Name: a model to simulate clinically relevant hypoxia in humans
Uploaded: 2016-12-22T14:00:00
Description: Watch this Scientific Journal Video about A Model to Simulate Clinically Relevant Hypoxia in Humans at JoVE.com

Special thanks to all volunteers who participated in the original study. The work of L. Eichhorn was supported through a scholarship of the Else-Kr&#246;ner-Fresenius Foundation. The authors would like to thank Springer, Part of Springer Science+Business Media, for copyright clearance (License Number 3894660871180) and the kind permission of reusing previously published data.

Ethics statement 
All procedures performed in studies involving human participants were in accordance with the ethical standards of the 1964 Helsinki declaration and its later amendments. The design of this study was approved by the local ethics committee of the University Hospital of Bonn, Germany.
NOTE: Ensure that subjects are in good and healthy condition, free of any anti-hypertensive medicine and at least 24 hours free of catecholamine inducing agents like caffeine or equal substances.
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<ol>
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The total apnea time is mainly caused by lung size and oxygen consumption per minute and influenced by an individuals&#39; ability to withstand the breathing reflex caused by increasing pCO2 or decreasing pO2. Apnea divers are trained to maximize their breath-hold duration and are used to doing so in maximal inspiration. Therefore, the time until hypoxia is detectable differs between individuals and depends on the subject&#39;s physical condition and training status and might even vary by their dail...

Clinically relevant acute hypoxia and concomitant hypercapnia is mostly seen in patients with obstructive sleep apnea syndrome (OSAS), acute airway obstruction or during cardiopulmonary resuscitation. Major limitations in the field of OSAS and other hypoxemic conditions include the limited transferable knowledge about the pathophysiology derived from animal studies and that human models are non-existent 1. To mimic hypoxia in humans, hypoxic gas mixtures have so far been used 2-7. However, these conditions are more representative of high altitude surroundings than of clinical situations where hypoxia, in general, is accompanied by hypercapnia. To monitor tissue oxygenation during cardiac arrest and resuscitation, animal studies have been performed 8 to investigate physiological compensatory mechanisms.
Apneic divers are healthy athletes capable of depressing the breathing impulse that is evoked by low arterial oxygen saturation 9 and an increased pCO2 10,11. We investigated apneic divers in order to mimic clinical situations of acute hypoxia and concomitant hypercapnia 12. This model can be used to evaluate clinical setups, improve the pathophysiological understanding of patients with OSAS or pathological breathing disorders, and reveal new possibilities for studying a potential counter balancing mechanism in cases of apnea. Furthermore, different techniques to detect hypoxia in humans can be tested for feasibility and accuracy in the case of dynamic hypoxia that is present in emergency situations (i.e., airway obstructions, laryngospasm or cannot intubate, cannot ventilate situations) or to simulate intermittent hypoxia in patients with OSAS.
Noninvasive techniques to detect hypoxia in humans are limited. Peripheral pulse oximetry (SpO2) is an approved tool in pre-hospital and hospital settings to detect hypoxia 13. The method is based on light absorption of hemoglobin. However, SpO2 measurement is limited to peripheral arterial oxygenation and cannot be used in cases of pulseless electrical activity (PEA) or centralized minimal circulation 14. In contrast, Near-Infrared Spectroscopy can be used to evaluate cerebral tissue oxygen saturation (rSO2) in real-time during PEA, during hemorrhagic shock or following subarachnoid hemorrhage 15-19. Its use is constantly growing 20 and methodological studies have revealed a positive correlation between SpO2 and rSO2 3,4.
In this study, we provide a model to simulate clinically relevant hypoxia in humans and present a step-by-step methodology to compare peripheral pulse oximetry and NIRS in case of de- and re-saturation. By analyzing physiological data in case of apnea, our understanding of counter balancing mechanisms can be improved.

