Neonatal pain response to automatic lancet versus needle heel-prick blood sampling: A prospective randomized controlled clinical trial.

BACKGROUND: Automatic lancets have been reported to be superior to manual lancets in terms of pain and treatment time. However, no studies have yet been published comparing automatic lancet and needle puncture heel-prick blood sampling. The objective of this study was to compare the pain response and efficiency between the automatic lancet and needle at the time of heel blood sampling. The design was a randomized controlled trial. The inclusion criteria for the participants were a birthweight of ≧1,500 g and a gestational age of ≧30 weeks. METHODS: The study examined a total of 105 neonates who were randomized into an automatic lancet group (n = 53) and a needle group (n = 52). The parameters measured included blood collection time, number of calf squeezes, duration of audible crying, and the Neonatal Infant Pain Scale (NIPS) score. The main outcome measure was audible crying duration. RESULTS: The duration of audible crying was significantly shorter in the automatic lancet group when compared to the needle group (median 3 s, interquartile range (IQR) 0-33 s vs median 39 s, IQR 5-91.5 s, P = 0.0023). The NIPS score at the time of puncture was significantly lower in the automatic lancet group than in the needle group (median 1, IQR 0-5 vs median 5, IQR 3-6, P = 0.0060). There was no significant difference in the blood collection time and the number of calf squeezes between the two groups. The automatic lancet was found to be less painful than the needle puncture in neonatal heel-prick blood sampling with no significant difference in blood sampling time. CONCLUSION: The automatic lancet was found to be less painful than the needle puncture in neonatal heel-prick blood sampling with no significant difference in blood sampling time.

Corticotrophin-releasing hormone stimulation tests in late-onset circulatory collapse.

BACKGROUND: Late-onset circulatory collapse (LCC) is the transient development of refractory hypotension and oliguria after the early neonatal period, which may cause periventricular leukomalacia (PVL). The aim of this study was to evaluate the endogenous cortisol response to corticotrophin-releasing hormone (CRH) and determine whether it is effective for elucidating the pathology and selecting treatment in LCC. METHODS: This retrospective study examined infants admitted to the neonatal intensive care unit. Included were preterm (gestational age <34 weeks) infants who underwent CRH stimulation test and were treated for LCC with no obvious cause. Hydrocortisone (HC; 3.3-10 mg/kg) was given by bolus injection to the LCC infants. At 2 h after treatment, infants without a 20% rise in blood pressure (systolic or mean) from before treatment were defined as non-responsive to HC, and given catecholamine and/or vasopressin. RESULTS: Sixteen infants (median gestational age, 24 weeks 3 days; birthweight, 638 g) were eligible. Six of the infants had a good response to the CRH stimulation test. HC was effective in only three CRH good-response cases, and catecholamine and/or vasopressin was needed in the three other cases. HC was effective, however, for all CRH non-response cases. CONCLUSIONS: Although HC is the first-choice treatment for LCC, the CRH stimulation test facilitates prompt treatment of LCC, which may prevent PVL. The present findings help elucidate the pathology and aid in the selection of treatment for infants with LCC.

Case report of Pierre Robin sequence with severe upper airway obstruction who was rescued by fiberoptic nasotracheal intubation.

BACKGROUND: Pierre Robin sequence (PRS) refers to the association of micrognathia, glossoptosis, and airway obstruction. Cases with severe dyspnea due to upper airway obstruction immediately after birth are very rare. We here report two cases with PRS who developed severe dyspnea due to morphological abnormality immediately after birth and were rescued by fiberoptic nasotracheal intubation. CASE PRESENTATION: The patient in case 1 had micrognathia and cleft palate, and his tongue protruded into the nasal cavity via a cleft palate. His invaginated tongue was considered an extreme type of glossoptosis and he was diagnosed as Pierre Robin sequence. The patient in case 2 also had micrognathia and cleft palate same as case 1 and accompanied some anomalad. Her chromosome analysis confirmed a diagnosis of 1p36 deletion syndrome and she diagnosed as 1p36 deletion syndrome complicated with Pierre Robin sequence. In both cases, tongue protruded into the nasal cavity via a cleft palate occupied pharynx and nasal cavity, resulting in severe dyspnea. Only the backside of the tongue was visible by laryngoscopy and oropharyngeal intubation was impossible. Therefore, fiberoptic nasotracheal intubation was done to secure the airway for resuscitation. CONCLUSION: We conclude that extreme type of glossoptosis in PRS concludes tongue invaginated into nasal cavity which have not reported before and that such cases require resuscitation by fiberoptic intubation immediately after birth. As such, neonatologists should obtain the skill of fiberoptic intubation.

