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BACKGROUND: Quantitative analysis of ventricular cerebrospinal fluid (vCSF) proteins following acute brain injury (ABI) may help identify pathophysiological pathways and potential biomarkers that can predict unfavorable outcome. METHODS: In this prospective proteomic analysis study, consecutive patients with severe ABI expected to require intraventricular catheterization for intracranial pressure (ICP) monitoring for at least 5 days and patients without ABI admitted for elective clipping of an unruptured cerebral aneurysm were included. vCSF samples were collected within the first 24 h after ABI and ventriculostomy insertion and then every 24 h for 5 days. In patients without ABI, a single vCSF sample was collected at the time of elective clipping. Data-independent acquisition and sequential window acquisition of all theoretical spectra (SWATH) mass spectrometry were used to compare differences in protein expression in patients with ABI and patients without ABI and in patients with traumatic and nontraumaticABI. Differences in protein expression according to different ICP values, intensive care unit outcome, subarachnoid hemorrhage (SAH) versus traumatic brain injury (TBI), and good versus poor 3-month functional status (assessed by using the Glasgow Outcome Scale) were also evaluated. vCSF proteins with significant differences between groups were compared by using linear models and selected for gene ontology analysis using R Language and the Panther database. RESULTS: We included 50 patients with ABI (SAH n = 23, TBI n = 15, intracranial hemorrhage n = 6, ischemic stroke n = 3, others n = 3) and 12 patients without ABI. There were significant differences in the expression of 255 proteins between patients with and without ABI (p

OBJECTIVES To characterize renin in critically ill patients. Renin is fundamental to circulatory homeostasis and could be a useful marker of tissue-perfusion. However, diurnal variation, continuous renal replacement therapy and drug-interference could confound its use in critical care practice. DESIGN Prospective observational study. SETTING Single-center, mixed medical-surgical ICU in Europe. PATIENTS Patients over 18 years old with a baseline estimated glomerular filtration rate greater than 30 mL/min/1.73 m and anticipated ICU stay greater than 24 hours. Informed consent was obtained from the patient or next-of-kin. INTERVENTIONS Direct plasma renin was measured in samples drawn 6-hourly from arterial catheters in recumbent patients and from extracorporeal continuous renal replacement therapy circuits. Physiologic variables and use of drugs that act on the renin-angiotensin-aldosterone system were recorded prospectively. Routine lactate measurements were used for comparison. MEASUREMENTS AND MAIN RESULTS One-hundred twelve arterial samples (n = 112) were drawn from 20 patients (65% male; mean ± SD, 60 ± 14 yr old) with septic shock (30%), hemorrhagic shock (15%), cardiogenic shock (20%), or no circulatory shock (35%). The ICU mortality rate was 30%. Renin correlated significantly with urine output (repeated-measures correlation coefficient = -0.29; p = 0.015) and mean arterial blood pressure (repeated-measures correlation coefficient = -0.35; p < 0.001). There was no diurnal variation of renin or significant interaction of renin-angiotensin-aldosterone system drugs with renin in this population. Continuous renal replacement therapy renin removal was negligible (mass clearance ± SD 4% ± 4.3%). There was a significant difference in the rate of change of renin over time between survivors and nonsurvivors (-32 ± 26 μU/timepoint vs +92 ± 57 μU/timepoint p = 0.03; mean ± SEM), but not for lactate (-0.14 ± 0.04 mM/timepoint vs +0.15 ± 0.21 mM/timepoint; p = 0.07). Maximum renin achieved significant prognostic value for ICU mortality (receiver operator curve area under the curve 0.80; p = 0.04), whereas maximum lactate did not (receiver operator curve area under the curve, 0.70; p = 0.17). CONCLUSIONS In an heterogeneous ICU population, renin measurement was not significantly affected by diurnal variation, continuous renal replacement therapy, or drugs. Renin served as a marker of tissue-perfusion and outperformed lactate as a predictor of ICU mortality.

Coronary blood flow adapts to metabolic demand ("metabolic regulation") and remains relatively constant over a range of pressure changes ("autoregulation"). Coronary metabolic regulation and autoregulation are usually studied separately. We developed an intact animal experimental model to explore both regulatory mechanisms of coronary blood flow. Coronary pressure and flow‐velocities were measured in four anesthetized and closed‐chest pigs using an intracoronary Doppler wire. Metabolic regulation was assessed by coronary flow reserve defined as the ratio between the maximally vasodilated and the basal flow, with hyperemia achieved using intracoronary administration of adenosine (90 µg) or bradykinin (10–6 M) as endothelium‐independent and ‐dependent vasodilators respectively. For both vasodilators, we found a healthy coronary flow reserve ≥ 3.0 at baseline, which was maintained at 2.9 ± 0.2 after a 6‐hr period. Autoregulation was assessed by the lower breakpoint of coronary pressure‐flow relationships, with gradual decrease in coronary pressure through the inflation of an intracoronary balloon. We found a lower limit of autoregulation between 42 and 55 mmHg, which was stable during a 6‐hr period. We conclude that this intact animal model is adequate for the study of pharmacological interventions on the coronary circulation in health and disease, and as such suitable for preclinical drug studies., Metabolic regulation adapts the coronary blood flow (CBF) to the myocardial demand. Autoregulation maintains CBF constant over a wide range of pressure. These CBF regulation mechanisms were to date studied separately. We developed here a new method to comprehensively assess CBF regulation in an intact large animal experimental model.

Tight glycemic control using intermittent blood glucose measurements is associated with a risk of hypoglycemia. Glucose concentrations can now be measured near continuously (every 5-15 min). We assessed the quality and safety of glycemic control guided by a near-continuous glucose monitoring system in ICU patients.Prospective, cluster-randomized, crossover study.Thirty-five-bed medico-surgical department of intensive care with four separate ICUs.Adult patients admitted to the department and expected to stay for at least 3 days were considered for inclusion if they had persistent hyperglycemia (blood glucose150 mg/dL) up to 6 hours after admission and/or were receiving insulin therapy.A peripheral venous catheter was inserted in all patients and connected to a continuous glucose monitoring sensor (GlucoClear; Edwards Lifesciences, Irvine, CA). The four ICUs were randomized in pairs in a crossover design to glycemic control using unblinded or blinded continuous glucose monitoring monitors. The insulin infusion rate was adjusted to keep blood glucose between 90 and 150 mg/dL using the blood glucose values displayed on the continuous glucose monitor (continuous glucose monitoring group-unblinded units) or according to intermittent blood glucose readings (intermittent glucose monitoring group-blinded units).The quality and safety of glycemic control were assessed using the proportion of time in range, the frequency of blood glucose less than 70 mg/dL, and the time spent with blood glucose less than 70 mg/dL (TB70), using blood glucose values measured by the continuous glucose monitoring device. Seventy-seven patients were enrolled: 39 in the continuous glucose monitoring group and 38 in the intermittent glucose monitoring group. A total of 43,107 blood glucose values were recorded. The time in range was similar in the two groups. The incidence of hypoglycemia (8/39 [20.5%] vs 15/38 [39.5%]) and the TB70 (0.4% ± 0.9% vs 1.6% ± 3.4%; p0.05) was lower in the continuous glucose monitoring than in the intermittent glucose monitoring group.Use of a continuous glucose monitoring-based strategy decreased the incidence and severity of hypoglycemia, thus improving the safety of glycemic control.

