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Biomedical subjects

Mervyn Singer

Publications and source records attributed to Mervyn Singer.

At least 37 records · Page 2Linked to original sources
PubMed2004

Prospective audit of bacteraemia management in a university hospital ICU using a general strategy of short-course monotherapy.

OBJECTIVE: As optimal antibiotic therapy for bacteraemia remains unknown, different strategies have evolved. Routine practice in the University College London Hospitals intensive care unit (ICU) is to use short-course (5-6 days) monotherapy, unless specifically indicated (e.g. endocarditis, osteomyelitis). We decided to assess this approach for treating community-, hospital-, and ICU-acquired bacteraemia by monitoring clinical response, relapse rate and patient outcome. DESIGN: Six-month prospective observational study from February to July 2000. SETTING: Mixed medical-surgical tertiary referral ICU. PATIENTS: All 713 patients admitted to the ICU over the study period. MEASUREMENTS AND RESULTS: In total, 102 bacteraemic episodes occurred in 84 patients. Eight (57%) of 14 community-acquired bacteraemias, 22 (79%) of 28 hospital-acquired bacteraemias, and 48 (80%) of 60 ICU-acquired bacteraemias (in 49 patients) were treated with short-course monotherapy. Compared with previous reported studies, these patients had a low rate (23.8%) of death directly attributable to the bacteraemia and a satisfactory clinical response in 72%. Of six relapses (all Gram-negative), four had received combination therapy for severe deep-seated infections. ICU-acquired multidrug-resistant Gram-negative bacteraemias (6.5%) and fungaemias (3%) were also uncommon. No patient discharged from ICU subsequently developed a new bacteraemia relapse, or any long-term complication such as osteomyelitis. CONCLUSIONS: Our general strategy of short-course antibiotic monotherapy for treating bacteraemia in the critically ill appears to provide a satisfactory clinical response, low relapse rate and no long-term complications in a well-defined group of patients. Multicentre studies are warranted to compare short versus long course therapy, and monotherapy versus combination therapy.

Anti-Bacterial Agents↗
PubMed2004

The validity of trans-esophageal Doppler ultrasonography as a measure of cardiac output in critically ill adults.

OBJECTIVE: To determine the validity of the esophageal Doppler monitor (EDM) and echo-esophageal Doppler (Echo-ED) in measuring cardiac output in the critically ill. DESIGN: Systematic search of relevant international literature and data synthesis. SEARCH STRATEGY: Literature search (1989-2003) using Ovid interface to Medline, Embase and Cochrane databases aimed at finding studies comparing EDM or Echo-ED cardiac output with that derived from simultaneous pulmonary artery thermodilution (PAC(TD)) with Bland Altman measures of validity. PATIENTS: Critically ill adults in operating departments or intensive care units. DATA SYNTHESIS: Summary validity measures synthesized from Bland Altman analyses included pooled median bias and the median percentage of clinical agreement (PCA) derived from the limits of agreement. MAIN RESULTS: Eleven validation papers for EDM (21 studies) involving 314 patients and 2,400 paired measurements. The pooled median bias for PAC(TD) versus EDM was 0.19 l/min (range -0.69 to 2.00 l/min) for cardiac output (16 studies), and 0.6% (range 0-2.3%) for changes in cardiac output (5 studies). The pooled median percentage of clinical agreement for PAC(TD) versus EDM was 52% (interquartile range 42-69%) for cardiac output and 86% (interquartile range 55-93%) for changes in cardiac output. These differences in PCA were significant ( p=0.03 Mann-Whitney) for bolus PAC(TD) as the clinical "gold standard". We found an insufficient number of studies (2 papers) to assess the validity of Echo-ED. CONCLUSIONS: The esophageal Doppler monitor has high validity (no bias and high clinical agreement with pulmonary artery thermodilution) for monitoring changes in cardiac output.

Adult↗
PubMed2004

Randomised controlled trial assessing the impact of a nurse delivered, flow monitored protocol for optimisation of circulatory status after cardiac surgery.

