The trajectory of life.Decreasing physiological network complexity through changing fractal patterns

In this position paper, we submit a synthesis of theoretical models based on physiology, non-equilibrium thermodynamics, and non-linear time-series analysis. Based on an understanding of the human organism as a system of interconnected complex adaptive systems, we seek to examine the relationship between health, complexity, variability, and entropy production, as it might be useful to help understand ageing, and improve care for patients. We observe the trajectory of life is characterized by the growth, plateauing and subsequent loss of adaptive function of organ systems, associated with loss of functioning and coordination of systems. Understanding development and ageing requires the examination of interdependence among these organ systems. Increasing evidence suggests network interconnectedness and complexity can be captured/measured/associated with the degree and complexity of healthy biologic rhythm variability (e.g. heart and respiratory rate variability). We review physiological mechanisms linking the omics, arousal/stress systems, immune function, and mitochondrial bioenergetics; highlighting their interdependence in normal physiological function and ageing. We argue that ageing, known to be characterized by a loss of variability, is manifested at multiple scales, within functional units at the small scale, and reflected by diagnostic features at the larger scale. While still controversial and under investigation, it appears conceivable that the integrity of whole body complexity may be, at least partially, reflected in the degree and variability of intrinsic biologic rhythms, which we believe are related to overall system complexity that may be a defining feature of health and it’s loss through ageing. Harnessing this information for the development of therapeutic and preventative strategies may hold an opportunity to significantly improve the health of our patients across the trajectory of life

Do physiological and pathological stresses produce different changes in heart rate variability?

Although physiological (e.g. exercise) and pathological (e.g. infection) stress affecting the cardiovascular system have both been documented to be associated with a reduction in overall heart rate variability (HRV), it remains unclear if loss of HRV is ubiquitously similar across different domains of variability analysis or if distinct patterns of altered HRV exist depending on the stressor. Using Continuous Individualized Multiorgan Variability Analysis (CIMVATM) software, heart rate (HR) and four selected measures of variability were measured over time (windowed analysis) from two datasets, a set (n=13) of patients who developed systemic infection (i.e. sepsis) after bone marrow transplant, and a matched set of healthy subjects undergoing physical exercise under controlled conditions. HR and the four HRV measures showed similar trends in both sepsis and exercise. The comparison through Wilcoxon sign-rank test of the levels of variability at baseline and during the stress (i.e. exercise or after days of sepsis development) showed similar changes, except for LF/HF, ratio of power at low and high frequencies (associated with sympathovagal modulation), which was affected by exercise but did not show any change during sepsis. Furthermore, HRV measures during sepsis showed a lower level of correlation with each other, as compared to HRV during exercise. In conclusion, this exploratory study highlights similar responses during both exercise and infection, with differences in terms of correlation and inter-subject fluctuations, whose physiologic significance merits further investigation

Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit

International audienceBACKGROUND Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.)