Ten important articles on noninvasive ventilation in critically ill patients and insights for the future: A report of expert opinions.

BACKGROUND: Noninvasive ventilation is used worldwide in many settings. Its effectiveness has been proven for common clinical conditions in critical care such as cardiogenic pulmonary edema and chronic obstructive pulmonary disease exacerbations. Since the first pioneering studies of noninvasive ventilation in critical care in the late 1980s, thousands of studies and articles have been published on this topic. Interestingly, some aspects remain controversial (e.g. its use in de-novo hypoxemic respiratory failure, role of sedation, self-induced lung injury). Moreover, the role of NIV has recently been questioned and reconsidered in light of the recent reports of new techniques such as high-flow oxygen nasal therapy. METHODS: We conducted a survey among leading experts on NIV aiming to 1) identify a selection of 10 important articles on NIV in the critical care setting 2) summarize the reasons for the selection of each study 3) offer insights on the future for both clinical application and research on NIV. RESULTS: The experts selected articles over a span of 26 years, more clustered in the last 15 years. The most voted article studied the role of NIV in acute exacerbation chronic pulmonary disease. Concerning the future of clinical applications for and research on NIV, most of the experts forecast the development of innovative new interfaces more adaptable to patients characteristics, the need for good well-designed large randomized controlled trials of NIV in acute "de novo" hypoxemic respiratory failure (including its comparison with high-flow oxygen nasal therapy) and the development of software-based NIV settings to enhance patient-ventilator synchrony. CONCLUSIONS: The selection made by the experts suggests that some applications of NIV in critical care are supported by solid data (e.g. COPD exacerbation) while others are still waiting for confirmation. Moreover, the identified insights for the future would lead to improved clinical effectiveness, new comparisons and evaluation of its role in still "lack of full evidence" clinical settings.

Recognition of pulmonary hypertension in the rheumatology community: lessons from a Quality Enhancement Research Initiative.

OBJECTIVES: The aim of this study was to utilise the Quality Enhancement Research Initiative in Systemic Sclerosis (QuERI-SSc) to measure and reduce a perceived gap in the diagnosis of pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc). METHODS: Rheumatologists enrolled patients with SSc (aged ≥ 18 years) and provided data on a panel of diagnostic tests over 3 years. Pulmonary function testing, echocardiography, 6-minute walk distance, N-terminal pro-brain natriuretic peptide assays, high-resolution computed tomography of the lungs, and ventilation/perfusion scan plus right heart catheterisation (RHC; when appropriate) were emphasised. Exclusion criteria included previously documented PAH, interstitial lung disease, and SSc overlapping with other connective tissue disease. RESULTS: Participating rheumatologists enrolled 207 patients with SSc (90% female; 80% white), with a median age of 57 years and median disease duration of 5 years. A total of 82% of patients were classified as New York Heart Association functional class I and II; of these patients, 177 had an echocardiogram at enrolment and 191 at any time during the study. Of those who met study-specified criteria for RHC at enrolment, only 3 of 7 patients underwent RHC. CONCLUSIONS: The screening algorithm was successful in identifying patients with mild impairment. Although specific tools were recommended for screening PAH in patients with SSc, results indicate that significant diagnostic care gaps still exist in the general rheumatology community. Better understanding and adherence to guidelines could improve the care and, ideally, outcomes of these high-risk patients.

Ruminal ergovaline and volatile fatty acid dynamics: Association with poor performance and a key growth regulator in steers grazing toxic tall fescue.

Fescue toxicosis (FT) is produced by an ergot alkaloid (i.e., ergovaline [EV])-producing fungus residing in toxic fescue plants. Associations between EV, decreased weight gain and ruminal volatile fatty acids are unclear. Feces, rumen fluid, and blood were collected from 12 steers that grazed non-toxic (NT) or toxic (E +) fescue for 28 days. The E + group exhibited decreased propionate (P), increased acetate (A), and increased ruminal A:P ratio, with similar trends in feces. Plasma GASP-1 (G-Protein-Coupled-Receptor-Associated-Sorting-Protein), a myostatin inhibitor, decreased (day 14) only in E + steers. Ergovaline was present only in E + ruminal fluid and peaked on day 14. The lower ruminal propionate and higher A:P ratio might contribute to FT while reduced GASP-1 might be a new mechanism linked to E + -related weight gain reduction. Day 14 ergovaline zenith likely reflects ruminal adaptations favoring EV breakdown and its presence only in rumen points to local, rather than systemic effects.

