Anton Burykin

Plasticity of the Systemic Inflammatory Response to Acute Infection during Critical Illness: Development of the Riboleukogram

Background Diagnosis of acute infection in the critically ill remains a challenge. We hypothesized that circulating leukocyte transcriptional profiles can be used to monitor the host response to and recovery from infection complicating critical illness. Methodology/Principal Findings A translational research approach was employed. Fifteen mice underwent intratracheal injections of live P. aeruginosa, P. aeruginosa endotoxin, live S. pneumoniae, or normal saline. At 24 hours after injury, GeneChip microarray analysis of circulating buffy coat RNA identified 219 genes that distinguished between the pulmonary insults and differences in 7-day mortality. Similarly, buffy coat microarray expression profiles were generated from 27 mechanically ventilated patients every two days for up to three weeks. Significant heterogeneity of VAP microarray profiles was observed secondary to patient ethnicity, age, and gender, yet 85 genes were identified with consistent changes in abundance during the seven days bracketing the diagnosis of VAP. Principal components analysis of these 85 genes appeared to differentiate between the responses of subjects who did versus those who did not develop VAP, as defined by a general trajectory (riboleukogram) for the onset and resolution of VAP. As patients recovered from critical illness complicated by acute infection, the riboleukograms converged, consistent with an immune attractor. Conclusions/Significance Here we present the culmination of a mouse pneumonia study, demonstrating for the first time that disease trajectories derived from microarray expression profiles can be used to quantitatively track the clinical course of acute disease and identify a state of immune recovery. These data suggest that the onset of an infection-specific transcriptional program may precede the clinical diagnosis of pneumonia in patients. Moreover, riboleukograms may help explain variance in the host response due to differences in ethnic background, gender, and pathogen. Prospective clinical trials are indicated to validate our results and test the clinical utility of riboleukograms.

Using systems biology to simplify complex disease: Immune cartography

What if there was a rapid, inexpensive, and accurate blood diagnostic that could determine which patients were infected, identify the organism(s) responsible, and identify patients who were not responding to therapy? We hypothesized that systems analysis of the transcriptional activity of circulating immune effector cells could be used to identify conserved elements in the host response to systemic inflammation, and furthermore, to discriminate between sterile and infectious etiologies. We review herein a validated, systems biology approach demonstrating that 1) abdominal and pulmonary sepsis diagnoses can be made in mouse models using microarray (RNA) data from circulating blood, 2) blood microarray data can be used to differentiate between the host response to Gram-negative and Gram-positive pneumonia, 3) the endotoxin response of normal human volunteers can be mapped at the level of gene expression, and 4) a similar strategy can be used in the critically ill to follow septic patients and quantitatively determine immune recovery. These findings provide the foundation of immune cartography and demonstrate the potential of this approach for rapidly diagnosing sepsis and identifying pathogens. Further, our data suggest a new approach to determine how specific pathogens perturb the physiology of circulating leukocytes in a cell-specific manner. Large, prospective clinical trails are needed to validate the clinical utility of leukocyte RNA diagnostics (e.g., the riboleukogram).

Multiscale Poincaré plots for visualizing the structure of heartbeat time series

BackgroundPoincaré delay maps are widely used in the analysis of cardiac interbeat interval (RR) dynamics. To facilitate visualization of the structure of these time series, we introduce multiscale Poincaré (MSP) plots.MethodsStarting with the original RR time series, the method employs a coarse-graining procedure to create a family of time series, each of which represents the system’s dynamics in a different time scale. Next, the Poincaré plots are constructed for the original and the coarse-grained time series. Finally, as an optional adjunct, color can be added to each point to represent its normalized frequency.ResultsWe illustrate the MSP method on simulated Gaussian white and 1/f noise time series. The MSP plots of 1/f noise time series reveal relative conservation of the phase space area over multiple time scales, while those of white noise show a marked reduction in area. We also show how MSP plots can be used to illustrate the loss of complexity when heartbeat time series from healthy subjects are compared with those from patients with chronic (congestive) heart failure syndrome or with atrial fibrillation.ConclusionsThis generalized multiscale approach to Poincaré plots may be useful in visualizing other types of time series.

Dynamical density delay maps: simple, new method for visualising the behaviour of complex systems

BackgroundPhysiologic signals, such as cardiac interbeat intervals, exhibit complex fluctuations. However, capturing important dynamical properties, including nonstationarities may not be feasible from conventional time series graphical representations.MethodsWe introduce a simple-to-implement visualisation method, termed dynamical density delay mapping (“D3-Map” technique) that provides an animated representation of a system’s dynamics. The method is based on a generalization of conventional two-dimensional (2D) Poincaré plots, which are scatter plots where each data point, x(n), in a time series is plotted against the adjacent one, x(n + 1). First, we divide the original time series, x(n) (n = 1,…, N), into a sequence of segments (windows). Next, for each segment, a three-dimensional (3D) Poincaré surface plot of x(n), x(n + 1), h[x(n),x(n + 1)] is generated, in which the third dimension, h, represents the relative frequency of occurrence of each (x(n),x(n + 1)) point. This 3D Poincaré surface is then chromatised by mapping the relative frequency h values onto a colour scheme. We also generate a colourised 2D contour plot from each time series segment using the same colourmap scheme as for the 3D Poincaré surface. Finally, the original time series graph, the colourised 3D Poincaré surface plot, and its projection as a colourised 2D contour map for each segment, are animated to create the full “D3-Map.”ResultsWe first exemplify the D3-Map method using the cardiac interbeat interval time series from a healthy subject during sleeping hours. The animations uncover complex dynamical changes, such as transitions between states, and the relative amount of time the system spends in each state. We also illustrate the utility of the method in detecting hidden temporal patterns in the heart rate dynamics of a patient with atrial fibrillation. The videos, as well as the source code, are made publicly available.ConclusionsAnimations based on density delay maps provide a new way of visualising dynamical properties of complex systems not apparent in time series graphs or standard Poincaré plot representations. Trainees in a variety of fields may find the animations useful as illustrations of fundamental but challenging concepts, such as nonstationarity and multistability. For investigators, the method may facilitate data exploration.

