Body mass index is associated with the development of acute respiratory distress syndrome.

BACKGROUND: The relationship between body mass index (BMI) and development of acute respiratory distress syndrome (ARDS) is unknown. METHODS: A cohort study of critically ill patients at risk for ARDS was carried out. BMI was calculated from admission height and weight. Patients were screened daily for AECC (American European Consensus Committee)-defined ARDS and 60-day ARDS mortality. RESULTS: Of 1795 patients, 83 (5%) patients were underweight (BMI <18.5 kg/m(2)), 627 (35%) normal (BMI 18.5-24.9), 605 (34%) overweight (BMI 25-29.9), 364 (20%) obese (BMI 30-39.9) and 116 (6%) severely obese (BMI > or =40). Increasing weight was associated with younger age (p<0.001), diabetes (p<0.0001), higher blood glucose (p<0.0001), lower prevalence of direct pulmonary injury (p<0.0001) and later development of ARDS (p = 0.01). BMI was associated with ARDS on multivariate analysis (OR(adj) 1.24 per SD increase; 95% CI 1.11 to 1.39). Similarly, obesity was associated with ARDS compared with normal weight (OR(adj) 1.66; 95% CI 1.21 to 2.28 for obese; OR(adj) 1.78; 95% CI 1.12 to 2.92 for severely obese). Exploratory analysis in a subgroup of intubated patients without ARDS on admission (n = 1045) found that obese patients received higher peak (p<0.0001) and positive end-expiratory pressures (p<0.0001) than non-obese patients. Among patients with ARDS, increasing BMI was associated with increased length of stay (p = 0.007) but not with mortality (OR(adj) 0.89 per SD increase; 95% CI 0.71 to 1.12). CONCLUSION: BMI was associated with increased risk of ARDS in a weight-dependent manner and with increased length of stay, but not with mortality. Additional studies are needed to determine whether differences in initial ventilator settings may contribute to ARDS development in the obese.

Serum bilirubin levels on ICU admission are associated with ARDS development and mortality in sepsis.

BACKGROUND: Hyperbilirubinaemia is a common complication of sepsis. Elevated bilirubin may induce inflammation and apoptosis. It was hypothesised that increased serum bilirubin on Intensive Care Unit (ICU) admission contributes to sepsis-related acute respiratory distress syndrome (ARDS). METHODS: Serum bilirubin on ICU admission was measured in 1006 patients with sepsis. Serial serum bilirubin was analysed prospectively in patients with sepsis who had ARDS for a period of 28 days. The effects of clinical factors and variants of the UGT1A1 gene on serum bilirubin levels were determined. Outcomes were ARDS risk and mortality. RESULTS: During 60-day follow-up, 326 patients with sepsis developed ARDS, of whom 144 died from ARDS. The hyperbilirubinaemia (>or=2.0 mg/dl) rate in patients with ARDS (22.4%) was higher than in those without ARDS (14.1%, p = 0.002). For each 1.0 mg/dl increase in admission bilirubin, ARDS risk and 28- and 60-day ARDS mortalities were increased by 7% (OR = 1.07; p = 0.003), 20% (OR = 1.20; p = 0.002) and 18% (OR = 1.18; p = 0.004), respectively. Compared with subjects with bilirubin levels <2.0 mg/dl, patients with hyperbilirubinaemia had higher risks of ARDS (OR = 2.12; p = 0.0007) and 28-day (OR = 2.24; p = 0.020) and 60-day ARDS mortalities (OR = 2.09; p = 0.020). In sepsis-related ARDS, serial bilirubin levels in non-survivors were consistently higher than in survivors (p<0.0001). Clinical variables explained 29.5% of the interindividual variation in bilirubin levels, whereas genetic variants of UGT1A1 contributed 7.5%. CONCLUSION: In sepsis, a higher serum bilirubin level on ICU admission is associated with subsequent ARDS development and mortality.

Sex-specific association of epidermal growth factor gene polymorphisms with acute respiratory distress syndrome.

