Hemorrhagic Shock: Blood Marker Sequencing and Pulmonary Gas Exchange.

BACKGROUND: The early identification of internal hemorrhage in critically ill patients may be difficult. Besides circulatory parameters, hemoglobin and lactate concentration, metabolic acidosis and hyperglycemia serve as laboratory markers for bleeding. In this experiment, we examined pulmonary gas exchange in a porcine model of hemorrhagic shock. Moreover, we sought to investigate if a chronological order of appearance regarding hemoglobin, lactatemia, standard base excess/deficit (SBED) and hyperglycemia exists in early severe hemorrhage. METHODS: In this prospective, laboratory study, twelve anesthetized pigs were randomly allocated to exsanguination or a control group. Animals in the exsanguination group (n = 6) endured a 65% blood loss over 20 min. No intravenous fluids were administered. Measurements were taken before, immediately after, and at 60 min after the completed exsanguination. Measurements included pulmonary and systemic hemodynamic variables, hemoglobin concentration, lactate, base excess (SBED), glucose concentration, arterial blood gases, and a multiple inert gas assessment of pulmonary function. RESULTS: At baseline, variables were comparable. Immediately after exsanguination, lactate and blood glucose were increased (p = 0.001). The arterial partial pressure of oxygen was increased at 60 min after exsanguination (p = 0.04) owing to a decrease in intrapulmonary right-to-left shunt and less ventilation-perfusion inequality. SBED was different to the control only at 60 min post bleeding (p < 0.001). Hemoglobin concentration did not change at any time (p = 0.97 and p = 0.14). CONCLUSIONS: In experimental shock, markers of blood loss became positive in chronological order: lactate and blood glucose concentrations were raised immediately after blood loss, while changes in SBED lagged behind and became significant one hour later. Pulmonary gas exchange is improved in shock.

Oxygen availability in a HAPE-positive and a HAPE-negative woman before and during a visit to 3480 meters.

BACKGROUND: Testing the hypoxic ventilatory response (HVR) at low-altitude helps to detect those who do not hyperventilate appropriately in hypoxia but might not necessarily predict the HVR and the risk to develop acute mountain sickness (AMS) at high altitude. However, a low HVR seems to be particularly prevalent in individuals susceptible to high-altitude pulmonary edema (HAPE+). In this short communication, we assessed differences in physiological parameters in two comparable women before and 3 hours after exposure to 3,480 meters. One woman had a (clinically diagnosed) history of high-altitude pulmonary edema (HAPE+) while the other did well at previous exposures to high altitude (HAPE-). METHODS: Heart rate, blood pressure, ventilation, arterial blood gas variables, arterial haemoglobin saturation, haemoglobin concentration, arterial oxygen content and delta plasma volume were measured or calculated before and after arrival at high altitude. RESULTS: At high altitude, plasma volume decreased in the HAPE- woman which in turn increased haemoglobin concentration. Ventilation was elevated in the HAPE- but not in the HAPE + woman. Arterial oxygen content fell in the HAPE + while it was preserved in the HAPE- woman. This resulted from lower peripheral oxygen saturation (-35%), lower haemoglobin concentration (-12%) and lower arterial partial pressure of oxygen (-59%) in the HAPE+. CONCLUSION: Considerable haemoglobin desaturation and lack of haemoconcentration were characteristics of the HAPE + woman when exposed to high altitude, while the higher arterial oxygen content in the HAPE- woman was related to both haemoconcentration and hyperventilation (and associated haemoglobin saturation).

A Focused Review on the Maximal Exercise Responses in Hypo- and Normobaric Hypoxia: Divergent Oxygen Uptake and Ventilation Responses.

