases cardiac output and, furthermore, exacerbates hypoxic pulmonary vasoconstriction, as respiratory alkalosis is frequently induced as a therapy for persistent pulmonary hypertension of the newborn despite a lack of controlled evidence of improved outcomes. Potential adverse effects of prolonged alkalosis have been demonstrated.¶Method: Two groups (control, n = 6, and hypocapnic alkalosis, n = 6) of 1–3 day old fentanyl-anesthetized, vecuronium-paralyzed piglets were instrumented to measure cardiac index (CI) and mean systemic (MAP) and pulmonary (PAP) arterial pressures. Baseline values were recorded. Alveolar hypoxia was then induced to achieve an arterial oxygen saturation of between 50 and 60 % for 15 min. Respiratory alkalosis was then induced, by increasing ventilation to achieve a pH between 7.55–7.60, and was continued for 240 min. Inspired carbon dioxide was used with hyperventilation in the control group to maintain pressure of arterial carbon dioxide (PaCO2) at 35–45 mmHg and pH of 7.35–7.45. Hypoxia was induced again at 15 and 240 min. Pulmonary and systemic vascular resistances (PVR and SVR) were calculated.¶Results: Prolonged alkalosis led to a significant and progressive fall in mean MAP from 61 (SD 7) mmHg at the start of the study falling to 50 (SD 6.9, p = 0.043), with no effect on CI. Calculated SVR decreased (0.45 SD 0.03 vs 0.36 SD 0.05). There were no statistically significant changes in any of the variables in the control group. Neither acute nor prolonged respiratory alkalosis had a significant effect on hypoxic pulmonary vasoconstriction.¶Conclusions: Prolonged hyperventilation leads to systemic hypotension, however it does not exacerbate hypoxic pulmonary vasoconstriction.

Inhaled nitric oxide (INO) is a novel selective pulmonary vasodilator without significant effects on the systemic circulation. Initial case studies of near-term newborn infants with hypoxic respiratory failure and persistent pulmonary hypertension of the newborn showed that INO was associated with improvements in oxygenation. There have now been at least 11 prospective randomized controlled trials evaluating the use of INO in the near-term neonate with hypoxic respiratory failure, 10 of which have been published. A meta-analysis of these trials provides evidence that INO improved the PaO 2 in the INO treated infants by 46.4 torr (weighted mean difference) compared with controls(95% CI, 34.2, 58.5) and significantly decreased the oxygenation index by 10.7 compared with controls (95% CI, −14.1, −7.4). The incidence of death or need for extracorporeal membrane oxygenation (ECMO) was significantly reduced by treatment with INO, relative risk (RR) 0.72 compared to control (95% CI, 0.6, 0.87) with the majority of the improvement seen in the reduction in the need for ECMO. Infants with congenital diaphragmatic hernia do not appear to benefit from early INO therapy. The only prospective trials evaluating INO in premature infants to date have not found that this therapy is associated with significant clinical benefit. The long-term evaluations of near-term and full-term infants who have received INO suggest that this therapy does not increase the incidence of adverse neurodevelopmental sequelae in these high-risk infants. INO is an effective therapy for the hypoxic term neonate and will reduce the occurrence of death or the need for ECMO in this population. Further research is required to evaluate the benefit of this therapy in the hypoxic preterm infant.

The object of this study was to determine the effects of partial liquid ventilation (PLV) with and without inhaled nitric oxide (NO) over a 4-h period on lung mechanics, gas exchange, and hemodynamics in an animal model of meconium aspiration syndrome (MAS). Twenty-four fentanyl-anesthetized piglets were instrumented and administered a slurry of human meconium to create a model with hypoxia, hypercarbia, acidosis, and pulmonary hypertension. They were then randomly assigned to conventional ventilation, conventional ventilation plus inhaled NO at 40 ppm, PLV using perfluorodecalin, or PLV plus inhaled NO. The perfluorocarbon was added until a meniscus was visible in the endotracheal tube during expiration. Hemodynamics, lung mechanics, and gas exchange were monitored for 4 h, and then the animals were killed. The conventionally ventilated animals continued to deteriorate, and three of the six died prior to 4 h. All the animals in the remaining groups survived. Oxygenation improved significantly immediately with the start of inhaled NO (from 43.8 SD 10.3 to 62.6 SD 11.7 mm Hg after 30 min) and stayed elevated compared with the control group for the remainder of the study (62.4 SD 21.8 mm Hg at 4 h compared with 44.9 SD 1.6 mm Hg for the control group, p0.05). Oxygenation improved more slowly in the PLV alone group, being slightly less than control at 30 min (p = NS) but increasing to 104 SD 34.9 after 4 h (p0.01 compared with the control group), at which time it was also greater than inhaled NO alone (p0.05). The combined group had an acute increase in oxygenation indistinguishable from the NO alone group and maintained this until the end of the study. Lung compliance was unaffected in the inhaled NO group. In both the liquid ventilation groups the lung compliance improved with the instillation of perfluorodecalin (from 0.46 SD 0.18 to 0.62 SD 0.09 ml/cm H(2)O/kg in the PLV alone group at 1 h, p0.05 compared with the control group) and remained stable for the remainder of the study. Cardiac output and pulmonary vascular resistance were not significantly affected by any of the treatments. It was concluded that in this animal model of MAS, inhaled NO led to an acute improvement in gas exchange and prolonged survival compared with conventional therapy. PLV improved lung mechanics, which was maintained over the course of the study. The combination of PLV and inhaled NO produced both effects, acutely improving both gas exchange and lung mechanics. Combined therapy with PLV and inhaled NO may have benefits in the MAS.

