Craig G. Rusin

Engineering Complex Dynamical Structures: Sequential Patterns and Desynchronization

We used phase models to describe and tune complex dynamic structures to desired states; weak, nondestructive signals are used to alter interactions among nonlinear rhythmic elements. Experiments on electrochemical reactions on electrode arrays were used to demonstrate the power of mild model-engineered feedback to achieve a desired response. Applications are made to the generation of sequentially visited dynamic cluster patterns similar to reproducible sequences seen in biological systems and to the design of a nonlinear antipacemaker for the destruction of pathological synchronization of a population of interacting oscillators.

Zona glomerulosa cells of the mouse adrenal cortex are intrinsic electrical oscillators

Aldosterone, which plays a central role in the regulation of blood pressure, is produced by zona glomerulosa (ZG) cells of the adrenal gland. When dysregulated, aldosterone is pathogenic and contributes to the development and progression of cardiovascular and renal disease. Although sustained production of aldosterone requires persistent Ca2+ entry through low-voltage activated Ca2+ channels, isolated ZG cells are considered nonexcitable, with recorded membrane voltages that are too hyperpolarized to permit Ca2+ entry. Here, we show that mouse ZG cells within adrenal slices spontaneously generate membrane potential oscillations of low periodicity. This innate electrical excitability of ZG cells provides a platform for the production of a recurrent Ca2+ signal that can be controlled by Ang II and extracellular potassium, the 2 major regulators of aldosterone production. We conclude that native ZG cells are electrical oscillators, and that this behavior provides what we believe to be a new molecular explanation for the control of Ca2+ entry in these steroidogenic cells.

A new algorithm for detecting central apnea in neonates

Apnea of prematurity is an important and common clinical problem, and is often the rate-limiting process in NICU discharge. Accurate detection of episodes of clinically important neonatal apnea using existing chest impedance (CI) monitoring is a clinical imperative. The technique relies on changes in impedance as the lungs fill with air, a high impedance substance. A potential confounder, however, is blood coursing through the heart. Thus, the cardiac signal during apnea might be mistaken for breathing. We report here a new filter to remove the cardiac signal from the CI that employs a novel resampling technique optimally suited to remove the heart rate signal, allowing improved apnea detection. We also develop an apnea detection method that employs the CI after cardiac filtering. The method has been applied to a large database of physiological signals, and we prove that, compared to the presently used monitors, the new method gives substantial improvement in apnea detection.

Anemia, Apnea of Prematurity, and Blood Transfusions

OBJECTIVE To compare the frequency and severity of apneic events in very low birth weight (VLBW) infants before and after blood transfusions using continuous electronic waveform analysis. STUDY DESIGN We continuously collected waveform, heart rate, and oxygen saturation data from patients in all 45 neonatal intensive care unit beds at the University of Virginia for 120 weeks. Central apneas were detected using continuous computer processing of chest impedance, electrocardiographic, and oximetry signals. Apnea was defined as respiratory pauses of >10, >20, and >30 seconds when accompanied by bradycardia (<100 beats per minute) and hypoxemia (<80% oxyhemoglobin saturation as detected by pulse oximetry). Times of packed red blood cell transfusions were determined from bedside charts. Two cohorts were analyzed. In the transfusion cohort, waveforms were analyzed for 3 days before and after the transfusion for all VLBW infants who received a blood transfusion while also breathing spontaneously. Mean apnea rates for the previous 12 hours were quantified and differences for 12 hours before and after transfusion were compared. In the hematocrit cohort, 1453 hematocrit values from all VLBW infants admitted and breathing spontaneously during the time period were retrieved, and the association of hematocrit and apnea in the next 12 hours was tested using logistic regression. RESULTS Sixty-seven infants had 110 blood transfusions during times when complete monitoring data were available. Transfusion was associated with fewer computer-detected apneic events (P < .01). Probability of future apnea occurring within 12 hours increased with decreasing hematocrit values (P < .001). CONCLUSIONS Blood transfusions are associated with decreased apnea in VLBW infants, and apneas are less frequent at higher hematocrits.

Synchronization engineering: Theoretical framework and application to dynamical clustering.