The literature suggests that acute hypobaric (HH) and normobaric (NH) hypoxia exposure elicits different physiological responses. Only limited information is available on whether maximal cardiorespiratory exercise test outcomes, performed on either the treadmill or the cycle ergometer, are affected differently by NH and HH. A focused literature review was performed to identify relevant studies reporting cardiorespiratory responses in well-trained male athletes (individuals with a maximal oxygen uptake, VO2max > 50 mL/min/kg at sea level) to cycling or treadmill running in simulated acute HH or NH. Twenty-one studies were selected. The exercise tests in these studies were performed in HH (n = 90) or NH (n = 151) conditions, on a bicycle ergometer (n = 178) or on a treadmill (n = 63). Altitudes (simulated and terrestrial) varied between 2182 and 5400 m. Analyses (based on weighted group means) revealed that the decline in VO2max per 1000 m gain in altitude was more pronounced in acute NH vs. HH (-7.0 ± 1.4% vs. -5.6 ± 0.9%). Maximal minute ventilation (VEmax) increased in acute HH but decreased in NH with increasing simulated altitude (+1.9 ± 0.9% vs. -1.4 ± 1.8% per 1000 m gain in altitude). Treadmill running in HH caused larger decreases in arterial oxygen saturation and heart rate than ergometer cycling in acute HH, which was not the case in NH. These results indicate distinct differences between maximal cardiorespiratory responses to cycling and treadmill running in acute NH or HH. Such differences should be considered when interpreting exercise test results and/or monitoring athletic training.

Carry-Over Quality of Pre-acclimatization to Altitude Elicited by Intermittent Hypoxia: A Participant-Blinded, Randomized Controlled Trial on Antedated Acclimatization to Altitude.

Intermittent normobaric hypoxia (IH) is increasingly used to pre-acclimatize for a sojourn to high altitude. There is a number of hypoxia - protocols observing the hypoxic ventilatory response (HVR), but little is known about the carry - over quality of the Lake Louise Score (LLS). We thus studied a week - long, 1 h per day poikilocapnic hypoxia protocol on whether acclimatization could be carried over for one week. Rationale for this was that it usually takes one week to get from Europe, Britain or the United States to the base camp of a major mountain. Forty-nine healthy volunteers of both sexes were exposed to daily bouts of 1 h at an inspiratory fraction of oxygen (FiO2) of 0.11 or 0.21 (control) for 7 consecutive days. Seven days after cessation of IH or sham exposures participants were again subjected to hypoxia (FiO2 = 0.11) for 6 h and measurements of isocapnic HVR and blood gases out of the arterialized earlobe were taken and LLS was assessed. In those with IH exposures LLS was reduced which was not the case in those with sham exposure (87 vs. 50%). Changes in HVR or the arterial hemoglobin saturation were not observed. Gender neither affected LLS nor HVR nor blood gases or carry -over quality. We found that our week - long, hypoxia protocol grants a reduction in LLS that can be carried over the time span of one week. In this way, antedated acclimatization may improve safety and comfort on the mountain.

Red Bull Increases Heart Rate at Near Sea Level and Pulmonary Shunt Fraction at High Altitude in a Porcine Model.

Red Bull energy drink is popular among athletes, students and drivers for stimulating effects or enhancing physical performance. In previous work, Red Bull has been shown to exert manifold cardiovascular effects at rest and during exercise. Red Bull with caffeine as the main ingredient increases blood pressure in resting individuals, probably due to an increased release of (nor)-epinephrine. Red Bull has been shown to alter heart rate or leaving it unchanged. Little is known about possible effects of caffeinated energy drinks on pulmonary ventilation/perfusion distribution at sea level or at altitude. Here, we hypothesized a possible alteration of pulmonary blood flow in ambient air and in hypoxia after Red Bull consumption. We subjected eight anesthetized piglets in normoxia (FiO2 = 0.21) and in hypoxia (FiO2 = 0.13), respectively, to 10 mL/kg Red Bull ingestion. Another eight animals served as controls receiving an equivalent amount of saline. In addition to cardiovascular data, ventilation/perfusion distribution of the lung was assessed by using the multiple inert gas elimination technique (MIGET). Heart rate increased in normoxic conditions but was not different from controls in acute short-term hypoxia after oral Red Bull ingestion in piglets. For the first time, we demonstrate an increased fraction of pulmonary shunt with unchanged distribution of pulmonary blood flow after Red Bull administration in acute short-term hypoxia. In summary, these findings do not oppose moderate consumption of caffeinated energy drinks even at altitude at rest and during exercise.

Pharmacologic Agents for the Treatment of Vasodilatory Shock.

