Marc Chikhani

Can computer simulators accurately represent the pathophysiology of individual COPD patients

BackgroundComputer simulation models could play a key role in developing novel therapeutic strategies for patients with chronic obstructive pulmonary disease (COPD) if they can be shown to accurately represent the pathophysiological characteristics of individual patients.MethodsWe evaluated the capability of a computational simulator to reproduce the heterogeneous effects of COPD on alveolar mechanics as captured in a number of different patient datasets.ResultsOur results show that accurately representing the pathophysiology of individual COPD patients necessitates the use of simulation models with large numbers (up to 200) of compartments for gas exchange. The tuning of such complex simulation models ‘by hand’ to match patient data is not feasible, and thus we present an automated approach based on the use of global optimization algorithms and high-performance computing. Using this approach, we are able to achieve extremely close matches between the simulator and a range of patient data including PaO2, PaCO2, pulmonary deadspace fraction, pulmonary shunt fraction, and ventilation/perfusion (V̇/Q) curves. Using the simulator, we computed combinations of ventilator settings that optimally manage the trade-off between ensuring adequate gas exchange and minimizing the risk of ventilator-associated lung injury for an individual COPD patient.ConclusionsOur results significantly strengthen the credibility of computer simulation models as research tools for the development of novel management protocols in COPD and other pulmonary disease states.

High PEEP in acute respiratory distress syndrome: quantitative evaluation between improved arterial oxygenation and decreased oxygen delivery

Background. Positive end-expiratory pressure (PEEP) is widely used to improve oxygenation and prevent alveolar collapse in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS). Although PEEP improves arterial oxygenation predictably, high-PEEP strategies have demonstrated equivocal improvements in ARDS-related mortality. The effect of PEEP on tissue oxygen delivery is poorly understood and is difficult to quantify or investigate in the clinical environment. Methods. We investigated the effects of PEEP on tissue oxygen delivery in ARDS using a new, high-fidelity, computational model with highly integrated respiratory and cardiovascular systems. The model was configured to replicate published clinical trial data on the responses of 12 individual ARDS patients to changes in PEEP. These virtual patients were subjected to increasing PEEP levels during a lung-protective ventilation strategy (0–20 cm H2O). Measured variables included arterial oxygenation, cardiac output, peripheral oxygen delivery, and alveolar strain. Results. As PEEP increased, tissue oxygen delivery decreased in all subjects (mean reduction of 25% at 20 cm H2O PEEP), despite an increase in arterial oxygen tension (mean increase 6.7 kPa at 20 cm H2O PEEP). Changes in arterial oxygenation and tissue oxygen delivery differed between subjects but showed a consistent pattern. Static and dynamic alveolar strain decreased in all patients as PEEP increased. Conclusions. Incremental PEEP in ARDS appears to protect alveoli and improve arterial oxygenation, but also appears to impair tissue oxygen delivery significantly because of reduced cardiac output. We propose that this trade-off may explain the poor improvements in mortality associated with high-PEEP ventilation strategies.

Apnoeic oxygenation in pregnancy: a modelling investigation†

Recent studies have shown that nasal oxygen delivery can prolong the time to desaturation during apnoea in the non‐pregnant population. We investigated the benefits of apnoeic oxygenation during rapid sequence induction in the obstetric population using computational modelling. We used the Nottingham Physiology Simulator, and pre‐oxygenated seven models of pregnancy for 3 min using FiO2 1.0, before inducing apnoea. We found that increasing FiO2 at the open glottis increased the time to desaturation, extending the time taken for SaO2 to reach 40% from 4.5 min to 58 min in the average parturient model (not in labour). Our study suggests that a small increase in time to desaturation could be achieved at FiO2 0.4–0.6, which could be delivered by standard nasal cannulae. The greatest increases in time to desaturation were seen at FiO2 1.0, which could be delivered by high‐flow nasal cannulae under ideal conditions.

Development of an integrated model of cardiovascular and pulmonary physiology for the evaluation of mechanical ventilation strategies.

We describe the development of an integrated cardiovascular and pulmonary model for use in the investigation of novel mechanical ventilation strategies in the intensive care unit. The cardiac model includes the cardiac chambers, the pulmonary circulation and the systemic circulation. The modeling of complex mechanisms for vascular segments, time varying elastance functions of cardiovascular components and the effect of vascular resistances, in health and disease under the influence of mechanical ventilation is investigated. The resulting biomedical simulator can aid in understanding the underlying pathophysiology of critically-ill patients and facilitate the development of more effective therapeutic strategies for evaluation in clinical trials.

Creating virtual ARDS patients

This paper presents the methodology used in patient-specific calibration of a novel highly integrated model of the cardiovascular and pulmonary pathophysiology associated with Acute Respiratory Distress Syndrome (ARDS). We focus on data from previously published clinical trials on the static and dynamic cardio-pulmonary responses of three ARDS patients to changes in ventilator settings. From this data, the parameters of the integrated model were identified using an optimization-based methodology in multiple stages. Computational simulations confirm that the resulting model outputs accurately reproduce the available clinical data. Our results open up the possibility of creating in silico a biobank of virtual ARDS patients that could be used to evaluate current, and investigate novel, therapeutic strategies.

