Group B Streptococcal Infusion Research Articles

Hemodynamic Effects of Conventional and High Frequency Oscillatory Ventilation in Normal and Septic Piglets

The cardiovascular effects of high frequency oscillation (HFO) and conventional ventilation (CMV) were evaluated in 10 piglets prior to and during an infusion of group B streptococci (GBS). Animals were randomized to begin ventilation with either HFO or CMV. Arterial blood gases, cardiac output (CO), and pulmonary artery (Ppa), pulmonary wedge (Ppw) and arterial blood pressures were measured. These values were recorded at a mean airway pressure (MAP) of 2 cm H2O for both modes of ventilation after which a continuous infusion of GBS (4 X 10(7) CFU/kg/min) was begun. MAP was increased in both ventilators in the following sequence: 4, 8 and 12 cm H2O. Prior to GBS infusion, HFO was associated with small but significant changes in hemodynamic parameters when compared to CMV for the following: Ppa (15 +/- 4 vs. 13 +/- 4.0 mm Hg; p less than 0.03), Ppw (3 +/- 1 vs. 2 +/- 1 mm Hg; p less than 0.02), and CO (0.24 +/- 0.08 vs. 0.25 +/- 0.09 l/min/kg; p less than 0.05). Similar statistically significant increases in Ppa (p less than 0.005) and Ppw (p less than 0.0001), and decrease in CO (p less than 0.007) were present during GBS infusion when animals were ventilated with HFO, irrespective of the MAP used. Our results suggest that the use of HFO in both normal piglets and those receiving an infusion of GBS results in mild but consistent impairment in cardiovascular function compared to CMV. In summary, these data demonstrate that HFO has no beneficial effect compared to CMV at similar MAP in the management of the septic piglet model and may in fact further compromise the animal's hemodynamic status.

Intra-aortic Balloon Counterpulsation in Newborn Lambs Infected with Group B Streptococcus

To determine the efficacy of intra-aortic balloon counterpulsation (IABC) in neonatal group B Streptococcal (GBS) infection, we studied five lambs, 10-14 days old, weighing from 4.7 to 6.7 kg. The lambs were instrumented with arterial and venous catheters, and a 5 French intra-aortic balloon catheter with balloon volumes of 3-5 ml was inserted into the femoral artery. A continuous infusion of heat-killed GBS organisms was infused at a rate of 1.7 to 6.2 x 10(8) org/kg/min, until a 30-50% decrease in cardiac output was attained. IABC was then instituted for 30 minutes, hemodynamic measurements repeated, and IABC was stopped. GBS infusion caused significant decreases in cardiac output (282 +/- 62 vs. 165 +/- 38 ml/min/kg) and pH (7.39 +/- 0.02 vs. 7.33 +/- 0.06), and significant increases in mean pulmonary artery pressure (14.4 +/- 2.1 vs. 36.2 +/- 12.1 mm Hg) and pulmonary vascular resistance (1.20 +/- 0.38 vs. 5.08 +/- 1.49 mm Hg/L/min/kg). Institution of IABC during continuous GBS infusion significantly increased cardiac output (225 +/- 1.27 ml/min/kg). The institution of the IABC also resulted in a significant decrease in pulmonary vascular resistance (2.6 +/- 1.3 mm Hg/L/min/kg). The authors conclude that IABC improves cardiac output and decreases pulmonary vascular resistance in newborn lambs with GBS infection.

