Jan Goddard-Finegold

Effects of perfusion mode on regional and global organ blood flow in a neonatal piglet model

BACKGROUND Organ injury (brain, kidney, and heart) has been reported in up to 30% of pediatric open heart surgery patients after conventional hypothermic non-pulsatile cardiopulmonary bypass (CPB) support with or without deep hypothermic circulatory arrest (DHCA). The effects of pulsatile (with a Food and Drug Administration approved modified roller pump) versus non-pulsatile perfusion on regional and global cerebral, renal, and myocardial blood flow were investigated during and after CPB with 60 minutes of DHCA in a neonatal piglet model. METHODS Piglets, mean weight 3 kg, were used in both pulsatile (n = 7) and non-pulsatile (n = 7) groups. After initiation of CPB, all animals were subjected to hypothermia for 25 minutes, reducing the rectal temperatures to 18 degrees C, 60 minutes of DHCA followed by 10 minutes of cold reperfusion and 40 minutes of rewarming with a pump flow of 150 mL/kg/min. During cooling and rewarming, alpha-stat acid-base management was used. Differently labeled radioactive microspheres were injected pre-CPB, on normothermic CPB, pre-DHCA, post-DHCA, and after CPB to measure the regional and global cerebral, renal, and myocardial blood flows. RESULTS Global cerebral blood flow was significantly higher in the pulsatile group compared to the non-pulsatile group at normothermic CPB (100.4 +/- 6.3 mL/100 gm/min versus 70.2 +/- 8.1 mL/100 gm/min, p < 0.05) and pre-DHCA (77.2 +/- 5.2 mL/100 gm/min versus 56.1 +/- 6.7 mL/100 gm/min, p < 0.05). Blood flow in cerebellum, basal ganglia, brain stem, and right and left cerebral hemispheres had an identical pattern with the global cerebral blood flow. Renal blood flow appeared higher in the pulsatile group compared to the non-pulsatile group during CPB, but the results were statistically significant only at post-CPB (94.8 +/- 9 mL/100 gm/min versus 22.5 +/- 22 mL/100 gm/min, p < 0.05). Pulsatile flow better maintained the myocardial blood flow compared to the non-pulsatile flow after CPB (316.6 +/- 45.5 mL/100 gm/min versus 188.2 +/- 19.5 mL/100 gm/min, p < 0.05). CONCLUSIONS Pulsatile perfusion provides superior vital organ blood flow compared to non-pulsatile perfusion in this model.

Cognitive and adaptive behavior profiles of children with Angelman syndrome.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by maternal deficiency of the UBE3A gene that encodes E6‐AP ubiquitin‐protein ligase. Expression of the UBE3A gene from the maternal chromosome is essential to prevent AS. AS is characterized by severe mental retardation, ataxia, and a defined behavioral pattern characterized mainly by happy/sociable disposition. This study used the Bayley Scales of Infant Development and the Vineland Adaptive Behavior Scales to examine the cognitive abilities and adaptive behavior of children (n = 20) with the four known molecular classes of AS, including patterns of strengths and weaknesses across adaptive behavior domains, and the relationship between adaptive behavior and overall cognitive abilities. Cognitive skills fell within the severe to profound range of mental deficiency. Differences in cognitive skills according to genetic subtype only partially supported previous research and suggest that there is overlap in abilities across genetic subtypes of AS. Adaptive behavior skills were also significantly delayed, with participants demonstrating a significant strength in socialization, and a weakness in motor skills. Strong, positive correlations emerge between cognitive ability scores and adaptive behaviors scores. These results provide further delineation of a cognitive/behavioral phenotype in AS.