Predicting 30-day mortality in patients with sepsis: An exploratory analysis of process of care and patient characteristics:

Background Sepsis represents a significant public health burden, costing the NHS £2.5 billion annually, with 35% mortality in 2006. The aim of this exploratory study was to investigate risk factors predictive of 30-day mortality amongst patients with sepsis in Nottingham. Methods Data were collected prospectively from adult patients with sepsis in Nottingham University Hospitals NHS Trust as part of an on-going quality improvement project between November 2011 and March 2014. Patients admitted to critical care with the diagnosis of sepsis were included in the study. In all, 97 separate variables were investigated for their association with 30-day mortality. Variables included patient demographics, symptoms of systemic inflammatory response syndrome, organ dysfunction or tissue hypoperfusion, locations of early care, source of sepsis and time to interventions. Results A total of 455 patients were included in the study. Increased age (adjOR = 1.05 95%CI = 1.03–1.07 p < 0.001), thrombocytopenia (adjOR = 3.10 95%CI = 1.23–7.82 p = 0.016), hospital-acquired sepsis (adjOR = 3.34 95%CI = 1.78–6.27 p < 0.001), increased lactate concentration (adjOR = 1.16 95%CI = 1.06–1.27 p = 0.001), remaining hypotensive after vasopressors (adjOR = 3.89 95%CI = 1.26–11.95 p = 0.02) and mottling (adjOR = 3.80 95%CI = 1.06–13.55 p = 0.04) increased 30-day mortality odds. Conversely, fever (adjOR = 0.46 95%CI = 0.28-0.75 p = 0.002), fluid refractory hypotension (adjOR = 0.29 95%CI = 0.10–0.87 p = 0.027) and being diagnosed in surgical wards (adjOR = 0.35 95%CI = 0.15–0.81 p = 0.015) were protective. Treatment timeliness were not significant factors. Conclusion Several important predictors of 30-day mortality were found by this research. Retrospective analysis of our sepsis data has revealed mortality predictors that appear to be more patient-related than intervention-specific. With this information, care can be improved for those identified most at risk of death.

Investigating the effect of cardiac oscillations and deadspace gas mixing during apnea using computer simulation

Gaseous mixing in the anatomical deadspace with stimulation of respiratory ventilation through cardiogenic oscillations is an important physiological mechanism at the onset of apnea, which has been credited with various beneficial effects, e.g. reduction of hypercapnia during the use of low flow ventilation techniques. In this paper, a novel method is proposed to investigate the effect of these mechanisms in silico. An existing computational model of cardio-pulmonary physiology is extended to include the apneic state, gas mixing within the anatomical deadspace, insufflation into the trachea and cardiogenic oscillations. The new model is validated against data published in an experimental animal (dog) study that reported an increase in arterial partial pressure of carbon dioxide (PaCO2) during apnea. Computational simulations confirm that the model outputs accurately reproduce the available experimental data. This new model can be used to investigate the physiological mechanisms underlying clearance of carbon dioxide during apnea, and hence to develop more effective ventilation strategies for apneic patients.

The effect of prone positioning with surgical bolsters on liver blood flow in healthy volunteers

This study sought to identify changes in hepatic flood flow and cardiac output during prone positioning on surgical bolsters in awake volunteers, and was prompted by a local incident of significant hepatic dysfunction following surgery in the prone position. Cardiac output was determined using the non‐invasive Peñáz technique, and plasma disappearance rate of indocyanine green (ICG‐PDR) was measured as a surrogate maker for hepatic blood flow along with serum hepatic enzyme assays. Measurements were made after one hour in supine, prone and returned supine positions. Ten volunteers completed the study. There were significant changes in the disappearance rate of indocyanine green, which decreased this from mean (SD) 31.1 (9.70) supine to 19.6 (4.37)%.min prone, respectively (p = 0.02), increasing on return to the supine position to 24.6 (5.54)%.min (p = 0.019). Cardiac output was also significantly reduced when changing from the supine to the prone position, from mean (SD) 4.7 (1.0 to 3.5 (1.1) (l.min−1), respectively (p = 0.002). We demonstrated an acute and reversible change in both hepatocellular function and cardiac output associated with the prone position.

Injury after non-judicial hanging

Hanging is an important and increasingly common method of suicide in developed countries. Little is known about the true human pathophysiological changes and injury patterns associated with hanging and near hanging. Cervical spine injury is commonly reported; however, there is a paucity of large data sets concerning this injury. This review article focuses on the incidence of cervical spine and associated neck injuries and their role in morbidity and mortality following non-judicial hanging. A total of 26 heterogeneous studies were identified examining injury after hanging or near hanging. In total, there were 2795 patients; 1530 (54.7%) with true hanging and 1265 (45.3%) with near hanging. Cervical spine injury was reported in a total of 58 (2.08%) patients. Injuries to the airway and vessels of the neck seem rare. This is somewhat lower than the current accepted incidence for cervical spine injury after hanging or blunt force trauma. The overall incidence of cervical spine injury after hanging is low. Spinal immobilisation should probably be instituted depending on the mechanism of the hanging. However, a patient presenting with signs of life to an emergency department is unlikely to have a severe cervical spine injury.