Background: In order to decrease the incidence of ventilator-associated pneumonia (VAP) in Belgium, a national campaign for implementing a VAP bundle involving assessment of sedation, cuff pressure control, oral care with chlorhexidine and semirecumbent position, was launched in 2011–2012. This report will document the impact of this campaign. Methods: On 1 day, once a year from 2010 till 2016, except in 2012, Belgian ICUs were questioned about their ventilated patients. For each of these, data about the application of the bundle and the possible treatment for VAP were recorded. Results: Between 36.6 and 54.8% of the 120 Belgian ICUs participated in the successive surveys. While the characteristics of ventilated patients remained similar throughout the years, the percentage of ventilated patients and especially the duration of ventilation significantly decreased before and after the national VAP bundle campaign. Ventilator care also profoundly changed: Controlling cuff pressure, head positioning above 30° were obtained in more than 90% of cases. Oral care was more frequently performed within a day, using more concentrated solutions of chlorhexidine. Subglottic suctioning also was used but in only 24.7% of the cases in the last years. Regarding the prevalence of VAP, it significantly decreased from 28% of ventilated patients in 2010 to 10.1% in 2016 (p ≤ 0.0001). Conclusion: Although a causal relationship cannot be inferred from these data, the successive surveys revealed a potential impact of the VAP bundle campaign on both the respiratory care of ventilated patients and the prevalence of VAP in Belgian ICUs encouraging them to follow the guidelines., SCOPUS: ar.j, info:eu-repo/semantics/published

Hyponatremia occurs commonly after acute brain injury and is often due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Urea administration is 1 therapeutic option. In our Department, enteral urea is routinely administered to patients with acute brain injury who develop hyponatremia consistent with SIADH and do not respond to an initial sodium load. We reviewed the records of all patients over a 2-year period, who had acute brain injury, received enteral urea because of hyponatremia, and had intracranial pressure (ICP) monitoring using an intraventricular catheter. We recorded demographic, biological, and clinical data; mean ICP values during the 6 hours before and after the first dose of urea were also recorded. We included 40 patients (23 subarachnoid hemorrhage, 8 traumatic brain injury, 6 intracranial hemorrhage, 2 postbrain tumor surgery, and 1 ischemic stroke); median age was 54 years (IQRs, 44 to 63 y) and median admission APACHE II score was 19 (13 to 19); 6-month survival was 63%. Median baseline sodium was 133 mEq/L (131 to 135 mEq/L). No patients received additional therapy to decrease ICP during the 6 hours following urea initiation. After the first urea dose (15 g), ICP decreased from 14 (13 to 18 mm Hg) to 11 mm Hg (8 to 13 mm Hg) (P

SCOPUS: le.j, info:eu-repo/semantics/published

BACKGROUND: High-flow nasal cannula (HFNC) oxygen therapy is used to deliver an FIO2 from 0.21 to 1.0. The double-trunk mask (DTM) is a device designed to increase the FIO2 in patients with a high inspiratory flow demand. The aim of our study was to evaluate the effect of DTM in hypoxemic subjects already receiving HFNC. METHODS: We report a prospective multi-center crossover pilot study including 15 subjects treated with HFNC for acute hypoxemic respiratory failure. Measurements were performed at the end of 30-min periods with HFNC only, with HFNC + DTM, and again with HFNC only. RESULTS: Compared with HFNC alone, HFNC + DTM increased PaO2 from 68 ± 14 mm Hg to 85 ± 22 mm Hg (P < .001) and did not affect PaCO2 (P = .18). In the 11 responders, the PaO2 increased from 63 ± 12 mm Hg to 88 ± 23 mm Hg (P < .001). No complications were reported during DTM use. CONCLUSION: In subjects receiving oxygen via HFNC, the addition of the DTM over the HFNC increased PaO2 without changing the PaCO2 ., SCOPUS: ar.j, info:eu-repo/semantics/published

Background Acute transient pulmonary hypertension may induce a state of persistent right ventricular (RV) failure. We hypothesized that this could be related to an activation of inflammatory processes and reduced by prostacyclin therapy. Methods Sixteen dogs were assigned to a 90-minute pulmonary artery banding ( n = 8), or to a sham operation ( n = 8). Hemodynamic variables were measured 30 minutes after banding release. This was repeated in 7 dogs with pulmonary artery banding–induced RV failure, followed by a 60-minute epoprostenol infusion. After euthanasia of the animals, myocardial tissue was sampled. Results Persistent RV failure was associated with increased myocardial expression of interleukin (IL)-1β, IL-6, monocyte chemoattractant protein 1, pro-inflammatory IL-6/IL-10, and neutrophil and macrophage infiltration, whereas heme oxygenase 1 expression was decreased. These changes were observed in RV and to a lesser extent in the left ventricle (LV). In the RV only, expressions of prostacyclin synthase and anti-inflammatory IL-10 and IL-33 decreased and vascular cell adhesion molecule expression increased, whereas macrophage inflammatory protein-1α and intercellular adhesion molecule 1 expressions remained unchanged. After epoprostenol infusion, there was decreased expression of IL-1β, macrophage inflammatory protein-1α, and vascular cell adhesion molecule 1 and increased IL-10 expression in the RV and the LV, whereas monocyte chemoattractant protein-1 decreased in the RV only. Epoprostenol infusion resulted in decreased RV IL-6/IL-10 and pro-apoptotic Bax/Bcl-2, together with decreased RV neutrophil and RV and LV macrophage infiltration. The RV ratio of end systolic-to-pulmonary arterial elastances was inversely correlated to RV IL-6/IL-10, macrophage, and neutrophil infiltration, and to RV heme oxygenase-1 and IL-33 expression. Conclusions Acute afterload-induced persistent RV failure is associated with an activation of inflammatory processes, which are limited by epoprostenol.

Right ventricular (RV) function is a major determinant of the symptomatology and outcome in pulmonary hypertension. The normal RV is a thin-walled flow generator able to accommodate large changes in venous return but unable to maintain flow output in the presence of a brisk increase in pulmonary artery pressure. The RV chronically exposed to pulmonary hypertension undergoes hypertrophic changes and an increase in contractility, allowing for preserved flow output in response to peripheral demand. Failure of systolic function adaptation (homeometric adaptation, described by Anrep's law of the heart) results in increased dimensions (heterometric adaptation; Starling's law of the heart), with a negative effect on diastolic ventricular interactions, limitation of exercise capacity, and vascular congestion. Ventricular function is described by pressure-volume relationships. The gold standard of systolic function is maximum elastance (E max), or the maximal value of the ratio of pressure to volume. This value is not immediately sensitive to changes in loading conditions. The gold standard of afterload is arterial elastance (E a), defined by the ratio of pressure at E max to stroke volume. The optimal coupling of ventricular function to the arterial circulation occurs at an E max/E a ratio between 1.5 and 2. Patients with severe pulmonary hypertension present with an increased E max, a trend toward decreased E max/E a, and increased RV dimensions, along with progression of the pulmonary vascular disease, systemic factors, and left ventricular function. The molecular mechanisms of RV systolic failure are currently being investigated. It is important to refer biological findings to sound measurements of function. Surrogates for E max and E a are being developed through bedside imaging techniques.