Cerebral hypoxia-ischemia increases microsomal iron in newborn piglets

The primary cause of neurologic impairment in newborn infants is hypoxic-ischemic injury. Studies of the mechanisms involved in the damaging effects of hypoxia-ischemia and reperfusion in brain tissue indicate significant contributions from reactive oxygen species, with the loss of homeostatic control of intracellular iron an important determinant of oxidant-mediated damage. We investigated the effects of cerebral hypoxiaischemia and reperfusion on the redistribution of nonheme iron in newborn piglets. Anesthetized newborn piglets were subjected to reductions in cerebral blood flow by phlebotomy and cervical cuff compression. Control animals were sham-operated. Subcellular fractions were isolated from brain tissue homogenates by differential centrifugation, and nonheme iron contents of these fractions were measured with ferene-S. Iron contents in the homogenates were not altered. However, iron contents of the microsomal fractions of animals subjected to 30 minutes of hypoxia-ischemia increased from 0.517±0.053 to 0.930±0.061 nmol/mg protein (p<0.01); 120 minutes of reperfusion caused no further changes. This translocation of iron may be linked to oxidative alterations of brain proteins, which we investigated by detection of dinitrophenylhydrazine-derivitized protein carbonyls, which are characteristic of iron-catalyzed oxidation reactions.

Barbiturates and hyperventilation during intracranial hypertension

OBJECTIVE The purpose of this study was to determine the effect of hyperventilation alone and hyperventilation plus barbiturate therapy on intracranial pressure, global and regional cerebral blood flow rates, cerebrovascular resistance, and cerebral perfusion pressure in adult dogs with and without intracranial hypertension induced by epidural balloon. DESIGN Prospective, randomized, controlled study. SETTING An animal laboratory of a university hospital. Four sequential global and regional cerebral blood flow determinations were made in each animal during monitoring of heart rate and systemic arterial pressure, during respiratory control and arterial blood gas monitoring, intracranial pressure monitoring, and with or without inflation of an epidural balloon catheter. SUBJECTS Acute mongrel dogs obtained from the Baylor Center for Comparative Medicine. Five groups of animals were studied. In group 1, the response to hyperventilation was assessed in dogs without increased intracranial pressure. In group 2, the response to hyperventilation was assessed in animals with acute intracranial hypertension. In group 3, the response to hyperventilation plus barbiturate therapy was assessed in dogs without increased intracranial pressure. In group 4, the response to hyperventilation plus barbiturate therapy was assessed in dogs with acute increased intracranial pressure. In group 5, a group of dogs with increased intracranial pressure was treated with neither hyperventilation nor barbiturates. INTERVENTIONS Hyperventilation, hyperventilation plus barbiturate therapy, or no interventions were studied in these experimental paradigms. MEASUREMENTS AND MAIN RESULTS The main outcome measures were changes in intracranial pressure and/or changes in regional or total cerebral blood flow. A significant decrease in intracranial pressure and cerebral blood flow rate was produced by hyperventilation alone in groups with intracranial hypertension. Combined hyperventilation and barbiturate therapy resulted in a significant further decrease in cerebral blood flow rate in animals with normal and increased intracranial pressure, but no greater decrease in intracranial pressure was seen compared with treatment with hyperventilation alone. Cerebral perfusion pressures remained normal despite significant decreases in cerebral blood flow rates. CONCLUSIONS These studies suggest that barbiturate administration in this model of intracranial hypertension was no more effective in reducing increased intracranial pressure than hyperventilation alone.

Review Article: Understanding and Preventing Perinatal, Intracerebral, Peri- and Intraventricular Hemorrhage

Antenatal anticipation of problem pregnancies and improvements in resuscitation and care of newborns have led to increasing survival of babies born prematurely. Nevertheless, the potential for neurologic handicaps is significant in this population of children, and the prevention of intracerebral, peri- and intraventricular hemorrhages and associated brain lesions remains a high priority. In this review, we consider (1) the clinical problem of periventricular, intraventricular hemorrhage; (2) means of diagnosis; (3) the EEG and periventricular, intraventricular hemorrhage; (4) sequelae; (5) hypotheses of pathogenesis; (6) experimental approaches to understanding periventricular, intraventricular hemorrhage; (7) agents being tested for use in preventing hemorrhage; and (8) future areas for research toward the prevention of hemorrhage and other neonatal brain lesions. (J Child Neurol 1987;2:170-185).

