Implementation of a quality improvement programme to support advance care planning in five hospitals across a health region.

OBJECTIVES: Advance care planning (ACP) can help patients with a terminal illness to prepare for the end of their lives. This report describes a regional service improvement initiative to increase the identification of hospital inpatients at this stage in their illnesses and to increase the number of such patients who are offered the opportunity to start the process of ACP. METHODS: Data were collected prospectively over a 7 month period from four acute hospital trusts and a specialist cancer centre in the South-West London region. Each unit identified a specific patient population who were screened for eligibility to engage in the process of ACP. Data concerning the reasons for eligibility, the suitability for discussion and the various reasons why patients did not complete the process, were recorded. RESULTS: Over a 7 month period 1980 patients were screened and 559 (28.2%) were found to be potentially eligible for an ACP discussion. Of these 227/559 (40.6%) were deemed suitable for a discussion by medical staff. The majority of these patients (195/227; 86%) were offered the opportunity to undergo ACP discussions and 144/195 (73.8%) agreed to begin the process of ACP. CONCLUSIONS: This report shows that a targeted approach can result in increased uptake in the number of patients who engage in ACP. However, systematic identification of potentially eligible patients requires a significant investment of clinical time and resources.

Combined dysfunctions of immune cells predict nosocomial infection in critically ill patients.

BACKGROUND: Nosocomial infection occurs commonly in intensive care units (ICUs). Although critical illness is associated with immune activation, the prevalence of nosocomial infections suggests concomitant immune suppression. This study examined the temporal occurrence of immune dysfunction across three immune cell types, and their relationship with the development of nosocomial infection. METHODS: A prospective observational cohort study was undertaken in a teaching hospital general ICU. Critically ill patients were recruited and underwent serial examination of immune status, namely percentage regulatory T-cells (Tregs), monocyte deactivation (by expression) and neutrophil dysfunction (by CD88 expression). The occurrence of nosocomial infection was determined using pre-defined, objective criteria. RESULTS: Ninety-six patients were recruited, of whom 95 had data available for analysis. Relative to healthy controls, percentage Tregs were elevated 6-10 days after admission, while monocyte HLA-DR and neutrophil CD88 showed broader depression across time points measured. Thirty-three patients (35%) developed nosocomial infection, and patients developing nosocomial infection showed significantly greater immune dysfunction by the measures used. Tregs and neutrophil dysfunction remained significantly predictive of infection in a Cox hazards model correcting for time effects and clinical confounders {hazard ratio (HR) 2.4 [95% confidence interval (CI) 1.1-5.4] and 6.9 (95% CI 1.6-30), respectively, P=0.001}. Cumulative immune dysfunction resulted in a progressive risk of infection, rising from no cases in patients with no dysfunction to 75% of patients with dysfunction of all three cell types (P=0.0004). CONCLUSIONS: Dysfunctions of T-cells, monocytes, and neutrophils predict acquisition of nosocomial infection, and combine additively to stratify risk of nosocomial infection in the critically ill.

Evaluation of the effect of diagnostic methodology on the reported incidence of ventilator-associated pneumonia.

BACKGROUND: The optimal method for diagnosing ventilator-associated pneumonia (VAP) is controversial and its effect on reported incidence uncertain. This study aimed to model the impact of using either endotracheal aspirate or bronchoalveolar lavage on the reported incidence of pneumonia and then to test effects suggested from theoretical modelling in clinical practice. METHODS: A three-part single-centre study was undertaken. First, diagnostic performance of aspirate and lavage were compared using paired samples from 53 patients with suspected VAP. Secondly, infection surveillance data were used to model the potential effect on pneumonia incidence and antibiotic use of using exclusively aspirate or lavage to investigate suspected pneumonia (643 patients; 110 clinically suspected pneumonia episodes). Thirdly, a practice change initiative was undertaken to increase lavage use; pneumonia incidence and antibiotic use were compared for the 12 months before and after the change. RESULTS: Aspirate overdiagnosed VAP compared with lavage (89% vs 21% of clinically suspected cases, p<0.0001). Modelling suggested that changing from exclusive aspirate to lavage diagnosis would decrease reported pneumonia incidence by 76% (95% CI 67% to 87%) and antibiotic use by 30% (95% CI 20% to 42%). After the practice change initiative, lavage use increased from 37% to 58%. Although clinically suspected pneumonia incidence was unchanged, microbiologically confirmed VAP decreased from 18 to 9 cases per 1000 ventilator days (p = 0.001; relative risk reduction 0.61 (95% CI 0.46 to 0.82)), and mean antibiotic use fell from 9.1 to 7.2 antibiotic days (21% decrease, p = 0.08). CONCLUSIONS: Diagnostic technique impacts significantly on reported VAP incidence and potentially on antibiotic use.

