Dennis Mujsce

Cerebral Blood Flow and Edema in Perinatal Hypoxic-Ischemic Brain Damage

ABSTRACT: The relationship between cerebral blood flow (CBF) and the evolution of brain edema was investigated in an experimental model of perinatal hypoxic-ischemic brain damage. Seven-d postnatal rats were subjected to unilateral common carotid artery ligation followed by 3 h of hypoxia with 8% oxygen at 37°C. This insult produces neuronal necrosis and/or infarction only in the cerebral hemisphere ipsilateral to the arterial occlusion in the majority of animals; hypoxia alone produces no damage. CBF, measured by the indicator diffusion technique using iodo-[14C]-antipyrine, and tissue water content were determined concurrently in both cerebral hemispheres at specific intervals during recovery from cerebral hypoxia-ischemia. Water contents in the ipsilateral cerebral hemisphere were 89.1, 89.6, 89.7, 91.0, and 88.3% at 30 min, 4 h, 24 h, 3 d, and 6 d, respectively (p < 0.001); whereas the percent tissue water in the contralateral hemisphere was unchanged from values in nonligated, hypoxic control rats (87.7%). CBF was similar in both cerebral hemispheres at 30 min, 4 h, and 24 h of recovery (50–65 mL/100 g/min) and not different from age-matched controls. At 3 and 6 d, CBF in the ipsilateral cerebral hemisphere was 30 and 26% of the contralateral hemisphere and 23 and 29% of the control animals, respectively (P < 0.001). No inverse correlation existed between the changes in brain water content and CBF at any interval until 6 d of recovery. Thus, an early hypoperfusion does not follow perinatal cerebral hypoxiaischemia, as occurs in adults. A late hypoperfusion takes place that results from rather than causes tissue necrosis seen histologically at 15–50 h of recovery. The results suggest that therapeutic attempts to improve CBF by reducing cerebral edema after hypoxia-ischemia will not alter ultimate neuropathologic outcome.

Effect of Glucose on Perinatal Hypoxic-Ischemic Brain Damage

Investigations suggest that hyperglycemia superimposed on hypoxia-ischemia or cerebral ischemia accentuates brain damage in adult experimental animals and humans. Such does not appear to be the case in immature animals. The present review discusses fundamental differences in immature and adult brain metabolism which account for the age-specific paradox. Based on currently available data, it is recommended that glucose supplementation not be curtailed during labor and delivery of asphyxiated human infants; on the contrary, glucose therapy might substantially reduce hypoxic-ischemic brain damage.

Neuropathologic aspects of hypothermic circulatory arrest in newborn dogs

SummaryA model of hypothermic circulatory arrest with recovery has been developed in the newborn dog. Eleven puppies were anesthetized with halothane, paralyzed and artificially ventilated with 70% nitrous oxide −30% oxygen to paO2>60 mm Hg, paCO2=33–42 mm Hg and pHa=7.35–7.42. Animals were surface cooled to 20°C, following which cardiac arrest was effected with i.v. KCl. Dogs remained asystolic without ventilation for 1.0, 1.5 or 1.75. Resuscitation was accomplished with closed-chest compression, mechanical ventilation, i.v. epinephrine and NaHCO3, and rewarming to 37°C. Thereafter, the puppies were allowed to recover from anesthesia and maintained for either 18–22 h (n=9) or 72 h (n=2), at which time they underwent perfusion-fixation of their brains for pathologic analysis. Of the total, four out of four puppies arrested for 1.0 h exhibited no brain damage, including one recovered for 72 h; whereas one out of three and four out of four puppies arrested for 1.5 and 1.75 h, respectively, showed brain damage predominantly of the cerebral cortex but also of the basal ganglia and amygdaloid nucleus. The hippocampus was spared, even in a 1.75-h-arrested animal which was maintained for 72 h. No differences in pre- or post-arrest systemic blood pressure, heart rate, or acid-base balance were observed between the brain damaged and undamaged animals except for the single damaged animal arrested for 1.5 h, for which the blood pressure prior to cardiac arrest and during recovery was the lowest of all survivors. We conclude that newborn dogs undergoing hypothermic circulatory arrest for 1.0–1.5 h and which are fully recoverable without systemic hypotension exhibit no brain damage, whereas puppies arrested for 1.75 h exhibit brain damage entirely on the basis of global cerebral ischemia arising during the cardiac arrest. The experimental model has relevance to newborn human infants undergoing hypothermic circulatory arrest for the operative correction of congenital heart defects and should be useful for studying mechanisms of cellular injury in brain and other organs during prolonged ischemia.

Mannitol therapy in perinatal hypoxic-ischemic brain damage in rats.

