Development and validation of a clinical model to predict the presence of ß-lactam resistance in viridans group streptococci causing bacteremia in neutropenic cancer patients.

BACKGROUND: Concern for serious infection due to ß-lactam-resistant viridans group streptococci (VGS) is a major factor driving empiric use of an anti-gram-positive antimicrobial in patients with febrile neutropenia. We sought to develop and validate a prediction model for the presence of ß-lactam resistance in VGS causing bloodstream infection (BSI) in neutropenic patients. METHODS: Data from 569 unique cases of VGS BSI in neutropenic patients from 2000 to 2010 at the MD Anderson Cancer Center were used to develop the clinical prediction model. Validation was done using 163 cases from 2011 to 2013. In vitro activity of ß-lactam agents was determined for 2011-2013 VGS bloodstream isolates. RESULTS: In vitro resistance to ß-lactam agents commonly used in the empiric treatment of febrile neutropenia was observed only for VGS isolates with a penicillin minimum inhibitory concentration (MIC) of ≥ 2 µg/mL. One hundred twenty-nine of 732 patients (17%) were infected with VGS strains with a penicillin MIC ≥ 2 µg/mL. For the derivation and validation cohorts, 98% of patients infected by VGS with a penicillin MIC of ≥ 2 µg/mL had at least 1 of the following risk factors: current use of a ß-lactam as antimicrobial prophylaxis, receipt of a ß-lactam antimicrobial in the previous 30 days, or nosocomial VGS BSI onset. Limiting empiric anti-gram-positive therapy to neutropenic patients having at least 1 of these 3 risk factors would have reduced such use by 42%. CONCLUSIONS: Simple clinical criteria can assist with targeting of anti-gram-positive therapy to febrile neutropenic patients at risk of serious ß-lactam-resistant VGS infection.

Outcome predictors of limb salvage in traumatic popliteal artery injury.

BACKGROUND: Significantly reduced amputation rates for traumatic popliteal artery injuries have been achieved with improved revascularization and resuscitative techniques. Predictive scores have failed to accurately predict outcomes in patients who sustain popliteal artery damage. This study aimed to identify predictors of limb salvage in a civilian cohort after popliteal artery trauma. METHODS: A single-institution, retrospective review was performed of all patients with popliteal artery trauma presenting between January 2002 and June 2009. Data were compiled using the institutional trauma registry, with demographics, mechanism of injury, associated injury, fasciotomy, Mangled Extremity Severity Score (MESS), and Injury Severity Score (ISS) all documented. Statistical analysis included descriptive statistics, univariate analysis, and multiple exact logistic regression. RESULTS: Seventy traumatic popliteal artery injuries were identified in 68 patients with a mean age of 33 years (range: 5-88 years). The majority of patients were male (n = 57; 81%), and 73% sustained blunt injury. Associated venous injury was present in 16 (23%) cases. Associated orthopedic injuries included 19 (27%) dislocations and 49 (70%) fractures. The median MESS was 5 (range: 2-9) and the median ISS was 9 (range: 4-41). Revascularization was performed in 62 cases (89%). Twenty-three percent of patients had compartment syndrome and 56% underwent fasciotomy. Fifteen (21%) patients required amputation, 11% of which were primary and 10% secondary. Variables associated with amputation included ISS >10 compared to ISS <9 (odds ratio [OR]: 7.4; P < 0.045), blunt injury (OR: 10.7; P = 0.009), MESS >7 (OR: 2.4; P < 0.0001), and fractures (OR: 0.13; P < 0.045). In a multiple exact logistic regression analysis, a MESS >7 (P < 0.05) was the only significant predictor of amputation. CONCLUSION: Patients with traumatic popliteal artery injury are at high risk for amputation. Blunt injury, fractures, ISS >9, and MESS >7 were associated with an increased odds of amputation. Although in our data, MESS was the strongest predictor of amputation, we recognize that MESS was previously invalidated as a scoring system. New methods to determine limb viability in the mangled extremity are needed.

