Hemorrhage is the leading cause of death in both civilian and military trauma. The work submitted in this review is important because it advances the understanding of mechanisms that contribute to the total integrated physiological compensations for inadequate tissue oxygenation (i.e. shock) that arise from hemorrhage. Unlike an animal model, we introduce the utilization of lower body negative pressure as a noninvasive model that allows for the study of progressive reductions in central blood volume similar to those reported during actual hemorrhage in conscious humans to the onset of hemodynamic decompensation (i.e. early phase of decompensatory shock), and is repeatable in the same subject. Understanding the fundamental underlying physiology of human hemorrhage helps to test paradigms of critical care medicine, and identify and develop novel clinical practices and technologies for advanced diagnostics and therapeutics in patients with life-threatening blood loss. AbstractThe ability to quickly diagnose hemorrhagic shock is critical for favorable patient outcomes. Therefore, it is important to understand the time course and involvement of the various physiological mechanisms that are active during volume loss and that have the ability to stave off hemodynamic collapse. This review provides new insights about the physiology that underlies blood loss and shock in humans through the development of a simulated model of hemorrhage using lower body negative pressure. In this review, we present controlled experimental results through utilization of the lower body negative pressure human hemorrhage model that provide novel insights on the integration of physiological mechanisms critical to the compensation for volume loss. We provide data obtained from more than 250 human experiments to classify human subjects into two distinct groups: those who have a high tolerance and can compensate well for reduced central blood volume (e.g. hemorrhage) and those with low tolerance with poor capacity to compensate.We include the conceptual introduction of arterial pressure and cerebral blood flow oscillations, reflexmediated autonomic and neuroendocrine responses, and respiration that function to protect adequate tissue oxygenation through adjustments in cardiac output and peripheral vascular resistance. Finally, unique time course data are presented that describe mechanistic events associated with the rapid onset of hemodynamic failure (i.e. decompensatory shock).

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Schiller AM, Haack KK, Pellegrino PR, Curry PL, Zucker IH. Unilateral renal denervation improves autonomic balance in conscious rabbits with chronic heart failure. Am J Physiol Regul Integr Comp Physiol 305: R886 -R892, 2013. First published September 4, 2013 doi:10.1152/ajpregu.00269.2013.-A hallmark of chronic heart failure (CHF) is an increased sympathetic tone resulting in autonomic imbalance. Renal denervation (DNx) in CHF patients has resulted in symptomatic improvement, but the protective mechanisms remain unclear. We hypothesized in CHF, unilateral renal DNx would improve cardiac autonomic balance. The present study used conscious, chronically instrumented New Zealand White rabbits undergoing renal DNx prior to pacing-induced CHF. Four treatment groups were used: nonpace, non-DNx [Sham-Innervated (Sham-INV)], nonpace DNx (sham-DNx), pace non-DNx (CHF-INV) or pace DNx (CHFDNx). We examined several markers indicative of autonomic balance. Baroreflex sensitivity and time domain heart rate variability (HRV) were both decreased in the CHF-INV group compared with sham-INV and were restored to sham levels by renal DNx. Power spectral analysis indicated an increase in low-frequency/high-frequency (LF/ HF) ratio in the CHF-INV compared with the sham-INV, which was normalized to sham levels by DNx. To assess whether this was due to a withdrawal of sympathetic tone or an increase in parasympathetic tone, the heart rate response was measured after an intravenous bolus of metoprolol or atropine. Bradycardia induced by intravenous metoprolol (indicative of cardiac sympathetic tone) was exacerbated in CHF-INV rabbits compared with sham-INV but was normalized in CHF-DNx. Conversely, the tachycardia in response to intravenous atropine (indicative of cardiac vagal tone) was not improved in CHF-DNx vs. CHF-INV animals. Renal DNx also prevented the increase in circulating plasma NE seen in CHF-INV rabbits. These results suggest renal DNx improves cardiac autonomic balance in CHF by a reduction of sympathetic tone. sympathetic nerves; baroreflex; cardiac function; kidney BILATERAL RENAL DENERVATION (DNx) has recently entered clinical practice as a successful therapy for drug-resistant hypertension (35). This treatment, using a radiofrequency catheter to ablate the renal nerves, chronically lowers arterial pressure while producing virtually no short-term side effects (2,14). It is well established that most forms of hypertension are correlated with an overactive sympathetic nervous system, as indicated by elevated plasma norepinephrine (NE) or increases in muscle sympathetic nerve activity and increases in whole body NE spillover (27). There is anecdotal and recent evidence to suggest that renal DNx can reduce excessive sympathetic tone in hypertension (34, 17) in some cases. However, recent studies by Brinkmann et al. (4) and Hart et al.

The function of the renal nerves has been an area of scientific and medical interest for many years. The recent advent of a minimally invasive catheter-based method of renal denervation has renewed excitement in understanding the afferent and efferent actions of the renal nerves in multiple diseases. While hypertension has been the focus of much this work, less attention has been given to the role of the renal nerves in the development of chronic heart failure (CHF). Recent studies from our laboratory and those of others implicate an essential role for the renal nerves in the development and progression of CHF. Using a rabbit tachycardia model of CHF and surgical unilateral renal denervation, we provide evidence for both renal efferent and afferent mechanisms in the pathogenesis of CHF. Renal denervation prevented the decrease in renal blood flow observed in CHF while also preventing increases in Angiotensin-II receptor protein in the microvasculature of the renal cortex. Renal denervation in CHF also reduced physiological markers of autonomic dysfunction including an improvement in arterial baroreflex function, heart rate variability, and decreased resting cardiac sympathetic tone. Taken together, the renal sympathetic nerves are necessary in the pathogenesis of CHF via both efferent and afferent mechanisms. Additional investigation is warranted to fully understand the role of these nerves and their role as a therapeutic target in CHF.