Epidermal growth factor (EGF) is involved in alveolar epithelial repair, lung fluid clearance and inflammation, and is regulated by sex hormones. An unmatched, nested case-control study was conducted to evaluate the associations of EGF variants with acute respiratory distress syndrome (ARDS) and the role of sex on the associations between EGF variants and ARDS. Patients with ARDS risk factors upon intensive care unit admission were enrolled. Cases were 416 Caucasians who developed ARDS and controls were 1,052 Caucasians who did not develop ARDS. Cases were followed for clinical outcomes and 60-day mortality. One functional single nucleotide polymorphism (SNP), rs4444903, and six haplotype-tagging SNPs spanning the entire EGF gene were genotyped. No individual SNP or haplotype was associated with ARDS risk or outcomes in all subjects. Sex-stratified analyses showed opposite effects of EGF variants on ARDS in males versus in females. SNPs rs4444903, rs2298991, rs7692976 and rs4698803, and haplotypes GGCGTC and ATCAAG were associated with ARDS risk in males. No associations were observed in females. Interaction analysis showed that rs4444903, rs2298991, rs7692976 and rs6533485 significantly interacted with sex for ARDS risk. The present study suggests that associations of epidermal growth factor gene variants with acute respiratory distress syndrome risk are modified by sex. The current findings should be replicated in other populations.

Safety of enteral naloxone for the reversal of opiate-induced constipation in the intensive care unit.

BACKGROUND: Opiates are the mainstay of analgesia in the intensive care unit (ICU). Unfortunately, constipation is a common adverse effect associated with opioid use. Naloxone is a pure opiate antagonist that is frequently utilized in practice for the prophylaxis or treatment of opiate-induced constipation in the ICU. Despite extensive first pass metabolism in the liver there remains the potential for opiate reversal after oral administration. We sought to assess the safety of enteral naloxone in the ICU for the treatment of opiate-induced constipation. METHODS: Patients who were ordered enteral naloxone while in the ICU were identified through the Pharmacy's computer system. Patients were included in the data analysis if they had received at least one dose of enteral naloxone and had received standing opiates for at least 48 h prior to the initial naloxone dose. Patients were excluded from data analysis if the Richmond agitation-sedation scale (RASS) score was not utilized, they were paralysed or the medical record indicated that extubation was planned within the following 24 h. Data points were recorder at the following times with respect to each naloxone dose administered; time -2, -1, 0, 1, 2 and 4 h. The following data points were collected before and after each naloxone dose; blood pressure, heart rate, respiratory rate, RASS score, pain assessment score (recorded as present or absent), midazolam dose, propofol dose and fentanyl dose. In order to assess for possible opiate reversal the peak fentanyl, propofol and midazolam dose, vital sign value, RASS score and pain score were compared before and after each dose of naloxone. RESULTS: The mean naloxone dose was 3.6 +/- 0.9 mg. There was no significant change in RASS score around the naloxone doses, -2.9 +/- 1.4 before and -2.8 +/- 1.6 after (P = 0.28). There were no significant changes in mean fentanyl, propofol or midazolam dose around naloxone administration. There were also no significant changes in heart rate, blood pressure and respiratory rate or in the presence of pain. CONCLUSION: These results demonstrate that the administration of enteral naloxone to patients on intravenous opiates in the ICU setting was not associated with changes in sedation score, vital signs, fentanyl dose, midazolam dose or propofol dose.

Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury.

OBJECTIVES: To determine whether baseline plasma levels of the receptor for advanced glycation end products (RAGE), a novel marker of alveolar type I cell injury, are associated with the severity and outcomes of acute lung injury, and whether plasma RAGE levels are affected by lower tidal volume ventilation. DESIGN, SETTING AND PARTICIPANTS: Measurement of plasma RAGE levels from 676 subjects enrolled in a large randomised controlled trial of lower tidal volume ventilation in acute lung injury. MEASUREMENTS AND MAIN RESULTS: Higher baseline plasma RAGE was associated with increased severity of lung injury. In addition, higher baseline RAGE was associated with increased mortality (OR for death 1.38 (95% CI 1.13 to 1.68) per 1 log increment in RAGE; p = 0.002) and fewer ventilator free and organ failure free days in patients randomised to higher tidal volumes. These associations persisted in multivariable models that adjusted for age, gender, severity of illness and the presence of sepsis or trauma. Plasma RAGE was not associated with outcomes in the lower tidal volume group (p = 0.09 for interaction in unadjusted analysis). In both tidal volume groups, plasma RAGE levels declined over the first 3 days; however, the decline was 15% greater in the lower tidal volume group (p = 0.02; 95% CI 2.4% to 25.0%). CONCLUSIONS: Baseline plasma RAGE levels are strongly associated with clinical outcomes in patients with acute lung injury ventilated with higher tidal volumes. Lower tidal volume ventilation may be beneficial in part by decreasing injury to the alveolar epithelium.

