Name: integrated compensatory responses in a human model of hemorrhage
Uploaded: 2016-11-20T15:00:00
Description: Watch this Scientific Journal Video about Integrated Compensatory Responses in a Human Model of Hemorrhage at JoVE.com

This work is supported by funding from the United States Army, Medical Research and Materiel Command, Combat Casualty Care Program.&#160;We thank LTC Kevin S. Akers, MD and Ms. Kristen R. Lye for their assistance in making the video.

Prior to any human procedure, the institutional&#160;review board (IRB) must approve the protocol. The protocol used in this study was approved by the US Army Medical Research and Materiel Command IRB. The protocol is designed to demonstrate the physiological responses of compensation to a progressive reduction in central blood volume similar to that experienced by individuals during ongoing hemorrhage in a controlled and reproducible laboratory setting. The laboratory room temperature is controlled at 23 - 25 &#730;C.
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<ol>
	<li>Convertino, V. A., Wirt, M. D., Glenn, J. P., Lein, B. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+compensatory+reserve+for+early+and+accurate+prediction+of+hemodynamic+compromise:+a+review+of+the+underlying+physiology.">The compensatory reserve for early and accurate prediction of hemodynamic compromise: a review of the underlying physiology.</a> Shock. 45 (6), 580-590 (2016).</li><li>Eastridge, B. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Death+on+the+battlefield+(2001-2011):+Implications+for+the+future+of+combat+casualty+care.">Death on the battlefield (2001-2011): Implications for the future of combat casualty care.</a> Journal of Trauma and Acute Care Surgery. 73 (6), S431-S437 (2012).</li><li>Orlinsky, M., Shoemaker, W., Reis, E. D., Kerstein, M. 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A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Lower+body+negative+pressure+as+a+model+to+study+progression+to+acute+hemorrhagic+shock+in+humans.">Lower body negative pressure as a model to study progression to acute hemorrhagic shock in humans.</a> J. Appl. Physiol. 96, 1249-1261 (2004).</li><li>Convertino, V. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inspiratory+resistance+maintains+arterial+pressure+during+central+hypovolemia:+implications+for+treatment+of+patients+with+severe+hemorrhage.">Inspiratory resistance maintains arterial pressure during central hypovolemia: implications for treatment of patients with severe hemorrhage.</a> Crit Care Med. 35 (4), 1145-1152 (2007).</li><li>Carter, R., Hinojosa-Laborde, C., Convertino, V. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Variability+in+integration+of+mechanisms+associated+with+high+tolerance+to+progressive+reductions+in+central+blood+volume:+the+compensatory+reserve.">Variability in integration of mechanisms associated with high tolerance to progressive reductions in central blood volume: the compensatory reserve.</a> Physiol Reports. 4 (1), (2016).</li><li>Convertino, V. A., Sather, T. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Vasoactive+neuroendocrine+responses+associated+with+tolerance+to+lower+body+negative+pressure+in+humans.">Vasoactive neuroendocrine responses associated with tolerance to lower body negative pressure in humans.</a> Clin. Physiol. 20, 177-184 (2000).</li><li>Convertino, V. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Use+of+advanced+machine-learning+techniques+for+noninvasive+monitoring+of+hemorrhage.">Use of advanced machine-learning techniques for noninvasive monitoring of hemorrhage.</a> J. Trauma. 71 (1 Suppl), S25-S32 (2011).</li><li>Convertino, V. A., Rickards, C. A., Ryan, K. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Autonomic+mechanisms+associated+with+heart+rate+and+vasoconstrictor+reserves.">Autonomic mechanisms associated with heart rate and vasoconstrictor reserves.</a> Clin. Auton. Res. 22, 123-130 (2012).</li><li>Rickards, C. A., Ryan, K. L., Cooke, W. H., Convertino, V. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tolerance+to+central+hypovolemia:+the+influence+of+oscillations+in+arterial+pressure+and+cerebral+blood+velocity.">Tolerance to central hypovolemia: the influence of oscillations in arterial pressure and cerebral blood velocity.</a> J. Appl. Physiol. 111 (4), 1048-1058 (2011).</li><li>Johnson, B. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reductions+in+central+venous+pressure+by+lower+body+negative+pressure+of+blood+loss+elicit+similar+hemodynamic+responses.">Reductions in central venous pressure by lower body negative pressure of blood loss elicit similar hemodynamic responses.</a> J. Appl. Physiol. 117, 131-141 (2014).</li><li>van Helmond, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Coagulation+Changes+during+Lower+Body+Negative+Pressure+and+Blood+Loss+in+Humans.">Coagulation Changes during Lower Body Negative Pressure and Blood Loss in Humans.</a> Am. J. Physiol. Heart Circ. Physiol. 309, H1591-H1597 (2015).</li><li>Gerhardt, R., Berry, J., Blackbourne, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Analysis+of+life-saving+interventions+performed+by+out-of-hospital+combat+medical+personnel.">Analysis of life-saving interventions performed by out-of-hospital combat medical personnel.</a> J. Trauma. 71, S109-S113 (2011).</li><li>Pinsky, M. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hemodynamic+evaluation+and+monitoring+in+the+ICU.">Hemodynamic evaluation and monitoring in the ICU.</a> Chest. 132 (6), 2020-2029 (2007).</li><li>Rivers, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Early+goal-directed+therapy+in+the+treatment+of+severe+sepsis+and+septic+shock.">Early goal-directed therapy in the treatment of severe sepsis and septic shock.</a> N.Engl.J.Med. , 1368-1377 (2001).</li><li>Rivers, E. 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Using LBNP to cause progressive and continuous reductions in central blood volume, we were able to induce a typical response of hemodynamic decompensation in the subject, characterized by a sudden onset of hypotension and bradycardia (Figure 7). It is important to understand that the integrated compensatory response to hemorrhage is very complex,19 resulting in significant individual variability in the tolerance to blood loss.1 As such, some individuals have relatively responsive co...

