Impact of Initial Central Venous Pressure on Outcomes of Conservative Versus Liberal Fluid Management in Acute Respiratory Distress Syndrome.

OBJECTIVES: In acute respiratory distress syndrome, conservative fluid management increases ventilator-free days without affecting mortality. Response to fluid management may differ based on patients' initial central venous pressure. We hypothesized that initial central venous pressure would modify the effect of fluid management on outcomes. DESIGN: Retrospective analysis of the Fluid and Catheter Treatment Trial, a multicenter randomized trial comparing conservative with liberal fluid management in acute respiratory distress syndrome. We examined the relationship between initial central venous pressure, fluid strategy, and 60-day mortality in univariate and multivariable analysis. SETTING: Twenty acute care hospitals. PATIENTS: Nine hundred thirty-four ventilated acute respiratory distress syndrome patients with a central venous pressure available at enrollment, 609 without baseline shock (for whom fluid balance was managed by the study protocol). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among patients without baseline shock, those with initial central venous pressure greater than 8 mm Hg experienced similar mortality with conservative and liberal fluid management (18% vs 18%; p = 0.928), whereas those with central venous pressure of 8 mm Hg or less experienced lower mortality with a conservative strategy (17% vs 36%; p = 0.005). Multivariable analysis demonstrated an interaction between initial central venous pressure and the effect of fluid strategy on mortality (p = 0.031). At higher initial central venous pressures, the difference in treatment between arms was predominantly furosemide administration, which was not associated with mortality (p = 0.122). At lower initial central venous pressures, the difference between arms was predominantly fluid administration, with additional fluid associated with increased mortality (p = 0.013). CONCLUSIONS: Conservative fluid management decreases mortality for acute respiratory distress syndrome patients with a low initial central venous pressure. In this population, the administration of IV fluids seems to increase mortality.

Effects of the menstrual cycle on lung function variables in women with asthma.

RATIONALE: Angiogenesis is a defining pathologic feature of airway remodeling and contributes to asthma severity. Women experience changes in asthma control over the menstrual cycle, a time when vessels routinely form and regress under the control of angiogenic factors. One vital function modulated over the menstrual cycle in healthy women is gas transfer, and this has been related to angiogenesis and cyclic expansion of the pulmonary vascular bed. OBJECTIVES: We hypothesized that changes in gas transfer and the pulmonary vascular bed occur in women with asthma over the menstrual cycle and are associated with worsening airflow obstruction. METHODS: Twenty-three women, 13 with asthma and 10 healthy control subjects, were evaluated over the menstrual cycle with weekly measures of spirometry, gas transfer, nitric oxide, hemoglobin, factors affecting hemoglobin binding affinity, and proangiogenic factors. MEASUREMENTS AND MAIN RESULTS: Airflow and lung diffusing capacity varied over the menstrual cycle with peak levels during menses that subsequently declined to nadir in early luteal phase. In contrast to healthy women, changes in lung diffusing capacity (DL(CO)) were associated with changes in membrane diffusing capacity and DL(CO) was not related to proangiogenic factors. DL(CO) did not differ between the two groups, although methemoglobin and carboxyhemoglobin were higher in women with asthma than in healthy women. CONCLUSIONS: Women with asthma experience cyclic changes in airflow as well as gas transfer and membrane diffusing capacity supportive of a hormonal effect on lung function.

Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury.