Feasibility of dexmedetomidine in facilitating extubation in the intensive care unit.

BACKGROUND: Spontaneous breathing trials (SBT) and intermittent mandatory ventilation (IMV) are common techniques utilized to expedite the ventilator weaning process. These techniques often require the reduction and/or discontinuation of sedatives and analgesics. Reducing these medications can lead to agitation and the inability to conduct SBTs or weaning by IMV. Adding dexmedetomidine (dex), a potent alpha-2-adrenergic receptor agonist that possesses sedative, anxiolytic and analgesic effects without causing significant respiratory depression, may facilitate extubation in these patients. OBJECTIVE: To assess the feasibility of adding dex to facilitate extubation in a group of difficult-to-extubate patients secondary to agitation. METHODS: Mechanically ventilated patients who were deemed difficult to wean and extubate secondary to agitation were evaluated for dex therapy. Inclusion criteria were location in an intensive care unit, intubated and mechanically ventilated, required IV sedation, deemed suitable by unit criteria for weaning and extubation within 24 h of dex initiation, previous attempts at weaning sedation and/or analgesia resulted in agitation causing either severe patient ventilator dyssynchrony, prolong need for intubation, or an inability to conduct a successful SBT. Additional inclusion criteria were unsuccessful use of traditional intravenous agents to control agitation. Recommended dex dosing was a bolus of 1 microg/kg followed by an infusion of 0.2-0.7 microg/kg/h. RESULTS: Twenty-five patients were evaluated for dex therapy with 20 meeting the criteria to treat. All had failed prior attempts at weaning. Fourteen of the 20 patients were successfully weaned and extubated and one patient was reintubated within 48 h, giving a 65% success rate. Heart rate trended down after dex initiation in most patients but did not result in the discontinuation of dex in any patient. The addition of dex was associated with minimal changes in mean arterial pressure. CONCLUSIONS: Dexmedetomidine was initiated in a group of mechanically ventilated patients who failed previous attempts at weaning and extubation secondary to agitation. After dex initiation, 65% of the patients was successfully extubated. Dexmedetomidine was associated with a reduction in concomitant sedative and analgesic use with minimal adverse effect.

Hemodynamic effects of inhaled nitric oxide in heart failure.

OBJECTIVES: This study was performed to assess the utility of inhaled nitric oxide as a selective pulmonary vasodilator in patients with severe chronic heart failure and to compare its hemodynamic effects with those of nitroprusside, a nonselective vasodilator. BACKGROUND: Preoperative pulmonary vascular resistance is a predictor of right heart failure after heart transplantation. Non-selective vasodilators administered preoperatively to assess the reversibility of pulmonary vasoconstriction cause systemic hypotension, limiting their utility. METHODS: Systemic and pulmonary hemodynamic measurement were made at baseline, during oxygen inhalation and with the addition of graded doses of inhaled nitric oxide or intravenous nitroprusside in 16 patients with New York Heart Association class III or IV heart failure referred for heart transplantation. RESULTS: Pulmonary vascular resistance decreased to a greater extent with 80 ppm nitric oxide (mean +/- SEM 256 +/- 41 to 139 +/- 14 dynes.s.cm-5) than with the maximally tolerated dose of nitroprusside (264 +/- 49 to 169 +/- 30 dynes.s.cm-5, p < 0.05, nitric oxide vs. nitroprusside). Pulmonary capillary wedge pressure increased with 80 ppm nitric oxide (26 +/- 2 to 32 +/- 2 mm Hg, p < 0.05). Mean arterial pressure did not change with nitric oxide but decreased with nitroprusside. Seven of the 16 patients, including 1 patient who did not have an adequate decrease in pulmonary vascular resistance with nitroprusside but did with nitric oxide, have undergone successful heart transplantation. CONCLUSIONS: Inhaled nitric oxide is a selective pulmonary vasodilator in patients with pulmonary hypertension due to left heart failure and may identify patients with reversible pulmonary vasoconstriction in whom agents such as nitroprusside cause systemic hypotension. Inhaled nitric oxide causes an increase in left ventricular filling pressure by an unknown mechanism.

Propranolol-induced pulmonary edema and shock in a patient with pheochromocytoma.