The time constant of the pulmonary circulation, or product of pulmonary vascular resistance (PVR) and compliance (Ca), called the RC-time, has been reported to remain constant over a wide range of pressures, etiologies of pulmonary hypertension, and treatments. We wondered if increased wave reflection on proximal pulmonary vascular obstruction, like in operable chronic thromboembolic pulmonary hypertension, might also decrease the RC-time and thereby increase pulse pressure and right ventricular afterload. Pulmonary hypertension of variable severity was induced either by proximal obstruction (pulmonary arterial ensnarement) or distal obstruction (microembolism) eight anesthetized dogs. Pulmonary arterial pressures (Ppa) were measured with high-fidelity micromanometer-tipped catheters, and pulmonary flow with transonic technology. Pulmonary ensnarement increased mean Ppa, PVR, and characteristic impedance, decreased Ca and the RC-time (from 0.46 ± 0.07 to 0.30 ± 0.03 s), and increased the oscillatory component of hydraulic load (Wosc/Wtot) from 25 ± 2 to 29 ± 2%. Pulmonary microembolism increased mean Ppa and PVR, with no significant change in Ca and characteristic impedance, increased RC-time from 0.53 ± 0.09 to 0.74 ± 0.05 s, and decreased Wosc/Wtot from 26 ± 2 to 13 ± 2%. Pulse pressure increased more after pulmonary ensnarement than after microembolism. Concomitant measurements with fluid-filled catheters showed the same functional differences between the two types of pulmonary hypertension, with, however, an underestimation of Wosc. We conclude that pulmonary hypertension caused by proximal vs. distal obstruction is associated with a decreased RC-time and increased pulsatile component of right ventricular hydraulic load.

Metabolic alkalosis occurs in up 51% of abnormal acid-base samples in the hospital. It is characterized by a primary increase in bicarbonate concentration and is always associated with chloride depletion. In critically-ill patients, it is most often generated by diuretic administration, digestive losses, alkali administration, or rapid correction of hypercapnia. Even after all causal factor are removed, it can be maintained by blood volume depletion and potassium depletion. Metabolic alkalosis results in hypercapnia, hypoxaemia, cardiac arrhythmias, altered consciousness, and neuromuscular hyperexcitability. It is first treated by removing the causal factors, whenever possible. Maintaining factors must be reversed by sodium chloride and/or potassium chloride administration. Acetazolamide and renal replacement therapy, when given for specific indications, can also correct the alkalosis. Lysine and arginine chloride are no longer used. If metabolic alkalosis is severe or when other treatments are contraindicated or ineffective, hydrochloric acid infusion is useful. Dilute hydrochloric acid can be infused safely, provided adequate precautions are taken to prevent extravascular leakage, vessel damage, and tissue necrosis.

Pulmonary hypertension on heart failure (HF) limits exercise capacity and survival probably because of associated right ventricular (RV) failure. This study investigated the mechanisms of RV function adaptation to early pulmonary hypertension in experimental HF. Seven weeks of rapid ventricular pacing in six dogs induced a HF characterized by cardiomegaly and decreased left ventricular ejection fraction. Compared with eight control dogs, pulmonary hypertension was borderline, with a mean pulmonary artery pressure increased to only 23 ± 2 (means ± SE) mmHg. However, the pulmonary vascular impedance spectrum was globally shifted to higher pressures, with an increase in 0 Hz impedance (resistance) to 662 ± 69 vs. 455 ± 41 dynes·cm−5·m2 in controls ( P < 0.01) and in characteristic impedance to 183 ± 20 vs. 104 ± 7 dynes·cm−5·m2 in controls ( P < 0.01). There was no change in RV end-systolic elastance (Ees), but arterial elastance (Ea) was increased to 1.8 ± 0.3 vs. 0.9 ± 0.1 mmHg/ml in controls so that RV-arterial coupling defined by the Ees-to-Ea ratio (Ees/Ea) was decreased to 0.8 ± 0.1 vs. 1.5 ± 0.1 in controls ( P < 0.01). Inhaled nitric oxide, 40 ppm or 5 μg·kg−1·min−1 nitroprusside iv, did not affect Ees/Ea. Fifty milligrams (iv) of milrinone increased Ees/Ea to 1.6 ± 0.2 by an isolated increase in Ees. We conclude that overpacing-induced HF is accompanied by a borderline pulmonary hypertension but profound RV-arterial uncoupling explained by the failure of RV systolic function to adapt combined effects of increased pulmonary arterial resistance and elastance.

Background: General anesthetics interfere with arterial and ventricular mechanical properties, often altering left ventricular–arterial (LVA) coupling. We hypothesized that sevoflurane and propofol alter LVA coupling by different effects on arterial and ventricular properties. Methods: Experiments were conducted in six anesthetized open-chest dogs for the measurement of left ventricular pressure and aortic pressure and flow. Measurements were performed during anesthesia with 0.5, 1.0 and 1.5 minimum alveolar concentration sevoflurane and 12, 24 and 36 mg/kg/h propofol. LVA coupling was assessed as the ratio of ventricular end-systolic elastance (Ees, measuring ventricular contractility) to effective arterial elastance (Ea, measuring ventricular afterload). The steady component of afterload, arterial tone, was assessed by systemic vascular resistance and arterial pressure–flow curves. The pulsatile component of afterload was assessed by aortic impedance and compliance. Results: Sevoflurane decreased aortic pressure and cardiac output more than propofol. Sevoflurane reduced arterial tone, increased arterial stiffness and did not affect wave reflections. It increased Ea, decreased Ees and reduced LVA coupling. Propofol reduced arterial tone, did not affect arterial stiffness and decreased wave reflections. It did not affect Ea, Ees or LVA coupling. Conclusions: Sevoflurane increased ventricular afterload and decreased ventricular performance, thereby altering LVA coupling. Propofol did not affect ventricular afterload or ventricular performance, thereby preserving LVA coupling. Thus, propofol preserves LVA coupling in dogs better, and might be a better choice for patients with compromised left ventricular function.

Background The pathogenic mechanisms of dilated cardiomyopathy are still uncertain. A number of cytokines and growth factors participate in the remodeling process of the disease. Methods We investigated the cardiac myostatin, transforming growth factor (TGF)β, and activin-A/Smad growth inhibitory signaling pathway in experimental dilated cardiomyopathy. Transvenous endomyocardial biopsies of the interventricular septum were taken weekly in 15 beagle dogs during the development of heart failure (HF) induced by rapid pacing over a period of 7 weeks. Genes involved in the myostatin-TGFβ-activin-A/Smad signaling pathway and the cardiac hypertrophic process were quantified by real-time quantitative polymerase chain reaction. Left ventricular volume, function, and mass were evaluated by echocardiography. Results Overpacing was associated with increased left ventricular volumes and decreased ejection fraction, whereas the left ventricular mass remained unchanged. TGFβ was increased in moderate HF. Activin-A mRNA expression was 4-fold higher in overt congestive HF than at baseline. A 2-fold decrease of activin type II receptors and activin receptor interacting protein 2 gene expressions were observed, as well as a transient decrease of follistatin. Activin type I receptors, activin receptor interacting protein 1, follistatin-related gene, and myostatin remained unchanged. The inhibitory Smad 7, a negative feedback loop regulator of the Smad pathway, was overexpressed in severe HF. Gene expression of the cyclin-dependent kinase inhibitor p21, a direct target gene of the Smad pathway, was 8-fold up-regulated in HF, whereas cyclin D1 was down-regulated. Conclusion We conclude that tachycardia-induced dilated cardiomyopathy is characterized by gene overexpression of the TGFβ-activin-A/Smad signaling pathway and their target gene p21 and by the absence of ventricular hypertrophy.