Vasodilatory shock is a life-threatening syndrome in critically ill patients and is characterized by severe hypotension and resultant tissue hypoperfusion. This shock state requires the use of vasopressor agents to restore adequate vascular tone. Norepinephrine is still recommended as first-line vasopressor in the management of critically ill patients suffering from severe vasodilation. In the recent time, catecholaminergic vasopressor drugs have been associated with possible side effects at higher dosages. This so-called catecholamine toxicity has focused on alternative noncatecholaminergic vasopressors or the use of moderate doses of multiple vasopressors with complementary mechanisms of action. Besides vasopressin and terlipressin, angiotensin II may be a promising drug for the management of vasodilatory shock. In addition, adjunctive drugs, such as hydrocortisone, methylene blue or ascorbic acid can be added to conventional vasopressor therapy. The objective of this review is to give an overview of the current available vasopressor agents used in vasodilatory shock. A thorough search of PubMed was conducted in order to identify the majority of studies related to the subject. Data on the outcome of several drugs and future perspective of possible management strategies for the therapy of vasodilatory shock are discussed.

Intravenous Levosimendan and Vasopressin in New-Onset Acute Pulmonary Hypertension After Weaning from Cardiopulmonary Bypass.

OBJECTIVE: A novel treatment with intravenous levosimendan and vasopressin for new-onset acute pulmonary hypertension after weaning from cardiopulmonary bypass is described. DESIGN: Retrospective analysis of a case series. SETTING: Single-center study. PARTICIPANTS: Nineteen patients undergoing cardiac surgery exhibited new-onset acute pulmonary hypertension with acute right ventricular dysfunction after cardiopulmonary bypass. INTERVENTION: Pulmonary hypertension with acute right heart dysfunction was treated with levosimendan as inodilator therapy and vasopressin combined with norepinephrine for systemic vasopressor therapy. MEASUREMENTS AND MAIN RESULTS: Mean pulmonary artery pressure decreased from 32 ± 9 to 26 ± 6 mmHg (p = 0.039) in the first 24 hours along with an increase in cardiac output (3.2 ± 1 to 4.2 ± 1.1 L/min; p = 0.012) and resolution of lactic acidosis. The ratio between mean pulmonary artery pressure and mean arterial pressure decreased from 1:2 to 1:3, and Wood units decreased from 3 ± 1 to 1.5 ± 2 (p = 0.042). At 30 days after intervention, 3 patients died. CONCLUSION: The combination of levosimendan for inotropic support of the right ventricle in conjunction with its vasodilatory effect on the pulmonary circulation, along with the combination of vasopressin and norepinephrine for systemic vasopressor therapy, may be an effective alternative for the treatment of acute new-onset pulmonary hypertension and acute right heart dysfunction after cardiopulmonary bypass. Although there are many confounding variables in this case series, these findings justify additional sufficiently powered trials.

Cutaneous Microvascular Blood Flow and Reactivity in Hypoxia.

As is known, hypoxia leads to an increase in microcirculatory blood flow of the skin in healthy volunteers. In this pilot study, we investigated microcirculatory blood flow and reactive hyperemia of the skin in healthy subjects in normobaric hypoxia. Furthermore, we examined differences in microcirculation between hypoxic subjects with and without short-term acclimatization, whether or not skin microvasculature can acclimatize. Fourty-six healthy persons were randomly allocated to either short-term acclimatization using intermittent hypoxia for 1 h over 7 days at an FiO2 0.126 (treatment, n = 23) or sham short-term acclimatization for 1 h over 7 days at an FiO2 0.209 (control, n = 23). Measurements were taken in normoxia and at 360 and 720 min during hypoxia (FiO2 0.126). Microcirculatory cutaneous blood flow was assessed with a laser Doppler flowmeter on the forearm. Reactive hyperemia was induced by an ischemic stimulus. Measurements included furthermore hemodynamics, blood gas analyses and blood lactate. Microcirculatory blood flow increased progressively during hypoxia (12.3 ± 7.1-19.0 ± 8.1 perfusion units; p = 0.0002) in all subjects. The magnitude of the reactive hyperemia was diminished during hypoxia (58.2 ± 14.5-40.3 ± 27.4 perfusion units; p = 0.0003). Short-term acclimatization had no effect on microcirculatory blood flow. When testing for a hyperemic response of the skin's microcirculation we found a diminished signal in hypoxia, indicative for a compromised auto-regulative circulatory capacity. Furthermore, hypoxic short-term acclimatization did not affect cutaneous microcirculatory blood flow. Seemingly, circulation of the skin was unable to acclimatize using a week-long short-term acclimatization protocol. A potential limitation of our study may be the 7 days between acclimatization and the experimental test run. However, there is evidence that the hypoxic ventilatory response, an indicator of acclimatization, is increased for 1 week after short-term acclimatization. Then again, 1 week is what one needs to get from home to a location at significant altitude.

