Distortion product otoacoustic emissions (DPOAEs) have been proposed for monitoring the intracranial pressure (ICP) noninvasively. Aim of this study was to establish an animal model in the guinea pig for a detailed characterisation of ICP-related DPOAE alterations. In guinea pigs, the ICP was elevated experimentally and the DPOAE levels were continuously monitored. Two different patterns of DPOAE level changes were observed: (1) a decrease of few decibels affecting mainly the frequency
Elevated intracranial pressure (ICP) can complicate the course of several common pathologies such as head injury, intracranial hemorrhage, hydrocephalus, stroke, hypoxic brain injury, central nervous system infection, and acute liver failure. Early diagnosis and treatment of ICP elevation is considered crucial to prevent permanent brain damage, and monitoring the ICP is usually recommended for patients at risk. In the clinical routine, the external ventricular drain and parenchymal probes are commonly used for monitoring the ICP. Both procedures are cost-intensive, invasive, and carry a risk of hemorrhage and infection [
One possibility to monitor the ICP noninvasively is an assessment of the perilymphatic pressure by audiologic techniques. The cerebrospinal fluid (CSF) and the perilymph communicate through the cochlear aqueduct, the vestibular aqueduct, and perineural and perivascular spaces [
The cerebral perfusion pressure is the difference between the mean arterial pressure and the ICP. When the cerebral perfusion pressure is reduced below the lower threshold of autoregulation, the cerebral blood flow (CBF) decreases and cerebral ischemia ensues [
It is hypothesized that a continuous increase of the ICP should consecutively produce two distinct patterns of DPOAE changes: firstly, a decrease of the lower frequencies due to altered middle ear sound transmission and—at higher ICP values—a decrease across all measured frequencies due to a critical drop in the CoBF. An animal model was developed to characterize different patterns of DPOAE level changes due to increased ICP. This might help to better interpret DPOAE level alterations observed during ICP monitoring and possibly to derive additional information about critical ICP values leading to a reduction of the CoBF and the CBF.
16 albino guinea pigs weighing 350–520 g were anesthetized by intramuscular administration of midazolam (1.0 mg/kg), medetomidine (0.2 mg/kg), and fentanyl (0.025 mg/kg). In order to maintain anesthesia, half the dose had to be injected approximately every 45 min when the heart rate and/or the blood pressure started to rise. The rectal temperature was kept stable at 38 ± 0.1°C using a feedback regulated heating blanket. The animals were arterially catheterized for monitoring the blood pressure. The mean arterial blood pressure remained stable at 49.68 ± 4.39 mmHg (66.23 ± 5.85 hPa) during the course of the measurements. The capillary oxygen saturation (SaO2) was continuously monitored via pulse oximetry. If SaO2 fell below 80% during the course of a step of ICP elevation, the experiment was terminated.
A craniotomy extending from the sagittal suture medially, the origin of the temporal muscle laterally, the lambdoid suture posteriorly, and the coronal suture anteriorly was drilled, and the dura mater was loosened from the skull around the craniotomy. A cylinder was fixated to the rim of the craniotomy with cyanoacrylate glue for a waterproof seal. The tip of a digital ICP probe (Codman ICP-Express) was inserted into the parenchyma via a burr hole on the contralateral side and fixated with dental cement (Aqualox). The outer ear canal was cleaned, and a small myringotomy was performed under microscopic control in order to prevent a pressure gradient between the outer ear canal and the middle ear. Finally, a silicone tube connected to the DPOAE probe was inserted into the outer ear canal and fixated with cyanoacrylate glue.
The “Principles of laboratory animal care” (NIH publication no. 86-23, revised 1985) were followed. The experimental protocol and use of the animals reported on in this study were approved by the Animal Care Committee of the University of Munich (Reg-Nr. 55.2-1-54-2531-14/05).
