Elevated CA-125 in IgG4 mesenteritis: a red herring or a disease biomarker? Case report and literature review.

Mesenteric panniculitis (MP) is a rare chronic disease characterized by inflammation and subsequently fibrosis of adipose tissue of the omentum. Only recently it has been associated with IgG4-related disease. Cancer antigen 125 (CA-125) is a high-molecular mass glycoprotein, traditionally associated with ovarian cancer, although it can be elevated in other conditions. Herein we describe a case of a 56-year-old man with IgG4 related mesenteric panniculitis associated with very high levels of CA-125 at the onset of disease. The CA-125 levels corresponded to clinical disease activity and improved with steroid therapy and rituximab. A literature review was performed concerning possible association of MP, IgG4-related disease and CA-125. The review of literature suggests that high levels of CA-125 can be raised in non-malignant, inflammatory conditions including IgG4-related mesenteritis and can improve with treatment.

Effect of azithromycin on the LPS-induced production and secretion of phospholipase A2 in lung cells.

Azithromycin is a member of macrolides, utilized in the treatment of infections. Independently, these antibiotics also possess anti-inflammatory and immunomodulatory properties. Phospholipase A2 isotypes, which are implicated in the pathophysiology of inflammatory lung disorders, are produced by alveolar macrophages and other lung cells during inflammatory response and can promote lung injury by destructing lung surfactant. The aim of the study was to investigate whether in lung cells azithromycin can inhibit secretory and cytosolic phospholipases A2, (sPLA2) and (cPLA2), respectively, which are induced by an inflammatory trigger. In this respect, we studied the lipopolysaccharide (LPS)-mediated production or secretion of sPLA2 and cPLA2 from A549 cells, a cancer bronchial epithelial cell line, and alveolar macrophages, isolated from bronchoalveolar lavage fluid of ARDS and control patients without cardiopulmonary disease or sepsis. Pre-treatment of cells with azithromycin caused a dose-dependent decrease in the LPS-induced sPLA2-IIA levels in A549 cells. This inhibition was rather due to reduced PLA2G2A mRNA expression and secretion of sPLA2-IIA protein levels, as observed by western blotting and indirect immunofluorescence by confocal microscopy, respectively, than to the inhibition of the enzymic activity per se. On the contrary, azithromycin had no effect on the LPS-induced production or secretion of sPLA2-IIA from alveolar macrophages. The levels of LPS-induced c-PLA2 were not significantly affected by azithromycin in either cell type. We conclude that azithromycin exerts anti-inflammatory properties on lung epithelial cells through the inhibition of both the expression and secretion of LPS-induced sPLA2-IIA, while it does not affect alveolar macrophages.

Mild stretch activates cPLA2 in alveolar type II epithelial cells independently through the MEK/ERK and PI3K pathways.

Alveolar epithelial type II cells (AT II) in which lung surfactant synthesis and secretion take place, are subjected to low magnitude stretch during normal breathing. The aim of the study was to explore the effect of mild stretch on phospholipase A(2) (PLA(2)) activation, an enzyme known to be involved in surfactant secretion. In A549 cells (a model of AT II cells), we showed, using a fluorometric assay, that stretch triggers an increase of total PLA(2) activity. Western blot experiments revealed that the cytosolic isoform cPLA(2) is rapidly phosphorylated under stretch, in addition to a modest increase in cPLA(2) mRNA levels. Treatment of A549 cells with selective inhibitors of the MEK/ERK pathway significantly attenuated the stretch-induced cPLA(2) phosphorylation. A strong interaction of cPLA(2) and pERK enzymes was demonstrated by immunoprecipitation. We also found that inhibition of PI3K pathway attenuated cPLA(2) activation after stretch, without affecting pERK levels. Our results suggest that low magnitude stretch can induce cPLA(2) phosphorylation through the MEK/ERK and PI3K-Akt pathways, independently.

Propofol prevents lung injury following intestinal ischemia-reperfusion.

