Expression of CD11c and EMR2 on neutrophils: potential diagnostic biomarkers for sepsis and systemic inflammation.

There is a need for cellular biomarkers to differentiate patients with sepsis from those with the non-infectious systemic inflammatory response syndrome (SIRS). In this double-blind study we determined whether the expression of known (CD11a/b/c, CD62L) and putative adhesion molecules [CD64, CD97 and epidermal growth factor (EGF)-like molecule containing mucin-like hormone receptor (EMR2)] on blood neutrophils could serve as useful biomarkers of infection and of non-infectious SIRS in critically ill patients. We studied 103 patients with SIRS, 83 of whom had sepsis, and 50 healthy normal subjects, using flow cytometry to characterize neutrophils phenotypically in whole blood samples. Patients with SIRS had an increased prevalence of neutrophils expressing CD11c, CD64 and EMR2 in comparison with healthy subjects (P < 0.001), but normal expression of CD11a, CD11b, CD62L and CD97. An increase in the percentage of neutrophils bearing CD11c was associated with sepsis, EMR2 with SIRS and CD64 with sepsis and SIRS. Neutrophils expressing CD11c had the highest sensitivity (81%) and specificity (80%) for the detection of sepsis, and there was an association between the percentage of neutrophils expressing EMR2 and the extent of organ failure (P < 0.05). Contrary to other reports, we did not observe an abnormal expression of CD11b or CD62L on neutrophils from patients with SIRS, and suggest that this discrepancy is due to differences in cell processing protocols. We propose that blood neutrophils expressing CD11c and EMR2 be considered as potential biomarkers for sepsis and SIRS, respectively.

Metabolic effects of intensive insulin therapy in critically ill patients.

Our aim was to investigate the effects of glycemic control and insulin concentration on lipolysis, glucose, and protein metabolism in critically ill medical patients. For our methods, the patients were studied twice. In study 1, blood glucose (BG) concentrations were maintained between 7 and 9 mmol/l with intravenous insulin. After study 1, patients entered one of four protocols for 48 h until study 2: low-insulin high-glucose (LIHG; variable insulin, BG of 7-9 mmol/l), low-insulin low-glucose (LILG; variable insulin of BG 4-6 mmol/l), high-insulin high-glucose [HIHG; insulin (2.0 mU . kg(-1).min(-1) plus insulin requirement from study 1), BG of 7-9 mmol/l], or high-insulin low-glucose [HILG; insulin (2.0 mU.kg(-1).min(-1) plus insulin requirement from study 1), BG of 4-6 mmol/l]. Age-matched healthy control subjects received two-step euglycemic hyperinsulinemic clamps achieving insulin levels similar to the LI and HI groups. In our results, whole body proteolysis was higher in patients in study 1 (P < 0.006) compared with control subjects at comparable insulin concentrations and was reduced with LI (P < 0.01) and HI (P = 0.001) in control subjects but not in patients. Endogenous glucose production rate (R(a)), glucose disposal, and lipolysis were not different in all patients in study 1 compared with control subjects at comparable insulin concentrations. Glucose R(a) and lipolysis did not change in any of the study 2 patient groups. HI increased glucose disposal in the patients (HIHG, P = 0.001; HILG, P = 0.07 vs. study 1), but this was less than in controls receiving HI (P < 0.03). In conclusion, low-dose intravenous insulin administered to maintain BG between 7-9 mmol/l is sufficient to limit lipolysis and endogenous glucose R(a) and increase glucose R(d). Neither hyperinsulinemia nor normoglycemia had any protein-sparing effect.

Neutrophils in development of multiple organ failure in sepsis.

Multiple organ failure is a major threat to the survival of patients with sepsis and systemic inflammation. In the UK and in the USA, mortality rates are currently comparable with and projected to exceed those from myocardial infarction. The immune system combats microbial infections but, in severe sepsis, its untoward activity seems to contribute to organ dysfunction. In this Review we propose that an inappropriate activation and positioning of neutrophils within the microvasculature contributes to the pathological manifestations of multiple organ failure. We further suggest that targeting neutrophils and their interactions with blood vessel walls could be a worthwhile therapeutic strategy for sepsis.

Relationship between TISS and ICU cost.