Sudden onset of pulmonary edema after administration of intravenous propranolol hydrochloride developed in a patient with pheochromocytoma but without clinical or histological evidence of heart disease. Previous cases of pulmonary edema have been reported in association with oral propranolol therapy but have failed to document histological absence of cardiac pathology. The mechanism for the development of pulmonary edema may have been a propranolol-induced beta 1- and beta 2-blockade that led to unopposed alpha effects and sudden elevation of afterload. This case underlines the caution that should be used in the administration of propranolol when the diagnosis of pheochromocytoma is considered.

Diffusing capacity is not measurably affected by routine lung perfusion scanning.

Lung scanning with radiolabeled macroaggregated albumin (MAA) has caused cardiovascular collapse and death in patients with extensive pulmonary vascular disease. These adverse reactions have been suggested to be secondary to MAA embolic occlusion of a significant portion of the remaining pulmonary circulation. The single breath diffusing capacity for carbon monoxide (SBDLCO) is heavily dependent on the status of the pulmonary microcirculation and is reduced in clinical pulmonary embolism. The effect of MAA particles on the lung microcirculation was measured by SBDLCO in 11 patients undergoing clinically indicated lung perfusion scanning. SBDLCO was measured before and immediately after injection of 256,000 to 448,000 20-40 micron particles of [99mTc]MAA. Mean SBDLCO prior to injection was 18.9 +/- 1.7 (s.e.m.) and immediately after injection was unchanged at 19.0 +/- 1.6 ml/min/mmHg. The lowest pre-injection SBDLCO values were 11.5 and 6.2 ml/min/mmHg (54% and 28% of predicted, respectively); in neither of these patients was there a detectable change in SBDLCO measured after injection of MAA. Thus occlusion of as many as 448,000 20-40 micron pulmonary vessels by MAA is without detectable impact on the transfer of carbon monoxide even in patients with sufficient pulmonary disease to lower the SBDLCO to 28% of predicted.

Esmolol and ventilatory function in cardiac patients with COPD.

To assess the effects of acute cardioselective beta blockade on ventilatory function in patients with COPD and active cardiac disorders, 50 patients were studied during intravenous infusion of esmolol. All patients had an obstructive ventilatory component on baseline pulmonary function testing, and 58 percent had a significant bronchodilator response to inhaled albuterol. Esmolol infusion (8 to 24 mg/min) produced large decreases in heart rate (84 +/- 2 to 69 +/- 2 beats/min, p less than 0.01) and SBP (124 +/- 3 to 106 +/- 3 mm Hg, p less than 0.01). Despite this marked hemodynamic response, there was no significant group effect of beta blockade on pulmonary function. No patient experienced dyspnea or wheezing with acute esmolol infusion; however, three patients (6 percent) developed asymptomatic decreases of FEV1. It is concluded that acute beta blockade with esmolol can be achieved in patients with COPD and cardiac disorders with little risk of bronchospasm.

Clinicians' approaches to mechanical ventilation in acute lung injury and ARDS.

STUDY OBJECTIVES: To examine clinicians' approaches to mechanical ventilation in patients with acute lung injury (ALI; PaO(2)/fraction of inspired oxygen [FIO(2)] 35 cm H(2)O in 26% of patients. Seventy-eight percent of patients with ARDS received

Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease.

The history, physical examination, chest radiograph, electrocardiogram and blood gases were evaluated in patients with suspected acute pulmonary embolism (PE) and no history or evidence of pre-existing cardiac or pulmonary disease. The investigation focused upon patients with no previous cardiac or pulmonary disease in order to evaluate the clinical characteristics that were due only to PE. Acute PE was present in 117 patients and PE was excluded in 248 patients. Among the patients with PE, dyspnea or tachypnea (greater than or equal to 20/min) was present in 105 of 117 (90 percent). Dyspnea, hemoptysis, or pleuritic pain was present in 107 of 117 (91 percent). The partial pressure of oxygen in arterial blood on room air was less than 80 mm Hg in 65 of 88 (74 percent). The alveolar-arterial oxygen gradient was greater than 20 mm Hg in 76 of 88 (86 percent). The chest radiograph was abnormal in 98 of 117 (84 percent). Atelectasis and/or pulmonary parenchymal abnormalities were most common, 79 of 117 (68 percent). Nonspecific ST segment or T wave change was the most common electrocardiographic abnormality, in 44 of 89 (49 percent). Dyspnea, tachypnea, or signs of deep venous thrombosis was present in 107 of 117 (91 percent). Dyspnea or tachypnea or pleuritic pain was present in 113 of 117 (97 percent). Dyspnea or tachypnea or pleuritic pain was present in 113 of 117 (97 percent). Dyspnea or tachypnea or pleuritic pain or atelectasis or a parenchymal abnormality on the chest radiograph was present in 115 of 117 (98 percent). In conclusion, among the patients with pulmonary embolism that were identified, only a small percentage did not have these important manifestations or combinations of manifestations. Clinical evaluation, though nonspecific, is of considerable value in the selection of patients in whom there is a need for further diagnostic studies.