To study the efficacy of mannitol in reducing cerebral edema and improving the ultimate neuropathologic outcome in perinatal cerebral hypoxia-ischemia, 67 7-day postnatal rats were subjected to unilateral common carotid artery ligation followed by exposure to 8% oxygen at 37 degrees C for 3 hours. Twenty-seven rat pups received a subcutaneous injection of 0.1 ml mannitol in a dosage of 4 mg/kg body wt immediately following cerebral hypoxia-ischemia and every 12 hours thereafter for a total of four doses. Control animals received either no therapy (n = 16) or an equivalent volume of normal saline (n = 24). Mannitol injections in six rat pups not subjected to hypoxia-ischemia produced no mortality but significantly increased serum osmolality from 287 to 361 mos/l (p less than 0.01). Preliminary studies indicated that substantial mortality occurred when greater doses of mannitol were administered to rats. After 48 hours of recovery from hypoxia-ischemia, the animals were killed and their brains were examined for either tissue water content (33 rat pups) or the presence of neuropathologic alterations (34 rat pups). Mannitol significantly reduced (p less than 0.001) brain water content, as a reflection of cerebral edema, in both the ipsilateral (88.5% compared with 90.6% in controls) and the contralateral (85.0% compared with 87.2% in controls) cerebral hemispheres. Mannitol therapy did not ameliorate the incidence, distribution, or severity of tissue injury in the cerebral cortex, subcortical white matter, hippocampus, striatum, or thalamus of the ipsilateral cerebral hemisphere compared with the controls. Thus, while mannitol substantially reduces the extent of cerebral edema following hypoxia-ischemia, no beneficial affect on ultimate brain damage occurs.(ABSTRACT TRUNCATED AT 250 WORDS)

Reducing Unplanned Extubations in the NICU

BACKGROUND AND OBJECTIVES: Unplanned extubation can be a significant event that places the patient at risk for adverse events. Our goal was to reduce unplanned extubations to <1 unplanned extubation per 100 patient-intubated days. METHODS: All unplanned extubations in the NICU beginning in October 2009 were audited. Data collected included time of day, patient weight, and patient care activity at the time of the event. Bundles of potentially better practices were implemented in sequential Plan-Do-Study-Act cycles. Rates of unplanned extubation (number per patient-intubated day) for each month were analyzed by using control charts, and causes of unplanned extubation were analyzed by using Pareto charts. RESULTS: We found a significant decrease in the unplanned extubation rate after implementation of the first bundle of potentially better practices in May 2010 (2.38 to 0.41 per 100 patient-intubated days). Several more Plan-Do-Study-Act cycles were conducted to sustain this improvement. A persistent reduction in the unplanned extubation rate (0.58 per 100 patient-intubated days) began in February 2013. Causes included dislodgement during care and procedures and variation in the fixation of the endotracheal tube. The majority of events occurred in very low birth weight infants during the daytime shift. CONCLUSIONS: Unplanned extubations in the NICU can be reduced by education of staff and by implementing standard practices of care. Sustainability of any practice change to improve quality is critically dependent on culture change within the NICU. We suggest that the benchmark for unplanned extubation should be a rate <1 per 100 patient-intubated days.

Physiologic and Neuropathologic Aspects of Hypothermic Circulatory Arrest in Newborn Dogs

ABSTRACT: A modle of hypothermic circulatory arrest has been developed in the newborn dog. Ten puppies were anesthetized with halothane, paralyzed, and artificially ventilated with 70% nitrous oxide 30% oxygen to arterial oxygen pressure >8.0 kPa (60 mm Hg), arterial carbon dioxide pressure of 4.4–5.6 kPa (33–42 mm Hg), and arterial pH of 7.35–7.42. Animals were surface cooled to 20°C, after which cardiac arrest was produced with i.v. KCI. Dogs remained asystolic without ventilation for 1.0 (n = 4), 1.5 (n = 3), or 2.0 (n = 3) th Rescucitation was accomplished with closed-chest compression, mechanical ventilation, i.v. epinephrine and NaHCO3, and rewarming to 37°C. Postarrest recovery was maintained for 3–4 h; thereafter, the puppies underwent perfusion-fixation of their brains for pathologic analysis. Plasma glucose (control = 8.3 mmol/L) increased slightly during hypothermic cardiac arrest (+36%) but was markedly elevated at 15 min postarrest (20 mmol/L). Blood lactate (control = 1.1 mmol/L) increased almost 200% during hypothermic circulatory arrest, with a further rise to 9.0 mmol/L at 15 min postarrest. Thereafter, lactate decreased in the 1-h arrested dogs bat increased progressively in the other groups. Mean arterial blood pressure returned to baseline (73 mm Hg) by 15 min postarrest, remained stable in the 1-h dogs, but fell at 3 h to 62 and 34 mm Hg in the 1.5-and 2.0-h groups, respectively. No neuropathologic alterations were seen in puppies arrested for 1 h, whereas all pnppies arrested for 1.5 or 2 h had varying degrees of cerebral cortical and hippocampal damage. Thus, newborn dogs tolerate 1 h of hypothermic circulatory arrest without brain damage, with graded neuronal injury thereafter. The experimental model has direct clinical relevance and can be used to study mechanisms of cellular injory in brain, heart, and other organs during prolonged ischemia.