OBJECTIVE: To determine whether the therapeutic intervention scoring system (TISS) reliably reflects the cost of the overall intensive care unit (ICU) population, subgroups of that population and individual ICU patients. DESIGN: Prospective analysis of individual patient costs and comparison with TISS. SETTING: Adult, 12 bedded general medical and surgical ICU in a university teaching hospital. SUBJECTS: Two hundred fifty-seven consecutive patients including 52 coronary care (CCU), 99 cardiac surgery (CS) and 106 general ICU (GIC) cases admitted to the ICU during a 12-week period in 1994. A total of 916 TISS-scored patient days were analysed MAIN OUTCOME MEASURES: A variable cost (VC) that included consumables and service usage (nursing, physiotherapy, radiology and pathology staff costs) for individual patients was measured daily. Nursing costs were calculated in proportion to a daily nursing dependency score. A fixed cost (FC) was calculated for each patient to include medical, technical and clerical salary costs, capital equipment depreciation, equipment and central hospital costs. The correlation between cost and TISS was analysed using regression analysis. RESULTS: For the whole group (n = 257) the average daily FC was pound sterling 255 and daily VC was pound sterling 541 (SEM 10); range pound sterling 23-pound sterling 2,806. In the patient subgroups average daily cost (FC + VC) for CCU was pound sterling 476 (SEM 17.5), for CS pound sterling 766 (SEM 13.8) and for GIC pound sterling 873 (SEM 13.6). In the group as a whole, a strong correlation was demonstrated between VC and the TISS for each patient day (r = 0.87, p < 0.001) and this improved further when the total TISS score was compared with the total VC of the entire patient episode (r = 0.93, p < 0.001). This correlation was maintained in CCU, CS and GIC patient cohorts with only a small median difference between actual and predicted cost (2.2 % for GIC patients). However, in the individual patient, the range of error was up to +/- 65 % of the true variable cost. For the whole group the variable cost per TISS point was pound sterling 25. CONCLUSION: These results demonstrate that TISS reliably measures overall ICU population costs as well as those of the subgroups CCU, CS and GIC. However, the relationship between TISS and cost is less reliable for the individual patient.

Bicarbonate-based haemofiltration in the management of acute renal failure with lactic acidosis.

Continuous haemofiltration with lactate-based replacement fluid is widely used for the treatment of acute renal failure (ARF). In the presence of lactic acidosis, such treatment exacerbates rather than improves the clinical state. Continuous haemofiltration using a locally-prepared bicarbonate-based replacement fluid was performed in 200 patients over 7 years. All the patients had ARF with concomitant lactic acidosis, or demonstrated lactate intolerance after starting haemofiltration with lactate-based replacement fluids. In every case it was possible to correct the acidosis without inducing either extracellular volume expansion or hypernatraemia. In 89 patients (45%), the lactic acidosis resolved while being treated with bicarbonate-based haemofiltration. Fifty-seven patients (28.5%) survived. Significant differences at presentation in the group who survived, compared with those who died, were seen in age (50.8 vs. 57.1), mean arterial pressure (68.5 vs. 60.0 mmHg) and APACHE II score (32.1 vs. 38.9). Neither the severity of the presenting acidosis nor the arterial blood lactate appeared to predict outcome. Patients who developed ARF and lactic acidosis after cardiac surgery had a low survival rate. The combination of ARF and lactic acidosis that cannot safely be treated by haemofiltration using lactate-based replacement fluids can be managed with bicarbonate-based haemofiltration.

Critical illness poly-neuropathy following severe hyperpyrexia.

Two patients developed critical illness polyneuropathy after severe hyperpyrexia. Fever was secondary to a phaeochromocytoma in one patient and sepsis in the other. These observations suggest that high fever may be one possible aetiology of critical illness polyneuropathy.

The relationship between oxygen delivery and consumption.

The primary function of the heart and lungs is to generate a flow of oxygenated blood to respiring tissues to sustain aerobic metabolism. Teleologically, such a transport system has several basic requirements. It should be energy efficient, avoiding unnecessary cardiorespiratory work, but it should be sensitive to the fluctuating demands of cellular metabolism. Ideally, metabolic demand and oxygen distribution should be matched regionally when at rest, during exercise, and in different disease states. Finally, oxygen should pass efficiently across the extravascular tissue matrix. The mechanisms that control oxygen distribution are complex and not completely understood. In the critically ill patient, these mechanisms may have an important role in determining the clinical outcome. The relationship between oxygen delivery and consumption has not been clearly established despite considerable investigation during the last decade. However, these variables are often measured to define a population of critically ill patients in whom oxygen consumption is limited by oxygen delivery, the state of so-called delivery-dependent oxygen consumption or pathologic supply dependency. The recent literature in critical care and many leading intensive care units has emphasized the importance of raising oxygen delivery to "supranormal" levels in an attempt to satisfy the increased metabolic demands of these patients. This practice has been justified by the observation that increasing oxygen delivery improves oxygen debt and outcome in postoperative surgical patients requiring intensive care. In the severely hypovolemic patient, most physicians would agree that volume replacement to improve oxygen delivery must be beneficial. However, in patients with more complex problems, including sepsis, cardiovascular collapse, and hypoxic hypoxemia, controlled trials to examine the influence of such strategies on clinical outcome have produced conflicting data. Several methodologic factors may have contributed to these contradictory and often controversial results. These factors include failure to define the disease and patient population adequately, the relationship between the time of investigation and the evolution of the disease process, and the accuracy and frequency of measurement.(ABSTRACT TRUNCATED AT 400 WORDS)

Outcomes, cost and long term survival of patients referred to a regional weaning centre.

