Recombinant angiotensin-converting enzyme 2 suppresses pulmonary vasoconstriction in acute hypoxia.

OBJECTIVE: Alveolar hypoxia as a result of high altitude leads to increased pulmonary arterial pressure. The renin-angiotensin system is involved in the regulation of pulmonary arterial pressure through angiotensin-converting enzyme 2 (ACE2). It remains unknown whether ACE2 administration alters pulmonary vascular pressure in hypoxia. METHODS: We investigated 12 anesthetized pigs instrumented with arterial, central venous, and Swan-Ganz catheters exposed to normobaric hypoxia (fraction of inspired oxygen = 0.125) for 180 minutes. After taking baseline measurements in normoxia and hypoxia, ACE2 400 µg·kg(-1) was administered to 6 animals, and another 6 served as control. Ventilatory variables, arterial blood gases, ventilation/perfusion (V̇A/Q̇) relationships, and plasma angiotensin II concentrations were assessed before and at 30, 90, and 150 minutes in hypoxia after ACE2 or placebo administration. Hemodynamic variables and cardiac output were observed every 30 minutes. RESULTS: We observed lower pulmonary arterial pressure (maximum: 30 vs 39 mm Hg, P < .01) and lower pulmonary vascular resistance (maximum: 4.1 vs 7.5 Wood units, P <.01) in animals treated with ACE2. There was a trend (P =.09) toward lower angiotensin II plasma concentrations among ACE2-treated animals. Cardiac variables and systemic arterial pressure in hypoxia remained unaffected by ACE2. Ventilation/perfusion relationships and Pao(2) did not differ between groups. CONCLUSIONS: In acute pulmonary hypertension, administration of ACE2 blunts the rise in pulmonary arterial pressure that occurs in response to hypoxia. Recombinant ACE2 may be a treatment option for high altitude pulmonary edema and hypoxia-associated pulmonary hypertension.

Hypoxia has a greater effect than exercise on the redistribution of pulmonary blood flow in swine.

Strenuous exercise combined with hypoxia is implicated in the development of high-altitude pulmonary edema (HAPE), which is believed to result from rupture of pulmonary capillaries secondary to high vascular pressures. The relative importance of hypoxia and exercise in altering the distribution of pulmonary blood flow (PBF) is unknown. Six chronically catheterized specific pathogen-free Yorkshire hybrid pigs (25.5 +/- 0.7 kg, means +/- SD) underwent incremental treadmill exercise tests in normoxia (Fi(O(2)) = 0.21) and hypoxia (Fi(O(2)) = 0.125, balanced order), consisting of 5 min at 30, 60, and 90% of the previously determined Vo(2max). At steady state (~4 min), metabolic and cardiac output data were collected and fluorescent microspheres were injected over approximately 30 s. Later the fluorescent intensity of each color in each 2-cm(3) lung piece was determined and regional perfusion was calculated from the weight-normalized fluorescence. Both hypoxia and exercise shifted PBF away from the ventral cranial lung regions toward the dorsal caudal regions of the lung, but hypoxia caused a greater dorsal caudal shift in PBF at rest than did near-maximal exercise in normoxia. The variance in PBF due to hypoxia, exercise, and vascular structure was 16 +/- 4.2, 4.0 +/- 4.4, and 59.4 +/- 11.4%, respectively, and the interaction between hypoxia and exercise represented 12 +/- 6.5%. This observation implies that there is already a maximal shift with in PBF with hypoxia in the dorsal-caudal regions in pigs that cannot be exceeded with the addition of exercise. However, exercise greatly increases the pulmonary arterial pressures and therefore the risk of capillary rupture in high flow regions.

Tidal volume dependency of gas exchange in bronchoconstricted pig lungs.

