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.

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.

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.

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.

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.

Interleukin-10 polymorphism in position -1082 and acute respiratory distress syndrome.

The GG genotype of the interleukin (IL)-10 promoter polymorphism in position -1082 (-1082GG) has been associated with increased IL-10 production. The current authors hypothesised that the -1082GG genotype is associated with the development of, and outcomes in, acute respiratory distress syndrome (ARDS). A nested case-control study was conducted in 211 Caucasian cases of ARDS and 429 controls who were admitted to an intensive care unit with sepsis, trauma, aspiration or massive transfusions. Cases were followed for organ failure and 60-day mortality. The -1082GG genotype was associated with the development of ARDS, but only in the presence of a significant interaction between the -1082GG genotype and age. Among patients with ARDS, the -1082GG genotype was associated with decreased severity of illness on admission, lower daily organ dysfunction scores and lower 60-day mortality. In conclusion, the high interleukin-10-producing -1082GG genotype may be associated with variable odds for acute respiratory distress syndrome development depending on age. Among those with acute respiratory distress syndrome, the -1082GG genotype is associated with lower mortality and organ failure. Further studies are needed to confirm these findings.

-308GA and TNFB polymorphisms in acute respiratory distress syndrome.

The -308GA and TNFB1/2 polymorphisms of the tumour necrosis factor genes have been associated with increased susceptibility to, and mortality in sepsis, although, prior studies are not consistent. Their role in acute respiratory distress syndrome (ARDS) has not been evaluated. The current authors hypothesised that the -308A allele and TNFB22 genotype would be associated with increased susceptibility to, and mortality in ARDS. The above hypothesis was investigated in a nested case-control study of 441 Caucasian controls and 212 cases admitted to an intensive care unit with sepsis, trauma, aspiration or hyper-transfusions. The -308A and TNFB1 alleles were in linkage disequilibrium. These polymorphisms were not associated with ARDS susceptibility on crude analysis. On subgroup analyses, they were associated with either increased or decreased odds of developing ARDS depending on whether the clinical risk for ARDS results in direct or indirect pulmonary injury. The -308A allele was associated with increased 60-day mortality in ARDS, with the strongest association found among younger patients. There was no association between the TNFB polymorphism and ARDS mortality. The -308GA, but not the TNFB12, polymorphism was associated with increased mortality in acute respiratory distress syndrome, but their association with acute respiratory distress syndrome susceptibility depended on the site of injury predisposing to acute respiratory distress syndrome.

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

Structural determinants of antiproliferative activity of heparin on pulmonary artery smooth muscle cells.

In addition to its anticoagulant properties, heparin (HP), a complex polysaccharide covalently linked to a protein core, inhibits proliferation of several cell types including pulmonary artery smooth muscle cells (PASMCs). Commercial lots of HP exhibit varying degrees of antiproliferative activity on PASMCs that may due to structural differences in the lots. Fractionation of a potent antiproliferative HP preparation into high and low molecular weight components does not alter the antiproliferative effect on PASMCs, suggesting that the size of HP is not the major determinant of this biological activity. The protein core of HP obtained by cleaving the carbohydrate-protein linkage has no growth inhibition on PASMCs, demonstrating that the antiproliferative activity resides in the glycosaminoglycan component. Basic sugar residues of glucosamine can be replaced with another basic sugar, i.e., galactosamine, without affecting growth inhibition of PASMCs. N-sulfonate groups on these sugar residues of HP are not essential for growth inhibition. However, O-sulfonate groups on both sugar residues are essential for the antiproliferative activity on PASMCs. In whole HP, in contrast to an earlier finding based on a synthetic pentasaccharide of HP, 3-O-sulfonation is not critical for the antiproliferative activity against PASMCs. The amounts and distribution of sulfonate groups on both sugar residues of the glycosaminoglycan chain are the major determinant of antiproliferative activity.

Effect of fully sulfated glycosaminoglycans on pulmonary artery smooth muscle cell proliferation.

Fully sulfated heparin and other glycosaminoglycans, namely heparan, chondroitin, and dermatan sulfates, and hyaluronan have been prepared by using sulfur trioxide under mild chemical conditions. All these derivatives were assayed for antiproliferative activity on cultured bovine pulmonary artery smooth muscle cells (BPASMCs). No appreciable difference was found between heparin and fully sulfated heparin. Chondroitin and dermatan sulfates actually stimulated BPASMCs growth but full sulfonation made them strongly antiproliferative. Native hyaluronan was not antiproliferative but became strongly so after sulfonation. Neither acharan sulfate nor N-sulfoacharan sulfate had any antiproliferative activity. This suggests that O-sulfonation of the polysaccharide is critical for antiproliferative activity, whereas N-sulfonation of glucosamine residues is not.

