Optimization of the incubator air temperature during LED phototherapy treatment for the preterm infant.

Light-emitting diode phototherapy treatment for jaundice of the preterm infant presents adverse effects, such as discomfort, changes in metabolism, and overheating. This study quantified the body heat exchanges between the environment and a simulated preterm infant requiring phototherapy treatment in a closed incubator. Phototherapy treatment increased the mean incubator roof temperature by 2.9 °C (p < 0.001) and the incubator air temperature by 1 °C (p < 0.001). Analytical calorimetry was used to calculate the additional energy received during phototherapy and thus deduce the optimal incubator air temperature for ensuring thermoneutrality and preventing hyperthermia. The optimal air temperature settings inside the incubator during phototherapy were - 0.51 to - 1.25 °C lower than references, for preterm infant weighing 500 to 2000 g.Conclusion: Phototherapy treatment for jaundice of the preterm infant increased the incubator air temperature. To prevent overheating in the preterm during phototherapy, new curves for optimal air temperature settings inside the incubator were calculated with analytic calorimetry. What is Known •Phototherapy treatment is the first-line treatment for jaundice in the preterm infant. •Phototherapy treatment increases the risk of overheating. What is New •The heat transfers and risk of overheating were quantified using a thermal manikin during phototherapy treatment. •Phototherapy treatment increased the incubator roof temperature and heat transfers. •New incubator's air temperature settings during phototherapy treatment were calculated with analytical calorimetry for preterm infant weighing 500-2000 g.

Failing to meet relative humidity targets for incubated neonates causes higher heat loss and metabolic costs in the first week of life.

AIM: Frequent nursing procedures can modify a newborn infant's thermal environment when their incubator is opened. This study evaluated the impact of relative humidity (RH) on preterm infants in closed incubators and calculated their heat loss and additional metabolic cost. METHODS: We studied 45 preterm infants born before 32 + 0 weeks, nursed at the neonatal intensive care unit at Amiens University Hospital, France from January 2009 to November 2011. Their body, skin and air temperatures and the incubator's RH were continuously recorded from day 1 to 8 of life, and the differences between the measured and target RH were calculated. Body heat loss (BHL) was also calculated. RESULTS: On day one, the measured RH (68.7 ± 1.0%) was significantly lower than the target RH (75%, p < 0.05), but this difference, together with BHL (p < 0.001) and evaporative heat loss (p < 0.001), fell significantly over time (p < 0.05). The additional metabolic cost correlated with the difference between measured and target RH (p < 0.001). CONCLUSION: RH from day 1 to 8 was below the recommended target value for preterm infants and resulted in high evaporative and greater total BHL and additional metabolic cost. The findings pose numerous challenges, including nursing care and incubator design.

Safety study of Ciprofloxacin in newborn mice.

Ciprofloxacin, a broad-spectrum antimicrobial agent belonging to the fluoroquinolone family, is prescribed off-label in infants less than one year of age. Ciprofloxacin is included in the European Medicines Agency priority list of off-patent medicinal products requiring evaluation in neonates. This evaluation is undergoing within the TINN (Treat Infections in Neonates) FP7 EU project. As part of the TINN project, the present preclinical study was designed to assess the potential adverse effects of Ciprofloxacin on neurodevelopment, liver and joints in mice. Newborn mice received subcutaneous Ciprofloxacin at 10, 30 and 100 mg/kg/day from 2 to 12 postnatal days. Peak plasma levels of Ciprofloxacin were in the range of levels measured in human neonates. We examined vital functions in vivo, including cardiorespiratory parameters and temperature, psychomotor development, exploratory behavior, arthro-, nephro- and hepato-toxic effects. We found no effect of Ciprofloxacin at 10 and 30 mg/kg/day. In contrast, administration at 100 mg/kg/day delayed weight gain, impaired cardiorespiratory and psychomotor development, caused inflammatory infiltrates in the connective tissues surrounding the knee joint, and moderately increased extramedullary hematopoiesis. The present study pleads for careful watching of cardiorespiratory and motor development in neonates treated with Ciprofloxacin, in addition to the standard surveillance of arthrotoxicity.

Neuromuscular defects and breathing disorders in a new mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein leading to muscle paralysis and respiratory failure. In mouse, introducing the human SMN2 gene partially rescues Smn(-)(/)(-) embryonic lethality. However current models were either too severe or nearly unaffected precluding convenient drug testing for SMA. We report here new SMN2;Smn(-/-) lines carrying one to four copies of the human SMN2 gene. Mice carrying three SMN2 copies exhibited an intermediate phenotype with delayed appearance of motor defects and developmental breathing disorders reminiscent of those found in severe SMA patients. Although normal at birth, at 7 days of age respiratory rate was decreased and apnea frequency was increased in SMA mice in parallel with the appearance of neuromuscular junction defects in the diaphragm. With median survival of 15 days and postnatal onset of neurodegeneration, these mice could be an important tool for evaluating new therapeutics.

Warming the premature infant in the delivery room: Quantification of the risk of hyperthermia.

