Objective To test the hypothesis that heart rate characteristics (HRC) monitoring improves neonatal outcomes. Study design Two-group, parallel, individually randomized controlled clinical trial of 3003 very low birth weight infants in 9 NICUs. In one group, HRC monitoring was displayed; in the other, it was masked. The primary outcome was number of days alive and ventilator-free in the 120 days after randomization. Secondary outcomes were mortality, number of ventilator days, NICU stay and antibiotic use. Results Mortality was reduced in infants whose HRC monitoring was displayed, from 10.2% to 8.1% (HR = 0.78, 95% CI = 0.61 to 0.99, P = 0.04, number needed to monitor 48), and there was a trend toward increased days alive and ventilator-free (95.9 of 120 days compared to 93.6 in controls, P = 0.08). Mortality benefit was concentrated in infants with birth weight <1000g (HR=0.74, 95% CI 0.57 to 0.95, P=0.02, number needed to monitor 23). There were no significant differences in the other outcomes. Conclusion Heart rate characteristics monitoring can reduce mortality in very low birth weight infants.
Neutrophils contribute to ischemic brain injury in adult animals. The role of neutrophils in perinatal hypoxic-ischemic (HI) brain injury is unknown. Allopurinol reduces neutrophil accumulation after tissue ischemia and is protective against HI brain injury. This study was designed to investigate how neutrophils contribute to perinatal hypoxic ischemic brain injury and how neutropenia compared with allopurinol in its neuroprotective effects. A HI insult was produced in the right cerebral hemisphere of 7-d-old rats by right common carotid artery ligation and systemic hypoxia. Half the rats were rendered neutropenic with an anti-neutrophil serum (ANS). At 15 min of recovery from hypoxia, half the neutropenic and nonneutropenic rats received allopurinol (135 mg/kg, s.c.). The protective effect of the four treatment combinations was determined on brain swelling at 42 h of recovery. Neutropenia reduced brain swelling by about 70%, p < 0.01. Allopurinol alone produced similar protection so that the relatively small number of animals studied did not permit assessment of an additive effect. Neutrophil accumulation in cerebral hemispheres was measured by myeloperoxidase (MPO) activity assay and by neutrophil counts in 6-microm sections stained by MPO and ANS immunostaining. MPO activity peaked between 4 and 8 h of recovery in both hemispheres. Hemispheric neutrophil counts peaked at the end of the HI insult and again at 18 h of recovery. Neutrophils were stained within blood vessels and did not infiltrate the injured brain before infarction had occurred. We conclude that neutrophils contribute to HI brain injury in the neonate and that neutrophil depletion before the insult is neuroprotective.
Background Abnormal heart rate characteristics (HRC) wax and wane in early stages of culture-positive, late-onset septicemia (LOS) in patients in the neonatal intensive care unit (NICU). Continuously monitoring an HRC index leads to a reduction in mortality among very low birth weight (VLBW) infants. We hypothesized that the reduction in mortality was due to a decrease in septicemia-associated mortality. Methods This is a secondary analysis of clinical and HRC data from 2989 VLBW infants enrolled in a randomized controlled trial of HRC monitoring in 9 NICUs from 2004–2010. Results LOS was diagnosed 974 times in 700 patients, and the incidence and distribution of organisms were similar in HRC display and non-display groups. Mortality within 30 days of LOS was lower in the HRC display compared to the non-display group (11.8% vs 19.6%, RR 0.61, 95% CI 0.43, 0.87, p<0.01), but mortality reduction was not statistically significant for patients without LOS. There were fewer large, abrupt increases in the HRC index in the days leading up to LOS diagnosis in infants whose HRC index was displayed. Conclusions Continuous HRC monitoring is associated with a lower septicemia-associated mortality in VLBW infants, possibly due to diagnosis earlier in the course of illness.
To gain insights into the pathogenesis and management of perinatal hypoxic-ischemic brain damage, the authors have used an immature rat model which they developed many years ago. The model entails ligation of one common carotid artery followed thereafter by systemic hypoxia. The insult produces permanent hypoxic-ischemic brain damage limited to the cerebral hemisphere ipsilateral to the carotid artery occlusion. The mini-review describes recently accomplished research pertaining to the use of the immature rat model, specifically, investigations involving energy metabolism, glucose transporter proteins, free radical injury, and seizures superimposed upon cerebral hypoxia-ischemia. Future research will focus on molecular mechanisms of neuronal injury with a continuing focus on therapeutic strategies to prevent or minimize hypoxic-ischemic brain damage.