The impact of endotoxin on jejunal tissue oxygenation.

OBJECTIVE: We examined the effects of systemic ETX on jejunal mucoal microcirculatory parameters in anesthetized pigs. METHODS: Jejunal mucosal tissue PO2 was measured employing Clark-type surface oxygen electrodes. Oxygen saturation of jejunal microvascular hemoglobin was determined by tissue reflectance spectrophotometry. Jejunal microcirculatory blood flow was assessed by laser Doppler flowmetry. Microvascular conductance and rhythmical oscillation of the tissue PO2 were calculated. Systemic hemodynamic variables, mesenteric venous and systemic acid base and blood gas variables, and lactate measurements were recorded. Measurements were taken at BL and after Escherichia coli LPS administration in 20 minutes intervals for 110 minutes. RESULTS: ETX infusion led to a significant (P<.05) decrease of PO2 muc (from 24±4 to 8±4 mm Hg) and microvascular HbO2 (from 41±13 to 24±12%). Microcirculatory conductivity increased in ETX animals, microvascular blood flow remained unchanged (PU; from 228±45 to 232±58). ETX induced an increase in oscillation frequency of mucosal tissue oxygenation. CONCLUSIONS: Endotoxinemia resulted in a significant depression of mucosal tissue oxygenation despite a constant microcirculatory blood flow. This impairment of tissue oxygenation resulted in an increase in the vasomotion pattern in a futile attempt to counteract the undersupply of oxygen to the jejunal tissue.

Ultrasound-guided regional anesthesia for carotid endarterectomy induces early hemodynamic and stress hormone changes.

OBJECTIVE: Locoregional anesthesia is an effective method for evaluating cerebral function during carotid endarterectomy (CEA). Landmark-guided regional anesthesia (RA) is currently used for CEA and can provoke substantial perioperative hypertension. Ultrasound-guided RA (US-RA) is a new method for performing RA in CEA; however, the effect on sympathetic activity and blood pressure is uncertain. This study assessed early sympathetic activity during CEA in US-RA compared with general anesthesia (GA). METHODS: Patients were prospectively randomized to receive US-RA (n = 32) or GA (n = 28) for CEA. The primary end point was the change in systolic arterial blood pressure after induction of anesthesia (just before starting surgery) comparing US-RA with GA. We also recorded heart rate and analyzed concentrations of plasma blood hormones, including cortisol, metanephrine, and normetanephrine at five different times. Creatinine kinase, troponin I, and N-terminal pro-B-type natriuretic peptide were analyzed to detect potential changes in cardiac biomarkers during the procedure. RESULTS: Systolic arterial blood pressure (mean ± standard deviation) increased significantly in US-RA patients compared with GA patients even before surgery was initiated (180 ± 26 mm Hg vs 109 ± 24 mm Hg; P < .001), then remained elevated during the entire surgery and returned to baseline values 1 hour after admission to the postoperative anesthesia care unit. Heart rate (US-RA: 78 ± 16 beats/min, GA: 52 ± 12 beats/min; P < .001) and cortisol levels (US-RA: 155 ± 97 µg/L, GA: 99 ± 43 µg/L; P = .006) were also significantly higher in the US-RA group after induction of anesthesia. Other values did not differ. CONCLUSIONS: The US-RA technique for CEA induces temporary intraoperative hypertension and an increase in stress hormone levels. Nevertheless, US-RA is a feasible, effective, and safe form of locoregional for CEA that enables targeted placement of low volumes of local anesthesia under direct visualization.

The physiologic perspective in fluid management in vascular anesthesiology.