Repeated episodes of pulmonary embolism can persistently increase pulmonary arterial pressure and depress right ventricular contractility. We investigated the effects of levosimendan on right ventricular-pulmonary arterial coupling in this model of right ventricular failure.Prospective, controlled, randomized animal study.University research laboratory.Fourteen anesthetized piglets.Repeated acute pulmonary embolisms were induced with autologous blood clots to induce persistent right ventricular failure. Animals were randomly assigned to a control or levosimendan group. Levosimendan 20 microg/kg was administered in 10 mins followed by 0.2 microg/kg/min or same volumes of isotonic saline.Pulmonary artery distal resistance and proximal elastance by pressure-flow relationships and vascular impedance were measured. We noted right ventricle contractility by the end-systolic pressure-volume relationship (Ees), pulmonary artery effective elastance by the end-diastolic to end-systolic relationship (Ea), and right ventricular-pulmonary arterial coupling efficiency by the Ees/Ea ratio. The gradual pulmonary artery embolism increased pulmonary artery resistance and elastance, increased Ea from 1.01 +/- 0.17 to 5.58 +/- 0.37 mm Hg/mL, decreased Ees from 1.75 +/- 0.12 to 1.29 +/- 0.20 mm Hg/mL, and decreased Ees/Ea from 1.74 +/- 0.20 to 0.24 +/- 0.09. Compared with placebo, levosimendan decreased pulmonary arterial elastance and characteristic impedance. Right ventricular-pulmonary arterial coupling was restored by both an increase in right ventricular contractility and a decrease in right ventricular afterload.A gradual increase in pulmonary artery pressure induced by pulmonary embolism persistently worsens pulmonary artery hemodynamics, right ventricular contractility, right ventricular-pulmonary arterial coupling, and cardiac output. Levosimendan restores right ventricular-pulmonary arterial coupling better than placebo, because of combined pulmonary vasodilation and increased right ventricular contractility.

There are few data on long-term outcomes in mixed groups of intensive care unit (ICU) patients with prolonged stays. We evaluated the relationship between length of stay in the ICU and long-term outcome in all patients admitted to our 31-bed department of medico-surgical intensive care over a one-year period who stayed in the department for more than 10 days (n=189, 7% of all ICU admissions). Mortality increased with length of stay from 1 to 10 days (1 day 5%, 5 days 15%, 9 days 24%, 10 days 33%) but remained stable at about 35% for longer ICU stays. In the long-stay patients, the most common reasons for ICU admission were intracranial bleeding (23%), polytrauma (14%), respiratory failure (13%) and septic shock (11%). The main reasons for prolonged ICU stay were ventilator dependency (40%), infectious complications (23%) and coma (16%). Long-stay patients had a 65% ICU survival, 55% hospital survival and 37% one-year survival. At one-year follow-up, 73% of surviving patients reported no or minor persistent physical complaints compared to before the acute illness; 27% had a major functional impairment, including 8% who required daily assistance. In conclusion, in ICU patients, mortality increases with length of stay up to 10 days. Patients staying in the ICU for more than 10 days have a relatively good long-term survival. Most survivors have an acceptable quality of life.

OBJECTIVE: A transient increase in pulmonary arterial (PA) pressure can persistently depress right ventricular (RV) contractility. We investigated the effects of dobutamine and levosimendan on RV-PA coupling in this model of RV failure. DESIGN: Prospective, controlled, randomized animal study. SETTING: University research laboratory. SUBJECTS: Fifteen anesthetized dogs. INTERVENTIONS: Transient (90-min) PA constriction to induce persistent RV failure. Random assignment to dobutamine 5 and 10 μg/kg/min or levosimendan 12 μg/kg for 10 mins followed by 0.1 and 0.2 μg/kg/min. MEASUREMENTS AND MAIN RESULTS: We measured PA distal resistance and proximal elastance by pressure-flow relationships and vascular impedance. We measured RV contractility by the end-systolic pressure-volume relationship (Ees), PA effective elastance by the end-diastolic to end-systolic relationship (Ea), and RV-PA coupling efficiency by the Ees/Ea ratio. PA constriction persistently increased PA resistance and elastance, increased Ea from 0.95 ± 0.07 to 3.01 ± 0.28 mm Hg/mL, decreased Ees from 1.17 ± 0.09 to 0.58 ± 0.07 mm Hg/mL, and decreased Ees/Ea from 1.26 ± 0.09 to 0.22 ± 0.03 (p < .05). Dobutamine did not affect pulmonary hemodynamics, markedly increased RV contractility, and improved RV-PA coupling. Levosimendan decreased PA resistance and elastance, increased RV contractility, and restored RV-PA coupling. Compared with dobutamine, levosimendan decreased RV afterload and therefore better restored RV-PA coupling at similar inotropic state. CONCLUSIONS: A transient increase in PA pressure persistently worsens PA hemodynamics, RV contractility, RV-PA coupling, and cardiac output. Levosimendan restores RV-PA coupling better than dobutamine because of similar inotropic effects and additional pulmonary vasodilatory effects. © 2006 Lippincott Williams & Wilkins, Inc.

The renin-ANG system has been reported to be overexpressed in pulmonary arterial hypertension (PAH). We investigated the effects of ANG receptor-1 blockade by losartan on hemodynamics and signaling molecules in a piglet overflow model of early PAH. Twenty-six 3-wk-old piglets were randomized to placebo or losartan therapy (1 mg·kg−1·day−1) after anastomosis of the inominate to the main pulmonary artery or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative-PCR. Chronic systemic-to-pulmonary shunting increased the pulmonary vascular resistance from 2.5 ± 0.2 to 6.2 ± 0.3 mmHg·l−1·min·m−2and arteriolar medial thickness from 13.6 to 25.4%. These changes were associated with increased expressions of ANG II and its type 1 (AT1) and type 2 (AT2) receptors, endothelin-1 (ET-1) and its type B receptor (ETB), and angiopoietin-1, together with decreased expressions of bone morphogeneic protein receptor-1A and -2 (BMPR-1A and BMPR-2, respectively) and unchanged expression of the receptor tyrosine kinase with immunoglobulin and EGF homology domains-2 (Tie 2). Pretreatment with losartan decreased shunt-induced pulmonary vascular resistance and medial thickness by 51% and 35%, respectively. Losartan therapy was associated with persistent overexpressions of ANG II, AT2, ET-1, ETB, and angiopoietin-1 and with a return to normal of the BMPR-2 expression. These results suggest that ANG II contributes to left-to-right, shunt-induced PAH.

Background Halogenated anesthetics depress left ventricular function, but their effects on the right ventricle have been less well studied. Therefore, the authors studied the effects of isoflurane and desflurane on pulmonary arterial (PA) and right ventricular (RV) properties at baseline and in hypoxia. Methods Right ventricular and PA pressures were measured by micromanometer catheters, and PA flow was measured by an ultrasonic flow probe. PA mechanics were assessed by flow-pressure relations and by impedance spectra derived from flow and pressure waves. RV contractility was assessed by end-systolic elastance (Ees), RV afterload was assessed by effective PA elastance (Ea), and RV-PA coupling efficiency was assessed by the Ees:Ea ratio. Anesthetized dogs were randomly assigned to increasing concentrations (0.5, 1, and 1.5 times the minimum alveolar concentration) of isoflurane (n = 7) or desflurane (n = 7) in hyperoxia (fraction of inspired oxygen, 0.4) and hypoxia (fraction of inspired oxygen, 0.1). Results Isoflurane and desflurane had similar effects. During hyperoxia, both anesthetics increased PA resistance and characteristic impedance, increased Ea (isoflurane, from 0.82 to 1.44 mmHg/ml; desflurane, from 0.86 to 1.47 mmHg/ml), decreased Ees (isoflurane, from 1.09 to 0.66 mmHg/ml; desflurane, from 1.10 to 0.72 mmHg/ml), and decreased Ees:Ea (isoflurane, from 1.48 to 0.52; desflurane, from 1.52 to 0.54) in a dose-dependent manner (all P < 0.05). Hypoxia increased PA resistance, did not affect characteristic impedance, increased afterload, and increased contractility. During hypoxia, isoflurane and desflurane had similar ventricular effects as during hyperoxia. Conclusions Isoflurane and desflurane markedly impair RV-PA coupling efficiency in dogs, during hyperoxia and hypoxia, both by increasing RV afterload and by decreasing RV contractility.

