Donough J. O'Donovan

Free Radicals and Diseases in Premature Infants

Free radicals have been implicated in the pathogenesis of a wide spectrum of human diseases. Premature infants are probably developmentally unprepared for extrauterine life in an oxygen-rich environment and exhibit a unique sensitivity to oxidant injury. Diseases associated with premature infants, including bronchopulmonary dysplasia, periventricular leukomalacia, intraventricular hemorrhage, retinopathy of prematurity, and necrotizing enterocolitis, have been linked to free radical-mediated cell and tissue injury. With the advent of therapies designed to combat the injurious effects of free radicals, the role of these highly reactive chemical molecules in the pathogenesis of neonatal diseases needs to be fully determined.

Necrotizing Enterocolitis and Gastrointestinal Complications After Indomethacin Therapy and Surgical Ligation in Premature Infants With Patent Ductus Arteriosus

BACKGROUND: Indomethacin is the most frequently used pharmacological agent for closure of a patent ductus arteriosus (PDA) in premature infants. However, reports of complications, particularly, necrotizing enterocolitis (NEC) and isolated gastrointestinal perforation have generated concerns about the use of this medication.OBJECTIVES: A retrospective study to compare the incidence of NEC, NEC-related gastrointestinal complications and isolated gastrointestinal perforation among premature infants treated for a PDA with either, indomethacin alone (I), surgical ligation alone (L), or indomethacin followed by surgical ligation (I–L).METHODS: The medical records of 224 infants that underwent treatment, either pharmacological or surgical, for a PDA, confirmed by echocardiography, over a 4-year period (1995 to 1998) were analyzed. Treatment history and gastrointestinal complications were reviewed.RESULTS: Of the 224 infants, 108 (48.2%) were treated with I, 50 (22.3%) by L, 66 (29.5%) with I–L. The clinical characteristics of the three treatment groups were similar and no differences in the incidence of NEC were observed between groups. NEC occurred in 14 (13%) of the I group, seven (14%) of the L group, and eight (12%) of the I–L group. The rate of NEC related gastrointestinal complications and isolated gastrointestinal perforation were also similar among groups.CONCLUSION: In this large retrospective study, indomethacin treatment for a significant PDA in premature infants was not associated with a greater risk for NEC or NEC-related gastrointestinal complications than surgical ligation.

Platelet transfusions in infants with necrotizing enterocolitis do not lower mortality but may increase morbidity.

OBJECTIVE:Necrotizing enterocolitis (NEC), a serious multisystemic inflammatory disease most commonly seen in premature neonates, is often associated with thrombocytopenia. Infants with severe forms of NEC commonly have platelet counts of less than 50,000/mm3, occasionally less than 10,000/mm3. Despite an absence of data to support the practice, platelet transfusions are commonly used to maintain a certain arbitrary platelet count in an effort to prevent bleeding. As platelet transfusions contain a variety of bioactive factors including pro-inflammatory cytokines, we hypothesized that a higher number and volume of platelet transfusions would not be associated with an improvement in mortality or morbidity.STUDY DESIGN:A retrospective cohort analysis was conducted of the medical records of all infants between 1997 and 2001 with Bells Stage 2 or 3 NEC associated with platelet counts of <100,000/mm3. The medical records were evaluated for the following variables: platelet counts, number and volume of platelet transfusions, symptoms of bleeding, and hospital course. Mortality and development of short bowel syndrome and/or cholestasis were correlated to the total number and volume (total ml and ml/kg) of platelet transfusions. Differences between the outcome groups were compared using the independent t-test, Fishers exact test and Mann–Whitney tests.RESULTS:A total of 46 infants met the study criteria (gestational age 28±4 weeks and birth weight 1166±756 g, mean±SD). There were a total of 406 platelet transfusions administered to the study population. Of these, 151 (37.2%) were given in the presence of active bleeding, with 62% of these resulting in the cessation of bleeding within 24 hours. Other listed indications for platelet transfusions were hypovolemia and severe thrombocytopenia. On analysis of the entire cohort, there was no statistical improvement in either mortality or morbidity (short bowel syndrome and cholestasis) with greater number and/or volume of platelet transfusions. Furthermore, we found that infants who developed short bowel syndrome and/or cholestasis had been given a significantly higher number and volume of platelet transfusions when compared to those who did not have these adverse outcomes [median (minimum – maximum)−number of transfusions : 9 (0 to 33) vs 1.5 (0 to 20), p=0.010; volume of transfusions (ml/kg) : 121.5 (0 to 476.6) vs 33.2 (0 to 224.3), p=0.013].CONCLUSION:This retrospective analysis suggests that greater number and volume of platelet transfusions in infants with necrotizing enterocolitis are associated with greater morbidity in the form of short bowel syndrome and/or cholestasis without the benefit of lower mortality.