The diagnosis of acute pulmonary embolism in patients with chronic obstructive pulmonary disease.

The clinical features and noninvasive tests, including ventilation perfusion (V/Q) lung scans, were assessed in 108 patients with chronic obstructive pulmonary disease (COPD) suspected of having pulmonary embolism (PE). Twenty-one (19 percent) of 108 patients had PE. In the majority of patients, it was impossible to distinguish between patients with and without PE by clinical assessment alone. However, when a high clinical index of suspicion was present, PE was confirmed by angiography in three of three patients, but the V/Q scan was of intermediate probability. No roentgenographic abnormalities distinguished between PE and no PE. There was no difference between the alveolar-arterial oxygen gradients in either group, nor was there evidence of a reduction in the PaCO2 in patients with PE who had prior hypercapnia. Among the 108 patients with COPD, high, intermediate, low, and normal/near normal probability scans were present in 5 percent, 60 percent, 30 percent, and 5 percent, respectively. The frequency of PE in these V/Q scan categories was five (100 percent) of five, 14 (22 percent) of 65, two (6 percent) of 33, and zero (0 percent) of five, respectively. In conclusion, in the majority of patients, the V/Q scan diagnosis is usually intermediate and such patients require further investigational studies, including angiography. However, among the few patients who demonstrated a high probability lung scan, there was a high positive predictive value for PE effectively avoiding the need for further studies. In those patients with low probability or near normal/normal V/Q scans, the negative predictive value was not lower than the general hospital population.

Polycythemia and vascular remodeling in chronic hypoxic pulmonary hypertension in guinea pigs.

Chronic hypoxia increases pulmonary arterial pressure (PAP) as a result of vasoconstriction, polycythemia, and vascular remodeling with medial thickening. To determine whether preventing the polycythemia with repeated bleeding would diminish the pulmonary hypertension and remodeling, we compared hemodynamic and histological profiles in hypoxic bled (HB, n = 6) and hypoxic polycythemic guinea pigs (H, n = 6). After 10 days in hypoxia (10% O2), PAP was increased from 10 +/- 1 (SE) mmHg in room air controls (RA, n = 5) to 20 +/- 1 mmHg in H (P less than 0.05) but was lower in HB (15 +/- 1 mmHg, P less than 0.05 vs. H). Cardiac output and pulmonary artery vasoreactivity did not differ among groups. Total pulmonary vascular resistance increased from 0.072 +/- 0.011 mmHg.ml-1.min in RA to 0.131 mmHg.ml-1.min in H but was significantly lower in HB (0.109 +/- 0.006 mmHg.ml-1.min). Hematocrit increased with hypoxia (57 +/- 3% in H vs. 42 +/- 1% in RA, P less than 0.05), and bleeding prevented the increase (46 +/- 4% in HB, P less than 0.05 vs. H only). The proportion of thick-walled peripheral pulmonary vessels (53.2 +/- 2.9% in HB and 50.6 +/- 4.8% in H vs. 31.6 +/- 2.6% in RA, P less than 0.05) and the percent medial thickness of pulmonary arteries adjacent to alveolar ducts (7.2 +/- 0.6% in HB and 7.0 +/- 0.4% in H vs. 5.2 +/- 0.4% in RA, P less than 0.05) increased to a similar degree in both hypoxic groups. A similar tendency was present in larger bronchiolar vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic hypoxic pulmonary hypertension in the guinea pig: effect of three levels of hypoxia.