We investigated the possible contributions of reactive oxygen species and of viscosity changes to hemodilution-induced inhibition of hypoxic pulmonary vasoconstriction (HPV) in dogs. Fourteen isoflurane-anesthetized dogs were randomly assigned to receive N-acetylcysteine (NAC) 200 mg/kg IV (n = 7) or placebo (n = 7). Mean pulmonary artery pressure (Ppa) was measured with cardiac output maintained constant by a manipulation of venous return in hyperoxia (fraction of inspired oxygen, 0.4) and in hypoxia (fraction of inspired oxygen, 0.1) at baseline and after stepwise reductions in hematocrit from 40% to 20%. Measured Ppa was compared with predicted Ppa by using a viscoelastic model. HPV was expressed as hypoxic Ppa minus hyperoxic Ppa. Hemodilution was associated with a decrease in HPV from 7 +/- 1 mm Hg to 3 +/- 1 mm Hg (P0.01), and this was completely prevented by NAC (HPV was unchanged, from 8 +/- 1 to 8 +/- 1 mm Hg; not significant). Hemodilution in the model decreased HPV from 8 +/- 1 mm Hg to 6 +/- 1 mm Hg (P0.05). We conclude that hemodilution-induced inhibition of HPV is in part explained by viscosity changes and can be prevented by the administration of NAC, which is possibly explained by the scavenging of reactive oxygen species.

Objectives Right ventricular (RV) afterload is best described by a pulmonary arterial impedance (PVZ) spectrum, which integrates pulmonary vascular resistance (PVR), elastance, and wave reflection. We evaluated the feasibility of PVZ determinations in patients with pulmonary arterial hypertension (PAH) during routine right heart catheterization and Doppler echocardiography. Design Prospective study. Setting Academic hospital. Patients: Twenty-two patients with PAH. Interventions Right heart catheterization with a fluid-filled Swan-Ganz catheter, Doppler echocardiography, and administration of inhaled nitric oxide (NO) [10 to 20 ppm; 17 patients], maximum tolerated dose of IV epoprostenol (average, 8.5 ng/kg/min; 5 patients), and IV dobutamine (8 μg/kg/min; 8 patients). Measurements and results PVZ was calculated from the spectral analysis of synchronized pulmonary artery pressure (Ppa) and flow waves. The mean (± SE) Ppa was 63 ± 3 mm Hg, and the mean PVR was 16 ± 2 Wood units. The PVZ spectrum was markedly shifted to higher than normal pressures and frequencies, with a mean 0-Hz impedance (Z 0 ) of 1,506 ± 138 dyne · s · cm −5 , and a mean characteristic impedance (Zc) of 124 ± 11 dyne · s · cm −5 , which are in keeping with data from previous studies. Inhaled NO levels decreased Ppa, PVR, Z 0 , and Zc without a change in cardiac output. Epoprostenol administration did not affect Ppa, increased cardiac output, and decreased Z 0 and Zc. Dobutamine administration increased cardiac output and Ppa, and decreased PVR and Z 0 , without changing Zc. Conclusions The determination of PVZ to quantify RV afterload is feasible during routine right heart catheterization and Doppler echocardiography. The measurement is sensitive to pharmacologic interventions.

SCOPUS: ar.j, info:eu-repo/semantics/published

Assessement of right ventricular (RV) contractility from end-systolic pressure-volume relationships (ESPVR) is difficult due to problems in measuring RV instantaneous volume and to effects of changes in RV preload or afterload. We therefore investigated in anesthetized dogs whether RV ESPVR and contractility can be determined without measuring RV volume and without changing RV preload or afterload. The maximal RV pressure of isovolumic beats (Pmax) was predicted from isovolumic portions of RV pressure during ejecting beats and compared with Pmaxmeasured during the first beat after pulmonary artery clamping. In RV pressure-volume loops obtained from RV pressure and integrated pulmonary arterial flow, end-systolic elastance ( E es) was assessed as the slope of Pmax-derived ESPVR, pulmonary artery effective elastance ( E a) as the slope of end-diastolic to end-systolic relation, and coupling efficiency as the E es-to- E a ratio ( E es/ E a). Predicted Pmax correlated with observed Pmax( r = 0.98 ± 0.02). Dobutamine increased E es from 1.07 to 2.00 mmHg/ml and E es/ E a from 1.64 to 2.49, and propranolol decreased E es/ E a from 1.64 to 0.91 (all P < 0.05). After adrenergic blockade, preload reduction did not affect E es, whereas hypoxia and arterial constriction markedly increased E aand somewhat increased E es due to the Anrep effect. Low preload did not affect E es/ E a and high afterload decreased E es/ E a. In conclusion, in the right ventricle 1) Pmax can be calculated from normal beats, 2) Pmax can be used to determine ESPVR without change in load, and 3) Pmax-derived ESPVR can be used to assess ventricular contractility and ventricular-arterial coupling efficiency.

Pulmonary hypertension is characterised by the chronic elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) leading to right ventricular enlargement and hypertrophy. Pulmonary hypertension may result from respiratory and cardiac diseases, the most severe forms occurring in thromboembolic and primary pulmonary hypertension. Pulmonary hypertension is most often defined as a mean PAP >25 mmHg at rest or >30 mmHg during exercise, the pressure being measured invasively with a pulmonary artery catheter. Doppler echocardiography allows serial, noninvasive follow-up of PAPs and right heart function. When the adaptive mechanisms of right ventricular dilatation and hypertrophy cannot compensate for the haemodynamic burden, right heart failure occurs and is associated with poor prognosis. The haemodynamic profile is the major determinant of prognosis. In both primary and secondary pulmonary hypertension, special attention must be paid to the assessment of pulmonary vascular resistance index (PVRI), right heart function and pulmonary vasodilatory reserve. Recent studies have stressed the prognostic values of exercise capacity (6-min walk test), right atrial pressure, stroke index and vasodilator challenge responses, as well as an interest in new imaging techniques and natriuretic peptide determinations. Overall, careful haemodynamic evaluation may optimise new diagnostic and therapeutic strategies in pulmonary hypertension.

To investigate the role of hypoxic pulmonary vasoconstriction in the intrapulmonary blood flow redistribution and gas exchange protection during oleic acid acute lung injury.Prospective, controlled animal study.Research laboratory of an academic institution.Three groups of five mongrel dogs.Induction of acute lung injury by 0.08 mL/kg oleic acid intravenously. Hypoxic pulmonary vasoconstriction inhibition by Escherichia coli endotoxin microdose (15 microg/kg) pretreatment or by metabolic alkalosis (pH 7.60).Pulmonary arterial and venous resistances were determined by flow-pressure curves and by capillary pressure estimation. Regional lung water and pulmonary blood flow were assessed by positron emission tomography. Oleic acid alone increased the arterial and venous resistances, redistributed blood flow away from edematous areas, and decreased the Pao2 from 507 +/- 16 to 373 +/- 60 torr. on Fio2 1.0 and positive end-expiratory pressure 5 cm H2O. Endotoxin pretreatment inhibited the increase in arterial resistance, suppressed the redistribution, and decreased the Pao2 to 105 +/- 22 torr. Alkalosis inhibited the increase in arterial and venous resistances, suppressed the redistribution, and decreased the Pao2 to 63 +/- 12 torr. Reversal of the alkalosis increased the arterial and venous resistances, restored the perfusion redistribution, and improved the Pao2 to 372 +/- 63 torr. Changes in blood gases conformed to predictions of a computer lung model in which hypoxic pulmonary vasoconstriction was suppressed by endotoxin and alkalosis.We conclude that in oleic acid-induced lung injury, a) pulmonary hypertension results from increases in both arterial and venous resistances; b) the increase in arterial resistance is the primary mechanism responsible for the perfusion redistribution and the gas exchange protection; and c) the increase in arterial resistance is most consistent with hypoxic pulmonary vasoconstriction.

