Emmalee S Setzer

Platelet dysfunction and coagulopathy in intraventricular hemorrhage in the premature infant

We investigated platelet count, bleeding time, platelet aggregation, prothrombin time, activated partial thromboplastin time, and fibrinogen level in 58 very low-birth-weight infants during the first postnatal day to determine the relationship between hemostatic disorders and intraventricular hemorrhage. Thirty-two of the 58 infants (55%) were found to have periventricular-intraventricular hemorrhage by computerized tomography or autopsy. Nine patients (16%) had subarachnoid hemorrhage only and 17 (29%) had no evidence of intracranial hemorrhage. Infants with IVH had a significantly lower mean platelet count than did infants with no SAH/IVH. However, only five patients with IVH had initial thrombocytopenia. The IVH group had a mean bleeding time which was significantly prolonged compared to that of the group without SAH/IVH. Similarly, patients with IVH had a mean platelet aggregation response which was significantly diminished in comparison to that of patients with no SAH/IVH. Infants with IVH had a significantly longer mean PT than did infants with no SAH/IVH. In addition, babies with IVH had a significantly longer mean APTT compared to that of babies without SAH/IVH. The groups did not differ significantly with respect to fibrinogen levels. Three infants with IVH had disseminated intravascular coagulation in the early neonatal period. These data suggest that disorders of platelet-capillary interaction and defects in the intrinsic and extrinsic coagulation pathways may play important roles in intraventricular hemorrhage in the premature infant.

Cardiovascular changes in group B streptococcal sepsis in the piglet: response to indomethacin and relationship to prostacyclin and thromboxane A2.

Summary: Seventeen piglets were infected with a continuous intravenous infusion of live group B β-hemolytic streptococci (GBS). Hemodynamic changes were recorded, and blood samples were drawn for measurement of thromboxane B2 (TxB2) (stable metabolite of thromboxane A2) and 6-keto-PGF1α (stable metabolite of prostacyclin). Control animals (n =9) received only bacteria, while treatment animals (n =8) received indomethacin, 3 mg/kg IV, 15 min after the start of the bacterial infusion. Control animals responded to the bacteria within 15 min with marked elevation in mean pulmonary artery pressure (Ppa) from 15 ± 8 to 39 ± 6 mm Hg and decline in Pao2 from 80 ± 11 to 51 ± 6 mm Hg and cardiac output (CO) from 0.24 ± 0.07 to 0.13 ± 0.07 liters/min/ kg. Mean arterial blood pressure (AoP) significantly decreased from baseline value of 95 ± 13 to 51 ± 32 mm Hg by 180 min. In animals treated with indomethacin, these changes were reversed or significantly attenuated. The hemodynamic changes were associated temporally with elevations in plasma concentrations of TxB2 or 6-keto-PGF1α. In he first 60 min, TxB2 levels in both groups correlated with Ppa (r =0.72, p < 0.001) and Pao2 (r =-0.60, p < 0.001). A strong negative correlation between TxB2 and CO was observed over the first 180 min (r =-0.73, p < 0.001). There was a statistically significant correlation between AoP and 6-keto-PGF1α concentration between 60 and 180 min (r =-0.54, p < 0.002). Indomethacin improved the hemodynamic function in this model of GBS sepsis. This improvement was related in part to inhibition of synthesis of thromboxane A2 and prostacyclin.

Coronary sinus thrombosis: A central venous catheter complication*

This is a report of a fatal thrombotic complication in a centrally alimented premature infant with a venous malformation.

PROPHYLACTIC INDOMETHACIN AND INTRAVENTRICULAR HEMORRHAGE (IVH) IN THE PREMATURE

We have previously shown significant hemostatic derangements associated with IVH and have questioned the use of indomethacin [I] , a potent platelet anti-aggregating agent in infants vulnerable to IVH. During a prospective study of [I] prophylaxis for patent ductus arteriosus (PDA), we assessed the impact of [I] upon the incidence of IVH.Sixty one inborn infants were randomized by birth weight (Group A: <900 gm; Group B: 900-1300 gm) to receive either placebo [P] or [I] . The first dose (0.2 mg/kg), given within 12 hours after birth, was followed by two q 12 hourly doses (0.1 mg/kg). Cranial ultrasonography was performed prior to dose # 1, daily for 3 days and at 1 week. Abnormal scans were repeated weekly. The most severe grade of IVH (Papile criteria) sustained by each infant is shown below:In Group A, 2 of 10 (20%) of infants who received I developed IVH (Grades II-IV) in contrast to 8 of 10 (80%) of infants given [P], p < 0.025. In Group B, there was no significant difference in IVH between [I] and [P] These preliminary data suggest that prophylactic [I] may diminish the incidence of IVH in infants < 900 grams, perhaps by preventing clinically significant PDA or by altering prostaglandin-related central nervous system vascular phenomena.

