A common UCP2 polymorphism predisposes to stress hyperglycaemia in severe sepsis.

BACKGROUND: Insulin resistance and hyperglycaemia are common in severe sepsis. Mitochondrial uncoupling protein 2 (UCP2) plays a role in insulin release and sensitivity. OBJECTIVES: To determine if a common, functional polymorphism in the UCP2 gene promoter region (the -866 G/A polymorphism) contributes to the risk of hyperglycaemia in severe sepsis. RESULTS: In the prospective group 120 non-diabetic patients who were carriers of the G allele had significantly higher maximum blood glucose recordings than non-carriers (mean (SD) AA 8.5 (2.2) mmol/l; GA 8.5 (2.4) mmol/l; GG 10.1 (3.1) mmol/l; p = 0.0042) and required significantly more insulin to maintain target blood glucose (p = 0.0007). In the retrospective study 103 non-diabetic patients showed a similar relationship between maximum glucose and UCP genotype (AA 6.8 (2.3) mmol/l; GA 7.8 (2.2) mmol/l; GG 9.2 (2.9) mmol/l; p = 0.0078). CONCLUSIONS: A common, functional polymorphism in the promoter region of the UCP2 gene is associated with hyperglycaemia and insulin resistance in severe sepsis. This has implications for our understanding of the genetic pathophysiology of sepsis and is of use in the stratification of patients for more intensive management.

The effect of noradrenaline on the ability of rat papillary muscle to resist an acute respiratory acidosis.

We have studied the effect of an increase in extracellular calcium and of noradrenaline on the ability of rat right ventricular papillary muscle in vitro to resist an acute fall in extracellular pH (pHe) produced by a rise in superfusate PCO2. We found a steep linear relationship, slope 0.86(SEM 0.06), r = 0.94, between a plot of logarithmic change in tension against pHe for control muscles (superfusate containing 1.8 mmol.litre-1 calcium). An increase in extracellular calcium (3.6 mmol.litre-1) increased absolute tension but did not alter the slope significantly. Increasing concentrations of noradrenaline (6.3 x 10(-8) to 6.3 x 10(-6) M) progressively reduced the slope of the tension/pHe plot from 0.82(0.05) to 0.35(0.07), p less than 0.001. Noradrenaline improved the ability of rat papillary muscle to resist an acute acidosis by a mechanism independent of changes in calcium concentration.

Effect of amiloride on contractility of rat cardiac muscle exposed to chronic hypercapnia and acute acidosis.

Papillary muscle preparations from rats with normal arterial oxygen and carbon dioxide tensions and from rats which had been maintained with normal oxygen tension but with hypercapnia for 28 days (FICO2 = 5%) were subjected to acute hypercapnia with or without amiloride, a competitive inhibitor of the Na+/H+ pump. Acclimatisation to hypercapnia reduced the slope of the line relating log tension against the extracellular pH from 0.96(SEM0.06) to 0.71(0.07) (p less than 0.02). Amiloride increased the slope in unacclimatised muscle to 1.39(0.09), p less than 0.001 and in muscles acclimatised to hypercapnia to 1.03(0.13), p less than 0.05. The slope in acclimatised muscles was significantly less steep than in unacclimatised muscle (p less than 0.05). The sarcolemmal Na+H+ exchanger is important in the protection of rat cardiac muscle against acute respiratory acidosis.

Expression of chemokine receptors CXCR1 and CXCR2 during cardiopulmonary bypass.