The use of theophylline in 'irreversible' chronic obstructive pulmonary disease. An update.

The use of theophylline in patients with "irreversible" chronic obstructive pulmonary disease is controversial. Possible favorable actions of theophylline, including improved mucociliary clearance, stimulation of respiratory drive, enhanced cardiovascular function, and increased diaphragmatic contractility and endurance, have either been shown to be minor in degree, or have not been demonstrated in patients with irreversible chronic obstructive pulmonary disease. No well-designed trial has yet shown improved exercise capacity following theophylline treatment in these patients. Nevertheless, considering that some patients benefit symptomatically in the absence of objective improvement, a cautious trial of theophylline appears indicated in patients with severe irreversible chronic obstructive pulmonary disease, with discontinuation if there is no objective or subjective improvement. Theophylline therapy should be initiated via the intravenous route during acute exacerbations, but otherwise should start with sustained-release oral preparations of anhydrous theophylline. Oral therapy should begin at low doses in stable patients to avoid side effects, and dosing should take into account the many factors, such as age, cardiovascular and liver function, smoking status, and possible drug interactions, that can affect theophylline metabolism.

Fluid and electrolyte considerations in diuretic therapy for hypertensive patients with chronic obstructive pulmonary disease.

When a patient with chronic obstructive pulmonary disease (COPD) requires medical therapy for systemic hypertension, a number of special considerations may affect the choice of antihypertensive drug and subsequent management. Thiazide diuretics have no adverse effect on airway function and are the agents of choice for initial therapy. beta-Antagonists are usually considered first-line agents in antihypertensive therapy, but even relatively cardioselective ones may increase airway resistance in patients with obstructive lung diseases, and they should be used with caution, if at all, in such patients. Although potassium-wasting diuretics are the preferred agents for treating hypertension in patients with COPD, they may worsen carbon dioxide retention in hypoventilating patients and potentiate hypokalemia in those receiving corticosteroids. In addition, beta-agonists may substantially lower serum potassium levels in patients already rendered hypokalemic by diuretics. Patients with COPD receiving potassium-wasting diuretics who have chronic respiratory acidosis or are receiving corticosteroids or beta-agonists should undergo close monitoring of electrolyte levels and be considered for therapy with potassium supplements or, preferably, potassium-sparing agents.

Frequency and prognostic significance of pericardial effusion in primary pulmonary hypertension. PPH Study Group. Primary pulmonary hypertension.

Pericardial effusion was noted in 43 of 79 patients (54%) with severe primary pulmonary hypertension. Larger effusion was associated with hemodynamic and echocardiographic evidence of right heart failure, impaired exercise tolerance, and a poor 1-year prognosis.

Environmental noise as a cause of sleep disruption in an intermediate respiratory care unit.

Our laboratory previously reported continuously monitored peak sound levels in several areas at Rhode Island Hospital. The number of sound peaks greater than 80 A-weighted decibels (dBA) was found to be high in the intensive and intermediate respiratory care unit (IRCU) areas, even at night. Environmental noise of this magnitude is potentially sleep-disruptive. Therefore, we hypothesized that nocturnal peak sound levels of > or = 80 dBA would be associated with an increase in EEG arousals from sleep in patients in the IRCU. Six patients underwent sleep monitoring while environmental peak sound levels were continuously recorded. Each 8-hour period (2200 to 0600 hours) was broken down into 30-minute segments. If there were 10 minutes or more of wakefulness in a segment, that segment was dropped from further analysis. Of the remaining 61 segments, there was a very strong correlation (r = 0.57, p = 0.0001) between the number of sound peaks of > or = 80 dBA and arousals from sleep. These 61 periods were then classified as quiet, moderately loud, and very loud based on the number of sound peaks (< or = 5, 6-15, and > 15, respectively). Analysis of variance revealed a significant difference between the number of arousals (p = 0.001) in quiet periods and that in very loud periods. We conclude that environmental noise may be an important cause of sleep disruption in the IRCU.

Air leaking through the mouth during nocturnal nasal ventilation: effect on sleep quality.

