Quantifying the associations between antibiotic exposure and resistance - a step towards personalised antibiograms.

Empirical antibiotic treatment is selected to target causative bacteria with antibiotics to which they are not resistant. We analysed the increase in bacterial resistance among individual patients associated with antibiotic exposure in the month prior to infection onset, compared to unexposed patients. From a series of prospective cohort studies in the period 2002-2011 at Beilinson Hospital, Israel, 4232 consecutive patients suspected of infection were included. We analysed resistance to antibiotics in bacterial isolates from patients with clinically significant and microbiologically documented infections, starting antibiotics after obtaining cultures (n = 775). In Gram-negative bacteria, significantly higher rates of resistance was associated with exposure to antibiotics, while no significant associations were found for Gram-positive bacteria. Significant odds ratios (ORs) for increased resistance to classes of antibiotics ranged from 2.1 to 3.3 in Gram-negative bacteria from patients exposed to any antibiotic(s), with quinolones having the highest OR, followed by aminoglycosides, penicillins with ß-lactamase inhibitor and cephalosporins. The majority of significant associations also had significant ORs after exposure to another class of antibiotics, indicating a substantial effect of cross-resistance. In conclusion, increased resistance was observed following exposure to antibiotics, both from the same class and from other classes. The results indicate a reason to adjust the expected coverage of empirical antibiotic treatments for patients recently exposed to antibiotics, with some antibiotics being more affected than others.

A model of perfusion of the healthy human lung.

This study presents a model that simulates the pulmonary capillary perfusion. The model describes the lungs as divided into horizontal layers and includes: capillary geometry; capillary wall elasticity; pressure at the pulmonary artery; blood viscosity; the effect of the chest wall; the change in lung height and hydrostatic effects of the lung tissue and of the blood during breathing. The model simulates pulsatile blood perfusion with an increasing blood distribution down the lungs, in agreement with previous experimental studies. Moreover the model is in agreement with experimentally measured total capillary perfusion, total capillary volume, total capillary surface area and transition time of red blood cells passing through the pulmonary capillary network. The presented model is the first to be validated against the mentioned experimental data and to model the link between airway pressure, lung volume and perfusion.

A model of ventilation of the healthy human lung.

This paper presents a model of the lung mechanics which simulates the pulmonary alveolar ventilation. The model includes aspects of: the alveolar geometry; pressure due to the chest wall; pressure due to surface tension determined by surfactant activity; pressure due to lung tissue elasticity; and pressure due to the hydrostatic effects of the lung tissue and blood. The cross-sectional area of the lungs in the supine position derived from computed tomography is used to construct a horizontally layered model, which simulates heterogeneous ventilation distribution from the non-dependent to the dependent layers of the lungs. The model is in agreement with experimentally measured hysteresis of the pressure-volume curve of the lungs, static lung compliance, changes in lung depth during breathing and density distributions at total lung capacity (TLC) and residual volume (RV). In the dependent layers of the lungs, alveolar collapse may occur at RV, depending on the assumptions concerning lung tissue elasticity at very low alveolar volumes. The model simulations showed that ventilation increased with depth in the lungs, although not as pronounced as observed experimentally. The model simulates alveolar ventilation including all of the mentioned components of the respiratory system and to be validated against all the above mentioned experimental data.

Reproduction of inert gas and oxygenation data: a comparison of the MIGET and a simple model of pulmonary gas exchange.

PURPOSE: The multiple inert gas elimination technique (MIGET) is the reference method for evaluating pulmonary gas exchange. MIGET includes a complex experimental method and mathematical model, and has not been used routinely in clinical practice. A simpler mathematical model has been proposed, and was shown previously to fit inert gas data from oleic acid damage. This paper explores the capability of this simple model to describe more complex damage, and to calculate oxygenation data upon changing the inspired oxygen fraction (FIO(2)), comparing these results with those obtained using MIGET. METHODS: The comparison of oxygenation was done at different ventilator settings and at varying values of FIO(2) in order to mimic the clinical conditions that occur in the intensive care unit. RESULTS: The simple model describes inert gas data from heterogeneous lung damage within measurement noise. Model simulations performed using the MIGET and the simple model are comparable, the MIGET model simulating partial pressure of oxygen (PaO(2)) values on average 0.22 ± 0.59 kPa (± SD) higher than the simple model. Model simulations are also accurate with a difference between model simulated and measured values of PaO(2) of 0.33 ± 1.48 kPa (± SD) for the MIGET model and 0.12 ± 1.33 kPa (± SD) for the simple model. This comparability and accuracy was similar over different ventilator settings. CONCLUSIONS: The simple model provides a description of lung damage and arterial oxygenation which is comparable to the MIGET, calculating PaO(2) with acceptable accuracy and precision over the clinically relevant range of PaO(2), and for different values of FIO(2), positive end-expiratory pressure (PEEP), and inspiratory-to-expiratory ratio (I:E).

