Frank J. Jacono

Cardiovascular alterations by chronic intermittent hypoxia: Importance of carotid body chemoreflexes

1. Humans experiencing intermittent hypoxia (IH) owing to recurrent apnoea syndromes exhibit serious cardiovascular morbidity, including high blood pressure, increased sympathetic nerve activity, cardiac arrhythmia and myocardial infarction. Although apnoeas are accompanied by a simultaneous decrease in arterial O2 (hypoxia) and an increase in CO2 (hypercapnia), studies on experimental animals suggest that hypoxia, rather than hypercapnia, is the primary stimulus for developing hypertension and enhanced sympathetic nerve activity. Enhanced hypoxic‐sensing ability of the carotid bodies and the ensuing reflex activation of the sympathetic nervous system have been suggested to play a critical role in cardiorespiratory alterations resulting from recurrent apnoeas.

Comparative analysis of neonatal and adult rat carotid body responses to chronic intermittent hypoxia

Previous studies suggest that carotid body responses to long-term changes in environmental oxygen differ between neonates and adults. In the present study we tested the hypothesis that the effects of chronic intermittent hypoxia (CIH) on the carotid body differ between neonates and adult rats. Experiments were performed on neonatal (1-10 days) and adult (6-8 wk) males exposed either to CIH (9 episodes/h; 8 h/day) or to normoxia. Sensory activity was recorded from ex vivo carotid bodies. CIH augmented the hypoxic sensory response (HSR) in both groups. The magnitude of CIH-evoked hypoxic sensitization was significantly greater in neonates than in adults. Seventy-two episodes of CIH were sufficient to evoke hypoxic sensitization in neonates, whereas as many as 720 CIH episodes were required in adults, suggesting that neonatal carotid bodies are more sensitive to CIH than adult carotid bodies. CIH-induced hypoxic sensitization was reversed in adult rats after reexposure to 10 days of normoxia, whereas the effects of neonatal CIH persisted into adult life (2 mo). Acute intermittent hypoxia (IH) evoked sensory long-term facilitation of the carotid body activity (sensory LTF, i.e., increased baseline neural activity following acute IH) in CIH-exposed adults but not in neonates. The effects of CIH were associated with hyperplasia of glomus cells in neonatal but not in adult carotid bodies. These observations demonstrate that responses to CIH differ between neonates and adults with regard to the magnitude of sensitization of HSR, susceptibility to CIH, induction of sensory LTF, reversibility of the responses, and morphological remodeling of the chemoreceptor tissue.

Sepsis: Something old, something new, and a systems view

Sepsis is a clinical syndrome characterized by a multisystem response to a microbial pathogenic insult consisting of a mosaic of interconnected biochemical, cellular, and organ-organ interaction networks. A central thread that connects these responses is inflammation that, while attempting to defend the body and prevent further harm, causes further damage through the feed-forward, proinflammatory effects of damage-associated molecular pattern molecules. In this review, we address the epidemiology and current definitions of sepsis and focus specifically on the biologic cascades that comprise the inflammatory response to sepsis. We suggest that attempts to improve clinical outcomes by targeting specific components of this network have been unsuccessful due to the lack of an integrative, predictive, and individualized systems-based approach to define the time-varying, multidimensional state of the patient. We highlight the translational impact of computational modeling and other complex systems approaches as applied to sepsis, including in silico clinical trials, patient-specific models, and complexity-based assessments of physiology.

5‐HT evokes sensory long‐term facilitation of rodent carotid body via activation of NADPH oxidase

5‐Hydroxytryptamine (5‐HT) evokes long‐term activation of neuronal activity in the nervous system. Carotid bodies, the sensory organs for detecting arterial oxygen, express 5‐HT. In the present study we examined whether 5‐HT evokes sensory long‐term facilitation (LTF) of the carotid body, and if so by what mechanism(s). Experiments were performed on anaesthetized adult rats and mice. Sensory activity was recorded from carotid bodies ex vivo. Spaced (3 × 15 s of 100 nm at 5 min intervals) but not mass (300 nm, 45 s) application of 5‐HT elicited LTF, whereas both modes of 5‐HT application evoked initial sensory excitation of the carotid bodies in rats. Ketanserin, a 5‐HT2 receptor antagonist prevented sensory LTF but not the initial sensory excitation. Spaced application of 5‐HT activated protein kinase C (PKC) as evidenced by increased phosphorylations of PKC at Thr514 and myristoylated alanine‐rich C kinase substrate (MARCKS) and these effects were abolished by ketanserin as well as bisindolylmaleimide (Bis‐1), an inhibitor of PKC. Bis‐1 prevented 5‐HT‐evoked sensory LTF. 5‐HT increased NADPH oxidase activity and PKC‐dependent phosphorylation of p47phox subunit of the oxidase complex. NADPH oxidase inhibitors (apocynin and diphenyl iodinium), as well as an anti‐oxidant (N‐acetyl cysteine), prevented 5‐HT‐evoked sensory LTF. Mice deficient in gp91phox, the membrane subunit of the NADPH oxidase complex, showed no sensory LTF, although responding to 5‐HT with initial afferent nerve activation, whereas both LTF and initial excitation by 5‐HT were seen in wild‐type mice. These results demonstrate that spaced but not mass application of 5‐HT elicits sensory LTF of the carotid body via activation of 5‐HT2 receptors, which involves a novel signalling mechanism coupled to PKC‐dependent activation of NADPH oxidase.