The most important function of the cardiovascular system is the control of adequate perfusion (blood flow and oxygen delivery) to all tissues of the body through homeostatic regulation of arterial blood pressure. Various mechanisms of compensation (e.g., autonomic nervous system activity, cardiac rate and contractility, venous return, vasoconstriction, respiration) contribute to maintain normal physiological levels of oxygen in the tissues.1 Reductions in circulating blood volume such as those caused by hemorrhage can compromise the ability of cardiovascular compensatory mechanisms and ultimately lead to low arterial blood pressure, serious tissue hypoxia, and circulatory shock that can be fatal.
Circulatory shock caused by severe bleeding (i.e., hemorrhagic shock) is a leading cause of death due to trauma.2 One of the most challenging aspects of preventing a patient from developing shock is our inability to recognize its early onset. Early and accurate assessment of the progression toward the development of shock is currently limited in the clinical setting by technologies (i.e., medical monitors) that provide measurements of vital signs that change very little in the early stages of blood loss because of the body&#39;s numerous compensatory mechanisms for regulating blood pressure.3-6 As such, the capability to measure the sum total of the body&#39;s reserve to compensate for blood loss represents the most accurate reflection of tissue perfusion state and the risk of developing shock.1 This reserve is called the compensatory reserve which can be accurately assessed by real-time measurements of changes in features of the arterial waveform.1 Depletion of the compensatory reserve replicates the terminal cardiovascular instability observed in critically ill patients with sudden onset of hypotension; a condition known as hemodynamic decompensation.7
The relationship between the utilization of the compensatory reserve and regulation of blood pressure during ongoing blood loss in humans can be demonstrated in the laboratory using a comprehensive set of physiological measurements (e.g., blood pressures, heart rate, arterial blood oxygen saturation, stroke volume, cardiac output, vascular resistance, respiration rate, pulse character, mental status, end-tidal CO2, tissue oxygen) provided by standard physiological monitoring during continuous progressive reductions in central blood volume similar to those that occur during hemorrhage. Lowered central blood volume can be induced noninvasively with progressive increases in Lower Body Negative Pressure (LBNP).8 Using this combination of physiological measurements and LBNP, the conceptual understanding of how to assess the body&#39;s ability to compensate for reduced central blood volume can easily be demonstrated. This study depicts the prelab preparation, the demonstration of compensatory response in relation to other physiological responses during simulated hemorrhage, and the postlab evaluation of results. The experimental techniques necessary for making measurements of compensatory reserve are demonstrated in a human volunteer.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Dynamic Research Evaluation Workstation (DREW) data acquisition syetem</td>
			<td>NA</td>
			<td>NA</td>
			<td>Custom Built by ISR personnel.&#160; The DREW allows for time synchronization of both digital and analog signal data collection from up to 16 independent instruments with a sampling rate of 1000 Hz.</td>
		</tr>
		<tr>
			<td>Finometer</td>
			<td>Finapress Medical Systems (FMS)</td>
			<td>Model 1</td>
			<td>Device that provides non-invasive, continuous measurements of brachial artery blood pressure and arterial oxygen saturation (SpO2) using two separate infrared finger photophlethymography cuff sensors.</td>
		</tr>
		<tr>
			<td>BCI Capnocheck Plus</td>
			<td>Smith Medical PM Inc.</td>
			<td>9004</td>
			<td>Capnograph used to measure&#160; end tidal CO2 and respiration rate</td>
		</tr>
		<tr>
			<td>CipherOX&#160;</td>
			<td>Flashback Technologies Inc.</td>
			<td>R200</td>
			<td>Investigational device used to calculate Compensatory Reserve Index (CRI)</td>
		</tr>
		<tr>
			<td>Nonin 9560 Pulse Oximeter</td>
			<td>Nonin</td>
			<td>9560</td>
			<td>finger pulse oximeter</td>
		</tr>
		<tr>
			<td>Lower Body Negative Pressure Chamber (LBNP)</td>
			<td>NASA</td>
			<td>79K32632-1</td>
			<td>Custom Chamber built by NASA</td>
		</tr>
		<tr>
			<td>ECG Biotach</td>
			<td>Gould</td>
			<td>13-6615-65</td>
			<td>Electrocardiograph for measuring ECG</td>
		</tr>
		<tr>
			<td>Nasal CO2 Sample Line</td>
			<td>Salter Labs</td>
			<td>REF 4000</td>
			<td>Latex free nasal cannula for sampling expired air</td>
		</tr>
	</tbody>
</table>