Influence of an antagonist of slow-reacting substance of anaphylaxis on the cardiovascular manifestations of hypoxia in piglets

ABSTRACT: Leukotrienes have been implicated in the pathogenesis of hypoxic pulmonary hypertension in adult animals and in persistent pulmonary hypertension with accompanying hypoxemia in the neonate. In order to elucidate the role of leukotrienes in hypoxic pulmonary hypertension in a young animal model, the effects of a leukotriene antagonist, FPL 57231, were evaluated in anesthetized piglets. Cardiac output and vascular pressures were measured and pulmonary and systemic vascular resistances calculated prior to and during hypoxia. These measurements were compared during continued hypoxia between a control and treatment group which received FPL 57231. FPL 57231 infusion resulted in significant decreases in mean pulmonary artery pressure (p < 0.04), pulmonary vascular resistance (p < 0.01) and the ratio of pulmonary/systemic vascular resistance (p < 0.01). Systemic vascular resistance fell approximately 25% from hypoxic baseline (p < 0.01) while PVR decreased 54%. There were no differences between groups in mean systemic arterial pressure, cardiac output, pH, or PaCO2. In addition, pretreatment with FPL 57231 attenuated the hemodynamic response to hypoxia. These data suggest that leukotrienes may, in part, mediate hypoxic pulmonary vasoconstriction in piglets.

Exchange transfusion using washed red blood cells reconstituted with fresh-frozen plasma for treatment of severe hyperkalemia in the neonate

Typically, patients who showed no improvement with lateral decubitus positioning already had widespread bilateral pulmonary injury and were not good candidates for either selective bronchial obstruction or intubation. Whether Iobectomy or pleurotomy would have been beneficial is uncertain, but this would certainly have involved substantial risk in these critically ill neonates. Although lateral decubitus positioning frequently necessitated minor adjustments of ventilatory support, our patients tolerated it well and responded to this therapy. Our observations are in agreement with recent research 1~ that indicates that when infants are placed in the lateral decubitus position, the uppermost good lung receives a greater portion of ventilation. Thus, the lateral decubitus position appears to be a relatively benign, noninvasive therapeutic maneuver that should be attempted before more invasive methods are used to treat serious focal pulmonary interstitial emphysema. REFERENCES 1. Campbell RE: Intrapulmonary interstitial emphysema: A complication of hyaline membrane disease. Am J Roentgenol Rad Ther Nucl Med 110:449, 1970. 2. Leonidas JC, Hall RT, Rhodes PG: Conservative management of unilateral pulmonary interstitial emphysema under tension. J Pediatr 87:776, 1975. 3. Broo]~s JG, Bustamante SA, Koops BL: Selective bronchial intubation for the treatment of severe localized pulmonary interstitial emphysema in newborn infants. J Pediatr 91:648, 1977. 4. Dickman GL, Short BL, Krauss DR: Selective bronchial intubation in the management of unilateral pulmonary interstitial emphysema. Am J Dis Child 131:365, 1977. 5. Fletcher BD, Outerbridge EW, Youssef S, Bolande RP: Pulmonary interstitial emphysema in a newborn infant treated by lobectomy. Pediatrics 54:808, 1974. 6. Magilner AD, Capitanio MA, Wertheimer I, Burko H: Persistent localized intrapulmonary interstitial emphysema: An observation in three infants. Radiology 111:379, 1974. 7. Levine DH, Trump DS, Waterkotte G: Unilateral pulmonary interstitial emphysema: A surgical approach to treatment. Pediatrics 68:510, 1981. 8. Matthew OP, Thach BT: Selective bronchial obstruction for treatment of bullous interstitial emphysema. J Pediatr 96:475, 1980. 9. Swischuk LE: Bubbles in hyaline membrane disease. Radiology 122:417, 1977. 10. tteaf DP, Melms P, Gordon I, Turner HM: Postural effects on gas exchange in infants. N Engl J Med 308:i505, 1983.