Modulation of the hypoxic sensory response of the carotid body by 5-hydroxytryptamine: role of the 5-HT2 receptor

Previous studies have shown that glomus cells of the carotid body express 5-hydroxytryptamine (5-HT). The aim of this study was to elucidate the role of 5-HT on the hypoxic sensory response (HSR) of the carotid body. Sensory activity was recorded from multi-fiber (n=16) and single-fiber (n=8) preparations of ex vivo carotid bodies harvested from anesthetized, adult rats. 5-HT (3 microM) had no significant effect on the magnitude or on the onset of the HSR. However, 5-HT consistently prolonged the time necessary for the sensory activity to return to baseline following the termination of the hypoxic challenge. Ketanserin (40 microM), a 5-HT2 receptor antagonist completely prevented 5-HT-induced prolongation of the HSR, whereas had no effect on the control HSR (onset, magnitude, and time for decay without 5-HT). Carotid bodies expressed 5-HT, but hypoxia did not facilitate 5-HT release. These observations suggest that 5-HT is not critical for the HSR of the rat carotid body, but it modulates the dynamics of the HSR via its action on 5-HT2 receptors.

Linking Inflammation, Cardiorespiratory Variability, and Neural Control in Acute Inflammation via Computational Modeling.

Acute inflammation leads to organ failure by engaging catastrophic feedback loops in which stressed tissue evokes an inflammatory response and, in turn, inflammation damages tissue. Manifestations of this maladaptive inflammatory response include cardio-respiratory dysfunction that may be reflected in reduced heart rate and ventilatory pattern variabilities. We have developed signal-processing algorithms that quantify non-linear deterministic characteristics of variability in biologic signals. Now, coalescing under the aegis of the NIH Computational Biology Program and the Society for Complexity in Acute Illness, two research teams performed iterative experiments and computational modeling on inflammation and cardio-pulmonary dysfunction in sepsis as well as on neural control of respiration and ventilatory pattern variability. These teams, with additional collaborators, have recently formed a multi-institutional, interdisciplinary consortium, whose goal is to delineate the fundamental interrelationship between the inflammatory response and physiologic variability. Multi-scale mathematical modeling and complementary physiological experiments will provide insight into autonomic neural mechanisms that may modulate the inflammatory response to sepsis and simultaneously reduce heart rate and ventilatory pattern variabilities associated with sepsis. This approach integrates computational models of neural control of breathing and cardio-respiratory coupling with models that combine inflammation, cardiovascular function, and heart rate variability. The resulting integrated model will provide mechanistic explanations for the phenomena of respiratory sinus-arrhythmia and cardio-ventilatory coupling observed under normal conditions, and the loss of these properties during sepsis. This approach holds the potential of modeling cross-scale physiological interactions to improve both basic knowledge and clinical management of acute inflammatory diseases such as sepsis and trauma.

Post-sigh breathing behavior and spontaneous pauses in the C57BL/6J (B6) mouse.

The purpose was to examine sighs and spontaneous pauses in regard to the stability of resting breathing in the B6 strain, compared to the A/J strain. A 5-HT1A receptor agonist (buspirone) and a chromosomal substitution strain (B6a1) were used to further alter breathing patterning. Ten-minute recordings of room air breathing were collected from unanaesthetized B6, A/J, and B6a1 mice. Despite no differences between strains in the magnitude and incidence of sighs, post-sigh apneas, the variation for duration of expiration (Te) after sighs, and the number of spontaneous pauses were greater in the B6, while Shannon Entropy (nonlinear metrics) for Te after sighs was lower in B6, compared to the other strains. Buspirone and chromosomal substitution eliminated post-sigh apneas and decreased spontaneous pauses. A greater irregularity and the lower complexity of post-sigh breathing in B6 are reversed by elements on A/J chromosome 1 and by increased 5-HT1A serotonergic tone.

