Linda M Sacks

Effect of sustained pharmacologic vitamin E levels on incidence and severity of retinopathy of prematurity: A controlled clinical trial

The incidence and severity of retinopathy of prematurity (ROP) as affected by vitamin E prophylaxis at pharmacologic serum levels (5 mg/dl) were evaluated in a double-masked clinical trial of infants with a birth weight less than or equal to 2000 gm or a gestational age less than or equal to 36 weeks. The infants were enrolled by age 5 days and randomly assigned to receive parenterally administered, and later orally administered, free alpha-tocopherol (vitamin E) or its placebo. Study medication was continued until retinal vascularization was complete or active ROP had subsided, except in infants with a diagnosis of severe disease, in whom vitamin E was substituted for study medication. Acute ROP data were collected on 755 infants. Logistic regression analysis, with control for immaturity, oxygen exposure, and other illness risk factors, showed a decrease in incidence of ROP in vitamin E-treated infants (p = 0.003, all infants; p = 0.035, infants weighing less than or equal to 1500 gm at birth). Among the 424 infants weighing less than or equal to 1500 gm at birth, the age at enrollment influenced treatment effect (age day 0 to 1, p = 0.006 (n = 288) vs age day 2 to 5, p greater than 0.1 (n = 136]. Overall, 77.6% of infants with ROP had mild disease. Moderate to severe ROP was confined to infants weighing greater than or equal to 1500 gm at birth (25 given placebo, 25 given vitamin E), with progression to severe disease in nine placebo-treated versus three vitamin E-treated infants (p = 0.048). The incidence of severe ROP per se was not significantly decreased (all birth weights, p = 0.086; less than or equal to 1500 gm birth weight, p = 0.080); the sample size was too small, however, to assess this end point adequately. An increased incidence of sepsis and late-onset necrotizing enterocolitis was found among vitamin E-treated infants weighing less than or equal to 1500 gm at birth who received study medication for greater than or equal to 8 days (p = 0.006). Because most ROP is mild in degree and regresses completely, the risk/benefit ratio of pharmacologic prophylaxis for ROP is unfavorable. Treatment of moderate and severe ROP with vitamin E above physiologic serum levels (greater than 3 mg/dl) appears promising and should be further investigated. The interpretation of cicatricial outcome was confounded by the small number of patients involved and by subsequent treatment of severe ROP in placebo-treated infants with vitamin E.

Cerebral Metabolic Response and Mitochondrial Activity following Insulin-Induced Hypoglycemia in Newborn Lambs

We evaluated the newborn lambs cerebral cellular activity and metabolism following acute insulin-induced hypoglycemia. Eleven animals received an insulin bolus followed by a continuous infusion to maintain a plasma glucose of 1 mM/l for 2 h, while 8 other animals received an equivalent dose of saline. Following the induction of hypoglycemia, the animals became quiet and transient seizures were observed in 3 animals. A significant increase in heart rate (p less than 0.01), and a decrease in arterial PaCO2 at 30 min (p less than 0.01), and pH at 2 h (p = 0.02), following hypoglycemia, were observed in the experimental group. Hypoglycemia did not significantly alter the cerebral blood flow, mitochondrial respiratory control ratio or the state-3 activity. The cerebral arteriovenous difference (CAVD) for oxygen did not change, while the glucose CAVD was significantly reduced from 0.47 +/- 0.21 to 0.24 +/- 0.16 mM/l (p less than 0.05) at the end of the hypoglycemia period, suggesting consumption of alternate substrates of energy by the brain. Insulin-induced hypoglycemia was associated with a significant increase in arterial lactate (p less than 0.01), and a significant correlation (p less than 0.01) between arterial and CAVD for lactate and beta-hydroxybutyrate (BOB) was observed. Cerebral consumption of alternate substrates of energy was inconsistent, and only observed for lactate in 5 and for BOB in 3 experimental animals following hypoglycemia. These data indicate that the newborn lambs cerebral cellular activity is not affected by the degree of hypoglycemia achieved in these studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Red cell glycolytic intermediates and adenosine triphosphate in preterm infants on the first day of life.