Children undergoing liver transplantation for treatment of inherited metabolic diseases are prone to higher oxidative stress, complement activity and transforming growth factor-ß1.

BACKGROUND: Main indications for liver transplantation in the pediatric population include biliary atresia and inherited metabolic diseases. The present study evaluated whether there are differences between pediatric patients undergoing living-related liver transplantation due to the two diseases in terms of their oxidative and immunological status during their regular outpatient follow-up visits. MATERIAL AND METHODS: A clinical outpatient study measuring serum oxidative stress index (calculated as serum oxidant/antioxidant ratio, in the form of serum total hydroperoxide/serum biological antioxidative potential), serum terminal complement component 5a, as an indicator of complement activity and immunological status, and transforming growth factor-ß1, as a marker of liver fibrosis, in 16 patients (6 males and 10 females, 2.5-15 years old) who received living-related liver transplantation due to inherited metabolic diseases (n=6; in the form of propionic acidemia [n=1], methylmalonic acidemia [n=1], arginase deficiency [n=1], tyrosinemia [n=2], and glycogen storage disease type 1b [n=1], with an age range of 2.4-14.6 years old) and due to biliary atresia ([n=10], with an age range of 2.9-14.5 years old). RESULTS: Serum oxidative stress index, complement component-5a, and transforming growth factor-ß1 were significantly higher in the inherited metabolic diseases group than in the biliary atresia group. In all patients, serum oxidative stress index correlated positively with complement component-5a and transforming growth factor-ß1. CONCLUSIONS: Patients who receive living-related liver transplantation due to inherited metabolic diseases are prone to higher oxidative stress, complement activity, and serum transforming growth factor-ß1.

Endothelin receptor antagonist attenuates oxidative stress in a neonatal sepsis piglet model.

BACKGROUND: Oxidative stress (oxidant-antioxidant imbalance) plays an important role in the pathophysiology of neonatal sepsis. This study evaluated whether an antisense peptide endothelin receptor antagonist, ETR-P1/fl, could attenuate oxidative stress in a neonatal sepsis model. METHODS: A total of 18 3-d-old piglets were anesthetized and mechanically ventilated. Six piglets received cecal ligation and perforation (CLP group) for induction of sepsis. Six piglets also received continuous infusion (0.05 mg/kg/h) of ETR-P1/fl 30 min after CLP (ETR-P1/fl group). Six piglets received a sham operation. Serum total hydroperoxide (TH), biological antioxidant potentials (BAPs), oxidative stress index (OSI, calculated as TH/BAP), interleukin (IL)-6, serum glutamic oxaloacetic transaminase (GOT), and creatinine were measured before CLP and at 1, 3, and 6 h after CLP. RESULTS: CLP evoked a state of shock resulting in elevated TH, OSI, and IL-6 levels. ETR-P1/fl administration after CLP resulted in lower serum TH at 1 and 3 h after CLP, OSI at 1 and 3 h after CLP, IL-6 at 1 and 3 h after CLP, and GOT at 3 and 6 h after CLP as compared with the CLP group. CONCLUSION: ETR-P1/fl treatment significantly attenuated the elevation of serum oxidative stress markers (TH and OSI), IL-6, and GOT in a progressive neonatal sepsis CLP model.

Periventricular leukomalacia is decreasing in Japan.

