The 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, reflex-mediated 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).
Impact Statement
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.
An exaggerated exercise pressor reflex (EPR) is associated with excessive sympatho-excitation and exercise intolerance in the chronic heart failure (CHF) state. We hypothesized that brain-derived ...neurotrophic factor (BDNF) causes the exaggerated EPR via sensitizing muscle mechanosensitive afferents in CHF. Increased BDNF expression was observed in lumbar dorsal root ganglia (DRGs) from CHF rats compared to sham rats. Immunofluorescence data showed a greater increase in the number of BDNF-positive neurons in medium and large-sized DRG subpopulations from CHF rats. Patch clamp data showed that incubation with BDNF for 4⁻6 h, significantly decreased the current threshold-inducing action potential (AP), threshold potential and the number of APs during current injection in Dil-labeled isolectin B4 (IB4)-negative medium-sized DRG neurons (mainly mechano-sensitive) from sham rats. Compared to sham rats, CHF rats exhibited an increased number of APs during current injection in the same DRG subpopulation, which was significantly attenuated by 4-h incubation with anti-BDNF. Finally, chronic epidural delivery of anti-BDNF attenuated the exaggerated pressor response to either static contraction or passive stretch in CHF rats whereas this intervention had no effect on the pressor response to hindlimb arterial injection of capsaicin. These data suggest that increased BDNF in lumbar DRGs contributes to the exaggerated EPR in CHF.
•Providers are at risk for contracting COVID-19 due to close patient contact.•Proper personal protective equipment use is critical to providing a safe environment.•Face shields are an alternative for ...enhancing protection given the shortage of N95.•We present the detailed protocol for printing 3D face shields in a timely manner.•This protocol is aimed to individuals with little to no 3D printing experience.
Anesthesia providers are at risk for contracting COVID-19 due to close patient contact, especially during shortages of personal protective equipment. We present an easy to follow and detailed protocol for producing 3D printed face shields and an effective decontamination protocol, allowing their reuse.
The University of Nebraska Medical Center (UNMC) produced face shields using a combination of 3D printing and assembly with commonly available products, and produced a simple decontamination protocol to allow their reuse. To evaluate the effectiveness of the decontamination protocol, we inoculated bacterial suspensions of E. coli and S. aureus on to the face shield components, performed the decontamination procedure, and finally swabbed and enumerated organisms onto plates that were incubated for 12-24 hours. Decontamination effectiveness was evaluated using the average log10 reduction in colony counts.
Approximately 112 face shields were constructed and made available for use in 72 hours. These methods were successfully implemented for in-house production at UNMC and at Tripler Army Medical Center (Honolulu, Hawaii). Overall, the decontamination protocol was highly effective against both E. coli and S. aureus, achieving a ≥4 log10 (99.99%) reduction in colony counts for every replicate from each component of the face shield unit.
Face shields not only act as a barrier against the soiling of N95 face masks, they also serve as more effective eye protection from respiratory droplets over standard eye shields. Implementation of decontamination protocols successfully allowed face shield and N95 mask reuse, offering a higher level of protection for anesthesiology providers at the onset of the COVID-19 pandemic.
In a time of urgent need, our protocol enabled the rapid production of face shields by individuals with little to no 3D printing experience, and provided a simple and effective decontamination protocol allowing reuse of the face shields.
Renal sympathetic denervation, a potentially revolutionary interventional treatment for hypertension, faces an existential problem due to the inability to confirm successful ablation of the targeted ...renal sympathetic nerves. Based on the observation that renal sympathetic nerve activity exerts rhythmic, baroreflex-driven, and vasoconstrictive control of the renal vasculature, we developed a novel technique for identifying rhythmic sympathetic vascular control using a time-varying, 2-component Windkessel model of the renal circulation. This technology was tested in 2 different animal models of renal denervation; 10 rabbits underwent chronic, surgical renal denervation, and 9 pigs underwent acute, functional renal denervation via intrathecal administration of ropivacaine. Both methods of renal denervation reduced negative admittance gain, negative phase shift renal vascular control at known sympathetic vasomotor frequencies, consistent with a reduction in vasoconstrictive, baroreflex-driven renal sympathetic vasomotion. Classic measures like mean renal blood flow and mean renal vascular resistance were not significantly affected in either model of renal denervation. Renal sympathetic vasomotion monitoring could provide intraprocedural feedback for interventionists performing renal denervation and serve more broadly as a platform technology for the evaluation and treatment of diseases affecting the sympathetic nervous system.
Elevated sympathetic tone and activation of the renin–angiotensin system are pathophysiologic hallmarks of hypertension, and the interactions between these systems are particularly deleterious. The ...importance of Rho kinase as a mediator of the effects of angiotensin-II (AngII) in the periphery is clear, but the role of Rho kinase in sympathoexcitation caused by central AngII is not well established. We hypothesized that AngII mediates its effects in the brain by the activation of the RhoA/Rho kinase pathway. Chronically instrumented, conscious rabbits received the following intracerebroventricular infusion treatments for 2 weeks via osmotic minipumpAngII, Rho kinase inhibitor Fasudil, AngII plus Fasudil, or a vehicle control. AngII increased mean arterial pressure over the course of the infusion, and this effect was prevented by the coadministration of Fasudil. AngII increased cardiac and vascular sympathetic outflow as quantified by the heart rate response to metoprolol and the depressor effect of hexamethonium; coadministration of Fasudil abolished both of these effects. AngII increased baseline renal sympathetic nerve activity in conscious animals and impaired baroreflex control of sympathetic nerve activity; again Fasudil coinfusion prevented these effects. Each of these end points showed a statistically significant interaction between AngII and Fasudil. Quantitative immunofluorescence of brain slices confirmed that Rho kinase activity was increased by AngII and decreased by Fasudil. Taken together, these data indicate that hypertension, elevated sympathetic outflow, and baroreflex dysfunction caused by central AngII are mediated by Rho kinase activation and suggest that Rho kinase inhibition may be an important therapeutic target in sympathoexcitatory cardiovascular diseases.