Dimethylthiourea Reverses Sepsis-Induced Pulmonary Hypertension in Piglets

Dimethylthiourea (DMTU), a putative hydroxyl radical scavenger, attenuates thromboxane generation and pulmonary hypertension in the piglet model of group B streptococcal (GBS) sepsis. This study tested the hypothesis that DMTU reverses ongoing GBS-induced pulmonary hypertension coincident with decreased thromboxane production. Piglets (n = 15) received a 60 min infusion of GBS (10(-8) cfu/kg/min). Mean pulmonary artery pressure (Ppa), arterial blood gases (ABGs), and thromboxane B2 (TXB) levels were measured at 10 min intervals throughout the study. GBS infusion resulted in a marked increase in pulmonary artery pressure (mean delta Ppa = 31 mm Hg) and a significant decline in PaO2 (mean = -80 torr) within 10 min of beginning the infusion. pH decreased from a mean of 7.47 to 7.37. DMTU, 750 mg/kg, or normal saline vehicle was infused over 10-15 min beginning 10 min after initiating GBS. Ppa decreased significantly within 10 min of DMTU infusion. Piglets receiving vehicle had a slow decline in Ppa. Piglets receiving DMTU also had an improvement in PaO2 and showed no further drop in pH. Piglets receiving vehicle had no improvement in PaO2 and demonstrated a continued decline in pH. TXB levels did not differ between the groups at any time interval. We conclude that DMTU can partially reverse GBS-induced pulmonary hypertension, but may function through mechanisms independent of thromboxane generation.

Organ-Specific Disposition of Group B Streptococci in Piglets: Evidence for a Direct Interaction with Target Cells in the Pulmonary Circulation

Despite the serious pulmonary manifestations of early onset group B streptococcal (GBS) sepsis, it is not known whether the organism distributes into lung tissue and whether adverse pulmonary hemodynamic abnormalities relate to an interaction between the organism and target cells in the pulmonary vascular bed. Accordingly, this study evaluated the distribution and fate of GBS in the lung, liver, and spleen of anesthetized infant piglets and in isolated, salt solution-perfused piglet lung preparations. GBS were radiolabeled with 111Indium-oxine and infused at a dose of 10(8) organisms/kg/min for 15 min into anesthetized piglets ranging in age from 5-10 d. Forty-five min after termination of the infusion, animals were killed and specimens of lung, liver, spleen, and blood were excised and the relative deposition and viability of GBS were determined. Most of the recovered bacteria were detected in the lung (53.2 +/- 3.9%) followed by the liver (41.4 +/- 2.0%) and spleen (2.2 +/- 0.38%). GBS detected in the blood was estimated to be only 3.2 +/- 1.0% of the infused dose. Viability of GBS was least in the lung (21.4 +/- 2.6%) relative to the liver (45.7 +/- 11.2%) and spleen (83.4 +/- 19.5%). After a 60-min GBS infusion, transmission electron microscopy localized the organism within pulmonary intravascular macrophages in the lung; there was no evidence for bacterial interaction with either neutrophils or endothelial cells. In the liver, GBS was found exclusively in Kupffer cells. In isolated piglet lungs perfused at a constant flow rate with blood-free physiologic salt solution, GBS (10(6) to 10(8) organisms/mL) provoked concentration-dependent increases in pulmonary vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxygen Radical-dependent Bacterial Killing and Pulmonary Hypertension in Piglets Infected with Group B Streptococci

The mechanism by which bacteria are cleared by the pulmonary circulation and the relation of this process to development of hemodynamic abnormalities are not understood. This study tested the hypotheses that clearance of Group B Streptococcus (GBS) during transit through the pulmonary circulation of infant piglets is related to oxygen radical-dependent bacterial killing and that killing of the organism is linked to development of pulmonary hypertension. GBS were radiolabeled with 111In and infused intravenously for 15 min (10(8) organisms/kg/min) into infant piglets ranging in age from 5 to 14 days. Lung specimens were excised at termination of the GBS infusion or 45 min thereafter, and both the relative deposition and viability of the bacteria were determined. The percentage of infused GBS recovered in lung tissue did not differ between the two time points (26 +/- 7% versus 29 +/- 8%), but the relative viability at termination of the infusion, 50 +/- 11%, was reduced to 19 +/- 4% within 45 min. Treatment with an oxygen radical scavenger, dimethylthiourea (DMTU), failed to influence the pulmonary deposition of GBS but significantly increased viability of the organism from 21.4 +/- 2.6 to 33.3 +/- 5.3%. As expected, GBS infusion was accompanied by pulmonary hypertension and arterial hypoxemia; DMTU attenuated these responses by 52 and 78%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Roles of platelet-activating factor and thromboxane in group B Streptococcus-induced pulmonary hypertension in piglets.