Therapeutic hypothermia in comatose patients after out-of-hospital cardiac arrest.

Our intensive care unit has been treating comatose patients, following an out-of-hospital cardiac arrest, with therapeutic hypothermia since 2002. In all, 139 out-of-hospital cardiac arrest patients were admitted in the 4-year period 2002-5. Of these, 27% had a favourable outcome (discharged home or to rehabilitation). Forty-one per cent of patients presenting with ventricular fibrillation (VF) and 7% of non-VF patients had a favourable outcome. No patient with an estimated time from collapse to first attempt at cardiopulmonary resuscitation over 12 min survived to hospital discharge. Twenty-two per cent of patients over 70 years were discharged home, suggesting age was not a barrier to surviving out-of-hospital cardiac arrest. The introduction of a therapeutic hypothermia clinical pathway, at the end of 2003 improved the efficiency of cooling. The percentage of patients cooled to below 34 degrees C within 4 h increased from 15 to 51% and those cooled for more than 12 h increased from 30 to 83%.

Somatic mitochondrial DNA mutations in primary and metastatic ovarian cancer.

OBJECTIVE: To date, most mtDNA mutations in cancer have been identified in the control region (D-loop) containing the major promoters. However, almost all studies used one sample per tumor and there is no clear evidence whether metastatic deposits harbor different mtDNA variants. To establish whether different mtDNA variants can be found in the same cancer but at different sites, we analyzed a series of unilateral and bilateral primary epithelial ovarian cancers as well as paired metastatic tumor deposits. METHODS: We sequenced the D-loop region in 52 different tumor samples of 35 ovarian cancer cases, as well as matched normal tissues. Seventeen of those 35 cases had bilateral ovarian cancer, with a sample from each tumor analyzed. RESULTS: Eighty-six polymorphisms (4 new in ovarian cancer) were detected, and 9 different somatic mtDNA mutations were found in 26% (9 of 35) of ovarian cancer cases; all were homoplasmic in nature. Six of the mutations were novel in ovarian cancer. In 24% (4 of 17) of cases with bilateral ovarian tumors, different mtDNA variants were found between paired tumors, suggesting the presence of different clonal populations of cancer cells. Metastatic tumor deposits showed identical mtDNA variants to those found in at least one of the ovarian tumors in cases with bilateral ovarian cancer. CONCLUSION: Our data demonstrate that multiple tumor samples from the same patient may harbor different mtDNA variants.

One year outcome of intensive care patients with decompensated alcoholic liver disease.

BACKGROUND: We aimed to examine the outcome of patients with decompensated alcoholic liver disease (ALD) admitted to a general intensive care unit (ICU). METHODS: Retrospective observational cohort study of intensive care admissions over a 3 yr period was conducted. The study was set in an ICU in a UK university hospital with a tertiary liver referral unit. One hundred and ten admissions, involving 107 patients, with decompensated ALD were included. Intensive care, hospital, and 6 and 12 months mortality were recorded along with the outcome in diagnostic and organ system support subgroups. Intensive care, hospital, 6 month and 12 month mortality rates were 58, 71, 78 and 81%. RESULTS: Hospital mortality in the sepsis/multiorgan failure group was 88%. Sixty-nine per cent of patients who were ventilated but required no other organ support survived to hospital discharge. However, the requirement for any other organ support, or a raised creatinine (>120 micromol litre(-1)) in the first 24 h, reduced the hospital survival to <15%. In those patients requiring acute renal replacement therapy, the hospital mortality was 94%. CONCLUSION: Decompensated ALD requiring intensive care admission is associated with a high hospital mortality and consideration should be given to the futility of escalating organ support measures, particularly when renal replacement therapy is required.