A young woman presented with cardiac arrest following ingestion of yew tree leaves of the Taxus baccata species. The toxin in yew tree leaves has negative inotropic and dromotropic effects. The patient had a cardiac rhythm that alternated between pulseless electrical activity with a prolonged QRS interval and ventricular fibrillation. When standard resuscitation therapy including digoxin immune Fab was ineffective, a combination of extracorporeal membrane oxygenation (ECMO) and hypothermia was initiated. The total duration of low flow/no flow was 82 minutes prior to the initiation of ECMO. After 36 hours of ECMO (including 12 hours of electrical asystole), the patient’s electrocardiogram had normalized and the left ventricular ejection fraction was 50%. At this time, dobutamine and the ECMO were stopped. The patient had a full neurologic recovery and was discharged from the intensive care unit after 5 days and from the hospital 1 week later.

Current recommendations for mechanical ventilation in the acute respiratory distress syndrome (ARDS) include the use of small tidal volumes (VT), even at the cost of respiratory acidosis. We evaluated the effects of this permissive hypercapnia on pulmonary gas exchange with the multiple inert gas elimination technique (MIGET) in eight patients with ARDS. After making baseline measurements, we induced permissive hypercapnia by reducing VT from 10 +/- 2 ml/kg to 6 +/- 1 ml/kg (mean +/- SEM) at constant positive end-expiratory pressure. After restoration of initial VT, we infused dobutamine to increase cardiac output (Q) by the same amount as with hypercapnia. Permissive hypercapnia increased Q by an average of 1.4 L. min(-)(1). m(2), decreased arterial oxygen tension from 109 +/- 10 mm Hg to 92 +/- 11 mm Hg (p0.05), markedly increased true shunt (Q S/Q T), from 32 +/- 6% to 48 +/- 5% (p0.0001), and had no effect on the dispersion of VA/Q.VA/Q. On reinstatement of baseline V T with maintenance of a high Q, Q S/Q T remained increased, to 38 +/- 6% (p0.05), and Pa(O(2 ))remained decreased, to 93 +/- 4 mm Hg (p0. 05). These results agreed with effects of changes in VT and Q predicted by the mathematical lung model of the MIGET. We conclude that permissive hypercapnia increases pulmonary shunt, and that deterioration in gas exchange is explained by the combined effects of increased Q and decreased alveolar ventilation.

Non-heart-beating donation (NHBD) is under considerable ethical debate including concerns that the donor is not really dead when organs are procured and that withdrawing therapy may be expedited to harvest needed organs. We suggest a two-step process to NHBD based largely on the ethical principle of beneficence. First, once a decision has been made that there is no reasonable hope of survival for the patient and that active treatment is of no further benefit and should be withdrawn, NHBD can be suggested. Second, once the decision for NHBD has been made, there is no reason for further delay and withdrawal of treatment should be implemented as rapidly as possible to ensure that the quality of the donated organs remains optimal for the maximal benefit of the organ recipient.

Objectives: To determine whether patients with clinically identified infection have the same outcome as patients with apparent sepsis but no identified infectious source.¶Design: Retrospective analysis of patient data.¶Patients: All patients treated with septic shock in a 31-bed intensive care unit (ICU) over a 3-year period.¶Results: Data from 227 patients were analysed. Eighty-seven percent had a clinically identified source of infection. ICU mortality was higher in septic shock patients without a clinically identified source of infection than in those with an identified source of infection (86 % versus 66 %, p < 0.05).¶Conclusions: A small number of patients presenting with septic shock have no clinically identified infection. These patients have a higher mortality rate than patients in whom an infection is identified.

In six dogs and six weight-matched miniature pigs at baseline and after pulmonary embolization, pulmonary arterial compliance was determined using the pulse pressure method (CPPM), the three-element windkessel model (CWK-3), and the ratio of stroke volume to pulse pressure (SV/PP). CPPM was lower in pigs than in dogs at baseline (0.72 ± 0.23 vs. 1.14 ± 0.29 ml/mmHg, P < 0.05) and after embolism (0.37 ± 0.14 vs. 0.54 ± 0.16 ml/mmHg, P = 0.07) at matched flow, but not at matched flow and pressure. CPPM showed the expected inverse relation with pressure and a direct relation with flow. CWK-3 was closely correlated with CPPM, except for all dogs at baseline where CWK-3 was up to 100% higher than CPPM. Excluding these data, regression analysis yielded CWK-3 = −0.01 + 1.30 ⋅ CPPM( r 2 = 0.97). CWK-3 was found to be unreliable when input impedance first harmonic modulus was close to characteristic impedance, i.e., when reflections were small. SV/PP correlated well with CPPM (SV/PP = −0.10 + 1.76 ⋅ CPPM, r 2 = 0.89). We conclude that 1) CPPM is a consistent estimate of pulmonary arterial compliance in pigs and dogs, 2) CWK-3 and SV/PP overestimate compliance, and 3) CWK-3 is unreliable when wave reflections are small.

Objective: Flow-pressure curves and vascular impedance are commonly used to investigate pulmonary circulation, but they may be affected at low flow by reflex neurohumoral activation. We therefore investigated the mechanical effects and the reflex effects of decreased flow on pulmonary vascular resistance and impedance. Methods: In ten anaesthetized dogs, we compared flow-pressure curves generated in less than 10 s to prevent sympathetic activation (fast curves), or generated over 20-30 min to allow neurohumoral equilibration (slow curves), in hyperoxia (inspired oxygen, 40%) and in hypoxia (inspired oxygen, 10%), before and after adrenergic blockade by phentolamine and propranolol. Resistance was assessed from the flow-pressure relationship. Impedance was computed from instantaneous flow and pressure obtained with an ultrasonic flowmeter and a micromanometer-tipped catheter. Results: At baseline, fast flow-pressure curves were steeper and had a lower pressure intercept. Transient low flow did not affect heart rate or pulmonary arterial elastance. Sustained low flow increased heart rate, resistance and elastance, suggesting baroreceptor-induced sympathetic stimulation. After adrenergic blockade, no difference persisted between effects of transient and sustained low flow. In hypoxia, slow and fast flow-pressure curves were similar. Hypoxia increased heart rate and resistance but did not decrease elastance, suggesting chemoreceptor-induced sympathetic stimulation. In hypoxia, differences between transient and sustained low flow were no longer significant, and were completely suppressed by adrenergic blockade. In two additional dogs, epinephrine infusion increased pulmonary vascular resistance and elastance. Conclusions: We conclude that (1) compared to transient low flow, sustained low flow is associated with increases in distal resistance and proximal elastance due to sympathetic stimulation and (2) these differences between the effects of transient and sustained low flow do not persist in hypoxia, because of an already present chemoreceptor-induced sympathetic stimulation.

