Extrapulmonary Organ Dysfunction Research Articles

Survival and outcomes after lung transplantation for non-scleroderma connective tissue–related interstitial lung disease

Patients with non-scleroderma connective tissue-related lung disease (NS-CTLD), including rheumatoid arthritis, idiopathic inflammatory myopathies, Sjögren syndrome, mixed connective tissue disease, and systemic lupus erythematosus, may be at risk for worse outcomes after lung transplantation because of immune dysregulation or extrapulmonary manifestations of their underlying disease. We compared survival, acute and chronic rejection, and extrapulmonary organ dysfunction after transplantation in patients with NS-CTLD and idiopathic pulmonary fibrosis (IPF). This was a retrospective cohort study of patients with NS-CTLD and IPF who were listed in the Scientific Registry of Transplant Recipients and underwent lung transplantation from May 5, 2005, to March 1, 2016. Patients with NS-CTLD (n = 275) were younger, a higher percentage female and non-white than patients with IPF (n = 6,346). NS-CTLD patients did not have worse adjusted survival (hazard ratio, 1.14, 95% confidence interval [CI], 0.92-1.42; p = 0.24). They were not more likely to have an episode of acute cellular rejection (odds ratio, 0.96; 95% CI, 0.72-1.28; p = 0.77) or to develop bronchiolitis obliterans syndrome (odds ratio, 0.82; 95% CI, 0.60-1.12; p = 0.21). Patients with NS-CTLD were not more likely to require plasmapheresis or dialysis or to develop a lymphoproliferative malignancy or liver disease after transplantation. We found no significant differences in survival, acute or chronic rejection, or extrapulmonary organ dysfunction in patients who underwent lung transplantation for NS-CTLD compared with IPF. In appropriately selected candidates, NS-CTLD should not be considered a contraindication to lung transplantation.

Outcomes and survival prediction models for severe adult acute respiratory distress syndrome treated with extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS) has known a growing interest over the last decades with promising results during the 2009 A(H1N1) influenza epidemic. Targeting populations that can most benefit from this therapy is now of major importance.Survival has steadily improved for a decade, reaching up to 65% at hospital discharge in the most recent cohorts. However, ECMO is still marred by frequent and significant complications such as bleeding and nosocomial infections. In addition, physiological and psychological symptoms are commonly described in long-term follow-up of ECMO-treated ARDS survivors. Because this therapy is costly and exposes patients to significant complications, seven prediction models have been developed recently to help clinicians identify patients most likely to survive once ECMO has been initiated and to facilitate appropriate comparison of risk-adjusted outcomes between centres and over time. Higher age, immunocompromised status, associated extra-pulmonary organ dysfunction, low respiratory compliance and non-influenzae diagnosis seem to be the main determinants of poorer outcome.

Therapeutic Effects of Bone Marrow-Derived Mesenchymal Stem Cells in Models of Pulmonary and Extrapulmonary Acute Lung Injury.

Bone marrow-derived mesenchymal stem cells (MSCs) offer a promising therapy for acute lung injury (ALI). However, whether the same MSC treatments possess similar potential for different ALI models is not fully clear. The present study evaluated the distribution and therapeutic effects of intravenous MSC administration for the treatment of intratracheal lipopolysaccharide (LPS)-induced intrapulmonary ALI and intravenous LPS/zymosan-induced extrapulmonary ALI, matched with lung injury severity, at 30 min and 1, 3, and 7 days. We found that MSC transplantation attenuated lung injury and inhibited lung inflammation in both ALI models. The benefits of MSCs were more significant in the intrapulmonary ALI mice. In vivo and ex vivo fluorescence imaging showed that MSCs primarily homed into the lung. However, more MSCs were recruited into the lungs of the intrapulmonary ALI mice than those of the extrapulmonary ALI mice over the time course. A few MSCs were also detected in the liver and spleen at days 3 and 7. In addition, the two ALI models showed different extrapulmonary organ dysfunction. A lower percentage of cell apoptosis and SDF-1α levels was found in the liver and spleen of the intrapulmonary ALI mice than in those of the extrapulmonary ALI mice. These results suggested that the two ALI models were accompanied with different degrees of extrapulmonary organ damage, which resulted in differences in the trafficking and accumulation of MSCs to the injured lung and consequently accounted for different therapeutic effects of MSCs for lung repair in the two ALI models. These data suggest that intravenous administration of MSCs has a greater potential for the treatment of intrapulmonary ALI than extrapulmonary ALI matched with lung injury severity; these differences were due to more recruitment of MSCs in the lungs of intrapulmonary ALI mice than those of extrapulmonary ALI mice. This finding may contribute to the clinical use of MSCs for the treatment of ALI.

