Inhalation injury increases the anastomotic bronchial blood flow in the pouch model of the left ovine lung.

Pulmonary parenchymal damage often occurs after airway injury. Bronchial venous drainage empties into the pulmonary microvasculature. We developed an in vivo model to study the bronchopulmonary portal system after smoke inhalation injury. Eight ewes were instrumented with hydraulic occluders on the left pulmonary artery (LPA), the left pulmonary vein, and the bronchoesophageal artery (BEA); a catheter in the LPA; and Swan-Ganz and femoral artery catheters. The vasculature between the occluders was defined as pouch. At stable mean arterial and right pulmonary arterial pressures, LPA occlusion reduced the left pulmonary artery pressure (LPAP) from 17 +/- 1 mmHg to 8 +/- 1 mmHg (p < .05). After left pulmonary vein occlusion, LPAP rose to 28 +/- 4 mmHg (p < .05 vs. baseline), indicating that systemic blood had entered the pouch. Opening the pouch to atmospheric pressure revealed an anastomotic bronchial blood flow (anastomotic Qbr) of .76 +/- .11% of cardiac output (CO). BEA occlusion reduced the anastomotic Qbr to .32 +/- .06% of CO (p < .05). Smoke inhalation injury resulted in a further increase in the maximal LPAP to 38 +/- 5 mmHg (p < .05 vs. right pulmonary artery pressure). The anastomotic Qbr rose to 1.29 +/- .13% of CO (p < .05) and was reduced to .40 +/- .09% of CO (p < .05) by BEA occlusion. Inhalation injury increased the anastomotic Qbr mainly due to BEA vasodilatation. Because the BEA supplies the injured airway, it may deliver deleterious material to the lung parenchyma.

Improved gas exchange performance of the intravascular oxygenator by active blood mixing.

The intravascular oxygenator and carbon dioxide removal device (IVOX; CardioPulmonics, Salt Lake City, UT) has been shown to perform 30% of the gas exchange in animals and patients with acute respiratory failure. Among the factors that limit gas exchange is the mass transfer resistance in the blood phase. To determine if a reduction in mass transfer resistance by mixing venous blood can enhance the O2 transfer and CO2 removal by IVOX, a right atrium-pulmonary artery venovenous bypass circuit was used in sheep to model the adult vena cava. A size 9 IVOX (894 fibers with 0.41 m2 surface area, n = 5) was incorporated in the bypass circuit and the blood flow controlled by a roller pump ranging from 1 to 4 l/min. An intra-aortic balloon was placed near the shaft of the IVOX and pulsated at the rate adjusted to best improve CO2 removal (100-120 bpm). O2 transfer and CO2 removal were measured with balloon pulsation on and off at different flow rates. Results showed that blood mixing by pulsation of the balloon caused a 25-49% increase in O2 transfer by IVOX, and this increase remained relatively constant throughout the full flow range. CO2 removal was also increased by up to 35%, but at flows between 3.5 and 4 l/min, the effect of mixing was diminished. It is concluded that reduction in the mass transfer resistance by blood mixing improves gas exchange. Because O2 is more diffusion limited, it is more dependent upon mixing of blood for gas exchange than CO2. More design improvements to incorporate active mixing may further enhance the gas exchange performance of IVOX.

Inhaled nitric oxide selectively reduces pulmonary hypertension after ovine smoke inhalation but does not improve oxygenation.

Inhaled nitric oxide (NO) is known to selectively reduce pulmonary hypertension and improve the ventilation-perfusion relationship in subjects with lung injury of various origin. However, some forms of lung injury do not react to inhaled NO at all, or show only a reduction in pulmonary arterial pressure. Very little is known about the effects of inhaled NO after smoke inhalation injury. We investigated the effects of inhaled NO in an established model of ovine smoke inhalation injury. Chronically instrumented sheep (n = 8) had tracheostomies and were insufflated with smoke generated from burning cotton cloth (4 times at 12 breaths each). They were then connected to a ventilator with oxygen-enriched air to achieve arterial oxygen tensions within the normal range. After 48 hours, NO was added to the inspired gas in ascending concentrations of up to 100 ppm. Systemic and pulmonary hemodynamics as well as oxygen transport were analyzed. Inhaled NO dose dependently lowered the pulmonary hypertension. Concentrations higher than 20 ppm did not further reduce the pulmonary artery pressure. Right ventricular stroke work index was significantly improved owing to the reduction in pulmonary vascular resistance. Arterial oxygenation, however, was not optimized by inhaled NO, probably because of interstitial edema formation.

Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence.

Emerging preclinical and clinical evidence suggests that pregnenolone may be a promising novel therapeutic candidate in schizophrenia. Pregnenolone is a neurosteroid with pleiotropic actions in rodents that include the enhancement of learning and memory, neuritic outgrowth, and myelination. Further, pregnenolone administration results in elevations in downstream neurosteroids such as allopregnanolone, a molecule with neuroprotective effects that also increases neurogenesis, decreases apoptosis and inflammation, modulates the hypothalamic-pituitary-adrenal axis, and markedly increases GABA(A) receptor responses. In addition, pregnenolone administration elevates pregnenolone sulfate, a neurosteroid that positively modulates NMDA receptors. There are thus multiple mechanistic possibilities for pregnenolone as a potential therapeutic agent in schizophrenia, including the amelioration of NMDA receptor hypofunction (via metabolism to pregnenolone sulfate) and the mitigation of GABA dysregulation (via metabolism to allopregnanolone). Additional evidence consistent with a therapeutic role for pregnenolone in schizophrenia includes neurosteroid changes following administration of certain antipsychotics in rodent models. For example, clozapine elevates pregnenolone levels in rat hippocampus, and these increases may potentially contribute to its superior antipsychotic efficacy [Marx et al. (2006a) Pharmacol Biochem Behav 84:598-608]. Further, pregnenolone levels appear to be altered in postmortem brain tissue from patients with schizophrenia compared to control subjects [Marx et al. (2006c) Neuropsychopharmacology 31:1249-1263], suggesting that neurosteroid changes may play a role in the neurobiology of this disorder and/or its treatment. Although clinical trial data utilizing pregnenolone as a therapeutic agent in schizophrenia are currently limited, initial findings are encouraging. Treatment with adjunctive pregnenolone significantly decreased negative symptoms in patients with schizophrenia or schizoaffective disorder in a pilot proof-of-concept randomized controlled trial, and elevations in pregnenolone and allopregnanolone post-treatment with this intervention were correlated with cognitive improvements [Marx et al. (2009) Neuropsychopharmacology 34:1885-1903]. Another pilot randomized controlled trial recently presented at a scientific meeting demonstrated significant improvements in negative symptoms, verbal memory, and attention following treatment with adjunctive pregnenolone, in addition to enduring effects in a small subset of patients receiving pregnenolone longer-term [Savitz (2010) Society of Biological Psychiatry Annual Meeting New Orleans, LA]. A third pilot clinical trial reported significantly decreased positive symptoms and extrapyramidal side effects following adjunctive pregnenolone, in addition to increased attention and working memory performance [Ritsner et al. (2010) J Clin Psychiatry 71:1351-1362]. Future efforts in larger cohorts will be required to investigate pregnenolone as a possible therapeutic candidate in schizophrenia, but early efforts are promising and merit further investigation. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Effects of inhaled nitric oxide and nebulized prostacyclin on hypoxic pulmonary vasoconstriction in anesthetized sheep.

