Biomedical subjects
C S Garrard
Publications and source records attributed to C S Garrard.
TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study.
Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine produced in sepsis. Studies examining the association of individual TNF single nucleotide polymorphisms with sepsis have produced conflicting results. This study investigated whether common polymorphisms of the TNF locus and the two receptor genes, TNFRSF1A and TNFRSF1B, influence circulating levels of encoded proteins, and whether individual polymorphisms or extended haplotypes of these genes are associated with susceptibility, severity of illness or outcome in adult patients with severe sepsis or septic shock. A total of 213 Caucasian patients were recruited from eight intensive care units (ICU) in the UK and Australia. Plasma levels of TNF (P = 0.02), sTNFRSF1A (P = 0.005) and sTNFRSF1B (P = 0.01) were significantly higher in those who died on ICU compared to those who survived. There was a positive correlation between increasing soluble receptor levels and organ dysfunction (increasing SOFA score) (sTNFRSF1A R = 0.51, P < 0.001; sTNFRSF1B R = 0.53, P < 0.001), and in particular with the degree of renal dysfunction. In this study, there were no significant associations between the selected candidate TNF or TNF receptor polymorphisms, or their haplotypes, and susceptibility to sepsis, illness severity or outcome. The influence of polymorphisms of the TNF locus on susceptibility to, and outcome from sepsis remains uncertain.
Local activation of coagulation and inhibition of fibrinolysis in the lung during ventilator associated pneumonia.
BACKGROUND: Fibrin deposition is a hallmark of pneumonia. To determine the kinetics of alterations in local coagulation and fibrinolysis in relation to ventilator associated pneumonia (VAP), a single centre prospective study of serial changes in pulmonary and systemic thrombin generation and fibrinolytic activity was conducted in patients at risk for VAP. METHODS: Non-directed bronchial lavage (NBL) was performed on alternate days in patients expected to require mechanical ventilation for more than 5 days. A total of 28 patients were studied, nine of whom developed VAP. RESULTS: In patients who developed VAP a significant increase in thrombin generation was observed in the airways, as reflected by a rise in the levels of thrombin-antithrombin complexes in NBL fluid accompanied by increases in soluble tissue factor and factor VIIa concentrations. The diagnosis of VAP was preceded by a decrease in fibrinolytic activity in NBL fluid. Indeed, before VAP was diagnosed clinically, plasminogen activator activity levels in NBL fluid gradually declined, which appeared to be caused by a sharp increase in NBL fluid levels of plasminogen activator inhibitor 1. CONCLUSION: VAP is characterised by a shift in the local haemostatic balance to the procoagulant side, which precedes the clinical diagnosis of VAP.
Outcome for cardiothoracic surgical patients requiring multidisciplinary intensive care.
BACKGROUND AND OBJECTIVE: Patients who require multidisciplinary intensive care after cardiac surgery have a poor prognosis. The aim was to investigate factors in the mortality of this group of patients at 6 months. METHODS: A retrospective analysis was made of the 6-month mortality rate in 301 adults who required admission to a multidisciplinary intensive care unit following cardiac surgery from 1991 to 1997. Mortality was correlated with clinical and patient characteristic variables. RESULTS: The intensive care mortality rate was 34% and at 6 months after patients' discharge from intensive care it was 51%. There were positive correlations with death at 6 months for ventricular failure (odds ratio of death 3.4, P = 0.002), sepsis (odds ratio 3.0, P = 0.004) and age over 80 yr (odds ratio of death 9.2, P = 0.034). Patients who had undergone isolated coronary artery graft surgery (odds ratio of death 0.28, P = 0.036) or thoracic surgery (odds ratio of death 0.22, P = 0.042) had better 6-month outcomes. Patients with respiratory or renal failure in the absence of ventricular failure or sepsis had a 6-month mortality rate of 36%; but the lower mortality rate did not achieve statistical significance. CONCLUSIONS: The 6-month mortality rate of 51% in a group of patients requiring multidisciplinary intensive care after cardiac surgery is consistent with previous studies; mortality was particularly high in extreme old age and in patients referred with sepsis or ventricular failure. Those patients with uncomplicated respiratory or renal failure had a better outcome than the group as a whole.