BACKGROUND: Regional weaning centres provide cost effective care for patients who have undergone prolonged mechanical ventilation. There are few published European data on outcomes in these patients. METHODS: Patients admitted for weaning to the Lane Fox Respiratory Unit (LFU) between January 1997 and December 2000 were identified. The proportion weaned from mechanical ventilation, in-hospital mortality, and subsequent survival after discharge were examined. RESULTS: A total of 153 patients had been ventilated for a median of 26 days before transfer. The daily cost per patient stay was 1350. Fifty eight patients (38%) were fully weaned, 42 (27%) died, and 53 (35%) required ventilatory support at discharge from hospital of whom 36 (24%) required only nocturnal ventilation. Univariate analysis showed increasing age (OR 1.06, p<0.001), length of ICU stay (OR 1.02, p = 0.001), APACHE II predicted risk of death score (OR 1.02, p = 0.05), and a surgical cause for admission (OR 4.04) were associated with mortality. Neuromuscular/chest wall conditions were associated with low mortality (OR 0.36) but low likelihood of weaning from ventilation (OR 0.28). Female sex (OR 2.13, p = 0.03) and COPD (OR 2.81) were associated with successful weaning. Overall survival at 3 years from admission was 47%. Long term survival was lowest in patients with COPD. CONCLUSIONS: Most patients survived to leave hospital, the majority having been liberated from ventilatory support. Survivors were younger and spent less time ventilated in the referring ICU. The underlying diagnosis determined success of weaning, hospital survival, and long term outcome.

Clinical aspects of hypoxic pulmonary vasoconstriction.

Although frequently unrecognized, hypoxic pulmonary vascular disease is an important cofactor in the morbidity and mortality of a wide spectrum of disease processes. The hypoxic response incorporates two distinct phases, the acute hypoxic vasoconstrictor response and vascular remodelling associated with prolonged alveolar hypoxia. Understanding of the mechanisms causing both processes has increased rapidly and may result in the near future in specific treatment aimed at correcting underlying physiological abnormalities. However, currently available therapies remain limited to correction of the hypoxaemia and generalized non-specific pulmonary vasodilatation. The recent development of inhaled NO therapy represents a significant advance in the management of the acute hypoxic pulmonary vasoconstriction occurring during critical illness.

The pulmonary physician in critical care * 2: oxygen delivery and consumption in the critically ill.

Early detection and correction of tissue hypoxia is essential if progressive organ dysfunction and death are to be avoided. However, hypoxia in individual tissues or organs caused by disordered regional distribution of oxygen delivery or disruption of the processes of cellular oxygen uptake and utilisation cannot be identified from global measurements. Regional oxygen transport and cellular utilisation have an important role in maintaining tissue function. When tissue hypoxia is recognised, treatment must be aimed at the primary cause. Supplemental oxygen may be life saving in some situations but cannot correct inadequate oxygen delivery caused by a low cardiac output or impaired ventilation. Recent innovations include artificial oxygen carrying proteins and "haemoglobin" molecules designed to improve tissue blood flow by reducing viscosity. Regulating cell metabolism using different substrates or drugs has so far been poorly explored but is an exciting area for further research. A minimum level of global oxygen delivery and perfusion pressure must be maintained in the critically ill patient with established "shock", but advances in the understanding and control of regional distribution and other "downstream" factors in the oxygen cascade are needed to improve outcome in these patients.

Yersinia colitis associated with Crohn's disease.

A previously healthy patient developed serologically-proven Yersinia pseudotuberculosis enterocolitis and made a complete recovery. Over a year later, further gastrointestinal symptoms developed and Crohn's disease was diagnosed. The possible relevance to the aetiology of Crohn's disease is discussed.

A 25-year study of nosocomial bacteremia in an adult intensive care unit.