BACKGROUND: The antioxidant properties of propofol have been shown to improve ischemia/reperfusion injury. We investigated whether anesthesia with propofol can ameliorate remote lung injury induced by intestinal ischemia-reperfusion (IIR). MATERIALS AND METHODS: Thirty male Wistar rats were randomly allocated in three groups (n = 10 each): animals in group Sham were anesthetized with ketamine and xylazine and then laparotomy and sham IIR followed. Animals in group IIR received ketamine and xylazine and were then subjected to clamping of the superior mesenteric artery for 45 min and reperfusion for 4 h. Group IIR+P received anesthesia with propofol and then IIR was induced, as in group IIR. Blood samples for blood gases and malondialdehyde measurements were drawn at the end of reperfusion. Bronchoalveolar lavage fluid (BALF) was obtained to measure cell counts, total protein, and phospholipids levels. RESULTS: Induction of IIR resulted in deteriorated oxygenation, acidemia, and inflammatory cells sequestration, along with increased BALF protein content and increased proportions of small surfactant aggregates. Anesthesia with propofol alleviated intestinal injury and efficiently prevented lipid oxidation. In group IIR+P inflammatory cell infiltration and pulmonary histologic changes were significantly limited. The increase in BALF total protein and the changes in surfactant aggregates were prevented, leading to normal systemic oxygenation. CONCLUSION: Using propofol to induce and maintain anesthesia efficiently prevented IIR-induced lung injury. Systemic antioxidant protection, improvement of intestinal injury, inhibition of the inflammatory response, and preservation of the alveolar-capillary permeability seem to be crucial mediating mechanisms for this simple and clinically relevant intervention.

Impaired phospholipases A2production by stimulated macrophages from patients with acute respiratory distress syndrome.

The aim of this study was to investigate whether early phase of acute respiratory distress syndrome (ARDS) is associated with changes in immune response, either systemic or localized to the lung. ARDS and control mechanically ventilated patients, as well as healthy volunteers were studied. Alveolar macrophages (AMΦ) and blood monocytes (BM) were treated ex vivo with lipopolysaccharide (LPS), interferon-γ (IFNγ), and surfactant. Phospholipase A2 (PLA2) activity and TLR4 expression were evaluated as markers of cell response. AMΦ from ARDS patients did not respond upon treatment with either LPS or IFN-γ by inducing PLA2 production. On the contrary, upon stimulation, in control patients the intracellular PLA2, (mainly cPLA2) levels were increased, but secretion of PLA2 (mainly sPLA2-IIA) was observed only after treatment with LPS. Surfactant suppressed PLA2 production in cells from both groups of patients. Increased relative changes of total PLA2 activity and an upregulation of TLR4 expression upon stimulation was observed in BM from primary ARDS, control patients and healthy volunteers. In BM from secondary ARDS patients, however, no PLA2 induction was observed, with a concomitant down-regulation of TLR4 expression. Cytosolic PLA2, its activated form, p-cPLA2, and sPLA2-IIA were the predominant PLA2 types within the cells, while extracellularly only sPLA2-IIA was identified. These results support the concept of down-regulated innate immunity in early ARDS that is compartmentalized in primary and systemic in secondary ARDS. PLA2 isoforms could serve as markers of the immunity status in ARDS. Finally, our data highlight the role of surfactant in controlling inflammation.

A specific phospholipase C activity regulates phosphatidylinositol levels in lung surfactant of patients with acute respiratory distress syndrome.

Lung surfactant (LS) is a lipid-rich material lining the inside of the lungs. It reduces surface tension at the liquid/air interface and thus, it confers protection of the alveoli from collapsing. The surface-active component of LS is dipalmitoyl-phosphatidylcholine, while anionic phospholipids such as phosphatidylinositol (PtdIns) and primarily phosphatidylglycerol are involved in the stabilization of the LS monolayer. The exact role of PtdIns in this system is not well-understood; however, PtdIns levels change dramatically during the acute respiratory distress syndrome (ARDS) evolution. In this report we present evidence of a phosphoinositide-specific phospholipase C (PI-PLC) activity in bronchoalveolar lavage (BAL) fluid, which may regulate PtdIns levels. Characterization of this extracellular activity showed specificity for PtdIns and phosphatidylinositol 4,5-bisphosphate, sharing the typical substrate concentration-, pH-, and calcium-dependencies with mammalian PI-PLCs. Fractionation of BAL fluid showed that PI-PLC did not co-fractionate with large surfactant aggregates, but it was found mainly in the soluble fraction. Importantly, analysis of BAL samples from control subjects and from patients with ARDS showed that the PI-PLC specific activity was decreased by 4-fold in ARDS samples concurrently with the increase in BAL PtdIns levels. Thus, we have identified for the first time an extracellular PI-PLC enzyme activity that may be acutely involved in the regulation of PtdIns levels in LS.