The early response to major trauma and intramedullary nailing.

The stress response to trauma is the summation of the physiological response to the injury (the 'first hit') and by the response to any on-going physiological disturbance or subsequent trauma surgery (the 'second hit'). Our animal model was developed in order to allow the study of each of these components of the stress response to major trauma. High-energy, comminuted fracture of the long bones and severe soft-tissue injuries in this model resulted in a significant tropotropic (depressor) cardiovascular response, transcardiac embolism of medullary contents and activation of the coagulation system. Subsequent stabilisation of the fractures using intramedullary nails did not significantly exacerbate any of these responses.

The coagulative and cardiorespiratory responses to reamed intramedullary nailing of isolated fractures.

We measured the changes during operation in seven markers of coagulation in a prospective series of 84 patients with fractures of the tibia or femur who were undergoing reamed intramedullary nailing. All patients were also continually monitored using transoesophageal echocardiography to assess marrow embolism. In a subset of 40 patients, intraoperative cardiopulmonary function was monitored, using pulmonary and systemic arterial catheterisation. The procedure produced a significant increase in prothrombin time, activated partial thromboplastin time, the level of prothrombin fragments F1+2 and D-dimers, and a decrease in the fibrinogen level, suggesting activation of both the coagulation and fibrinolytic pathways. There was evidence of both platelet hyper-reactivity and depletion, as estimated by an increase in beta-thromboglobulin levels and a decrease in the platelet count. In the patients who had invasive monitoring there was an incremental increase in mean pulmonary arterial pressure, with the changes being greatest during insertion of the guide-wire and reaming. The change in markers of coagulation, pulmonary artery pressure and arterial oxygen partial pressures correlated with the intraoperative embolic response. Greater changes in these parameters were observed during stabilisation of pathological fractures and in those patients in whom surgery had been delayed for more than 48 hours. Seven patients with pathological fractures developed more severe hypoxic episodes during reaming, which were associated with significantly greater arterial hypoxaemia, a fall in the right ventricular ejection fraction and an increase in the mean pulmonary artery pressure, pulmonary capillary wedge pressure, central venous pressure and the pulmonary vascular resistance index. These changes suggested that the patients had transient intraoperative right heart strain. Eight patients developed significant postoperative respiratory compromise. They all had severe intraoperative embolic responses and, in the three who had invasive monitoring, there was a significantly greater increase in pulmonary artery pressure and alveolar-arterial oxygen gradient, and a fall in the ratio of arterial partial pressure of oxygen to the inspired oxygen concentration. Operative delay, intraoperative paradoxical embolisation and the scores for the severity of the coagulative and embolic responses were predictive of the development of postoperative respiratory complications on univariate logistic regression analysis. On multivariate analysis, however, only the embolic and coagulative scores were significant independent predictors of respiratory complications.

Exposure to passive smoke in a sample of children in North Western Ireland.

Passive smoke causes significant detrimental effects on the health of both children and adults. This study involved distributing a questionnaire to a sample of 265 school children aged between 12 and 17 years in North West Ireland. The aims were to establish the prevalence of passive smoking and to discern whether exposure to passive smoke takes place within or outside the home. Of the 262 valid questionnaires, 188 pupils (72%) classified themselves as non-smokers. Sixty-five pupils (25%) described their mothers as current smokers whilst sixty-one (23%) described their fathers as current smokers. Eighty-five pupils (32%) were exposed to smoke at home and 195 (74%) were exposed to smoke in the wider community, whilst 69 (26%) were exposed to smoke both at home and in the community. Two hundred and eleven pupils (81%) were therefore exposed to passive smoke at some location. Further measures are required to reduce the level of passive smoking. It is important that interventions should restrict smoking in public places in addition to promoting a smoke-free environment in the home.

Goodpasture syndrome: pathophysiology, diagnosis, and management.

