Pulmonary veno-occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology.

Pulmonary veno-occlusive disease (PVOD) is defined by specific pathologic changes of the pulmonary veins. A definite diagnosis of PVOD thus requires a lung biopsy or pathologic examination of pulmonary explants or postmortem lung samples. However, lung biopsy is hazardous in patients with severe pulmonary hypertension, and there is a need for noninvasive diagnostic tools in this patient population. Patients with PVOD may be refractory to pulmonary arterial hypertension (PAH)-specific therapy and may even deteriorate with it. It is important to identify such patients as soon as possible, because they should be treated cautiously and considered for lung transplantation if eligible. High-resolution computed tomography of the chest can suggest PVOD in the setting of pulmonary hypertension when it shows nodular ground-glass opacities, septal lines, lymph node enlargement, and pleural effusion. Similarly, occult alveolar hemorrhage found on bronchoalveolar lavage in patients with pulmonary hypertension is associated with PVOD. We conducted the current study to identify additional clinical, functional, and hemodynamic characteristics of PVOD. We retrospectively reviewed 48 cases of severe pulmonary hypertension: 24 patients with histologic evidence of PVOD and 24 randomly selected patients with idiopathic, familial, or anorexigen-associated PAH and no evidence of PVOD after meticulous lung pathologic evaluation. We compared clinical and radiologic findings, pulmonary function, and hemodynamics at presentation, as well as outcomes after the initiation of PAH therapy in both groups. Compared to PAH, PVOD was characterized by a higher male:female ratio and higher tobacco exposure (p < 0.01). Clinical presentation was similar except for a lower body mass index (p < 0.02) in patients with PVOD. At baseline, PVOD patients had significantly lower partial pressure of arterial oxygen (PaO2), diffusing lung capacity of carbon monoxide/alveolar volume (DLCO/VA), and oxygen saturation nadir during the 6-minute walk test (all p < 0.01). Hemodynamic parameters showed a lower mean systemic arterial pressure (p < 0.01) and right atrial pressure (p < 0.05), but no difference in pulmonary capillary wedge pressure. Four bone morphogenetic protein receptor II (BMPR2) mutations have been previously described in PVOD patients; in the current study we describe 2 additional cases of BMPR2 mutation in PVOD. Computed tomography of the chest revealed nodular and ground-glass opacities, septal lines, and lymph node enlargement more frequently in patients with PVOD compared with patients with PAH (all p < 0.05). Among the 16 PVOD patients who received PAH-specific therapy, 7 (43.8%) developed pulmonary edema (mostly with continuous intravenous epoprostenol, but also with oral bosentan and oral calcium channel blockers) at a median of 9 days after treatment initiation. Acute vasodilator testing with nitric oxide and clinical, functional, or hemodynamic characteristics were not predictive of the subsequent occurrence of pulmonary edema on treatment. Clinical outcomes of PVOD patients were worse than those of PAH patients.

Early veno-venous haemodiafiltration for sepsis-related multiple organ failure.

INTRODUCTION: We conducted a prospective observational study from January 1995 to December 2004 to evaluate the impact on recovery of a major advance in renal replacement therapy, namely continuous veno-venous haemodiafiltration (CVVHDF), in patients with refractory septic shock. METHOD: CVVHDF was implemented after 6-12 hours of maximal haemodynamic support, and base excess monitoring was used to evaluate the improvement achieved. Of the 60 patients studied, 40 had improved metabolic acidosis after 12 hours of CVVHDF, with a progressive improvement in all failing organs; the final mortality rate in this subgroup was 30%. In contrast, metabolic acidosis did not improve in the remaining 20 patients after 12 hours of CVVHDF, and the mortality rate in this subgroup was 100%. The crude mortality rate for the whole group was 53%, which is significantly lower than the predicted mortality using Simplified Acute Physiology Score II (79%). CONCLUSION: Early CVVHDF may improve the prognosis of sepsis-related multiple organ failure. Failure to correct metabolic acidosis rapidly during the procedure was a strong predictor of mortality.

Incidence, causes and prognosis of hypotension related to meprobamate poisoning.