The pulmonary physician in critical care . 12: Acute severe asthma in the intensive care unit.
Most deaths from acute asthma occur outside hospital, but the at-risk patient may be recognised on the basis of prior ICU admission and asthma medication history. Patients who fail to improve significantly in the emergency department should be admitted to an HDU or ICU for observation, monitoring, and treatment. Hypoxia, dehydration, acidosis, and hypokalaemia render the severe acute asthmatic patient vulnerable to cardiac dysrrhythmia and cardiorespiratory arrest. Mechanical ventilation may be required for a small proportion of patients for whom it may be life saving. Aggressive bronchodilator (continuous nebulised beta agonist) and anti-inflammatory therapy must continue throughout the period of mechanical ventilation. Recognised complications of mechanical ventilation include hypotension, barotrauma, and nosocomial pneumonia. Low ventilator respiratory rates, long expiratory times, and small tidal volumes help to prevent hyperinflation. Volatile anaesthetic agents may produce bronchodilation in patients resistant to beta agonists. Fatalities in acute asthmatics admitted to HDU/ICU are rare.
Indices of nitric oxide synthesis and outcome in critically ill patients.
We measured the concentrations of serum nitrates/nitrites and plasma cyclic guanosine monophosphate as markers of nitric oxide synthesis in patients with or without septic shock for 5 days following admission to intensive care. We found that nitrate/nitrite concentrations, when corrected for the effect of renal failure, were significantly higher in patients with septic shock, both on admission and in the final samples drawn. In a logistic regression analysis, the rate of change of nitrate/nitrite concentration was associated with survival to day 28 (falling in survivors). The concentration of cyclic guanosine monophosphate when corrected for the confounding effects of renal function and platelet count, was only associated with the septic shock group on admission.
Human-computer interactions: can computers improve the way doctors work?
As medicine becomes more complex and the knowledge base expands, the integration of computer systems into clinical practice would appear to be an inescapable necessity rather than an option. The issues of security and reliability have largely been solved by industrial and business applications of computer technology. The larger challenge lies in designing convenient, efficient and acceptable interfaces between the clinician and computer for data input and presentation. In the future, decision making algorithms are likely to assist the clinician in diagnosis and management to a degree that should significantly improve clinical effectiveness.
Colorectal surgery comes in from the cold.
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Autonomic control of skin microvessels: assessment by power spectrum of photoplethysmographic waves.
1. Although it is well known that the microvessels of the skin constantly undergo spontaneous variations in volume, the significance of these rhythmic changes remains uncertain. 2. In 10 healthy males and in 15 patients in intensive care, we assessed the origin of the autonomic influences on spontaneous fluctuations in the microcirculation of the skin, obtained by an infra-red photoplethysmographic device; we used spectral analysis techniques to compare these fluctuations (which were recorded simultaneously in two sites) with those of blood pressure, in order to test the presence of autonomic control of any synchronous fluctuations in these different measurements from the cardiovascular system. In order to minimize mechanical fluctuations caused by occasional slow breaths, rather than nervously mediated fluctuations in skin blood flow, respiration was controlled at 15 breaths/min (0.25 Hz). 3. Spontaneous infra-red photoplethysmographic fluctuations were observed in different body areas (left index finger and left ear lobe, right and left index finger), and all were evident at 0.1 Hz, as well as respiration-related components at 0.25 Hz. Active standing increased the power of the 0.1 Hz fluctuations (sympathetic activity) in both blood pressure (from 62.7 +/- 7.1 to 79.2 +/- 3.7 normalized units, P < 0.05) and IRP (finger: from 68.5 +/- 6.4 to 86.9 +/- 3.4 normalized units, P < 0.05; ear: from 59.0 +/- 5.9 to 88.1 +/- 2.0, P < 0.01). There was a high (> 0.5) coherence between the fluctuations obtained in blood pressure, in IRP signals obtained simultaneously at the finger and at the ear, and in R-R interval. This synchronization between the oscillations in all these signals, which were unrelated to the respiratory frequency or to the pulse rate, suggests a common neural, non-local origin. The phase between IRP and blood pressure was positive in the 0.1 Hz region (+1.65 +/- 0.41 radians, i.e. IRP was leading blood pressure, showing that 0.1 Hz fluctuations were not passively transmitted to the skin microvessels from large arteries) and negative in the 0.25 Hz region (-0.74 +/- 0.19 radians, P < 0.01 compared with phase in the 0.1 Hz region, i.e. IRP was lagging behind blood pressure, suggesting possible passive transmission to the skin microvessels of blood pressure fluctuations caused by respiration). Fluctuations at lower frequency were observed in all IRP recordings, suggesting a local origin for these. Intra-arterial and IRP fluctuations were compared in the 15 intensive care patients and gave similar results. 4. The skin microcirculation is thus not only under local control, but also reflects changes in sympathetic activity; the effect of these changes on the skin microcirculation can be easily evaluated by the spectral analysis of the IRP signal obtained simultaneously in multiple areas, in conjunction with the spectra of R-R interval and blood pressure.