OBJECTIVE: To assess whether a nurse led, flow monitored protocol for optimising circulatory status in patients after cardiac surgery reduces complications and shortens stay in intensive care and hospital. DESIGN: Randomised controlled trial. SETTING: Intensive care unit and cardiothoracic unit of a university teaching hospital. PARTICIPANTS: 174 patients who underwent cardiac surgery between April 2000 and January 2003. INTERVENTIONS: Patients were allocated to conventional haemodynamic management or to an algorithm guided by oesophageal Doppler flowmetry to maintain a stroke index above 35 ml/m2. RESULTS: 26 control patients had postoperative complications (two deaths) compared with 17 (four deaths) protocol patients (P = 0.08). Duration of hospital stay in the protocol group was significantly reduced from a median of nine (interquartile range 7-12) days to seven (7-10) days (P = 0.02). The mean duration of hospital stay was reduced from 13.9 to 11.4 days, a saving in hospital bed days of 18% (95% confidence interval -12% to 47%). Usage of intensive care beds was reduced by 23% (-8% to 59%). CONCLUSION: A nurse delivered protocol for optimising circulatory status in the early postoperative period after cardiac surgery may significantly shorten hospital stay.

Aged↗
PubMed2004

Linezolid versus teicoplanin in the treatment of Gram-positive infections in the critically ill: a randomized, double-blind, multicentre study.

OBJECTIVES: Linezolid, the only commercially available oxazolidinone, is indicated for the treatment of Gram-positive infections, although little has been published specifically on its use in the critically ill. A randomized, prospective study was therefore performed to compare linezolid with the glycopeptide antibiotic, teicoplanin, for the treatment of suspected or proven Gram-positive infections in an intensive care population. METHODS: Using a double-blind, double-dummy, prospective design, patients were randomized to (i) intravenous linezolid (600 mg/12 h) plus teicoplanin dummy [one dose/12 h for three doses then every 24 h intravenously (iv)] or (ii) teicoplanin (400 mg/12 h for three doses then 400 mg/24 h iv) plus linezolid dummy (one dose/12 h iv). Other antibiotics were used in combination with the trial agents in empirical treatment. Clinical and microbiological assessments were made daily in the first week, and at 8 and 21 days after treatment. RESULTS: One hundred patients received linezolid plus placebo-teicoplanin, whereas 102 received teicoplanin plus placebo-linezolid. Population baseline characteristics were similar in both groups. At end of treatment, clinical success [71 (78.9%) linezolid versus 67 (72.8%) teicoplanin] and microbiological success [49 (70.0%) versus 45 (66.2%)] rates were similar, as were adverse effects, intensive care unit mortality, and success rates at short- and long-term follow-up. Linezolid was superior at initial clearance of methicillin-resistant Staphylococcus aureus (MRSA) colonization (end of treatment, 51.1% versus 18.6%, P = 0.002). Two MRSA isolates showed reduced susceptibility to teicoplanin. CONCLUSIONS: Linezolid has similar safety and efficacy to teicoplanin in treating Gram-positive infections in the critically ill. Short-term MRSA clearance achieved with linezolid suggests better skin and mucosal penetration.

Acetamides↗
PubMed2004

Human septic myopathy: induction of cyclooxygenase, heme oxygenase and activation of the ubiquitin proteolytic pathway.

BACKGROUND: Skeletal muscle failure and wasting are manifestations of sepsis in humans that leads to serious and prolonged complications. The authors investigated the role of the major proinflammatory and antiinflammatory pathways, namely the inducible isoforms cyclooxygenase (COX-2) and heme oxygenase (HO-1), and the ubiquitin proteolytic pathway in skeletal muscle of septic patients. METHODS: Protein expression was detected by Western blot techniques. Muscle biopsies were taken from two muscle groups, rectus abdominis and vastus lateralis, of septic and control patients. RESULTS: The study showed an increase in COX-2 and HO-1 proteins expression and an activation of the proteolytic ubiquitin pathway with a parallel increase in free ubiquitin and ubiquitinated proteins in skeletal muscle of septic but not of control patients. In addition, those patients who would die from septic shock expressed more COX-2 and HO-1 proteins in muscle biopsies than did those patients who would survive. CONCLUSIONS: This study showed a marked involvement of local proinflammatory and antiinflammatory pathways and, more importantly, demonstrated the existence of an active ubiquitin proteolytic pathway in skeletal muscle of septic patients. Activation of ubiquitin pathway could be involved in sepsis-related muscle catabolism and wasting.

Adult↗
PubMed2003

Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure.

Although sepsis is the major cause of mortality and morbidity in the critically ill, precise mechanism(s) causing multiorgan dysfunction remain unclear. Findings of impaired oxygen utilization in septic patients and animals implicate nitric oxide-mediated inhibition of the mitochondrial respiratory chain. We recently reported a relationship between skeletal muscle mitochondrial dysfunction, clinical severity, and poor outcome in patients with septic shock. We thus developed a long-term, fluid-resuscitated, fecal peritonitis model utilizing male Wistar rats that closely replicates human physiological, biochemical, and histological findings with a 40% mortality. As with humans, the severity of organ dysfunction and eventual poor outcome were associated with nitric oxide overproduction and increasing mitochondrial dysfunction (complex I inhibition and ATP depletion). This was seen in both vital (liver) and nonvital (skeletal muscle) organs. Likewise, histological evidence of cell death was lacking, suggesting the possibility of an adaptive programmed shutdown of cellular function. This study thus supports the hypothesis that multiorgan dysfunction induced by severe sepsis has a bioenergetic etiology. Despite the well-recognized limitations of laboratory models, we found clear parallels between this long-term model and human disease characteristics that will facilitate future translational research.