Vascular surgery patients frequently suffer from atherosclerosis and peripheral arterial occlusive disease generating endothelial dysfunction. Furthermore, ischemia and reperfusion during surgery damage endothelial cells and, especially, the endothelial glycocalix. The damage of the glycocalix promotes an increase in permeability. Not only crystalloids, which freely diffuse between the intravascular and the interstitial compartment, but also colloidal fluids cross from the intravascular space in the interstitial space with the consequence of edema formation. Possible tissue edema may result in an impairment of tissue oxygenation, leading to wound healing disturbances and initiation of inflammatory responses up to tissue apoptosis. Particularly in vascular anesthesia, this possibly means that colloids only should be administered in acute volume resuscitation immediately after unclamping a big vessel for immediate volume restoration. Which colloidal fluid should be administered is still under intense discussion. From a theoretical physiologic point of view, iso-osmolar albumin is the best choice regarding volume effect, antioxidative properties, and protection against destruction of the glycocalix. Nonetheless, albumin experimentally has not lived up to its promise in the clinical setting. Thus, further well-conducted large randomized clinical trials are necessary to ascertain the optimal fluid therapy in vascular surgery patients.

Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB.

OBJECTIVE: Hypoxia affects body iron homeostasis; however, the underlying mechanisms are incompletely understood. DESIGN: Using a standardised hypoxia chamber, 23 healthy volunteers were subjected to hypoxic conditions, equivalent to an altitude of 5600 m, for 6 h. Subsequent experiments were performed in C57BL/6 mice, CREB-H knockout mice, primary hepatocytes and HepG2 cells. RESULTS: Exposure of subjects to hypoxia resulted in a significant decrease of serum levels of the master regulator of iron homeostasis hepcidin and elevated concentrations of platelet derived growth factor (PDGF)-BB. Using correlation analysis, we identified PDGF-BB to be associated with hypoxia mediated hepcidin repression in humans. We then exposed mice to hypoxia using a standardised chamber and observed downregulation of hepatic hepcidin mRNA expression that was paralleled by elevated serum PDGF-BB protein concentrations and higher serum iron levels as compared with mice housed under normoxic conditions. PDGF-BB treatment in vitro and in vivo resulted in suppression of both steady state and BMP6 inducible hepcidin expression. Mechanistically, PDGF-BB inhibits hepcidin transcription by downregulating the protein expression of the transcription factors CREB and CREB-H, and pharmacological blockade or genetic ablation of these pathways abrogated the effects of PDGF-BB toward hepcidin expression. CONCLUSIONS: Hypoxia decreases hepatic hepcidin expression by a novel regulatory pathway exerted via PDGF-BB, leading to increased availability of circulating iron that can be used for erythropoiesis.

Pulmonary function after emergence on 100% oxygen in patients with chronic obstructive pulmonary disease: a randomized, controlled trial.

BACKGROUND: During emergence from anesthesia, breathing 100% oxygen is frequently used to provide a safety margin toward hypoxemia in case an airway problem occurs. Oxygen breathing has been shown to cause pulmonary gas exchange disorders in healthy individuals. This study investigates how oxygen breathing during emergence affects lung function specifically whether oxygen breathing causes added hypoxemia in patients with chronic obstructive pulmonary disease. METHODS: This trial has been conducted in a parallel-arm, case-controlled, open-label manner. Fifty-three patients with chronic obstructive pulmonary disease were randomly allocated (computer-generated lists) to breathe either 100 or 30% oxygen balanced with nitrogen during emergence from anesthesia. Arterial blood gas measurements were taken before induction and at 5, 15, and 60 min after extubation. RESULTS: All participants tolerated the study well. Patients treated with 100% oxygen had a higher alveolar-arterial oxygen pressure gradient (primary outcome) compared with patients treated with 30% oxygen (25 vs. 20 mmHg) and compared with their baseline at the 60-min measurement (25 vs. 17 mmHg). At the 60-min measurement, arterial partial pressure of oxygen was lower in the 100% group (62 vs. 67 mmHg). Arterial partial pressure of carbon dioxide and pH were not different between groups or measurements. CONCLUSIONS: In this experiment, the authors examined oxygen breathing during emergence-a widely practiced maneuver known to generate pulmonary blood flow heterogeneity. In the observed cohort of patients already presenting with pulmonary blood flow disturbances, emergence on oxygen resulted in deterioration of oxygen-related blood gas parameters. In the perioperative care of patients with chronic obstructive pulmonary disease, oxygen breathing during emergence from anesthesia may need reconsideration.