DPOAEs were recorded in a sound attenuated chamber (Industrial Acoustics Company) using an ER-10C probe (Etymotic Research), the DP2000 software (Mimosa Acoustics), and a standard laptop. DPOAE levels were monitored continuously at the frequencies
DPOAE levels were recorded continuously during the course of the whole experiment starting 5 min before elevating the ICP to verify a stable baseline level. Then, the cylinder was filled stepwise with 0.9% sodium chloride solution in order to elevate the ICP to defined pressure values (18, 22, and 24 mmHg = 24, 29, and 32 hPa). These pressure values were chosen, because preliminary experiments had revealed, that no measurable DPOAE level changes occurred below 18 mmHg and that the animals did not tolerate ICP values above 24 mmHg well. The cylinder was emptied after each pressure step for 10 min to verify stability of DPOAE levels at normal pressure. After recalibration of the probe, DPOAE levels were again recorded for 5 min before elevating the ICP again.
Six animals had to be excluded from further data processing because ICP could not be kept stable due to fluid leakage between the cylinder and the craniotomy. In ten animals a total of 25 ICP intervals were recorded, where the desired pressure value could be kept stable in the range of ±2 mmHg for 4–7 min. In two animals, the experiment was terminated at 22 mmHg, and in one animal, at 24 mmHg due to a drop in oxygen saturation, which explains the total number of 25 ICP intervals instead of 30 (Table
Overview of all measured ICP intervals with stable ICP in the range of ±2 mmHg of the target value indicated in the table and the information whether they were valid. For valid ICP intervals the pattern of DPOAE level alterations is given. For explanation of the two patterns see Figure
Animal no. | ICP [mmHg] | Valid | Pattern |
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1 | 18 | yes | first |
22 | yes | first | |
24 | yes | second | |
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2 | 18 | no1 | |
22 | yes | first | |
24 | yes | first | |
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3 | 18 | yes | no change |
22 | yes | first | |
24 | yes | second | |
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4 | 18 | yes | first |
22 | no2 | ||
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5 | 18 | yes | first |
22 | yes | first | |
24 | yes | second | |
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6 | 18 | yes | no change |
22 | no2 | ||
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7 | 18 | no1 | |
22 | no1 | first | |
24 | yes | ||
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8 | 18 | no1 | |
22 | yes | no change | |
24 | no1 | ||
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9 | 18 | yes | first |
22 | yes | second | |
24 | no2 | ||
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10 | 18 | yes | first |
22 | yes | first | |
24 | yes | second |
1invalid because meanpostICP did not stabilize in the range of ±2 SDbaseline compared to meanpreICP in all frequencies.
2invalid because SaO2 dropped below 80%. In these cases, no further pressure steps were recorded.
See Section
Only DPOAE measurements with a signal-to-noise ratio of >6 dB were used for the further data processing. DPOAE measurements during unstable ICP while filling or emptying the cylinder, defined by a variation >2 mmHg from the baseline or the target value, respectively, were discarded.
For every animal and each frequency, the arithmetic mean (mean) and the standard deviation (SD) of the DPOAE levels were calculated for each period with elevated ICP (meanICP, and SDICP) and for each period with normal ICP before and after an ICP interval (meanpreICP, SDpreICP, meanpostICP and SDpostICP). Additionally, the SD for all measurements with normal ICP was calculated as measure for the baseline stability of the DPOAE levels of the specific animal at a given frequency (SDbaseline).
Mean and range of ICP-induced DPOAE level changes (ΔDP), range of the standard deviation during elevated ICP (SDICP), and number of valid intervals for different frequencies
First pattern of DPOAE level alterations attributed to altered sound transmission. Note that there is a significant DPOAE level decrease only at
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MeanΔDP | −3.17* | −0.69 | −0.13 | +0.20 | −0.53 |
RangeΔDP | −8.05–+1.13 | −4.42–+1.43 | −1.26–+1.28 | −0.63–+2.51 | −1.55–+0.61 |
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0.83–1.66 | 0.35–2.06 | 0.34–0.74 | 0.36–1.33 | 0.21–1.13 |
Number of valid intervals | 10 | 12 | 14 | 14 | 13 |
Second pattern of DPOAE level alterations that might be attributed to reduced CoBF. Note the pronounced DPOAE level decrease at all measured frequencies and the much larger SDICP
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MeanΔDP | −2.80 | −7.66 | −9.76 | −11.47 | −12.36 |
RangeΔDP | −1.53–−3.98 | −1.97–−13.46 | −3.67–−14.25 | −5.25–−22.18 | −4.44–−21.36 |
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3.83–7.36 | 3.74–12.84 | 3.00–10.24 | 7.27–17.51 | 5.25–13.56 |
Number of valid intervals | 4 | 5 | 5 | 5 | 5 |
Data from 20 intervals with elevated ICP in ten animals were included into the main data analysis. The DPOAE levels and the ICP were plotted versus time for each interval and each measured frequency.
