Age, exercise, and the outcome of sepsis

Critical Care, Nov 2017

Debasree Banerjee, Steven M. Opal

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Age, exercise, and the outcome of sepsis

Banerjee and Opal Critical Care Age, exercise, and the outcome of sepsis Debasree Banerjee 0 1 Steven M. Opal 0 1 0 Lifespan Hospital System , Providence, RI , USA 1 Department of Medicine, Warren Alpert Medical School of Brown University , 593 Eddy St., Providence, RI 02903 , USA We report on the increasingly important need to diagnose and care for the elderly with sepsis as a distinct patient population. We share an overview of age-related changes in sepsis physiology and the potential role of exercise. Sepsis; Septic shock; Aging and immunity; Immunosenescence; Exercise and infections; Sepsis in the elderly - For all the supposed benefits attributable to moderate exercise in the elderly population (better cardiovascular fitness, improved microcirculation, less obesity, etc.) [ 1–3 ], improved outcome from sepsis has not been listed among them until now [ 4 ]. At least in inbred, old mice, voluntary exercise appears to provide a survival benefit from experimentally induced intra-abdominal sepsis. If these results could be translated into aging human populations, the ramifications would be substantial indeed. Sepsis is a critical issue in old age and is among the top causes for intensive care unit (ICU) admission in the elderly [ 5 ]. The incidence of sepsis in our aging population is predicted to rise precipitously in the next decade as the “baby boomer” population reaches old age. Older adults and particularly nursing home residents have higher rates of ICU admission, longer length of stay, and increased hospital mortality than younger adults [ 6 ]. The mechanism(s) underpinning the disproportionate susceptibility to sepsis in the elderly is not yet fully understood. Elderly patients are at higher risk for sepsis likely related to the higher rates of comorbidities, including dementia, poor dentition, and diabetes. With age, intact integument and physiologic reflexes (intact cough reflex, balance, and mobility) that contribute to the body’s physical defense mechanisms to infection can degrade. Additionally, institutionalization, implanted devices, and surgical procedures can predispose patients to infection [ 7 ]. All mammals age over their lifetime, manifest by gradual development of telomere shortening of chromosomes, degenerative arthritis, loss of hair, inactivity, atherosclerosis, impaired T- and B-cell responses, and age-related malignancies [ 7, 8 ]. Mice age over a 2-year lifespan rather than the typical 80-year lifespan of humans, making mice a convenient animal model to study the effects of aging on a range of pathophysiologic responses. Elderly septic patients often do not have typical clinical responses to sepsis, making diagnosis by the Sepsis-3 quick Sepsis-Related Organ Failure Assessment (qSOFA) criteria difficult. Older patients may present with inverse signs and symptoms (hypothermia, leukopenia), or nonspecific signs of infection [ 6 ]. Accepted thresholds for biomarkers levels for diagnosis may not be appropriate in the older population, particularly among patients with pre-existing organ dysfunction. Thus, given the protean manifestations of infection in the elderly, diagnosis of sepsis is often delayed. Once infected, older patients experience a disadvantaged host immune response with defects in humoral and cellular immune function [ 9 ]. The pattern of cytokine release during sepsis in the elderly demonstrates higher levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 [ 7, 10 ]. A smoldering inflammatory state during aging termed “inflammaging” can affect sepsis physiology [11]. However, despite evidence of increased baseline inflammation, after insult, an immunosuppressed state is commonly observed in the elderly. This is part of the “immunosenescence” of aging, which results in quantitative and qualitative changes in lymphocytes (CD4, CD8 T cells and B cells) and myeloid cells [ 12, 13 ]. Specifically, elderly patients experience attenuated cell-mediated immunity in the form of a truncated T-cell repertoire, decreased IL-12 release, decreased lymphocyte proliferation, and dampened signal transduction. Humoral immunity is also adversely affected with aging. Decreased B-cell function with blunted antibody responses to neoantigens is commonplace due to lack of helper T-cell signals and decreased expression of costimulatory molecules [13]. Elderly mice experience many of the same age-related defects in immune function and increased risk of infection as observed in the older adult human patients [ 7 ]. Aged mice are more susceptible than young mice to endotoxininduced systemic inflammation, and are more likely to succumb as a result of systemic infection in pneumonia models and from intra-abdominal infection following cecal ligation and puncture [ 8 ]. While it might be speculated that exercised old mice in good cardiovascular fitness might fare better in sepsis than nonexercised, aged mice, limited experimental data exist to answe (...truncated)


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Debasree Banerjee, Steven M. Opal. Age, exercise, and the outcome of sepsis, Critical Care,