Phospholipase A2 subclasses in acute respiratory distress syndrome.

Phospholipases A2 (PLA2) catalyse the cleavage of fatty acids esterified at the sn-2 position of glycerophospholipids. In acute lung injury-acute respiratory distress syndrome (ALI-ARDS) several distinct isoenzymes appear in lung cells and fluid. Some are capable to trigger molecular events leading to enhanced inflammation and lung damage and others have a role in lung surfactant recycling preserving lung function: Secreted forms (groups sPLA2-IIA, -V, -X) can directly hydrolyze surfactant phospholipids. Cytosolic PLA2 (cPLA2-IVA) requiring Ca2+ has a preference for arachidonate, the precursor of eicosanoids which participate in the inflammatory response in the lung. Ca(2+)-independent intracellular PLA2s (iPLA2) take part in surfactant phospholipids turnover within alveolar cells. Acidic Ca(2+)-independent PLA2 (aiPLA2), of lysosomal origin, has additionally antioxidant properties, (peroxiredoxin VI activity), and participates in the formation of dipalmitoyl-phosphatidylcholine in lung surfactant. PAF-AH degrades PAF, a potent mediator of inflammation, and oxidatively fragmented phospholipids but also leads to toxic metabolites. Therefore, the regulation of PLA2 isoforms could be a valuable approach for ARDS treatment.

Intestinal preconditioning ameliorates ischemia-reperfusion induced acute lung injury in rats: an experimental study.

BACKGROUND: Phospholipases A(2) (PLA(2)) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS) induced by intestinal ischemia-reperfusion (IIR). Intestinal ischemic preconditioning (IIP) has been shown to improve intestinal tolerance to subsequent sustained ischemia and limit the systemic inflammatory response. We tested the effect of IIP on the intestinal ischemia-reperfusion-induced ARDS, with particular focus on PLA(2). METHODS: Rats were randomized into three groups: (1) sham surgery group (sGroup), 45 min sham intestinal ischemia-4 h reperfusion, (2) IIR group (IIRGroup), 45 min intestinal ischemia-4 h reperfusion, (3) IIP group (ipGroup), three cycles of intestinal ischemia for 4 min and reperfusion for 10 min followed by 45 min intestinal ischemia-4 h reperfusion. At the end of each experiment, blood gases were obtained and bronchoalveolar lavage (BAL) followed. Biochemical (total protein, PLA(2), PAF-AcH) and cytological parameters of the BAL fluid were quantified. Plasma MDA was measured as an indicator of systemic oxidative stress. Comparisons between groups were made using one-way ANOVA followed by post hoc comparison with a Tukey test or Mann-Whitney test when appropriate. Differences were considered significant if P < 0.05. RESULTS: Alveolar-arterial O(2) gradient values and wet to dry lung ratio were significantly (P < 0.05) increased in the IIRGroup and this increase was prevented in the ipGroup. Following the same pattern, BAL total protein, PLA(2), and PAF-AcH were significantly lower in the ipGroup. Ischemic preconditioning significantly abolished neutrophil count in BAL fluid. Plasma MDA was significantly lower in the ipGroup. Despite a significant tissue polymorphonuclear reduction, no significant lung or intestinal histologic damage score changes were revealed. CONCLUSIONS: Intestinal preconditioning protects IIR-induced lung injury, partly by modulating the arachidonic acid cascade.

Secretory Phospholipase A2-IIA Protein and mRNA Pools in Extracellular Vesicles of Bronchoalveolar Lavage Fluid from Patients with Early Acute Respiratory Distress Syndrome: A New Perception in the Dissemination of Inflammation?