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.
Abstract Tubuloglomerular feedback and the myogenic response are widely appreciated as important regulators of renal blood flow, but the role of the sympathetic nervous system in physiological renal ...blood flow control remains controversial. Where classic studies using static measures of renal blood flow failed, dynamic approaches have succeeded in demonstrating sympathetic control of renal blood flow under normal physiological conditions. This review focuses on transfer function analysis of renal pressure-flow, which leverages the physical relationship between blood pressure and flow to assess the underlying vascular control mechanisms. Studies using this approach indicate that the renal nerves are important in the rapid regulation of the renal vasculature. Animals with intact renal innervation show a sympathetic signature in the frequency range associated with sympathetic vasomotion that is eliminated by renal denervation. In conscious rabbits, this sympathetic signature exerts vasoconstrictive, baroreflex control of renal vascular conductance, matching well with the rhythmic, baroreflex-influenced control of renal sympathetic nerve activity and complementing findings from other studies employing dynamic approaches to study renal sympathetic vascular control. In this light, classic studies reporting that nerve stimulation and renal denervation do not affect static measures of renal blood flow provide evidence for the strength of renal autoregulation rather than evidence against physiological renal sympathetic control of renal blood flow. Thus, alongside tubuloglomerular feedback and the myogenic response, renal sympathetic outflow should be considered an important physiological regulator of renal blood flow. Clinically, renal sympathetic vasomotion may be important for solving the problems facing the field of therapeutic renal denervation.
Heart rate variability (HRV) is a function of cardiac autonomic tone that is widely used in both clinical and animal studies. In preclinical studies, HRV measures are frequently derived using the ...arterial pulse waveform from an implanted pressure telemetry device, termed pulse rate variability (PRV), instead of the electrocardiogram signal in accordance with clinical guidelines. The acceptability of PRV as a surrogate for HRV in instrumented animals is unknown. Using rabbits implanted with intracardiac leads and chronically implanted pressure transducers, we investigated the correlation and agreement of time-domain, frequency-domain, and nonlinear indexes of HRV and PRV at baseline. We also investigated the effects of ventricular pacing and autonomic blockade on both measures. At baseline, HRV and PRV time- and frequency-domain parameters showed robust correlations and moderate to high agreement, whereas nonlinear parameters showed slightly weaker correlations and varied agreement. Ventricular pacing almost completely eliminated HRV, and spectral analysis of the PRV signal revealed a HRV-independent rhythm. After cardiac autonomic blockade with atropine or metoprolol, the changes in time- and non-normalized frequency-domain measures of PRV continued to show strong correlations and moderate to high agreement with corresponding changes in HRV measures. Blockade-induced changes in nonlinear PRV indexes correlated poorly with HRV changes and showed weak agreement. These results suggest that time- and frequency-domain measures of PRV are acceptable surrogates for HRV even in the context of changing cardiac autonomic tone, but caution should be used when nonlinear measures are a primary end point or when HRV is very low as HRV-independent rhythms may predominate.
Hemorrhage remains the leading cause of death following traumatic injury in both civilian and military settings. Heart rate variability (HRV) and heart rate complexity (HRC) have been proposed as ...potential "new vital signs" for monitoring trauma patients; however, the added benefit of HRV or HRC for decision support remains unclear. Another new paradigm, the compensatory reserve measurement (CRM), represents the integration of all cardiopulmonary mechanisms responsible for compensation during relative blood loss and was developed to identify current physiologic status by estimating the progression toward hemodynamic decompensation. In the present study, we hypothesized that CRM would provide greater sensitivity and specificity to detect progressive reductions in central circulating blood volume and onset of decompensation as compared with measurements of HRV and HRC.
Continuous, noninvasive measurements of compensatory reserve and electrocardiogram signals were made on 101 healthy volunteers during lower-body negative pressure (LBNP) to the point of decompensation. Measures of HRV and HRC were taken from electrocardiogram signal data.
Compensatory reserve measurement demonstrated a superior sensitivity and specificity (receiver operator characteristic area under the curve ROC AUC = 0.93) compared with all HRV measures (ROC AUC ≤ 0.84) and all HRC measures (ROC AUC ≤ 0.86). Sensitivity and specificity values at the ROC optimal thresholds were greater for CRM (sensitivity = 0.84; specificity = 0.84) than HRV (sensitivity, ≤0.78; specificity, ≤0.77), and HRC (sensitivity, ≤0.79; specificity, ≤0.77). With standardized values across all levels of LBNP, CRM had a steeper decline, less variability, and explained a greater proportion of the variation in the data than both HRV and HRC during progressive hypovolemia.
These findings add to the growing body of literature describing the advantages of CRM for detecting reductions in central blood volume. Most importantly, these results provide further support for the potential use of CRM in the triage and monitoring of patients at highest risk for the onset of shock following blood loss.
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