Balancing the benefits and costs of antibiotic drugs: the TREAT model.

TREAT is a computerized decision support system aimed at improving empirical antibiotic treatment of inpatients with suspected bacterial infections. It contains a model that balances, for each antibiotic choice (including 'no antibiotics'), expected benefit and expected costs. The main benefit afforded by appropriate, empirical, early antibiotic treatment in moderate to severe infections is a better chance of survival. Each antibiotic drug was consigned three cost components: cost of the drug and administration; cost of side effects; and costs of future resistance. 'No treatment' incurs no costs. The model worked well for decision support. Its analysis showed, yet again, that for moderate to severe infections, a model that does not include costs of resistance to future patients will always return maximum antibiotic treatment. Two major moral decisions are hidden in the model: how to take into account the limited life-expectancy and limited quality of life of old or very sick patients; and how to assign a value for a life-year of a future, unnamed patient vs. the present, individual patient.

Can new pulmonary gas exchange parameters contribute to evaluation of pulmonary congestion in left-sided heart failure?

BACKGROUND: Assessment of pulmonary congestion in left-sided heart failure is necessary for guiding anticongestive therapy. Clinical examination and chest x-ray are semiquantitative methods with poor diagnostic accuracy and reproducibility. OBJECTIVES: To establish reference values, describe reproducibility, and investigate the diagnostic and monitoring properties in relation to pulmonary congestion of new pulmonary gas exchange parameters describing ventilation/perfusion mismatch (variable fraction of ventilation [fA2] or the drop in oxygen pressure from the mixed alveolar air of the two ventilated compartments to the nonshunted end-capillary blood [DeltaPO(2)]) and pulmonary shunt. METHODS: Sixty healthy volunteers and 69 patients requiring an acute chest x-ray in a cardiac care unit were included. The gas exchange parameters were estimated by analyzing standard bedside respiratory and circulatory measurements obtained during short-term exposure to different levels of inspired oxygen. Nine patients were classified as having pulmonary congestion using a reference diagnosis and were followed during 30 days of anticongestive therapy. Diagnostic and monitoring properties were compared with chest x-ray, N-terminal probrain natriuretic peptide (NT-proBNP), spirometry values, arterial oxygen tension, alveolar-arterial oxygen difference and venous admixture. RESULTS: The 95% reference intervals for healthy subjects were narrow (ie, fA2 [0.75 to 0.90], DeltaPO(2) [0.0 kPa to 0.5 kPa] and pulmonary shunt [0.0% to 8.2%]). Reproducibility was relatively good with small within subject coefficients of variation (ie, fA2 [0.05], DeltaPO(2) [0.4 kPa] and pulmonary shunt [2.0%]). fA2, DeltaPO(2) and NT-proBNP had significantly better diagnostic properties, with high sensitivities (100%) but low specificities (30% to 40%). During successful anticongestive therapy, fA2, DeltaPO(2), NT-proBNP and spirometry values showed significant improvements. CONCLUSIONS: The gas exchange parameter for ventilation/perfusion mismatch but not pulmonary shunt can have a possible role in rejecting the diagnosis of pulmonary congestion and in monitoring anticongestive therapy.

Evaluation of a method for converting venous values of acid-base and oxygenation status to arterial values.

