Intravenous tezosentan and vardenafil attenuate acute hypoxic pulmonary hypertension

Abstract Geiger, Ralk, Benedikt Treml, Axel Kleinsasser, Nikolaus Neu, Victoria Fischer, Joerg I. Stein, and Alexander Loeckinger. Intravenous tezosentan and vardenafil attenuate acute hypoxic pulmonary hypertension. High Alt. Med. Biol. 9:223-227, 2008-Excessive hypoxic pulmonary hypertension imposes right ventricular strain by increasing afterload that may lead to right heart failure and death. Increased phosphodiesterase activity, as well as increased levels of endothelin-1, has been discussed as molecular mechanisms. We investigated the hemodynamic and intrapulmonary effects of the intravenous dual endothelin A and B receptor blocker tezosentan, and of the phosphodiesterase-5 (PDE-5) antagonist vardenafil in a pig model of acute normobaric hypoxic pulmonary hypertension. Eighteen 4-week-old ventilated white farm pigs were exposed to normobaric hypoxia (FiO(2) 12%) and randomly assigned to three groups (n = 6) in order to receive either intravenous tezosentan or vardenafil or to serve as control. Arterial alveolar oxygen differences were the same with both drugs. After 90 min of treatment, pulmonary artery pressure and vascular resistance were significantly lower in both treatment groups when compared to controls (p < 0.001). Cardiac index increased significantly with vardenafil alone (2.8 l . min(1) . m(2) +/- 0.7 to 4.2 l . min . m(2) +/- 0.7, p = 0.0003). Intravenous tezosentan, as well as vardenafil equipotently attenuate acute hypoxic pulmonary hypertension without afflicting pulmonary gas exchange. However, cardiac index increases with vardenafil only.     

Sustained Prolongation of the QTc Interval after Anesthesia with Sevoflurane in Infants during the First 6 Months of Life

Background: Sevoflurane, an inhalational anesthetic frequently administered to infants, prolongs the QT interval of the electrocardiogram in adults. A long QT interval resulting in fatal arrhythmia may also be responsible for some cases of sudden death in infants. As the QT interval increases during the second month of life and returns to the values recorded at birth by the sixth month, we evaluated the effect of sevoflurane on the QT interval during and after anesthesia in this particular population.

Methods: In this prospective two-group trial we examined pre-, peri-, and postoperative electrocardiograms of 36 infants aged 1 to 6 months scheduled for elective inguinal or umbilical hernia repair. Anesthesia was induced and maintained with either sevoflurane, or the well-established pediatric anesthetic halothane. Heart rate corrected (c) QTc and JTc interval (indicator of intraventricular conduction delays) were recorded from electrocardiograms before and during anesthesia, and at 60 min after emergence from anesthesia.

Results: Prolonged QTc was observed during sevoflurane anesthesia (mean [+/-SD], 473 +/- 19 ms, P < 0.01). Sixty minutes after emergence from anesthesia, QTc was still prolonged (433 +/- 15 ms) in infants treated with sevoflurane compared with those treated with halothane (407 +/- 33 ms, P < 0.01). Analogous differences were found for the JTc interval.     

Tezosentan decreases pulmonary artery pressure and improves survival rate in an animal model of meconium aspiration

Acute pulmonary arterial hypertension in acute lung injury aggravates the clinical course and complicates treatment. Increased release and turnover of endogenous endothelin-1 is known to be a major determinant in the pathophysiology of pulmonary arterial hypertension of various etiologies. We tested whether intravenous tezosentan, a dual endothelin receptor antagonist, reduced pulmonary artery pressure in a pig model of acute lung injury induced by meconium aspiration. Acute pulmonary arterial hypertension was induced in 12 anesthetized and instrumented pigs by instillation of human pooled meconium in a 20% solution. Hemodynamic and gas exchange parameters were recorded every 30 min. Six animals received tezosentan 5 mg/kg after 0 and 90 min; six animals served as controls. Tezosentan led to a decrease of mean pulmonary artery pressure (PAP) from 33.4 +/- 4.0 mm Hg to 24.7 +/- 2.1 mm Hg and pulmonary vascular resistance (PVR) from 7.8 +/- 1.4 mm Hg.L(-1).min.m2 to 5.2 +/- 0.7 mm Hg.L(-1).min.m2. All animals treated with tezosentan survived, whereas in the control group four out of six animals died. Tezosentan improved survival and decreased pulmonary artery pressure in a porcine model of acute pulmonary arterial hypertension after meconium aspiration. Tezosentan has the potential for effective pharmacological treatment of pulmonary arterial hypertension following acute lung injury.     