OBJECTIVE: This study investigated the effects of cardiopulmonary bypass on neutrophil expression of chemokine receptors, CXCR1 and CXCR2, and the beta2 integrin CD11b. METHODS: Ten patients undergoing coronary artery grafting with cardiopulmonary bypass were studied. Blood samples were collected preoperatively, before bypass, at termination of bypass, and 12 to 18 hours postoperatively. In vitro studies were performed on control subjects to determine changes in the surface expression of CXCR1, CXCR2, and CD11b on stimulation with interleukin 8. Receptor expression was measured by flow cytometry. Plasma levels of interleukin 8 from the patients were determined by enzyme-linked immunoassay. RESULTS: After bypass, CXCR2 expression fell by 66% (P <.0001) and remained low postoperatively (P <.0001). CXCR1 expression persisted at preoperative levels. CD11b expression increased significantly after bypass (P <.0001), returning to prebypass levels postoperatively. In vitro studies showed a dose-related fall of both CXCR1 (P <.0001) and CXCR2 expression (P <.0001) and a significant rise in CD11b expression (P <.0001). Plasma interleukin 8 increased significantly after bypass (P <.0001), remaining elevated 12 to 18 hours postoperatively (P =.02). Correlations between interleukin 8 levels and CXCR2 expression (P <.0001) and CD11b expression (P <.03) were demonstrated. CONCLUSIONS: CXCR2 expression is significantly down-regulated after bypass; in contrast, CXCR1 expression remains unchanged. In addition, whereas interleukin 8 is an important determinant of both CXCR1 and CXCR2 expression in vitro, it only correlates with CXCR2 and CD11b expression in vivo. This has implications in the search for antagonists against CXC chemokines and their receptors.

Sleep-related breathing disorders following discharge from intensive care.

OBJECTIVES: To determine the incidence of sleep-related breathing disorders and nocturnal hypoxaemia in patients discharged from ICU following prolonged mechanical ventilation. DESIGN: Prospective, consecutive patient observational study. SETTING: The medical and surgical wards of a University Hospital. PATIENTS AND PARTICIPANTS: Fifteen consecutive, adult patients discharged from the ICU who had received more than 48 h of mechanical ventilation were studied. Ten healthy volunteers acted as controls. MEASUREMENTS AND RESULTS: Overnight, multi-channel pneumographic studies were performed on all patients and controls. Chest and abdominal wall movement, air flow, oxygen saturation and snoring were continuously recorded. Data was analysed by both visual inspection of the traces and by computer-based algorithms. An apnoea/hypopnoea index was calculated for each patient and volunteer. Volunteers had an apnoea/hypopnoea index of less than 5 and had no episodes of nocturnal oxygen desaturation (SaO2 < 90%). Despite oxygen therapy 13/15 patients had episodes of desaturation and 9/15 spent more than 2 h with an SaO2 < 90%. Eleven patients had an abnormal apnoea/hypopnoea index (range 5-34 events/h). Four patients had predominantly obstructive events while 7 primarily had hypopnoeas. CONCLUSIONS: Significant overnight oxygen desaturation is common in patients discharged from ICU who have received prolonged mechanical ventilation. This group also has a significant incidence of sleep-related breathing disorders and this mechanism is likely to be important in the pathogenesis of the hypoxaemia.

Continuous veno-venous haemofiltration following cardio-pulmonary bypass. Indications and outcome in 35 patients.

OBJECTIVE: To study the impact of continuous veno-venous haemofiltration on survival in patients with acute renal failure (ARF) following cardio-pulmonary bypass (CPB) surgery. DESIGN: A retrospective study of all patients requiring haemofiltration after CPB over a 2 year period. SETTING: A 20 bedded, adult cardothoracic intensive care unit in a postgraduate teaching hospital. PATIENTS: 35 patients (26 male, age range 24-74 years) required haemofiltration (2.7% of the total number of patients undergoing CPB). MAIN RESULTS: Cardiovascular failure post CPB was the commonest causes of ARF (n = 16). Indications for haemofiltration were uremia (21), oligo-anuria (11), volume overload (2) and hyperkalaemia (1). Mean time from CPB to the initiation of haemofiltration was 8 days (range 0-15 days). Mean urea was 30 mmol/l and creatinine 362 mumol/l immediately prior to treatment. Urea was well-controlled in all patients, although 2 needed haemodiafiltration. Twenty-six patients died during their admission to the ICU (74% mortality). A further 3 patients died during their hospital admission, following discharge from ICU. Outcome was particularly poor in patients with cardiovascular failure following CPB (16 cases, 0 survivors). Survivors tended to commence filtration earlier (mean of 4 vs 7 days for non-survivors) and required treatment for a mean period of 8 days (range 1-26 days). Survival was determined by the number of failed organ systems at the start of haemofiltration. Thus, 100% of patients with single system failure survived, compared to only 10% with 3 or more system failure. CONCLUSIONS: Despite the theoretical advantages of haemofiltration and the effective control of uraemia the mortality associated with ARF following CPB remains high and is probably determined by the number of failed organs systems.

