Elizabeth E Nardis

Blood-Brain Barrier Permeability to Lactic Acid in the Newborn Dog: Lactate as a Cerebral Metabolic Fuel

The arteriovenous difference (A-V) method was utilized to assess the permeability of the blood-brain barrier to lactic acid in paralyzed and artificially ventilated newborn dogs. A femoral artery and the sagittal sinus were cannulated to sample arterial and cerebral venous blood simultaneously for measurements of glucose and lactate during normoglycemia, normoglycemia and hyperlactatemia, insulin-induced hypoglycemia, or hypoglycemia and hyperlactatemia. During normoglycemia, arterial lactate concentrations remained less than 2 mmoles/liter for up to 2 h; mean A-Vlactate was essentially zero. Arterial lactate increased up to 8 mmoles/liter during intravenous infusion of neutralized 10 mM L-lactic acid. During hyperlactatemia, the A-Vlactate was directly proportional to the arterial concentration of the metabolite, a finding which is consistent with transport into brain either by simple diffusion or via a carrier with saturability greater than 8 mmoles/liter. During hypoglycemia (mean arterial glucose = 27 mg/dl), A-Vglucose was reduced by 71% with a significant increase in A-Vlactate at an arterial lactate level of 1.3 mmoles/liter. Hyperlactatemia combined with hypoglycemia resulted in A-Vlactate which was 2–3 fold greater than during normoglycemia at similar arterial lactate concentrations. Brain/blood lactate ratios declined by 83% during hypoglycemia compared with normogly-cemic ratios, indicating that, once in brain, lactic acid was actively consumed for oxidative processes. These experimental observations may have clinical relevance in newborn human infants when concentrations of lactate in blood often approach or even exceed those of glucose.Speculation: Lactic acid, which is elevated in blood immediately following birth, may enter the perinatal brain to supplement glucose as a metabolic fuel.

The accuracy and precision of an open-circuit system to measure oxygen consumption and carbon dioxide production in neonates.

ABSTRACT: We measured the oxygen consumption, carbon dioxide production, and respiratory quotient during the combustion of a known mass of anhydrous ethanol and methanol to assess the accuracy of an open-circuit flowthrough system. Continuous measurements were made of the mass of alcohol burned, the velocity of gas flow through the apparatus, and simultaneous measurements of the fractional concentration of oxygen, carbon dioxide and nitrogen of the inlet and outlet gas using paramagnetic oxygen analyzer, infrared carbon dioxide meter, and mass spectrometer. Standard respiratory and stoichiometric equations were used to calculate the oxygen consumption, carbon dioxide production and RQ for the mass of absolute alcohol combustion per unit time. In a series of 12 consecutive laboratory experiments (on 7 days), the measured values of gas exchange (similar to the rate of respiratory gas exchange by an infant of 1-4 kg) were in agreement within 5% of the true values for ethanol and methanol combustion, confirming the validity of the open-circuit method. The paramagnetic oxygen analyzer and the mass spectrometer gave similar oxygen consumption results and differed very little when the rate of absolute alcohol combustion was used to quantify the accuracy of the complete measurement system. A positive measurement error was observed for the carbon dioxide production results from both the IR meter and mass spectrometer, with the result that the respiratory quotient measurements were 3.4-4.7% higher than the true value. The mass spectrometer gave more precise oxygen consumption results, whereas smaller variance of carbon dioxide production measurements was observed using the infrared CO2 meter. The sources of error and methods to reduce the overall system error were considered. By using a rigorous set of calculations we showed that the rate of combustion of a known mass of absolute alcohol was a suitable laboratory method for validation of respiratory gas exchange measurements made in the neonate.

Day-to-Day Energy Expenditure Variability in Low Birth Weight Neonates

ABSTRACT: We estimated the metabolic rate of 13 low birth weight infants over a 9-day period, using indirect calorimetry in conjunction with serial measurements of oxygen consumption, carbon dioxide production, and total urinary nitrogen excretion. The mean percent error for oxygen consumption and carbon dioxide production measurements (determined by alcohol combustion experiments) assignable to the open-circuit system was 0.4 and 3.8%, respectively. Error in the total urinary nitrogen excretion measurement was <1% by the Kjeldahl technique. In the clinical setting, however, the range of deviation of measured oxygen consumption, carbon dioxide production and total urinary nitrogen excretion was ±12, 12, and 15% of the mean value respectively for an individual patient under standardized controlled conditions. The variability of metabolic rate between infants may be as much as 76%. Factors that had a small effect on metabolic rate were difficult to detect because of the variability inherent in the short-term measurement of metabolic rate. It was virtually impossible to control the sources of variation in the resting metabolism of low birth weight neonates over extended experimental periods. Day-to-day variations in resting energy expenditure may explain, in part, the widely different growth rates of premature infants receiving similar caloric intakes.