OBJECTIVE: Meprobamate self-poisoning has been reported as potentially inducing hypotension. We examined the incidence and causes of hypotension induced by this poisoning and its prognosis. DESIGN AND SETTING: Retrospective observational study conducted in a medical ICU between June 1997 and October 2003. Seventy-four patients admitted for meprobamate poisoning and needing mechanical ventilation were included. Demographic, clinical, and laboratory data were compared between patients with and without hypotension. All echocardiograms recorded in patients with hypotension were reviewed, and left ventricular (LV) and right ventricular (RV) functions were assessed. RESULTS: Twenty-nine (40%) patients exhibited hypotension without any significant difference in age, gender, cardiac history, or meprobamate concentration in blood when compared to patients without hypotension. Base excess was significantly lower in patients with hypotension. Echocardiography demonstrated a hypokinetic state, associating decreased LV ejection fraction (45+/-15%) and cardiac index (2+/-0.7 l min(-1) m(-2)), and increased inferior vena cava diameter. Most patients with hypotension received inotropic drugs by infusion, and were ventilated for significantly longer. CONCLUSIONS: Meprobamate self-poisoning induces hypotension, notably related to cardiac failure, in about 40% of cases. This has important therapeutic consequences, as frequent inotropic drug infusion. The mechanisms of cardiac toxicity remain largely unknown, and no predictive factor could be isolated.

Norfloxacin reduces aortic NO synthases and proinflammatory cytokine up-regulation in cirrhotic rats: role of Akt signaling.

BACKGROUND & AIMS: Arterial vasodilation plays a role in the pathogenesis of the complications of cirrhosis. This vasodilation is caused by the overproduction of arterial nitric oxide (NO). Bacterial translocation may be involved in NO synthase (NOS) up-regulation by activating both endothelial NOS (eNOS) and inducible NOS (iNOS). The prevention of intestinal gram-negative translocation by norfloxacin administration corrects systemic circulatory changes by decreasing NO production in cirrhosis. However, the signaling mechanisms for NO overproduction from bacterial translocation are unknown. In this study, we investigated the signal transduction pathway of bacterial translocation-induced aortic NOS up-regulation in cirrhotic rats. METHODS: Proinflammatory cytokine levels, Akt and NOS activities, eNOS phosphorylation, and NOS expressions were assessed in aorta from norfloxacin-treated and untreated cirrhotic rats. Norfloxacin was administered to reduce intestinal bacterial translocation. RESULTS: Aortic eNOS and iNOS protein expressions, Akt activity, and eNOS phosphorylation by Akt at serine 1177 were up-regulated in cirrhotic rats. Norfloxacin administration significantly decreased the incidence of gram-negative translocation and proinflammatory cytokine (tumor necrosis factor-alpha, interferon-gamma, and interleukin-6) levels; norfloxacin also decreased aortic Akt activity, eNOS phosphorylation, and NOS expressions and activities. The decrease in aortic Akt activity and NOS expressions also was obtained after colistin or anti-tumor necrosis factor-alpha antibody administration to cirrhotic rats. CONCLUSIONS: This study identifies a signaling pathway in which bacterial translocation induces aortic NOS up-regulation and thus NO overproduction in cirrhotic rats. These results strongly suggest that bacterial translocation and proinflammatory cytokines play a role in systemic NO overproduction in cirrhosis by the Akt pathway.

Prone position improves mechanics and alveolar ventilation in acute respiratory distress syndrome.

OBJECTIVE: We tested the hypothesis that ventilation in the prone position might improve homogenization of tidal ventilation by reducing time-constant inequalities, and thus improving alveolar ventilation. We have recently reported in ARDS patients that these inequalities are responsible for the presence of a "slow compartment," excluded from tidal ventilation at supportive respiratory rate. DESIGN: In 11 ARDS patients treated by ventilation in the prone position because of a major oxygenation impairment (PaO(2)/FIO(2)

Superior vena caval collapsibility as a gauge of volume status in ventilated septic patients.