The alterations of the DPOAE levels described due to elevated ICP affect only the lower frequencies, occur 8–30 s after elevation of the ICP, and recover even more quickly after lowering the ICP, with stable DPOAE levels when the ICP is stable [
A Wilcoxon signed rank test was performed (
Microsoft Excel was used for figure creation.
The final data analysis encompassed ten animals and 20 intervals with elevated ICP. Two clearly distinct patterns of DPOAE level alterations were observed.
In 12 intervals, the maximum of the observed changes was reached immediately after the ICP had reached a stable value and then remained stable until the ICP was lowered. Stable DPOAE levels in the range of the levels before ICP elevation could be measured immediately after normalization of the ICP (Figure
DPOAE levels (left vertical axis) and ICP (right vertical axis) plotted versus time for one pressure step in a single animal. The shaded areas mark data sets with stable ICP included into the final data analysis. The horizontal dotted lines mark the mean DPOAE level before ICP elevation (meanpreICP), under elevated ICP (meanICP), and after ICP normalization (meanpostICP). For the second pattern, meanpostICP was calculated after the supposedly postischemic alterations of the DPOAE levels had abated. (a) First pattern of DPOAE level changes, attributed to altered middle ear sound transmission. Note the prompt level decrease with ICP elevation, the stable DPOAE levels during constant ICP, and the instant recovery of the DPOAE levels after ICP normalization (
Five animals exhibited a different pattern of DPOAE alterations at the respective highest ICP value, consisting of a much larger decay and instability of the DPOAE levels during elevated ICP affecting all frequencies. After normalization of the ICP, the DPOAE levels started to recover but then decreased again sharply. After reaching a minimum, the DPOAE levels recovered steadily to pre-ICP values over a time of approximately 5 min (Figure
Our study in guinea pigs showed two clearly distinct patterns of DPOAE level alterations due to elevated ICP. One consisted in a level decay of few decibels mainly affecting the frequency
The second pattern showed a much larger decay and instability of the DPOAE levels affecting all frequencies and a prolonged course of DPOAE level alterations after lowering the ICP, where the DPOAE levels started to recover but then decreased again sharply. After reaching a minimum, DPOAE levels recovered steadily to pre-ICP values over a time of approximately 5 min (Figure
The individual pattern of the DPOAE levels at different frequencies is highly variable among different ears but remains fairly stable in repeated measurements of the same ear [
Previous studies about DPOAEs under the influence of ICP elevation focused on the first pattern of DPOAE alterations that mainly affects the lower frequency range [
Furthermore, our study identified the stability of the DPOAE levels during repeated measurements as a measure to distinguish between changes due to alteration of middle ear sound transmission and due to a decrease of the CoBF. The SD of the DPOAE levels during elevated ICP (SDICP) was always <2.5 dB at all frequencies in the first (Table
The effects of elevated ICP on the CoBF and the CBF seem to be interrelated with the CBF being even more vulnerable in a guinea pig model [
For a future clinical noninvasive monitoring of the ICP with audiologic measures, the DPOAE levels have some disadvantages. The observed alterations are small (in the range of few dB) and have to be detected in a noisy environment with possible confounding factors, such as altered middle ear pressure and ototoxic drugs. The alterations of the DPOAE phases due to elevated ICP might provide valuable additional information [
This work was presented at an Oral Presentation at the 8th Congress of the German ENT Society 2009 (preliminary data).
The authors declare that they have no conflict of interests.