Platelet-activating factor causes pulmonary hypertension, shock, hypoxemia, neutropenia, and increased pulmonary vascular permeability; some of its effects are due to thromboxane A2 release. Evidence for a possible role of these mediators in the genesis of group B Streptococcus (GBS)-induced pulmonary hypertension was sought using specific receptor antagonists for PAF and thromboxane A2 (TxA2) in anesthetized, ventilated piglets (less than or equal to 12 d of age; n = 22). Infusion of 1 X 10(8) GBS/kg/min for one hour resulted in a sustained and significant increase in pulmonary artery pressure (PPA) from 17 +/- 1 to 35 +/- 3 torr. Pretreatment with the TxA2 antagonist SQ 29548 (0.75 mg/kg intravenous), completely inhibited the effect of GBS on PPA. Pretreatment with either platelet-activating factor antagonists SRI 63072 (3 mg/kg intravenous) or SRI 63441 (1 mg/kg) did not affect the pulmonary hypertension due to GBS infusion. GBS-induced pulmonary hypertension could be reversed by SQ 29548; SRI 63072 did not affect PPA when administered to pigs with GBS-induced elevation in PPA. Inasmuch as prevention and reversal of GBS-induced pulmonary hypertension are accomplished with the TxA2 antagonist but not with PAF antagonists, these data suggest that TxA2, rather than PAF, is responsible for the early pulmonary hypertension in this model of neonatal GBS sepsis. Therefore, TxA2 antagonists may be clinically useful in treating pulmonary hypertension related to GBS sepsis.

Hypoxic Pulmonary Vasoconstriction during and after Infusion of Group BStreptococcusin Neonatal Piglets: Vascular Pressure-Flow Analysis

Hypoxic pulmonary vasoconstriction (HPV) is attenuated after endotoxin infusion into adult dogs and sheep. High dose infusions of Group B Streptococcus (GBS), a neonatal pathogen, into newborn animals produce pulmonary hypertension, hypoxemia, and reduced cardiac output similar to high dose endotoxin infusions in adult animals. To avoid the compounding effects of reduced arterial and mixed venous PO2, HPV was studied after low dose endotoxin in adult animals. We hypothesized that HPV would be attenuated in piglets after a low dose GBS infusion. Both PVR and pressure-flow (P/Q) relationships were measured in piglets to characterize the neonatal pulmonary vascular response to alveolar hypoxia before and after GBS infusion. Hemodynamic measurements were made under Zone 3 conditions in 5 piglets breathing room air and 13% FIO2: (1) prior to GBS, (2) 20 min into a 1-h infusion of 3 +/- 1 x 10(8) cfu/kg/h live GBS, (3) 1 h, and (4) 3 h after completion of the GBS infusion. Prior to GBS, alveolar hypoxia increased PVR (14 +/- 1.3 to 33 +/- 3.6 mm Hg/L/min) and P/Q slope (12 +/- 2.3 to 41 +/- 6.8 mm Hg/L/min). During all subsequent exposures to 13% FIO2, the PVR and P/Q slopes were similar to pre-GBS values. When animals breathed room air, the PVR and P/Q slopes were greater than pre-GBS values during but not after the GBS infusion. We conclude that HPV is not altered 1 and 3 h after a 1-h low dose GBS infusion in neonatal piglets. Infusion of GBS and alveolar hypoxia independently increase pulmonary vascular resistance.

Neonatal group B streptococcal sepsis: effects of late treatment with dazmegrel.