Effect of renal function on serum nitrogen oxide concentrations.
Nitric oxide is too short-lived to measure in vivo, but its production can be estimated by measuring its stable oxidation products, nitrites and nitrates, in serum. Renal elimination of these ions has been demonstrated, but the effect of renal function on their concentrations in serum is currently unknown. We evaluated serum and urine nitrates + nitrites as serum nitrogen oxides (sNOx), nitrogen oxide (NOx) clearance, and creatinine clearance in 71 patients on the Intensive Therapy Unit. The correlation between sNOx and plasma creatinine was strong and highly significant (P <0.001). These results suggest that renal function has a significant effect on sNOx concentrations. Studies in which the sNOx concentration is used as an index of nitric oxide production can therefore be interpreted only if renal function has been taken into account.
Autonomic control of the heart and peripheral vessels in human septic shock.
OBJECTIVE: Circulating endotoxin impairs the sympathetic regulation of the cardiovascular system in animals. We studied the changes in the autonomic control of the heart and circulation during septic shock in humans. DESIGN: 12 patients (age 43.0 +/- 6, 17-83 years) were investigated during septic shock (mean duration: 3.5 +/- 0.5 days) and during recovery, fluctuations in R-R interval, invasive arterial pressure (AP) and peripheral arteriolar circulation (PC, photoplethysmography) were evaluated by spectral analysis as a validated noninvasive measure of sympathovagal tone. Apache II score was adopted as the disease severity index. Low frequency components (0.03-0.15 Hz) of the frequency spectra were expressed as relative to the overall variability (LFnu) for each cardiovascular variable. RESULTS: LFnu were low or absent during shock but, in the 10 patients who recovered, increased by the time of discharge (post-shock). R-R LFnu increased from 17 +/- 6 to 47 +/- 9 (p < 0.03), AP LFnu from 6 +/- 3 to 35 +/- 4 (p < 0.02) and PC LFnu from 18 +/- 3 to 66 +/- 4 (p < 0.001). Apache II fell from 23.1 +/- 1, at admission, to 14.8 +/- 1.8 at discharge (p < 0.005). Two patients died showing no LFnu increase. CONCLUSION: Reduced LF components of the variability of cardiovascular signals are characteristic of septic shock, confirming the presence of abnormal autonomic control. Restored sympathetic (LF) modulation seems to be associated with a favourable prognosis.
Effects of propofol and thiopentone, and benzodiazepine premedication on heart rate variability measured by spectral analysis.
We studied the effects of temazepam premedication and induction of anaesthesia with thiopentone or propofol on the heart rate power spectrum in 47 patients undergoing elective minor surgery. Eighteen patients received temazepam 20 mg orally as premedication. There was a significant reduction in high frequency power and total power, and an increase in the ratio of low to high frequency power after induction of anaesthesia with either propofol or thiopentone. Patients who had received temazepam premedication had significantly greater low frequency, high frequency and total power than those who were not premedicated. There was no significant difference between premedicated and unpremedicated patients in the ratio of low to ventilatory frequency power.
