Inflammation and altered metabolism impede efficacy of functional electrical stimulation in critically ill patients.

BACKGROUND: Critically ill patients suffer from acute muscle wasting, which is associated with significant physical functional impairment. We describe data from nested muscle biopsy studies from two trials of functional electrical stimulation (FES) that did not shown improvements in physical function. METHODS: Primary cohort: single-centre randomized controlled trial. Additional healthy volunteer data from patients undergoing elective hip arthroplasty. Validation cohort: Four-centre randomized controlled trial. INTERVENTION: FES cycling for 60-90min/day. ANALYSES: Skeletal muscle mRNA expression of 223 genes underwent hierarchal clustering for targeted analysis and validation. RESULTS: Positively enriched pathways between healthy volunteers and ICU participants were "stress response", "response to stimuli" and "protein metabolism", in keeping with published data. Positively enriched pathways between admission and day 7 ICU participants were "FOXO-mediated transcription" (admission = 0.48 ± 0.94, day 7 = - 0.47 ± 1.04 mean log2 fold change; P = 0.042), "Fatty acid metabolism" (admission = 0.50 ± 0.67, day 7 = 0.07 ± 1.65 mean log2 fold change; P = 0.042) and "Interleukin-1 processing" (admission = 0.88 ± 0.50, day 7 = 0.97 ± 0.76 mean log2 fold change; P = 0.054). Muscle mRNA expression of UCP3 (P = 0.030) and DGKD (P = 0.040) decreased in both cohorts with no between group differences. Changes in IL-18 were not observed in the validation cohort (P = 0.268). Targeted analyses related to intramuscular mitochondrial substrate oxidation, fatty acid oxidation and intramuscular inflammation showed PPARγ-C1α; (P < 0.001), SLC25A20 (P = 0.017) and UCP3 (P < 0.001) decreased between admission and day 7 in both arms. LPIN-1 (P < 0.001) and SPT1 (P = 0.044) decreased between admission and day 7. IL-18 (P = 0.011) and TNFRSF12A (P = 0.009) increased in both arms between admission and day 7. IL-1ß (P = 0.007), its receptor IL-1R1 (P = 0.005) and IL-6R (P = 0.001) decreased in both arms between admission and day 7. No between group differences were seen in any of these (all p > 0.05). CONCLUSIONS: Intramuscular inflammation and altered substrate utilization are persistent in skeletal muscle during first week of critical illness and are not improved by the application of Functional Electrical Stimulation-assisted exercise. Future trials of exercise to prevent muscle wasting and physical impairment are unlikely to be successful unless these processes are addressed by other means than exercise alone.

Associations between nutritional energy delivery, bioimpedance spectroscopy and functional outcomes in survivors of critical illness.

BACKGROUND: Patients who survive critical illness frequently develop muscle weakness that can impact on quality of life; nutrition is potentially a modifiable risk factor. The present study aimed to explore the associations between cumulative energy deficits (using indirect calorimetry and estimated requirements), nutritional and functional outcomes. METHODS: A prospective single-centre observational study of 60 intensive care unit (ICU) patients, who were mechanically ventilated for at least 48 h, was conducted. Cumulative energy deficit was determined from artificial nutrition delivery compared to targets. Measurements included: (i) at recruitment and ICU discharge, weight, fat-free mass (bioimpedance spectroscopy) and malnutrition (Subjective Global Assessment score B/C); (ii) at awakening and ICU discharge, physical function (Physical Function in Intensive Care Test-scored) and muscle strength (Medical Research Council sum-score (MRC-SS). ICU-acquired weakness was defined as a MRC-SS score of less than 48/60. RESULTS: The median (interquartile range) cumulative energy deficit compared to the estimated targets up to ICU day 12 was 3648 (2514-5650) kcal. Adjusting for body mass index, age and severity of illness, cumulative energy deficit (per 1000 kcal) was independently associated with greater odds of ICU-acquired weakness [odds ratio (OR) = 2.1, 95% confidence interval (CI) = 1.4-3.3, P = 0.001] and malnutrition (OR = 1.9, 95% CI = 1.1-3.2, P = 0.02). In similar multivariable linear models, cumulative energy deficit was associated with reductions in fat-free mass (-1.3 kg; 95% CI = -2.4 to -0.2, P = 0.02) and physical function scores (-0.6 points; 95% CI = -0.9 to -0.3, P = 0.001). CONCLUSIONS: Cumulative energy deficit from artificial nutrition support was associated with reduced functional outcomes and greater loss of fat-free mass in ventilated ICU patients.