A method for engineering the global behavior of populations of rhythmic elements is presented. The framework, which is based on phase models, allows a nonlinear time-delayed global feedback signal to be constructed which produces an interaction function corresponding to the desired behavior of the system. It is shown theoretically and confirmed in numerical simulations that a polynomial, delayed feedback is a versatile tool to tune synchronization patterns. Dynamical states consisting of one to four clusters were engineered to demonstrate the application of synchronization engineering in an experimental electrochemical system.

Accurate automated apnea analysis in preterm infants.

OBJECTIVE In 2006 the apnea of prematurity (AOP) consensus group identified inaccurate counting of apnea episodes as a major barrier to progress in AOP research. We compare nursing records of AOP to events detected by a clinically validated computer algorithm that detects apnea from standard bedside monitors. STUDY DESIGN Waveform, vital sign, and alarm data were collected continuously from all very low-birth-weight infants admitted over a 25-month period, analyzed for central apnea, bradycardia, and desaturation (ABD) events, and compared with nursing documentation collected from charts. Our algorithm defined apnea as > 10 seconds if accompanied by bradycardia and desaturation. RESULTS Of the 3,019 nurse-recorded events, only 68% had any algorithm-detected ABD event. Of the 5,275 algorithm-detected prolonged apnea events > 30 seconds, only 26% had nurse-recorded documentation within 1 hour. Monitor alarms sounded in only 74% of events of algorithm-detected prolonged apnea events > 10 seconds. There were 8,190,418 monitor alarms of any description throughout the neonatal intensive care unit during the 747 days analyzed, or one alarm every 2 to 3 minutes per nurse. CONCLUSION An automated computer algorithm for continuous ABD quantitation is a far more reliable tool than the medical record to address the important research questions identified by the 2006 AOP consensus group.

The ontogeny of cerebrovascular pressure autoregulation in premature infants

Objective:To quantify cerebrovascular autoregulation as a function of gestational age (GA) and across the phases of the cardiac cycle.Study design:The present study is a hypothesis-generating re-analysis of previously published data. Premature infants (n=179) with a GA range of 23 to 33 weeks were monitored with umbilical artery catheters and transcranial Doppler insonation of the middle cerebral artery for 1-h sessions over the first week of life. Autoregulation was quantified by three methods, as a moving correlation coefficient between: (1) systolic arterial blood pressure (ABP) and systolic cerebral blood flow (CBF) velocity (Sx); (2) mean ABP and mean CBF velocity (Mx); and (3) diastolic ABP and diastolic CBF velocity (Dx). Comparisons of individual and cohort cerebrovascular pressure autoregulation were made across GA for each aspect of the cardiac cycle.Results:Systolic, mean and diastolic ABP increased with GA (r=0.3, 0.4 and 0.4; P<0.0001). Systolic CBF velocity was pressure-passive in infants with the lowest GA, and Sx decreased with advancing GA (r=−0.3; P<0.001), indicating increased capacity for cerebral autoregulation during systole during development. By contrast, Dx was elevated, indicating dysautoregulation, in all subjects and showed minimal change with advancing GA (r=−0.06; P=0.05). Multivariate analysis confirmed that both GA (P<0.001) and ‘effective cerebral perfusion pressure’ (ABP minus critical closing pressure (CrCP); P<0.01) were associated with Sx.Conclusion:Premature infants have low and usually pressure-passive diastolic CBF velocity. By contrast, the regulation of systolic CBF velocity by pressure autoregulation developed in this cohort between 23 and 33 weeks GA. Elevated effective cerebral perfusion pressure derived from the CrCP was associated with dysautoregulation.