Adenosine Monophosphate↗
PubMed2003

Variability of treatment duration for bacteraemia in the critically ill: a multinational survey.

OBJECTIVES: No definitive evidence is available to inform 'best' antibiotic practice for treating bacteraemia in the critically ill patient, either in terms of duration of therapy, or the use of mono- versus combination therapy. We therefore undertook a large-scale international survey to assess the variability of current practice. METHODS: A questionnaire was sent to membership lists of national and international intensive care societies. RESULTS: Responses from 254 intensive care units in 34 countries revealed a wide variation in antibiotic strategy for all types of bacteraemia, ranging from short course ( or=10 days) use of broad-spectrum combinations. Two factors were significantly associated with antibiotic prescribing practice, namely the country of origin (in those with >or=10 responders) and the level of microbiologist and/or infectious diseases specialist input. The greater the specialist input, the shorter the duration of therapy (P < 0.0001). CONCLUSIONS: The wide variability in antibiotic prescribing patterns suggests an urgent need to produce high-quality evidence to identify optimal antibiotic prescribing policies for bacteraemia in the critically ill patient.

Anti-Bacterial Agents↗
PubMed2003

Large variation in MRSA policies, procedures and prevalence in English intensive care units: a questionnaire analysis.

OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) is a major problem in intensive care units in most countries. Despite recommendations for screening and isolation of patients with MRSA our perception has been that there is little uniformity in approach in ICUs besides adherence to basic infection control procedures. We thus sought to identify MRSA prevalence and the variation of infection control policy across intensive care units in England. DESIGN AND SETTING: Postal questionnaire with telephone follow-up in English intensive care units. MEASUREMENTS AND RESULTS: Responses were obtained from 217 (96%) ICUs. Marked variation in practice was noted in terms of patient screening, staff screening, infection control procedures, isolation or cohorting of colonised/infected patients, and ward discharge policy. Point prevalence data showed that 16.2% of ICU patients were known to be colonised or infected with MRSA. There was a regional bias, but no difference was noted between high and low prevalence regions in terms of unit demographics or infection control policies. CONCLUSIONS: This study highlights the lack of consistent policy across English ICUs regarding isolation, screening and discharge practices for MRSA. Prospective studies are urgently needed to determine best practice.

Cross Infection↗
PubMed2003

Inhibition of mitochondrial respiration during early stage sepsis.

It is known that nitric oxide (NO) is produced in response to a septic insult such as bacterial invasion and that overproduction of NO can have serious debilitating consequences. The mechanism by which NO causes damage at the cellular level is less clear. We have therefore studied the response to a septic insult in an anaesthetised spontaneously breathing Sprague-Dawley rat model. Six rats were given either an intravenous infusion of bacterial cell wall lipopolysaccharide (LPS, 5 mg/kg) or saline control over 1 hour. For electron paramagnetic resonance (EPR) studies, blood samples were collected every hour for a further two hours and liver tissue samples were collected postmortem. Measurement was also made of PaO2, blood pressure, base deficit, aortic and renal blood flow and hepatic microvascular pO2 (using porphyrin phosphoresence). Tissue samples were also collected for mitochondrial complex activity analysis. After the administration of LPS blood pressure, blood flow and microvascular PO2 were diminished and the base deficit increased. In addition a clear difference was observed by EPR between control and insulted blood and tissue samples. A large heam-nitrosyl signal is observed as well as an increase in the signal at g = 1.94, corresponding to the iron-sulphur centres of complex I becoming more reduced. However, no significant difference was observed for any of the mitochondrial complex activities. The effect of the NO produced was to depress the circulatory variables and increase base deficit, combined with a reduced oxygen consumption this implies an impairment of normal aerobic respiration. This was supported by increased iron-sulphur signals observed by EPR indicating a blockage in the mitochondrial redox chain with the subsequent accumulation of electrons. As no effect was observed in the mitochondrial complex activities this indicates that this inhibition is reversible in early stage sepsis. We conclude that nitric oxide produced in response to a septic insult can inhibit mitochondria causing an impairment of oxygen utilisation by aerobic respiration.