BACKGROUND: The balance between the benefits and the risks of pulmonary-artery catheters (PACs) has not been established. METHODS: We evaluated the relationship of benefits and risks of PACs in 1000 patients with established acute lung injury in a randomized trial comparing hemodynamic management guided by a PAC with hemodynamic management guided by a central venous catheter (CVC) using an explicit management protocol. Mortality during the first 60 days before discharge home was the primary outcome. RESULTS: The groups had similar baseline characteristics. The rates of death during the first 60 days before discharge home were similar in the PAC and CVC groups (27.4 percent and 26.3 percent, respectively; P=0.69; absolute difference, 1.1 percent; 95 percent confidence interval, -4.4 to 6.6 percent), as were the mean (+/-SE) numbers of both ventilator-free days (13.2+/-0.5 and 13.5+/-0.5; P=0.58) and days not spent in the intensive care unit (12.0+/-0.4 and 12.5+/-0.5; P=0.40) to day 28. PAC-guided therapy did not improve these measures for patients in shock at the time of enrollment. There were no significant differences between groups in lung or kidney function, rates of hypotension, ventilator settings, or use of dialysis or vasopressors. Approximately 90 percent of protocol instructions were followed in both groups, with a 1 percent rate of crossover from CVC- to PAC-guided therapy. Fluid balance was similar in the two groups, as was the proportion of instructions given for fluid and diuretics. Dobutamine use was uncommon. The PAC group had approximately twice as many catheter-related complications (predominantly arrhythmias). CONCLUSIONS: PAC-guided therapy did not improve survival or organ function but was associated with more complications than CVC-guided therapy. These results, when considered with those of previous studies, suggest that the PAC should not be routinely used for the management of acute lung injury. (ClinicalTrials.gov number, NCT00281268.).

Comparison of two fluid-management strategies in acute lung injury.

BACKGROUND: Optimal fluid management in patients with acute lung injury is unknown. Diuresis or fluid restriction may improve lung function but could jeopardize extrapulmonary-organ perfusion. METHODS: In a randomized study, we compared a conservative and a liberal strategy of fluid management using explicit protocols applied for seven days in 1000 patients with acute lung injury. The primary end point was death at 60 days. Secondary end points included the number of ventilator-free days and organ-failure-free days and measures of lung physiology. RESULTS: The rate of death at 60 days was 25.5 percent in the conservative-strategy group and 28.4 percent in the liberal-strategy group (P=0.30; 95 percent confidence interval for the difference, -2.6 to 8.4 percent). The mean (+/-SE) cumulative fluid balance during the first seven days was -136+/-491 ml in the conservative-strategy group and 6992+/-502 ml in the liberal-strategy group (P<0.001). As compared with the liberal strategy, the conservative strategy improved the oxygenation index ([mean airway pressure x the ratio of the fraction of inspired oxygen to the partial pressure of arterial oxygen]x100) and the lung injury score and increased the number of ventilator-free days (14.6+/-0.5 vs. 12.1+/-0.5, P<0.001) and days not spent in the intensive care unit (13.4+/-0.4 vs. 11.2+/-0.4, P<0.001) during the first 28 days but did not increase the incidence or prevalence of shock during the study or the use of dialysis during the first 60 days (10 percent vs. 14 percent, P=0.06). CONCLUSIONS: Although there was no significant difference in the primary outcome of 60-day mortality, the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing nonpulmonary-organ failures. These results support the use of a conservative strategy of fluid management in patients with acute lung injury. (ClinicalTrials.gov number, NCT00281268 [ClinicalTrials.gov].).

Use of sedatives, opioids, and neuromuscular blocking agents in patients with acute lung injury and acute respiratory distress syndrome.

OBJECTIVE: The use of sedatives, opioids, and neuromuscular blocking agents (NMBAs) may delay weaning and prolong intensive care unit length of stay. We hypothesized that in patients on higher positive end-expiratory pressure (PEEP), sedatives, opioids, and NMBAs are used in a higher proportion of patients and in higher doses and that the use of these medications is associated with prolongation of weaning and mortality. DESIGN: Retrospective analysis. SETTING: The ALVEOLI trial. PATIENTS: Five hundred forty-nine patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) who were enrolled in the ALVEOLI trial. INTERVENTIONS: We analyzed prospectively collected data regarding the impact of sedatives, opioids, and NMBAs in ALI/ARDS patients on duration of mechanical ventilation, time to weaning landmarks, and mortality. MEASUREMENTS AND MAIN RESULTS: Sedatives and opioids were used in >80% of the patients in similar proportion in the two groups. The use of sedatives and opioids, but not the use of NMBAs, was associated with longer time on mechanical ventilation and an increased time to achieve a 2-hr spontaneous breathing trial (p < .0001). Sedatives were also associated with increased time to achieve unassisted breathing. NMBAs were used for a short period of time, in a higher proportion of patients in the lower PEEP group, and for a longer time (0.23 days). CONCLUSIONS: Sedatives and opioids use was similar in the higher and lower PEEP groups. The use of sedatives and opioids, but not NMBAs, was associated with a longer time to achieve important weaning landmarks.