integrated compensatory responses in a human model of hemorrhage

Hemorrhage is the leading cause of trauma-related deaths, partly because early diagnosis of the severity of blood loss is difficult. Assessment of hemorrhaging patients is difficult because current clinical tools provide measures of vital signs that remain stable during the early stages of bleeding due to compensatory mechanisms. Consequently, there is a need to understand and measure the total integration of mechanisms that compensate for reduced circulating blood volume and how they change during ongoing progressive hemorrhage. The body&#39;s reserve to compensate for reduced circulating blood volume is called the &#39;compensatory reserve&#39;. The compensatory reserve can be accurately evaluated with real-time measurements of changes in the features of the arterial waveform measured with the use of a high-powered computer. Lower Body Negative Pressure (LBNP) has been shown to simulate many of the physiological responses in humans associated with hemorrhage, and is used to study the compensatory response to hemorrhage. The purpose of this study is to demonstrate how compensatory reserve is assessed during progressive reductions in central blood volume with LBNP as a simulation of hemorrhage.

The LBNP procedure causes a reduction in air pressure around the lower torso and legs. As this vacuum is progressively increased, blood volume shifts from the head and upper torso to the lower body to create a state of central hypovolemia. The progressive reduction in central blood volume (i.e., LBNP) produces significant alterations in the features of the arterial waveform measured with the infrared finger photoplethysmograph (Figure 5). The Compensatory Reserve...

Watch this Scientific Journal Video about Integrated Compensatory Responses in a Human Model of Hemorrhage at JoVE.com

Integrated Compensatory Responses in a Human Model of Hemorrhage

The purpose of this protocol is to demonstrate the techniques for measuring compensatory responses to reduced central blood volume using lower body negative pressure as a noninvasive experimental model of human hemorrhage which can be used to quantify the total integration of compensatory mechanisms to blood volume deficit in humans.

Hemorrhage is the leading cause of trauma-related deaths, partly because early diagnosis of the severity of blood loss is difficult. Assessment of ...