Chronic hypoxia [inspiratory PO2 (PIO2) = 76 Torr for 10 days] produces pulmonary hypertension and vascular remodeling in the guinea pig. Increasing the duration of hypoxia from 10 to 21 days does not increase further pulmonary arterial pressure or medial thickening. To see if increasing severity of hypoxia affects the magnitude of pulmonary hypertension and remodeling, we exposed three groups of male Hartley guinea pigs to three levels of normobaric hypoxia for 10 days: PIO2 = 90 (n = 6), 78 (n = 6), and 65 Torr (n = 5). Pulmonary arterial pressure increased from 14 +/- 1 (+/- SE, n = 7) in room air to 23 +/- 3 mmHg when PIO2 = 90 Torr (P < 0.05). Pulmonary arterial pressure was slightly higher when PIO2 = 78 or 65 Torr (25 +/- 1 and 26 +/- 1 mmHg, respectively) but did not reach statistical significance vs. PIO2 = 90 Torr. Total pulmonary vascular resistance increased from 0.049 +/- 0.004 in room air to between 0.084 +/- 0.006 and 0.101 +/- 0.003 mmHg.min.kg.ml-1 (P < 0.05) in the three hypoxic groups; again there was no difference in total pulmonary vascular resistance among hypoxic groups. Medial thickness of alveolar duct and terminal bronchiole arteries increased with hypoxia, but there was no significant difference among the hypoxic groups. The percentage of intra-acinar vessels with thick walls (a measure of muscular extension) increased when PIO2 = 78 Torr and nearly doubled when PIO2 = 65 Torr in comparison to control.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and chronic hypoxic pulmonary hypertension in guinea pigs.

To determine whether the strength of acute hypoxic vasoconstriction predicts the magnitude of chronic hypoxic pulmonary hypertension, we performed serial studies on guinea pigs. Unanesthetized, chronically catheterized guinea pigs increased mean pulmonary arterial pressure (PAP) from 11 +/- 0.5 to 13 +/- 0.7 Torr in acute hypoxia (10% O2 for 65 min). The response was maximal at 5 min, remained stable for 1 h, and was reversible on return to room air. Cardiac index did not change with acute hypoxia or recovery. Guinea pigs exposed to chronic hypoxia increased PAP, measured in room air 1 h after removal from the hypoxic chamber, to 18 +/- 1 Torr by 5 days with little further increase in PAP to 20 +/- 1 Torr after 21 days. Cardiac index fell from 273 +/- 12 to 206 +/- 7 ml.kg-1.min-1 (P less than 0.05) after 21 days of hypoxia. Medial thickness of pulmonary arteries adjacent to terminal bronchioles and alveolar ducts increased significantly by 10 days. The magnitude of the pulmonary vasoconstriction to acute hypoxia persisted and was unabated during the development and apparent stabilization of chronic hypoxic pulmonary hypertension, suggesting that if vasoconstriction is the stimulus for remodeling, then the importance of the stimulus lessens with duration of hypoxia. In individual animals followed serially, we found no correlation between the magnitude of the acute vasoconstrictor response before chronic hypoxia and the severity of chronic pulmonary hypertension that subsequently developed either because the initial response was small and variable or because vasoconstriction may not be the sole stimulus for vascular remodeling in the guinea pig.

Functional and structural changes with hypoxia in pulmonary circulation of spontaneously hypertensive rats.

Chronic hypoxic pulmonary hypertension involves both vasoconstriction and vascular remodeling. Spontaneously hypertensive rats (SHR) have an increased systemic vascular resistance and a greater responsiveness to constricting stimuli. We hypothesized that, in contrast to age-matched normotensive Wistar-Kyoto rats (WKY), SHR also display spontaneous pulmonary hypertension in normoxia and increased vascular response to acute and chronic hypoxia. Baseline mean pulmonary arterial pressure (PAP) and total pulmonary resistance (TPR) were higher in SHR than in WKY. With acute hypoxia (10% O2 for 15 min), PAP increased to the same extent in SHR and WKY and cardiac output (CO) was unchanged in WKY but increased in SHR. Thus, the rise in PAP in the SHR might be accounted for by the rise in CO, as TPR did not rise, but not that in the WKY, as TPR increased. After 12 days in hypoxia (10% O2), mean arterial pressure was unchanged in WKY but decreased significantly in SHR without a change in CO. PAP increased by 59% in SHR and 54% in WKY when the rats were taken from the hypoxic chamber for 1 h. Acute hypoxic challenge caused a further increase in PAP only in WKY. Medial wall thickness of alveolar duct and terminal bronchial vessels was similar in WKY and SHR after chronic hypoxia. We conclude that SHR exhibit mild baseline pulmonary hypertension in normoxia and that chronic hypoxia does not produce a disproportionate increase in SHR pulmonary vascular remodeling and pulmonary hypertension.