Differences in intraischemic temperature influence neurological outcome after deep hypothermic circulatory arrest in newborn dogs.

Background and Purpose Hypothermia to core temperatures ranging from 16°C to 24°C has become an established procedure to extend the “safe” interval of cardiac arrest during open heart surgery in human infants. The present experiment was designed to ascertain whether differences in core (rectal) temperature during hypothermic circulatory arrest influence the presence and extent of ischemic brain damage in newborn dogs. Methods Newborn dogs (postnatal age, 3 to 5 days) were anesthetized with halothane (4% induction; 0.5% maintenance), intubated, paralyzed, and artificially ventilated with 70% nitrous oxide/30% oxygen. Thereafter, the dogs were surface cooled with ice packs to either 16°C (n=6), 20°C (n=8), or 24°C (n=6). The dogs then were subjected to circulatory arrest for 1.75 hours by the intravenous injection of KC1, following which they were resuscitated with intravenous NaHCO3 and epinephrine, artificial ventilation, and closed chest cardiac massage. Those dogs that survived for 8 hours of recovery (n=16) underwent neurobehavioral examination followed by perfusion‐fixation of their brains for pathological analysis. Results All newborn dogs were successfully resuscitated after 1.75 hours of cardiac arrest, rewarmed to 37°C, and ultimately weaned from anesthesia and ventilatory support. Four dogs sustained secondary systemic complications with death at 4 to 7 hours. All surviving dogs remained stable, with systemic blood pressure, heart rate, arterial oxygen, and acid‐base balance within the normal, normothermic range. Of the 16 surviving dogs, all except 1 showed histological evidence of brain damage at 8 hours of recovery. Morphometric analysis of the number of necrotic neurons in the vulnerable gray matter structures showed the greatest damage to cerebral cortex at 24°C and the least damage to this structure at 16°C by either regression analysis (r=.62; P=.01) or a repeated‐measures model (P=.008). The extent of damage to the caudate nucleus was similar in the three temperature groups, while damage to the amygdaloid nucleus was greater at 24°C compared with 20°C but with no difference in the severity of damage between 20°C and 16°C. A close correlation existed between neurobehavioral deficits in the surviving dogs and the severity of damage to the cerebral cortex (r=.72; P=.001). Conclusions The findings indicate that differences in intraischemic core temperature during deep hypothermic circulatory arrest influence the severity of damage to the cerebral cortex of newborn dogs. Specifically, the lower the temperature below 24°C, the more protected the structure from ischemic injury. Furthermore, the greater the cortical damage, the more severe the neurobehavioral deficits. Such was not the case for the amygdaloid nucleus and especially for the caudate nucleus. Accordingly, differences in core temperature, even at very low levels, appear critical for optimal protection of the newborn brain during hypothermic circulatory arrest. (Stroke. 1994;25:1433‐1442.)

Cerebral Oxidative Metabolism during Hypothermia and Circulatory Arrest in Newborn Dogs

To ascertain the alterations in cerebral oxidative and energy metabolism that occur during hypothermic circulatory arrest, nitrous oxide-anesthetized, paralyzed, and artificially ventilated newborn dogs were surface cooled to 18–20±C, after which their hearts were arrested with KC1. At 10, 30, 60, and 105 min of circulatory arrest, their brains were prepared by in situ freezing for the regional analysis of glycolytic intermediates and high-energy phosphate reserves. Hypothermia alone was associated with optimal preservation of labile metabolites in brain, even in caudal brainstem and cerebellum, compared with barbiturate-anesthetized littermates. After onset of hypothermic circulatory arrest, glucose decreased progressively in cerebral cortex, caudate nucleus, hippocampus, and subcortical white matter to negligible levels by 30 min. Pyruvate increased transiently (+50%) at 10 min, whereas lactate increased and plateaued (10–11 mmol/kg) at 30 min. The disproportionate increases in pyruvate and lactate resulted in a progressive rise in the lactate/pyruvate ratio. Phosphocreatine fell precipitously to <0.5 mmol/kg in all structures, with a preservation of ATP for the first 10 min of cerebral ischemia. Thereafter, ATP decreased to <0.1 mmol/kg in cerebral cortex and between 0.1 and 0.2 mmol/kg in caudate nucleus, hippocampus, and white matter. Total adenine nucleotides (ATP + ADP + AMP) were partially depleted by 30 min in the gray matter structures but were unchanged from control for 60 min in white matter. The findings showed a direct correlation between preservation of cerebral energy stores during hypothermic circulatory arrest and the selective resistance of subcortical white matter to ischemic damage. However, no such correlation existed for the hippocampus, in which other factors must influence the resistance of this structure to ischemic injury during hypothermia.