OBJECTIVE: In mechanically ventilated patients inspiratory increase in pleural pressure during lung inflation may produce complete or partial collapse of the superior vena cava. Occurrence of this collapse suggests that at this time external pressure exerted by the thoracic cavity on the superior vena cava is greater than the venous pressure required to maintain the vessel fully open. We tested the hypothesis that measurement of superior vena caval collapsibility would reveal the need for volume expansion in a given septic patient. DESIGN AND SETTING: Prospective data collection for 66 successive patients in septic shock admitted in a medical intensive care unit and mechanically ventilated for an associated acute lung injury. MEASUREMENTS AND RESULTS: We simultaneously measured superior vena caval collapsibility by echocardiography and cardiac index by the Doppler technique at baseline and after a 10 ml/kg volume expansion by 6% hydroxyethyl starch in 30 min. The threshold superior vena caval collapsibility of 36%, calculated as (maximum diameter on expiration-minimum diameter on inspiration)/maximum diameter on expiration, allowed discrimination between responders (defined by an increase in cardiac index of at least 11% induced by volume expansion) and nonresponders, with a sensitivity of 90% and a specificity of 100%. CONCLUSIONS: Superior vena cava measurement should be systematically performed during routine echocardiography in septic shock as it gives an accurate index of fluid responsiveness.

Pulmonary hypertension: CT of the chest in pulmonary venoocclusive disease.

OBJECTIVE: Pulmonary venoocclusive disease is a rare cause of pulmonary hypertension that is often difficult to distinguish from severe primary pulmonary hypertension. Unfortunately, medical treatment of primary pulmonary hypertension with prostacyclin can be fatal in patients with venoocclusive disease, and an early pretreatment diagnosis of this uncommon condition is critical. The aim of our study was to evaluate this disease noninvasively using CT of the chest. MATERIALS AND METHODS: We reviewed cross-referenced records from 1996 to 2001 in our departments of radiology and pathology and identified 15 patients with initial pretreatment CT scans who had pathologically confirmed pulmonary venoocclusive disease. Their CT scans were compared with the CT scans of 15 consecutive patients with pathologically confirmed primary pulmonary hypertension. All patients had undergone a postmortem or posttransplantation examination. RESULTS: Ground-glass opacities were significantly more frequent in pulmonary venoocclusive disease (p = 0.003); the opacities were abundant with random zonal predominance and preferentially centrilobular distribution (p = 0.03). Subpleural septal lines and adenopathy were also significantly more frequent (p < 0.0001). CONCLUSION: On the initial pretreatment chest CT scan, the presence of ground-glass opacities (particularly with a centrilobular distribution), septal lines, and adenopathy are indicative of pulmonary venoocclusive disease in patients displaying pulmonary hypertension. Caution should be exercised before vasodilator therapy is initiated in the patients whose scans show such radiologic abnormalities.

Prevention of gram-negative translocation reduces the severity of hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) is characterized by intrapulmonary vascular dilatations and an increased alveoloarterial oxygen difference (AaPO(2)). These abnormalities are related to augmented pulmonary nitric oxide (NO) production, dependent primarily on increases in the expression and activity of inducible NO-synthase (iNOS) within pulmonary intravascular macrophages and, to a lesser extent, of endothelial NOS (eNOS). Production of iNOS by pulmonary intravascular macrophages might be related to translocated gut bacteria present in the pulmonary circulation. To test this hypothesis, we determined whether macrophage sequestration, lung iNOS expression and activity, and HPS severity were decreased after norfloxacin was given for 5 weeks to prevent Gram-negative bacterial translocation in rats with common bile duct ligation-induced cirrhosis. Norfloxacin decreased the incidence of Gram-negative translocation from 70 to 0% and the percentage of pulmonary microvessels containing more than 10 macrophages from 52 +/- 7 to 21 +/- 8% (p < 0.01). AaPO(2) and cerebral uptake of intravenous (99m)Tc-labeled albumin macroaggregates (reflecting intrapulmonary vascular dilatations) were intermediate to those of untreated cirrhotic and sham-operated rats. The activity and expression of lung iNOS, but not eNOS, were reduced to normal. Norfloxacin may reduce HPS severity by inhibiting Gram-negative bacterial translocation, thereby decreasing NO production by pulmonary intravascular macrophages. Bacterial translocation may be the key to the pathogenesis of HPS.