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.

Sildenafil and bosentan improve arterial oxygenation during acute hypoxic exercise: a controlled laboratory trial.

OBJECTIVES: Sildenafil and, recently, bosentan have been reported to increase arterial saturation and exercise capacity at altitude. The mechanisms behind this are still poorly defined but may be related to attenuation of hypoxic pulmonary vasoconstriction (HPV) and improved gas exchange. This study was designed to examine and compare the effect of sildenafil and bosentan on pulmonary gas exchange during acute hypoxic exercise in a controlled laboratory setting. METHODS: Sixteen athletic university students (8 males, 8 females) were examined during exercise in a hypoxic chamber (11% oxygen) before and after the administration of either sildenafil (n=10) or bosentan (n=6). Respiratory and metabolic measurements were taken at rest and during increasing exercise intensity (up to 90% of their individual maximal oxygen uptake [VO(2)max]) in concert with arterial blood gas sampling. RESULTS: Both drugs resulted in small, but significant increases in arterial PO(2) (2-3 Torr) and O(2) saturation (3-4%) at rest and during hypoxic exercise, in both men and women. No significant changes in arterial PCO(2) or ventilation were seen at rest or during exercise in hypoxia; however, heart rate (both at rest and during exercise) was increased with both sildenafil and bosentan in both men and women. CONCLUSIONS: These data demonstrate that sildenafil and bosentan equally improve arterial oxygenation in acute hypoxia in both men and women, which could account for improved physical performance at altitude.

[Respiratory system at high altitude: pathophysiology and novel therapy options]. / Das Respiratorische System auf großer Höhe: Pathophysiologie und neue Therapieoptionen.

This mini-review conveys information on lung function in hypoxia. Included are presentations of shape and layering of the atmosphere, physiologic basics of lung function at high altitude, pathophysiology of high altitude pulmonary edema (HAPE) and of current and potential therapy approaches for HAPE.

Recombinant angiotensin-converting enzyme 2 improves pulmonary blood flow and oxygenation in lipopolysaccharide-induced lung injury in piglets.

OBJECTIVE: To study angiotensin-converting enzyme 2 in a piglet model with acute respiratory distress syndrome and to evaluate the therapeutic potential of this substance in a preclinical setting, as this model allows the assessment of the same parameters required for monitoring the disease in human intensive care medicine. The acute respiratory distress syndrome is the most severe form of acute lung injury with a high mortality rate. As yet, there is no specific therapy for improving the clinical outcome. Recently, angiotensin-converting enzyme 2, which inactivates angiotensin II, has been shown to ameliorate acute lung injury in mice. DESIGN: Prospective, randomized, double-blinded animal study. SETTING: Animal research laboratory. SUBJECTS: Fifteen anesthetized and mechanically ventilated piglets. INTERVENTIONS: Acute respiratory distress syndrome was induced by lipopolysaccharide infusion. Thereafter, six animals were assigned randomly into angiotensin-converting enzyme 2 group, whereas another six animals served as control. Three animals received angiotensin-converting enzyme 2 without lipopolysaccharide pretreatment. MEASUREMENTS AND MAIN RESULTS: Systemic and pulmonary hemodynamics, blood gas exchange parameters, tumor necrosis factor-alpha, and angiotensin II levels were examined before acute respiratory distress syndrome induction and at various time points after administering angiotensin-converting enzyme 2 or saline. In addition, ventilation-perfusion distribution of the lung tissue was assessed by the multiple inert gas elimination technique. Animals treated with angiotensin-converting enzyme 2 maintained significantly higher PaO2 than the control group, and pulmonary hypertension was less pronounced. Furthermore, angiotensin II and tumor necrosis factor-alpha levels, both of which were substantially increased, returned to basal values. Multiple inert gas elimination technique revealed a more homogeneous pulmonary blood flow after treatment with angiotensin-converting enzyme 2. In intergroup comparisons, there were no differences in pulmonary blood flow to lung units with subnormal ventilation/perfusion ratios. CONCLUSIONS: Angiotensin-converting enzyme 2 attenuates arterial hypoxemia, pulmonary hypertension, and redistribution of pulmonary blood flow in a piglet model of acute respiratory distress syndrome, and may be a promising substance for clinical use.