Pilot randomized trial of hydrocortisone in ventilator-dependent extremely preterm infants: effects on regional brain volumes.

OBJECTIVE: To test the hypothesis that high-risk ventilator-dependent extremely low birth weight (birth weight ≤1000 g) infants treated with 7 days of hydrocortisone will have larger total brain tissue volumes than placebo treated infants. STUDY DESIGN: A predetermined sample size of 64 extremely low birth weight infants, between 10-21 days old and ventilator-dependent with a respiratory index score ≥2, were randomized to systemic hydrocortisone (17 mg/kg cumulative dose) or saline placebo. Primary outcome was total brain tissue volume. Volumetric magnetic resonance imaging was performed at 38 weeks postmenstrual age; brain tissue regions were segmented and quantified automatically with a high degree of accuracy and 9 structures were segmented manually. All analyses of regional brain volumes were adjusted by postmenstrual age at magnetic resonance imaging scan. RESULTS: The study groups were similar at baseline and 8 infants died in each arm. Unadjusted total brain tissue volume (mean ± SD) in the hydrocortisone (N = 23) and placebo treated infants (N = 21) was 272 ± 40.3 cm(3) and 277.8 ± 59.1 cm(3), respectively (adjusted mean difference: 6.35 cm(3) (95% CI: (-20.8, 32.5); P = .64). Three of the 31 hydrocortisone treated infants and 5 of the 33 placebo treated infants survived without severe bronchopulmonary dysplasia (relative risk 0.62, 95% CI: 0.13, 2.66; P = .49). No significant differences were noted in prespecified secondary outcomes of regional structural volumes or days on respiratory support. No adverse effects of hydrocortisone were observed. CONCLUSIONS: Low dose hydrocortisone in high-risk ventilator-dependent infants after a week of age had no discernible effect on regional brain volumes or pulmonary outcomes prior to neonatal intensive care unit discharge.

The role of voltage dependence of the NMDA receptor in cellular and network oscillation.

Unraveling the mechanisms underlying oscillatory behavior is critical for understanding normal and pathological brain processes. Here we used electrophysiology in mouse neocortical slices and principles of nonlinear dynamics to demonstrate how an increase in the N-methyl-d-aspartic acid receptor (NMDAR) conductance can create a nonlinear whole-cell current-voltage (I-V) relationship which leads to changes in cellular stability. We discovered two behaviorally and morphologically distinct pyramidal cell populations. Under control conditions, both cell types responded to depolarizing current injection with regular spiking patterns. However, upon NMDAR activation, an intrinsic oscillatory (IO) cell type (n = 44) showed a nonlinear whole-cell I-V relationship, intrinsic voltage-dependent oscillations plus amplification of alternating input current, and these properties persisted after disabling action potential generation with tetrodotoxin (TTX). The other non-oscillatory (NO) neuronal population (n = 24) demonstrated none of these behaviors. Simultaneous intra- and extracellular recordings demonstrated the NMDAR's capacity to promote low-frequency seizure-like network oscillations via its effects on intrinsic neuronal properties. The two pyramidal cell types demonstrated different relationships with network oscillation--the IO cells were leaders that were activated early in the population activity cycle while the activation of the NO cell type was distributed across network bursts. The properties of IO neurons disappeared in a low-magnesium environment where the voltage dependence of the receptor is abolished; concurrently, the cellular contribution to network oscillation switched to synchronous firing. Thus, depending upon the efficacy of NMDAR in altering the linearity of the whole-cell I-V relationship, the two cell populations played different roles in sustaining network oscillation.

The effects of aggressive vs. conservative phototherapy on the brainstem auditory evoked responses of extremely-low-birth-weight infants.