Severe Thrombocytopenia Predicts Outcome in Neonates with Necrotizing Enterocolitis

OBJECTIVE:Necrotizing enterocolitis (NEC) is a common and serious gastrointestinal disorder that predominately affects premature infants. Few prognostic indices are available to guide physicians through the expected course of the disease. We hypothesized that the degree and timing of onset of severe thrombocytopenia (platelet count <100,000/mm3) would be a predictor of adverse outcome and an indication for surgical intervention in infants with NEC.STUDY DESIGN:The clinical presentation and outcome of all infants with Bell stage II or III NEC treated at Texas Childrens Hospital between 1997 and 2001 were retrospectively reviewed. Patients were stratified into two groups based on the presence (Group1) or absence (Group 2) of severe thrombocytopenia (platelet count <100,000/mm3) within 3 days of a diagnosis of NEC. Differences between groups were compared using logistic regression to estimate adjusted odds ratios.RESULTS:A total of 91 infants met inclusion criteria (average birth weight 1288±135 g; average gestational age 29.0±3.0 weeks). Compared to infants in Group 2, infants in Group 1 were more premature (28.0±4.1 vs 30.0±4.2 weeks; p=0.02), more likely to have received postnatal steroids (42.5% vs 20.4%; p=0.02), and more likely to require laparotomy for gangrenous bowel (adjusted OR 16.33; p<0. 001). The presence of severe thrombocytopenia was also a predictor of mortality (adjusted OR 6.39; p=0.002) and NEC-related gastrointestinal complications including cholestatic liver disease and short bowel syndrome (adjusted OR 5.47; p=0.006).CONCLUSION:Severe thrombocytopenia within the first 3 days after a diagnosis of NEC suggests a higher likelihood of bowel gangrene, morbidity, and mortality. Prospective studies of infants with early and severe thrombocytopenia may help determine the optimal timing of laparotomy in infants with NEC.

Urinary F2-isoprostanes are poor prognostic indicators for the development of bronchopulmonary dysplasia

Objective:Oxygen toxicity is thought to contribute to the development of bronchopulmonary dysplasia (BPD). Oxidant injury leads to formation of F2-isoprostanes (F2-IsoP). We hypothesized that urinary excretion of the stable metabolite of F2-IsoP, 8-iso-PGF2α, would be higher in infants who develop BPD than those who did not.Methods:Forty infants <30-weeks gestational age (GA) were enrolled, 24 infants with BPD and 16 without BPD. Urine specimens were collected weekly and stored at −80°C until analyzed. Urinary 8-iso-PGF2α was measured by gas chromatography/mass spectrometry (GC-MS) and normalized to creatinine excretion.Results:GA and birth weight (BW) were lower in infants who developed BPD than those who did not. Urinary 8-iso-PGF2α levels in the first or third weeks of age were not significantly different between the two groups.Conclusion:Urinary excretion of 8-iso-PGF2α in early postnatal life in preterm infants is not correlated with the development of BPD.

De novo interstitial deletion 2q14.1q22.1: is there a recognizable phenotype?

In this report we describe a male patient with a rare de novo interstitial deletion of chromosome 2q14.1–q22.1. His karyotype was reported as 46,XY,del(2)(q13q21) but subsequent array comparative genomic hybridization (array CGH) analysis redefined the deletion breakpoints as 2q14.1 and 2q22.1. Eight patients have been reported with deletions either within or spanning the region 2q13 or 2q14 to 2q22.1. In five patients the diagnosis was made by karyotype analysis alone and in three reported patients and the proband array CGH analysis was also performed. When the proband was compared with the eight previously reported patients it was apparent that they shared many clinical findings suggesting that patients with a de novo interstitial deletion involving 2q13 or 2q14 to 2q21 or 2q22 may have a recognizable phenotype. There are 14 known disease‐associated genes in the deleted region of 2q14.1–q22.1 and their possible phenotypic effects on the proband and the eight previously reported patients are discussed.