Low tidal volume ventilation ameliorates left ventricular dysfunction in mechanically ventilated rats following LPS-induced lung injury.

BackgroundHigh tidal volume ventilation has shown to cause ventilator-induced lung injury (VILI), possibly contributing to concomitant extrapulmonary organ dysfunction. The present study examined whether left ventricular (LV) function is dependent on tidal volume size and whether this effect is augmented during lipopolysaccharide(LPS)-induced lung injury.MethodsTwenty male Wistar rats were sedated, paralyzed and then randomized in four groups receiving mechanical ventilation with tidal volumes of 6 ml/kg or 19 ml/kg with or without intrapulmonary administration of LPS. A conductance catheter was placed in the left ventricle to generate pressure-volume loops, which were also obtained within a few seconds of vena cava occlusion to obtain relatively load-independent LV systolic and diastolic function parameters. The end-systolic elastance / effective arterial elastance (Ees/Ea) ratio was used as the primary parameter of LV systolic function with the end-diastolic elastance (Eed) as primary LV diastolic function.ResultsEes/Ea decreased over time in rats receiving LPS (p = 0.045) and high tidal volume ventilation (p = 0.007), with a lower Ees/Ea in the rats with high tidal volume ventilation plus LPS compared to the other groups (p < 0.001). Eed increased over time in all groups except for the rats receiving low tidal volume ventilation without LPS (p = 0.223). A significant interaction (p < 0.001) was found between tidal ventilation and LPS for Ees/Ea and Eed, and all rats receiving high tidal volume ventilation plus LPS died before the end of the experiment.ConclusionsLow tidal volume ventilation ameliorated LV systolic and diastolic dysfunction while preventing death following LPS-induced lung injury in mechanically ventilated rats. Our data advocates the use of low tidal volumes, not only to avoid VILI, but to avert ventilator-induced myocardial dysfunction as well.

Unraveling the mysteries of Middle East respiratory syndrome coronavirus.

Unraveling the mysteries of Middle East respiratory syndrome coronavirus.

Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection

Since September 2012, 170 confirmed infections with Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported to the World Health Organization, including 72 deaths. Data on critically ill patients with MERS-CoV infection are limited. To describe the critical illness associated with MERS-CoV. Case series. 3 intensive care units (ICUs) at 2 tertiary care hospitals in Saudi Arabia. 12 patients with confirmed or probable MERS-CoV infection. Presenting symptoms, comorbid conditions, pulmonary and extrapulmonary manifestations, measures of severity of illness and organ failure, ICU course, and outcome are described, as are the results of surveillance of health care workers (HCWs) and patients with potential exposure. Between December 2012 and August 2013, 114 patients were tested for suspected MERS-CoV; of these, 11 ICU patients (10%) met the definition of confirmed or probable cases. Three of these patients were part of a health care-associated cluster that also included 3 HCWs. One HCW became critically ill and was the 12th patient in this case series. Median Acute Physiology and Chronic Health Evaluation II score was 28 (range, 16 to 36). All 12 patients had underlying comorbid conditions and presented with acute severe hypoxemic respiratory failure. Most patients (92%) had extrapulmonary manifestations, including shock, acute kidney injury, and thrombocytopenia. Five (42%) were alive at day 90. Of the 520 exposed HCWs, only 4 (1%) were positive. The sample size was small. MERS-CoV causes severe acute hypoxemic respiratory failure and considerable extrapulmonary organ dysfunction and is associated with high mortality. Community-acquired and health care-associated MERS-CoV infection occurs in patients with chronic comorbid conditions. The health care-associated cluster suggests that human-to-human transmission does occur with unprotected exposure. None.