Inhaled but not i.v. anaesthetics are reported to decrease pulmonary vascular resistance. The aim of this study was to compare the effects of isoflurane with those of propofol on the interaction between right ventricular (RV) function and the pulmonary vascular system in embolic pulmonary hypertension. Nine dogs received in random sequence propofol 18 mg kg-1 h-1 and 1.4% end-tidal isoflurane. Pulmonary haemodynamic state was evaluated by pulmonary arterial pressure/flow (PAP/Q) plots and pulmonary vascular impedance (PVZ) spectra. Right ventricular function was assessed by total hydraulic power (Wtot), ratio of oscillatory power (Wosc) to Wtot, and dP/dtmax. Measurements were obtained, with both anaesthetics, before and after pulmonary embolic hypertension induced by autologous blood clots. Embolism increased PAP, 0 Hz and low frequency input impedance, displaced first minimum of PAP/Q moduli and zero crossing of phase to higher frequencies, decreased characteristic impedance, decreased Wosc/Wtot without affecting Wtot, and increased dP/dtmax. Compared with propofol, isoflurane at baseline did not affect PAP/Q plots, PVZ or hydraulic power data, but decreased dP/dtmax. After embolism, isoflurane shifted PAP/Q plots to lower PAP without affecting PVZ, did not affect hydraulic power data and decreased dP/dtmax. We conclude that in canine embolic pulmonary hypertension, isoflurane compared with propofol impeded RV vascular coupling caused by decreased RV contractility, while after-load remained unchanged despite some decrease in pulmonary vascular tone.

The effects of the sympathetic nervous system on hypoxic pulmonary vasoconstriction (HPV) have been reported variably. We studied the effects of adrenergic receptor blockade and epidural blockade on HPV in 32 pentobarbital-anaesthetised intact dogs.Pulmonary arterial flow-pressure relationships were determined in hyperoxia and hypoxia, at baseline and after alpha-blockade (phentolamine 2 mg/kg + 50 micrograms.kg-1.-1), beta-blockade (propranolol 2 mg/kg), alpha beta-blockade, epidural blockade (lignocaine 20 mg/kg), and alpha beta-plus epidural blockade.At reference flow of 3.5 1.min-1.m-2, the mean hypoxic response (hypoxia-induced increase in transpulmonary pressure gradient, each n = 8) changed from 6.0 +/- 0.9 to 3.5 +/- 1.0 mmHg after alpha-blockade, from 5.8 +/- 0.9 to 0.7 mmHg after beta-blockade, from 4.1 +/- 0.8 to 0.9 +/- 1.4 mmHg after alpha beta-blockade from 3.4 +/- 1.0 to 4.3 +/- 0.9 mmHg after epidural blockade (all P0.05), and was not affected by epidural blockade after alpha beta-blockade.In pentobarbital-anaesthetised dogs, (1) HPV is attenuated by alpha- and enhanced by beta-, alpha beta- and epidural blockade, and (2) epidural blockade has no significant adrenergic-unrelated effect on the pulmonary vasculature.

Vascular effects of general anesthesia are usually described by changes in vascular resistance, which assumes a linear pressure-flow relationship passing through the zero-flow zero-pressure point, and neglects the pulsatile properties of the circulation. We compared the systemic vascular effects of isoflurane versus propofol anesthesia by measurements of aortic pressure-flow relationships, systemic vascular impedance (SVZ), and pressure transfer function (PTF). Eight mechanically ventilated dogs received isoflurane 1.4% end-tidal and propofol 18 mg [centered dot] kg-1 [centered dot] h-1 in a random sequence. During both periods, pressure-flow data and SVZ data were obtained at baseline and after stepwise reduction of the cardiac output by inflation of a balloon in the inferior vena cava. Instantaneous pressure and flow were measured at the aortic root using a micromanometer-tipped catheter and an ultrasonic flow probe. Compared to baseline, low flow decreased the aortic pressure and increased the resistance, characteristic impedance, and oscillatory/total work ratio. Compared with isoflurane, propofol resulted in higher aortic pressure, lower characteristic impedance, and lower oscillatory/total work ratio. Low-frequency PTF moduli decreased at low flow and increased with propofol. We conclude that, compared with isoflurane, propofol better preserves aortic pressure and increases aortic compliance, and thus improves the energy transmission from the left ventricle to the arterial system. (Anesth Analg 1996;83:958-64)

Brimioulle, Serge, Philippe Lejeune, and Robert Naeije.Effects of hypoxic pulmonary vasoconstriction on pulmonary gas exchange. J. Appl. Physiol. 81(4): 1535–1543, 1996.—Several reports have suggested that hypoxic pulmonary vasoconstriction (HPV) might result in deterioration of pulmonary gas exchange in severe hypoxia. We therefore investigated the effects of HPV on gas exchange in normal and diseased lungs. We incorporated a biphasic HPV stimulus-response curve observed in intact dogs (S. Brimioulle, P. Lejeune, J. L. Vachièry, M. Delcroix, R. Hallemans, and R. Naeije, J. Appl. Physiol. 77: 476–480, 1994) into a 50-compartment lung model (J. B. West, Respir. Physiol. 7: 88–110, 1969) to control the amount of blood flow directed to each lung compartment according to the local hypoxic stimulus. The resulting model accurately reproduced the blood gas modifications caused by HPV changes in dogs with acute lung injury. In single lung units, HPV had a moderate protective effect on alveolar oxygenation, which was maximal at near-normal alveolar[Formula: see text] (75–80 Torr), mixed venous[Formula: see text] (35 Torr), and[Formula: see text] at which hemoglobin is 50% saturated (24 Torr). In simulated diseased lungs associated with 40–60 Torr arterial [Formula: see text], however, HPV increased arterial [Formula: see text]by 15–20 Torr. We conclude that HPV can improve arterial oxygenation substantially in respiratory failure.

Background Hyponatremia occurring as a result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or cerebral salt wasting syndrome is a common complication in patients with subarachnoid hemorrhage (SAH). The efficacy and safety of urea as treatment for SIADH-induced hyponatremia has not been reported in this population. Methods This is a retrospective analysis of all patients admitted to our department for nontraumatic SAH between January 2003 and December 2008 (n = 368). All patients with SIADH-induced hyponatremia (plasma sodium < 135 mEq/L, urine sodium > 20 mEq/L, and osmolality > 200 mOsm/kg; absence of overt dehydration or hypovolemia; no peripheral edema or renal failure; no history of adrenal or thyroid disease) routinely received urea per os when hyponatremia was associated with clinical deterioration or remained less than 130 mEq/L despite saline solution administration. Results Forty-two patients developed SIADH and were treated with urea. Urea was started after a median of 7 (IQR, 5-10) days and given orally at doses of 15-30 g tid or qid for a median of 5 (IQR, 3-7) days. The median plasma sodium increase over the first day of treatment was 3 (IQR, 1-6) mEq/L. Hyponatremia was corrected in all patients, with median times to Na + >130 and >135 mEq/L of 1 (IQR, 1-2) and 3 (IQR, 2-4) days, respectively. Urea was well tolerated, and no adverse effects were reported. Conclusions Oral urea is an effective and well-tolerated treatment for SIADH-induced hyponatremia in SAH patients. © 2012 Pierrakos et al., SCOPUS: ar.j, info:eu-repo/semantics/published

Systemic-to-pulmonary shunting in growing pigs has been proposed as an experimental model of high-flow pulmonary hypertension associated with congenital heart defects. We investigated multipoint pulmonary arterial pressure (Ppa) vs. cardiac output (Q) plots and pulmonary vascular impedance spectra in 13 piglets aged approximately 4 mo and ventilated alternatively in hyperoxia (inspired O2 fraction 0.4) and in hypoxia (inspired O2 fraction 0.12). The measurements were done 8 wk after either an anastomosis between the thoracic aorta and the pulmonary trunk (n = 7 piglets) or a sham operation (n = 6). Cardiac output was altered by a manipulation of venous return. In the sham-operated piglets, hypoxia increased Ppa by an average of 12 mmHg over the entire range of Q studied, from 60 to 120 ml/kg, and increased both 0 Hz (Z0) and characteristic (Zc) pulmonary vascular impedance. In the shunted piglets compared with the sham-operated piglets in hyperoxia, Ppa was increased by an average of 5–6 mmHg at all levels of Q studied, from 60 to 120 ml/kg (P < 0.01), and Zc was also increased (P < 0.01), whereas Z0 was unchanged. In the shunted piglets, hypoxia increased Ppa at all levels of Q studied only to an average of 3 mmHg, and neither Z0 nor Zc was altered by hypoxia. We conclude that an aortopulmonary shunt of 2-mo duration in growing pigs increases both pulmonary vascular resistance and impedance and is associated with a blunting of pulmonary vascular reactivity to hypoxia.