Goodpasture syndrome is an autoimmune disease characterized by glomerulonephritis, pulmonary hemorrhage, and autoantibodies to the glomerular and alveolar basement membranes. The cause is unknown, and if untreated, Goodpasture syndrome usually is fatal. Early diagnosis and prompt initiation of therapy can decrease disease progression and increase chances of survival. Treatment modalities remain controversial and vary among practitioners.

A longitudinal study of Sin Nombre virus prevalence in rodents, southeastern Arizona.

We determined the prevalence of Sin Nombre virus antibodies in small mammals in southeastern Arizona. Of 1,234 rodents (from 13 species) captured each month from May through December 1995, only mice in the genus Peromyscus were seropositive. Antibody prevalence was 14.3% in 21 white-footed mice (P. leucopus), 13.3% in 98 brush mice (P. boylii), 0.8% in 118 cactus mice (P. eremicus), and 0% in 2 deer mice (P. maniculatus). Most antibody-positive mice were adult male Peromyscus captured close to one another early in the study. Population dynamics of brush mice suggest a correlation between population size and hantavirus-antibody prevalence.

Analysis of murine gammaherpesvirus-68 transcription during lytic and latent infection.

Murine gammaherpesvirus-68 (MHV-68) is a gamma2-herpesvirus that upon experimental infection of laboratory mice establishes a latent infection in B lymphocytes. To date, no virus-encoded gene products have been reported to be expressed during latent infection. In this study, viral transcription has been analysed in a persistently infected B-cell line and abundant and preferential transcription of open reading frame M3 has been identified. Significantly, in situ hybridization analysis of latently infected mouse spleens with probes corresponding to 20 MHV-68 ORFs demonstrated active transcription of a single ORF, corresponding to M3. The kinetics and pattern of transcription of M3 were compared with that of the virally encoded tRNAs (vtRNAs), previously demonstrated to constitute a marker for latent infection in the spleen. Transcription of vtRNAs in splenic tissue could be first detected at 7 days post-inoculation (p.i.) in scattered cells in periarteriolar lymphoid sheaths (PALS). At 10 days p.i., vtRNA transcription was widespread and localized not only to cells in PALS but also to cells within developing germinal centres and from 21 days p.i. expression was detected exclusively within lymphoid follicles. Transcription of vtRNAs could be detected as late as 70 days p.i. In contrast, the histological localization of M3 transcription, which was first detected at 7 days p.i. in scattered cells in PALS, never changed and transcription could not be detected beyond 21 days p.i. These results suggest that M3 is an ORF that is expressed early during the establishment of latency in vivo.

Effect of dietary manipulation on substrate flux and energy balance in obese women taking the appetite suppressant dexfenfluramine.

BACKGROUND: Studies in lean men show poor regulation of energy (EB) and fat balance (FB) during manipulation of dietary ratios of fat to carbohydrate. High-fat (HF), high-energy diets cause hyperphagia and a positive EB and FB. OBJECTIVE: The protocol was designed to measure substrate flux and EB in obese women taking dexfenfluramine (DF) or placebo (PL) during an HF (50% of energy) or low-fat (25% of energy; LF) diet. We hypothesized that alterations in dietary fat would not be regulated and would lead to a positive EB and FB. DESIGN: The study was double-blind, randomized, and placebo-controlled, with 4 treatments (LF/DF, HF/DF, LF/PL, and HF/PL) and a crossover. Five days of continuous, whole-body calorimetry measurements were made in 6 subjects after 8 d of home DF/PL treatment. Macronutrient balance and EB were measured within the chamber as the cumulative difference between ad libitum intake and oxidation. RESULTS: The HF diet increased energy (HF, 10.50 MJ/d; LF, 8.13 MJ/d; P < 0.0001) and fat intakes (HF, 5.34 MJ/d; LF, 2.06 MJ/d; P < 0.0001), leading to a positive EB (delta = 2.37 MJ/d) and FB (delta = 2.31 MJ/d). DF reduced energy (DF, 8.96 MJ/d; PL, 9.66 MJ/d; P < 0.01) and macronutrient intakes, but did not increase energy expenditure (delta = -0.31 MJ/d; P < 0.01), or 24-h fat oxidation (delta = 0.03 MJ/d; P = 0.46). CONCLUSIONS: EB and FB are poorly regulated with HF, energy-dense diets in obese women, which leads to fat deposition and weight gain.