Medusa's Ugly Head Again: From SARS to MERS-CoV

In this issue, Arabi and colleagues report a case series of severely ill patients infected with the Middle East respiratory syndrome coronavirus. The editorialists comment on the report and emphasi...

Effects of methyl prednisolone in early ARDS

IntroductionGlucocorticoid induced down-regulation of systemic inflammation in ARDS is associated with a significant improvement in pulmonary and extrapulmonary organ dysfunction and a reduction in duration of mechanical ventilation and ICU length of stay [1].We aimed in this study to evaluate the effect of methyl prednisolone when used early in ARDS. Patients and methodsWe studied 27 patients with ARDS, we divided them randomly into two groups the first group consists of 18 patients received methyl prednisolone and the other group consists of 9 patients did not receive it. All patients were subjected daily to: history taking and clinical examination, Chest X-ray, routine blood investigation (CBC–LFT–RFT–electrolytes), ABG, Serum lactate, INR, fibrinogen, and aptt, CRP, protein C, protein S, and D-dimer at the beginning and at the end of study. ResultsAfter 7days there were significant improvements of clinical parameters (pulse, temperature, and systolic blood pressure), peep (one parameter from lung injury score), lactate, D-dimer, AST, and a highly significant improvement of creatinine in the methyl prednisolone group when compared to the control group. After 14days from starting treatment there were significant improvements of clinical parameters (pulse and systolic BP), ventilator parameters (FIO2, peep, and RR), systemic inflammation markers organ functions (O2sat, lactate, creatinine, WBCs, AST, and GGT) and CRP. And a significant improvement of CX-ray, earlier extubation from mechanical ventilation and improvement of mortality in the methyl prednisolone group when compared with the control group. ConclusionWe conclude that methyl prednisolone when used on first 2days in ARDS patients improves the LIS, decreases the systemic inflammation, earlier extubation from mechanical ventilation, and decreases the incidence of hospital acquired infection.

Corticosteroid treatment in severe community-acquired pneumonia: duration of treatment affects control of systemic inflammation and clinical improvement

Dear Editor, In a preliminary randomized trial of patients with severe communityacquired pneumonia (CAP), we reported that glucocorticoid treatment was associated with attenuation of systemic inflammation and improvement in pulmonary and extrapulmonary organ dysfunction [1]. Response to glucocorticoid treatment—ineffective, effective, or toxic—is influenced by drug dosage and duration of administration. In CAP, the effect of duration of glucocorticoid treatment on systemic inflammation and clinical outcome is unknown. We hypothesized that longer duration of treatment prevents rebound systemic inflammation and clinical deterioration. We conducted a post hoc analysis of 51 patients meeting American Thoracic Society criteria for severe pneumonia [2] recruited in two separate randomized trials [3, 4]. CAP patients with acute respiratory distress syndrome (ARDS) received methylprednisolone (1 mg/kg/day) for more than 21 days [3], patients without ARDS received hydrocortisone (240 mg/day) for 7 days [4]. Patients receiving glucocorticoids [methyprednisolone (n = 18) and hydrocortisone (n = 15)] were compared to placebo (n = 18). Baseline characteristics were similar between the two groups, with the exception of a higher proportion of patients requiring mechanical ventilation in the steroid group (97 vs. 78%; p = 0.05). As shown in Fig. 1, by study day 7, those randomized to glucocorticoids had significant improvements in C-reactive protein (CRP) levels, a higher proportion of extubated patients (64 vs. 28%; p = 0.02), a lower multiple organ dysfunction syndrome (MODS) score (0.66 ± 1 vs. 1.4 ± 1; p = 0.05), and a non-significant change in mortality (7 vs. 22%; p = 0.17). The extubation rate was similar in the methylprednisolone and hydrocortisone group (61 vs. 67%). After discontinuation of hydrocortisone treatment, 7 (44%) patients had rebound systemic inflammation (threeto fivefold increase in CRP) and associated clinical deterioration (3 had worsening MODS and 3 required re-intubation). To the contrary, continuation of methylprednisolone treatment was associated with a sustained antiinflammatory effect without re-exacerbation of respiratory failure. Overall treatment was associated with reduction in median (IQR) duration of mechanical ventilation [5.5 (4.5) vs. 10.0 (6.0); p = 0.05] but no significant change in duration of hospital stay [11.0 (9.0) vs. 15.5 (16.0); p = 0.43] or intensive care unit (ICU) survival (82 vs. 72%; p = 0.49). Our findings, in agreement with the recent literature for patients without CAP [5], indicate that the initial biological and physiological benefits observed during glucocorticoid administration may be lost if discontinuation of treatment is not preceded by slow tapering. For this reason a recent consensus statement [5] recommended that glucocorticoid