INTRODUCTION: This study was a two-center, stratified, parallel-group randomized trial comparing the effects of aggressive vs. conservative phototherapy on brainstem auditory evoked response (BAER) latencies in infants with extremely low birth weight (ELBW, ≤ 1,000 g). RESULTS: BAER latencies of 751-1,000 g birth-weight infants were shorter by 0.37 ms (95% confidence interval (CI) = 0.02, 0.73) for wave V, 0.39 ms (0.08, 0.70) for wave III, and 0.33 ms (0.01, 0.65) for wave I after aggressive phototherapy at one center. Interwave intervals did not differ significantly. Similar nonsignificant trends were recorded for 501-750 g birth-weight infants. At the other participating center, no significant differences were recorded, cautioning against overgeneralizing these results. DISCUSSION: The effects of bilirubin on the auditory pathway in ELBW infants depend on a complex interaction of bilirubin exposure, newborn characteristics, and clinical management. METHODS: Aggressive phototherapy was initiated sooner and continued at lower bilirubin levels than conservative phototherapy. A total of 174 ELBW infants were enrolled in the study; 111 infants were successfully tested at 35 weeks postmenstrual age (PMA); 57 died; and 6 were not successfully tested.

In vitro evaluation of new approach to digital dental model articulation.

PURPOSE: The purpose of the present study was to evaluate the accuracy of our newly developed approach to digital dental model articulation. MATERIALS AND METHODS: Twelve sets of stone dental models from patients with craniomaxillofacial deformities were used for validation. All the models had stable occlusion and no evidence of early contact. The stone models were hand articulated to the maximal intercuspation (MI) position and scanned using a 3-dimensional surface laser scanner. These digital dental models at the MI position served as the control group. To establish an experimental group, each mandibular dental model was disarticulated from its original MI position to 80 initial positions. Using a regular office personal computer, they were digitally articulated to the MI position using our newly developed approach. These rearticulated mandibular models served as the experimental group. Finally, the translational, rotational, and surface deviations in the mandibular position were calculated between the experimental and control groups, and statistical analyses were performed. RESULTS: All the digital dental models were successfully articulated. Between the control and experimental groups, the largest translational difference in mandibular position was within 0.2 mm ± 0.6 mm. The largest rotational difference was within 0.1° ± 1.1°. The averaged surface deviation was 0.08 ± 0.07. The results of the Bland and Altman method of assessing measurement agreement showed tight limits for the translational, rotational, and surface deviations. In addition, the final positions of the mandibular articulated from the 80 initial positions were absolutely agreed on. CONCLUSION: The results of our study have demonstrated that using our approach, the digital dental models can be accurately and effectively articulated to the MI position. In addition, the 3-dimensional surface geometry of the mandibular teeth played a more important role in digital dental articulation than the initial position of the mandibular teeth.

Outcome study of computer-aided surgical simulation in the treatment of patients with craniomaxillofacial deformities.

PURPOSE: The purpose of this study was to determine whether the surgical outcomes achieved with computer-aided surgical simulation (CASS) are better than those achieved with traditional methods. MATERIALS AND METHODS: Twelve consecutive patients with craniomaxillofacial (CMF) deformities were enrolled. According to the CASS clinical protocol, a 3-dimensional computer composite skull model for each patient was generated and reoriented to the neutral head posture. These models underwent 2 virtual surgeries: 1 was based on CASS (experimental group) and the other was based on traditional methods 1 year later (control group). Once the 2 virtual surgeries were completed, 2 experienced oral and maxillofacial surgeons at 2 different settings evaluated the 2 surgical outcomes. They were blinded to the planning method used on the virtual models and each other's evaluation results. The primary outcome was overall CMF skeletal harmony. The secondary outcomes were individual maxillary, mandibular, and chin harmonies. Statistical analyses were performed. RESULTS: Overall CMF skeletal harmony achieved with CASS was statistically significantly better than that achieved with traditional methods. In addition, the maxillary and mandibular surgical outcomes achieved with CASS were significantly better. Furthermore, although not included in the statistical model, the chin symmetry achieved by CASS tended to be better. A regression model was established between mandibular symmetry and overall CMF skeletal harmony. CONCLUSION: The surgical outcomes achieved with CASS are significantly better than those achieved with traditional planning methods. In addition, CASS enables the surgeon to better correct maxillary yaw deformity, better place proximal/distal segments, and better restore mandibular symmetry. The critical step in achieving better overall CMF skeletal harmony is to restore mandibular symmetry.

