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Our intent was to observe the effect of simulated altitude exposure on the intracranial pressure (ICP) of New Zealand white rabbits. It is theorized that the hypoxia of high altitude causes a rise in ICP, which may play a role in the pathogenesis of acute mountain sickness (AMS). Dexamethasone is a medication used to treat AMS, but its mechanism of action in this disease is unknown. It is believed that dexamethasone may lower ICP and thereby relieve the symptoms of AMS, but to our knowledge no study has demonstrated the effect dexamethasone has on ICP during altitude exposure.
Methods.
We placed subdural ICP catheters in 10 rabbits and then placed the rabbits in an altitude chamber at simulated 5000 m for 6 hours. Each rabbit was exposed to simulated altitude twice, once after several doses of dexamethasone and once after several doses of saline (placebo). We followed ICP measurements throughout the altitude chamber flights, comparing baseline with 6-hour ICP levels.
Results.
After 6 hours of altitude exposure, there was no significant change in the ICP of rabbits with either saline or dexamethasone administration. We were unable to replicate the altitude-induced rise in ICP observed in other animal studies.
Conclusions.
Intracranial pressure does not rise within the subdural space in rabbits during altitude exposures of 6 hours or less. Further, we are unable to draw conclusions regarding the mechanism of action of dexamethasone in the cerebral dynamics of AMS.
Acute mountain sickness (AMS) commonly occurs in individuals who ascend quickly from sea level to high altitudes. It is a syndrome marked by headache and generalized malaise, and its symptoms include anorexia, nausea, vomiting, lassitude, apathy, and fatigue.
The pathophysiologic mechanism responsible for AMS has not been clearly demonstrated. The most widely accepted theory is that altitude-induced hypoxia initiates the cascade of events resulting in AMS.
It is thought that hypoxia induces a change in cerebral dynamics, but the exact nature of that change is unclear. Numerous human and animal studies have been done to study various cerebral parameters to include cerebral blood flow, cerebral metabolic rate for oxygen, brain weight, magnetic resonance imaging of the corpus callosum, and intracranial pressure (ICP) measurements.
For our study we chose to investigate the response of ICP to hypoxia in an animal model.
Several animal studies have investigated the relationship of ICP to hypoxia. The studies have had mixed results, but some of them have demonstrated a rise in ICP when animals were exposed to hypoxic conditions.
This rise in ICP may be an indicator of AMS. Taking the model one step further, we also wanted to see if one of the treatments for AMS, dexamethasone, had an effect on ICP.
Dexamethasone is useful in the treatment of AMS, and numerous studies have documented its effectiveness as both prophylaxis and treatment of this syndrome.
Although it is useful, the mechanism of action of dexamethasone in this disorder is unclear. To our knowledge, no study has actually documented the cerebral dynamics of AMS in response to dexamethasone. More precisely, the ICP response to dexamethasone during altitude exposure has not been evaluated.
To evaluate the effects of altitude exposure and dexamethasone on ICP, we placed subdural ICP catheters in New Zealand white rabbits and then exposed the rabbits to simulated altitude within a hypobaric chamber. Our study was a prospective, placebo-controlled trial conducted in crossover fashion. The aims of this study were 1) to observe the effect of altitude exposure on ICP and 2) to measure the prophylactic effect of dexamethasone on ICP.
Methods
Animals
Ten New Zealand white rabbits (Oryctolagus cuniculus) were obtained for this study (Myrtle's Rabbitry, Thompson Station, TN), and our local Institute Animal Care and Use Committee approved the protocol. The animals were cared for under the surveillance of our staff veterinarians and in compliance with US Department of Health and Human Services Guide for the Care and Use of Laboratory Animals. The rabbits weighed 3.6–6.2 kg and were specific pathogen free. They were housed separately in cages and had ad libitum access to food and water. However, the animals were not fed during their hypobaric exposure because of the relatively small confines of the animal chamber.
Surgery
The technique of ICP catheter placement is based upon a method described by Storrow and Hoxie.