Global Clinical Networking and Pandemic Influenza

From June 2009 to February 2010, the Health Protection Agency hosted a clinical network including regular teleconferences, with the aim of sharing clinical experiences of the international participants about pandemic influenza. The minutes of the teleconferences over a two month period were analysed to identify clinical themes. A systematic literature search was then undertaken to identify peer-reviewed publications that either supported or refuted these themes. Observations relating to patient demographics, clinical features and clinical management were supported by published literature. Younger adults and children were more likely to be infected, but young adults were more likely to require intensive care. Obesity, pregnancy and asthma were confirmed as risk factors for severe influenza illness. Extra-pulmonary organ dysfunction was common, often requiring specific interventions. The benefit of certain ventilatory and non-ventilatory interventions remains unclear, although they were frequently used. This global clinical networking model facilitated the real-time exchange of valuable clinical information and provided the basis for clinical practice notes.

Activation and Regulation of Systemic Inflammation in ARDS: Rationale for Prolonged Glucocorticoid Therapy

Experimental and clinical evidence has demonstrated a strong cause-and-effect relationship between persistence vs reduction in systemic inflammation and progression (unresolving) vs resolution (resolving) of ARDS. In this review, the cellular mechanisms involved in activating and regulating inflammation are contrasted between patients with resolving and unresolving ARDS. At the cellular level, patients with unresolving ARDS have deficient glucocorticoid (GC)-mediated down-regulation of inflammatory cytokine and chemokine transcription despite elevated levels of circulating cortisol, a condition defined as systemic inflammation-associated acquired GC resistance. These patients, contrary to those with resolving ARDS, have persistent elevation in levels of both systemic and BAL fluid inflammatory cytokines and chemokines, markers of alveolar-capillary membrane permeability and fibrogenesis. At the tissue level, the continued production of inflammatory mediators leads to tissue injury, intravascular and extravascular coagulation, and the proliferation of mesenchymal cells, all resulting in maladaptive lung repair and progression of extrapulmonary organ dysfunction. In ARDS, down-regulation of systemic inflammation is essential to restoring homeostasis, decreasing morbidity, and improving survival. Prolonged low-to-moderate dose GC therapy promotes the down-regulation of inflammatory cytokine transcription at the cellular level. Eight controlled studies have consistently reported a significant reduction in markers of systemic inflammation, pulmonary and extrapulmonary organ dysfunction scores, duration of mechanical ventilation, and ICU length of stay. In the aggregate (n = 628), reduction in mortality was substantial for all patients (relative risk [RR], 0.75; 95% CI, 0.63 to 0.89; p < 0.001; I(2), 43%) and for those treated before day 14 (RR, 0.71; 95% CI, 0.59 to 0.85; p < 0.001; I(2), 40%).