The Influence of Cuff Volume and Anatomic Location on Pharyngeal, Esophageal, and Tracheal Mucosal Pressures with the Esophageal Tracheal Combitube

Background: The authors determined the influence of cuff volume and anatomic location on pharyngeal, esophageal, and tracheal mucosal pressures for the esophageal tracheal combitube.

Methods: Twenty fresh cadavers were studied. Microchip sensors were attached to the anterior, lateral, and posterior surfaces of the distal and proximal cuffs of the small adult esophageal tracheal combitube. Mucosal pressure for the proximal cuff in the pharynx was measured at 0- to 100-ml cuff volume in 10-ml increments, and for the distal cuff in the esophagus and trachea were measured at 0- to 20-ml cuff volume in 2-ml increments. The proximal cuff volume to form an oropharyngeal seal of 30 cm H2O was determined. In addition, mucosal pressures for the proximal cuff in the pharynx were measured in four awake volunteers with topical anesthesia.

Results: There was an increase in mucosal pressure in the trachea, esophagus, and pharynx at all cuff locations with increasing volume (all:P < 0.001). Pharyngeal mucosal pressures were highest posteriorly (50-ml cuff volume: 99 +/- 62 cm H2O; 100-ml cuff volume: 255 +/- 161 cm H2O). Esophageal mucosal pressures were highest posteriorly (10-ml cuff volume: 108 +/- 55 cm H2O; 20-ml cuff volume: 269 +/- 133 cm H2O). Tracheal mucosal pressures were highest anteriorly (10-ml cuff volume: 98 +/- 53 cm H2O; 20-ml cuff volume: 236 +/- 139 cm H2O). The proximal cuff volume to obtain an oropharyngeal seal of 30 cm H2O was 47 +/- 12 ml. Pharyngeal mucosal pressures were similar for cadavers and awake volunteers.     

Proportional assist ventilation reduces the work of breathing during exercise at moderate altitude

Reducing the work of breathing (WOB) during exercise and thus the oxygen required solely for ventilation may be an option to increase the oxygen available for nonventilatory physiological tasks at altitude. This study evaluated whether pressure support ventilation (PSV) and proportional assist ventilation (PAV) may partially reduce WOB during exercise at altitude. Seven volunteers breathing with either PSV or PAV or without support (control) were examined for WOB, inspiratory pressure time product (iPTP), and (O(2)) before and during pedaling at 160 W for 4 min on an ergometer at an altitude of 2860 m, where barometric pressure and oxygen partial pressure are approximately 30% less than at sea level. PSV and PAV reduced WOB from 4.5 +/- 0.9 J/L(-1)/min(-1) during unsupported breathing to 3.7 +/- 0.4 (p < 0.05) and 3.2 +/- 0.7 (p < 0.01), respectively. iPTP was reduced during PAV (570 +/- 151 cm H(2)O/sec/min(-1), p < 0.01), but not during PSV (727 +/- 116, p = 0.58) compared with unsupported ventilation during exercise (763 +/- 90). During PSV and PAV breathing, higher arterial oxygen saturations (84 +/- 2%, p < 0.05, and 86 +/- 1%, p < 0.01, respectively) were observed compared with control (80 +/- 3%), indicating that PSV and PAV attenuated hypoxemia during exercise at altitude. Total body (O(2)), however, was not reduced during PSV or PAV. In conclusion, both PSV and PAV reduced the WOB during exercise at altitude, but only PAV reduces iPTP. Both modes reduce hypoxemia, which may be due to higher alveolar ventilation or decreased ventilation-perfusion heterogeneity compared to unsupported breathing.     

Reversing sevoflurane-associated Q-Tc prolongation by changing to propofol

Congenital or acquired forms of the long Q-T syndrome may result in ventricular tachycardia known as torsade de pointes. Many drugs including volatile anaesthetics modify the Q-T interval. Sevoflurane is known to prolong of the rate-corrected Q-T interval (Q-Tc). The objective of this study was to determine whether the sevoflurane-associated Q-Tc prolongation is rapidly reversible when propofol is substituted for sevoflurane. Thirty-two female patients were allocated to two groups. All patients received sevoflurane induction and anaesthesia for 15 min. In one group, sevoflurane was then discontinued and anaesthesia maintained on propofol for another 15 min. The second group received sevoflurane anaesthesia for 30 min. Measurements were taken before, and 15, 20, 25 and 30 min after induction. Q-Tc prolongation was significantly reduced 5, 10 and 15 min after propofol had been substituted for sevoflurane. We conclude that the sevoflurane-associated Q-Tc prolongation is fully reversible within 15 min when propofol is substituted for sevoflurane.     