Cerebral Metabolism during Hypoglycemia and Asphyxia in Newborn Dogs

The cerebral metabolic responses to perinatal hypoglycemia (blood glucose less than or equal to 1 mmol/l) combined with asphyxia were studied in paralyzed, lightly anesthetized newborn dogs. No major differences in heart rate, blood pressure or arterial acid-base balance between control and hypoglycemic animals occurred either prior to or during asphyxia. The electroencephalogram, unaltered by hypoglycermia alone, became isoelectric at the same intervals in both groups following respiratory arrest. Intravenous carbon black infusion at 5 min of asphyxia demonstrated no relationship between blood glucose level and cerebral perfusion (p > 0.05), whereas a positive correlation did exist between systemic blood pressure and cerebral perfusion (p < 0.01). During asphyxia, anaerobic glycolysis in brain was less enhanced in hypoglycemic dogs, resulting in a more rapid exhaustion of high-energy phosphate reserves (phosphocreatine, ATP and ADP). Thus, the cerebral metabolic responses to asphyxia superimposed upon hypoglycemia were the direct consequence of insufficient cerebral glucose stores coupled with deficient circulating glucose to brain. These metabolic disturbances were no more the result of cerebral ischemia than that which occurs during asphyxia alone. The findings also suggest that systemic physiological monitoring may be an inadequate means of appraising cerebral homeostasis during combined hypoglycemia ad hypoxia.

The effect of intraventricular blood on cerebral blood flow in newborn dogs.

ABSTRACT.: We investigated the effect of intraventricular blood on cerebral blood flow in the newborn puppy by infusing autologous blood into the lateral ventricle to produce and maintain an intraventricular pressure of approximately 15 mm Hg (mild insult), 30 mm Hg (moderate insult), or 50 mm Hg (severe insult) for 20 min. As the intraventricular pressure increased, flow decreased progressively to all areas of the brain directly proportional to the cerebral perfusion pressure. On return of the intraventricular pressure to baseline level, cerebral blood flow normalized despite the continued presence of a large amount of blood within the lateral ventricles. We suggest that blood within the ventricular system can result in a significant acute reduction of cerebral blood flow which appears to be mediated through the effect on cerebral perfusion pressure.

A WARMING MATTRESS FOR PREMATURE INFANTS

We measured temperatures and metabolic rate of healthy infants (gestational age 28-33 wks and postnatal age 2-26 days) in contact with a heated water mattress. Infants were randomized with/without the mattress ≥8 hrs in a single wall forced convection incubator, unrestrained, diapered and supine. Tmattress (35.2±.1°C) was regulated by continuous circulation of H2O through a thermostatically controlled bath. Mid-inc air temp (Ta) was within the thermoneutral range. No humidity was added to inc. Heating effects measured q half hrly: skin temp at 6 sites → mean skin temp (Ts), esophageal temp (Te), heart rate (HR), resp rate (RR) and O2 consumption (VO2) at the end of each period. N=10 patients. Results(mean±SD): No mattress vs mattress p value by paired t-test: Ta (°C) 32.4±1.3 vs 31.6±0.9 p<0.05; Ts (°C) 35.3±0.3 vs 36.3±0.3 p<0.01; Te (°C) 36.5±0.3 vs 37.2±0.4 p<0.01; HR (beats/min) 155±8 vs 161±10 p<0.01; RR (breaths/min) 41±6 vs 48±8 p<0.01; VO2 (ml/kg/min) STPD 5.33±1.4 vs 4.94±1.55 NS. Results indicate that heat storage occurred due to alteration of balance between body heat production and losses. To determine the rate of dry (sensible) heat exchange we used a metabolic simulator, an electrically-heated 10 cm diam sphere. At a representative incubator Ta of 31.5°C and simulator Ts of 35°C, the dry heat loss was reduced from 60 W/m2 to 35 W/m2 on the heated pad. This was brought about by a combination of heat conduction to the simulator and decreased radiation losses from the simulator to the surrounding mattress.