TISS and mortality after discharge from intensive care.

OBJECTIVE: To examine the effect of high levels of pre-intensive care unit (ICU) discharge care, as assessed by the Therapeutic Intervention Scoring System (TISS), on subsequent hospital mortality. DESIGN: A 1-year prospective, observational study. SETTING: The ICU and wards of a university teaching hospital with no high dependency facility (HDU). PATIENTS: A total of 283 patients were discharged to hospital wards between July 1997 and June 1998. ++ RESULTS: 11 % of all ICU discharges subsequently died in hospital. Patients discharged with a TISS of 20 or greater had a 21.4 % mortality compared to 3.7 % for those with a TISS of less than 10. Increasing age, Acute Physiology Score (APS) on admission and male sex were also significantly associated with post-discharge death. CONCLUSIONS: In a hospital without HDU facilities, patients who are receiving HDU levels of care on discharge from the ICU have a high in-hospital mortality.

Liver scintiscanning as a screening test in the detection of alcoholic cirrhosis.

Ninety-nine patients with alcohol related problems underwent a liver scintiscan and biopsy. The scan changes were graded and compared with the histological changes found from percutaneous liver biopsy. The overall correlation between scan and biopsy changes was poor. However, scintiscanning was found to be highly sensitive (90%) in detecting cirrhosis and for this reason is useful as a screening test in selecting alcoholic patients for biopsy.

The prognostic variables predictive of mortality in patients with an exacerbation of COPD admitted to the ICU: an integrative review.

INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) frequently presents with an acute exacerbation (AECOPD). Debate exists as to whether these patients should be admitted to intensive care units (ICUs). An integrative review was performed to determine whether clinical variables available at the time of ICU admission are predictive of the intermediate-term mortality of patients with an AECOPD. METHODS: An integrative review was structured to incorporate a five-stage review framework to facilitate data extraction, analysis and presentation. The quality of the studies contributing to the integrative review was assessed with a novel scoring system developed from previously published data and adapted to this setting. RESULTS: The integrative review search strategy identified 28 studies assessing prognostic variables in this setting. Prognostic variables associated with intermediate-term mortality were low Glasgow Coma Scale (GCS) on admission to ICU, cardio-respiratory arrest prior to ICU admission, cardiac dysrhythmia prior to ICU admission, length of hospital stay prior to ICU admission and higher values of acute physiology scoring systems. Premorbid variables such as age, functional capacity, pulmonary function tests, prior hospital or ICU admissions, body mass index and long-term oxygen therapy were not found to be associated with intermediate-term mortality nor was the diagnosis attributed to the cause of the AECOPD. DISCUSSION: Variables associated with intermediate-term mortality after AECOPD requiring ICU admission are those variables, which reflect underlying severity of acute illness. Premorbid and diagnostic data have not been shown to be predictive of outcome. A scoring system is proposed to assess studies of prognosis in AECOPD.

Large scale mtDNA sequencing reveals sequence and functional conservation as major determinants of homoplasmic mtDNA variant distribution.

The mitochondrial DNA (mtDNA) is highly variable, containing large numbers of pathogenic mutations and neutral polymorphisms. The spectrum of homoplasmic mtDNA variation was characterized in 730 subjects and compared with known pathogenic sites. The frequency and distribution of variants in protein coding genes were inversely correlated with conservation at the amino acid level. Analysis of tRNA secondary structures indicated a preference of variants for the loops and some acceptor stem positions. This comprehensive overview of mtDNA variants distinguishes between regions and positions which are likely not critical, mainly conserved regions with pathogenic mutations and essential regions containing no mutations at all.

Patient flow from critical care to renal services: a year-long survey in a critical care network.