Use of partial liquid ventilation to manage pulmonary complications of acute verapamil-sustained release poisoning.

INTRODUCTION: Verapamil is a papaverine-derived calcium channel blocker widely used for the treatment of hypertension and supraventricular tachyarrhythmias. It is one of the leading agents involved in pharmaceutical poisoning-related deaths among adults. CASE REPORT: We report a case of severe sustained-release verapamil poisoning associated with respiratory failure in an adult man who survived after receiving 4 days of partial liquid ventilation as a part of his medical management.

Olanzapine overdose with serum concentrations.

Olanzapine, a new atypical antipsychotic drug, has been prescribed in the treatment of schizophrenia and psychotic mood disorders for approximately 2.3 million patients worldwide. Considering the increase in olanzapine prescriptions and the increased risk of suicide in this patient population, the number of reported cases of olanzapine overdose may be expected to increase. This report describes the clinical course and serum concentrations in a patient who consumed an olanzapine overdose (800 mg). Profound central nervous system depression and tachycardia without arrhythmia occurred within 2 hours after the ingestion. Additional clinical findings (ie, fever, mutism, agitation, dystonia, akathisia, elevated creatine kinase, and increased leukocyte count) were similar to those of neuroleptic malignant syndrome. After intubation, gut decontamination, and supportive care, the patient recovered and was discharged.

Amiloride analogs inhibit chronic hypoxic pulmonary hypertension.

Na+/H+ exchange regulation of intracellular pH may play a permissive role in pulmonary artery smooth muscle cell (PASM) proliferation. Our laboratory has demonstrated that dimethyl amiloride (DMA), an amiloride derivative with enhanced selectivity as an inhibitor of the Na+/H+ antiporter, can inhibit bovine PASM proliferation in vitro. We hypothesized that DMA would inhibit development of hypoxic pulmonary hypertension by interfering with PASM growth in vivo. Sprague-Dawley rats were exposed to 10% O2 for 14 d without (n 9) or with (n = 7) DMA continuous infusion 3 mg/ kg/d. The animals treated with DMA had significant reductions in pulmonary artery pressure and total pulmonary vascular resistance index (TPVRI) when compared with hypoxic control rats (p < 0.05). Pulmonary vascular remodeling was significantly reduced in animals treated with DMA as measured by percent wall thickness and percentage of thick-walled intra-acinous vessels (p < 0.05). We used a second Na+/H+ exchange inhibitor, ethylisopropyl amiloride (EIPA, 3 mg/kg/d, n = 9), and found similar reductions in pulmonary artery pressure, TPVRI, and pulmonary vascular remodeling. Polycythemia during hypoxia was unchanged by treatment with DMA or EIPA. In conclusion, despite the hypertensive effects of polycythemia, DMA and EIPA can significantly reduce pulmonary vascular remodeling induced by chronic hypoxia.

Influence of molecular weight, protein core and charge of native heparin fractions on pulmonary artery smooth muscle cell proliferation.

Heparin macromolecules have been shown to inhibit cultured pulmonary artery smooth muscle cell proliferation in vitro and prevent hypoxic vascular remodeling in vivo. In an attempt to understand the structural determinants of heparin's antiproliferative properties, we have fractionated an antiproliferative preparation of commercial heparin into low and high molecular weight fractions. Then the high molecular weight heparin fraction was further fractionated on a DEAE-cellulose column by charge density eluting with 0 - 1 M NaCl linear gradient. The heparin protein peptides were both removed and isolated. These heparin fractions were assayed for antiproliferative effects on cultured bovine pulmonary artery smooth muscle cells. No appreciable differences were found among high and low molecular weight heparin fractions The core peptides showed no antiproliferative activity. However, higher charge density fraction was less antiproliferative.

Antiproliferative role of 3-O-sulfate glucosamine in heparin on cultured pulmonary artery smooth muscle cells.

Heparin macromolecules inhibit vascular remodeling associated with hypoxic pulmonary hypertension. Heparin's antiproliferative effect on smooth muscle cells, based on studies of synthetic pentasaccharide fragments, has been attributed to 3-O-sulfate on the internal glucosamine. To determine the role of 3-O-sulfation in smooth muscle cell growth, we treated three heparins of varying potency with heparitinases I and II, which degrade heparin fragments containing 3-O-sulfate on the glucosamine residue to delta-tetrasaccharides only. Our most antiproliferative heparin gave the least amount of delta-tetrasaccharides. This heparin was then fractionated according to degree of sulfation using ETOH precipitation. Again we found no antiproliferative difference between the highly sulfated fractions and those with a lesser degree of sulfation. These studies suggest that 3-O-sulfate of glucosamine residue is not critical in whole heparins for antiproliferative activity.