Disease risk and mortality prediction in intensive care patients with pneumonia. Australian and New Zealand practice in intensive care (ANZPIC II)

This study of ventilated patients investigated pneumonia risk factors and outcome predictors in 476 episodes of pneumonia (48% community-acquired pneumonia, 24% hospital-acquired pneumonia, 28% ventilator-associated pneumonia) using a prospective survey in 14 intensive care units within Australia and New Zealand. For community acquired pneumonia, mortality increased with immunosuppression (OR 5.32, CI 95% 1.58-17.99, P < 0. 01), clinical signs of consolidation (OR 2.43, CI 95% 1.09-5.44, P = 0. 03) and Sepsis-Related Organ Failure Assessment (SOFA) scores (OR 1.19, CI 95% 1.08-1.30, P < 0. 001) but improved if appropriate antibiotic changes were made within three days of intensive care unit admission (OR 0.42, CI 95% 0.20-0.86, P = 0.02). For hospital-acquired pneumonia, immunosuppression (OR 6.98, CI 95% 1.16-42.2, P = 0.03) and non-metastatic cancer (OR 3.78, CI 95% 1.20-11.93, P = 0.02) were the principal mortality predictors. Alcoholism (OR 7.80, CI 95% 1.20-1750, P < 0.001), high SOFA scores (OR 1.44, CI 95% 1.20-1.75, P = 0.001) and the isolation of high risk organisms including Pseudomonas aeruginosa, Acinetobacter spp, Stenotrophomonas spp and methicillin resistant Staphylococcus aureus (OR 4.79, CI 95% 1.43-16.03, P = 0.01), were associated with increased mortality in ventilator-associated pneumonia. The use of non-invasive ventilation was independently protective against mortality for patients with community-acquired and hospital-acquired pneumonia (OR 0.35, CI 95% 0.18-0.68, P = 0.002). Mortality was similar for patients requiting both invasive and non-invasive ventilation and non-invasive ventilation alone (21% compared with 20% respectively, P = 0.56). Pneumonia risks and mortality predictors in Australian and New Zealand ICUs vary with pneumonia type. A history of alcoholism is a major risk factor for mortality in ventilator-associated pneumonia, greater in magnitude than the mortality effect of immunosuppression in hospital-acquired pneumonia or community-acquired pneumonia. Non-invasive ventilation is associated with reduced ICU mortality. Clinical signs of consolidation worsen, while rationalising antibiotic therapy within three days of ICU admission improves mortality for community-acquired pneumonia patients.

S100A8 chemotactic protein is abundantly increased, but only a minor contributor to LPS-induced, steroid resistant neutrophilic lung inflammation in vivo

Neutrophilic lung inflammation is an essential component of host defense against diverse eukaryotic and prokaryotic pathogens, but in chronic inflammatory lung diseases, such as chronic obstructive lung disease (COPD), severe asthma, cystic fibrosis, and bronchiolitis, it may damage the host. Glucocorticosteroids are widely used in these conditions and in their infectious exacerbations; however, the clinical efficacy of steroids is disputed. In this study, we used a proteomic approach to identify molecules contributing to neutrophilic inflammation induced by transnasal administration of lipopolysaccharide (LPS) that were also resistant to the potent glucocorticosteroid dexamethasone (Dex). We confirmed that Dex was biologically active at both the transcript (suppression of GM-CSF and TNFalpha transcripts) and protein levels (induction of lipocortin) and used 2D-PAGE/MALDI-TOF to generate global expression profiles, identifying six LPS-induced proteins that were Dex resistant. Of these, S100A8, a candidate neutrophil chemotactic factor, was profiled in detail. Steroid refractory S100A8 expression was highly abundant, transcriptionally regulated, secreted into lung lavage fluid and immunohistochemically localized to tissue infiltrating neutrophils. However, in marked contrast to other vascular beds, neutralizing antibodies to S100A8 had only a weak anti-neutrophil recruitment effect and antibodies against the related S100A9 were ineffective. These data highlight the need for extensive in vivo profiling of proteomically identified candidate molecules and demonstrates that S100A8, despite its abundance, resistance to steroids and known chemotactic activity, is unlikely to be an important determinant of LPS-induced neutrophilic lung inflammation in vivo.

Pulse transit time changes observed with different limb positions

Pulse transit time (PTT) is a non-invasive measure of arterial compliance. It can be used to assess instantaneous blood pressure (BP) changes in continual cardiovascular measurement such as during overnight respiratory sleep studies. In these studies, periodic changes in limb position can occur randomly. However, little is known about their possible effects on PTT monitored on the various limbs. The objective of this study was to evaluate PTT differences on all four limbs during two positional changes (lowering and raising of a limb). Ten healthy adults (seven male) with a mean age of 27.0 years were recruited in this study. The results showed that the limb that underwent a positional change had significant (p < 0.05) local PTT differences when compared to its nominal baseline value, whereas PTT changes in the other remaining limbs were insignificant (p > 0.05). The mean PTT value measured from a vertically-raised limb increased by 42.7 ms, while it decreased by 28.1 ms with a half-lowered limb. The PTT differences observed during positional change can be contributed to by the complex interactions between hydrostatic pressure changes, autonomic and local autoregulation experienced in these limbs. Hence the findings herein suggest that PTT is able to reflect local circulatory responses despite changes in the position of other limbs. This can be useful in prolonged clinical observations where limb movements are expected.