Dietary manipulation and energy compensation: does the intermittent use of low-fat items in the diet reduce total energy intake in free-feeding lean men?

OBJECTIVE: The effect of two low-fat treatments on ad libitum energy intake (EI) was investigated in five lean men living within a metabolic facility. DESIGN: Diet was controlled over two consecutive periods of 12 d when either, i) all foods eaten or ii) only a single (lunch) meal, was manipulated to increase the fat content from 20, 40 to 60% of energy, and ad libitum EI measured. RESULTS: All foods: EI increased from 8.6 (2.9 s.d.)-14.8 (3.1 s.d.) MJ/d and energy density (ED) from 4.1 (0.8 s.d.)-7.7 (1.6 s.d.) kJ/g as fat content increased from 20-60% (P < 0.0001). There was no decrease in weight of food eaten across diets (P > 0.05) and hence no energy compensation. Lunch meal: EI (20%:13.1 MJ/d, 40%:13.8 MJ/d, 60%:14.8 MJ/d) and ED (6.03 kJ/g, 5.89 kJ/g, 6.41 kJ/g) increased but not significantly across treatments (P > 0.05). There was partial energy compensation on the low-fat 20% diet (due in part to compensatory increase in fat intake), but no compensation for the high-fat 60% diet. CONCLUSIONS: Changes in total dietary fat and ED result in concomitant changes in EI; low fat diets reducing EI. However, the dietary strategy of intermittent use of low- and high-fat items fail to significantly alter ED, and hence EI, in free-feeding lean men. Whilst there is a trend towards reduction in intake, manipulation of the fat content of a single meal may not be sufficient to induce significant long-term weight loss.

Hyaluronic acid enhances peripheral nerve regeneration in vivo.

Hyaluronic acid has been shown to enhance peripheral nerve regeneration in vitro. It has been proposed that, during the fibrin matrix phase of regeneration, hyaluronic acid organizes the extracellular matrix into a hydrated open lattice, thereby facilitating migration of the regenerating axons. Hyaluronic acid solutions and saline control solutions were injected into a nerve guide spanning a transected gap in the sciatic nerve of Sprague-Dawley rats (five in each group). Nerve conduction velocities were measured at 4 weeks by electromyography (EMG) before sacrifice of the animals. These studies demonstrated increased conduction velocities in the hyaluronic acid group compared with control animals (P = 0.006). After the animals were sacrificed, regenerated axon cables were quantified histologically, and axon branching was delineated by retrograde tracer analysis. In addition, the hyaluronic acid group showed an increase in myelinated axon counts at 4 weeks (P= 0.03). An increase in retrograde flow was demonstrated in the hyaluronic acid groups compared with animals receiving saline solution.

Assessment of selective under-reporting of food intake by both obese and non-obese women in a metabolic facility.

OBJECTIVE: To investigate the degree of bias in under-reporting of food intake in obese and non-obese subjects, hypothesising that under-reporting may be selective for either macronutrient content (carbohydrate (CHO), fat, protein, alcohol), specific food types or eating occasions (meals, snacks). DESIGN: Thirty-three women (18 obese, 15 non-obese) were recruited to a long-stay metabolic facility for 24h. Ad libitum food intake was covertly measured throughout the study and a reported food intake completed at the end of 24h. RESULTS: Reported total daily energy intake was significantly lower than measured intake. Whilst meals were accurately reported, energy from snack foods eaten between meals was significantly under-reported. (P< 0.001) Reported total carbohydrate and added sugar intakes were significantly lower than measured, whilst reported protein and fat intakes were not significantly different from measured. Reported alcohol intake was also considerably lower than measured, but high variability prevented significance. CONCLUSIONS: In both obese and non-obese women the major cause of under-reporting, as assessed by covert study design in subjects restricted within a metabolic facility, is the failure to report between-meal snack foods. There is some evidence for increased under-reporting in high CHO, but no evidence of a bias in under-reporting towards high fat or high protein foods.