Do heart and respiratory rate variability improve prediction of extubation outcomes in critically ill patients

IntroductionProlonged ventilation and failed extubation are associated with increased harm and cost. The added value of heart and respiratory rate variability (HRV and RRV) during spontaneous breathing trials (SBTs) to predict extubation failure remains unknown.MethodsWe enrolled 721 patients in a multicenter (12 sites), prospective, observational study, evaluating clinical estimates of risk of extubation failure, physiologic measures recorded during SBTs, HRV and RRV recorded before and during the last SBT prior to extubation, and extubation outcomes. We excluded 287 patients because of protocol or technical violations, or poor data quality. Measures of variability (97 HRV, 82 RRV) were calculated from electrocardiogram and capnography waveforms followed by automated cleaning and variability analysis using Continuous Individualized Multiorgan Variability Analysis (CIMVA™) software. Repeated randomized subsampling with training, validation, and testing were used to derive and compare predictive models.ResultsOf 434 patients with high-quality data, 51 (12%) failed extubation. Two HRV and eight RRV measures showed statistically significant association with extubation failure (P <0.0041, 5% false discovery rate). An ensemble average of five univariate logistic regression models using RRV during SBT, yielding a probability of extubation failure (called WAVE score), demonstrated optimal predictive capacity. With repeated random subsampling and testing, the model showed mean receiver operating characteristic area under the curve (ROC AUC) of 0.69, higher than heart rate (0.51), rapid shallow breathing index (RBSI; 0.61) and respiratory rate (0.63). After deriving a WAVE model based on all data, training-set performance demonstrated that the model increased its predictive power when applied to patients conventionally considered high risk: a WAVE score >0.5 in patients with RSBI >105 and perceived high risk of failure yielded a fold increase in risk of extubation failure of 3.0 (95% confidence interval (CI) 1.2 to 5.2) and 3.5 (95% CI 1.9 to 5.4), respectively.ConclusionsAltered HRV and RRV (during the SBT prior to extubation) are significantly associated with extubation failure. A predictive model using RRV during the last SBT provided optimal accuracy of prediction in all patients, with improved accuracy when combined with clinical impression or RSBI. This model requires a validation cohort to evaluate accuracy and generalizability.Trial registrationClinicalTrials.gov NCT01237886. Registered 13 October 2010.

A method for analyzing temporal patterns of variability of a time series from Poincaré plots

The Poincaré plot is a popular two-dimensional, time series analysis tool because of its intuitive display of dynamic system behavior. Poincaré plots have been used to visualize heart rate and respiratory pattern variabilities. However, conventional quantitative analysis relies primarily on statistical measurements of the cumulative distribution of points, making it difficult to interpret irregular or complex plots. Moreover, the plots are constructed to reflect highly correlated regions of the time series, reducing the amount of nonlinear information that is presented and thereby hiding potentially relevant features. We propose temporal Poincaré variability (TPV), a novel analysis methodology that uses standard techniques to quantify the temporal distribution of points and to detect nonlinear sources responsible for physiological variability. In addition, the analysis is applied across multiple time delays, yielding a richer insight into system dynamics than the traditional circle return plot. The method is applied to data sets of R-R intervals and to synthetic point process data extracted from the Lorenz time series. The results demonstrate that TPV complements the traditional analysis and can be applied more generally, including Poincaré plots with multiple clusters, and more consistently than the conventional measures and can address questions regarding potential structure underlying the variability of a data set.

Differences in Breathing Patterning During Wakefulness in Patients With Mixed Apnea-Dominant vs Obstructive-Dominant Sleep Apnea

BACKGROUND Mixed apneas share both central and obstructive components and are often treated as if they are obstructive events. The hypothesis is that patients with obstructive sleep apnea syndrome (OSAS) who exhibit a majority of mixed apneas will differ in ventilatory control from those with predominantly obstructive apneas during wakefulness; moreover, this difference could affect nasal continuous positive airway pressure (CPAP) adherence. METHODS In a retrospectively derived case-control study, 5 min of respiratory inductance plethysmography signals during wakefulness prior to sleep onset were extracted from a diagnostic polysomnogram in these groups: (1) mixed apnea-dominant OSAS (mix-OSAS) (n = 36), (2) obstructive apnea-dominant OSAS (pure-OSAS) (n = 20), (3) central apnea-dominant sleep apnea syndrome (pure-CSAS) (n = 6), and (4) control subjects (n = 10). Breathing patterning was compared between the groups using the coefficient of variation (CV) for breath-to-breath inspiration time (TI), expiration time (TE), TI + TE (Ttot), and tidal volume, and an information theory-based metric of signal pattern variability (sample entropy). Subsequent CPAP adherence over 12 months was determined in OSAS groups. RESULTS Breath-to-breath CV parameters and sample entropy in the mix-OSAS group were significantly greater as compared with the pure-OSAS and control groups. In a subanalysis, CV and sample entropy were similar in the mix-OSAS and the pure-CSAS groups. CPAP adherence was significantly poorer in mix-OSAS compared with pure-OSAS. CONCLUSIONS During wakefulness, both breath patterning and sample entropy in mix-OSAS are similar to pure-CSAS and more variable than in pure-OSAS. In addition, CPAP adherence was decreased in patients with mix-OSAS, which may be related to basic differences in respiratory control.