BACKGROUND: The NSF for Renal Services stresses the importance of collaboration between renal services and critical care networks in managing patients with acute renal failure in the most clinically appropriate setting. Anecdotal evidence in our region suggested that some patients were remaining on critical care inappropriately because of a lack of capacity for step-down care in local renal units. AIM: To determine the number of extra days patients spend on critical care receiving single-organ renal support before transfer to a renal unit. DESIGN: Prospective, multi-centre, service evaluation. METHODS: Prospective data were collected over a one-year period by either daily telephone calls or bedside review. Follow-up data were retrieved from electronic and patient records. RESULTS: Five hundred and forty-two patients received renal replacement therapy (RRT) in critical care. With 68 (12.5%) patients already receiving RRT for end-stage renal failure, this gave an incidence of new RRT on critical care of 234 per million population per year. The median duration of RRT on critical care was 4 days (range 1-30). One hundred and twenty-seven patients (23%) were discharged from critical care still requiring RRT. A period of single-organ renal support (median 2 days, range 1-8) was provided to 74 of these patients (58%) using 113 critical care bed days. DISCUSSION: Over half of patients receiving RRT on discharge from critical care in our network received a short period of single-organ renal support before step-down. This may represent either delayed discharge from critical care or a potential opportunity for care in an alternative high-dependency facility.

Weaning units: lessons from North America?

In the United Kingdom over 5% of critical care beds are occupied by stable patients weaning from mechanical ventilation. In North America, diagnosis related groups (DRGs) were introduced over a decade ago. These provided an economic impetus to develop more cost effective regional weaning centres. The imminent introduction of Payment By Results may encourage similar developments in the UK. The evidence for weaning centres is reviewed and detailed organisational and outcome data from two North American centres presented. These units differ from UK critical care units in terms of nurse : patient ratios and types and numbers of ancillary staff. Limited data, mostly from North America, suggest that weaning centres may be better at improving outcome in ventilator-dependent patients compared with standard critical care. The existing evidence is not conclusive and highlights the need for UK-based studies on organisational approaches to the provision of weaning and longer term critical care.

A comparison of CFU-GM, BFU-E and endothelial progenitor cells using ex vivo expansion of selected cord blood CD133(+) and CD34(+) cells.

BACKGROUND: CD133 is a newly developed hematopoietic stem cell marker but little is known about its function. Whether CD133(+) cell selection provides any advantage over CD34(+) selection for hematopoietic stem cell isolation and transplantation is unclear. The present study compared colony formation and endothelial cell differentiation of these two cell types from umbilical cord blood (UCB). METHODS: Mononuclear cells from the same UCB samples were used for both CD133(+) and CD34(+) cell selection. Cells with 97.1% purity were incubated in semi-solid culture medium containing stem cell growth factor (SCGF) and G-CSF or erythropoietin (EPO). Purified cells were also cultured in M199 containing vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and insulin-like growth factor-1 (IGF-1). RESULTS: CD34(+) and CD133(+) cells produced similar numbers of CFU-GM colonies (median 43.25 and 30.5, respectively; P>0.2). However, a greater than four-fold difference in BFU-E colony formation was observed from CD34(+) cells compared with CD133(+) cells (median 35 and 8, respectively; P<0.04). CD34(+) cells gave rise to endothelial-like cells when stimulated with VEGF, bFGF and IGF-1. CD133(+) cells were unable produce this cell type under the same conditions. DISCUSSION: CD133(+) cells produced smaller BFU-E colonies and were unable to differentiate into mature endothelial cells. CD34(+) cells contained endothelial progenitors that could differentiate into mature cells of this lineage. Based on these data, it appears that CD133 offers no distinct advantage over CD34 as a selective marker for immunoaffinity-based isolation of hematopoietic stem cells and endothelial progenitor cells.

The pulmonary physician in critical care . 3: critical care management of community acquired pneumonia.

Severe community acquired pneumonia carries a high mortality. Early recognition of the severity of the illness, rapid and appropriate resuscitation, targeted antibiotic treatment, and the critical care support of multiple failing organ systems are all important in this group of patients. Only by improving all these aspects of care is it likely that survival will increase.

Contractility of papillary muscle from rats exposed to 28 days of hypoxia, hypercapnia, and hypoxia with hypercapnia.