ABSTRACT: Red cell glycolytic intermediates and ATP were evaluated in 47 appropriate for gestational age preterm infants on the 1st day of life who were divided into three groups on the basis of gestational age: 28-30, 31- 33, and 34-36 wk. The results were compared to those previously obtained in term infants. The concentrations of glucose-6-phosphate, total triose phosphates, and ATP were significantly higher than in term infants but appeared to be appropriately elevated for the young mean age of the red cell population. The concentration of red cell 2,3- diphosphoglycerate (2,3-DPG) was significantly decreased when compared to term infants and was lowest at 28-30 wk gestation. The content of red cell 3-phosphoglycerate was increased in term infants and was inappropriately elevated for the age of the red cell population at 28-30 wk gestation. This pattern of glycolytic intermediates was suggestive of a young red cell population metabolizing at an increased glycolytic rate with increased flow through the phosphoglycerate kinase step rather than the 2,3-DPG bypass in “normal” preterm infants. Two preterm infants of 28-30 wk gestation with low red cell intracellular pH were also evaluated and had markedly decreased concentrations of red cell 2,3-DPG and ATP and all phosphorylated intermediates distal to the phosphofructokinase reaction, indicative of a cross-over at the phosphofructokinase step secondary to acidosis. These studies demonstrate that the “normal” preterm infant has a decreased concentration of red cell 2,3-DPG in the steady state and in the presence of acidosis additional red cell metabolic perturbations occur which lead to a further fall in red cell 2,3- DPG and a decrease in the concentration of red cell ATP.

866 RELATIVE EFFECT OF BLOOD OXYGEN (O2) TRANSPORT CHARACTERISTICS ON OPTIMAL OXYGEN DELIVERY TO THE TISSUES

The present study investigates the relative importance of altering O2 content and/or hemoglobin O2 affinity (P50) in changing cardiac output (C.O.) and O2 delivery to the tissues. 18 newborn (NB) lambs were divided into 3 groups. Blood gases, [Hb], P50 (mm Hg), regional blood flow (ml/min/100g tissue) and C.O. (ml/min/kg) were measured before and 2 hrs after alteration of O2 affinity and/or content by means of exchange transfusing the lambs with fetal or maternal blood of varying Hct. O2 content was increased 38% in Gr 1 (n=6) with no change in P50. O2 content and P50 were increased 9% and 32% in Gr 2 (n=5), and 38% and 32% in Gr 3 (n=7), respectively. C.O. decreased 39% (364-221), 45% (324-177) and 48% (318-166) in groups 1,2 and 3, respectively. Systemic O2 delivery decreased 22% in Gr 2 (52.9-32.4) and 26% in Gr 3 (45-33) and was unchanged in Gr 1. PVO2 increased in Gr 2 from 31.8 to 34.6 and in Gr 3 from 23.4 to 32.3. O2 consumption was unchanged in all groups. These data suggest that in the NB lamb an increased P50 associated with increased Hct provides the same reduction of C.O. as a 4-fold increased Hct without change in P50. Higher increase in O2 content provides no further reduction in C.O. but a greater increase in PVO2, suggesting enhanced O2 availability to the tissues. These data suggest that the combined effect of increased P50 and increased O2 content achieves optimal O2 delivery, presumably at the greatest economy of the cardiovascular system.

1411 ALTERATION OF CEREBRAL AND MYOCARDIAL BLOOD FLOW IN NEWBORN (NB) LAMBS: ADAPTIVE RESPONSE OF MITOCHONDRIAL ACTIVITY

Previous studies have shown that mitochondria adapt to decreased PaO2 by increasing respiratory rate (RR). The present study investigates brain and heart mitochondrial RR in 14 NB lambs during states of decreased cerebral and myocardial blood flow induced by hyperventilation at constant O2 tension and content. Measurements of [Hb], blood gases, O2 saturation and regional blood flow were made at various PaCO2 levels. O2 delivery to segments of brain and heart from which mitochondria were isolated was calculated from the blood flow to those specific segments and O2 content. State 4 (substrate, no ADP) and state 3 (substrate, +ADP) RR of heart and brain mitochondria, expressed as nm O2/nm cytochrome oxidase (a+a3) were determined with glutamate-malate substrate. In the heart, as blood flow decreased from 176 to 56 ml/min/100g tissue, O2 delivery decreased from 30 to 13 ml/min/100g, and mitochondrial RR increased from 145 to 250 nm O2/min. In the brain, as blood flow decreased from 197 to 18 ml/min/100g O2 delivery decreased from 30 to 4 ml/min/100g and mitochondrial RR increased from 160 to 249 nm O2/min. The reduction of blood flow at constant O2 content elicited a mitochondrial response comparable to that reported during “hypoxemic” tissue hypoxia. Present data indicate that when decreased blood flow compromises O2 delivery and produces tissue hypoxia, heart and brain mitochondria sense low O2 availability and adapt by increasing their respiratory rate.