OBJECTIVE: To identify the organisms, their antibiotic susceptibility, and the associated focus on infection causing nosocomial bacteremia in patients in an adult intensive care unit (ICU) between 1971 and 1995. DESIGN: Prospective observational study. SETTING: A 12-bed general adult ICU in a 1,000-bed tertiary referral teaching hospital. PATIENTS: Four hundred eighty-six episodes of bacteremia involving 570 organisms in 425 patients. MEASUREMENTS AND MAIN RESULTS: Blood cultures taken from patients with suspected nosocomial infection were analyzed. Isolated organisms were identified, and their susceptibility to commonly used antibiotics was determined. Clinical details, including antibiotic treatment, were recorded for all patients. From 1986 to 1995, culture results of samples obtained from other sites were used to help identify the focus of infection causing bacteremia. All results were collected prospectively by clinical microbiologists. Between 1971 and 1990, the number of bacteremias and the relative frequency of isolation of individual organisms changed little, with Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Klebsiella species predominating. During 1991 to 1995, the number of bacteremias increased two-fold, largely attributable to increased isolation of Enterococcus species, coagulase-negative staphylococci, intrinsically antibiotic-resistant gram-negative organisms (particularly P. aeruginosa), and Candida species. The most commonly used antibiotics for the treatment of bacteremic patients throughout the 1970s were amoxicillin and gentamicin. After the introduction of cephalosporins in the early 1980s, their use increased progressively to equal that of gentamicin in the 1990s, whereas amoxicillin use decreased. Since the introduction of cephalosporins, increases in the antibiotic resistance of gram-negative organisms have been largely confined to an outbreak of gentamicin- and ceftazidime-resistant organisms caused by contaminated arterial pressure monitors during 1992 and 1993 and a two-fold increase in ceftazidime resistance of the Pseudomonas species. Gentamicin resistance of gram-negative aerobes remained unchanged (excluding the arterial pressure monitor outbreak), despite gentamicin being one of the most frequently prescribed antibiotics throughout the 25-yr period. Between 1986 and 1995, two thirds of all bacteremic organisms were cultured from intravascular catheters, which were designated as the focus of infection, 7% were secondary to gastrointestinal pathology, but only approximately 3% were secondary to wound, respiratory tract, or urinary tract infections. CONCLUSIONS: Bacteremias have become more frequent in the ICU, probably because of the increased use of intravascular catheters, which are the most frequent foci for bacteremic infection. The spectrum of organisms has changed, and this can be temporally related to the changes in the antibiotics prescribed. Gentamicin resistance of gram-negative organisms has not increased during a 25-yr period, despite being one of the most frequently prescribed antibiotics in the ICU.

Gastrointestinal permeability and absorptive capacity in sepsis.

OBJECTIVE: To assess gastrointestinal permeability and functional absorptive capacity in patients with sepsis. DESIGN: Case control study to analyze gastrointestinal permeability and functional absorptive capacity of septic patients by differential saccharide absorption (from an oral test solution) and excretion. SETTING: The intensive Therapy Unit of St. Thomas' Hospital, London, UK. PATIENTS: Twenty patients with a mean Acute Physiology and Chronic Health Evaluation (APACHE) II score of 18.4 who were admitted to the intensive care unit with a diagnosis of sepsis. All patients were on enteral feeding. Patients with abdominal pathology were excluded. INTERVENTIONS: An oral test solution containing 5 g of lactulose, 1 g of L-rhamnose, 0.5 g of D-xylose, and 0.2 g of 3-O-methyl-D-glucose dissolved in water to a final volume of 100 mL was administered to patients and controls. Urine was collected for 5 hrs starting immediately after administration of the test solution and the saccharide content of the urine was estimated and expressed as a percentage recovery of the oral test solution. MEASUREMENTS AND MAIN RESULTS: Septic patients had increased lactulose/L-rhamnose urine excretion ratios (0.23 +/- 0.19) compared with control subjects (0.03 +/- 0.01, p < .001), consistent with increased gastrointestinal permeability in sepsis. Septic patients had decreased L-rhamnose/3-O-methyl-D-glucose urine excretion ratios (0.14 +/- 0.07) compared with normal controls (0.28 +/- 0.08, p < .001), consistent with decreased gastrointestinal functional absorptive capacity in sepsis. CONCLUSIONS: Patients with acute sepsis exhibit increased gastrointestinal permeability and decreased gastrointestinal functional absorptive capacity in comparison with healthy control subjects. These abnormalities may contribute to the pathophysiology of sepsis.

Irritable bowel syndrome: is a barium enema necessary?

A retrospective analysis was made of 114 new patients attending a gastroenterology clinic, in whom the initial clinical diagnosis was irritable bowel syndrome. Barium enemas were performed in 84 patients (74%), 15 of whom were found to have significant other disease. In each case this would have been suspected from the routine haematological and biochemical screening tests. It is suggested that, in the investigation of patients under 50 years of age presenting to a gastroenterology clinic with a typical history of irritable bowel syndrome, a barium enema should only be performed if the clinical examination, sigmoidoscopy, rectal biopsy or routine blood tests are abnormal. This policy would reduce substantially the number of normal barium enemas performed.