The effects of chronic respiratory failure (hypoxia and hypercapnia) on the contractile properties of cardiac muscle are not established. A study was performed of the isometric contractile properties of isolated papillary muscle removed from rats exposed in a normobaric environmental chamber to 28 days of hypoxia (fractional inspired oxygen (FIO2) 10%, fractional inspired carbon dioxide (FICO2) less than 1%), hypercapnia (FIO2 21%, FICO2 5%), and hypoxia with hypercapnia (FIO2 10%, FICO2 5%). Rats exposed to both hypoxia and hypoxia with hypercapnia developed selective right ventricular hypertrophy. Exposure to hypercapnia alone did not alter right ventricular weight. No change in right ventricular papillary muscle contractility per unit muscle mass was observed as measured by maximum active tension, maximum rate of rise or fall of tension, or time to peak tension. Rat cardiac muscle adapts successfully to the altered acid-base environment and increased work load associated with prolonged exposure to hypoxia and mild hypercapnia.

Blood pressure readings in rural Black South African children--a pointer to future adult hypertension?

The blood pressures of 394 rural Black South African children were recorded and compared with existing records on the blood pressures of Black and White American children. It was found that the blood pressures of these rural Blacks were not significantly different from those of the American Negroes, but that they were higher than those of the White children. If blood pressure readings in the children of a population are a good predictor of future hypertension among the adults of that population, then the rural South African Black population will increasingly suffer from hypertensive disease.

Action of carbon dioxide on hypoxic pulmonary vasoconstriction in the rat lung: evidence against specific endothelium-derived relaxing factor-mediated vasodilation.

OBJECTIVES: The effect of hypercapnia on pulmonary vascular tone is controversial with evidence for both a vasoconstrictor and vasodilator action. The objective of this study was to investigate the possibility that this dual response to CO2 could be explained by a direct constrictor action on smooth muscle and an indirect dilator action via the release of endothelium-derived relaxing factor. The effect of ventilation with hypercapnia (FICO2 0.15) on pulmonary pressor response to hypoxia (FIO2 0.3) was investigated. DESIGN: Prospective, randomized study. SETTING: The National Heart and Lung Institute, UK. SUBJECTS: The isolated, blood-perfused rat lung. INTERVENTIONS: Angiotensin-II and a blocker of endothelium-derived relaxing factor synthesis, NG-monomethyl-L-arginine (L-NMMA). MEASUREMENTS AND MAIN RESULTS: The vasomotor effect of hypercapnia depended on pulmonary arterial pressure. Under resting tone, CO2 acted as a mild constrictor (change in mean pulmonary arterial pressure from 14 +/- 2 to 15 +/- 2 mm Hg, n = 4; p < .05. At increased tone, induced either by hypoxia or Angiotensin-II, CO2 was a vasodilator. Thus, hypoxia increased mean pulmonary arterial pressure from 17 +/- 2 to 32 +/- 2 mm Hg (n = 8; p < .01), but simultaneous ventilation with hypoxia and hypercapnia reduced this by 16 +/- 1% (p < .01). Angiotensin-II (1 microgram) increased pulmonary arterial pressure from 14 +/- 2 to 39 +/- 5 mm Hg (n = 8; p < .01), but with hypercapnia, this angiotensin-induced pulmonary vasoconstriction was reduced by 18 +/- 6% (p < .001). The reduction in hypoxic pulmonary vasoconstriction induced by hypercapnia was not significantly different from that seen with Angiotensin-II hypercapnia. Blocking endothelium-derived relaxing factor synthesis using 30 microM NG-monomethyl-L-arginine did not significantly change either basal pulmonary arterial pressure or the response to hypercapnia, but increased hypoxic pulmonary vasoconstrictor by 24 +/- 4% (n = 4; p < .01). There was no significant difference between the change in hypoxic pulmonary vasoconstriction induced by hypercapnia after saline control (21 +/- 8% decrease) and the change in hypoxic pulmonary vasoconstriction caused by CO2 after 30 microM L-NMMA (25 +/- 10% decrease, p < .05, n = 8). CONCLUSION: Endothelium-derived relaxing factor seems unlikely to specifically modulate CO2-induced vasodilation in the rat pulmonary circulation.