A perspective on the fluids and catheters treatment trial (FACTT). Fluid restriction is superior in acute lung injury and ARDS.

Restricting fluid intake and promoting fluid excretion (a "dry" or conservative strategy) is more effective than a "we or liberal strategy in patients with acute lung injury and acute respiratory distress syndrome. In a multicenter, randomized, prospective clinical comparison of the two strategies in 1000 patients, those in the conservative-strategy group experienced faster improvement in lung function and spent significantly fewer days on ventilation and in the intensive care unit (N Engl J Med 2006; 354:2564-2574). No significant differences were observed in the incidence of death by 60 days or of nonpulmonary organ failure at 28 days except for days of central nervous system failure, which were fewer in the conservative-strategy group.

Pulmonary gas transfer related to markers of angiogenesis during the menstrual cycle.

Gas transfer in the female lung varies over the menstrual cycle in parallel with the cyclic angiogenesis that occurs in the uterine endometrium. Given that vessels form and regress in the uterus under the control of hormones, angiogenic factors, and proangiogenic circulating bone marrow-derived progenitor cells, we tested the possibility that variation in pulmonary gas transfer over the menstrual cycle is related to a systemic cyclic proangiogenic state that influences lung vascularity. Women were evaluated over the menstrual cycle with weekly measures of lung diffusing capacity and its components, the pulmonary vascular capillary bed and membrane diffusing capacity, and their relation to circulating CD34(+)CD133(+) progenitor cells, hemoglobin, factors affecting hemoglobin binding affinity, and proangiogenic factors. Lung diffusing capacity varied over the menstrual cycle, reaching a nadir during the follicular phase following menses. The decline in lung diffusing capacity was accounted for by approximately 25% decrease in pulmonary capillary blood volume. In parallel, circulating CD34(+)CD133(+) progenitor cells decreased by approximately 24% and were directly related to angiogenic factors and to lung diffusing capacity and pulmonary capillary blood volume. The finding of a greater number of lung microvessels in ovariectomized female mice receiving estrogen compared with placebo verified that pulmonary vascularity is influenced by hormonal changes. These findings suggest that angiogenesis in the lungs may participate in the cyclic changes in gas transfer that occur over the menstrual cycle.

Pulmonary artery catheter and fluid management in acute lung injury and the acute respiratory distress syndrome.

The PAC provides a wealth of information about circulatory and respiratory systems and intravascular fluid volume over time. Specifically, the PAC allows measurement of central venous and pulmonary arterial pressure, pulmonary artery occlusion pressure, mixed venous blood gases, and indicator-dilution cardiac output. Based on these quantitative date, systemic and pulmonary vascular resistance can be derived. The PAC is frequently used in patients with ALI and ARDS, both to confirm the diagnosis and to optimize hemodynamic management. In this article, we review the evidence on the use of the PAC in patients with ALI/ARDS, paying particular attention to the recently published fluid and catheter treatment trial by the ARDS Clinical Trials Network.

Mortality in individuals with severe deficiency of alpha1-antitrypsin: findings from the National Heart, Lung, and Blood Institute Registry.