A new method to orient 3-dimensional computed tomography models to the natural head position: a clinical feasibility study.

PURPOSE: The purpose of this study was to evaluate the clinical feasibility of a new method to orient 3-dimensional (3D) computed tomography models to the natural head position (NHP). This method uses a small and inexpensive digital orientation device to record NHP in 3 dimensions. This device consists of a digital orientation sensor attached to the patient via a facebow and an individualized bite jig. The study was designed to answer 2 questions: 1) whether the weight of the new device can negatively influence the NHP and 2) whether the new method is as accurate as the gold standard. PATIENTS AND METHODS: Fifteen patients with craniomaxillofacial deformities were included in the study. Each patient's NHP is recorded 3 times. The first NHP was recorded with a laser scanning method without the presence of the digital orientation device. The second NHP was recorded with the digital orientation device. Simultaneously, the third NHP was also recorded with the laser scanning method. Each recorded NHP measurement was then transferred to the patient's 3D computed tomography facial model, resulting in 3 different orientations for each patient: the orientation generated via the laser scanning method without the presence of the digital orientation sensor and facebow (orientation 1), the orientation generated by use of the laser scanning method with the presence of the digital orientation sensor and facebow (orientation 2), and the orientation generated with the digital orientation device (orientation 3). Comparisons are then made between orientations 1 and 2 and between orientations 2 and 3, respectively. Statistical analyses are performed. RESULTS: The results show that in each pair, the difference (Δ) between the 2 measurements is not statistically significantly different from 0°. In addition, in the first pair, the Bland-Altman lower and upper limits of the Δ between the 2 measurements are within 1.5° in pitch and within a subdegree in roll and yaw. In the second pair, the limits of the Δ in all 3 dimensions are within 0.5°. CONCLUSION: Our technique can accurately record NHP in 3 dimensions and precisely transfer it to a 3D model. In addition, the extra weight of the digital orientation sensor and facebow has minimal influence on the self-balanced NHP establishment.

Spectral analysis of time series of events: effect of respiration on heart rate in neonates.

Certain types of biomedical processes such as the heart rate generator can be considered as signals that are sampled by the occurring events, i.e. QRS complexes. This sampling property generates problems for the evaluation of spectral parameters of such signals. First, the irregular occurrence of heart beats creates an unevenly sampled data set which must either be pre-processed (e.g. by using trace binning or interpolation) prior to spectral analysis, or analyzed with specialized methods (e.g. Lomb's algorithm). Second, the average occurrence of events determines the Nyquist limit for the sampled time series. Here we evaluate different types of spectral analysis of recordings of neonatal heart rate. Coupling between respiration and heart rate and the detection of heart rate itself are emphasized. We examine both standard and data adaptive frequency bands of heart rate signals generated by models of coupled oscillators and recorded data sets from neonates. We find that an important spectral artifact occurs due to a mirror effect around the Nyquist limit of half the average heart rate. Further we conclude that the presence of respiratory coupling can only be detected under low noise conditions and if a data-adaptive respiratory band is used.

Early lead exposure effects on an auditory threshold task in the rhesus monkey (Macaca mulatta).

