Karl Komar

Prostanoids in neonates with persistent pulmonary hypertension

7. Heird WC, Winters RW. Total parenteral nutrition: the state of the art. J PEDIATR 1975;86:2-16. 8. Black DD, Suttle EA, Whitington PF, et al. The effect of short-term total parenteral nutrition on hepatic function in the human neonate: a prospective randomized study demonstrating alteration of hepatic canalicular function. J PEDIATR 1981;99:445-9. 9. Helms RA, Miller JL, Burckart G J, et al. Clinical outcome assessed by anthropometric parameters, albumin and cellular immune function in high-risk infants receiving total parenteral nutrition. Pediatr Surg 1983;18(5):564-9. 10. Wu PYK, Edwards NB, Storm MC. Characterization of the plasma amino acid pattern of normal term breast-fed infants. J PEDIATR 1986;109:347-9. 11. Ramakrishnan RR, Tao R, Yoshimura NN, et al. In vitro and in vivo hydrolysis of N-acetyl-L-tyrosine in rats [Abstract]. J Parenter Enter Nutr 1984;8:92.

Failure of prophylactic indomethacin to improve the outcome of the very low birth weight infant.

Prophylactic closure of the patent ductus arteriosus (PDA) has been recommended as a means of decreasing early respiratory distress, and thereby chronic respiratory sequelae in the very low birth weight (VLBW) neonate. This study was undertaken to evaluate some possible mechanisms for the observed failure of early indomethacin therapy to achieve such improvement. 24 VLBW infants with echocardiographic evidence of PDA were randomized to receive either indomethacin or placebo at 48 h of life; and then they were studied for clinical, metabolic and laboratory signs of ductal constriction and/or reopening. Early indomethacin conferred no improvement in respiratory sequelae. However, this was not secondary to a short-term therapeutic failure. Prophylactic indomethacin, even in the VLBW infant, was successful in decreasing dilator prostaglandin production, and probably in closing the PDA and in decreasing the number of recurrences. The implications are that even with effective ductal constriction, overall morbidity is not affected.

Oxygen Delivery, Oxygen Consumption, and Metabolic Acidosis during Group B Streptococcal Sepsis in Piglets

ABSTRACT. The development of metabolic acidosis during neonatal sepsis with group B streptococci (GBS) has been attributed to progressive tissue ischemia resulting from reduced oxygen delivery (QO2). Using an animal model of GBS disease, we attempted to test this hypothesis by comparing the development of metabolic acidosis in two groups of piglets with comparably diminished systemic QO2, one septic and one not. Eighteen anaesthetized piglets were instrumented to observe aortic pressure, cardiac output, arterial and mixed venous blood gases, oxygen content, and hemoglobin concentration. QO2, oxygen consumption, and oxygen extraction ratio were calculated. Six piglets (group 1) received continuous infusion of live GBS organisms; six piglets (group 2) received continuous infusion of phenylephrine (PE), beginning with 10-μg/kg/min and increasing as required to match the PE-induced reduction in QO2 to the fall observed in the group 1 (GBS) piglets at each 30-min interval. Group 3 piglets (n = 6) received 0.9% saline and served as controls. No differences in either cardiac output or QO2 were noted comparing GBS and PE piglets at any time interval from 0 - 180 minutes. At 120, 150, and 180 minutes, both QO2 and cardiac output were lower in GBS and PE piglets compared to controls. Despite equivalent reductions in cardiac output and QO2, only GBS piglets developed significant metabolic acidosis, while pH and base deficit for PE piglets did not differ from controls. Oxygen consumption did not differ significantly among the three experimental groups at any observation time. Oxygen extraction ratio did not differ comparing PE and GBS piglets at any observation time. We conclude that the reduction of QO2 effected by GBS infusion in piglets is not, in itself, sufficient to account for the development of metabolic acidosis during these experiments.

Neither nitroglycerin nor nitroprusside selectively reduces sepsis-induced pulmonary hypertension in piglets

No therapeutic agent consistently decreases pulmonary arterial pressure (PAP) more than aortic pressure in neonates with persistent pulmonary hypertension of the newborn. We have investigated whether nitroglycerin (NG) or nitroprusside (NP) selectively decreases PAP in an animal model of sepsis-induced pulmonary hypertension. Piglets were anesthetized, intubated, and ventilated. Pulmonary hypertension was induced by an iv infusion of group B Streptococci. Piglets were then divided into three groups with group B Streptococci infusion ongoing. Neither PAP nor the pulmonary vascular resistance index was decreased significantly by either NP or NG. NP decreased significantly both mean aortic pressure and the systemic vascular resistance index. Cardiac index decreased significantly during both NG and placebo infusion. These data suggest that neither NP nor NG is likely to be beneficial in sepsis-induced pulmonary hypertension in newborns.

Oxygen transport in newborn piglets with pulmonary hypertension

Because of the neonates susceptibility to pulmonary hypertension (PHN) and his inefficiency in invoking the compensatory mechanisms often used by adults to maintain stable levels of O2 consumption (VO2) in the face of changes in O2 delivery (DO2) and metabolic demand, we have attempted to define the O2 handling capabilities of the newborn piglet affected with various types of pulmonary vasoconstriction. Hemodynamically similar levels of PHN were generated in 18 newborn piglets (six through group B beta-hemolytic Streptococci infusion; six through hypoxia; six through hypercarbia) and O2 transport was studied. At 60 min VO2 was similar in all groups, although DO2 was different (10.7 +/- 6.7, 7.2 +/- 1.6, and 21.7 +/- 8.9 ml/kg.min, in the septic, hypoxic, and hypercarbic groups, respectively). Extraction efficiency varied in an inverse fashion (43 +/- 12%, 72 +/- 12%, and 27 +/- 16%, in the septic, hypoxic, and hypercarbic groups, respectively). Supply dependency and a critical DO2 were observed in the septic and hypoxic PHN groups (18.4 and 12.2 ml/kg.min, respectively). Both of these were elevated as compared to healthy adult levels. Hypercarbic pulmonary hypertension was supply independent at the levels studied; however, DO2 remained elevated in these animals and may never have reached the critical DO2 level.