Methylprednisolone Infusion in Early Severe ARDS: Results of a Randomized Controlled Trial

To determine the effects of low-dose prolonged methylprednisolone infusion on lung function in patients with early severe ARDS. Randomized, double-blind, placebo-controlled trial. ICUs of five hospitals in Memphis. Ninety-one patients with severe early ARDS (</= 72 h), 66% with sepsis. Patients were randomized (2:1 fashion) to methylprednisolone infusion (1 mg/kg/d) vs placebo. The duration of treatment was up to 28 days. Infection surveillance and avoidance of paralysis were integral components of the protocol. The predefined primary end point was a 1-point reduction in lung injury score (LIS) or successful extubation by day 7. In intention-to-treat analysis, the response of the two groups (63 treated and 28 control) clearly diverged by day 7, with twice the proportion of treated patients achieving a 1-point reduction in LIS (69.8% vs 35.7%; p = 0.002) and breathing without assistance (53.9% vs 25.0%; p = 0.01). Treated patients had significant reduction in C-reactive protein levels, and by day 7 had lower LIS and multiple organ dysfunction syndrome scores. Treatment was associated with a reduction in the duration of mechanical ventilation (p = 0.002), ICU stay (p = 0.007), and ICU mortality (20.6% vs 42.9%; p = 0.03). Treated patients had a lower rate of infections (p = 0.0002), and infection surveillance identified 56% of nosocomial infections in patients without fever. Methylprednisolone-induced down-regulation of systemic inflammation was associated with significant improvement in pulmonary and extrapulmonary organ dysfunction and reduction in duration of mechanical ventilation and ICU length of stay.

Alpha glucocorticoid receptor expression in different experimental rat models of acute lung injury

Background and objectives Acute respiratory distress syndrome (ARDS) is a frequent form of hypoxiemic respiratory failure caused by the acute development of diffuse lung inflammation. Dysregulated systemic inflammation with persistent elevation of circulating inflammatory cytokines is the pathogenetic mechanism for pulmonary and extrapulmonary organ dysfunction in patients with ARDS. Glucocorticoids (GCs) have a broad range of inhibitory inflammatory effects, including inhibition of cytokines transcription, cellular activation and growth factor production. They inhibit the inflammatory pathways through two specific intracellular glucocorticoid receptors (GRs), named GR α and GR β. The aim of our study was to evaluate the histologic evidence of inflammatory injury and the GR α uptake of resident and inflammatory cells in different experimental models of acute lung injury (ALI). Methods We studied four groups of rats: three different experimental rat models of lung injury and a control group. The ALI was caused by barotrauma (due to an overventilation), oleic acid injection and mechanical ventilation. Results were compared to nonventilated rat control group. The duration of mechanical ventilation was of 2.5 h. At the end of each experiment, rats were sacrificed. Lung biopsies were evaluated for morphologic changes. The immunohistochemistry was performed to study GR α expression. Results Histologic evidence of lung injury (alveolar and interstitial edema, vascular congestion, alveolar haemorrhage, emphysema, number of interstitial cells and neutrophils, and destruction of alveolar attachments) were present in all ventilated groups. Barotrauma lead to an additional inflammatory response. GR α expression significantly increased in the three ventilated groups compared with nonventilated groups. GR α expression was highest in barotrauma group. Conclusions These data indicate that ALI is associated with diffuse alveolar damage, up-regulation of the inflammatory response and GR α overexpression. Barotrauma is the most effective mechanism inducing acute lung inflammation and GR α overexpression.