What is the clinical significance of pulmonary hypertension in acute respiratory distress syndrome? A review.

Elevated pulmonary arterial pressures appear to be a prominent feature of the acute respiratory distress syndrome (ARDS). Current clinical guidelines for the management of ARDS do not specifically address treatment of pulmonary hypertension or associated right ventricular dysfunction because the clinical significance of this entity remains unclear. Interpretation of elevated pulmonary arterial pressures, pulmonary vascular resistance, and transpulmonary gradient as well as signs of right ventricular dysfunction is confounded by the effects of positive pressure ventilation. There does not appear to be a consistent relationship between the diagnosis of pulmonary hypertension or right ventricular failure and mortality in patients with ARDS, but it is unclear if right ventricular failure contributes to the mortality risk per se or if the underlying cause of pulmonary hypertension, including intravascular micro and macro thrombosis, are simply markers for systemic dysregulation of coagulation and fibrinolysis that may lead to multiorgan failure in ARDS. While studies of pulmonary vasodilator therapies have not shown a mortality benefit in ARDS, such trials have targeted improved oxygenation rather than improved pulmonary hemodynamics so that the possible contribution of improved right ventricular function to better outcomes has not been directly tested in large trials. Future studies are needed to determine if treatment of pulmonary hypertension and associated right ventricular dysfunction will affect mortality in patients with ARDS.

An updated meta-analysis to understand the variable efficacy of drotrecogin alfa (activated) in severe sepsis and septic shock.

BACKGROUND: Significant debate continues over the efficacy of drotrecogin alpha activated (DAA) in sepsis. This updated meta-analysis provides an updated summary effect estimate and explores the reasons for outcome heterogeneity in placebo-controlled randomized clinical trials of DAA on 28-day all-cause mortality in patients with severe sepsis or septic shock. METHODS: Computer searches of MEDLINE, EMBASE, the Cochrane Library, ClinicalTrials.gov, published abstracts from major intensive care meetings and examination of reference lists were used to identify five placebo-controlled randomized clinical trials with 7260 patients. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 28-day incidence of severe bleeding and intracranial hemorrhage. RESULTS: DAA was not associated with improved 28-day all-cause mortality in patients with severe sepsis or septic shock (pooled relative risk (RR) of 0.97 [95% CI 0.83-1.14]), and is associated with an increase in serious bleeding. The significant heterogeneity in the pooled RR for 28-day mortality (I2 value of 59.4%, χ2 P-value 0.043) is no longer present with exclusion of the post-study amendment portion of PROWESS (I2 value of 0%, χ2 P-value 0.44 without PROWESS post-amendment). Using meta-regression, the best ranked predictor of outcome heterogeneity was baseline mortality in the placebo arm, which was among the highest in PROWESS. CONCLUSION: DAA is not associated with improved survival in patients with severe sepsis or septic shock. Further studies should be done to determine whether changes in supportive therapy for sepsis explain the variable efficacy of DAA in randomized controlled clinical trials observed over time.

Corticosteroids for ARDS.

The aim of this study was to describe the role of glucocorticoids in immune modulation during critical illness and to review clinical trials and recent meta-analyses of glucocorticoids in early and late acute respiratory distress syndrome (ARDS). Selected reviews of publications, clinical trials, and meta-analyses were considered for the study. Activation of the adrenal axis is an important component of the compensatory anti-inflammatory response to critical illness. A recent meta-analysis of high doses of corticosteroids in patients with or at risk for ARDS demonstrated a trend for greater risk of the development of ARDS and a fatal outcome. Additional meta-analyses of four randomized trials and five cohort studies in patients with established ARDS or pneumonia indicated an overall mortality benefit with corticosteroids but this finding was not confirmed in another meta-analysis limited to randomized trials and excluding the trial focused on pneumonia. Lung function is improved and the duration of mechanical ventilation is reduced with prolonged administration of lower doses. In conclusion, short-duration, high-dose glucocorticoid therapy is not effective in preventing ARDS and may be harmful. Lower doses for persistent ARDS improve lung function and shorten the duration of mechanical ventilation but the impact on long-term mortality is unclear. Additional trials are needed to determine if corticosteroids improve important clinical outcomes before they can be recommended for the routine use of patients with unresolved ARDS.