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			<td height="60" style="height:60px;width:88px;">SpO2</td>
			<td style="width:88px;">Dr&#228;ger Medical AG&#38;CO.KG</td>
			<td style="width:88px;">SHP ACC MCABLE-Masimo Set</td>
			<td style="width:88px;">peripheral SpO2-Monitoring</td>
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		<tr height="80">
			<td height="80" style="height:80px;width:88px;">Non Invasive Blood Pressure (NIBP)</td>
			<td style="width:88px;">Dr&#228;ger Medical AG&#38;CO.KG</td>
			<td style="width:88px;">NIBP cuff M+,&#160; MP00916&#160;</td>
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			<td height="60" style="height:60px;width:88px;">Electrocardiographic (ECG) &#160;</td>
			<td style="width:88px;">Dr&#228;ger Medical AG&#38;CO.KG</td>
			<td style="width:88px;">Infinity M540 Monitor</td>
			<td style="width:88px;">ECG monitoring</td>
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			<td height="60" style="height:60px;width:88px;">Docking station</td>
			<td style="width:88px;">Dr&#228;ger Medical AG&#38;CO.KG</td>
			<td style="width:88px;">M500 Docking Station</td>
			<td style="width:88px;">connection of M540 to laptop</td>
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			<td height="80" style="height:80px;width:88px;">NIRS</td>
			<td style="width:88px;">NONIN Medical&#8217;s EQUANOX</td>
			<td style="width:88px;">Model 7600 Regional Oximeter System</td>
			<td style="width:88px;">measuring of cerebral and&#160; tissue oxygenation</td>
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		<tr height="120">
			<td height="120" style="height:120px;width:88px;">NIRS diodes</td>
			<td style="width:88px;">EQUANOX Advance Sensor</td>
			<td style="width:88px;">Model 8004CA</td>
			<td style="width:88px;">suited for measuring cerebral and somatic oxygen-saturation</td>
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		<tr height="20">
			<td height="20" style="height:20px;width:88px;">Laptop&#160;</td>
			<td style="width:88px;"></td>
			<td style="width:88px;"></td>
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			<td height="80" style="height:80px;width:88px;">DataGrabber</td>
			<td style="width:88px;">Dr&#228;ger Medical AG&#38;CO.KG</td>
			<td style="width:88px;">DataGrabber v2005.10.16</td>
			<td style="width:88px;">software to synchronize M540 with laptop</td>
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			<td height="80" style="height:80px;width:88px;">eVision</td>
			<td style="width:88px;">Nonin Medical. Inc.</td>
			<td style="width:88px;">Version 1.3.0.0</td>
			<td style="width:88px;">software to synchronize NONIN with laptop</td>
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a model to simulate clinically relevant hypoxia in humans

In case of apnea, arterial partial pressure of oxygen (pO2) decreases, while partial pressure of carbon dioxide (pCO2) increases. To avoid damage to hypoxia sensitive organs such as the brain, compensatory circulatory mechanisms help to maintain an adequate oxygen supply. This is mainly achieved by increased cerebral blood flow. Intermittent hypoxia is a commonly seen phenomenon in patients with obstructive sleep apnea. Acute airway obstruction can also result in hypoxia and hypercapnia. Until now, no adequate model has been established to simulate these dynamics in humans. Previous investigations focusing on human hypoxia used inhaled hypoxic gas mixtures. However, the resulting hypoxia was combined with hyperventilation and is therefore more representative of high altitude environments than of apnea. Furthermore, the transferability of previously performed animal experiments to humans is limited and the pathophysiological background of apnea induced physiological changes is poorly understood. In this study, healthy human apneic divers were utilized to mimic clinically relevant hypoxia and hypercapnia during apnea. Additionally, pulse-oximetry and Near Infrared Spectroscopy (NIRS) were used to evaluate changes in cerebral and peripheral oxygen saturation before, during, and after apnea.

Figure 1 displays simultaneous recordings of SpO2 and NIRS values (NIRScerebral and NIRStissue) during apnea in one patient. Total apnea time was 363 sec. Following apnea NIRS and SpO2 values remained stable for approximately 140 sec. A decrease in SpO2 was detected after 204 sec by peripheral SpO2 whereas a decrease of NIRScerebral was detected after 238 sec. The lowest measured SpO2 ...