The diagnosis of pneumonia in the critically ill.
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Serum nitrates as markers of postoperative morbidity.
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Spectral analysis of heart rate variability in the sepsis syndrome.
Sympathetic and parasympathetic activity was evaluated on 39 occasions in 17 patients with the sepsis syndrome, by measurement of the variation in resting heart rate using frequency spectrum analysis. Heart rate was recorded by electrocardiography and respiratory rate by impedance plethysmography. The sepsis syndrome was established on the basis of established clinical and physiological criteria. Subjects were studied, whenever possible, during the period of sepsis and during recovery. Spectral density of the beat-to-beat heart rate was measured within the low frequency band 0.04 to 0.10 Hz (low frequency power, LFP) modulated by sympathetic and parasympathetic activity, and within a 0.12 Hz band width at the respiratory frequency mode (respiratory frequency power, RFP) modulated by parasympathetic activity. Results were expressed as the total variability (total area beneath the power spectrum), as the spectral components normalized to the total power (LFPn, RFPn) or as the ratio of LFP/RFP. During the sepsis syndrome, total heart rate variability and the sympathetically mediated component, LFPn were significantly lower than during the following recovery phase (ANOVA, p < 0.0001, p < 0.01 respectively). Both APACHE II (Acute Physiological and Chronic Health Evaluation) and TISS (Therapeutic Intervention Scoring System) scores showed an inverse correlation with total heart rate variability, logLFP, LFPn and the LFP/RFP ratio (p < 0.002 to 0.0001). Sympathetically mediated heart rate variability was significantly lower during the sepsis syndrome and was inversely proportional to disease severity.
Microbiological lung surveillance in mechanically ventilated patients, using non-directed bronchial lavage and quantitative culture.
We surveyed bronchial microflora by alternate-day, non-directed bronchial lavage (NBL) in 150 patients requiring mechanical ventilation on an intensive care unit. This simple technique uses a 20 ml non-bronchoscopic lung lavage, then quantitative bacterial culture. NBL bacteriological findings were identical to those obtained by same-day bronchoscopic broncho-alveolar lavage on 16/20 occasions. Using serial NBLs, the bronchial bacterial population was characterized during 65 episodes of pneumonia defined by clinical and retrospective criteria. Mean bacterial colony counts increased significantly during the 2 days preceding the clinical onset of pneumonia, from < or = 10(3) cfu/ml to > or = 10(5) cfu/ml (p < 0.05). In 51 patients showing a clinical response to antibiotic treatment, mean colony counts fell significantly after antibiotic initiation (p < 0.05). By contrast, in 14 patients who showed progressive clinical deterioration or relapse, there was no significant fall in NBL counts, and serial NBLs revealed antibiotic resistance or superinfection. The surveillance data altered clinical management in 42% of patients. Positive NBLs guided the choice of antibiotics, whilst negative NBLs encouraged the withholding of antibiotics, or detection of alternative pathology. We propose routine bacteriological lung surveillance of mechanically ventilated patients using this simple, inexpensive and safe technique.
Spectral analysis of heart rate variability in bronchial asthma.
Sympathetic and parasympathetic activity was evaluated in ten healthy controls, nine asymptomatic, untreated asthmatic subjects and ten asthmatic patients during treatment for acute asthma, by measurement of the variation in resting heart rate using frequency spectrum analysis. Heart rate was recorded by ECG and respiratory rate by impedance plethysmography. Spectral density of the beat-to-beat heart rate was measured within the low frequency band 0.04 to 0.10 Hz (low frequency power) modulated by sympathetic and parasympathetic activity, and within a 0.12 Hz band width at the respiratory frequency mode (respiratory frequency power) modulated by parasympathetic activity. Acute asthmatics had higher heart rates than either of the other two groups; this was probably related to the effects of beta-adrenoceptor agonist medication. Sympathetically mediated heart rate variability (normalized low frequency power) was significantly lower in both asymptomatic (p less than 0.002) and acute (p less than 0.02) asthma subjects compared to controls. This is consistent with altered sympathetic/parasympathetic regulation of heart rate in subjects with bronchial asthma.