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 circulation. 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 min after drug administration. Regional blood flow was measured and vascular resistances were calculated. Cardiovascular and respiratory variables were not significantly affected by either study drug or vehicle. Ibuprofen increased renal cortical and medullary resistance by 44 and 52% (p < 0.05). However, ibuprofen had no significant effects on gastrointestinal or cerebral resistance. Indomethacin raised renal cortical and medullary resistance by 66 and 71% at 60 min postinjection, respectively (p < 0.05). Indomethacin increased duodenojejunal, ileal and colon resistance by 97, 102 and 75% at 60 min, respectively (p < 0.05). Indomethacin increased cerebral cortical and cerebellar resistance by 92 and 86% at 90 min (p < 0.05). While indomethacin and, to a lesser extent, ibuprofen both increase renal vascular resistance, indomethacin vasoconstricts the gastrointestinal and cerebral circulations which are unaffected by ibuprofen.

Background Umbilical arterial catheters (UACs) are among the most commonly used monitoring methodologies in neonatal intensive care. There seems to be significant variance between neonatal intensive care units in exactly how these catheters are used. This variance involves heparin dosing, catheter materials and catheter design and positioning of the catheter. Objectives To determine whether the use of heparin in fluids infused through an umbilical arterial catheter in newborn infants influences the frequency of clinical ischemic events, catheter occlusion, aortic thrombosis, intraventricular hemorrhage, hypertension, death, or the duration of catheter usability. Search methods Randomized and quasi-randomized controlled trials of umbilical catheterization use were obtained using the search methods of the Cochrane Neonatal Review Group. The Cochrane Library, MEDLINE (search via PubMed), CINAHL and EMBASE were searched from 1999 to 2009. Selection criteria Randomized trials in newborn infants of any birthweight or gestation. Comparison of heparinised to non heparinised infusion fluids, including comparison of heparin in the infusate to heparin just in the flush solution. Clinically important end points such as catheter occlusion or aortic thrombosis. Data collection and analysis There were five randomized controlled trials retrieved. All gave details of the incidence of catheter occlusion. Two also reported the incidence of aortic thrombosis. The intervention was reasonably consistent: heparin in the infusate at a concentration of 1 unit/mL was investigated in all trials except one which used a concentration of 0.25 units/mL. Studies generally included both term and preterm infants. Main results Heparinization of the infusate decreases the incidence of catheter occlusion but does not affect the frequency of aortic thrombosis. Heparinization of the flush solution is not an adequate alternative. There does not appear to be an effect on frequency of intraventricular hemorrhage, death or clinical ischemic phenomena. Authors' conclusions Heparinization of the fluid infused through an umbilical arterial catheter decreases the likelihood of umbilical arterial catheters occluding. The lowest concentration tested so far (0.25 units/mL) has been shown to be effective. Heparinization of flushes without heparinizing the infusate is ineffective. The frequency of aortic thrombosis has not been shown to be affected; however, the confidence intervals for this effect are very wide. The frequency of intraventricular hemorrhage has not been shown to be affected by heparinization of the infusate, but again the confidence intervals are very wide and even a major increase in the incidence of grade 3 and 4 intraventricular hemorrhage would not have been detected.

The response of the systemic, pulmonary, hepatic and portal circulations to infusion of dopamine and epinephrine was studied in newborn piglets 1 to 3 d of age. Anesthetized animals were instrumented to measure cardiac index (CI), hepatic arterial flow, and portal venous blood flow. Catheters were inserted for measurement of systemic arterial pressure (SAP), pulmonary arterial pressure (PAP), and for sampling of arterial, portal venous, and mixed venous oxygen saturations and plasma lactate levels. Systemic, pulmonary and mesenteric vascular resistance indices (SVRI, PVRI, MVRI), and systemic and mesenteric oxygen extraction were calculated. Dopamine and epinephrine were infused in doses of 2, 10, 32 microg/kg/min and 0.2, 1.0, 3.2 microg/kg/min respectively, given in random order. Significant increases in SAP, PAP, and CI were demonstrated with 32 microg/kg/min of dopamine and the two higher doses (1.0 and 3.2 microg/kg/min) of epinephrine. There were no significant changes in SVRI and PVRI with dopamine infusions. Epinephrine at 3.2 microg/kg/min significantly elevated SVRI and PVRI. The SAP/PAP ratio was decreased with 32 microg/kg/min of dopamine whereas epinephrine did not affect the ratio. Dopamine had no significant effect on hepatic arterial flow, portal venous flow, or mesenteric vascular resistance. Epinephrine infusion at 3.2 microg/kg/min decreased portal venous blood flow, total hepatic blood flow, and hepatic oxygen delivery with an increase in calculated mesenteric vascular resistance. Systemic and mesenteric oxygen extraction were not affected by dopamine or epinephrine infusions. Plasma lactate levels were significantly elevated with epinephrine infusion 3.2 microg/kg/min. The differential responses of dopamine and epinephrine on pulmonary and mesenteric circulations may be significant in the pathophysiology and management of persistent fetal circulation and necrotizing enterocolitis.