Briefly, it involves placing an ICP catheter (Codman MicroSensorTM Pressure Transducer, Johnson & Johnson Professional, Raynham, MA) into the subdural space by drilling a trephination hole through the rabbit skull and then gently incising the dura for direct placement of the catheter.
Each rabbit was taken to the operating suite for placement of its ICP catheter under sterile conditions. They were endotracheally intubated and given a single intravenous dose of ceftriaxone, 50 mg/kg, immediately prior to surgery. General anesthesia (isoflurane or sevoflurane) was used to induce the rabbits and was maintained throughout the surgical procedure. A 2.5-cm incision was made in the skin over the coronal suture, and the periosteum was exposed by dissecting through the overlying soft tissue. A 2-mm diameter diamond burr was used to make a 5-mm trephination hole through the skull to expose the dura. The hole was made 5 mm rostral to the coronal suture and 3 mm to the left of the midline in a relatively flat portion of the skull. A vein pick was used to incise the dura as the tip of the ICP catheter was gently introduced into the subdural space. An acceptable ICP waveform and pressure reading was then verified on the monitor, and the catheter was adhered to its location using cyanoacrylate gel, allowing several minutes for drying.
Prior to insertion, the ICP catheter was placed within silicone tubing, which acted as a protective encasement. This tubing was tunneled subcutaneously from a point between the scapulae to the incision site in the scalp. Placing the catheter within silicone tubing helped prevent catheter fracture, and securing the tubing between the scapulae helped prevent catheter migration. Sutures were used to close the fascia and skin overlying the skull and to secure the catheter at its exit point between the scapulae. The rabbits were placed in special rabbit vests (Alice King Chatham Medical Arts, Hawthorne, CA) after surgery. The vests had a pocket to allow storage of the coiled ICP catheters when not in use. The animals were given intravenous buprenorphine for pain control postoperatively and rested 1 day prior to any simulated altitude exposure. Buprenorphine is the standard postoperative pain medication used by the veterinarians in our institution.
Simulated Altitude Exposure
During the next portion of the study, the rabbits were exposed to altitude twice, once after saline administration and once after dexamethasone administration. Not all the rabbits were given the same medication initially to account for interventions that may have either raised or lowered ICP. For instance, we believed that the surgical procedure itself might have the potential to raise ICP, whereas the use of buprenorphine, with its half-life of 37 hours, may have the potential to lower ICP. For these reasons, 4 rabbits received saline initially and 6 rabbits received dexamethasone initially.
Starting 24 hours prior to hypobaric exposure, the rabbits received either 0.5 mg of dexamethasone or an equivalent volume of saline intravenously every 8 hours for a total of 4 doses. Typically, the animals were dosed at 0800, 1600, 0000, and then finally at 0800 hours, just before hypobaric exposure. This regimen, adjusted for rabbit metabolism, was designed to simulate prophylactic dexamethasone taken by mountaineers before ascent to high altitudes.
Study rabbits were then placed in our small-animal altitude chamber, and a baseline ICP measurement was recorded. The animals were depressurized from local ambient pressure (local altitude 150 m, 760 mm Hg) to 5000 m over 30 minutes, and subsequent ICP measurements were recorded every 15 minutes until completion of the flight. Temperature, humidity, and oxygen content were also monitored every 15 minutes. At the completion of the hypobaric exposure, the chamber was repressurized to ambient pressure, the ICP catheters were disconnected from the monitors, and the animals were returned to their cages.
The rabbits were given 4 days for medication washout after their first exposure to hypobaric pressure. In the second phase of the study, the rabbits that had received saline were crossed over to the dexamethasone arm of the study, whereas the animals that had received dexamethasone were crossed over to the saline arm of the study. The same medication administration schedule was followed, and the rabbits were exposed to hypobaric pressure for a second time. Rabbits were euthanized at the completion of the study.