Clinical application of the Melbourne risk prediction tool in a high-risk upper abdominal surgical population: an observational cohort study.

OBJECTIVES: (1) To determine the ability of the Melbourne risk prediction tool to predict a pulmonary complication as defined by the Melbourne Group Scale in a medically defined high-risk upper abdominal surgery population during the postoperative period; (2) to identify the incidence of postoperative pulmonary complications; and (3) to examine the risk factors for postoperative pulmonary complications in this high-risk population. DESIGN: Observational cohort study. SETTING: Tertiary Australian referral centre. PARTICIPANTS AND METHODS: 50 individuals who underwent medically defined high-risk upper abdominal surgery. Presence of postoperative pulmonary complications was screened daily for seven days using the Melbourne Group Scale (Version 2). Postoperative pulmonary risk prediction was calculated according to the Melbourne risk prediction tool. OUTCOME MEASURES: (1) Melbourne risk prediction tool; and (2) the incidence of postoperative pulmonary complications. RESULTS: Sixty-six percent (33/50) underwent hepatobiliary or upper gastrointestinal surgery. Mean (SD) anaesthetic duration was 377.8 (165.5) minutes. The risk prediction tool classified 84% (42/50) as high risk. Overall postoperative pulmonary complication incidence was 42% (21/50). The tool was 91% sensitive and 21% specific with a 50% chance of correct classification. CONCLUSION: This is the first study to externally validate the Melbourne risk prediction tool in an independent medically defined high-risk population. There was a higher incidence of pulmonary complications postoperatively observed compared to that previously reported. Results demonstrated poor validity of the tool in a population already defined medically as high risk and when applied postoperatively. This observational study has identified several important points to consider in future trials.

Association of postoperative pulmonary complications with delayed mobilisation following major abdominal surgery: an observational cohort study.

OBJECTIVES: Previous Australian studies reported that postoperative pulmonary complications affect 13% of patients undergoing upper abdominal laparotomy. This study measured the incidence of postoperative pulmonary complications, risk factors for the diagnosis of postoperative pulmonary complications and barriers to physiotherapy mobilisation in a cohort of patients undergoing high-risk abdominal surgery. DESIGN: Prospective, observational cohort study. SETTING: Two surgical wards in a tertiary Australian hospital. PARTICIPANTS: Seventy-two patients undergoing high-risk abdominal surgery (participants in a larger trial evaluating a novel model of medical co-management). MAIN OUTCOME MEASURES: Incidence of, and risk factors for, postoperative pulmonary complications, barriers to mobilisation and length of stay. RESULTS: The incidence of postoperative pulmonary complications was 39%. Incision type and time to mobilise away from the bed were independently associated with a diagnosis of postoperative pulmonary complications. Patients were 3.0 (95% confidence interval 1.2 to 8.0) times more likely to develop a postoperative pulmonary complication for each postoperative day they did not mobilise away from the bed. Fifty-two percent of patients had a barrier to mobilisation away from the bed on the first postoperative day, with the most common barrier being hypotension, although cessation criteria were not defined objectively by physiotherapists. Development of a postoperative pulmonary complication increased median hospital length of stay (16 vs 13 days; P=0.046). CONCLUSIONS: This study demonstrated an association between delayed postoperative mobilisation and postoperative pulmonary complications. Randomised controlled trials are required to test the role of early mobilisation in preventing postoperative pulmonary complications in patients undergoing high-risk upper abdominal surgery.

Exercise intervention to improve exercise capacity and health related quality of life for patients with Non-small cell lung cancer: a systematic review.