AIM: The efficacy and safety of three polyethylene bags commonly used to prevent hypothermia in premature infants was assessed. METHODS: To simulate transfer from the delivery room to a secondary care unit, a thermally stable, bonneted mannequin (skin temperature: 34.4 °C) was placed in a climate chamber under different conditions: with a radiant warmer, with various polyethylene bags (open on one side, closed by a draw-string at the neck, or a "life support pouch" with several access points) or without a bag. RESULTS: With the radiant warmer turned on, the mean reduction in heat loss from the nude mannequin was 50.8 ±â€¯1.7% (p < 0.0001, vs. warmer off). The mean reduction in heat loss (vs. no bag) was 55.0 ±â€¯0.9% for the drawstring bag, 49.0 ±â€¯2.2% for the standard bag (p = 0.0001), and 48.1 ±â€¯0.7% for the life support pouch (p = 0.006). When a radiant warmer + polyethylene bag were used, heat stress (body temperature: 38 °C) and severe hyperthermia (40 °C) occurred after 11 and 34 min, respectively. CONCLUSION: Caution must be taken when using a radiant warmer and polyethylene bag with a premature infant. Heat stress can occur in only 11 min. Continuous body temperature monitoring is therefore required.

Use of a Polyethylene Bag to Reduce Perioperative Regional and Whole-Body Heat Losses in Low-Birth-Weight Neonates.

In the delivery room, wrapping a low-birth-weight neonate (defined as ≤2.499 g) in a polyethylene bag reduces the risk of hypothermia. However, extended use of the bag (e.g., during neonatal surgery) might conceivably increase the risk of thermal stress and thus body overheating. Here, we assessed the efficacy of a polyethylene bag in infants assigned to wrap (W) or nonwrap (NW, control) groups during placement of a percutaneous vena cava catheter by applying a new mathematical model that calculates heat exchanges for covered and uncovered body segments. At the end of the placement procedure, the W and NW groups did not differ significantly in terms of whole-body heat loss (15.80 versus 14.97 kJ·h-1·kg-1, resp.), whereas the abdominal skin temperature was slightly but significantly higher (by 0.32°C) in the W group. Greater evaporation in the W group (2.49 kJ·h-1·kg-1) was primarily balanced by greater whole-body radiant heat loss (3.44 kJ·h-1·kg-1). Wrapping the neonate in a polyethylene bag provides a small thermal benefit when catheter placement takes a long time. Given that polyethylene is transparent to radiant energy, it might be of value to incorporate polymers that are less transparent at infrared wavelengths.

Thermal management in closed incubators: New software for assessing the impact of humidity on the optimal incubator air temperature.

BACKGROUND: Low-birth-weight (LBW) neonates are nursed in closed incubators to prevent transcutaneous water loss. The RH's impact on the optimal incubator air temperature setting has not been studied. METHODS: On the basis of a clinical cohort study, we modelled all the ambient parameters influencing body heat losses and gains. The algorithm quantifies the change in RH on the air temperature, to maintain optimal thermal conditions in the incubator. RESULTS: Twenty-three neonates (gestational age (GA): 30.0 [28.9-31.6] weeks) were included. A 20% increase and a 20% decrease in the RH induced a change in air temperature of between -1.51 and +1.85°C for a simulated 650g neonate (GA: 26 weeks), between -1.66 and +1.87°C for a 1000g neonate (GA: 31 weeks), and between -1.77 and +1.97°C for a 2000g neonate (GA: 33 weeks) (p<0.001). According to regression analyses, the optimal incubator air temperature=a+b relative humidity +c age +d weight (p<0.001). CONCLUSIONS: We have developed new mathematical equations for calculating the optimal temperature for the incubator air as a function of the latter's relative humidity. The software constitutes a decision support tool for improving patient care in routine clinical practice.

Olfactory classical conditioning in newborn mice.

Determining the behavioural phenotype of genetically altered mice is a valuable approach for elucidating the function of genes and their role in cognitive disorders. Methods for phenotyping newborn mice are scarce and generally confined to sensorimotor reflexes. Here, we describe a simple method for assessing associative abilities in newborn mice. We used a two-odour-choice classical conditioning paradigm in mice from the day of birth (post-natal age 0, P0) to P6. Acquisition required 20 trials: 10 trials during which the pups were placed over the conditioned stimulus (CS+) odour (lemon or peppermint) for 30s and simultaneously stroked gently with a paintbrush and 10 trials during which the pups were placed over the other odour (CS-) for 30s, without stroking. Then, the pups were subjected to five odour-preference trials to test for conditioning. This sequence of five trials was repeated after 5 and 24h to assess retention of the conditioned odour preference. During the immediate post-acquisition sequence, the pups spent significantly more time over the CS+ than over the CS- (p<0.0001). No extinction of the conditioned preference was observed during this test. No preference was observed after 5 or 24h, indicating that the conditioned response was promptly lost. Conditioning was effective as soon as P0-P1. Thus, conditioning may emerge in newborn mice sooner than previously reported. This paradigm is well suited to phenotyping of large samples of genetically altered mice and may shed light on the role for genes in paediatric cognitive impairments.