Statistics
Student's paired t tests were used to test for changes in ICP for both groups at selected time intervals. Of primary interest to investigators was the change in ICP measurements from the start to the end of the 6-hour hypobaric exposure. A statistical power analysis indicates that a sample of 10 animals provided a 93% chance of detecting a pressure change of 4 mm when testing at the 0.05 alpha level.
Results
There were no significant rises in ICP in either group, as shown in Table 1. When the study rabbits received saline, 2 exhibited a rise in ICP after 6 hours in the hypobaric chamber, 1 exhibited no change, and 7 exhibited a decrease in ICP. When the study rabbits received dexamethasone, 4 exhibited a rise in ICP after 6 hours in the hypobaric chamber, 4 exhibited no change, and 2 exhibited a decrease in ICP. The changes in ICP were also analyzed after 3 hours of exposure to hypobaric pressure, and again no significant rise could be detected in either group. In short, regardless of whether saline or dexamethasone was administered, the ICP did not rise in animals exposed to an equivalent altitude of 5000 m after 3 or 6 hours. The Figure shows the mean ICP of the study animals throughout the simulated altitude time period.
Table 1ICP change from baseline*
Table 1ICP change from baseline*
Discussion
There have been very few experiments where direct ICP measurements were taken in humans during altitude exposure.
indirectly measured ICP via tympanic measurement displacement, but they did not find elevated ICP by this method in subjects who experienced AMS. The trend in these few human studies is that hypoxia may cause ICP to rise, but subjects with AMS do not necessarily have elevated ICP.
There have been 5 previous studies of altitude exposure and ICP monitoring in animal models (Table 2), 3 of which demonstrated a rise in ICP with hypoxic conditions.
Our study did not replicate the rise in ICP seen in several other studies. Furthermore, because ICP did not rise under placebo conditions, we are unable to draw conclusions regarding the mechanism of action of dexamethasone in the cerebral dynamics of altitude exposure.
Table 2Other animal studies of altitude exposure and ICP measurements*
Table 2Other animal studies of altitude exposure and ICP measurements*
placed catheters within the lateral ventricles of rabbits and exposed the rabbits to various altitudes, from 3000 m to 5500 m for 6 hours. They measured cerebrospinal fluid pressure from the catheters
Mean intracranial pressure throughout 6-hour simulated altitude exposure.
and documented an average rise of 15 ± 10 mm Hg. Although a rise in ICP was noted, there was not a direct correlation between the magnitude of the rise in cerebrospinal fluid pressure and the altitude to which the study animals had been exposed. In other words, the greatest increase in ICP did not necessarily occur with the higher altitude exposures.
studied goats that were exposed to a simulated altitude of 4000 m for 2 hours. In their model, they placed catheters into the subdural space and into the lateral ventricle, although they did not specify which location was used to obtain the results reported. The average ICP was 11.3 ± 1.34 mm Hg at baseline, and this rose to 21.25 ± 1.75 mm Hg at 4000 m. Interestingly, the ICP elevation occurred within 20 minutes and remained elevated throughout 2 hours of altitude exposure.
placed catheters within the sagittal sinus of 8 sheep and exposed the sheep to hypoxic conditions simulating approximately 4000 m for 3.5 hours. Sagittal sinus pressure (cerebral venous pressure) was considered to reflect ICP, and measurements were taken every 30 minutes throughout the study. They demonstrated a significant rise in the ICP (+11 mm Hg) over baseline level in this sheep model. The rise was seen within 30 minutes of exposure to hypoxia and sustained throughout the experiment.
In one experiment that did not produce a significant rise in ICP, Curran-Everett and others
implanted catheters into the superior sagittal sinus and lateral ventricles of 22 sheep and observed the sheep for 72 hours at hypoxic conditions equivalent to 4000 m. They took their measurements at 24-hour intervals and documented a very small rise in ICP that was not significant during the 72 hours. The mean sagittal sinus pressure increased only 1.8 mm Hg (95%, confidence interval −2.1 to 5.7), and the mean lateral ventricle pressure increased only 1.3 mm Hg (95%, confidence interval −1.9 to 4.5) (P = 1.0 for both). These authors believed that the brain's compensatory mechanisms (“viscoelastic properties”) may have prevented a visible ICP rise by the time the first study measurement was taken at 24 hours. In other words, a rise in ICP may have occurred during the first few hours of altitude exposure, but the brain may have compensated for this by the time 24 hours had passed.