CONTEXT: The role of exercise intervention for patients with Non-small cell lung cancer (NSCLC) has not been systematically reviewed to date. OBJECTIVE: To identify, evaluate and synthesize the evidence examining (1) the effect of exercise intervention on exercise capacity, health related quality of life (HRQoL), physical activity levels, cancer symptoms and mortality for patients with NSCLC; and (2) the safety and feasibility of exercise intervention for a population with NSCLC. DATA SOURCES: A systematic review of articles using the electronic databases MEDLINE (1950-2010), CINAHL (1982-2010), EMBASE (1980-2010), TRIP (1997-2010), Science Direct (1994-2010), PubMed (1949-2010), Cochrane Library (2010), Expanded Academic ASAP (1994-2010), Meditext Informit (1995-2010), PEDRO (1999-2010) and DARE (2010). Additional studies were identified by manually cross referencing all full text reports and personal files were searched. No publication date restrictions were imposed. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials (RCTs), case-control studies and case series assessing exercise intervention to improve exercise capacity, HRQoL, level of daily physical activity, cancer symptoms or mortality of patients with NSCLC were included. Only articles available in English and published in a peer reviewed journal were included. DATA EXTRACTION: A data collection form was developed by one reviewer and data extracted. Data extraction was cross checked by a second reviewer. RESULTS AND DATA SYNTHESIS: 16 studies on 13 unique patient groups totalling 675 patients with NSCLC met the inclusion criteria. The majority of studies were case series (n=9) and two RCTs were included. Studies exercising participants pre-operatively reported improvements in exercise capacity but no change in HRQoL immediately post exercise intervention. Studies exercising participants post-treatment (surgery, chemotherapy or radiotherapy) demonstrated improvements in exercise capacity but conflicting results with respect to the impact on HRQoL immediately post exercise intervention. Heterogeneity among studies was observed and a meta-analysis was deemed inappropriate. PRISMA guidelines were followed in reporting this systematic review. CONCLUSION: Exercise intervention for patients with NSCLC is safe before and after cancer treatment. Interventions pre-operatively or post-cancer treatment are associated with positive benefits on exercise capacity, symptoms and some domains of HRQoL. The majority of studies are small case series therefore results should be viewed with caution until larger RCTs are completed. Further research is required to establish the effect of exercise during and after cancer treatment and in the advanced stage of disease, the optimum type of exercise training and the optimum setting for delivery.

A classification and regression tree to assist clinical decision making in airway management for patients with cervical spinal cord injury.

STUDY DESIGN: This was a prospective observational study. OBJECTIVES: To review airway management of patients with acute cervical spinal cord injury (CSCI) who are admitted to the intensive care unit (ICU) and to develop a classification and regression tree (CART) to direct clinical decision making in airway management. SETTING: This study was carried out in Australia. METHODS: All patients with CSCI who required intubation and mechanical ventilation and who were admitted to ICU in three tertiary hospitals in Melbourne between October 2004 and May 2009 and two other interstate hospitals between December 2004 and December 2005 were included. Airway management was recorded. RESULTS: A total of 114 patients were included. Tracheostomy insertion occurred in 68 patients (59.7%). Using CART analysis, it was found that the variables forced vital capacity, the volume of pulmonary secretion and gas exchange were predictive of airway management on 82.3% occasions with an 8.7% extubation failure rate. CONCLUSION: A CART can be useful in clinical decision making regarding airway management in CSCI.

The acute respiratory management of cervical spinal cord injury in the first 6 weeks after injury: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVES: Identify, evaluate, and synthesize evidence regarding the effectiveness of various treatment strategies for the respiratory management of acute tetraplegia. SETTING: Melbourne, Australia. METHODS: A search of multiple electronic databases (Medline, Cinahl, EMBASE, Cochrane Library, Web of Science, http://www.guideline.gov and http://www.icord.org/scire) was undertaken accompanied by the reference lists of all relevant articles identified. Methodological quality was assessed using the Newcastle-Ottawa Scale and the PEDro Scale. Descriptive analysis was performed. RESULTS: Twenty-one studies including 1263 patients were identified. The majority of the studies were case series (n = 13). A variety of interventions were used for the management of respiratory complications. Mortality (ARR = 0.4, 95% confidence interval (CI) 0.18, 0.61), the incidence of respiratory complications (ARR = 0.36, 95% CI (0.08, 0.58)), and requirement for a tracheostomy (ARR = 0.18, 95% CI (-0.05, 0.4)) were significantly reduced by using a respiratory protocol. A clinical pathway reduced duration of mechanical ventilation by 6 days 95% CI (-0.56, 12.56), intensive care unit length of stay by 6.8 days 95% CI (0.17-13.77) and costs. Intubation, mechanical ventilation, and tracheostomy are the mainstay of respiratory management for complete injuries above the level of C5. CONCLUSION: This review showed a clinical pathway with a structured respiratory protocol that includes a combination of treatment techniques provided regularly is effective in reducing respiratory complications and cost. The overall study quality was moderate and further studies using specific interventions that target respiratory complications are associated with specific regions of the cervical spine using more methodologically rigorous designs are required.