Background and Purpose Iron catalyzes the formation of damaging reactive species during cerebral reperfusion. Brain iron concentration is highest at birth, so the brain of the asphyxiated newborn may be at increased risk of iron-dependent injury. We investigated whether the ferric iron chelator deferoxamine could reduce hypoxic-ischemic brain injury in neonatal rats. Because deferoxamine has concentrationdependent activities other than iron chelation, we measured brain deferoxamine levels and calculated deferoxamine pharmacokinetic parameters.Methods We produced hypoxic-ischemic injury to the right cerebral hemisphere of 7-day-old rats by right common carotid artery ligation followed by 2.25 hours of hypoxia in 8% oxygen. At 5 minutes of recovery from hypoxia the rats received 100 mg/kg deferoxamine mesylate or saline subcutaneously. Rats (saline, n=33; deferoxamine, n=38) were killed at 42 hours of recovery to assess early acute edema by measurement of hemispheric water content. Other rats (saline, n=31; deferox-
ABSTRACT. Cytotoxic free radicals are generated during cerebral hypoxia-ischemia and reperfusion. We studied the efficacy of allopurinol, a xanthine oxidase inhibitor and free radical scavenger, in reducing posthypoxic-ischemic damage in the developing brain of 7-d-old rat pups. Hypoxic-ischemic injury to the right cerebral hemisphere was produced by ligation of the right common carotid artery followed by 3 h of hypoxia with 8% oxygen. Thirty to 45 min before the hypoxia, the rats received either allopurinol Free radicals contribute to the pathogenesis of hypoxicischemic brain damage (1-5), and successful management of traumatic or ischemic brain injury includes prevention of free radical damage (6-10).During cerebral hypoxia-ischemia, tissue stores of ATP are degraded sequentially to ADP, AMP, adenosine, inosine, and hypoxanthine (1 I, 12). Hypoxanthine levels accumulate as further metabolism is impeded by tissue hypoxia (13, 14). During reperfusion and reoxygenation, there is a transient rise in xanthine with a concomitant fall in hypoxanthine, reflecting the conversion of hypoxanthine to xanthine by the enzyme xanthine oxidase (1 5). This reaction generates superoxide and secondarily derived cytotoxic species including hydroxyl radicals (2). Free radicals are highly reactive molecules capable of damaging cells by peroxidation of membrane phospholipids (16) and by oxidation of cellular proteins and nucleic acids (17).Allopurinol is both an inhibitor of xanthine oxidase (1 8) and a scavenger of free radicals (19, 20). It has been used successfully to reduce ischemic injury of the heart (21), kidney (22), small intestine (23), and adult rat brain (24, 25). Accordingly, we aimed to establish if allopurinol could reduce hypoxic-ischemic injury to the developing brain of the 7-d-old rat pup. MATERIALS AND METHODSTo evaluate the potential neuroprotective effect of allopurinol, we studied 7-d postnatal rat pups in which we induced a hypoxicischemic insult to the right cerebral hemisphere (see below). Animals were killed after either a short (42 h) or long (30 d) period of recovery to evaluate the extent of the lesion.Animals in the short recovery study were evaluated for brain water content, whereas those in the long recovery study were killed after 30 d of age to evaluate long-term neuropathologic alterations. The rat pups were treated alternately with either saline or allopurinol (see below).Animal model. Seven-d-old Wistar (Charles River, Wilmington, MA) rat pups of either sex, weighing between 12-18 g were anesthetized with a mixture of halothane (4% halothane, 1-1.5% for maintenance), 30% oxygen, and balance nitrous oxide. The right common carotid artery of each pup was ligated with 4-0 surgical silk. The wound was then sutured and the animal allowed to recover. The duration of anesthesia was about 5 min. After surgery, the rat pups were returned to their dams for 2' /2 h. Pups from mixed litters were then randomly divided into two equal treatment groups. One group received an injection of normal saline (0.2 mL)...
The global lockdown to mitigate COVID-19 pandemic health risks has altered human interactions with nature. Here, we report immediate impacts of changes in human activities on wildlife and environmental threats during the early lockdown months of 2020, based on 877 qualitative reports and 332 quantitative assessments from different studies. Hundreds of reports of unusual species observations from around the world suggest that animals quickly responded to the reductions in human presence. However, negative effects of lockdown on conservation also emerged, as confinement resulted in some park officials being unable to perform conservation, restoration and enforcement tasks, resulting in local increases in illegal activities such as hunting. Overall, there is a complex mixture of positive and negative effects of the pandemic lockdown on nature, all of which have the potential to lead to cascading responses which in turn impact wildlife and nature conservation. While the net effect of the lockdown will need to be assessed over years as data becomes available and persistent effects emerge, immediate responses were detected across the world. Thus, initial qualitative and quantitative data arising from this serendipitous global quasi-experimental perturbation highlights the dual role that humans play in threatening and protecting species and ecosystems. Pathways to favorably tilt this delicate balance include reducing impacts and increasing conservation effectiveness.
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