STUDY OBJECTIVE: To clarify the mortality rate and causes of death of individuals with alpha(1)-antitrypsin (AAT) deficiency, the Death Review Committee (DRC) of the National Heart, Lung, and Blood Institute Registry of Individuals with Severe AAT Deficiency reviewed all available medical records regarding the deaths of study subjects during Registry follow-up (up to 7.2 years). METHODS: Individual determinations by each member of the three-person DRC led to consensus judgments regarding the underlying cause and the immediate and contributing causes of death. RESULTS: Of the 1,129 Registry subjects, 204 died (18.1%) [approximately 3%/yr]. Record availability permitted detailed review in 120 decedents, and death certificates were available in 56 of the remaining 84 subjects (67%). Emphysema and cirrhosis were the most common underlying causes of death (72% and 10%, respectively), with malignancy and diverticulitis accounting for 3% of deaths each. To assess attributable mortality, standardized mortality ratio analysis was performed and indicated that excess mortality was ascribable entirely to lung and liver disease. CONCLUSIONS: We conclude that severe AAT deficiency poses a significant threat to health, that severe airflow obstruction is a major determinant of mortality, and that liver and lung disease account for the excess mortality in affected individuals. These findings support current efforts to enhance diagnostic recognition and treatment of AAT-deficient individuals.

The bronchopulmonary pathology of alpha-1 antitrypsin (AAT) deficiency: findings of the Death Review Committee of the national registry for individuals with Severe Deficiency of Alpha-1 Antitrypsin.

To assess the pathological changes in the lungs and liver of 42 individuals who died while enrolled in the Registry of Individuals with Severe Deficiency of Alpha-1 Antitrypsin (AAT), all available histopathologic surgical or postmortem-derived specimens were reviewed by the pathologist member of the Death Review Committee. The underlying cause of death was emphysema in 34 patients and cirrhosis in 2 patients. Slides of lung were graded for emphysema, and liver specimens were graded for fibrosis, using respective pictorial scoring systems. Correlations between the degree of pathological abnormality and clinical features were evaluated. All lungs exhibited severe panacinar emphysema (mean emphysema score, 7.9 +/- 1.06 [standard deviation], where 10 represents the greatest severity) with a lower lobe predominance. Centriacinar emphysema was minimal. No correlation was found between the pathological severity of emphysema and pulmonary function measurements, and no significant correlation was found between the degree of emphysema and the degree of hepatic fibrosis. Mildly increased bronchial gland-to-wall ratio accompanied mild inflammation and goblet cell hyperplasia. There were minimal changes in small airways. Dilatation of membranous bronchioles was a frequent finding; however, bronchiectasis of larger airways was a minor feature in only 6 patients (15%). Airway morphological features did not correlate with the clinical presence of chronic bronchitis or asthma. Although the lack of correlation between liver and lung pathological changes may reflect different pathogenetic mechanisms of liver disease and lung disease, the lack of correlation between emphysema grade and lung function likely reflects the skewed sample in a series of patients with advanced lung disease.

Incidence of ARDS in an adult population of northeast Ohio.

STUDY OBJECTIVES: To assess the incidence of the ARDS in a well-defined adult population. DESIGN: Kaiser Permanente of northeast Ohio, a health maintenance organization, uses the Cleveland Clinic Foundation as its only tertiary care center. In an ongoing prospective assessment in the Cleveland Clinic ICUs, we identified adult Kaiser Permanente patients with ARDS between 1996 and 1999. ARDS was defined according to the 1994 American-European Consensus Conference criteria. The denominator in the incidence calculation was the adult members of Kaiser Permanente of each year of the study period, and the numerator was the new adult ARDS patients in this particular year. The cause of ARDS, the mortality, and the cause of death were retrospectively identified, as well as other characteristics of the study population. RESULTS: ARDS was diagnosed in 66 patients during the 3-year study period. The incidence per 100,000 population was 11.4 in 1996, 19.8 in 1997, and 14.4 in 1998; the overall incidence was 15.3/100,000/yr. The mean PaO(2)/fraction of inspired oxygen (+/- SD) was 110.8 +/- 37.8, the mean APACHE II was 23.4 +/- 6.9, and the mean ICU stay was 12.0 +/- 9.5 days. The most common cause of ARDS was direct lung injury (75.8%), and the most common cause of death was septic shock (53.8%). CONCLUSION: The incidence of ARDS in an adult population in northeast Ohio was 15.3/100,000/yr, a number that is slightly higher but comparable to recent estimates reported by other researchers.