Secretory phospholipase-IIA A2 (sPLA2-IIA) is expressed in a variety of cell types under inflammatory conditions. Its presence in the bronchoalveolar lavage (BAL) fluid of patients with acute respiratory distress syndrome (ARDS) is associated with the severity of the injury. Exosomal type extracellular vesicles, (EVs), are recognized to perform intercellular communication. They may alter the immune status of recipient target cells through cargo shuttling. In this work, we characterized the exosomal type EVs isolated from BAL fluid of patients with early and late ARDS as compared to control/non-ARDS patients, through morphological (confocal and electron microscopy) and biochemical (dynamic light scattering, qRT-PCR, immunoblotting) approaches. We provide evidence for the presence of an sPLA2-IIA-carrying EV pool that coprecipitates with exosomes in the BAL fluid of patients with ARDS. PLA2G2A mRNA was present in all the samples, although more prominently expressed in early ARDS. However, the protein was found only in EVs from early phase ARDS. Under both forms, sPLA2-IIA might be involved in inflammatory responses of recipient lung cells during ARDS. The perception of the association of sPLA2-IIA to the early diagnosis of ARDS or even with a mechanism of development and propagation of lung inflammation can help in the adoption of appropriate and innovative therapeutic strategies.

The use of bedside diagnostic laparoscopy in the intensive care unit.

BACKGROUND: The clinical evaluation of the abdomen in intensive care (ICU) patients who are intubated can be very complex. Many bedside diagnostic tests are available to assist the clinician, including ultrasound, peritoneal lavage, and plain X-rays. However, in the ICU setting, these tests can be unreliable. An abdominal computed tomography (CT) scan is more reliable, but it requires transportation to the Radiology Department, which can be risky. In this paper, we present our experience with bedside laparoscopy in the general ICU population. METHODS: Between April 2004 and November 2007, 35 adult patients (19 male, 16 female), with a mean age of 69 years (range, 39-83), underwent bedside diagnostic laparoscopy (DL) in the ICU. Hemodynamic and ventilatory parameters as well as the time required for the DL and CT scan procedure were compared. In addition, the ASA, APACHE II, and SOFA scores were documented. RESULTS: Laparoscopic findings were negative for intra-abdominal disease in 57.1% (n = 20) patients. The remaining patients (42.9%; n = 15) had positive laparoscopic findings for intra-abdominal disease. The overall mortality rate in our group of patients was 60%. The time required for DL was less (21.8 +/- 7.6 minutes) than the time required for a CT scan (38.2 +/- 6.2 minutes; P < 0.05). Three patients went on to have a therapeutic procedure in the ICU. CONCLUSION: The evaluation of the critically ill patient for intra-abdominal pathology with DL is a practical solution and needs to be used more frequently in this setting. In this paper, we present our experience with diagnostic laparoscopy in the ICU and found it to be safe and, in certain cases, may have a potential role as a bedside therapeutic tool. Although a number of reports with small series of patients have addressed the benefits and feasibility of DL, it is still being underutilized in the ICU. A more aggressive attempt should be made to incorporate DL as a routine procedure in the ICU.

The contribution of left heart disease in COPD patients with pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH), regardless of its etiology, is associated with an impaired outcome in patients with chronic obstructive pulmonary disease (COPD). The aim of our study was to determine the incidence, cause, and effect of PH as detected by echocardiography in COPD patients. METHODS: Patients with confirmed COPD of any stage were evaluated by echocardiography for the likelihood of PH according to the proposed criteria. Patients with possible/likely to have PH underwent right heart catheterization, upon agreement, to confirm the presence, severity, and cause of PH. RESULTS: Of 91 patients, 39 were in stable condition (group A) and 52 with COPD exacerbation (group B). Group B patients presented with PH and left ventricular diastolic dysfunction more often than group A patients. One of two fulfilled the criteria for possible/likely PH. The incidence of likely/possible PH was significantly higher in group B. Nineteen group B patients with likely/possible PH underwent RHC, and PH was confirmed in 15 cases and in 73.3% was associated with left heart disease. The presence of possible/likely PH was associated with a statistically significant increase in mortality compared to those with unlikely PH. CONCLUSIONS: The use of echocardiographic criteria for the presence of PH is adequate for the screening of COPD patients. Patients with acute exacerbation of COPD and possible/likely PH demonstrate worse mortality compared to patients unlikely to have PH.