Behavioral thresholds to pure tones were obtained from adult rhesus monkeys that had been exposed to lead during early development and unexposed cohort controls. Thresholds were elevated (by 2-9 dB) for the previously lead exposed monkeys at all frequencies tested (125-8,000 Hz in octave steps). Although the magnitude and direction of the differences were similar to significant effects reported for children, the more difficult task and much smaller sample sizes in this study of monkeys may have precluded obtaining significant differences at the same magnitude of effects observed in children. Thresholds for one lead-exposed monkey were significantly elevated at midrange frequencies in agreement with electrophysiological results obtained in another study [Lasky, Maier, Snodgrass, Hecox, and Laughlin [1995] Neurotoxicology and Teratology, 17, 633-644]. Behavioral measurements during the threshold task indicated less engagement for lead exposed monkeys than for controls. In addition, the lead exposed monkeys completed testing at significantly fewer frequencies and were significantly more difficult to test than control monkeys by tester ratings. These results are consistent with reports concerning the behavior of lead exposed children.

Heart rate variability in response to pain stimulus in VLBW infants followed longitudinally during NICU stay.

The objective of this longitudinal study, conducted in a neonatal intensive care unit, was to characterize the response to pain of high-risk very low birth weight infants (<1,500 g) from 23 to 38 weeks post-menstrual age (PMA) by measuring heart rate variability (HRV). Heart period data were recorded before, during, and after a heel lanced or wrist venipunctured blood draw for routine clinical evaluation. Pain response to the blood draw procedure and age-related changes of HRV in low-frequency and high-frequency bands were modeled with linear mixed-effects models. HRV in both bands decreased during pain, followed by a recovery to near-baseline levels. Venipuncture and mechanical ventilation were factors that attenuated the HRV response to pain. HRV at the baseline increased with post-menstrual age but the growth rate of high-frequency power was reduced in mechanically ventilated infants. There was some evidence that low-frequency HRV response to pain improved with advancing PMA.

Intensive care noise and mean arterial blood pressure in extremely low-birth-weight neonates.

Noise in neonatal intensive care units (NICUs) may impede growth and development for extremely low-birth-weight (ELBW, < 1000 g) newborns. We calculated correlations between NICU sound levels and ELBW neonates' heart rate and arterial blood pressure to evaluate whether this population experiences noise-induced stress. Sound levels inside the incubator, heart rate (HR), and arterial blood pressure recordings were simultaneously collected for eight ELBW neonates for 15 minutes during the first week of life. Cross-correlation functions were calculated for NICU noise, HR, and mean arterial blood pressure (MABP) recordings for each subject. ELBW neonates' HR and MABP were significantly correlated ( R = 0.16 at 2-second lag time), with stronger correlation apparent for higher-birth-weight ELBW newborns (0.22 versus 0.10). Lower-birth-weight newborns responded to increased noise with HR acceleration from 45 to 130 seconds after noise events, and higher-birth-weight infants initially responded with an HR deceleration at 25 to 60 seconds, then HR acceleration ~175 seconds after noise increased. MABP was not as strongly correlated with NICU sound levels, although some correlation coefficients were slightly outside the 95% confidence interval. Higher-birth-weight newborns' more mature neurological systems may be responsible for stronger correlations between HR and MABP. NICU noise influenced newborns' HR, indicating that these infants hear and respond to NICU sounds. ELBW newborns in the first week of life seem to maintain a relatively stable blood pressure in response to moderate NICU sound levels (50 to 60 dBA).

Postnatal lead effects on the development of visual spatial acuity in rhesus monkeys (Macaca Mulatta).

High lead levels adversely affect visual function in humans and laboratory animals. The effects of lower lead levels are less certain. This study compared the development of photopic spatial acuity in rhesus monkeys exposed to lead (n = 43) with monkeys (n = 23) not exposed to lead. Lead exposure began at Day 8 postpartum and continued daily throughout the first 26 weeks of postnatal life achieving target blood lead levels of 35-40 microg/dl by about 15 weeks. Photopic spatial acuity was evaluated by a preferential looking technique used clinically to assess spatial acuity in human infants. Acuity increased rapidly over the first few postnatal weeks achieving the maximum acuity level assessed (26.3 c/deg) by 7 weeks of age for most monkeys. Postnatal lead exposure at the dosages and durations studied did not affect the development of photopic spatial acuity.