Periventricular leukomalacia is recognized as the leading cause of cerebral palsy in preterm infants. To clarify the prevalence of periventricular leukomalacia and cerebral palsy in Japan, a nationwide survey was performed. The prevalence of periventricular leukomalacia in the group of surviving preterm infants of gestational ages less than 33 weeks born in 2007 was 2.7% (78/2883) on ultrasound diagnosis, and 3.3% (92/2824) on magnetic resonance imaging. The prevalence of cerebral palsy was 4.3% (125/2883) on clinical diagnosis. In our previous study, the prevalences of periventricular leukomalacia in 1990-1991, 1993-1994, 1996, and 1999 were 4.8%, 4.9%, 4.9%, and 5.3% on ultrasound, and 7.9%, 7.7%, 6.9%, and 7.3% on magnetic resonance imaging, respectively. The prevalence of periventricular leukomalacia has decreased significantly in Japan.

Hypothermia attenuates the severity of oxidative stress development in asphyxiated newborns.

PURPOSE: This retrospective case-control study aimed to examine the development of oxidative stress in asphyxiated infants delivered at more than 37 weeks of gestation. MATERIAL AND METHODS: Thirty-seven neonates were stratified into 3 groups: the first group experienced hypothermia (n = 6); the second received hypothermia cooling cup treatment for 3 days, normothermia (n = 16); and the third was the control group (n = 15). Serum total hydroperoxide (TH), biological antioxidant potential, and oxidative stress index (OSI) (calculated as TH/biological antioxidant potential) were measured within 3 hours after birth. RESULTS: Serum TH and OSI levels gradually increased after birth in hypothermia and normothermia cases. At all time points, serum TH and OSI levels were higher in hypothermia and normothermia cases than in control cases. Serum TH and OSI levels were higher in normothermia cases than in hypothermia cases at days 3, 5, and 7. CONCLUSION: This study demonstrated that hypothermia attenuated the development of systemic oxidative stress in asphyxiated newborns.

Endogenous erythropoietin from astrocyte protects the oligodendrocyte precursor cell against hypoxic and reoxygenation injury.

The hypoxia-responsive cytokine erythropoietin (EPO) provides neuroprotective effects in the damaged brain during ischemic events and neurodegenerative diseases. The purpose of the present study is to evaluate the EPO/EPO receptor (EPOR) endogenous system between astrocyte and oligodendrocyte precursor cell (OPC) under hypoxia. We report here elevated EPO mRNA levels and protein release in cultured astrocytes following hypoxic stimulation by quantitative RT-PCR and ELISA. Furthermore, the EPOR gene expressions were detected in cultured OPCs as in astrocytes and microglias by quantitative RT-PCR. Cell staining revealed the EPOR expression in OPC. To evaluate the protective effect of endogenous EPO from astrocyte to OPCs, EPO/EPOR signaling was blocked by EPO siRNA or EPOR siRNA gene silencing in in vitro study. The suppression of endogenous EPO production in astrocytes by EPO siRNA decreased the protection to OPCs against hypoxic stress. Furthermore, OPC with EPOR siRNA had less cell survival after hypoxic/reoxygenation injury. This suggested that EPO/EPOR signaling from astrocyte to OPC could prevent OPC damage under hypoxic/reoxygenation condition. Our present finding of an interaction between astrocytes and OPCs may lead to a new therapeutic approach to OPCs for use against cellular stress and injury.

Edaravone, a hydroxyl radical scavenger, ameliorates the severity of pulmonary hypertension in a porcine model of neonatal sepsis.

Systemic infection in the newborn (neonatal sepsis) is the most common cause of neonatal mortality. Neonatal sepsis is complicated by pulmonary hypertension. In this study, we analyzed the effect of edaravone, a free radical scavenger that is known to reduce the production of inflammatory mediators, such as tumor necrosis factor α (TNFα), on pulmonary hypertension. Experimental and sham groups were drawn from 19 three-day-old piglets; 5 underwent a modified procedure of cecal ligation and perforation (CLP) (CLP group), 8 underwent CLP followed 30 min later by edaravone intravenous administration (edaravone group), and 6 did not undergo CLP and did not receive edaravone (sham group). To evaluate the pulmonary blood pressure despite the sepsis-induced low cardiac output, mean arterial blood pressure (mABP), mean pulmonary arterial pressure (mPAP), and comparative pulmonary hypertension ratio (mPAP/mABP) were determined. Serum TNFα levels were measured before the procedure and at 1, 3, and 6 h after. The mPAP levels were higher in the CLP group at 9 h compared to the edaravone group. The mPAP/mABP ratio was lower in the edaravone and sham groups compared to the CLP group at 6 and 9 h. TNFα in the edaravone and sham groups were lower at 1 and 3 h compared to that in the CLP group. In all animals, mPAP/mABP at 6 h correlated with serum levels of TNFα at 1, 3, and 6 h. These findings suggest that edaravone ameliorates the severity of pulmonary hypertension in a neonatal sepsis model by reducing serum TNFα levels.