1019 EXCHANGE TRANSFUSION AND RETROLENTAL FIBROPLASIA (RLF) - LACK OF CAUSE AND EFFECT

Exchange transfusion (ET) in preterm infants decreases Hb-O2 affinity and theoretically might enhance the development of RLF. We followed 62 infants ≥ 1500 gm. with repeated fundoscopic examinations by indirect ophthalmoscopy. They were divided into 2 groups: Group I consisted of 22 infants ≥ 1000 gm. of whom 14 were exchanged, and Group II consisted of 40 infants 1001-1500 gm. of whom 16 were exchanged. In Group I (mean O2 therapy 1118 hrs.), there was no difference in incidence of proliferative RLF between exchanged (79%) and non-exchanged infants (88%) (p > .9). In Group II, those infants with ≥ 120 hrs. exposure to O2 therapy (n=20) showed no significant difference in incidence of RLF between exchanged (0%) and non-exchanged infants (22%) (p > .45). In Group II, those infants with > 120 hrs. O2 therapy (n=20) showed no significant difference in incidence of RLF between exchanged and non-exchanged infants. In infants < 29 wks. gestation exposed to > 120 hrs. O2 therapy (n=22) there was no significant difference in incidence of RLF in exchanged (73%) and non-exchanged infants (88%) (p > .85), nor was there a significant difference in infants ≥ 29 wks. gestation exposed to > 120 hrs. O2 therapy (n=19) between exchanged (92%) and non-exchanged (72%) infants (p > .45). These data indicate that the occurrence of RLF is unrelated to ET when infants are matched for birth weight, gestational age, and duration of O2 therapy.

FETAL HEART MITOCHONDRIAL RESPIRATORY ACTIVITY FOLLOWING |[beta]|-RECEPTOR BLOCKADE IN UTERO DURING HYPOXIA

The present study investigates the contribution of endogenous β - receptor stimulation mediated through hypoxia to the adaptive response of MITO to hypoxia in fetal guinea pig hearts. Twenty pregnant guinea pigs were divided in 4 groups: Gr C (control), Gr H (hypoxia, 7-10% O2 for 1 hr), Gr P (propranolol HCI, 1.0 mg/kg, I.V.), Gr PH (propranolol + hypoxia). States 3 and 4 MITO respiratory rates (RR) (nmol O2/min/nmol a+a3) were assayed with glutamate-malate (GM), succinate (SU), and tetramethyl-p-phenylene-diamene HCl/ascorbate (TMDP). State 3 and 4 RRs in Gr C fetal hearts were 89.9 and 13.7 (GM), 81.3 and 25.5 (SU), 170 and 125 (TMPD), respectively. The Ca++ uptake (murexide method) was 51.3 nmol Ca++/min/nmol a+a3 in this group. Fetal hearts in Gr H had increased State 3 RR and Ca++ uptake (significantly to 159.9 nmol/min/nmol a+a3) but not State 4 RR. Gr P showed increases in States 3 and 4 RR over Gr C by 33% and 28% (GM), 57% and 37% (SU), 26% and 0% (TMPD) respectively. In similar studies in newborn pigs, Gr P State 3 (GM) increased to 137.7 from 70.4 (Gr C). In Gr PH, hypoxia had a less significant effect on the MITO RR and Ca++ uptake compared to Gr H and Gr P (107.7, GM; 147.2, SU; 245.2, TMPD for State 3 and 7.36, GM; 18.8, SU; 122.6, TMPD for State 4 and Ca++ uptake was 144.5). Propranolol increases MITO respiratory activity presumably through sympathomimetic actions. Since effects of propranolol and hypoxia are different (propranolol increased States 3 and 4 while hypoxia increased only State 3), it would appear that the adaptive response to hypoxia is not mediated through β-receptor activation.