The overall goal of this procedure is to simulate central hypovolimia associated with hemorrhage in humans using lower-body negative pressure and to assess the individual's capacity to compensate during this challenge. Lower-body negative pressure is a valid model of human hemorrhage, which has been used to identify early predictors of hemorrhagic shock. The main advantages of this procedure are that all measurements are acquired by non-invasive methods and that tolerance to hemorrhage can be safely assessed in the subjects.Using lower-body negative pressure, we developed the measurement of compensatory reserve which can provide an early assessment of the progression towards shock during hemorrhage and is more accurate than the current tools to monitor vital signs. Compensatory reserve reflects the integration of all physiological compensatory mechanisms involved in the response to hemorrhage in an individual patient and therefore tracks the progression to shock with a high degree of specificity. Prior to the study visit, instruct the subject to avoid caffeine, alcohol, and strenuous exercise 24 hours prior to testing and to avoid eating at least two hours prior in the even that hemodynamic decompensation induces nausea.On the study day, begin by turning on all the equipment that requires warm-up and calibration:a data acquisition system, two infrared finger sensors, a capnograph, and a finger pulse oximeter. Synchronize all of the instruments with internal clocks by adjusting the timestamp on each instrument to match a lab master-clock that should be used to mark time during the experiment. Next, escort the subject into an exam room and perform a medical screening exam to ensure that the subject meets minimal health requirements as well as all inclusion criteria.Then, bring the subject into the testing room, inform them about the experimental procedure, and obtain written consent to participate in the study. Next, place the neoprene lower-body negative pressure, or LBNP, skirt on the subject. Insure that the skirt is snug around the waist and torso in order to create an airtight seal.Instruct the subject to lay supine on the bed of the LBNP chamber while straddling a stationary post to secure the torso in place. Then, ask the subject to relax their lower body. Slide the bed into the chamber and attach the neoprene skirt to the chamber opening in order to create an airtight seal.Next, place electrocardiogram, or ECG, electrodes on the right and left humeral clavicular joints and on the right and left lower ribs in a modified lead to configuration for continuous measurement of heart rate. Position the subject's arms on the arm rests, adjusted so that the hands are supported at heart level. Place an infrared finger photoplethysmography device on the left and right middle fingers for continuous non-invasive beat to beat measurement of blood pressure.Enter subject information to enable the appropriate assumptions for calculation of stroke volume, cardiac output, and peripheral vascular resistance by the model flow algorithm. Then, attach the finger cuffs to the pressure monitors. Calibrate the devices and record blood pressure according to the manufacturer instructions.Then, place the finger pulse oximeter on the right index finger for continuous measurement of compensatory reserve. Finally, place an nasal cannula on the subject and instruct them to breathe through their nose to assure sensitive reflections in inspiration and expiration. Connect the nasal cannula to the capnograph for the continuous measurement of respiration and end tidal CO2.Begin data recording by clicking the start button on the data acquisition system and record baseline data for five minutes. Initiate the first level of central hypovolimia by turning on the vacuum motor and setting negative pressure to negative 15 millimeters of mercury and hold this pressure for five minutes. Then, increase the LBNP to negative 30 millimeters of mercury, negative 45 millimeters of mercury, negative 60 millimeters of mercury, and to negative 70 millimeters of mercury and hold each pressure for five minutes.Continue to increase LBNP levels by negative 10 millimeters of mercury every five minutes until negative 100 millimeters of mercury LBNP or the point of hemodynamic decompensation where the compensatory reserve index, or CRI value, is zero. During the experiment, observe the progressive decrease in the reserve to compensate which is represented by a gradual reduction in the colored bar on the screen. As the bar changes colors from green to yellow to red, notice that the measurement of the CRI moves from a value of one to zero.After the experiment is complete, terminate the LBNP by pressing the pressure release button on the LBNP chamber. Continue recording data on the data acquisition system for 10 minutes after the cessation of LBNP. Stop recording data at the end of the 10 minute recovery period by clicking the stop button on the data acquisition system.Detach all instrumentation from the subject and remove the subject from the LBNP chamber. Ask the subject to sit after stepping down from the LBNP platform to ensure they are symptom-free before leaving the laboratory. Finally, download data files from the acquisition system for extraction of the CRI, mean arterial pressure, heart rate, and SpO2 values.The progressive reduction in central blood volume, or LBNP, produces significant alterations in the features of the arterial wave form. Here, the values for mean arterial pressure, MAP, heart rate, SpO2, CRI, and LBNP are plotted against time. CRI decreases early and progressively throughout the multiple steps of LBNP while changes in heart rate, mean arterial pressure, and SpO2 occur during later phases of hemorrhage.The LBNP technique will continue to be used as a valid model of human hemorrhage to provide data for creating, testing, and refining future algorithms and devices to measure compensatory reserve. The ability to measure the compensatory changes associated with blood loss is critical to providing acute care in emergency situations in both military and civilian settings.

Research

JoVE Journal

Medicine

Stem Cell Transplantation in an in vitro Simulated Ischemia/Reperfusion Model

Stem Cell Transplantation in an in vitro Simulated Ischemia/Reperfusion Model

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