The importance of religious affiliation and culture on end-of-life decisions in European intensive care units.

OBJECTIVE: To determine the influence of religious affiliation and culture on end-of-life decisions in European intensive care units (ICUs). DESIGN AND SETTING: A prospective, observational study of European ICUs was performed on consecutive patients with any limitation of therapy. Prospectively defined end-of-life practices in 37 ICUs in 17 European countries studied from 1 January 1999 to 30 June 2000 were compared for frequencies, patterns, timing, and communication by religious affiliation of physicians and patients and regions. RESULTS: Of the 31,417 patients 3,086 had limitations. Withholding occurred more often than withdrawing if the physician was Jewish (81%), Greek Orthodox (78%), or Moslem (63%). Withdrawing occurred more often for physicians who were Catholic (53%), Protestant (49%), or had no religious affiliation (47%). End-of-life decisions differed for physicians between regions and who had any religious affiliation vs. no religious affiliation in all three geographical regions. Median time from ICU admission to first limitation of therapy was 3.2 days but varied by religious affiliation; from 1.6 days for Protestant to 7.6 days for Greek Orthodox physicians. Median times from limitations to death also varied by physician's religious affiliation. Decisions were discussed with the families more often if the physician was Protestant (80%), Catholic (70%), had no religious affiliation (66%) or was Jewish (63%). CONCLUSIONS: Significant differences associated with religious affiliation and culture were observed for the type of end of life decision, the times to therapy limitation and death, and discussion of decisions with patient families.

The impact of healthcare professionals' personality and religious beliefs on the decisions to forego life sustaining treatments: an observational, multicentre, cross-sectional study in Greek intensive care units.

OBJECTIVES: To assess the opinion of intensive care unit (ICU) personnel and the impact of their personality and religious beliefs on decisions to forego life-sustaining treatments (DFLSTs). SETTING: Cross-sectional, observational, national study in 18 multidisciplinary Greek ICUs, with >6 beds, between June and December 2015. PARTICIPANTS: 149 doctors and 320 nurses who voluntarily and anonymously answered the End-of-Life (EoL) attitudes, Personality (EPQ) and Religion (SpREUK) questionnaires. Multivariate analysis was used to detect the impact of personality and religious beliefs on the DFLSTs. RESULTS: The participation rate was 65.7%. Significant differences in DFLSTs between doctors and nurses were identified. 71.4% of doctors and 59.8% of nurses stated that the family was not properly informed about DFLST and the main reason was the family's inability to understand medical details. 51% of doctors expressed fear of litigation and 47% of them declared that this concern influenced the information given to family and nursing staff. 7.5% of the nurses considered DFLSTs dangerous, criminal or illegal. Multivariate logistic regression identified that to be a nurse and to have a high neuroticism score were independent predictors for preferring the term 'passive euthanasia' over 'futile care' (OR 4.41, 95% CI 2.21 to 8.82, p<0.001, and OR 1.59, 95% CI 1.03 to 2.72, p<0.05, respectively). Furthermore, to be a nurse and to have a high-trust religious profile were related to unwillingness to withdraw mechanical ventilation. Fear of litigation and non-disclosure of the information to the family in case of DFLST were associated with a psychoticism personality trait (OR 2.45, 95% CI 1.25 to 4.80, p<0.05). CONCLUSION: We demonstrate that fear of litigation is a major barrier to properly informing a patient's relatives and nursing staff. Furthermore, aspects of personality and religious beliefs influence the attitudes of ICU personnel when making decisions to forego life-sustaining treatments.

Burnout and job satisfaction of intensive care personnel and the relationship with personality and religious traits: An observational, multicenter, cross-sectional study.