Neonatal group B streptococcal (GBS) sepsis produces pulmonary arterial hypertension and hypoxemia that are preventable by pretreatment with the selective thromboxane A2 synthase inhibitor, dazmegrel. In the present experiment we administered dazmegrel (8 mg/kg) 2 h after the initiation of a 2 1/2 h infusion of 5 X 10(8) GBS/kg/h in ten 2- to 3-wk-old piglets. The multiple inert gas elimination technique was used to measure intrapulmonary shunt and alveolar ventilation to pulmonary perfusion mismatching. Thromboxane B2, the stable metabolite of thromboxane A2, and 6-keto-prostaglandin F1 alpha, the stable metabolite of prostacyclin, were assayed in arterial blood. Pulmonary arterial pressure increased immediately after initiation of the GBS infusion, rising from 12 +/- 2 to 34 +/- 4 torr (p less than 0.02); pulmonary vascular resistance increased by 400% (p less than 0.01). Arterial hypoxemia developed (p less than 0.02) in association with an increase in the low ventilation-perfusion ratio index but without a significant increase in intrapulmonary shunt. Thromboxane B2 levels increased 10-fold. Infusion of the carrier substance for dazmegrel after 2 h of GBS infusion produced no change in any variables. In contrast, infusion of the drug resulted in the return to pre-GBS infusion baseline values for both pulmonary arterial pressure and pulmonary vascular resistance. However, no improvement in arterial pO2 or in the low ventilation-perfusion ratio index occurred. Both pulmonary vascular resistance and pulmonary arterial pressure remained normal for 0.5 h after dazmegrel administration despite continued GBS infusion. Thromboxane B2 levels were decreased 30 min after dazmegrel (p less than 0.02), but remained greater than pre-GBS levels.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Prostaglandin synthetase inhibition in group B streptococcal shock: hematologic and hemodynamic effects.

A rabbit model of group B Streptococcal (GBS) shock was used to study the effects of prostaglandin synthetase inhibition on the hemodynamic and hematologic response to GBS shock. The infusion of heat-killed GBS in groups I and II produced significant decreases in mean arterial pressure, neutrophil counts, and platelet counts (p less than 0.05), and significant rises in concentrations of thromboxane B2 and 6-Keto-PGF1 alpha, the stable metabolites of thromboxane A2 and prostacyclin (p less than 0.05). Administration of indomethacin (4 mg/kg) after GBS infusion (group II) was associated with a significant rise in mean arterial pressure and a significant decline in thromboxane B2 and 6-Keto-PGF1 alpha concentrations (p less than 0.05) but had no effect on GBS-induced hematologic alterations. Indomethacin administration before GBS infusion (group III) prevented alterations in mean arterial pressure and was associated with a decrease in thromboxane B2 and 6-Keto-PGF1 alpha concentrations. Indomethacin in group III did not prevent neutropenia and thrombocytopenia and may have exacerbated neutropenia. Alteration of experimental GBS shock with prostaglandin synthetase inhibition produces disparate hemodynamic and hematologic response.

Effects of the thromboxane synthetase inhibitor, dazmegrel (UK 38,485), on pulmonary gas exchange and hemodynamics in neonatal sepsis.

Group B streptococcal (GBS) sepsis produces arterial hypoxemia in newborns. In piglets we previously found that hypoxemia develops because of increased ventilation perfusion heterogeneity, and reduced mixed venous pO2 occurring in association with decreased pulmonary blood flow. We hypothesize that increased thromboxane A2 (TxA2) synthesis mediates the immediate alterations in gas exchange found in GBS sepsis. We studied 18 anesthetized, ventilated piglets before, during, and after a 30-min infusion of 2 X 10(9) colony forming units/kg of GBS. Nine piglets were pretreated with 8 mg/kg of dazmegrel (DAZ), a TxA2 synthetase inhibitor, and nine animals received GBS without DAZ pretreatment. Pulmonary and systemic arterial pressures, pulmonary vascular resistance, pulmonary blood flow, respiratory gas tensions, intrapulmonary shunt, and SD of pulmonary blood flow, an index of ventilation perfusion mismatching, were measured. Systemic and pulmonary arterial levels of thromboxane B2 and 6-keto-PGF1 alpha were also measured. The sham-treated animals showed the expected rise in pulmonary arterial pressure from 12 +/- 3 to 29 +/- 7 torr, (p less than 0.02). By comparison, the animals pretreated with DAZ did not demonstrate pulmonary arterial hypertension and had a delay in the fall in pulmonary blood flow until 2 h postinfusion. Arterial PO2 did not decline significantly after the GBS infusion in the DAZ-pretreated animals; the untreated animals showed a significant fall in pO2 from baseline. There was no significant change in intrapulmonary shunt or SD of pulmonary blood flow compared to baseline in the DAZ-pretreated animals. The elevation in thromboxane B2 occurring with GBS sepsis did not occur in the DAZ-pretreated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