Mechanical ventilation induces inflammation, lung injury, and extra-pulmonary organ dysfunction in experimental pneumonia

Mechanical ventilation (MV) is frequently employed for the management of critically ill patients with respiratory failure. A major complication of mechanical ventilation (MV) is the development of ventilator-associated pneumonia (VAP), in which Staphylococcus aureus is a prominent pathogen. Moreover, previous studies suggest that MV may be an important cofactor in the development of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). S. aureus pulmonary infection was induced in spontaneously breathing mice (C57Bl/6) or mechanically ventilated mice to determine whether MV contributes to the development of ALI and/or systemic inflammation. The combination of MV and bacteria significantly increased the influx of neutrophils into bronchoalveolar lavage fluid (BALF), augmented pulmonary production of the proinflammatory cytokines KC, MIP-2, TNF-α, and IL-6, and increased alveolar-capillary permeability to proteins. MV also induced proinflammatory cytokine expression in peripheral blood, associated with extrapulmonary hepatic and renal dysfunction. Surprisingly, bacterial clearance in the lungs and extrapulmonary bacterial dissemination was not affected by MV. These data indicate that MV exacerbates both pulmonary and systemic inflammation in response to bacteria and contributes to the pathogenesis of both ALI and the multiple organ dysfunction syndrome, without necessarily affecting bacterial clearance or extra-pulmonary bacterial dissemination.

Mechanical ventilation interacts with endotoxemia to induce extrapulmonary organ dysfunction

IntroductionMultiple organ dysfunction syndrome (MODS) is a common complication of sepsis in mechanically ventilated patients with acute respiratory distress syndrome, but the links between mechanical ventilation and MODS are unclear. Our goal was to determine whether a minimally injurious mechanical ventilation strategy synergizes with low-dose endotoxemia to induce the activation of pro-inflammatory pathways in the lungs and in the systemic circulation, resulting in distal organ dysfunction and/or injury.MethodsWe administered intraperitoneal Escherichia coli lipopolysaccharide (LPS; 1 μg/g) to C57BL/6 mice, and 14 hours later subjected the mice to 6 hours of mechanical ventilation with tidal volumes of 10 ml/kg (LPS + MV). Comparison groups received ventilation but no LPS (MV), LPS but no ventilation (LPS), or neither LPS nor ventilation (phosphate-buffered saline; PBS).ResultsMyeloperoxidase activity and the concentrations of the chemokines macrophage inflammatory protein-2 (MIP-2) and KC were significantly increased in the lungs of mice in the LPS + MV group, in comparison with mice in the PBS group. Interestingly, permeability changes across the alveolar epithelium and histological changes suggestive of lung injury were minimal in mice in the LPS + MV group. However, despite the minimal lung injury, the combination of mechanical ventilation and LPS resulted in chemical and histological evidence of liver and kidney injury, and this was associated with increases in the plasma concentrations of KC, MIP-2, IL-6, and TNF-α.ConclusionNon-injurious mechanical ventilation strategies interact with endotoxemia in mice to enhance pro-inflammatory mechanisms in the lungs and promote extra-pulmonary end-organ injury, even in the absence of demonstrable acute lung injury.

Systemic inflammation-associated glucocorticoid resistance and outcome of ARDS.

Dysregulated systemic inflammation with excess activation of pro-inflammatory transcription factor nuclear factor-kappaB (NF-kappaB)-activated by inflammatory signals-compared to the anti-inflammatory transcription factor glucocorticoid receptor-alpha (GRalpha)-activated by endogenous or exogenous glucocorticoids (GCs)-is an important pathogenetic mechanism for pulmonary and extrapulmonary organ dysfunction in patients with acute respiratory distress syndrome (ARDS). Activation of one transcription factor in excess of the binding (inhibitory) capacity of the other shifts cellular responses toward increased (dysregulated) or decreased (regulated) transcription of inflammatory mediators over time. Recent data indicate that failure to improve in ARDS (unresolving ARDS) is frequently associated with failure of the activated GRs to downregulate the transcription of inflammatory cytokines despite elevated levels of circulating cortisol, a condition defined as systemic inflammation-associated acquired GC resistance; it is potentially reversible with prolonged GC supplementation. In the first part of this paper, after a brief description of inflammation in ARDS and our model of translational research, we review the two cellular signaling pathways that are central to the regulation of inflammation-the stimulatory NF-alphaB and the inhibitory GRalpha. In the second part, we review findings of recent studies indicating that excessive inflammatory activity in patients with unresolving ARDS may induce noncompensated GC resistance in target organs. In the third part, we review factors affecting cellular response to GC and potential mechanisms involved in inflammation-associated GC resistance.