Nasopharyngeal Surfactant Administration to Prevent Neonatal Respiratory Distress Syndrome

We read with interest Kattwinkel et al.’s article ‘‘Technique for Intrapartum Administration of Surfactant without Requirement for an Endotracheal Tube’’, and applaud the authors for their efforts in this feasibility study investigating early, easy techniques to reduce the incidence of neonatal respiratory distress syndrome (RDS). In the event, the authors or others wish to pursue investigation of the utility of this technique, we wish to raise certain issues that need to be addressed as part of investigating the feasibility of applying this technique in clinical practice. Firstly, the authors do not discuss their rationale for using the same dose of InfaSurf surfactant as is used for intratracheal instillation. As it is highly unlikely that the infants studied aspirated the entire dose of surfactant administered, their results would underestimate the benefit of prophylactic administration of nasopharyngeal surfactant. One possible solution to this problem would be to use a greater volume of surfactant for nasopharyngeal administration than is used for intratracheal instillation for prophylaxis/treatment of RDS. Alternatively, one could use a concentrated surfactant solution for nasopharyngeal instillation as was used in the animal studies by Enhorning et al. A solution that allowed quantification of the amount of nasopharyngeally instilled surfactant that did make its way into the lungs would be ideal. This last goal may be achieved by combining the desired surfactant with a small volume of perfluorocarbons as is used for partial liquid ventilation. This approach would have a dual advantage of allowing visualization of the radio-opaque perfluorocarbon on a postnatal chest radiograph, as well as have beneficial effects on lung function. As perfluorocarbons have been shown to improve oxygenation and lung compliance in neonates with surfactant-deficient lungs, it is possible that use of a concentrated solution of surfactant with perfluorocarbons might dramatically improve lung function, and decrease the numbers of preterm infants needing to be intubated. In the event, some small preterm infants are intubated for rescue surfactant therapy, a potential added benefit of using a perfluorocarbon–surfactant mixture might be a decreased incidence of bronchopulmonary dysplasia resulting from perfluorocarbon-mediated attenuation of pulmonary inflammatory response. Unquestionably, the benefits and risks of this innovative strategy need careful prospective evaluation. Secondly, of the 23 infants studied by Kattwinkel et al., only two and three infants were less than 1000 g and less than 28 weeks gestation, respectively. As surfactant treatment for RDS is inversely related to gestational age, smaller preterm infants most in need of prophylactic surfactant therapy were not studied. Hence, whether extremely low birth weight infants would be able to muster adequate respiratory effort to aspirate the exogenously administered surfactant or whether this type of therapeutic approach would be safe for smaller premature infants remains uncertain. In addition, while a benefit of this prophylactic approach was probably afforded to some of the study patients, others may not have benefited as surfactant therapy is only necessary for about 45 to 55% of infants at 28 to 29 weeks gestation compared to more than 80% of infants born at 24 to 26 weeks gestation (Vermont Oxford data). Further studies designed to investigate the utility of prophylactic administration of nasopharyngeal surfactant in smaller preterm infants would help resolve these issues. Lastly, although the technique described by the authors appears relatively easy, other pragmatic considerations remain. In the study described, a neonatologist was present to assist the obstetrician and instill the surfactant into the infant’s nasopharynx. As prophylactic surfactant treatment for infants at risk of RDS is more efficacious than selective treatment of established RDS and as neonatologists may not always be present at every preterm birth, the efficacy of using this technique to prevent RDS would necessarily depend on the combined efforts of both neonatologists and obstetricians in the delivery room.

Relationships between adaptive behaviours, personal factors, and participation of young children

ABSTRACT Aim: To examine the extent to which personal factors (age, socioeconomic grouping, and preterm birth) and adaptive behaviour explain the participation patterns of young children. Methods: 65 Children 2–5 years old with and without a history of preterm birth and no physical or intellectual disability were selected by convenience sampling from Galway University Hospital, Ireland. Interviews with parents were conducted using the Adaptive Behaviour Assessment System, Second Edition (ABAS-II) and the Assessment of Preschool Childrens Participation (APCP). Linear regression models were used to identify associations between the ABAS-II scores, personal factors, and APCP scores for intensity and diversity of participation. Results: Adaptive behaviour explained 21% of variance in intensity of play, 18% in intensity of Skill Development, 7% in intensity of Active Physical Recreation, and 6% in intensity of Social Activities controlling for age, preterm birth, and socioeconomic grouping. Age explained between 1% and 11% of variance in intensity of participation scores. Adapted behaviour (13%), Age (17%), and socioeconomic grouping (5%) explained a significant percentage of variance in diversity of participation controlling for the other variables. Conclusions: Adaptive behaviour had a unique contribution to childrens intensity and diversity of participation, suggesting its importance.