395 HEMODYNAMIC CONSEQUENCES OF NITROGLYCERIN INFUSION DURING GROUP B STREPTOCOCCAL SEPSIS IN PIGLETS

Cardiovascular collapse is a common cause of death in newborn sepsis. Vasodilator therapy has recently been suggested to be of significant hemodynamic benefit in a number of shock states. We assessed the effects of nitroglycerin (NG), a direct-acting smooth muscle relaxant, on systemic and pulmonary hemodynamics in a piglet model of Group 8 Streptococcal sepsis. Piglets (n=4) were anaesthetized, intubated, and ventilated. Systemic blood pressure (BP), pulmonary artery pressure (PAP), cardiac output (CO), and heart rate (HR) were monitored directly and continuously. Sepsis was induced by continuous infusion of serotype Ib Group B Streptococci (GBS) @ approximately 5 × 107 organisms/kg/min. Ventricular filling pressures were held constant during the entire experiment by adjustment of i.v. infusion rate. After 30 minutes of GBS infusion, CO fell by 32 ± 7% (S.D.), PAP rose by 225 ± 97% (both p< 0.01) while BP fell by 1 ± 6% and HR rose b 4 ± 4% (both p = N.S.) While GBS infusion continued, NG infusion was begun. For NG @ 8 mcg/kg/min and 16 mcg/kg/min respectively, CO fell by 7 ± 9% (p = N.S.) and 19 ± 11% (p< 0.01), BP fell by 9 ± 6% (p< 0.05) and 13 ± 4% (p< 0.01), PAP rose by 2 ± 9% and 4 ± 16% (both p = N.S.), and HR rose by 7 ± 9% (p = N.S.) and 11 ± 6% (p< 0.05). Conclusion: NG infusion during GBS sepsis in piglets had little apparent hemodynamic benefit.

396 SELECTIVE SYSTEMIC VASOCONSTRICTION WITH PRESERVED CARDIAC OUTPUT DURING GBS-INDUCED PULMONARY HYPER TENSION IN PIGLETS: AN ALTERNATIVE APPROACH TO PPHN?

Pharmacologic therapy directed at selectively lowering pulmonary artery pressure (PAP) in persistent pulmonary hypertension of the newborn (PPHN) has been largely unsuccessful. As an alternative approach, we have modelled PPHN in septic piglets, and achieved selective elevation of systemic blood pressure (BP) while preserving cardiac output (CO). Piglets (n=4) were anaesthetized, intubated, and ventilated. BP, PAP, and CO were measured directly and continuously. Pulmonary hypertension was induced by intravenous infusion of serotype Ib Group B Streptococci (GBS) @ approximately 5 × 107 organisms/kg/min. After 30 minutes of GBS infusion, PAP had risen by 225 ± 972 (S.D;), CO fell by 32 ± 7%, (both p < 0.01) and BP fell by 1 ± 6% (p = N.S.). While GBS continued, infusions of Nitroglycerin (NG) @ 16 mcg/kg/min plus Epinephrine (EPI) @ 2 mcg/kg/min were begun. After 1 hour of NG + EPI, BP had risen by 41 ± 18% (p < 0.01), while PAP fell by 3 ± 18% and CO fell by 18 ± 24% (both p = N.S.). Conclusions: 1) PPHN can be modelled by GBS infusion in piglets. 2) NG + EPI selectively elevated BP without raising PAP in this model. 3) NG + EPI induced selective elevation of systemic BP without significantly decreasing CO. 4) Selective systemic vasoconstriction with preserved CO may be a feasible strategy for human infants with PPHN.