CD5 (OKT1) augments CD3-mediated intracellular signaling events in human T lymphocytes.

CD5 is expressed on thymocytes, all mature T cells, and a subset of mature B cells, and probably contributes to T-cell-B-cell adhesion. We assessed whether CD5-crosslinking by mAb augments T-cell stimulation. Plate-bound anti-CD5 or anti-CD3 mAb alone had no effect on any of the assessed activation parameters of resting T cells. However, concomitant signaling through both CD5 and CD3 by plate-bound antibodies resulted in marked increases in T-cell surface CD69 expression and T-cell metabolism, as assessed by the T cell's ability to reduce 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxylmethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS) to formazen. In addition, simultaneous cross-linking of CD5 and CD3 caused a significant (p < 0.001) increase in phosphatidylinositol hydrolysis in resting T cells compared to stimulation with anti-CD3 mAb alone or anti-CD3 mAb plus anti-CD5 isotype control antibody. These results indicate that CD5 augments signaling through CD3 and consequently functions as a costimulatory molecule for resting T cells.

The use of positive pressure devices by physiotherapists.

The aim of this paper is to review the indications for use by physiotherapists, such as physiological rationale and the comparative efficacy of intermittent positive pressure breathing (IPPB) and continuous positive airway pressure (CPAP). A brief discussion of nasal intermittent positive airway pressure is also included. The use of IPPB for post operative prophylaxis has not been supported in the literature. In patients with low lung volumes resulting from neuromuscular disease or spinal injury, IPPB may be useful in the acute phase to improve tidal volume and cough effectiveness. The physiological benefits of CPAP to improve lung volumes are well documented in the literature. Physiotherapists use CPAP as an intermittent application in patients with low lung volumes following surgery. It is predominantly used as a second line intervention in the presence of refractory atelectasis and poor gas exchange. It may also be indicated in other patient groups with similar physiological problems. Nasal intermittent positive airway pressure combines the beneficial effects of intermittent positive pressure breathing and continuous positive airway pressure. There have been many studies evaluating its effectiveness. These have been supportive for patients with neuromuscular disease and sleep disordered breathing, but more research is needed in patients with acute respiratory failure.

CD2 (OKT11) augments CD3-mediated intracellular signaling events in human T lymphocytes.

CD2 (LFA-2) is expressed on thymocytes, natural killer cells, and virtually all peripheral T cells. CD2 binds to its primary ligand CD58 (LFA-3) on antigen presenting cells (APC) and stabilizes the T cell-APC interaction; this stable interaction then optimizes Ag-specific T-cell activation. We assessed whether CD2-cross-linking by mAb augments the process of T-cell stimulation through the TCR/CD3 complex. Plate-bound anti-CD2 or anti-CD3 mAb alone had no measurable effect on any of the assessed activation parameters of resting T cells. However, concomitant signaling through both CD2 and CD3 by plate-bound antibodies resulted in marked increases in CD69 expression on the T-cell surface and T-cell-cellular metabolism, as assessed by the ability of the cell to reduce 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxylmethoxyphenyl)-2-( 4-sulphophenyl)- 2H-tetrazolium (MTS) to formazen. In addition, simultaneous cross-linking of CD2 and CD3 caused a significant (P < 0.001) increase in phosphatidylinositol hydrolysis in resting T cells compared to stimulation with anti-CD3 mAb alone and anti-CD3 mAb plus anti-CD2 isotype control antibody. These results indicate that CD2 augments signaling through CD3, and consequently functions as a costimulatory molecule for resting T cells in the initial activation step.