Systemic lupus erythematosus in the intensive care unit.

SLE causes significant morbidity and mortality by multisystem organ involvement. Infections are the leading cause of morbidity and mortality in patients with SLE. Meticulous exclusion of infection is mandatory in patients with SLE, because infections may masquerade as exacerbation of underlying disease; and the immunosuppression used to treat severe forms of exacerbation of lupus can have catastrophic consequences in patients with infections. Corticosteroids are the first-line therapy for most noninfectious complications of SLE, with various adjuvant immunosuppressive agents such as cyclophosphamide being increasingly used in combination with plasmapheresis. Some recent series have shown an improved survival rate, but this improvement needs to be confirmed by further studies. Controlled trials comparing various therapeutic options are lacking, and optimal therapy has not been defined.

Emerging systemic pharmacologic approaches in acute respiratory distress syndrome.

The increased understanding of the pathophysiology of ALI that has been achieved over the last decade has led to several new pharmacologic approaches for the prevention and management of ALI and ARDS. Based on in vitro information and animal model data, many of these strategies seem quite compelling. Nevertheless, to date, no specific pharmacologic approach for the prevention or treatment of ARDS has been conclusively validated in clinical trials. Active basic and clinical research continues, and it is hoped that these investigations will lead to new therapies that can be applied by the clinician to improve clinical outcomes for patients who have ALI and ARDS.

Relative cost and outcomes in the intensive care unit of acute lung injury (ALI) due to pandemic influenza compared with other etiologies: a single-center study.

BACKGROUND: Critical illness due to 2009 H1N1 influenza has been characterized by respiratory complications, including acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), and associated with high mortality. We studied the severity, outcomes, and hospital charges of patients with ALI/ARDS secondary to pandemic influenza A infection compared with ALI and ARDS from other etiologies. METHODS: A retrospective review was conducted that included patients admitted to the Cleveland Clinic MICU with ALI/ARDS and confirmed influenza A infection, and all patients admitted with ALI/ARDS from any other etiology from September 2009 to March 2010. An itemized list of individual hospital charges was obtained for each patient from the hospital billing office and organized by billing code into a database. Continuous data that were normally distributed are presented as the mean ± SD and were analyzed by the Student's t test. The chi-square and Fisher exact tests were used to evaluate differences in proportions between patient subgroups. Data that were not normally distributed were compared with the Wilcoxon rank-sum test. RESULTS: Forty-five patients were studied: 23 in the H1N1 group and 22 in the noninfluenza group. Mean ± SD age was similar (44 ± 13 and 51 ± 17 years, respectively, p = 0.15). H1N1 patients had lower APACHE III scores (66 ± 20 vs. 89 ± 32, p = 0.015) and had higher Pplat and PEEP on days 1, 3, and 14. Hospital and ICU length of stay and duration of mechanical ventilation were comparable. SOFA scores over the first 2 weeks in the ICU indicate more severe organ failure in the noninfluenza group (p = 0.017). Hospital mortality was significantly higher in the noninfluenza group (77 vs. 39%, p = 0.016). The noninfluenza group tended to have higher overall charges, including significantly higher cost of blood products in the ICU. CONCLUSIONS: ALI/ARDS secondary to pandemic influenza infection is associated with more severe respiratory compromise but has lower overall acuity and better survival rates than ALI/ARDS due to other causes. Higher absolute charges in the noninfluenza group are likely due to underlying comorbid medical conditions.

Detectability of vasopressin in continuous venovenous hemodialysis effluent of patients with vasodilatory shock treated with exogenous arginine vasopressin.