In chronic heart failure (CHF), carotid body chemoreceptor (CBC) activity is increased and contributes to increased tonic and hypoxia-evoked elevation in renal sympathetic nerve activity (RSNA). Elevated RSNA and reduced renal perfusion may contribute to development of the cardio-renal syndrome in CHF. Exercise training (EXT) has been shown to abrogate CBC-mediated increases in RSNA in experimental heart failure; however, the effect of EXT on CBC control of renal blood flow (RBF) is undetermined. We hypothesized that CBCs contribute to tonic reductions in RBF in CHF, that stimulation of the CBC with hypoxia would result in exaggerated reductions in RBF, and that these responses would be attenuated with EXT. RBF was measured in CHF-sedentary (SED), CHF-EXT, CHF-carotid body denervation (CBD), and CHF-renal denervation (RDNX) groups. We measured RBF at rest and in response to hypoxia (FiO2 10%). All animals exhibited similar reductions in ejection fraction and fractional shortening as well as increases in ventricular systolic and diastolic volumes. Resting RBF was lower in CHF-SED (29 ± 2 ml/min) than in CHF-EXT animals (46 ± 2 ml/min, P < 0.05) or in CHF-CBD animals (42 ± 6 ml/min, P < 0.05). In CHF-SED, RBF decreased during hypoxia, and this was prevented in CHF-EXT animals. Both CBD and RDNX abolished the RBF response to hypoxia in CHF. Mean arterial pressure increased in response to hypoxia in CHF-SED, but was prevented by EXT, CBD, and RDNX. EXT is effective in attenuating chemoreflex-mediated tonic and hypoxia-evoked reductions in RBF in CHF.

Circulatory shock remains a leading cause of death in both military and civilian trauma. Early, accurate and reliable prediction of decompensation is necessary for the most efficient interventions and clinical outcomes. Individual tolerance to reduced central blood volume can serve as a model to assess the sensitivity and specificity of vital sign measurements. The compensatory reserve (CRM) is the measurement of this capacity. Measurements of muscle oxygen saturation (SmO2), blood lactate, and end tidal CO2 (EtCO2) have recently gained attention as prognostic tools for early assessment of the status of patients with progressive hemorrhage, but lack the ability to adequately differentiate individual tolerance to hypovolemia. We hypothesized that the CRM would better predict hemodynamic decompensation and provide greater specificity and sensitivity than metabolic measures. To test this hypothesis, we employed lower body negative pressure on healthy human subjects until symptoms of presyncope were evident. Receiver operating characteristic area under the curve (ROC AUC), sensitivity, and specificity were used to evaluate the ability of CRM, partial pressure of oxygen (pO2), partial pressure of carbon dioxide (pCO2), SmO2, lactate, EtCO2, potential of hydrogen (pH), base excess and hematocrit (Hct) to predict hemodynamic decompensation. The ROC AUC for CRM (0.94) had a superior ability to predict decompensation compared with pO2 (0.85), pCO2 (0.62), SmO2 (0.72), lactate (0.57), EtCO2 (0.74), pH (0.55), base excess (0.59), and Hct (0.67). Similarly, CRM also exhibited the greatest sensitivity and specificity. These findings support the notion that CRM provides superior detection of hemodynamic compensation compared with commonly used clinical metabolic measures.

Hypovolemic shock exists as a spectrum, with its early stages characterized by subtle pathophysiologic tissue insults and its late stages defined by multi-system organ dysfunction. The importance of timely detection of shock is well known, as early interventions improve mortality, while delays render these same interventions ineffective. However, detection is limited by the monitors, parameters, and vital signs that are traditionally used in the intensive care unit (ICU). Many parameters change minimally during the early stages, and when they finally become abnormal, hypovolemic shock has already occurred. The compensatory reserve (CR) is a parameter that represents a new paradigm for assessing physiologic status, as it comprises the sum total of compensatory mechanisms that maintain adequate perfusion to vital organs during hypovolemia. When these mechanisms are overwhelmed, hemodynamic instability and circulatory collapse will follow. Previous studies involving CR measurements demonstrated their utility in detecting central blood volume loss before hemodynamic parameters and vital signs changed. Measurements of the CR have also been used in clinical studies involving patients with traumatic injuries or bleeding, and the results from these studies have been promising. Moreover, these measurements can be made at the bedside, and they provide a real-time assessment of hemodynamic stability. Given the need for rapid diagnostics when treating critically ill patients, CR measurements would complement parameters that are currently being used. Consequently, the purpose of this article is to introduce a conceptual framework where the CR represents a new approach to monitoring critically ill patients. Within this framework, we present evidence to support the notion that the use of the CR could potentially improve the outcomes of ICU patients by alerting intensivists to impending hypovolemic shock before its onset.