Air leaking through the mouth has been reported in kyphoscoliotic patients receiving nasal ventilation via volume-limited ventilators. This study accessed the frequency of occurrence and effect on sleep quality of air leaking through the mouth during nocturnal nasal ventilation in patients with chest wall and neuromuscular disease using pressure-limited ventilation. Overnight and daytime polysomnography was performed in six stable experienced users of nocturnal nasal noninvasive positive-pressure ventilation (NPPV) who had chronic respiratory failure due to neuromuscular disease or chest wall deformity. All patients used the BiPAP S/T-D ventilatory support system (Respironics, Inc., Murrysville, PA). Measures included sleep scoring, leak quantitation, diaphragm and submental electromyograms (EMGs), and tidal and leak volumes. All patients had air leaking through the mouth for the majority of sleep. Sleep quality was diminished because of poor sleep efficiency and reduced percentages of slow-wave and rapid eye movement (REM) sleep. Air leaking through the mouth was associated with frequent arousals during stages 1 and 2 and REM sleep that contributed to sleep fragmentation, but arousals were infrequent during slow-wave sleep. Despite prevalent leaking, oxygenation was well maintained in all but one patient. Patients used a-combination of passive and active mechanisms to control air leaking. Although nasal ventilation improves nocturnal hypoventilation and symptoms in patients with restrictive thoracic disorders, air leaking through the mouth is very common during use. The leaking is associated with frequent arousals during lighter stages of sleep that interfere with progression to deeper stages, compromising sleep quality. Portable pressure-limited ventilators compensate for leaks, maintaining ventilation and oxygenation, but further studies are needed to determine which interfaces and ventilator techniques best control air leaking and optimize sleep quality.

Clinical applications of body ventilators.

Interest has been increasing in providing ventilatory support in the home for patients with chronic respiratory failure, mainly with the use of positive pressure ventilation via a chronic tracheostomy. However, body ventilators that assist ventilation by applying intermittent negative or positive pressure to the thorax, abdomen, or airway without requiring an artificial airway, can offer distinct advantages for selected patients over systems requiring a permanent airway. These ventilators include the iron lung, portable lung (Portalung), pneumowrap, chest cuirass, pneumobelt, rocking bed, and positive pressure provided via a face or nose mask. They have successfully stabilized or reversed chronic hypercarbia when used intermittently in patients with slowly progressive chronic respiratory failure due to certain neuromuscular diseases and kyphoscoliosis. How they achieve this stabilization has not been clarified, but reversal of chronic respiratory muscle fatigue following periodic rest probably contributes. These ventilators are generally less effective than positive pressure ventilation through a tracheostomy and should be reserved for patients with relatively stable chronic respiratory failure and intact upper airways. However, they have the advantages of simpler operation and less expense, and they allow maintenance of a normal airway.

Long-term follow-up of nocturnal ventilatory assistance in patients with respiratory failure due to Duchenne-type muscular dystrophy.

We followed eight patients with Duchenne-type muscular dystrophy for an average of 39 months after initiation of noninvasive intermittent ventilatory assistance using body ventilators. After one to three months of nocturnal use averaging 8 h, mean daytime PaCO2 fell from 63 +/- 2 to 45 +/- 3 mm Hg. At late follow-up, PaCO2 remained stable at 47 +/- 4 mm Hg, but vital capacity fell 33 percent compared with the initial value and the average duration of ventilator use had increased to 18 +/- 2 h daily. Three patients died and five survived; two continued using negative pressure ventilators and three had tracheostomies placed for administration of positive pressure ventilation. We conclude that noninvasive intermittent ventilatory assistance effectively reverses hypoventilation and symptoms in patients with late-stage Duchenne muscular dystrophy, but pulmonary function continues to deteriorate necessitating longer periods of ventilation, and often tracheostomy, within a few years.

Right ventricular dysfunction in chronic obstructive pulmonary disease. Evaluation and management.

