Robert K. Fitzgerald

Emergence of Smooth Muscle Cell Endothelin B–Mediated Vasoconstriction in Lambs With Experimental Congenital Heart Disease and Increased Pulmonary Blood Flow

Background—Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow. Methods and Results—Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2±113.8 versus 209.8±61.8 pg/g, P <0.05). In shunt lambs (n=9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ETA receptor antagonist PD 156707 (n=3). This pulmonary vasoconstriction was mimicked by exogenous Ala1,3,11,15 ET-1 (4 Ala ET-1), the ETB receptor agonist, and was blocked by the ETB receptor antagonist BQ 788 (n=3). However, in control lambs (n=7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ETB receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs. Conclusions—Over time, increased pulmonary blood flow and/or pressure results in the emergence of ETB-mediated vasoconstriction, which coincides with the emergence of ETB receptors on smooth muscle cells. These data suggest an important role for ETB receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.

Tezosentan, a combined parenteral endothelin receptor antagonist, produces pulmonary vasodilation in lambs with acute and chronic pulmonary hypertension

Objective: To investigate the hemodynamic effects of tezosentan in the intact lamb both at rest and during acute and chronic pulmonary hypertension. Design: Prospective, randomized experimental study. Setting: University-based research laboratory. Subjects: Lambs with and without pulmonary hypertension. Interventions: Six newborn lambs were instrumented to measure vascular pressures and left pulmonary blood flow. The hemodynamic effects of tezosentan (0.5, 1.0, 5.0 mg/kg, intravenously) were studied at rest and during U46619-induced pulmonary hypertension. Following in utero placement of an aortopulmonary vascular graft, nine additional lambs with increased pulmonary blood flow and chronic pulmonary hypertension (shunt) were also studied at 1 wk (n = 5) and 8 wks (n = 4) of age. Measurements and Main Results: At rest, tezosentan had no significant effect on any of the variables. During acute U46619-induced pulmonary hypertension, tezosentan caused a dose-dependent decrease in pulmonary arterial pressure (from 5.9% ± 4.7 to 16.0% ± 10.7; p < .05) and pulmonary vascular resistance (from 6.2% ± 8.0 to 21% ± 8.8; p < .05). Mean systemic arterial pressure was unchanged. In 1- and 8-wk-old shunt lambs with increased pulmonary blood flow, tezosentan (1 mg/kg) produced potent nonselective pulmonary vasodilation. Conclusions: Tezosentan, a combined endothelin receptor antagonist optimized for parenteral use, induces potent selective pulmonary vasodilation during acute U46619-induced pulmonary hypertension and potent nonselective vasodilation in chronic pulmonary hypertension secondary to increased pulmonary blood flow. In general, the hemodynamic effects of bolus doses of tezosentan occurred within 60 secs of administration and lasted ∼5–10 mins. The hemodynamic profile of intravenous tezosentan may make it a useful adjunct therapy for acute pulmonary hypertensive disorders and warrants further study.

Cost and safety of pediatric intensive care physician-placed broviac catheters.

Objective: To compare the cost and safety of placement of Broviac catheters in children by pediatric intensivists in a sedation suite versus placement by pediatric surgeons in the operating room. Design: Single-center retrospective analysis. Setting: Pediatric sedation suite and operating rooms in a tertiary care children’s hospital. Patients: All pediatric patients with Broviac catheters placed (n = 253) at this institution over a 3-year period from 2007 to 2009. Interventions: None. Measurements and Main Results: We reviewed the charts of all pediatric patients with Broviac catheters placed, either by intensivists or surgeons, and compared cost and outcomes. Procedure safety was assessed and categorized into immediate, short-term (within 2 wk of procedure), and long-term outcomes. Anesthetic safety and billing data for the procedure were also collected. Among similar patient populations, immediate complications, such as pneumothorax, procedure failure (p > 0.999), and anesthetic complications (p = 0.60), were not significantly different. Short-term outcomes, including infection (p = 0.27) and catheter malfunction (p > 0.999), were not different. Long-term outcomes, including mean indwelling catheter days (p = 0.60) and removal due to catheter infection (p = 0.09), were not different between the groups. Overall cost of the procedure was significantly different:

Alterations in ET-1, not nitric oxide, in 1-week-old lambs with increased pulmonary blood flow.

7,031 (±

Nitric oxide-endothelin-1 interactions after acute ductal constriction in fetal lambs

784) when performed by surgeons and

Endothelial alterations during inhaled NO in lambs with pulmonary hypertension: implications for rebound hypertension

3,565 (±

Nitric oxide-endothelin-1 interactions after surgically induced acute increases in pulmonary blood flow in intact lambs.

311) when performed by intensivists (p < 0.001). Conclusions: Pediatric critical care physicians can place Broviac catheters as safely as pediatric surgeons and at a lower cost in a defined patient population.