A simple method for short-term controlled anesthesia in newborn mice.

In this study, we describe a simple and inexpensive method for inducing short-term anesthesia and rapid recovery in newborn mice. Litters of Swiss mice pups were randomly allocated to testing on postnatal days 2, 5, and 8. Anesthesia was induced by placing the pup in a syringe and adding a volume of isoflurane-saturated gas that produced an estimated level of 32% isoflurane. Exposure to isoflurane lasted 30 s. All the pups survived the anesthesia. At all study ages, this method abolished the nociceptive response to tail clamp without inducing mortality, thus showing effective anesthesia. Recovery from anesthesia was assessed immediately after isoflurane exposure, based on two nonnoxious behavioral tests: the defensive response to a drop of water (10 tests, 1 min apart) and 10 min later the righting reflex, i.e., the time to recovery of the prone position (five tests, 10 min apart). The water drop test scores increased during the recovery phase toward the control values in all age groups. Treatment and time had no significant effect on righting reflex scores. The initial volume in the syringe, the volume of added isoflurane-saturated gas, and the duration of exposure may be adjusted according to postnatal age and specific strains or species (e.g., rats). This method is well suited to behavioral or physiological phenotype studies in developing mice, in which noxious procedures must precede functional testing, making rapid recovery from anesthesia a key requirement.

Ventilatory responses to hypercapnia and hypoxia in heterozygous c-ret newborn mice.

The c-ret proto-oncogene encodes a tyrosine-kinase receptor involved in survival and differentiation of neural crest cell lineages. Previous studies have shown that homozygous c-ret-/- mice die soon after birth and have impaired ventilatory responses to hypercapnia. Heterozygous c-ret +/- mice develop normally, but their respiratory phenotype has not been described in detail. We used whole-body flow plethysmography to compare baseline breathing and ventilatory and arousal responses to chemical stimuli in unrestrained heterozygous c-ret +/- newborn mice and their wild-type c-ret +/+ littermates at 10-12 h of postnatal age. The hyperpnoeic and arousal responses to hypoxia and hypercapnia were not significantly different in these two groups. However, the number and total duration of apnoeas and periodic breathing episodes were significantly higher in c-ret +/- than in c-ret +/+ pups during hypoxia and post-hypoxic normoxia. These results are further evidence that respiratory control at birth is heavily dependent on genes involved in the neural determination of neural crest cells.

Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice.

The ALK (Anaplastic Lymphoma Kinase) gene encodes a tyrosine kinase receptor preferentially expressed in the central and peripheral nervous systems. A syndromic presentation associating congenital neuroblastoma with severe encephalopathy and an abnormal shape of the brainstem has been described in patients harbouring de novo germline F1174V and F1245V ALK mutations. Here, we investigated the phenotype of knock-in (KI) mice bearing the AlkF1178L mutation (F1174L in human). Although heterozygous KI mice did not reproduce the severe breathing and feeding difficulties observed in human patients, behavioral tests documented a reduced activity during dark phases and an increased anxiety of mutated mice. Matings of heterozygotes yielded the expected proportions of wild-type, heterozygotes and homozygotes at birth but a high neonatal lethality was noticed for homozygotes. We documented Alk expression in several motor nuclei of the brainstem involved in the control of sucking and swallowing. Evaluation of basic physiological functions 12 hours after birth revealed slightly more apneas but a dramatic reduced milk intake for homozygotes compared to control littermates. Overall, our data demonstrate that Alk activation above a critical threshold is not compatible with survival in mice, in agreement with the extremely severe phenotype of patients carrying aggressive de novo ALK germline mutations.

Sleep-disordered breathing in newborn mice heterozygous for the transcription factor Phox2b.

RATIONALE: Central congenital hypoventilation syndrome (CCHS) is a rare autosomal dominant syndrome present from birth, and characterized by depressed ventilation during sleep. Heterozygous mutations of the homeobox gene Phox2b were recently found in a very high proportion of patients. OBJECTIVES: To determine whether newborn mice with heterozygous targeted deletion of the transcription factor Phox2b would display sleep-disordered breathing. METHODS: We measured breathing pattern using whole-body plethysmography in wild-type and mutant 5-day-old mice, and we classified sleep-wake states using nuchal EMG and behavioral scores. RESULTS: We found that sleep apnea total time was approximately six times longer (8.9 +/- 12 vs. 1.5 +/- 2.2 seconds, p < 0.0015), and ventilation during active sleep was 21% lower (18.4 +/- 5.1 vs. 23.3 +/- 5.5 ml/g/second, p < 0.006) in mutant than in wild-type pups. During wakefulness, apnea time and ventilation were not significantly different between mutant and wild-type pups. Mutant and wild-type pups showed highly similar sleep-wake states. CONCLUSION: Although their respiratory phenotype was much less severe than CCHS, the Phox2b(+/-) mutant mice showed sleep-disordered breathing, which partially modeled the key feature of CCHS.