Using off-the-shelf tools for terabyte-scale waveform recording in intensive care: Computer system design, database description and lessons learned

Until now, the creation of massive (long-term and multichannel) waveform databases in intensive care required an interdisciplinary team of clinicians, engineers and informaticians and, in most cases, also design-specific software and hardware development. Recently, several commercial software tools for waveform acquisition became available. Although commercial products and even turnkey systems are now being marketed as simple and effective, the performance of those solutions is not known. The additional expense upfront may be worthwhile if commercial software can eliminate the need for custom software and hardware systems and the associated investment in teams and development. We report the development of a computer system for long-term large-scale recording and storage of multichannel physiologic signals that was built using commercial solutions (software and hardware) and existing hospital IT infrastructure. Both numeric (1 Hz) and waveform (62.5-500 Hz) data were captured from 24 SICU bedside monitors simultaneously and stored in a file-based vital sign data bank (VSDB) during one-year period (total DB size is 4.21TB). In total, vital signs were recorded from 1,175 critically ill patients. Up to six ECG leads, all other monitored waveforms, and all monitored numeric data were recorded in most of the cases. We describe the details of building blocks of our system, provide description of three datasets exported from our VSDB and compare the contents of our VSDB with other available waveform databases. Finally, we summarize lessons learned during recording, storage, and pre-processing of physiologic signals.

Predicting clinical physiology: A Markov chain model of heart rate recovery after spontaneous breathing trials in mechanically ventilated patients

Analysis of heart rate (HR) dynamics before, during, and after a physiologic stress has clinical importance. For example, the celerity of heart rate recovery (HRR) after a cardiac stress test (eg, treadmill exercise test) has been shown to be an independent predictor of all-cause mortality. Heart rate dynamics are modulated, in part, by the autonomic nervous system. These dynamics are commonly abstracted using metrics of heart rate variability (HRV), which are known to be sensitive to the influence of the autonomic nervous system on HR. The patient-specific modulators of HR should be reflected both in the response to stress as well as in the recovery from stress. We therefore hypothesized that the patient-specific HR response to stress could be used to predict the HRR after the stress. We devised a Markov chain model to predict the poststress HRR dynamics using the parameters (transition matrix) calculated from HR data during the stress. The model correctly predicts the exponential shape of poststress HRR. This model features a simple analytical relationship linking poststress HRR time constant (T(off)) with a standard measure of HRV, namely the correlation coefficient of the Poincaré plot (first return map) of the HR recorded during the stress. A corresponding relationship exists between the time constant (T(on)) of R-R interval decrease at the onset of stress and the correlation coefficient of the Poincaré plot of prestress R-R intervals. Consequently, the model can be used for the prediction of poststress HRR using the HRV measured during the stress. This direct relationship between the event-to-event microscopic fluctuations (HRV) during the stress and the macroscopic response (HRR) after the stress terminates can be interpreted as an instance of a fluctuation-dissipation relationship. We have thus applied the fluctuation-dissipation theorem to the analysis of heart rate dynamics. The approach is specific neither to cardiac physiology nor to transitions between mechanical and free ventilation as a specific stress. It may therefore have wider applicability to physiologic systems subject to modest stresses.

Postreperfusion cardiac arrest and resuscitation during orthotopic liver transplantation: dynamic visualization and analysis of physiologic recordings.

ABSTRACT We recently reported on the Multi Wave Animator (MWA), a novel open-source tool with capability of recreating continuous physiologic signals from archived numerical data and presenting them as they appeared on the patient monitor. In this report, we demonstrate for the first time the power of this technology in a real clinical case, an intraoperative cardiopulmonary arrest following reperfusion of a liver transplant graft. Using the MWA, we animated hemodynamic and ventilator data acquired before, during, and after cardiac arrest and resuscitation. This report is accompanied by an online video that shows the most critical phases of the cardiac arrest and resuscitation and provides a basis for analysis and discussion. This video is extracted from a 33-min, uninterrupted video of cardiac arrest and resuscitation, which is available online. The unique strength of MWA, its capability to accurately present discrete and continuous data in a format familiar to clinicians, allowed us this rare glimpse into events leading to an intraoperative cardiac arrest. Because of the ability to recreate and replay clinical events, this tool should be of great interest to medical educators, researchers, and clinicians involved in quality assurance and patient safety.