Oxidative stress after living related liver transplantation subsides with time in pediatric patients.

BACKGROUND: Oxidative stress has been suspected to influence graft survival and prognosis in pediatric recipients of living related liver transplantation (LRLT). PURPOSE: We determined the oxidative status of pediatric LRLT recipients during their regular outpatient follow-up visits, and looked for a relationship between oxidative status and post-liver transplantation (post-LTx) duration. PATIENTS: The study included 43 patients (20 males and 23 females) between the ages of 1.6 and 25.1 years (median 10.7 years) who had undergone LRLT from 5 months to 17.5 years (median 7 years) prior to the study, between the ages of 1.2 and 14.4 years (median 3.5 years). METHODS: Serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), gamma-glutamyl transpeptidase (γ-GTP), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), direct bilirubin and choline-esterase were measured as part of the patients' regular follow-up visits. Serum total hydroperoxide (TH) and biological antioxidative potential (BAP) were measured using the free radical analytic system which requires 20 µl of serum and 10 min of processing time for each sample. Oxidative stress index (OSI) was calculated as the ratio of TH to BAP. RESULTS: Serum OSI correlated positively with serum levels of GOT, GPT, LDH, ALP, γ-GTP and direct bilirubin. Serum OSI, TH, LDH, ALP and GOT correlated negatively with post-LTx duration. Serum BAP correlated positively with post-LTx duration. Serum TH correlated positively with serum GOT and γ-GTP, but negatively with serum BAP. CONCLUSIONS: (1) The OSI, which can be calculated based on data acquired through a simple outpatient procedure, can serve as an index of our patients' laboratory results and oxidative status. (2) The LRLT recipients in our study were at risk for oxidative stress early in the post-operative period, but this risk subsided with time.

Pediatric patients receiving ABO-incompatible living related liver transplantation exhibit higher serum transforming growth factor-ß1, interferon-γ and interleukin-2 levels.

BACKGROUND: ABO-incompatible liver transplantation (LTx) is becoming more common in response to the paucity of liver allografts. Several studies have expressed concern about the effect of ABO compatibility on graft survival. PURPOSE: To evaluate the differences in serum cytokine levels between ABO-incompatible (ABO-i) and ABO-compatible (ABO-c; includes ABO-compatible and identical) pediatric LTx recipients during regular outpatient follow-up. Note that, in the field of organ transplantation, transplants are categorized as incompatible, compatible or identical; accordingly, these are the terms we use in the paper. MATERIALS AND METHODS: A clinical outpatient study measuring serum transforming growth factor (TGF)-ß1, interferon (IFN)-γ, interleukin (IL)-2 and IL-10 in 43 living related liver transplantation (LRLT) recipients, of whom 36 received ABO-c LRLT (34 were ABO-identical and 2 were non-identical) and 7 ABO-i LRLT. Serum glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase and bilirubin were measured as part of the patients' regular follow-up visits. RESULTS: There were no differences between the ABO-c and ABO-i groups in terms of recipient's age [mean 12.6 vs. 11.1 years (y)], post-LTx duration (mean 7.3 vs. 7.3 y), donor's age (mean 35.5 vs. 34.6 y), body weight (28.9 ± 2.9 vs. 27.9 ± 6.9 kg), or gender (19 female and 17 male vs. 4 female and 3 male). Serum TGF-ß1, IFN-γ and IL-2 were significantly higher in the ABO-i group than in the ABO-c group. IL-10, however, did not differ between the two groups. There was a tendency toward higher γGTP levels in the ABO-i group, but this difference did not reach significance. CONCLUSION: ABO-incompatible LRLTx patients have higher serum TGF-ß1, IFN-γ and IL-2 levels as measured at regular outpatient visits. As a result, they face a higher risk of T-helper 1 cell polarization, which could make graft rejection more likely.