STUDY OBJECTIVES: To determine whether vasopressin is detectable in the continuous venovenous hemodialysis (CVVHD) effluent of patients receiving exogenous arginine vasopressin, and to determine whether treatment-specific factors are associated with vasopressin levels in CVVHD effluent. DESIGN. Prospective observational study. SETTING. Intensive care units of a tertiary care academic medical center. PATIENTS. Twenty-seven adults with vasodilatory shock who received a stable-dose continuous intravenous infusion of arginine vasopressin with concomitant uninterrupted CVVHD for at least 4 hours between September 2008 and May 2010. MEASUREMENTS AND MAIN RESULTS. Vasopressin levels in CVVHD effluent were assessed by radioimmunoassay. Statistical analysis was performed with analysis of variance and Pearson correlation. A multivariate linear regression was used to assess for independent factors associated with vasopressin levels in CVVHD effluent. The CVVHD effluent of all patients was assessed for vasopressin levels. The median exogenous arginine vasopressin dose was 0.03 unit/minute (range 0.02-0.18 unit/min), whereas the median CVVHD effluent flow rate was 22.6 ml/kg/hour (interquartile range [IQR] 21.5-26.8 ml/kg/hr). Vasopressin was detectable in all effluent samples (median 88.8 pg/ml, IQR 36.4-113.7 pg/ml). There were no significant differences in CVVHD effluent vasopressin levels among CVVHD filter types (p=0.39). The CVVHD effluent vasopressin levels correlated with exogenous arginine vasopressin dose (r2=0.49, p<0.001). After adjustment for CVVHD effluent flow rate and administration of corticosteroids, with multivariate linear regression, only exogenous arginine vasopressin dose was independently associated with CVVHD effluent vasopressin level. CONCLUSION. Vasopressin is detectable in CVVHD effluent, suggesting that it is removed by CVVHD. In addition, exogenous arginine vasopressin infusion dose is independently associated with CVVHD effluent vasopressin level.

Partial liquid ventilation in adult patients with acute respiratory distress syndrome.

RATIONALE: Despite recent clinical trials demonstrating improved outcome in acute respiratory distress syndrome (ARDS), mortality remains high. Partial liquid ventilation (PLV) using perfluorocarbons has been shown to improve oxygenation and decrease lung injury in various animal models. OBJECTIVE: To determine if PLV would have an impact on outcome in patients with ARDS. METHODS: Patients with ARDS were randomized to (1) conventional mechanical ventilation (CMV; n=107), (2) "low-dose" perfluorocarbon (10 ml/kg; n=99), and (3) "high-dose" perfluorocarbon (20 ml/kg; n=105). Patients in all three groups were ventilated using volume ventilation, Vt or= 0.5, and positive end-expiratory pressure >or= 13 cm H(2)O. RESULTS: The 28-d mortality in the CMV group was 15%, versus 26.3% in the low-dose (p=0.06) and 19.1% in the high-dose (p=0.39) PLV groups. There were more ventilator-free days in the CMV group (13.0+/-9.3) compared with both the low-dose (7.4+/-8.5; p<0.001) and high-dose (9.9+/-9.1; p=0.043) groups. There were more pneumothoraces, hypoxic episodes, and hypotensive episodes in the PLV patients. CONCLUSIONS: PLV at both high and low doses did not improve outcome in ARDS compared with CMV and cannot be recommended for patients with ARDS.

Cor pulmonale: an overview.

Chronic cor pulmonale involves the enlargement of the right ventricle as a result of pulmonary hypertension due to pulmonary disorders involving the lung parenchyma, bellows function, or ventilatory drive. The right ventricular hypertrophy that occurs in chronic cor pulmonale is a direct result of chronic hypoxic pulmonary vasoconstriction and subsequent pulmonary artery hypertension, leading to increased right ventricular work and stress. We discuss methods by which hypoxic vasoconstriction and reduction in the pulmonary vascular bed lead to the development of pulmonary artery hypertension. This article reviews the interaction of the pulmonary vasculature and right ventricle in the non-diseased state as well as during disease exacerbations. Ventricular dependence and its contribution to the pathophysiology of right ventricular failure are also reviewed. In addition, we provide an overview of specific disease states that can result in the development of chronic cor pulmonale including chronic obstructive pulmonary disease (COPD), interstitial lung disease, sleep apnea, alveolar hypoventilation disorders, and primary pulmonary hypertension. We also review the current diagnostic studies used to evaluate and study cor pulmonale.