Increased levels of alternatively spliced interleukin 4 (IL-4delta2) transcripts in peripheral blood mononuclear cells from patients with systemic sclerosis.

Recent in vitro studies have shown that interleukin 4 (IL-4) induces and gamma interferon (IFN-gamma) inhibits collagen production. To define the TH1(IFN-gamma) and TH2(IL-4) cytokine profiles in systemic sclerosis (Sscl), a disease characterized by widespread fibrosis, we investigated IL-4 and IFN-gamma transcripts in peripheral blood mononuclear cells and plasma protein levels in 13 patients with Sscl. Two previously identified IL-4 transcripts, a full-length transcript and an alternatively spliced (truncated) transcript (designated IL-4delta2), were identified in patients and normal controls. Significantly increased levels of total IL-4 transcripts (full-length plus IL-4delta2 transcripts) were found in patients with Sscl in comparison to those found in healthy controls (P = 0.003), and this increase was primarily due to an increase in the level of the alternatively spliced IL-4delta2 form. The IL-4delta2/full-length-IL-4 transcript ratio was significantly increased in Sscl patients (P < 0.0001, versus healthy controls). Sequencing analysis revealed that the frequency of IL-4 clones carrying the IL-4delta2 transcript was also substantially increased in patients with Sscl. Plasma IL-4 protein levels were increased in Sscl patients compared to those in healthy controls (P = 0.001) and correlated with total IL-4 transcript levels. The up-regulation of the fibrogenic IL-4 (a TH2 cytokine) in Sscl suggests a pathogenic role for IL-4 in this disease.

ICAM-3 (CD50) cross-linking augments signaling in CD3-activated peripheral human T lymphocytes.

ICAM-3 is a pan-hematopoietic, constitutive adhesion molecule. ICAM-3 binds to LFA-1 on antigen-presenting cells (APC) stabilizing the T cell-APC interaction, facilitating signaling through the CD3/TCR complex. However, recent evidence using cultured and transformed T cells suggests ICAM-3 may also function in signaling. Because ICAM-3 is constitutively expressed on resting T cells, we postulated that signaling through ICAM-3 in resting T cells represents an important costimulatory mechanism in these cells. In purified resting human T cells, cross-linking both ICAM-3 and CD3 with plate-bound antibodies resulted in a marked increase in cell size (consistent with blastogenesis), synergistically increased surface expression of CD25 and CD69, and increased T cell metabolism. Similarly, concomitant ICAM-3 and CD3 stimulation significantly (P < 0.001) increased resting human T cell phosphatidylinositol hydrolysis and phospholipase C-gamma1 phosphorylation. These results indicate that ICAM-3 augments signaling through CD3, functioning as a costimulatory molecule for resting T cells in the initial activation step.

Activated T-lymphocytes express occludin, a component of tight junctions.

T-lymphocytes routinely traffic from the lymphoid and vascular compartments to the tissues during immune surveillance and inflammatory responses. This egress occurs without compromising endothelial barrier, which is maintained by tight junctions (zonula occludens). We report that T-lymphocytes up-regulate the expression of occludin, a major component of the tight junction in response to stimulation with phorbol ester (PMA) + calcium ionophore, CD3 antibody or T-cell receptor (TCR) antibody. Only activated T-lymphocytes express occludin; this adhesion molecule is nearly absent in resting T-lymphocytes. By immunofluorescence, occludin is seen in lymphocyte aggregates, but does not appear to mediate aggregation since only 50% of the cells in these clusters express occludin. Occludin is expressed between 8 and 24 h following stimulation, and persists for at least 48 h. These data indicate that activated T cells produce occludin which may regulate lymphocyte adhesion and trafficking.

Myosin-reactive autoantibodies in rheumatic carditis and normal fetus.