An Approach to the Treatment of Pulmonary Sarcoidosis With Corticosteroids: The Six Phases of Treatment

Corticosteroid therapy for pulmonary sarcoidosis is not standardized. There is no consensus on which patients should receive treatment, how patients should be monitored, and the dose of corticosteroids once the decision to treat has been made. These issues are important for several reasons. First, inappropriate use of corticosteroids may result in unnecessary toxic reactions. Second, inadequate use of corticosteroids might result in permanent pulmonary and extrapulmonary organ dysfunction from sarcoidosis. Third, patients who are inappropriately labeled as "corticosteroid failures" may be subjected to other potentially toxic drugs or even lung transplantation. Corticosteroid dosing involves six phases: (1) initial high doses to control inflammation; (2) tapering to a maintenance dose that will continue to suppress the inflammation but lessen the risk of corticosteroid toxic reactions; (3) continuing to receive the maintenance dose until a decision to taper off corticosteroids is made; (4) tapering off corticosteroid therapy; (5) observation for relapse; and (6) treatment if relapse occurs. Although these phases of treatment have been alluded to in the literature, few of them have been studied rigorously. This article describes the use of corticosteroids for pulmonary sarcoidosis in terms of the above six phases. The proposed dosing schedules are based on the natural history of the disease and the results from published treatment studies.

Effect of end-stage liver failure on the incidence and resolution of the adult respiratory distress syndrome

Multiple systems organ failure adversely affects outcome in the adult respiratory distress syndrome (ARDS). However, no clinical studies of the influence of preexisting single extrapulmonary organ dysfunction on the incidence and resolution of ARDS have been reported. Hepatic reticuloendothelial system (RES) and hepatic parenchymal cell uptake and detoxification of proinflammatory substances are major elements of systemic host defense and may, accordingly, be important pulmonary defense mechanisms. To better define the effects of liver-lung interactions on the resolution of acute lung injury with preexisting extreme hepatic dysfunction, we retrospectively analyzed the incidence, risk factors, and clinical characteristics of ARDS in 29 patients with end-stage liver failure (ESLF) who required intensive care while awaiting a liver transplantation. We compared data from these patients with those from a concurrent group of 44 intensive care patients without ESLF, and contrasted our findings with recent clinical studies of ARDS predisposition and outcome. ARDS occurred in 23 of 29 patients (79%) with ESLF; sepsis was the most common predisposing risk factor (18 of 29 patients, 62%). ARDS developed in 3 of 44 patients (6.8%) without ESLF (odds ratio comparison with ESLF patients, 42.9, P < .001). Once initiated, regardless of etiology and subsequent ventilatory support, ARDS was uniformly irreversible in all 23 ESLF patients. These findings identify a growing population of critically ill patients at increased risk for nonresolving severe acute lung injury despite current methods of intensive care. We conclude that compromise of systemic and pulmonary defense by impaired hepatic RES performance and hepatocyte function may both predispose to ARDS and critically modulate its resolution.

Extubation criteria after weaning from intermittent mandatory ventilation and continuous positive airway pressure.

The "traditional" weaning criteria, arterial blood gases, and a number of other physiologic variables were measured in 47 patients to evaluate to what extent reduced ventilatory reserves or extrapulmonary organ dysfunction affect successful extubation. All patients had been weaned from continuous positive airway pressure (CPAP) and from mechanical ventilation according to the intermittent mandatory ventilation (IMV) method; at the time of study, all patients had compromised arterial oxygenation relieved by supplemental inspired oxygen. No significant difference between patients successfully extubated and those who required reintubation was found using the traditional weaning criteria or blood gases. On the other hand, patients who required reintubation had significantly lower urine volume (p less than 0.01), lower respiratory quotient values (p less than 0.05), and a higher incidence of positive blood culture (p less than 0.05). These 3 variables also correlated best to the patients' outcome after extubation.