Endothelin receptor antagonist attenuates inflammatory response and prolongs the survival time in a neonatal sepsis model.

PURPOSE: To evaluate effects of endothelin receptor antagonist ETR-P1/fl in a neonatal sepsis model. METHOD: Eighteen anesthetized and mechanically ventilated 3-day-old piglets were divided into three groups. Six piglets received cecal ligation and perforation (CLP group). Six piglets were administrated a continuous infusion of ETR-P1/fl (0.05 mg/kg/h), an antisense homology box-derived peptide with an endothelin A receptor antagonist effect, starting 30 min after CLP (ETR-P1/fl group). Six piglets acted as the sham group. Mean arterial pressure (MAP), heart rate, cardiac output, arterial blood gas, body temp (BT), serum nitrite and nitrate (NOx), tumor necrosis factor (TNF)-α, and high-mobility group box 1 (HMGB-1) were measured before CLP and at 1, 3, 6, and 9 h after CLP. RESULTS: Cecal ligation and perforation exposure evoked a state of shock and showed deteriorated cardiac output, pulmonary hypertension, decreased MAP, low oxygen saturation, and base excess (BE) with elevated TNF-α, NOx, and HMGB1. ETR-P1/fl administration resulted in higher MAP at 6 and 9 h after CLP, less negative BE, lower mean pulmonary arterial pressure (mPAP)/MAP ratio at 9 h after CLP, and lower TNF-α, NOx, and HMGB-1 compared to the CLP group. BT showed no differences between the groups. Survival time in the ETR-P1/fl group was longer than in the CLP group (18.9 ± 2.3 h vs. 9.0 ± 0.8 h, p < 0.01). CONCLUSIONS: ETR-P1/fl treatment significantly attenuated the elevation of NOx, TNF-α, and HMGB-1, which improved the systemic hypotension, pulmonary hypertension, and blood gases, thereby causing improvement of survival time in a progressive neonatal sepsis CLP model.

High cerebrospinal fluid antioxidants and interleukin 8 are protective of hypoxic brain damage in newborns.

The objective was to explain the discrepancy in the development of hypoxic ischemic brain injury (HIE) in some asphyxiated newborns rather than others. Forty newborns were classified according to their cerebrospinal neuron-specific-enolase (CSF-NSE) levels on their 5th-day of life; group 1 with low-NSE (n = 25). The remaining 15 newborns had high-NSE and were further divided into a group with no HIE (n = 10, group 2) and another with HIE (n = 5, group 3). CSF-NSE, total-hydroperoxide (TH), biological-antioxidant-potentials (BAPs), 12 cytokines and erythropoietin (EPO) were measured. The TH/BAP gave the oxidative-stress-index (OSI). The BAPs of serial dilutions of three types of EPO were tested. CSF-NSE and TH and mean OSIs were higher in group 3. IL-8 and mean BAPs were higher in group 2 than in group 1. EPO was less detected in group 3. Serial EPO dilutions correlated with their BAPs. Compensatory antioxidants and IL-8 elevation could be protective of perinatal asphyxic brain injury. Antioxidative effect of EPO could be neuroprotective.

Effect of polymyxin B-immobilized fiber hemoperfusion on respiratory impairment, hepatocellular dysfunction, and leucopenia in a neonatal sepsis model.