OBJECTIVE: This paper evaluates a method in which arterial values of pH, carbon dioxide tension (Pco(2)) and oxygen tension (Po(2)) calculated from venous values and pulse oximetry are compared with simultaneously measured arterial values. METHODS: 103 adult patients from three departments (pulmonary medicine, thoracic intensive care and multidisciplinary intensive care) were studied. The patients belonged to three groups: (1) 31 haemodynamically stable patients with a diagnosis of chronic obstructive lung disease (COLD); (2) 49 haemodynamically stable patients without COLD; and (3) 23 haemodynamically unstable patients without COLD. Arterial and venous (peripheral and, where possible, central and mixed) blood samples were taken simultaneously and anaerobically. Peripheral arterial oxygen saturation was measured with a pulse oximeter. The principle of the method is to simulate the transport of venous blood back through the tissues using the respiratory quotient (adding oxygen and removing carbon dioxide) until simulated arterial oxygenation matches that measured by pulse oximetry. RESULTS: Calculated values of arterial pH and Pco(2) had very small bias and standard deviations regardless of the venous sampling site. In all cases these errors were within those considered acceptable for the performance of laboratory equipment, and well within the limits of error acceptable in clinical practice. In addition, the standard deviation (SD) of calculated values of pH and Pco(2) was similar to the variability between consecutive arterial samples. For peripheral oxygen saturation values < or =96%, the method can calculate Po(2) with an SD of 0.93, which may be useful in clinical practice. Calculations made from peripheral venous blood were significantly more accurate than those from central venous blood. CONCLUSION: Arterial pH and Pco(2) can be calculated precisely from peripheral venous blood in a broad patient population. The method has potential for use as a screening tool in emergency medical departments and in medical and surgical wards to assess a patient's acid-base and oxygenation status prior to sampling arterial blood or to help in the decision to refer the patient to the ICU. In departments where arterial blood gas values are used to monitor patients (eg, pulmonary medicine), the method might reduce the number of arterial samples taken by replacing them with peripheral venous blood samples, thus reducing the need for painful arterial punctures.

Model-based identification of PEEP titrations during different volemic levels.

A cardiovascular system (CVS) model has previously been validated in simulated cardiac and circulatory disease states. It has also been shown to accurately capture all main hemodynamic trends in a porcine model of pulmonary embolism. In this research, a slightly extended CVS model and parameter identification process are presented and validated in a porcine experiment of positive end-expiratory pressure (PEEP) titrations at different volemic levels. The model is extended to more physiologically represent the separation of venous and arterial circulation. Errors for the identified model are within 5% when re-simulated and compared to clinical data. All identified parameter trends match clinically expected changes. This work represents another clinical validation of the underlying fundamental CVS model, and the methods and approach of using them for cardiovascular diagnosis in critical care.

Prediction of hemodynamic changes towards PEEP titrations at different volemic levels using a minimal cardiovascular model.

A cardiovascular system model and parameter identification method have previously been validated for porcine experiments of induced pulmonary embolism and positive end-expiratory pressure (PEEP) titrations, accurately tracking all the main hemodynamic trends. In this research, the model and parameter identification process are further validated by predicting the effect of intervention. An overall population-specific rule linking specific model parameters to increases in PEEP is formulated to predict the hemodynamic effects on arterial pressure, pulmonary artery pressure and stroke volume. Hemodynamic changes are predicted for an increase from 0 to 10 cm H(2)O with median absolute percentage errors less than 7% (systolic pressures) and 13% (stroke volume). For an increase from 10 to 20 cm H(2)O median absolute percentage errors are less than 11% (systolic pressures) and 17% (stroke volume). These results validate the general applicability of such a rule, which is not pig-specific, but holds over for all analyzed pigs. This rule enables physiological simulation and prediction of patient response. Overall, the prediction accuracy achieved represents a further clinical validation of these models, methods and overall approach to cardiovascular diagnosis and therapy guidance.

Relative tachycardia in patients with sepsis: an independent risk factor for mortality.

BACKGROUND: Excess activation of the sympathetic nervous system may be a risk factor for mortality in patients with the systemic inflammatory response syndrome (SIRS) or sepsis. AIM: To examine whether excessive tachycardia, relative to the degree of fever is an independent risk factor for death in patients with SIRS. DESIGN: Prospective observational study. SETTING: Departments of medicine in three university hospitals in Israel, Germany and Italy. METHODS: We collected data for 3382 patients with SIRS, whether community- or hospital-acquired, 91% with sepsis, as part of an ongoing trial. RESULTS: Overall 30-day mortality was 12% (408/3382). The pulse/temperature ratio was significantly higher in patients who died than in survivors: mean +/- SD 2.55 +/- 0.57 vs. 2.40 +/- 0.48 bpm/ degrees C (p < 0.0001). Excessive tachycardia was significantly associated with a mortality in a logistic model accounting for other strong predictors of mortality (OR 1.54, 95%CI 1.10-2.17). Patients with septic shock were the only group for whom this association did not hold. DISCUSSION: Our data are compatible with the hypothesis that some patients with sepsis experience an excess activation of the sympathetic nervous system, leading to a fatal outcome.