373 SELECTIVE INHIBITION OF THROMBOXANE (Tx) SYNTHETASE PREFERENTIALLY REDUCES SEPTIC PULMONARY HYPERTENSION IN PIGLETS

Non-specific inhibition of prostaglandin (PG) synthesis reduces elevated pulmonary artery pressure (PAP) in animal models of newborn sepsis. We hypothesized that Tx was the PG which mediated the septic pulmonary hypertension, and investigated the effects of selective inhibition of Tx synthetase during Group B Streptococcal (GBS) sepsis in piglets. 4 piglets were anesthetized, intubated, ventilated and instrumented. Plasma Tx and prostacyclin (PC) metabolites were determined by RIA. Pulmonary hypertension was induced by continuous infusion of GBS. After induction of sepsis, PAP rose from 13±2 (SEM) to 42±5 mmHg, and cardiac output (CO) dropped from 104±6 to 52±6. BP remained unchanged. Concurrently, TxB2 levels rose from 451±264 to 3370±610 pg/ml (p<0.05) and 6 keto PGF1α levels rose from 323±55 to 1322±569. While GBS infusion continued, a thromboxane synthetase inhibitor, dazemgrel (Dz)(UK 38485) was then administered at 1 mg/kg. In response to treatment, PAP decreased rapidly to 16±1 mmHg, BP and CO remained stable. TxB2 levels dropped to 1960±360 and 6 keto PGF1α (a prostacyclin metabolite) levels increased to 2090±363. Conclusions: 1.GBS elevated PAP in piglets while raising both TxB2 and PC metabolites. 2. Dz selectively reduced TxB2 and shunted Pg production towards PC. 3. Dz preferentially diminished PAP during GBS sepsis. 4. Selective inhibition of specific prostaglandins may benefit septic infants with elevated PAP.

Nonhomogeneous redistribution of mesenteric blood flow after tolazoline during group B streptococcal sepsis in piglets.

The effect of tolazoline (Tz) on mesenteric blood flow was evaluated in a piglet model of group B streptococcal (GBS) sepsis. GBS infusion decreased cardiac output and mesenteric blood flow equivalently, while increasing systemic and mesenteric vascular resistance. At three doses between 2 and 25 mg/kg, Tz increased cardiac output and decreased systemic vascular resistance. However, at no dose did Tz improve the diminished mesenteric artery blood flow which accompanied GBS sepsis. The potential use of Tz in neonatal sepsis may be limited by its nonhomogeneous redistribution of blood flow.

Hemodynamic consequences of tolazoline in neonatal group B streptococcal bacteremia: an animal model.

Using a piglet model of neonatal sepsis, we have determined that Group B streptococcal (GBS) bacteremia is associated with a state of vascular hyper-resistance in both the pulmonary and systemic circulations. This elevated vascular resistance is accompanied by a significant fall in cardiac output despite the assurance of constant intravascular fluid volume. Pulmonary artery pressure rises extensively while systemic blood pressure remains essentially unchanged during this GBS infusion protocol. We report here our attempts to relieve the vascular hyperresistance of GBS infusion by administration of an alpha-sympathetic antagonist, tolazoline (Tz). We found that Tz, in a dose-related fashion, decreased both systemic and pulmonary vascular resistance over the entire range from 2 to 25 mg/kg. Further, at all doses tested, the resistance-reducing effect of Tz was equal in the systemic and pulmonary vascular beds. No selective pulmonary or systemic vasodilatory effect was demonstrated by Tz in this model of neonatal pulmonary hypertension. The reduction of systemic vascular resistance was accompanied by a significant elevation in total body cardiac output at all Tz doses. Compared to pre-Tz values, cardiac output rose by 24, 55, and 55% after Tz at 2, 8.3, and 25 mg/kg respectively. In addition, administration of Tz to septic normovolemic piglets reliably produced a transient decrease of systemic blood pressure. For Tz doses of 2 and 8.3 mg/kg, steady state systemic blood pressure returned to pre-Tz levels within 10 min. However, after Tz at 25 mg/kg, steady state systemic blood pressure remained significantly below pre-Tz levels.