1717 MITOCHONDRIAL RESPIRATORY ACTIVITY: RESPONSE TO INCREASED CARBOXYHEMOGLOBIN (COHb) IN BRAIN AND HEART OF GUINEA PIGS

Previous studies show that mitochondria adapt to changes of arterial PO2. The present study investigates heart and brain mitochondrial respiratory rate (RR) in 23 guinea pigs at varying blood COHb levels. Blood gases and [COHb] were recorded in all animals. Brain and heart mitochondria were isolated. State 4 RR, state 3 RR with glutamate-malate substrate, expressed as nm O2/min/nm cytochrome a+a3, respiratory control ratio(RCR) (state 3/state 4), and Ca++ uptake were measured. All preparations were well coupled with RCR 10.7±1.9 for heart and 8.3±1.2 for brain mitochondria. State 3 RR increased from 225 at 0% COHb to 500 at 40% COHb in the heart (r=.8) and from 260 at 0% COHb to 628 at 80% COHb in the brain (r=.7). There was an inverse correlation of state 3 RR and arterial O2 content. Mitochondrial activity increased from 190-525 as arterial O2 content decreased from 19-9 ml/dl (r=.9) and from 340 to 580 as arterial O2 content decreased from 16-4 ml/dl (r=.6) in heart and brain respectively. Ca++ uptake in heart and brain increased with increasing [COHb]. Blood flow was not measured but presumably circulatory adjustment failed to compensate for the decreased arterial O2 content, thus impairing O2 delivery to the tissues. These data suggest that increased mitochondrial activity with increased [COHb] and decreased O2 content, occurring in the presence of normal PaO2, represent an adaptive response to tissue hypoxia comparable to the changes reported during acute and chronic hypoxemia.

267 THE RELATIONSHIP BETWEEN CEREBRAL BLOOD FLOW AND MITOCHONDRIAL ACTIVITY OF FETAL LAMB BRAIN IN STATES OF REDUCED OXYGEN CAPACITY

Previous studies have shown that the increased respiratory rate (RR) of newborn and adult brain mitochondria seen in states of reduced arterial O2 tension is an adaptive response. The present study investigates the response of fetal lamb brain mitochondria to decreased O2 content produced by increasing carboxy-hemoglobin concentration [COHb]. Ten chronically catheterized fetal lambs were subjected to increased [COHb] for 2 hrs at a constant blood volume. Blood gases, [Hb], [COHb] and cerebral blood flow, determined by the microsphere technique, were measured before and after establishment of 0 - 25% [COHb]. State 4 (substrate, no ADP) and state 3 (substrate, +ADP) RR of brain mitochondria, expressed as nm O2/nm cytochrome oxidase (a+a3) were determined with glutamate-malate substrate. As left ventricular O2 content was reduced from 8 to 3.5 ml/dl, state 3 activity fell from 216 to 119 nm O2/min (r=.714), a response opposite to that reported in adult animals exposed to increased [COHb]. In spite of this decreasing O2 content, O2 delivery increased (r=.965) as a result of a large increase in cerebral blood flow (from 60 to 418 ml/min/100g). This rise in O2 delivery was associated with a reduction in state 3 activity (r=.654). Our data show that fetal brain mitochondria adapt to increased oxygen availability, a response similar to that seen in newborn lambs as PaO2 rises.

Follow-Up Studies of Very Low Birth Weight Infants (1,250 Grams or Less) Born and Treated within a Perinatal Center

The growth and development of inborn very low birth weight infants was evaluated in 50 of 60 survivors from 132 babies weighing less than or equal to 1,250 gm born July 1974 to December 1977. Mean +/- SE birth weight and gestation was 1,066 +/- 19.3 gm and 29.5 +/- 0.3 weeks, respectively, with 13 infants small-for-gestational age. Of the survivors, 26% weighed less than or equal to 1,000 gm. Male to female ratio was 1:1.4. Apgar scores less than or equal to 5 at five minutes occurred in 16% of the infants. Respiratory distress syndrome occurred in 56%, but only 10% (5/50) required mechanical ventilation. At 1 year, 46% small for gestational age (SGA) and 8% appropriate for gestational age (AGA) infants were less than the third percentile for weight. Major neurologic abnormality occurred in three infants (6%), one of whom is also blind. Grade V retrolental fibroplasia occurred in two others. Severe developmental delay (development quotient < 80, Gesell) occurred in these five infants and two other neurologically normal babies. Of 15 infants weighing less than or equal to 1,000 gm, two had major handicaps. Eight percent of the AGA infants and 30% of the SGA infants had major handicaps. These data indicate that infants born and treated in a perinatal center have a decreased incidence of asphyxia and severe respiratory distress syndrome and that the incidence of major handicaps is reduced, especially in the appropriate for gestational age baby.