Neonatal therapeutic hypothermia: practice and opinions in the Republic of Ireland

Therapeutic hypothermia (TH) improves mortality and neurological outcome for neonates affected by hypoxic-ischaemic encephalopathy.1 In the Republic of Ireland there are 20 maternity units, with over 50% of units having an annual delivery rate of 2500 or less. Neonatal care is provided in all maternity units but only the eight largest units have a consultant neonatologist. Smaller neonatal units would rarely encounter suitable candidates for TH and presently there is no national strategy in place for the provision of TH. In addition, the neonatal transport service in the Republic …

Gentamicin pharmacokinetics in term newborn infants receiving high-frequency oscillatory ventilation or conventional mechanical ventilation: A case-controlled study (multiple letters) [1]

We read with interest Bhatt-Mehta et al.’s article ‘‘Gentamicin Pharmacokinetics in Term Newborn Infants Receiving Highfrequency Oscillatory Ventilation or Conventional Ventilation: a Case-controlled Study,’’ which found that gentamicin pharmacokinetics are altered in patients receiving high-frequency oscillatory ventilation (HFOV). However, our enthusiasm was dampened by several concerns. Firstly, we were surprised by the failure of the authors to include any data to support their contention that altered vascular volume did not contribute to the altered pharmacokinetics observed in their study. In reading their article and the data presented, we would tend to agree that the patients who received HFOV would indeed be more critically ill than patients receiving conventional mechanical ventilation (CMV). As postnatal age at time of treatment was significantly greater in the HFOV group (11.7±11 vs 4.63±4.6 hours, p<0.001) than the CMV group and maintenance of adequate intravascular volume is critical for patients treated with HFOV, we speculate that the HFOV group might have received far greater fluid intake (L /kg/day) than the CMV group. The HFOV group is also more likely to have received more fluid boluses for blood pressure support, if, as reported, many of them needed ‘‘high-dose pressors’’. As gentamicin is a water-soluble drug whose volume of distribution is dramatically altered by increases in extracellular fluid volume, the substantially greater Vd of the HFOV patients might merely be a reflection of their substantially greater extracellular fluid status. While the authors comment ‘‘fluid overload does not appear to be a consistent problem in infants who receive HFOV’’, they do not provide any data to clarify whether this is a generic statement or a reference to the patients reported on. Given that they have access to the medical records and input/ output data, it would be seemingly easy and imminently useful to clarify this issue. At the very least, a comparison of the change (if any) in infants’ weights during the study period rather than a comparison of birthweights would be more relevant and useful. While clarifying this point will not preclude other pathophysiological mechanisms being responsible, it would support the fact that concomitant fluid therapy rather than ventilator therapy might be responsible for the differences in the two groups. Indeed, increases in extracellular fluid contributing to greater Vd of gentamicin (than the 0.49±0.09 l/kg of the CMV group) have previously been reported by the author and others in other critically ill infants treated with extracorporeal membrane oxygenation. Next, the authors’ comments regarding prolonged Kel and greater T1/2 in the HFOV group (p<0.002 and <0.007, respectively, when compared with the CMV group) being possibly due to a reduction in glomerular filtration rate (GFR) are contradictory to their subsequent comments regarding the ‘‘increase in clearance of gentamicin results from an increase in GFR’’. As Vd 1⁄4 TBC/Kel (where TBC1⁄4 total body clearance), a substantial increase in Vd will result in a decrease in Kel if TBC remains unchanged or minimally increased. The apparent contradictory results (of increased clearance and lower Kel) may be reconciled if one remembers that clearance refers to removal of drug from a volume of plasma in a given unit of time, while Kel refers to the fraction of the remaining drug removed per unit time. Given that the Vd of the HFOV group is substantially greater than that of the CMV group, it should be no surprise that the fraction of the drug removed per unit time is less in the HFOV group even though the clearance is slightly increased. Hence, the slower elimination rate constant and prolonged T1/2 more likely reflect the (greater) Vd of the HFOV group than a change (decrease) in renal function. As such, the authors’ results do not support their premise that HFOV causes a decrease in cardiac output, leading to a decrease in GFR, and reduced elimination of gentamicin. Lastly, given the results presented in the article, we fail to understand the authors’ recommendation to initiate therapy at 2.5 mg/kg every 18 hours. Based on their reported Vd of 0.98±0.46 l/kg and Kel of 0.081þ 0.02/hour of patients in the HFOV group, the above regimen would result in serum peaks being substantially below 5 mg/l, which, for a population of extremely sick neonates, is decidedly unacceptable as the therapeutic efficacy of gentamicin is correlated to its peak concentration. Given their results, a more appropriate recommendation for patients treated with HFOV might have been initiating therapy with 4 to 5 mg/kg/ dose every 24 hours as recommended by some, and measuring both peak and trough levels after the first dose to arrive at optimal individualized dosing. An alternative and possibly better approach might be the use of a 5 to 7 mg/kg loading dose followed by once-