The need for macrolides in hospitalised community-acquired pneumonia: propensity analysis.

The present study compared beta-lactam macrolide ("combination") therapy versus beta-lactam alone ("monotherapy") for hospitalised community-acquired pneumonia, using propensity scores to adjust for the differences between patients. A prospective multinational observational study was carried out. Baseline patient and infection characteristics were used to develop a propensity score for combination therapy. Patients were matched by the propensity score (three decimal point precision) and compared with 30-day mortality and hospital stay. The propensity score was used as a covariate in a logistic model for mortality. Patients treated with monotherapy (n = 169) were older (mean+/-sd age 70.6+/-17.3 versus 65.0+/-19.6 yrs), had a higher chronic diseases score and a different clinical presentation compared with patients treated with combination therapy (n = 282). Unadjusted mortality was significantly higher with monotherapy (37 (22%) out of 169 versus 21 (7%) out of 282). Only 27 patients in the monotherapy group could be matched to 27 patients in the combination group using the propensity score. The mortality in these groups was identical, with three (11%) demises each. The multivariable odds ratio for mortality associated with combination therapy, adjusted for the propensity score and the Pneumonia Severity Index, was 0.69 (95% confidence interval 0.32-1.48). The benefit of combination therapy versus monotherapy cannot be reliably assessed in observational studies, since the propensity to prescribe these regimens differs markedly.

Information needs following a diagnosis of oesophageal cancer; self-perceived information needs of patients and family members compared with the perceptions of healthcare professionals: a pilot study.

This pilot study was undertaken to describe patients' and family members' information needs following a diagnosis of oesophageal cancer and healthcare professionals' (HCP) perceptions concerning patients' and family members' information needs. Another aim was to describe patients' and family members' satisfaction with information provided. Data were collected by means of a self-report questionnaire. A total of 15 patients, 16 family members and 34 HCP participated. Patients and family members consider most information to be important. The high rating for information about tests/treatment and self-care means that both patients and family members consider this to be the most important areas of information. Healthcare professionals tend to underestimate both patients' and family members' needs for information. Patients and family members were only partly satisfied with the information received, with patients in general more satisfied with information given compared with family members. Patients' and family members' needs for information following a diagnosis of oesophageal cancer are substantial and have not been adequately met by HCP. A qualitative study might be helpful to complete the description of patients' and family members' needs. If a questionnaire is employed, it ought to be less extensive.

An automated method for measuring static pressure-volume curves of the respiratory system and its application in healthy lungs and after lung damage by oleic acid infusion.

Elastic pressure/volume (PV) curves of the respiratory system have attracted increasing interest, because they may be helpful to optimize ventilator settings in patients undergoing mechanical ventilation. Clinically applicable methods need to be fast, use routinely available equipment, draw the inspiratory and expiratory PV curve limbs, separate the resistive and viscoelastic properties of the respiratory system from the elastic properties, and provide reproducible measurements. This paper presents a computer-controlled method for rapid measurements of static PV curves using a long inflation-deflation with pauses, and its evaluation in six pigs before and after lung damage caused by oleic acid. The method is fast, i.e. 20.5 +/- 1.9 s (mean +/- SD) in healthy lungs and 17.7 +/- 4.1 s in diseased lungs, this including inspiratory and expiratory pauses of 1.1 s duration. In addition the only equipment used was a clinical ventilator and a PC. For healthy and damaged lungs expiratory PV curve limbs were very reproducible and were at higher volume than the inspiratory limbs, indicating hysteresis. For damaged lungs inspiratory PV limbs were reproducible. For healthy lungs the inspiratory limbs were reproducible but only after the first inflation-deflation. It is possible that during the first inflation alveoli are recruited which are not derecruited on deflation, shifting the inspiratory limb of the PV curve. The paused long inflation-deflation technique provides a quick, automated measurement of static PV curves on both inspiratory and expiratory limbs using routinely available equipment in the intensive care unit.

Using physiological models and decision theory for selecting appropriate ventilator settings.

OBJECTIVE: To present a decision support system for optimising mechanical ventilation in patients residing in the intensive care unit. METHODS: Mathematical models of oxygen transport, carbon dioxide transport and lung mechanics are combined with penalty functions describing clinical preference toward the goals and side-effects of mechanical ventilation in a decision theoretic approach. Penalties are quantified for risk of lung barotrauma, acidosis or alkalosis, oxygen toxicity or absorption atelectasis, and hypoxaemia. RESULTS: The system is presented with an example of its use in a post-surgical patient. The mathematical models describe the patient's data, and the system suggests an optimal ventilator strategy in line with clinical practice. CONCLUSIONS: The system illustrates how mathematical models combined with decision theory can aid in the difficult compromises necessary when deciding on ventilator settings.