Watch this Scientific Journal Video about A Model to Simulate Clinically Relevant Hypoxia in Humans at JoVE.com

A Model to Simulate Clinically Relevant Hypoxia in Humans

Hypoxia simulation in humans has usually been performed by inhaling hypoxic gas mixtures. For this study, apneic divers were used to simulate dynamic hypoxia in humans. Additionally, physiological changes in desaturation and re-saturation kinetics were evaluated with non-invasive tools such as Near-Infrared-Spectroscopy (NIRS) and peripheral oxygenation saturation (SpO2).

In case of apnea, arterial partial pressure of oxygen (pO2) decreases, while partial pressure of carbon dioxide (pCO2) increases. To avoid damage to ...

The overall goal of this model is to simulate apnoea caused hypoxia and hypercapnia in a human model with a focus on intermittent apnoea, which occurs during sleep apnoea, and emergencies such as air way obstruction. This model may help to understand physiological mechanisms to avoid hypoxic damage to the brain despite prolonged apnoea. The main advantage of this dynamic model is that we could simulate clinically relevant hypoxia in humans.Apnoea dependent hypoxia often decreases heart rate. Hypoxia caused by lowered oxygen and the inspired air increases heart rate. Thus, different models of hypoxia induce opposite effects in circulation.Our reproducible model enables us to investigate different technical devices. This gives us an opportunity to focus on different physiological aspects of apnoea without changing the setup or model. Prior to attaching electrodes to a subject, clean the attachment points using 70%alcohol.Now, place an NIRS electrode over the frontal polar two locus on the right side of the forehead above the eyebrow, and to the right of the midsagittal sulcus. Use a second electrode to measure the peripheral tissue oxygenation. Place it on the inside of the lower arm.Avoid placing this electrode above a venous plexus or an artery. The saturation should be greater than 80%Before taking a cerebral tissue oxygenation value, wait for the NIRS signal to show a variation of 3%or less for at least five minutes. Similarly, wait for the peripheral oxygen level signal to stabilize.Next, place the ECG electrodes on the chest where there is no hair. Place the R-lead on the sternocostal head of the pectoralis major right. Place the L-lead on the sternocostal head of pectoralis major left.Place the C-Lead on the fifth intercostal space in the middle of the medial clavicular line. Place the F-lead on the left lower rib edge, and place the N-lead on the right lower rib edge. Now, measure peripheral pulse oximetry from a fingertip on the same extremity used to measure peripheral tissue oxygenation.Next, measure non-invasive blood pressure using a blood pressure cuff on the contra-lateral extremity from the peripheral pulse oximetry measurement. In the programmable settings, choose a one-minute interval, and choose NIBP. At least 20 minutes before the apnoea, establish an intravenous line into the medial cubital vein on the right or left arm to draw blood samples during and after the apnoea.Before beginning, synchronize the internal clocks of the monitoring devices, so the measurements are synchronized. Next, send a network cable from the computer to the monitor device. Attach it at the docking station.Then, program in the correct network settings and the software will be able to control the device and save data. Also, position the monitor so the data is not visible to the subject. Check the signals from the NIRS electrodes.If any one is too erratic, reposition the electrode. Be sure to avoid placing the electrode over the bigger venous plexus, or any arteries. The signal should then stabilize.A highly variable cerebral NIRS signal may be due to hyperventilation. Instruct the subject to breathe more slowly with less tidal volume, and reevaluate the signal. Have the subjects rest for at least 15 minutes in a prone position, and instruct them to breathe normally using 15 or fewer breaths per minute.Before taking a baseline, draw blood samples. Two things to remember, are to not use the first five milliliters of drawn blood, and always flush the catheter after each collection using sterile saline. Throughout the test timeline draw blood samples as needed.Double check each device's functionality and signal quality before proceeding. Also, ensure that electrodes cannot be removed by involuntary movements of the test subject at the end of apnoea. In the last two minutes of preparation for the apnoea test, count down the time verbally.Then, have the subject indicate their last three inhalations with their fingers. The end of the final breath marks the start of the apnoea. Record this time point on the NIRS device.The apnoea should be performed as long as possible. During the second half, movements of the chest and stomach are common, and indicate the struggle phase. The end of apnoea is marked by the first inspiration.Record this time point on the NIRS device. To process the data from the monitor device, open the saved file on the computer. First, click review to access the trend monitor and select tools, and then option in the menu submask.If needed, the time interval can be changed via the trend interval. Now, select the mask trends and save the data. Use resultingtrends.txtdata to open it in a spreadsheet program, where it can be analyzed. To process the data from the NIRS device, open the software on the computer and connect the NIRS device via WiFi. Then, transfer the data from the NIRS device and save it in CSV format to open as a spreadsheet.In the analysis, do not include the final three inspirations pre-apnoea in the baseline values or the first 30 seconds after the maximal inspiration at the beginning of the apnoea. During a six minute apnoea of one subject, simultaneous recordings were made of peripheral oxygen saturation, and NIRS. Interestingly, after initiation of the apnoea, a decrease in oxygen saturation was detected earlier by peripheral oxygen saturation monitoring, compared to cerebral NIRS monitoring.In a study of ten apneic divers, cerebral NIRS values decreased significantly later than saturation values measured by pulse oximetry. Even in comparison to pulse oximetry, peripheral NIRS showed the earliest desaturation. After re-start of respiration, re-saturation was detected significantly earlier by cerebral NIRS compared to peripheral O2 saturation measured by pulse oximetry.There was no time delay notable between peripheral NIRS and pulse oximetry. From another point of view, de-saturation values and total apnoea time was normalized to 100%After watching this video, you should have a good understanding of how to measure O2 saturation in different parts of the body. Our investigation revealed physiological mechanisms to avoid hypoxic damage.In case of apnoea, redistribution of blood flow helps to maintain an adequate oxygen supply to the brain while peripheral tissues are already desataurated.