Animals↗
PubMed2003

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Blood Circulation↗
PubMed2003

Mitochondrial Dysfunction in Sepsis.

Sepsis is an increasingly common problem, particularly among critically ill patients. Mechanisms by which sepsis induces organ dysfunction have not been elucidated. The coexisting findings (unique to sepsis) of metabolic acidosis yet increased tissue oxygen tensions suggest cellular availability but decreased use of oxygen (tissue dysoxia). Because mitochondria use more than 90% of total body oxygen consumption for adenosine triphosphate (ATP) generation, a bioenergetic abnormality is implied. Cell and animal data have shown that nitric oxide (and its metabolites), produced in considerable excess in patients with sepsis, can affect oxidative phosphorylation by inhibiting several of its component respiratory enzymes. Human data are scarce. However, in skeletal muscle biopsies taken from patients with sepsis, we have recently demonstrated a relationship between increased nitric oxide production, antioxidant depletion, reduced respiratory chain complex I activity, and low ATP levels. These findings correlated with severity of disease and outcome and support the notion that mitochondrial dysfunction resulting in bioenergetic failure may be an important factor in the pathophysiology of sepsis-associated multiorgan failure. However, a reasonable argument can be made that the reduction in energy supply could represent a last-ditch adaptive response to ongoing inflammation, resulting in a cellular shutdown analogous to hibernation that allows eventual restoration of organ function and long-term survival in patients fit enough to survive the acute phase.

Journal Article↗
PubMed2003

Esophageal Doppler: noninvasive cardiac output monitor.

In this article we describe the esophageal Doppler, a noninvasive, instantaneous cardiac output monitor. Its reliability has been demonstrated to be comparable to that of other current techniques used in the clinical arena to measure cardiac output. It helps guiding intravascular fluid resuscitation by quantifying the increase in flow in response to fluid challenges and by indicating the plateau of the patient's cardiac function curve. When the plateau has been reached, further fluid loading may result in congestion without improvement in systemic flow. Thus, measuring cardiac output is the only way to determine the upper limit for fluid intake. In addition, a strategy based on cardiac output optimization has proven beneficial in high-risk surgical patients.

Cardiac Output↗
PubMed2003

Angiotensin II blockade augments renal cortical microvascular pO2 indicating a novel, potentially renoprotective action.

BACKGROUND: The existence of tubulointerstitial damage in most cases of progressive human glomerular disease suggests that this compartment of the kidney is likely to be targeted by renoprotective agents which slow the progression of disease. Angiotensin-converting enzyme (ACE) inhibitors have become the cornerstone of renal protection. Since we have proposed that perturbation of the interstitial capillary circulation with consequent chronic hypoxia could be critical to the progressive nature of many renal diseases, we developed a dynamic method of measuring renal cortical pO(2) and sought to determine whether agents which block the renal effects of angiotensin II (AII) could affect interstitial microvascular oxygenation in the normal rat kidney. METHODS: Instrumented, anaesthetised adult male Sprague-Dawley rats were studied. Cortical microvascular pO(2 )was measured on the surface of the exposed kidney using protoporphyrin phosphorescence. Blood pressure and renal artery blood flow (Doppler flowmetry) were measured concurrently over a 180-min experimental period. Animals received non-hypotensive doses of enalaprilat (100 microg/kg i.v.) or candesartan (40 microg/kg i.v.) either at the beginning of the experimental period or after an initial decline in cortical microvascular pO(2). RESULTS: After a 30-min stabilisation period there was a slow decline in pO(2 )from 48.6 +/- 4.1 to 38.5 +/- 6.9 mm Hg in control animals over the 180-min experimental period. Administration of the ACE inhibitor, enalaprilat at the beginning of the experimental period, completely abrogated this decline and protected pO(2) levels throughout this period with no effect on blood pressure or renal blood flow. In separate experiments, administration of enalaprilat after microvascular pO(2) had fallen by 5 mm Hg, resulted in a rise in RBF and pO(2 )within 15 min with pO(2) remaining elevated for up to 60 min post-injection. The angiotensin II AT(1) receptor antagonist, candesartan, had a similar effect to enalaprilat, inducing a rapid and sustained elevation in cortical pO(2). CONCLUSIONS: These studies indicate that blockade of AII raises pO(2 )in the interstitial microvascular compartment of the normal rat kidney. This effect may contribute to the renoprotective action of ACE inhibitors and AII receptor antagonists in slowing the progression of chronic renal diseases.

Angiotensin II↗