Reproduction of MIGET retention and excretion data using a simple mathematical model of gas exchange in lung damage caused by oleic acid infusion.

The multiple inert-gas elimination technique (MIGET) is a complex mathematical model and experimental technique for understanding pulmonary gas exchange. Simpler mathematical models have been proposed that have a limited view compared with MIGET but may be applicable for use in clinical practice. This study examined the use of a simple model of gas exchange to describe MIGET retention and excretion data in seven pigs before and following lung damage caused by oleic acid infusion and subsequently at different levels of positive end-expiratory pressure. The simple model was found to give, on average, a good description of MIGET data, as evaluated by a chi(2) test on the weighted residual sum of squares resulting from the model fit (P > 0.2). Values of the simple model's parameters (dead-space volume, shunt, and the fraction of alveolar ventilation going to compartment 2) compared well with the similar MIGET parameters (dead-space volume, shunt, log of the standard deviation of the perfusion, log of the standard deveation of the ventilation), giving values of bias and standard deviation on the differences between dead-space volume and shunt of 0.002 +/- 0.002 liter and 7.3 +/- 2.1% (% of shunt value), respectively. Values of the fraction of alveolar ventilation going to compartment 2 correlated well with log of the standard deviation of the perfusion (r(2) = 0.86) and log of the standard deviation of the ventilation (r(2) = 0.92). These results indicate that this simple model provides a good description of lung pathology following oleic acid infusion. It remains to be seen whether physiologically valid values of the simple model parameters can be obtained from clinical experiments varying inspired oxygen fraction. If so, this may indicate a role for simple models in the clinical interpretation of gas exchange.

Model predictive glycaemic regulation in critical illness using insulin and nutrition input: a pilot study.

Stress-induced hyperglycaemia is prevalent in intensive care, impairing the immune response. Nutritional support regimes with high glucose content further exacerbate the problem. Tight glucose control has been shown to reduce mortality by up to 43% if levels are kept below 6.1 mmol/L. This research develops a control algorithm with insulin and nutritional inputs for targeted glucose control in the critically ill. Ethics approval for this research was granted by the Canterbury Ethics Committee. Proof-of-concept clinical pilot trials were conducted on intubated, insulin-dependent Christchurch ICU patients (n=7) on constant nutritional support. A target 10-15% reduction in glucose level per hour for a desired glucose level of 4-6 mmol/L was set. 43% and 91% of glucose targets were achieved within +/-5 and +/-20%, respectively. The mean error was 8.9% (0.5 mmol/L), with an absolute range [0, 2.9] mmol/L. End glucose levels were 40% lower compared to initial values. All large target errors are attributable to sudden changes in patient physiology at low glucose values, rather than systemic deficiencies. Target errors are consistent with and explainable by published sensor error distributions. The results show that intensive model-based glucose management with nutrition control reduced absolute glucose levels progressively while reducing the severity of glycaemic fluctuation even with significant inter-patient variability and time-varying physiological condition. Trials spanning longer periods of time are in development to verify the short-term pilot studies performed and to test the adaptability of the controller. Clinically, these results indicate potential in clinical use to reduce ICU mortality as well as reduce risk of severe complications.

A method for calculation of arterial acid-base and blood gas status from measurements in the peripheral venous blood.

In non-emergency medical departments such as internal medicine sampling of arterial blood and analysis for acid-base status is not routinely performed. Peripheral venous blood is routinely taken but interpretation of its acid-base status is difficult. This paper presents a method for calculation of arterial acid-base and blood gas status from measurements in peripheral venous blood combined with a pulse oximeter measurement of arterial saturation. The use of the method has been illustrated using the data of three patients with different acid-base, haemodynamic, and metabolic conditions. The sensitivity of the method has been tested for measurement errors including venous blood acid-base and blood gas status and pulse oximetry; errors due to physiological assumptions including the values of RQ and strong acid production at the tissues; and errors due to air bubbles in the blood. Errors due to these effects are relatively insignificant except for errors in calculated arterial PO(2), particularly when SpO(2) is greater than 97%; and errors when the change in base excess across the sampling site due to strong acid production is greater that 1.3 mmol/l.