OBJECTIVES: To investigate if burnout in the Intensive Care Unit (ICU) is influenced by aspects of personality, religiosity and job satisfaction. RESEARCH METHODOLOGY: Cross-sectional study, designed to assess burnout in the ICU and to investigate possible determinants. Three different questionnaires were used: the Malach Burnout Inventory, the Eysenck Personality Questionnaire and the Spiritual/Religious Attitudes Questionnaire. Predicting factors for high burnout were identified by multivariate logistic regression analysis. SETTING/PARTICIPANTS: This national study was addressed to physicians and nurses working full-time in 18 Greek ICU departments from June to December 2015. RESULTS: The participation rate was 67.9% (n=149) and 65% (n=320) for ICU physicians and nurses, respectively). High job satisfaction was recorded in both doctors (80.8%) and nurses (63.4%). Burnout was observed in 32.8% of the study participants, higher in nurses compared to doctors (p<0.001). Multivariate analysis revealed that neuroticism was a positive and extraversion a negative predictor of exhaustion (OR 5.1, 95%CI 2.7-9.7, p<0.001 and OR 0.49, 95%CI 0.28-0.87, p=0.014, respectively). Moreover, three other factors were identified: Job satisfaction (OR 0.26, 95%CI 0.14-0.48, p<0.001), satisfaction with current End-of-Life care (OR 0.41, 95%CI 0.23-0.76, p=0.005) and isolation feelings after decisions to forego life sustaining treatments (OR 3.48, 95%CI 1.25-9.65, p=0.017). CONCLUSIONS: Personality traits, job satisfaction and the way End-of-Life care is practiced influence burnout in the ICU.

Biochemical parameters of bronchoalveolar lavage fluid in fat embolism.

OBJECTIVE: To identify diagnostic markers distinguishing between acute lung injury/acute respiratory distress syndrome (ALI/ARDS) due to fat embolism syndrome (FES) and that due to other causes, and to investigate whether phospholipase A2 and platelet-activating factor (PAF) play a role in the pathogenesis of ALI due to FES. DESIGN AND SETTING: A prospective study in a 14-bed ICU. PATIENTS: We studied 13 patients with FES, 11 with ALI/ARDS from other causes (6 without trauma, ALI/ARDS group 1; 7 with trauma, ALI/ARDS group 2) and 5 without cardiopulmonary disease. MEASUREMENTS AND RESULTS: We compared broncholveolar lavage (BAL) fluid alterations in the respective groups. Total BAL protein in FES group was significantly higher compared to in ALI/ARDS group 1 and controls but ALI/ARDS group 2. Higher total phospholipids were found than in other groups. The alterations in individual phospholipid classes were similar to those in ALI/ARDS patients. However, total cholesterol, lipid esters, and monoglycerides were significantly higher in FES than in other groups. The level of PAF in FES was significantly higher and there was an inverse correlation between PAF and PAF-acetylhydrolase. Phospholipase A2 activity was significantly higher in both FES and ALI/ARDS groups than in control. CONCLUSIONS: The levels of neutral lipids and especially cholesterol and cholesterol esters in BAL can be used to distinguish patients with FES from ALI/ARDS due to other predisposing factors. Phospholipase A(2) may be involved in the development, and PAF-acetylhydrolase in the downregulation of inflammation in FES.

Heterotopic ossification of the knee joint in intensive care unit patients: early diagnosis with magnetic resonance imaging.