1336 INTRAVENTRICULAR BLOOD AND CEREBRAL PERFUSION IN NEWBORN DOGS

We previously reported that blood in the lateral ventricle of the newborn dog acutely impairs cerebral blood flow (CBF). The current study sought to clarify the mechanism for these changes in imperfusion. For the first two groups of puppies autologous blood was infused into the lateral ventricle to maintain an intraventricular pressure (IVP) of approximately 50 mmHg for 20 minutes; CBF was determined at the end of the infusion in one of these groups and following return of the IVP to near baseline level in the other (mean time-25 rain). For a third group of puppies normal saline (NS) was infused for 20 min. prior to CBF determination and a fourth group served as controls. CBF was measured by [14C] iodoantipyrine autoradiography.The transient decrease in CBF following blood infusion appears to be due to the elevated IVP and reduced perfusion pressure. The reason mean arterial blood pressure (MABP) did not increase to maintain CBF following blood infusion as seen following NS infusion is not clear.

1448 GROWTH UNDER RADIANT WARMER (RW)

Based on the hypothesis that the thermal demands of an open RW as distinct from convection incubator (CI), may be responsible for a reduction in the metabolizable energy a premature infant has available for growth, we evaluated the relation between environment, metabolism and growth of 13 LBW infants on a given level of food intake. During the 9 day metabolic balance, infants (wt. 1319±149g, age 25±12d, concep age 34±3wk, m±SD) were randomized to RW (servocontrolled to maintain Tabd=36.5°C) and CI (Tinc within thermoneutral zone) each serving as his own control. Energy utilization and substrate oxidation rates (VO2, VCO2, indirect calorimetry), protein utilization (urine N), protein degradation (urine 3-methylhistidine) and sympathomedullary response (cathecholamines) were measured. Metabolic rate (MR) was 10% higher for infants under RW (2.42±.42 vs 2.19±.28kcal/kg/hr, m± SD, p=.05 vs CI). The significant reduction (p=.03) in nonprotein RQ for infants in CI (0.99 vs 1.07) indicates ↑ lipogenesis under RW. Protein utilization accounted for ∼ 3.5% of energy expended in both conditions. Urine 3MH, epinephrine, norepinephrine, volume and SG did not differ significantly from control conditions. Increments of weight, length, head circumference, midarm muscle circumference, dynamic skin fold thickness and body temperatures were similar. Under RW: 1) rate of energy utilization increases and is associated with shift to lipogenesis, 2) growth is not compromised acutely although methods of assessment may be too insensitive, 3)↑ MR is not mediated by catecholamine response to cold stress but rather by other environmental and/or behavioral causes.

THE EFFECT OF INTRAVENTRICULAR HEMORRHAGE (IVH) ON REGIONAL CEREBRAL BLOOD FLOW (rCBF) IN NEWBORN DOGS

To further understand cerebral hemodynamics associated with IVH we measured rCBF in newborn dogs following infusion of blood into the lateral ventricle. The puppies were anesthetized, tracheostomized, paralyzed, ventilated and a cannula placed through the skull into the lateral ventricle. Cardiac and respiratory variations of the pressure tracing verified proper cannula position. Once stabilized, 3 cc/kg of autologous blood were infused through the ventricular cannula over 20 min at which time rCBF was determined by [14C]iodoantipyrine autoradiography. Control animals underwent the identical protocol except for the infusion of blood. Brain sectioning revealed the presence of blood throughout the ventricular system and subarachnoid space.The reason for the acute decrease in gray and white matter CBF is unclear but is probably related to increased intracranial pressure (ICP) and, in part, to the modest decrease in PaCO2. Nevertheless, this secondary cerebral ischemia following induced IVH may be relevant to the neurological morbidity seen in the human newborn.

1577 CEREBRAL METABOLIC RESPONSES TO ASPHYXIA AND RECOVERY IN NEWBORN DOGS

We used the arterio-venous (A-V) difference method to assess metabolic restoration of the brain following asphyxia in newborn dogs. Brain metabolites and energy reserves were analyzed (after in situ freezing) during and following the asphyxia produced by respiratory arrest for 8 min. pHa 6.9, paCO2 96, paO2 10.These findings indicate that during asphyxia anerobic metabolism exceeds glucose availability leading to depletion of ATP and P ∼ Cr. During reoxygenation the increased pyruvate at 10 min, positive A-Vlact and rebound in brain glucose indicate that lactate becomes the preferred substrate for oxidative processes during recovery.