Effects of hypoxic-ischemic encephalopathy and whole-body hypothermia on neonatal auditory function: a pilot study.

We assessed the effects of hypoxic-ischemic encephalopathy (HIE) and whole-body hypothermia therapy on auditory brain stem evoked responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). We performed serial assessments of ABRs and DPOAEs in newborns with moderate or severe HIE, randomized to hypothermia ( N = 4) or usual care ( N = 5). Participants were five boys and four girls with mean gestational age (standard deviation) of 38.9 (1.8) weeks. During the first week of life, peripheral auditory function, as measured by the DPOAEs, was disrupted in all nine subjects. ABRs were delayed but central transmission was intact, suggesting a peripheral rather than a central neural insult. By 3 weeks of age, peripheral auditory function normalized. Hypothermia temporarily prolonged the ABR, more so for waves generated higher in the brain stem but the effects reversed quickly on rewarming. Neonatal audiometric testing is feasible, noninvasive, and capable of enhancing our understanding of the effects of HIE and hypothermia on auditory function.

Longitudinal assessment of heart rate variability in very low birth weight infants during their NICU stay.

BACKGROUND: Maturation of the autonomic nervous system has not been studied in high-risk very low birth weight (VLBW) infants in the first few weeks of life. AIM: To characterize developmental changes in autonomic nervous system activity of high-risk VLBW infants from 23 to 38 weeks post-menstrual age by measuring heart rate variability (HRV). STUDY DESIGN AND SUBJECTS: In this prospective cohort study 38 infants admitted to Children's Memorial Hermann Hospital NICU were longitudinally followed weekly or biweekly. Heart period data were recorded while infants were resting in active sleep. OUTCOME MEASURES: Growth of spectral power of HRV in low-frequency (0.05-0.25 Hz) and high-frequency (0.25-1.00 Hz) bands was modeled with linear mixed-effects models. The high-frequency power provides a measure of respiratory sinus arrhythmia (RSA). RESULTS: Low-frequency power increases with post-menstrual age, and intubated infants have lower HRV. The increase in low-frequency power is faster (0.50+/-0.12 dB/week) than the increase in RSA (0.17+/-0.09 dB/week). CONCLUSION: This longitudinal data exhibits developmental maturation of the RSA and of the low-frequency power of HRV in high-risk VLBW infants.

Auditory deficits in rats exposed to an environmental PCB mixture during development.

Previous studies have indicated that developmental exposure to polychlorinated biphenyls (PCBs) may result in hearing impairment in rats. The cochlea is the suggested site of action, based upon one study demonstrating a loss of outer hair cells on the basilar membrane, and another demonstrating deficits in distortion product otoacoustic emissions (DPOAEs). The current study was conducted to assess the possible ototoxic effects of a unique PCB mixture formulated to model the congener profile of PCBs found in fish consumed by a human population in northeastern Wisconsin. Female Long-Evans rats were dosed orally with the PCB mixture beginning 28 days prior to breeding and continuing until the pups were weaned. Dams were fed one-half of a cookie onto which was pipetted 0, 1, 3, or 6 mg/kg of the PCB mixture dissolved in a corn oil vehicle. On postnatal day (PND) 21, pups were weaned, and one male and one female from each litter were randomly selected for auditory assessment. DPOAEs were measured to assess cochlear function, and auditory brainstem responses (ABRs) were measured to determine effects on central nervous system auditory pathways. DPOAE amplitudes were decreased, and DPOAE and ABR thresholds were elevated across a range of frequencies in PCB-exposed rats. These results support and extend previous reports of auditory impairment in PCB-exposed rats. Developmental exposure to PCBs may also result in subtle auditory impairments in humans, and if so, this may contribute to some of the cognitive deficits that have been observed in epidemiological studies.

Do former preterm infants remember and respond to neonatal intensive care unit noise?