INTRODUCTION: Heterotopic ossification (HO) is the formation of bone in soft tissues. The purpose of the present study was to evaluate the magnetic resonance imaging (MRI) findings on clinical suspicion of HO in the knee joint of patients hospitalised in the intensive care unit (ICU). METHODS: This was a case series of 11 patients requiring prolonged ventilation in the ICU who had the following diagnoses: head trauma (nine), necrotising pancreatitis (one), and fat embolism (one). On clinical suspicion of HO, x-rays and MRI of the knee joint were performed. Follow-up x-rays and MRI were also performed. RESULTS: First x-rays were negative, whereas MRI (20.2 +/- 6.6 days after admission) showed joint effusion and in fast spin-echo short time inversion-recovery (STIR) images a 'lacy pattern' of the muscles vastus lateralis and medialis. The innermost part of the vastus medialis exhibited homogeneous high signal. Contrast-enhanced fat-suppressed T1-weighted images also showed a 'lacy pattern.' On follow-up (41.4 +/- 6.6 days after admission), STIR and contrast-enhanced T1-weighted images depicted heterogeneous high signal and heterogeneous enhancement, respectively, at the innermost part of the vastus medialis, whereas x-rays revealed a calcified mass in the same position. Overall, positive MRI findings appeared simultaneously with clinical signs (1.4 +/- 1.2 days following clinical diagnosis) whereas x-ray diagnosis was evident at 23 +/- 4.3 days (p = 0.002). CONCLUSION: MRI of the knee performed on clinical suspicion shows a distinct imaging pattern confirming the diagnosis of HO earlier than other methods. MRI diagnosis may have implications for early intervention in the development of HO.

Lung and 'end organ' injury due to mechanical ventilation in animals: comparison between the prone and supine positions.

INTRODUCTION: Use of the prone position in patients with acute lung injury improves their oxygenation. Most of these patients die from multisystem organ failure and not from hypoxia, however. Moreover, there is some evidence that the organ failure is caused by increased cell apoptosis. In the present study we therefore examined whether the position of the patients affects histological changes and apoptosis in the lung and 'end organs', including the brain, heart, diaphragm, liver, kidneys and small intestine. METHODS: Ten mechanically ventilated sheep with a tidal volume of 15 ml/kg body weight were studied for 90 minutes. Five sheep were placed in the supine position and five sheep were placed in the prone position during the experiment. Lung changes were analyzed histologically using a semiquantitative scoring system and the extent of apoptosis was investigated with the TUNEL method. RESULTS: In the supine position intra-alveolar hemorrhage appeared predominantly in the dorsal areas, while the other histopathologic lesions were homogeneously distributed throughout the lungs. In the prone position, all histological changes were homogeneously distributed. A significantly higher score of lung injury was found in the supine position than in the prone position (4.63 +/- 0.58 and 2.17 +/- 0.19, respectively) (P < 0.0001). The histopathologic changes were accompanied by increased apoptosis (TUNEL method). In the supine position, the apoptotic index in the lung and in most of the 'end organs' was significantly higher compared with the prone position (all P < 0.005). Interestingly, the apoptotic index was higher in dorsal areas compared with ventral areas in both the prone and supine positions (P < 0.003 and P < 0.02, respectively). CONCLUSION: Our results suggest that the prone position appears to reduce the severity and the extent of lung injury, and is associated with decreased apoptosis in the lung and 'end organs'.

The local component of the acute cardiovascular response to simulated apneas in brain-dead humans.

STUDY OBJECTIVES: To investigate the local cardiovascular response to hypoxemia and hypercapnia in a simulated central apnea model in which the central autonomic regulation was absent. DESIGN: Experimental study. SETTING: A university hospital. INTERVENTIONS: A simulated central apnea model achieved by a particular setting of the mechanical ventilator in 10 brain-dead patients. MEASUREMENTS: Hemodynamic studies using right-heart catheterization and continuous monitoring of arterial blood gas levels. RESULTS: Hypercapnic hypoxic apneas were associated with no change in heart rate, fall in mean systemic arterial pressure and systemic vascular resistance (from 83 +/- 9 to 68 +/- 7 mm Hg and 1,115 +/- 82 to 768 +/- 58 dyne.s.cm(-5), respectively; each p < 0.05), and rise in mean pulmonary artery pressure, pulmonary vascular resistance, and pulmonary capillary wedge pressure (PCWP) [from 17 +/- 1.5 to 26 +/- 3 mm Hg, 102 +/- 27 to 166 +/- 43 dyne.s.cm(-5), and 10 +/- 1 to 14 +/- 2 mm Hg, respectively; each p < 0.05]. CONCLUSION: Our results suggest that in the absence of central autonomic regulation in humans, apnea-induced hypoxemia and/or hypercapnia are associated with peripheral vasodilatation and pulmonary vasoconstriction, which are probably local in origin, as well as a significant increase in PCWP indicating cardiac dysfunction.