Global and regional cerebral blood flow in neonatal piglets undergoing pulsatile cardiopulmonary bypass with continuous perfusion at 25°C and circulatory arrest at 18°C

To investigate the influence of hypothermic cardiopulmonary bypass (HCPB) at 25°C and circulatory arrest at 18°C on the global and regional cerebral blood flow (CBF) during pulsatile perfusion, we performed the following studies in a neonatal piglet model. Using a pediatric physiologic pulsatile pump, we subjected six piglets to deep hypothermic circulatory arrest (DHCA) and six other piglets to HCPB. The DHCA group underwent hypothermia for 25 min, DHCA for 60min, cold reperfusion for 10 min, and rewarming for 40 min. The HCPB group underwent 15 min of cooling, followed by 60 min of HCPB, 10min of cold reperfusion, and 30 min of rewarming. The following variables remained constant in both groups: pump flow (150 ml/kg/min), pump rate (150 bpm), and stroke volume (1 ml/kg). During the 60-min aortic crossclamp period, the temperature was kept at 18°C for DHCA and at 25°C for HCPB. The global and regional CBF (ml/100g/min) was assessed with radiolabeled microspheres. The CBF was 48% lower during deep hypothermia at 18°C (before DHCA) than during hypothermia at 25°C (55.2± 14.3 ml/100 g/min vs 106.4±19.7 ml/100 g/min; p < 0.05). After rewarming, the global CBF was 45% lower in the DHCA group than in the HCPB group 48.3±18.1 ml/100 g/min vs (87±35.9 ml/100 g/min; p<0.05). Fifteen minutes after the termination of CPB, the global CBF was only 25% lower in the DHCA group than in the HCPB group (42.2±20.7 ml/100 g/min vs 56.4±25.8 ml/100 g/min; p=NS). In the right and left hemispheres, cerebellum, basal ganglia, and brain stem, blood flow resembled the global CBF. In conclusion, both HCPB and DHCA significantly decrease the regional and global CBF during CPB. Unlike HCPB, DHCA has a continued negative impact on the CBF after rewarming. However, 15 min after the end of CPB, there are no significant intergroup differences in the CBF.

Correlation of near infrared spectroscopy cerebral blood flow estimations and microsphere quantitations in newborn piglets

We compared cerebral blood flow (CBF) estimated using transmission mode near infrared spectroscopy (NIRS) and a modification of the Fick principle with CBF quantitations by radioactive microspheres (MSs) in newborn piglets. Thirteen piglets were studied during steady state, ischemia, and during two reflow periods. NIRS and MS flows were not significantly different during any measurement period. NIRS flows were compared to total brain blood flows and to regional brain blood flows quantitated with MSs and correlated best with temporal cortical flows. Linear regression analysis of the NIRS flows plotted against MS-quantitated temporal cortical flows showed r = 0.71. Thus, CBFs obtained with NIRS were not significantly different from, showed the same directional changes, and correlated acceptably with flows quantitated by MSs.

Brain Blood Flow Responses to Indomethacin during Hemorrhagic Hypotension in Newborn Piglets

Indomethacin has been shown to reduce cerebral blood flow and cerebral blood flow velocities in newborn infants and animals of various species. To answer the question of whether there may be a compromise of cerebral perfusion in hypotensive infants who have been treated with indomethacin, cerebral blood flow and cerebral vascular resistance were determined in 10 control and 16 indomethacin-treated 1-day-old piglets during (1) steady state conditions; (2) 10 min after the administration of saline or a 0.2-mg/kg dose of indomethacin; (3) 1 h after saline or indomethacin administration, and (4) 10 min after induction of moderate hemorrhagic hypotension. Mean arterial blood pressures increased immediately after the infusion of indomethacin in the experimental group. Cerebral blood flows did not change throughout the study despite hemorrhagic hypotension in controls; cerebral blood flows were significantly decreased 10 min after indomethacin infusion in the experimental animals. However, total and regional cerebral blood flows were not further decreased in the presence of moderate hypotension. Cerebral vascular resistance increased 10 min after indomethacin infusion but returned to steady state 1 h following the indomethacin dose. These results suggest that indomethacin lowers baseline cerebral blood flow, but does not impair cerebrovascular regulatory responses during acute, moderate hemorrhagic hypotension in the newborn piglet.