Recombinant human activated protein C improves pulmonary function in ovine acute lung injury resulting from smoke inhalation and sepsis

Objective: To investigate the effects of recombinant human activated protein C (rhAPC) on pulmonary function in acute lung injury (ALI) resulting from smoke inhalation in association with a bacterial challenge. Design: Prospective, randomized, controlled, experimental animal study with repeated measurements. Setting: Investigational intensive care unit at a university hospital. Subjects: Eighteen sheep (37.2 +/- 1.0 kg) were operatively prepared and randomly allocated to either the sham, control, or rhAPC group (n = 6 each). After a tracheotomy had been performed, ALI was produced in the control and rhAPC group by insufflation of 4 sets of 12 breaths of cotton smoke. Then, a 30 mL suspension of live Pseudomonas aeruginosa bacteria (containing 2-5 x 10(11) colony forming units) was instilled into the lungs according to an established protocol. The sham group received only the vehicle, i.e., 4 sets of 12 breaths of room air and instillation of 30 mL normal saline. The sheep were studied in the awake state for 24 hrs and were ventilated with 100% oxygen. RhAPC (24 mu g/kg/hr) was intravenously administered. The infusion was initiated 1 hr post-injury and lasted until the end of the experiment. The animals were resuscitated with Ringer's lactate solution to maintain constant pulmonary artery occlusion pressure. Measurements and Main Results., In comparison with nontreatment in controls, the infusion of rhAPC significantly attenuated the fall in PaO2/FiO(2) ratio (control group values were 521 +/- 22 at baseline [BL], 72 +/- 5 at 12 hrs, and 74 +/- 7 at 24 hrs, vs. rhAPC group values of 541 +/- 12 at BL, 151 +/- 29 at 12 hours [p < .05 vs. control], and 118 +/- 20 at 24 hrs), and significantly reduced the increase in pulmonary microvascular shunt fraction (Qs/Qt; control group at BL, 0.14 +/- 0.02, and at 24 hrs, 0.65 +/- 0.08; rhAPC group at BL, 0.24 +/- 0.04, and at 24 hrs, 0.45 +/- 0.02 [p < .05 vs. control]) and the increase in peak airway pressure (mbar; control group at BL, 20 +/- 1, and at 24 hrs, 36 +/- 4; rhAPC group at BL, 21 +/- 1, and at 24 hrs, 28 +/- 2 [p < .05 vs. control]). In addition, rhAPC limited the increase in lung 3-nitrotyrosine (after 24 hrs [%]: sham, 7 +/- 2; control, 17 +/- 1; rhAPC, 12 +/- 1 [p < .05 vs. control]), a reliable indicator of tissue injury. However, rhAPC failed to prevent lung edema formation. RhAPC-treated sheep showed no difference in activated clotting time or platelet count but exhibited less fibrin degradation products (1/6 animals) than did controls (4/6 animals). Conclusions. Recombinant human activated protein C attenuated ALI after smoke inhalation and bacterial challenge in sheep, without bleeding complications.

Effect of smoke inhalation on viscoelastic properties and ventilation distribution in sheep

Smoke inhalation injuries are the leading cause of mortality from burn injury. Airway obstruction due to mucus plugging and bronchoconstriction can cause severe ventilation inhomogeneity and worsen hypoxia. Studies describing changes of viscoelastic characteristics of the lung after smoke inhalation are missing. We present results of a new smoke inhalation device in sheep and describe pathophysiological changes after smoke exposure. Fifteen female Merino ewes were anesthetized and intubated. Baseline data using electrical impedance tomography and multiple-breath inert-gas washout were obtained by measuring ventilation distribution, functional residual capacity, lung clearance index, dynamic compliance, and stress index. Ten sheep were exposed to standardized cotton smoke insufflations and five sheep to sham smoke insufflations. Measured carboxyhemoglobin before inhalation was 3.87 +/- 0.28% and 5 min after smoke was 61.5 +/- 2.1%, range 50-69.4% ( P < 0.001). Two hours after smoke functional residual capacity decreased from 1,773 +/- 226 to 1,006 +/- 129 ml and lung clearance index increased from 10.4 +/- 0.4 to 14.2 +/- 0.9. Dynamic compliance decreased from 56.6 +/- 5.5 to 32.8 +/- 3.2 ml/ cmH(2)O. Stress index increased from 0.994 +/- 0.009 to 1.081 +/- 0.011 ( P < 0.01) ( all means +/- SE, P < 0.05). Electrical impedance tomography showed a shift of ventilation from the dependent to the independent lung after smoke exposure. No significant change was seen in the sham group. Smoke inhalation caused immediate onset in pulmonary dysfunction and significant ventilation inhomogeneity. The smoke inhalation device as presented may be useful for interventional studies.