BACKGROUND: Previous studies have shown that 4-month-old infants have a decrease in heart rate, a component of the orienting reflex, in response to interesting auditory stimuli and an increase in heart rate to aversive auditory stimuli. OBJECTIVE: To compare the heart rate responses of former preterm and term infants at 4-5 months corrected age to a recording of NICU noises. METHODS: 13 former preterm infants and 17 full-term infants were presented NICU noise and another noise of similar level and frequency content in random order. Heart rate 10s prior to the stimulus and for 20s during the stimulus was analyzed. Group differences in second by second heart rate changes in response to the two noise stimuli were compared by analysis of covariance. RESULTS: Both the preterm and term newborns responded similarly to the NICU noise and the control noise. The preterm infants did not alter their heart rate in response to either stimulus. In contrast, the term infants displayed an orienting response to the second stimulus presented regardless of whether it was the NICU or control noise. CONCLUSIONS: Former preterm infants at 4-5 months corrected age have reduced responsiveness to auditory stimulation in comparison to 4- to 5-month-old term infants. Furthermore, they did not respond to the NICU noise as an aversive stimulus.

The effects of early lead exposure on the brains of adult rhesus monkeys: a volumetric MRI study.

Little is known about direct effects of exposure to lead on central nervous system development. We conducted volumetric MRI studies in three groups of 17-year-old rhesus monkeys: (1) a group exposed to lead throughout gestation (n = 3), (2) a group exposed to lead through breast milk from birth to weaning (n = 4), and (3) a group not exposed to lead (n = 8). All fifteen monkeys were treated essentially identically since birth with the exception of lead exposure. The three-dimensional MRI images were segmented on a computer workstation using pre-tested manual and semi-automated algorithms to generate brain volumes for white matter, gray matter, cerebrospinal fluid, and component brain structures. The three groups differed significantly in the adjusted (for total brain size) volumes of the right cerebral white matter and the lateral ventricles. A significant reduction was noted in right cerebral white matter in prenatally exposed monkeys as compared to controls (p = 0.045). A similar reduction was detected in the white matter of the contralateral hemisphere; however, this difference did not achieve statistical significance (p = 0.143). Prenatally exposed monkeys also had larger right (p = 0.027) and left (p = 0.040) lateral ventricles. Depending on the timing of exposure during development, lead may exhibit differential effects with resultant life-long alterations in brain architecture.

Neurodevelopmental Outcomes of Extremely Preterm Infants Randomized to Stress Dose Hydrocortisone.

OBJECTIVE: To compare the effects of stress dose hydrocortisone therapy with placebo on survival without neurodevelopmental impairments in high-risk preterm infants. STUDY DESIGN: We recruited 64 extremely low birth weight (birth weight ≤1000 g) infants between the ages of 10 and 21 postnatal days who were ventilator-dependent and at high-risk for bronchopulmonary dysplasia. Infants were randomized to a tapering 7-day course of stress dose hydrocortisone or saline placebo. The primary outcome at follow-up was a composite of death, cognitive or language delay, cerebral palsy, severe hearing loss, or bilateral blindness at a corrected age of 18-22 months. Secondary outcomes included continued use of respiratory therapies and somatic growth. RESULTS: Fifty-seven infants had adequate data for the primary outcome. Of the 28 infants randomized to hydrocortisone, 19 (68%) died or survived with impairment compared with 22 of the 29 infants (76%) assigned to placebo (relative risk: 0.83; 95% CI, 0.61 to 1.14). The rates of death for those in the hydrocortisone and placebo groups were 31% and 41%, respectively (P = 0.42). Randomization to hydrocortisone also did not significantly affect the frequency of supplemental oxygen use, positive airway pressure support, or need for respiratory medications. CONCLUSIONS: In high-risk extremely low birth weight infants, stress dose hydrocortisone therapy after 10 days of age had no statistically significant effect on the incidence of death or neurodevelopmental impairment at 18-22 months. These results may inform the design and conduct of future clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00167544.