Cor pulmonale is an important consequence of COPD. Although the incidence is not precisely known, it is seen more frequently in patients with hypoxemia, CO2 retention and severely reduced FEV1. When present, it limits peripheral oxygen delivery, increases shortness of breath, and reduces exercise endurance. It is also associated with higher mortality rates independent of other prognostic variables. Numerous factors may contribute to the development of cor pulmonale in patients with COPD, but its primary cause is chronic alveolar hypoxia resulting in pulmonary vasoconstriction, vascular remodeling and pulmonary hypertension. The physical exam, chest radiograph and ECG may be helpful in detecting the presence of cor pulmonale, but because of anatomic changes that occur in the chest, these tests are often insensitive in patients with COPD. Noninvasive diagnostic techniques utilizing Doppler echocardiography and radionuclide angiography allow for detection of RV dysfunction at an earlier stage and in most cases, preclude the need for right heart catheterization. LTO2 is the only therapy shown to improve survival in patients with COPD. However, statistical proof correlating improvements in pulmonary hemodynamics with increased survival is lacking. Bronchodilators, such as the beta 2 agonists and especially theophylline, may have beneficial effects on pulmonary hemodynamics in addition to their effect on respiratory function and are useful in COPD when RV dysfunction is present. Diuretics and phlebotomy are also useful in improving symptoms in appropriate patients. Vasodilators such as calcium channel blockers and ACE-inhibitors may improve pulmonary hemodynamics acutely, but may lower arterial PO2 by worsening ventilation-perfusion matching or blunt the improvement in pulmonary hemodynamics seen with supplemental oxygen. The long-term benefits of these agents have not been proven and their routine use in patients with cor pulmonale due to COPD cannot be recommended.

Pulmonary hypertensive diseases.

Pulmonary hypertension may occur as a primary disorder of the pulmonary vasculature or secondary to a variety of cardiac or pulmonary diseases. The reversibility of pulmonary hypertension is dependent on the relative contribution of reversible vasoconstriction and irreversible structural changes in the pulmonary vessels. Despite recent advances in the understanding of pulmonary vascular physiology, knowledge of the pathogenesis and natural history of pulmonary hypertension has been limited by an inability to measure pulmonary arterial pressure noninvasively. Thus, when patients have symptoms or signs of pulmonary hypertension, the disease is usually at an advanced stage. It is possible that early in the course of hypoxic pulmonary disease, pulmonary hypertension may be protective in optimizing matching of ventilation and perfusion. It is not known at what point pulmonary hypertension per se becomes harmful. Certainly, treatment directed at underlying cardiac or pulmonary disease is indicated. It also seems reasonable to treat severe degrees of pulmonary hypertension complicated by right ventricular dysfunction. With the advent of orally effective pulmonary vasodilators, direct treatment of primary and secondary pulmonary hypertension may now be possible. Hopefully, with careful clinical evaluation of the response to vasodilator therapy, we will learn whether these drugs prolong life and reduce morbidity in primary and secondary pulmonary hypertension. In the meantime, much more information is needed regarding the mechanisms of acute pulmonary vasoconstriction and sustained pulmonary hypertension. In addition, a means of early identification of patients with mild hypertension is needed.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of endothelial cell injury on pulmonary vascular reactivity.

Using the thiocarbamide model of acute lung injury in rats, we found that alpha-naphthylthiourea (ANTU) caused lung endothelial cell injury, as evidenced by increased permeability edema and decreased angiotensin I conversion. These effects were associated with enhanced pulmonary vascular reactivity. Recurrent ANTU lung injury caused pulmonary hypertension. The water-soluble thiocarbamide thiourea caused cultured vascular endothelial cells to release neutrophil chemoattractant activity. We speculate that endothelial cell injury may modulate the function of vascular smooth muscle and blood leukocytes.

Sleep-disordered breathing in patients with Duchenne muscular dystrophy using negative pressure ventilators.

We studied the occurrence of nocturnal disordered breathing events and O2 desaturations in 12 patients with late-stage Duchenne muscular dystrophy (DMD) using negative pressure ventilators. We also assessed the effects of O2 supplementation and nasal continuous positive airway pressure (CPAP) on disordered breathing events in selected patients and examined sleep quality in a small subgroup. Average age was 23 + 2 years and FVC was 293 + 33 ml. Eleven of the 12 patients had more than five disordered breathing events per hour during nocturnal monitoring, and the lowest O2 saturation was < 85 percent in nine patients. Nasal O2 (2 L/min) during negative pressure ventilation in four patients did not alter the frequency of disordered breathing events, prolonged the mean and maximum durations of events, and failed to eliminate severe O2 desaturations in two patients. Nasal CPAP was used in two patients during negative pressure ventilation and completely eliminated disordered breathing events in both. Overnight polysomnography during negative pressure ventilation in three patients demonstrated frequent awakenings that fell in frequency following elective tracheostomy in two patients and use of nasal CPAP in one. We conclude that negative pressure ventilation in patients with late-stage DMD is associated with frequent disordered breathing events and severe O2 desaturations in many patients. Concomitant use of O2 supplementation may prolong the events, but a switch to positive pressure ventilation or addition of nasal CPAP is effective therapy.