EBV-transformed B cells from a 20-week human fetal spleen and from blood of patients with poststreptococcal rheumatic carditis were studied. Most antibodies from nine fetal and six patient myosin-reactive B cell clones were multireactive (reacting with cardiac myosin, Streptococcus pyogenes, and rat cardiac myocytes) which supports a role for molecular mimicry in stimulation of these autoantibodies. Sequence analysis revealed that fetal and patient anti-myosin repertoires were composed of unrelated clones with diverse V gene usages. Fetal and patient antibodies had reduced VH CDR3 length on average and reduced light chain N region addition with a low rate of somatic mutation in the variable region genes, characteristics generally associated with fetal B cells but also with some adult B cells. Five of six myosin-reactive patient clones used VH3, whereas only two of nine fetal clones used VH3, suggesting skewing from the average 50-60% VH3 gene usage found in randomly selected adult and fetal antibodies.

Susceptibility locus for IgA deficiency and common variable immunodeficiency in the HLA-DR3, -B8, -A1 haplotypes.

BACKGROUND: A common genetic basis for IgA deficiency (IgAD) and common variable immunodeficiency (CVID) is suggested by their occurrence in members of the same family and the similarity of the underlying B cell differentiation defects. An association between IgAD/CVID and HLA alleles DR3, B8, and A1 has also been documented. In a search for the gene(s) in the major histocompatibility complex (MHC) that predispose to IgAD/CVID, we analyzed the extended MHC haplotypes present in a large family with 8 affected members. MATERIALS AND METHODS: We examined the CVID proband, 72 immediate relatives, and 21 spouses, and determined their serum immunoglobulin concentrations. The MHC haplotype analysis of individual family members employed 21 allelic DNA and protein markers, including seven newly available microsatellite markers. RESULTS: Forty-one (56%) of the 73 relatives by common descent were heterozygous and nine (12%) were homozygous for a fragment or the entire extended MHC haplotype designated haplotype 1 that included HLA- DR3, -C4A-0, -B8, and -A1. The remarkable prevalence of haplotype 1 was due in part to marital introduction into the family of 11 different copies of the haplotype, eight sharing 20 identical genotype markers between HLA-DR3 and HLA-B8, and three that contained fragments of haplotype 1. CONCLUSION: Crossover events within the MHC indicated a susceptibility locus for IgAD/CVID between the class III markers D821/D823 and HLA-B8, a region populated by 21 genes that include tumor necrosis factor alpha and lymphotoxins alpha and beta. Inheritance of at least this fragment of haplotype 1 appears to be necessary for the development of IgAD/CVID in this family.

Phosphatidylinositol hydrolysis in freshly isolated human T lymphocytes.

Antigen receptor-mediated activation of T and B lymphocytes results in activation of phospholipase C-gamma isozymes with subsequent hydrolysis of membrane inositol phospholipids. As a method of screening autoimmune or immunodeficient patients for early receptor signaling defects, we have developed a rapid technique for studying phosphatidylinositol (PI) hydrolysis in cultured cells and fresh clinical specimens resulting from surface receptor crosslinking. Using staphylococcal alpha-toxin, we permeabilized freshly isolated, purified human T lymphocytes to facilitate incorporation of [3H]myoinositol into membrane phospholipids. Aggregation of surface antigen receptors (TCR-CD3 complex and CD28 on T cells) with specific antibodies produced extensive ATP and Mg(2+)-dependent hydrolysis of the membrane inositol phospholipids as measured by release of water soluble inositol phosphates. Anti-human CD3 antibody produced 18.5 +/- 1.6 net % PI hydrolysis and anti-human CD28 antibody produced 4.6 +/- 0.2 net % PI hydrolysis. Simultaneous anti CD3/CD28 crosslinking produced 30.8 +/- 1.2 net % PI hydrolysis, an increase over either stimulus alone (p = 0.0013 two tailed t test). Isotype matched control antibodies produced 11.6 +/- 0.4% PI hydrolysis. The tyrosine phosphatase inhibitor orthovanadate (Na3VO4) was used as a positive control because it induces maximal protein tyrosine kinase-dependent PI hydrolysis in permeabilized cells. Na3VO4 consistently induced hydrolysis of > 50% of the membrane inositol phospholipid pool. These data indicate that costimulation of T cells with antibodies to CD3 and CD28 is synergistic and reinforces the importance of CD28 as an accessory T cell stimulus. This easy technique allows quick evaluation of the integrity of the early signaling cascade in lymphocytes as a screen for autoimmune and immunodeficiency diseases.