Independent of airway pressure, pulmonary resistance is known to fall with increasing tidal volumes, traditionally thought to result from radial traction on the airways. R. C. Anafi and T. A. Wilson (J Appl Physiol 91: 1185-1192, 2001) recently presented a model of a single terminal airway that explains the tidal volume-associated fall in resistance with an additional mechanism pertinent to narrow airways: a stable, nearly closed airway that is challenged with an increase in tidal volume "pops open" to become a stable, well-opened airway, and thus resistance drops suddenly. To test this model in vivo, the effects of high (24 ml/kg) and low (9 ml/kg) tidal volume in bronchoconstricted lungs were assessed using 1) the multiple inert gas elimination technique (MIGET) and 2) a 15-breath multiple breath inert gas washout (MBW) technique in anesthetized pigs. With high tidal volume, ventilation/perfusion (Va/Q) mismatch was reduced (log SD Q from 1.30 +/- 0.11 to 1.09 +/- 0.12, P < 0.05), and blood flow to lung units with Va/Q ratios < 0.1 was significantly reduced (37 +/- 4% of cardiac output to 7 +/- 4%, P < 0.05). Dynamic compliance was twice as high during high-tidal-volume ventilation (P = 0.002). MBW analysis revealed that, while heterogeneity of ventilation during bronchoconstriction was not significantly different between either low or high tidal volume (log SD Vmbw = 1.39 +/- 0.09 and 1.34 +/- 0.02, respectively), preinspiratory lung volume (PILV) decreased by 42% with low-tidal-volume ventilation (P < 0.05), whereas it did not change with high-tidal-volume ventilation. The higher PILV during high tidal volume is also consistent with Anafi and Wilson's model. In summary, the outcomes from MIGET, and to some extent the MBW, in our anesthetized and mechanically ventilated pigs are consistent with a bistable terminal airway model as proposed by Anafi and Wilson. However, our data do not allow exclusion of other mechanisms that may lead to improved ventilatory distribution when tidal volume is increased.

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.

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.

Pulmonary gas exchange after cardiopulmonary resuscitation with either vasopressin or epinephrine.

OBJECTIVE: It is well established that epinephrine administered during cardiopulmonary resuscitation results in pulmonary gas exchange disturbances. It is uncertain how vasopressin affects gas exchange after cardiopulmonary resuscitation. DESIGN: Prospective, randomized experimental study. SETTING: Animal research laboratory. SUBJECTS: Twenty domestic pigs. INTERVENTIONS: Animals were subjected to ventricular fibrillation and cardiopulmonary resuscitation by using either vasopressin or epinephrine. Hemodynamic and pulmonary gas exchange (multiple inert gas elimination technique) variables were recorded before cardiopulmonary resuscitation and 10, 30, 60, and 120 mins after return of spontaneous circulation when either epinephrine (control) or vasopressin was used. MEASUREMENTS AND MAIN RESULTS: At 10 mins after return of spontaneous circulation, blood flow to low V /Q lung units was increased in animals treated with epinephrine (17.8 +/- 6 vs. 2.6 +/- 3%, mean +/- sd, p<.01). Resulting carbon dioxide elimination was impaired in animals treated with epinephrine but not in animals treated with vasopressin (PaCO2, 55 +/- 2 vs. 46 +/- 4 torr, p<.05). Thirty minutes after return of spontaneous circulation, blood flow to lung units with a normal VA /Q ratio was reduced in animals treated with epinephrine (79 +/- 1 vs. 84 +/- 12%, p<.05), resulting in a depressed PaO2 (147 +/- 4 vs. 127 +/- 10 torr, p<.05). CONCLUSION: Vasopressin compared with epinephrine for cardiopulmonary resuscitation resulted in better gas exchange variables in the early postresuscitation phase.

Brief report: pressure support ventilation during an ascent and on the summit of Mt. Everest? A theoretical approach.

At extreme altitude, air has an almost identical composition compared to air at sea level, while its pressure is altitude-dependently lower. When supplementary oxygen is used to achieve an acceptable inspiratory pressure of oxygen (PI(O2)) during climbing, the barometric pressure difference to lower altitudes is not compensated for. In this report, we tried theoretically to apply pressure support ventilation (PSV) to partially compensate for low barometric pressures. PSV is widely used for respiratory home care and is applicable via a nasal mask. Since there are light-weight units with long battery lives on the market, we speculated that these units may to some extent replace bottled oxygen. PSV was in theory applied at barometric pressures of 400 torr (Everest Base Camp), 284 torr (South Col), and 253 torr (summit of Mt. Everest). We found that during PSV at a mean airway pressure of 16.5 torr on the summit of Mt. Everest, a fraction of inspired oxygen (FI(O2)) of 0.34 sufficed to achieve an alveolar partial pressure (PA(O2)) of 67 torr. PSV increases PI(O2) by 3.5 torr, which in theory elevates the maximum oxygen consumption (V(O2max)) by 218 mL.min(-1) in an acclimatized climber in this setting. An additional benefit of PSV at extreme altitude may come from the unloading of the respiratory muscles.