PURPOSE: Sepsis and septic shock remain a major source of morbidity and mortality in neonates despite advances in antimicrobials and aggressive supportive care. Our aim was to study the effects of polymyxin-B direct hemoperfusion (PMX-DHP) therapy on sepsis-induced respiratory impairment, liver dysfunction and leucopenia in a neonatal cecal ligation and perforation (CLP) model. METHODS: Fourteen anesthetized and mechanically ventilated 3-day-old piglets underwent CLP and an arteriovenous extracorporeal circuit from 3 h until 6 h post-CLP, with a PMX column in the PMX-DHP treated group (7 piglets). Changes in oxygen saturation, PCO(2), base excess, white blood cell (WBC) count, platelet count, hematocrit (Hct%), serum glutamate pyruvate transaminase (SGPT), and serum glutamic oxaloacetic transaminase were measured before CLP and at 1, 3 and 6 h after. RESULTS: At 6 h, the PMX-DHP group showed lower Hct%, and SGPT in comparison to the control group, but higher oxygen saturation and WBC count. No effects on the platelet count were found. The survival times of the PMX-DHP group were longer than in control. CONCLUSION: PMX-DHP therapy limited the respiratory impairment, liver dysfunction and leucopenia in a neonatal septic model, which resulted in an improvement of survival time.

Edaravone, a novel free radical scavenger, reduces high-mobility group box 1 and prolongs survival in a neonatal sepsis model.

Free radicals play an important role in the inflammatory process of sepsis. We hypothesized that edaravone, a novel free radical scavenger, can suppress pathophysiological events and prolong survival in a neonatal sepsis cecal ligation and perforation (CLP) model. Of 32 3-day-old anesthetized and mechanically ventilated piglets, 11 received CLP only, 10 received CLP and edaravone treatment starting 30 min after CLP, and 11 constituted a sham (control) group. Mean arterial pressure (MAP), heart rate, cardiac output, arterial blood gas, serum total hydroperoxide, nitrite and nitrate, TNF-alpha, and high-mobility group box 1 (HMGB1) were measured before CLP and at 1, 3, and 6 h after CLP. Compared with the CLP group, the edaravone group showed higher MAP at 6 h, lower heart rate at 1 and 3 h, lower total hydroperoxide at 1 h, lower nitrite and nitrate at 3 and 6 h, and higher (although not significantly so) mean cardiac output at 1, 3, and 6 h. TNF-alpha elevation was delayed from 1 h in the CLP group to 3 h in the edaravone group. In the edaravone group, HMGB1 did not change significantly at any time, whereas in the CLP group, it increased at 6 h. Survival times were longer in the edaravone group than in the CLP group (15.4 +/- 1.4 vs. 10.2 +/- 1 h; P < 0.005). In addition, each of the serial dilutions of edaravone had a higher biological antioxidant potential than tempol does. In conclusion, edaravone suppressed free radicals, delayed the TNF-alpha surge, and prevented HMGB1 elevation, thereby maintaining MAP and prolonging survival time in a neonatal sepsis CLP model.

Reduction in cerebral blood flow volume in infants complicated with hypoxic ischemic encephalopathy resulting in cerebral palsy.

Hypoxic ischemic brain can result in cerebral palsy, mental retardation, and learning disabilities in surviving children. The purpose of this study was to elucidate the cerebral blood flow volume in infants complicated with brain damage after the birth. Nine term infants with hypoxic ischemic encephalopathy and 41 normal term infants were studied. Four infants with HIE suffered from CP or mental retardation, and the other five infants exhibited normal neurodevelopment. The mean blood flow velocity and diameter of the internal carotid artery and the vertebral artery were measured for 28 days. The intravascular flow volume was determined by calculating the flow velocity and the cross-sectional area. The ejection fraction and cardiac output were obtained, and the mean blood pressures were recorded. The summed flow volumes in both the ICA and VA, and the total CBFV increased after the birth in both the normal infants and the infants diagnosed with HIE with no disability complications. The total blood flow volume was significantly lower in infants with HIE and CP than in normal infants on days 0, 2, 5, 7, 10, 21, and 28, and significantly lower in infants with HIE and CP than in normal infants with HIE on days 2, 4, and 7. The ejection fraction was significantly lower in infants with HIE than in normal infants only on day 0. Our results suggest that the total cerebral blood supply is decreased in infants with HIE in those complicated with brain damage.