The effect of an algorithm-based sedation guideline on the duration of mechanical ventilation in an Australian intensive care unit

To examine the effect of an algorithm-based sedation guideline developed in a North American intensive care unit (ICU) on the duration of mechanical ventilation of patients in an Australian ICU. The intervention was tested in a pre-intervention, post-intervention comparative investigation in a 14-bed adult intensive care unit. Adult mechanically ventilated patients were selected consecutively (n =322) The pre-intervention and post-intervention groups were similar except for a higher number of patients with a neurological diagnosis in the pre-intervention group. An algorithm-based sedation guideline including a sedation scale was introduced using a multifaceted implementation strategy. The median duration of ventilation was 5.6 days in the post-intervention group, compared with 4.8 days for the pre-intervention group (P = 0.99). The length of stay was 8.2 days in the post-intervention group versus 7.1 days in the pre-intervention group (P = 0.04). There were no statistically significant differences for the other secondary outcomes, including the score on the Experience of Treatment in ICU 7 item questionnaire, number of tracheostomies and number of self-extubations. Records of compliance to recording the sedation score during both phases revealed that patients were slightly more deeply sedated when the guideline was used. The use of the algorithm-based sedation guideline did not reduce duration of mechanical ventilation in the setting of this study.

Chronic obstructive pulmonary disease: current burden and future projections

Information about the comparative magnitude of the burden from various diseases and injuries is a critical input into building the evidence base for health policies and programmes. Such information should be based on a critical evaluation of all available epidemiological data using standard and comparable procedures across diseases and injuries, including information on the age at death and the incidence, duration and severity of cases who do not die prematurely from the disease. A summary measure, disability-adjusted life yrs (DALYs), has been developed to simultaneously measure the amount of disease burden due to premature mortality and the amount due to the nonfatal consequences of disease.

Genetic manipulation of blood group carbohydrates alters development and pathfinding of primary sensory axons of the olfactory systems

Primary sensory neurons in the vertebrate olfactory systems are characterised by the differential expression of distinct cell surface carbohydrates. We show here that the histo-blood group H carbohydrate is expressed by primary sensory neurons in both the main and accessory olfactory systems while the blood group A carbohydrate is expressed by a subset of vomeronasal neurons in the developing accessory olfactory system. We have used both loss-of-function and gain-of-function approaches to manipulate expression of these carbohydrates in the olfactory system. In null mutant mice lacking the alpha(1,2)fucosyltransferase FUT1, the absence of blood group H carbohydrate resulted in the delayed maturation of the glomerular layer of the main olfactory bulb. In addition, ubiquitous expression of blood group A on olfactory axons in gain-of-function transgenic mice caused mis-routing of axons in the glomerular layer of the main olfactory bulb and led to exuberant growth of vomeronasal axons in the accessory olfactory bulb. These results provide in vivo evidence for a role of specific cell surface carbohydrates during development of the olfactory nerve pathways. (c) 2006 Elsevier Inc. All rights reserved.

Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects

Background: Inflammatory markers are increased in chronic obstructive pulmonary disease ( COPD) and are hypothesised to play an important part in muscle dysfunction and exercise intolerance. Methods: The Health Aging and Body Composition ( Health ABC) study is a prospective observational cohort of well functioning individuals aged 70 - 79 years. A cross sectional analysis of the baseline data was conducted to examine the association between inflammatory markers and ventilatory limitation, muscle strength, and exercise capacity. These associations were compared in participants with and without obstructive lung disease ( OLD). Results: Of the 3075 participants enrolled in the Health ABC cohort, OLD was identified by spirometric testing in 268 participants and 2005 participants had normal spirometric results. Of the participants with OLD, 35%, 38%, and 27% participants had mild, moderate, and severe OLD, respectively. Participants with OLD had lower quadriceps strength (102.5 Nm v 108.9 Nm, p = 0.02), lower maximum inspiratory pressure (64.7 cm H2O v 74.2 cm H2O, p< 0.0001), higher systemic interleukin (IL)-6 levels (2.6 pg/ml v 2.2 pg/ml, p< 0.0001), and higher C-reactive protein (CRP) levels (3.5 mg/l v 2.5 mg/l, p< 0.0001) than those with normal spirometry. In participants with OLD and those with normal spirometry, forced expiratory volume in 1 second (FEV1) was associated with IL-6 ( adjusted regression coefficients (beta) = -5.3 (95% CI -9.1 to -1.5) and -3.1 (95% CI -4.3 to -1.9), respectively). IL-6 and TNF were also associated with quadriceps strength among participants with OLD and those with normal spirometry (beta = -6.4 (95% CI -12.8 to -0.03) and -3.4 (95% CI -5.4 to -1.3), respectively, for IL-6 and beta = -10.1 (95% CI -18.7 to -1.5) and -3.8 (95% CI -7 to -0.6), respectively, for TNF). IL-6, quadriceps strength, and maximum inspiratory pressures were independent predictors of reduced exercise capacity in both groups. Conclusions: In well functioning elderly subjects with or without OLD, IL-6 is associated with reduced FEV1, quadriceps strength, and exercise capacity.