Vasoresponsiveness of sarcoidosis-associated pulmonary hypertension.

OBJECTIVE: To assess short-term and long-term responses to treatment with pulmonary vasodilators in patients with sarcoidosis-related pulmonary hypertension. METHODS: A prospective, observational study was performed on eight patients with moderate-to-severe sarcoidosis-related pulmonary hypertension. Patients underwent a short-term vasodilator trial, using inhaled nitric oxide (iNO), IV epoprostenol, and/or oral calcium-channel blockers. A favorable short-term response was considered a > or = 20% decrease in pulmonary vascular resistance (PVR). Five patients received long-term treatment with iNO (with one patient receiving epoprostenol in addition) and underwent follow-up hemodynamic and/or 6-min walk testing. Two patients received long-term treatment with calcium-channel blockers. RESULTS: Baseline (+/- SE) mean pulmonary artery pressure (mPAP) was 55 +/- 4 mm Hg and PVR was 896 +/- 200 dyne.s.cm(-5). A favorable short-term response was seen in seven of eight patients receiving iNO, four of six patients receiving epoprostenol, and two of five patients receiving calcium-channel blockers. With iNO, PVR decreased 31 +/- 5% (p = 0.006) and mPAP decreased 18 +/- 4% (p = 0.003); with epoprostenol, PVR decreased 25 +/- 6% (p = 0.016) and mPAP decreased 6 +/- 2% (p = not significant). Decreased systemic vascular resistance was the only significant response to treatment with calcium-channel blockers. Follow-up 6-min walk test results improved in all five patients receiving long-term treatment with iNO. Follow-up hemodynamic responses in three patients showed preserved vasoresponsiveness. These three patients subsequently died, as did the two patients receiving calcium-channel blockers. The two remaining patients continue to receive iNO. CONCLUSION: In the short term, pulmonary hypertension in patients with sarcoidosis is responsive to treatment with pulmonary vasodilators; these patients may benefit from long-term iNO therapy.

Adverse environmental conditions in the respiratory and medical ICU settings.

Sleep deprivation and fragmentation occurring in the hospital setting may have a negative impact on the respiratory system by decreasing respiratory muscle function and ventilatory response to CO2. Sleep deprivation in a patient with respiratory failure may, therefore, impair recovery and weaning from mechanical ventilation. We postulate that light, sound, and interruption levels in a weaning unit are major factors resulting in sleep disorders and possibly circadian rhythm disruption. As an initial test of this hypothesis, we sampled interruption levels and continuously monitored light and sound levels for a minimum of seven consecutive days in a medical ICU, a multiple bed respiratory care unit (RCU) room, a single-bed RCU room, and a private room. Light levels in all areas maintained a day-night rhythm, with peak levels dependent on window orientation and shading. Peak sound levels were extremely high in all areas representing values significantly higher than those recommended by the Environmental Protection Agency as acceptable for a hospital environment. The number of sound peaks greater than 80 decibels, which may result in sleep arousals, was especially high in the intensive and respiratory care areas, but did show a day-night rhythm in all settings. Patient interruptions tended to be erratic, leaving little time for condensed sleep. We conclude that the potential for environmentally induced sleep disruption is high in all areas, but especially high in the intensive and respiratory care areas where the negative consequences may be the most severe.

Acute changes in lipid, lipoprotein, apolipoprotein, and low-density lipoprotein particle size after an endurance triathlon.

The effect of an endurance triathlon (2.4-mile swim, 112-mile bicycle ride, 26.2-mile run, in succession) on plasma total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, apolipoprotein (apo) A-I and B levels, and LDL particle size was determined in 34 male and six female participants 6 to 12 hours before and immediately after the completion of the triathlon. Plasma TG decreased significantly (70% decrease) in both men and women. In men the change in plasma TG was inversely associated with baseline TG values (P less than .0001). Plasma TC and LDL cholesterol did not change significantly in male athletes but decreased significantly in women. A significant increase in HDL cholesterol was observed in both men (18% increase, P less than .0001) and women (5% increase, P less than .01). In men the increase in HDL cholesterol was inversely correlated with the decrease in triglycerides (P less than .0002). Plasma apo A-I levels increased significantly only in the male group (P less than .005), whereas plasma apo B levels decreased significantly in both men and women (P less than .0005). LDL particle size increased in seven males, whereas in the remaining males and all females no change in LDL size was observed. The increase in LDL particle size in these seven subjects was associated with a greater decline in plasma TG compared with the remaining men (P less than .005) and women (P less than .03). These results indicate that prolonged strenuous physical exercise can induce acute modifications of plasma lipoproteins, which may in part be related to enhanced lipolysis.