Research

JoVE Journal

Medicine

In vivo Bioluminescence Imaging of Tumor Hypoxia Dynamics of Breast Cancer Brain Metastasis in a Mouse Model

In vivo Bioluminescence Imaging of Tumor Hypoxia Dynamics of Breast Cancer Brain Metastasis in a Mouse Model

It is well recognized that tumor hypoxia plays an important role in promoting malignant progression and affecting therapeutic response negatively. There ...

Spectral Karyotyping to Study Chromosome Abnormalities in Humans and Mice with Polycystic Kidney Disease

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Optimization of High Grade Glioma Cell Culture from Surgical Specimens for Use in  Clinically Relevant Animal Models and 3D Immunochemistry

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Candida albicans biofilm development on biotic and/or abiotic surfaces represents a specific threat for hospitalized patients. So far, C. albicans ...

Glutamate and Hypoxia as a Stress Model for the Isolated Perfused Vertebrate Retina

Neuroprotection has been a strong field of investigation in ophthalmological research in the past decades and affects diseases such as glaucoma, retinal ...

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

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Although targeted therapies are initially effective, resistance inevitably emerges. Several methods, such as genetic analysis of resistant clinical ...

A Thrombotic Stroke Model Based On Transient Cerebral Hypoxia-ischemia

Stroke research has endured many setbacks in translating neuroprotective therapies into clinical practice. In contrast, the real-world therapy (tPA ...

A Protocol to Acquire the Degenerative Tenocyte from Humans

Tendinopathy, a painful condition that develops in response to tendon degeneration, is on the rise in the developed world due to increasing physical ...

Isometric Contractility Measurement of the Mouse Mesenteric Artery Using Wire Myography

The wire myograph technique is used to assess the contractility of vascular smooth muscles in response to depolarization, GPCR agonists/inhibitors and ...

Conducting Maximal and Submaximal Endurance Exercise Testing to Measure Physiological and Biological Responses to Acute Exercise in Humans

Regular physical activity has a positive effect on human health, but the mechanisms controlling these effects remain unclear. The physiologic and biologic ...