A quality improvement project to reduce hypothermia in infants undergoing MRI scanning

BackgroundHypothermia prevention strategies during MRI scanning under general anesthesia in infants may pose a challenge due to the MRI scanner’s technical constraints. Previous studies have demonstrated conflicting results related to increase or decrease in post-scan temperatures in children. We noted occurrences of post-scan hypothermia in anesthetized infants despite the use of routine passive warming techniques.ObjectiveThe aims of our quality improvement project were (a) to identify variables associated with post-scan hypothermia in infants and (b) to develop and implement processes to reduce occurrence of hypothermia in neonatal intensive care unit (NICU) infants undergoing MRI.Materials and methodsOne hundred sixty-four infants undergoing MRI scanning were prospectively audited for post-scan body temperatures. A multidisciplinary team identified potential variables associated with post-scan hypothermia and designed preventative strategies: protocol development, risk factor identification, vigilance and use of a vacuum immobilizer. Another audit was performed, specifically focusing on NICU infants.ResultsIn the initial phase, we found that younger age (P = 0.002), lower weight (P = 0.005), lower pre-scan temperature (P < 0.01), primary anesthetic technique with propofol (P < 0.01), advanced airway devices (P = 0.02) and being in the NICU (P < 0.01) were associated with higher odds for developing post-scan decrease in body temperature. Quality improvement processes decreased the occurrence of hypothermia in NICU infants undergoing MRI scanning from 65% to 18% (95% confidence interval for the difference, 26-70%, P < 0.001).ConclusionSeveral variables, including being in the NICU, are associated with a decrease in post-scan temperature in infants undergoing MRI scanning under sedation/general anesthesia. Implementation of strategies to prevent hypothermia in infants may be challenging in the high-risk MRI environment. We were able to minimize this problem in clinical practice by applying quality improvement principles.

Collaborative Quality Improvement for Neonatal Intensive Care. |[dagger]| 1026

We evaluated the effects of collaborative quality improvement and benchmarking on two specific neonatal outcomes in a study of 10 neonatal intensive care units (NICUs) in the Vermont Oxford Network. Multidisciplinary teams of neonatologists, nurses, quality coaches and administrators from the 10 NICUs worked closely together in facilitated large group meetings and conference calls beginning in January 1995. They chose specific clinical improvement goals, performed analyses of their care processes, evaluated the published evidence and performed site visits to project NICUs and others in the Network with superior performance. Reducing nosocomial infection for infants 501 to 1500 grams was the goal chosen by 6 NICUs; reducing chronic lung disease or death for infants 501 to 1000 grams was chosen by the other group of 4 NICUs. The groups developed lists of “potentially better practices” and each NICU implemented selected practices by the beginning of 1996. Outcomes were monitored with the Network Database. The project was evaluated by comparing outcomes in 1994 (pre-intervention) to those in 1996(post-intervention) and by comparing changes in outcomes at the project NICUs with those at the other 66 North American NICUs participating in the Vermont Oxford Network from 1994 to 1996. The rate of infection with coagulase negative Staphylococcus (cnS) decreased at the 6 infection group NICUs from 22.0% to 16.6% (p=0.007); infections with other pathogens did not change significantly. The 5.4% decline in cnS at the 6 NICUs was greater than the 0.8% decline seen at the 66 comparison NICUs (p=0.026). At the 4 NICUs in the chronic lung disease group, the percentage of infants receiving supplemental oxygen at 36 weeks post-conceptional age decreased from 43.5% to 31.5%(p=0.03); mortality did not change significantly. The 12% decline in oxygen at 36 weeks at the 4 NICUs was greater than the 0.1% decline seen at the 66 comparison NICUs (p=0.045). The magnitude of improvement in both cnS infection and oxygen at 36 weeks varied significantly among the NICUs. We conclude that collaborative quality improvement has the potential to improve the outcomes of neonatal intensive care.