Selective Inhibition of Thromboxane Synthetase Reduces Group-B-Beta-Hemolytic-Streptococci-Induced Pulmonary Hypertension in Piglets

13 newborn piglets with group-B-beta-hemolytic-streptococci (GBS)-induced pulmonary hypertension were assigned to receive either placebo (group 1) or Dazmegrel, a thromboxane synthetase inhibitor (group 2). All piglets with pulmonary hypertension had increased thromboxane B2 (TxB2) and 6-keto PGF1 alpha levels. With continued GBS infusion, the placebo group demonstrated a continued elevation of pulmonary artery pressure (PAP) and of TxB2. The Dazmegrel piglets, however, despite continued GBS infusion, demonstrated a selective decrease in PAP associated with a significant decrease in TxB2 levels and stability of systemic pressure and cardiac output. These data demonstrate that thromboxane synthetase inhibition is effective therapeutically in selectively reducing PAP.

VOLUME EXPANSION INCREASES CARDIAC OUTPUT (CO) BUT NOT OXYGEN DELIVERY (QO2) IN PIGLETS

Piglets (1-3 wks; n=12) were anaesthetized, intubated, and ventilated. Blood pressure (BP), pulmonary artery pressure (PAP), left atrial pressure (LAP), central venous pressure (CVP), and CO were measured directly. Arterial and mixed venous (PA) blood samples were obtained to determine QO2, O2 consumption (VO2), and O2 extraction. Six piglets (GENT) received 6% Gentran/0.9% NaCl to elevate LAP from approximately 5 to 15 mm Pig over 30 minutes. Six additional piglets (SAL) received 0.9% NaCl for 30 minutes.Cardiac index (CI) rose during GENT in each piglet, reaching a plateau (+54.2 +/- 38.5 (S.D.) cc/kg/min; p .01) at LAP between 12 - 15 mm Hg. CI fell at the highest LAP reading in 4/6 piglets. GENT raised LAP, PAP, and CVP equivalently (7.3 +/- 1-4, 7.2 +/- 2.6, 5.6 +/- 1.2 mm Hg; all p.01 vs SAL), but had no effect on BP or HR. Hb fell during GENT from 10.4 +/- 1.8 to 7.4 +/- 1.9 gm/dl (p .01) so that QO2 was not enhanced after GENT (17.6 +/- 1.5 vs 17.9 +/- 2.3 cc O2/kg/min) despite the rise in CO. VO2, O2 extraction, pH, and base excess did not change after GENT.Conclusions: 1. CO consistently rises with increased LAP from 5-12 mm Hg. At higher LAP, CO may fall. 2. QO2 does not rise and O2 extraction does not fall during GENT, as increased CO is opposed by hemodilution, 3. To the extent that improved QO2, not CO, is the endpoint of hemodynamic resuscitation, volume infusion without concurrent blood transfusion may be of little benefit.

ELEVATED CARDIAC OUTPUT (CO) WITHOUT ELEVATED O2 DELIVERY (QO2) DOES NOT PROTECT AGAINST METABOLIC ACIDOSIS DURING SEPSIS IN PIGLETS

Infants infected with Group B Streptococcus (GBS) develop reduced CO, reduced QO2, and metabolic acidosis. We investigated whether reduced CO is a necessary prerequisite for acidosis during GBS sepsis. Piglets (n=16) were anaesthetized and ventilated. Blood pressure, left atrial pressure (LAP), and CO were measured. Blood gases and O2 contents were determined q. 30 min × 4 hours from aorta and PA. Group 1 (GBS, n=6) received GBS X 4 hours. Group 2 (GBS/DEX, n=6) received GBS + 6% Dextran sufficient to raise LAP from 5 to 12 mm Hg. Group 2 piglets were phlebotomized to maintain QO2 equal to Group 1 during every 30-minute interval. Group 3 piglets (SAL, n=4) received 0.9% NaCl.After 240 minutes of GBS, CO and QO2 fell from 104.4 to 42.5 cc/min/kg and 14,2 to 5.7 cc O2/kg/min (both p<.01). After 240 minutes of GBS/DEX, QO2 fell from 16.8 to 7.3 cc O2/kg/min (p<0.01, 0 vs 240 mins; p=N.S. at each 30-minute interval vs GBS), while CO did not fall significantly (119.9 to 105 co/kg/min p=N.S. vs SAL; p<0.01 vs GBS). Both GBS and GBS/DEX developed lower pH (7.20; 7.22) and greater base deficit (-14.0; -9.7) than SAL (7.44, -2.7) (p<0.05 GBS S GBS/DEX vs SAL; p=N.S. GBS vs GBS/DEX). No differences in VO2 or O2 extraction were noted between GBS and GBS/DEX.Conclusions: 1. GBS infusion reduced CO, QO2, & pH in piglets. 2. Dextran raised LAP and CO during GBS sepsis. 3. Elevation of CO (but not QO2) during GBS did not protect against the development of metabolic acidosis. Reduced CO is not a hemodynamic prerequisite for acidosis during GBS sepsis in piglets.