Supplemental oxygen reduces right ventricular hypertrophy in monocrotaline-injected rats.

We evaluated the possible contributory role of hypoxia in the development of monocrotaline-induced pulmonary hypertension. Male Sprague-Dawley rats were injected subcutaneously with monocrotaline (60 mg/kg) or saline in controls and were kept in oxygen-enriched (inspired O2 fraction of 0.35) or compressed air chambers. After 21 days, rats were anesthetized while spontaneously breathing room air, hemodynamic parameters and arterial blood gases were measured, and animals were killed. Right ventricular peak systolic pressures (RVPP), right ventricular-to-left ventricular plus septal weight ratios (RV/LV + S), hematocrits, lung dry weight-to-body weight ratios, and medial thickness of pulmonary arteries were significantly reduced in monocrotaline-injected rats exposed to mild hyperoxia compared with air. The air-exposed monocrotaline-injected rats had significantly more arterial hypoxemia than the other groups, and mild hyperoxia had no effect on any of the measured variables in saline-injected rats. To determine whether the effects of mild hyperoxia occurred early or late after monocrotaline injection, we moved separate groups of rats from air to mild hyperoxia and vice versa 10 days after monocrotaline injection. After 21 days, significant reductions in RVPP and RV/LV + S occurred only in rats exposed to mild hyperoxia during the latter 11 days after injection. Our findings suggest that hypoxia contributes to the development of pulmonary hypertension relatively late after monocrotaline injection in rats but that it does not influence the early injury.

Does atrial natriuretic factor protect against right ventricular overload? II. Tissue binding.

Previous studies have led us to hypothesize that the physiological significance of the diuretic and pulmonary vaso-relaxant effects of atrial natriuretic factor (ANF) is to protect the right heart. This study was designed to evaluate the relative importance of various peripheral tissues as sites of ANF action by tracing the temporal pattern of distribution of 125I-ANF and quantitating the specific binding sites. An in vivo approach, utilizing trace amount of 125I-ANF was adopted to simulate physiological conditions. 125I-ANF injected either intravenously or intra-arterially was quickly bound to peripheral tissues with less than 5% remaining in the circulation after 1 min. The relative binding capacity was greatest in the lung, followed by the kidney, right ventricle, adrenal gland, and left ventricle. The magnitude of specific ANF binding sites per gram of tissue weight followed a similar order. The data demonstrate that ANF released under all circumstances is quickly bound to the target organs, particularly the lung and the kidney, and suggest that these two organs could be the most important target organs of ANF. This evidence provides further support for the proposed hypothesis that a major evolutionary role of ANF is the protection of the right ventricle from mechanical loads.

Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats.

Endothelin-1 (ET-1), a potent vasoactive and mitogenic peptide, has been implicated in the pathogenesis of several forms of pulmonary hypertension. We hypothesized that nonspecific blockade of ET receptors would blunt the development of monocrotaline (MCT)-induced pulmonary hypertension in rats. A single dose of the nonspecific ET blocker bosentan (100 mg/kg) given to intact rats by gavage completely blocked the pulmonary vasoconstrictor actions of Big ET-1 and partially blunted hypoxic pulmonary vasoconstriction. After 3 wk, MCT-injected (105 mg/kg sc) rats gavaged once daily with bosentan (200 mg/kg) had lower right ventricular (RV) systolic pressure (RVSP), RV-to-body weight (RV/BW) and RV-to-left ventricular (LV) plus septal (S) weight [RV/(LV+S)] ratios and less percent medial thickness of small pulmonary arteries than control MCT-injected rats. Lower dose bosentan (100 mg/kg) had no effect on these parameters after MCT or saline injection. Bosentan raised plasma ET-1 levels but had no effect on lung ET-1 levels. Bosentan (200 mg/kg) also had no effect on wet-to-dry lung weight ratios 6 days after MCT injection. When given during the last 10 days, but not the first 11 days of a 3-wk period after MCT injection, bosentan reduced RV/(LV+S) compared with MCT-injected controls. We conclude that ET-1 contributes to the pathogenesis of MCT-induced pulmonary hypertension and acts mainly during the later inflammatory rather than the acute injury phase after injection.