The frequency response of cerebral autoregulation

The frequency-response of pressure autoregulation is not well delineated; therefore, the optimal frequency of arterial blood pressure (ABP) modulation for measuring autoregulation is unknown. We hypothesized that cerebrovascular autoregulation is band-limited and delineated by a cutoff frequency for which ABP variations induce cerebrovascular reactivity. Neonatal swine (n = 8) were anesthetized using constant minute ventilation while positive end-expiratory pressure (PEEP) was modulated between 6 and 0.75 cycles/min (min(-1)). The animals were hemorrhaged until ABP was below the lower limit of autoregulation (LLA), and PEEP modulations were repeated. Vascular reactivity was quantified at each frequency according to the phase lag between ABP and intracranial pressure (ICP) above and below the LLA. Phase differences between ABP and ICP were small for frequencies of >2 min(-1), with no ability to differentiate cerebrovascular reactivity between ABPs above or below the LLA. For frequencies of <2 min(-1), ABP and intracranial pressure (ICP) showed phase shift when measured above LLA and no phase shift when measured below LLA [above vs. below LLA at 1 min(-1): 156° (139-174°) vs. 30° (22-50°); P < 0.001 by two-way ANOVA for both frequency and state of autoregulation]. Data taken above LLA fit a Butterworth high-pass filter model with a cutoff frequency at 1.8 min(-1) (95% confidence interval: 1.5-2.2). Cerebrovascular reactivity occurs for sustained ABP changes lasting 30 s or longer. The ability to distinguish intact and impaired autoregulation was maximized by a 60-s wave (1 min(-1)), which was 100% sensitive and 100% specific in this model.

Positive end-expiratory pressure oscillation facilitates brain vascular reactivity monitoring

The pressure reactivity index (PRx) identifies optimal cerebral perfusion pressure after traumatic brain injury. We describe a method to improve PRx precision by induced variations in arterial blood pressure (ABP) using positive end-expiratory pressure (PEEP) modulation (iPRx). Neonatal swine (n = 10) were ventilated with static PEEP and then with PEEP oscillated between 5 and 10 cmH(2)O at a frequency of 1/min. PRx was recorded as a moving correlation coefficient between ABP and intracranial pressure (ICP) from spontaneous ABP activity (0.05-0.003 Hz) during static PEEP. iPRx was similarly recorded with PEEP oscillation-induced ABP waves. The lower limit of autoregulation (LLA) was delineated with continuous cortical laser Doppler flux monitoring. PEEP oscillation increased autoregulation-monitoring precision. The ratios of median absolute deviations to range of possible values for the PRx and iPRx were 9.5% (8.3-13.7%) and 6.2% (4.2-8.7%), respectively (P = 0.006; median, interquartile range). The phase-angle difference between ABP and ICP above LLA was 161° (150°-166°) and below LLA, -31° (-42° to 12°, P < 0.0001). iPRx above LLA was -0.42 (-0.67 to -0.29) and below LLA, 0.32 (0.22-0.43, P = 0.0004). A positive iPRx was 97% specific and 91% sensitive for perfusion pressure below LLA. PEEP oscillation caused stable, low-frequency ABP oscillations that reduced noise in the PRx. Safe translation of these findings to clinical settings is expected to yield more accurate and rapid delineation of individualized optimal perfusion-pressure goals for patients.

Breath-by-breath analysis of cardiorespiratory interaction for quantifying developmental maturity in premature infants

In healthy neonates, connections between the heart and lungs through brain stem chemosensory pathways and the autonomic nervous system result in cardiorespiratory synchronization. This interdependence between cardiac and respiratory dynamics can be difficult to measure because of intermittent signal quality in intensive care settings and variability of heart and breathing rates. We employed a phase-based measure suggested by Schäfer and coworkers (Schäfer C, Rosenblum MG, Kurths J, Abel HH. Nature 392: 239-240, 1998) to obtain a breath-by-breath analysis of cardiorespiratory interaction. This measure of cardiorespiratory interaction does not distinguish between cardiac control of respiration associated with cardioventilatory coupling and respiratory influences on the heart rate associated with respiratory sinus arrhythmia. We calculated, in sliding 4-min windows, the probability density of heartbeats as a function of the concurrent phase of the respiratory cycle. Probability density functions whose Shannon entropy had a <0.1% chance of occurring from random numbers were classified as exhibiting interaction. In this way, we analyzed 18 infant-years of data from 1,202 patients in the Neonatal Intensive Care Unit at University of Virginia. We found evidence of interaction in 3.3 patient-years of data (18%). Cardiorespiratory interaction increased several-fold with postnatal development, but, surprisingly, the rate of increase was not affected by gestational age at birth. We find evidence for moderate correspondence between this measure of cardiorespiratory interaction and cardioventilatory coupling and no evidence for respiratory sinus arrhythmia, leading to the need for further investigation of the underlying mechanism. Such continuous measures of physiological interaction may serve to gauge developmental maturity in neonatal intensive care patients and prove useful in decisions about incipient illness and about hospital discharge.