A pig model of high altitude pulmonary edema

High altitude pulmonary edema (HAPE) affects unacclimatized individuals ascending rapidly to high altitude. The pathogenesis of HAPE is not fully elucidated, and many investigative techniques that could provide valuable information are not suitable for use in humans; thus, an animal model is desirable. Rabbits, sheep, dogs, and ferrets have been shown not to consistently develop HAPE, and studies in rats are limited by the animal's small size and inconsistent response. Pigs develop a marked pulmonary vasoconstrictive response to hypoxia, and preliminary studies of HAPE in pigs have been promising. To determine the suitability of pigs as an animal model of HAPE, we exposed six subadult (20 to 25 kg) pigs to normobaric hypoxia (10% oxygen) for 48 hr. One week before, and immediately after exposure to hypoxia, under anesthesia, arterial blood gases were obtained and bronchoalveolar lavage (BAL) and chest x-ray were performed. Hypoxia increased alveolar-arterial pressure difference for oxygen from 22 +/- 9 to 38 +/- 5 torr, p < 0.01) and red cell (from 12.3 +/- 5.9 to 27.4 +/- 5.3 cells x 10(5)/mL(-1), p < 0.001) and white cell (from 1.59 +/- 0.90 to 7.88 +/- 3.36 cells x 10(5)/mL(-1), p < 0.05) concentrations in BAL in all animals. Total BAL protein concentration increased by 64% and fractional albumin by 38% (both p < 0.05) posthypoxia. One animal had evidence of pulmonary edema on X ray. Some pigs develop findings consistent with early HAPE when exposed to normobaric hypoxia. Increasing the duration of hypoxic exposure or exercising the animals in hypoxia may better model the disease process observed in humans with clinically significant HAPE.     

Sustained prolongation of the QTc interval after anesthesia with sevoflurane in infants during the first 6 months of life

BACKGROUND: Sevoflurane, an inhalational anesthetic frequently administered to infants, prolongs the QT interval of the electrocardiogram in adults. A long QT interval resulting in fatal arrhythmia may also be responsible for some cases of sudden death in infants. As the QT interval increases during the second month of life and returns to the values recorded at birth by the sixth month, we evaluated the effect of sevoflurane on the QT interval during and after anesthesia in this particular population. METHODS: In this prospective two-group trial we examined pre-, peri-, and postoperative electrocardiograms of 36 infants aged 1 to 6 months scheduled for elective inguinal or umbilical hernia repair. Anesthesia was induced and maintained with either sevoflurane, or the well-established pediatric anesthetic halothane. Heart rate corrected (c) QTc and JTc interval (indicator of intraventricular conduction delays) were recorded from electrocardiograms before and during anesthesia, and at 60 min after emergence from anesthesia. RESULTS: Prolonged QTc was observed during sevoflurane anesthesia (mean [+/-SD], 473 +/- 19 ms, P< 0.01). Sixty minutes after emergence from anesthesia, QTc was still prolonged (433 +/- 15 ms) in infants treated with sevoflurane compared with those treated with halothane (407 +/- 33 ms, P< 0.01). Analogous differences were found for the JTc interval. CONCLUSIONS: Despite a shorter elimination time than better known inhalational anesthetics, sevoflurane induction and anesthesia results in sustained prolongations of QTc and JTc interval in infants in the first 6 months of life. Electrocardiogram monitoring until the QTc interval has returned to preanesthetic values may increase safety after sevoflurane anesthesia.     

Large cuff volumes impede posterior pharyngeal mucosal perfusion with the laryngeal tube airway

PURPOSE: The laryngeal tube airway (LTA) is a new extraglottic airway device with a large proximal cuff that inflates in the laryngopharynx and a distal conical cuff that inflates in the hypopharynx. We determine the influence of the cuff volume and anatomic location on pharyngeal mucosal pressures for the LTA. METHODS: Fifteen fresh cadavers were studied. Microchip sensors were attached to the (anatomic location) anterior, lateral and posterior surface of the distal cuff (hypopharynx) and proximal cuff (laryngopharynx) of the size 4 LTA. Oropharyngeal leak pressure (OLP) and mucosal pressures were measured at 0-140 mL cuff volume in 20-mL increments. In addition, mucosal pressures for the proximal cuff were measured in three awake, topicalized volunteers. RESULTS: OLP and mucosal pressure at all locations increased with cuff volume (all: P < 0.01). Mucosal pressures were highest posteriorly. Mucosal pressures only exceeded 35 cm H(2)O (pharyngeal mucosal perfusion pressure) in the anterior and posterior laryngopharynx and when the cuff volume was > 80-100 mL. Mucosal pressures were similar for cadavers and awake volunteers. CONCLUSION: Mucosal pressures for the LTA increase with cuff volume, are highest posteriorly and potentially exceed mucosal perfusion pressure when cuff volume exceeds 80-100 mL.