Hypoxic pulmonary vasoconstriction (HPV) has been reported to decrease during severe hypoxia in isolated lungs, but it remains unknown whether this decrease occurs in the intact animal and how it is affected by cyclooxygenase inhibition. We investigated the HPV stimulus-response relationship in eight pentobarbital sodium-anesthetized intact dogs with a naturally occurring response to hypoxia (“responders”). The pulmonary arterial minus wedge pressure difference (Ppa-Ppw) was measured at 11 inspired O2 fraction (FIO2) values between 0.40 and 0.04 while ventilation, cardiac output, and acid-base status were kept constant. Ppa-Ppw increased by 8 +/- 1 mmHg between FIO2 of 0.40 and 0.10 (alveolar PO2 of approximately 40 Torr) and decreased by 3 +/- 1 mmHg between FIO2 of 0.10 and 0.04. To assess the effects of cyclooxygenase inhibition, similar stimulus-response curves were obtained after administration of 20 mg/kg of acetylsalicylic acid (ASA) in 16 more dogs selected as either nonresponders or responders to hypoxia. ASA restored HPV in nonresponders and enhanced HPV in responders, with the difference between Ppa-Ppw at FIO2 of 0.10 and 0.40 increasing from 1 +/- 1 to 8 +/- 1 mmHg (P < 0.001) and from 7 +/- 1 to 10 +/- 1 mmHg (P < 0.05), respectively. In both groups, the shape of the stimulus-response curve after ASA was comparable to that of spontaneous HPV, with a maximum at FIO2 of 0.10 and a significant decrease at lower FIO2. We conclude that severe hypoxia attenuates HPV in the intact animal and that ASA restores or enhances HPV by affecting the magnitude of the hypoxic response and not the sensitivity to hypoxia.

Three-month chronic systemic-to-pulmonary shunting in growing piglets has been reported as an early pulmonary arterial hypertension (PAH) model with preserved right ventricular (RV) function. We sought to determine whether prolonged shunting might be associated with more severe PAH and RV failure.Fourteen growing piglets were randomized to a sham operation or the anastomosis of the left innominate artery to the pulmonary arterial trunk. Six months later, the shunt was closed and the animals underwent haemodynamic evaluation followed by tissue sampling for pathobiological assessment. Prolonged shunting had resulted in increased mean pulmonary artery pressure (22 ± 2 versus 17 ± 1 mmHg) and pulmonary arteriolar medial thickness, while cardiac output was decreased. However, RV-arterial coupling was markedly deteriorated, with a ~50% decrease in the ratio of end-systolic to pulmonary arterial elastances (Ees/Ea). Lung tissue expressions of endothelin-1, angiopoietin-1, and bone morphogenetic protein receptor-2 were similarly altered compared with previously observed after 3-month shunting. At the RV tissue level, pro-apoptotic ratio of Bax-to-Bcl-2 expressions and caspase-3 activation were increased, along with an increase in cardiomyocyte size, while expressions in voltage-gated potassium channels (Kv1.5 and Kv2.1) and angiogenic factors (angiopoietin-2 and vascular endothelial growth factor) were decreased. Right ventricular expressions of pro-inflammatory cytokines [interleukin (IL)-1α, IL-1β, tumour necrosis factor-α (TNF-α)] and natriuretic peptide precursors (NPPA and NPPB) were increased. There was an inverse correlation between RV Ees/Ea and pro-apoptotic Bax/Bcl-2 ratios.Prolonged left-to-right shunting in piglets does not further aggravate pulmonary vasculopathy, but is a cause of RV failure, which appears related to an activation of apoptosis and inflammation.

Background Normovolemic hemodilution is known to inhibit hypoxic pulmonary vasoconstriction. How the coupling between the pulmonary arterial (PA) circulation and the right ventricle (RV) is affected by normovolemic hemodilution and by the composition of replacement solutions remains unknown. Therefore, the effects of isotonic and hypertonic saline hydroxyethylstarch solutions on the pulmonary circulation and RV, in control and hypoxic conditions, were compared. Methods Anesthetized piglets (n = 14) were equipped with manometer-tipped catheters in the RV and main PA and an ultrasonic flow probe around the main PA. The pulmonary circulation was assessed by pressure-flow relations and vascular impedance, RV afterload by effective arterial elastance (Ea), RV contractility by end-systolic elastance (Ees), and RV-PA coupling by the Ees/Ea ratio. Measurements were done in control (Fio2 0.40) and hypoxic (Fio2 0.12) conditions before and after acute normovolemic hemodilution with either 20 ml/kg isotonic saline hydroxyethylstarch (hydroxyethylstarch 130/0.4 6% in NaCl 0.9%, Voluven, Fresenius-Kabi, Sevres, France) or 5 ml/kg hypertonic saline hydroxyethylstarch (hydroxyethylstarch 200/0.5 6% in NaCl 7.2%, HyperHES, Fresenius-Kabi) solutions. Results Hypoxic pulmonary vasoconstriction was associated with proportional increases in Ea and Ees and did not affect RV-PA coupling. Hemodilution attenuated the hypoxic response. Hemodilution with isotonic saline hydroxyethylstarch did not affect the RV-PA coupling, whereas hemodilution with hypertonic saline hydroxyethylstarch increased Ees and the Ees/Ea ratio. Conclusion In experimental normovolemic hemodilution, both in control and in hypoxic conditions, RV-PA coupling is unaffected by isotonic saline hydroxyethylstarch but improved by hypertonic saline hydroxyethylstarch, mainly because of an increase in RV contractility.

Background: Transient increase in pulmonary arterial (PA) pressure has been shown to induce a persistent right ventricular (RV) failure characterized by a RV-arterial decoupling, associated to activation of apoptotic pathways and local overexpression of TNF-alpha (Dewachter et al . Crit Care Med 2010; 38: 1405-13). Objectives: We hypothesized therefore that inflammatory cytokines might contribute to the development of persistent RV failure in this “pulmonary hypertension crisis” model. Methods: Sixteen dogs were randomized to a 90-min PA constriction- or to a SHAM-operation, followed 30 minutes later by hemodynamic measurements including effective pulmonary arterial elastance (Ea) to estimate RV afterload and RV end-systolic elastance (Ees) to estimate RV contractility determined by the single beat method (Brimioulle et al . Am J Physiol 2003; 284: H1625-30), but also blood sampling. After sacrifice of the animals, RV free wall was sampled to assess, by RTQPCR and ELISA, respectively gene and protein expressions of interleukin (IL)-1 beta, -6 and -10. Results: The transient increase in PA pressure persistently increased Ea, and decreased Ees, Ees/Ea and cardiac output, indicating RV failure with altered RV-arterial coupling. As compared to the SHAM group, 90-min PA constriction increased RV relative gene and protein expressions of IL-1 beta and IL-6, and decreased RV relative gene and protein expressions of IL-10, an anti-inflammatory cytokine. The pro-inflammatory IL-6/IL-10 ratio was increased in the RV and in the serum in the PA constriction- compared to the SHAM- group. Conclusions: Acute afterload-induced persistent RV failure appears to be related to local and systemic activation of inflammation.