Phenobarbital and Cerebral Blood Flow during Hypotension in Newborn Pigs

ABSTRACT: Phenobarbital sodium (PhS) has been used in anticonvulsant concentrations in premature newborns in attempts to prevent peri- and intraventricular hemorrhages (PIVH). Its effectiveness in preventing PIVH in clinical situations is still uncertain; however, PhS has reduced PIVH after hypertension in newborn beagles, and it has lowered cerebral blood flow (CBF) during hypertension in newborn beagles and piglets. We hypothesized that PhS might reduce CBF during systemic hypotension. Twelve control and 12 PhS-treated piglets (1 to 2 d old) were used for microsphere determinations of CBF during 1) steady state; 2) 30 min after PhS (treatment group) or saline infusion (controls); and 3 and 4) during two levels of graded hypotension. Mean arterial blood pressure (MABP) was 61 ± 13 (SD) mm Hg (controls) and 57 ± 13 (SD) mm Hg (PhS) during steady state. Thirty min after the PhS or saline infusion, MABP and CBF remained unchanged in both groups. CBF during hypotension at MABP of 41 ±5 (SD) mm Hg was significantly higher in controls than was CBF at MABP of 39 ± 6 (SD) mm Hg in the PhS-treated group (p = 0.044); CBF in the two groups during the second hypotensive phase was not significantly different. However, LOWESS regression suggested that the CBF from the controls dropped as the arterial pressure decreased to less than 37 mm Hg, whereas PhS treatment lowered CBF during hemorrhagic hypotension compared with controls at blood pressures greater than 37 mm Hg but did not lower CBF further at lower systemic blood pressures. This suggests that PhS would not, by itself, cause ischemia at blood pressures near the lower limit of autoregulation.

Brain Vasoactive Effects of Phenobarbital during Hypertension and Hypoxia in Newborn Pigs

ABSTRACT: Phenobarbital in anticonvulsant concentrations has been shown to lower cerebral blood flow (CBF) during hypertension and to reduce the incidence of intraventricular hemorrhage in newborn beagles after hypertensive insult. We proposed that hypoxic dilatation of brain blood vessels might alter the effect of phenobarbital (PBS) on blood flow during hypertension. Thus, in 14 control and nine PBS-treated 1– to 2-d-old newborn piglets, the radioactive microsphere technique was used to determine CBF during 1) steady state (SS), 2) hypertension (HT), and 3) HT plus hypoxia of 5 min duration. In seven controls and in four PBS-treated piglets, CBF was also determined during recovery from hypoxia. PBS was infused after SS in a 20-mg/kg dose, and serum levels were obtained 30 min later. Blood pressures were not significantly different between groups when compared during SS, HT, hypoxia, and recovery. Similarly, pH, Po2, and Pco2 were not significantly different between groups when compared during normoxia and hypoxia, and hematocrits were maintained by transfusions after reference sample withdrawals. CBF in control animals increased significantly during HT and remained significantly higher than SS values throughout the 5 min of hypoxia and into the recovery period. In PBS-treated piglets, however, there was no significant increase in CBF during HT. Blood flows also stayed at SS levels during HT plus 5 min hypoxia and recovery from hypoxia. Thus, in newborn piglets, PBS lowered CBF during HT. Furthermore, this blood flow lowering effect persisted during hypoxia, preventing compensatory increases in CBF that might have otherwise occurred. Although this may explain why PBS might be useful in preventing hemorrhages that result during hyperemia, further studies will determine if PBS pretreatment results in reduced oxygen delivery to brain tissues during hypoxia.