placed subdural catheters in rabbits to investigate the effect of simulated altitude exposure on ICP. They tested 2 different altitudes (5000 m and 5500 m) during 3-hour chamber exposures. Their study protocol did not yield a consistent rise in ICP in the animals. These authors believed that the hypobaric exposure period (3 hours) may not have been long enough. Indeed, AMS usually occurs after approximately 6 hours of hypoxia, and our study design took this into account.
Our study clearly did not reproduce the rise in ICP seen in some of the other animal studies, and the reason for different ICP responses between our experiment and others is difficult to explain. One contributing factor may be the anatomical location of the ICP catheter. In our study, the catheter was placed within the subdural space, which in retrospect seems to be less sensitive for detecting ICP rises than are other intracerebral locations. The studies that demonstrated a rise in ICP with altitude generally had catheters placed directly within the ventricles or within the venous sinuses (Table 2). Our results may be a reflection of the pathophysiology of AMS. It may be that in AMS, the cerebral dynamics are such that pressure rises within the ventricles and venous sinuses before it rises within the subdural space. Acute mountain sickness encompasses a spectrum of clinical presentations, from mild generalized malaise to frank cerebral edema and obtundation. Perhaps only advanced disease is associated with pressure changes within the subdural space. The parameters of hypobaric exposure produced in our study are thought to be capable of causing mild AMS (time of exposure, altitude achieved). The time of altitude exposure we selected, however, does not allow for progression to severe symptoms. Mild AMS may not result in increased ICP after all, at least to a degree that we can measure with a catheter placed in the subdural space.
Regardless, the connection between elevated ICP and the development of the symptoms of AMS is still not clear. As mentioned previously, other animal studies have demonstrated a rise in ICP with simulated altitude exposure. In these studies, the rise was detected almost immediately after exposure. Curiously, in vivo the symptoms of AMS generally do not occur until after several hours of altitude exposure. The correlation of ICP elevation to the onset of AMS symptoms has not yet been demonstrated. It is not clearly established that AMS symptoms result from a rise in ICP or that the relief of symptoms results from a reduction in ICP. That is, in the animal studies demonstrating a rise in ICP with altitude, it could not be established that the animals had AMS. After all, AMS is a clinical diagnosis based upon the syndrome of headache, lethargy, and malaise, and this cannot be determined with certainty in animals.
Conclusions
We undertook a study to observe the ICP response in an animal model to altitude exposure and dexamethasone administration. We hypothesized that altitude exposure would cause a rise in ICP and that prophylactic dexamethasone would attenuate this rise in ICP. We did not observe an elevated ICP in study rabbits exposed to 6 hours of hypobaric conditions, regardless of whether they received saline or dexamethasone prior to exposure. Our intention was to compare the change in ICP when given saline with the change in ICP when given dexamethasone. Because ICP did not rise under even placebo (saline) conditions, we were unable to draw conclusions regarding the mechanism of action of dexamethasone in the cerebral dynamics of altitude exposure. Our failure to measure a change in ICP in the subdural space may be an indication that the subdural space is not an appropriate anatomical location for documenting ICP changes in early or mild AMS.
Our study is part of the ongoing attempt to characterize the cerebral mechanisms that occur with altitude exposure. It is presumed that elevated ICP is one change that occurs, yet various investigations measuring ICP have had mixed results. The response of ICP to hypoxia remains unclear, but it further demonstrates that the cerebral pathophysiology of AMS is a complex and challenging subject that deserves further study.
Acknowledgments
This work was supported by the Clinical Investigations Directorate at Wilford Hall Medical Center, Lackland Air Force Base, TX. The authors would like to thank the Clinical Investigations Directorate staff for their assistance throughout this project.
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