OBJECTIVES: Inhaled nitric oxide has been shown to be a selective pulmonary vasodilator, leading to reduced pulmonary arterial pressure and improved ventilation/perfusion ratio in the acute respiratory distress syndrome. This local pulmonary vasodilation theoretically can be achieved by the airway application of a short-acting vasodilator, such as prostacyclin. We hypothesized that nebulized prostacyclin has the same properties for selective pulmonary vasodilation as inhaled nitric oxide. DESIGN: Prospective, experimental study in sheep. SETTING: Investigational intensive care unit in a university hospital. SUBJECTS: Six adult ewes of the Merino breed. INTERVENTIONS: Sheep (n = 6) were surgically prepared for chronic study. After 5 days of recovery, the sheep had tracheostomies performed under anesthesia. Intubation with a modified Robert-Shaw tube allowed side-separated ventilation. The entire left lung was ventilated with pure nitrogen, whereas the right lung was ventilated with pure oxygen. Nitric oxide and prostacyclin were added in different concentrations to the nitrogen, with which the left lung was ventilated. MEASUREMENTS AND MAIN RESULTS: The blood flows to the left and right lungs were measured with ultrasonic flow probes on the common and left pulmonary artery. Measurements were taken after each compound had been administered for 10 mins at a predefined dose. Both inhaled nitric oxide and nebulized prostacyclin caused effective, selective, dose-dependent pulmonary vasodilation. Inhaled nitric oxide was able to abolish hypoxic pulmonary vasoconstriction when insufflated into the animals at a concentration of 50 ppm of nitrogen, but 100 ppm of nitric oxide had no further effect. Prostacyclin, at a dosage of 10 micrograms/min, showed maximum pulmonary vasodilation, which could not be further increased by doubling the dosage. However, prostacyclin produced less dilation than high doses of nitric oxide, and its maximum pulmonary vasodilation was comparable with that effect obtained under ventilation with 20 ppm of nitric oxide. CONCLUSIONS: Both drugs selectively dilated the pulmonary vasculature in ventilated alveoli. Prostacyclin nebulization is an excellent tool to reduce pulmonary hypertension and to improve the ventilation/perfusion ratio. Prostacyclin nebulization can be used without the highly sophisticated technical equipment that is needed for controlled nitric oxide inhalation, and may therefore become a new, noninvasive therapeutic approach for treatment of adult respiratory distress syndrome in hospitals that cannot provide nitric oxide inhalation.

Mental disorders and use of cardiovascular procedures after myocardial infarction.

CONTEXT: A number of studies have found race- and sex-based differences in rates of cardiovascular procedures in the United States. Similarly, mental disorders might be expected to be associated with lower rates of such procedures on the basis of clinical, socioeconomic, patient, and provider factors. OBJECTIVE: To assess whether having a comorbid mental disorder is associated with a lower likelihood of cardiac catheterization and/or revascularization after acute myocardial infarction. DESIGN: Retrospective cohort study using data from medical charts and administrative files as part of the Cooperative Cardiovascular Project. SETTING: Acute care nongovernmental hospitals in the United States. PATIENTS: National cohort of 113653 eligible patients 65 years or older who were hospitalized for confirmed acute myocardial infarction between February 1994 and July 1995. MAIN OUTCOME MEASURES: Likelihood of cardiac catheterization, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass graft (CABG) surgery during the index hospitalization, comparing patients with and without mental disorders (classified as schizophrenia, major affective disorder, substance abuse/dependence disorder, or other mental disorder). RESULTS: Compared with the remainder of the sample, patients with any comorbid mental disorder (n = 5365; 4.7%) were significantly less likely to undergo PTCA (11.8% vs 16.8%; P<.001) or CABG (8.2% vs 12.6%; P<.001). After adjusting for demographic, clinical, hospital, and regional factors, individuals with mental disorders were 41% (for schizophrenia) to 78% (for substance use) as likely to undergo cardiac catheterization as those without mental disorders (P<.001 for all). Among those undergoing catheterization, rates of PTCA or CABG for patients with mental disorders were not significantly different from rates for patients without mental disorders (for those with any mental disorder, P = .12 for PTCA and P = .06 for CABG). In multivariate models, the 30-day mortality did not differ between patients with and without mental disorders. CONCLUSIONS: In this study, individuals with comorbid mental disorders were substantially less likely to undergo coronary revascularization procedures than those without mental disorders. Further research is needed to understand the degree to which patient and provider factors contribute to this difference and its implications for quality and long-term outcomes of care.