Temporal comparative analysis of computed tomography with ultrasound for intracranial hemorrhage in premature infants

SummaryThis study focuses on comparison of computed tomography and ultrasound in premature infants with intracranial hemorrhage and its complications. It was determined that close correlation (95%) exists between CT and ultrasound for evaluation of ventriculomegaly. Although there is reasonable correlation for the identification and localization of periventricular, intraventricular and choroidal hemorrhages, ultrasound defined such lesions at higher rates. Subarachnoid blood and periventricular edema were diagnosed better or exclusively by CT.

PHARMACOKINETICS OF PROPHYLACTIC INDOMETHACIN IN VERY LOW-BIRTHWEIGHT PREMATURE INFANTS

The pharmacokinetics of indomethacin (I) was assessed in infants who received prophylactic (I) for patent ductus arteriosus (PDA). The first dose (0.2 mg/kg), given within 12 hours after birth, was followed by two q 12 hourly doses (0.1 mg/kg). The mean birth weight (BW) of these infants was 923 ± 134.0 gm (range: 730-1070gm) with a mean gestational age of 28.1 ± 2 wks (range:31-25 wks). None of the infants subsequently developed a significant PDA. Plasma (I) levels were measured by high performance liquid chromatography at 1, 13, 36, 72, 96, 168 and 216 hours after the administration of the first dose.The mean plasma t 1/2 of (I) in these infants (71.3±39.1 hrs) was significantly prolonged when compared with previously reported values. Furthermore the mean plasma t 1/2 of (I) was significantly longer in the <1000 gm infants (p<0.05). While the minimum efficacious dose for prophylactic (I) has not been established, all but one infant had a level > .250μg 7 days following (I). These data strongly suggest that previously recommended dosages of (I) for very low birth weight infants in the first 48 hrs. may result in very elevated and prolonged levels.

406 PROPHYLACTIC INDOMETHACIN: EFFECTS ON RENAL FUNCTION

This controlled, double-blind, study assessed the renal impact of early (< 12 hr postnatal age) indomethacin [I], for prevention of patent ductus arteriosus (PDA), in O2 dependent inborn infants with birth weights (BW)≤1300 gm. Fifty infants randomly received 3 IV doses of [I] or placebo [P] at 12 hr intervals. Dose1 (D1) was 0.2 mg/kg;D2 and D3 were 0.1 mg/kg each. Fluid balance, serum sodium (Na), potassium (K), creatinine (Cr), blood urea nitrogen (BUN) and fractional Na excretion (FENa) were evaluated pre-D1, 6-12 hr post-D1, 12-36 hr post-D3, and 1 wk post-D3. Timed urine specimens were used to derive Cr clearance (CCr) post-D3 and 1 wk post-D3. The 25 infants in each group were comparable in BW, gestational age, APGARs, pH and base excess at study entry. [I]-treated infants had reduced urine output (UO) in the 12 hr period following D1 that was no longer evident post-D3. Fluid intake, Na, K, BUN, Cr, FENa, and CCF were similar throughout the study. Renal data (x±SEM) revealed:In contrast to reports of renal dysfunction induced by indomethacin therapy for symptomatic PDA, early [I] appears to alter renal function minimally in prematures without significant PDA.

SEVERITY OF PLATELET DYSFUNCTION INDUCED BY PROPHYLACTIC INDOMETHACIN IN THE PREMATURE

The effect of indomethacin [I] upon platelet dysfunction in the very-low-birth-weight infant was assessed during an investigator-blind trial of [I] prophylaxis for patent ductus arteriosus.Sixty-one inborn infants were randomized by birth weight (Group A: <900 gm; Group B: 900-1300 gm) to receive either placebo [P] or [I]. The first dose (0.2 mg/kg), given within 12 hours after birth, was followed by two q 12 hourly doses (0.1 mg/kg each). Platelet count (PC) and bleeding time (BT) were obtained prior to Dose # 1, twice within 1-72 hours following dose # 3, and at 1 week postnatal age.Pre-dose #1, mean PC and BT were normal in all groups. PC declined significantly during the first postnatal week in all groups. Maximum BT ≥10 min. post-dose # 3 was noted in 6/10 [P] and 9/10[I]infants in Group A and 3/20 [P] and 17/19 [I] infants in Group B; p<0.001. In Group A, severely abnormal PC (<75,000/mm3) rather than platelet dysfunction may have affected BT in 5 [P] infants, whereas only 1[I] infant had PC <75,000/mm3. By one week postnatal age, BT had returned to normal(<6 min) in the majority of [I] infants in both groups A and B.