Cerebral blood flow augmentation using a cardiac-gated intracranial pulsating balloon pump in a swine model of elevated ICP

Omer Doron Department of Neurosurgery, Hadassah-Hebrew University Medical Center, Jerusalem; and
Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel

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Tal Or Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel

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Limor Battino Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel

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Guy Rosenthal Department of Neurosurgery, Hadassah-Hebrew University Medical Center, Jerusalem; and

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Ofer Barnea Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel

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OBJECTIVE

Augmenting brain perfusion or reducing intracranial pressure (ICP) dose is the end target of many therapies in the neuro-critical care unit. Many present therapies rely on aggressive systemic interventions that may lead to untoward effects. Previous studies have used a cardiac-gated intracranial balloon pump (ICBP) to model hydrocephalus or to flatten the ICP waveform. The authors sought to sought to optimize ICBP activation parameters to improve cerebral physiological parameters in a swine model of raised ICP.

METHODS

The authors developed a cardiac-gated ICBP in which the volume, timing, and duty cycle (time relative to a single cardiac cycle) of balloon inflation could be altered. They studied the ICBP in a swine model of elevated ICP attained by continuous intracranial fluid infusion with continuous monitoring of systemic and cerebral physiological parameters, and defined two specific protocols of ICBP activation.

RESULTS

Eleven swine were studied, 3 of which were studied to define the optimal timing, volume, and duty cycle of balloon inflation. Eight swine were studied with two defined protocols at baseline and with ICP gradually raised to a mean of 30.5 mm Hg. ICBP activation caused a consistent modification of the ICP waveform. Two ICBP activation protocols were used. Balloon activation protocol A led to a consistent elevation in cerebral blood flow (8%–25% above baseline, p < 0.00001). Protocol B resulted in a modest reduction of ICP over time (8%–11%, p < 0.0001) at all ICP levels. Neither protocol significantly affected systemic physiological parameters.

CONCLUSIONS

The preliminary results indicate that optimized protocols of ICBP activation may have beneficial effects on cerebral physiological parameters, with minimal effect on systemic parameters. Further studies are warranted to explore whether ICBP protocols may be of clinical benefit in patients with brain injuries with increased ICP.

ABBREVIATIONS

ABP = arterial blood pressure; CBF = cerebral blood flow; ICBP = intracranial balloon pump; ICP = intracranial pressure.

OBJECTIVE

Augmenting brain perfusion or reducing intracranial pressure (ICP) dose is the end target of many therapies in the neuro-critical care unit. Many present therapies rely on aggressive systemic interventions that may lead to untoward effects. Previous studies have used a cardiac-gated intracranial balloon pump (ICBP) to model hydrocephalus or to flatten the ICP waveform. The authors sought to sought to optimize ICBP activation parameters to improve cerebral physiological parameters in a swine model of raised ICP.

METHODS

The authors developed a cardiac-gated ICBP in which the volume, timing, and duty cycle (time relative to a single cardiac cycle) of balloon inflation could be altered. They studied the ICBP in a swine model of elevated ICP attained by continuous intracranial fluid infusion with continuous monitoring of systemic and cerebral physiological parameters, and defined two specific protocols of ICBP activation.

RESULTS

Eleven swine were studied, 3 of which were studied to define the optimal timing, volume, and duty cycle of balloon inflation. Eight swine were studied with two defined protocols at baseline and with ICP gradually raised to a mean of 30.5 mm Hg. ICBP activation caused a consistent modification of the ICP waveform. Two ICBP activation protocols were used. Balloon activation protocol A led to a consistent elevation in cerebral blood flow (8%–25% above baseline, p < 0.00001). Protocol B resulted in a modest reduction of ICP over time (8%–11%, p < 0.0001) at all ICP levels. Neither protocol significantly affected systemic physiological parameters.

CONCLUSIONS

The preliminary results indicate that optimized protocols of ICBP activation may have beneficial effects on cerebral physiological parameters, with minimal effect on systemic parameters. Further studies are warranted to explore whether ICBP protocols may be of clinical benefit in patients with brain injuries with increased ICP.

In Brief

The authors have developed a novel method to improve brain perfusion. This method may assist in offering a new modality of treatment for neurocritically ill patients suffering from reduced cerebral blood flow states such as in traumatic brain injury or vasospasm.

Augmenting brain perfusion or reducing intracranial pressure (ICP) dose is the end target of many therapies in the neuro-critical care unit. Relatively few methods are available to improve cerebral perfusion in common clinical practice following traumatic brain injury, cerebral vasospasm, or stroke. Methods to improve cerebral blood flow (CBF) generally rely on aggressive systemic manipulations such as elevating mean arterial pressure, and these interventions may have untoward effects.2,3

The dynamic relations between the intracranial volumes of blood, CSF, and brain tissue are crucial to understanding the brain as a pulsatile organ.16,22 The heart, through its effect on the cerebral vasculature, is the main source of mechanical energy in the intracranial system. Under normal physiological conditions, the effects of this pulsatility are the constant shifts in volume between the intracranial vasculature, the CSF, and brain as over 10 ml of blood are injected into the cranium with every heartbeat. The effects of these volume changes with each cardiac cycle are translated to changes in intracranial pressure by the cranial volume-pressure relationship, first described by Monro and Kellie.1

Several previous studies have attempted to alter intracranial volume to manipulate the ICP waveform.4,11,13 These studies explored the effect of the cardiac cycle on intracranial volume-pressure dynamics, mainly with the goal of changing the CSF pulsations generated by the arterial vasculature. These studies sought to either augment the volume-pressure relationship in order to create a model of hydrocephalus or to counter it and cause ICP waveform flattening.

We sought to modify the ICP waveform by using an intracranial balloon pump (ICBP) to alter blood volume distribution between the venous and arterial compartments of the vasculature during different phases of the cardiac cycle. We hypothesized that carefully timed changes in ICP in the cranium within the cardiac cycle may increase CBF. We presumed that precisely timed inflation of the balloon at diastole, causing increased diastolic ICP, might lead to increased diastolic venous blood flow and a greater expulsion of venous blood out of the cranium. A subsequent precisely timed balloon deflation at systole might then lead to a lower than usual resistance to inflow of blood into the cranium that could potentially result in increased CBF. In a similar fashion, we hypothesized that differently timed changes in intracranial pressure induced by balloon inflation and deflation may reduce overall ICP dose. To test these hypotheses, we developed a system composed of a microballoon driven by a computer-controlled pump. We applied two different cardiac-gated activation protocols, each timed to a different point in the cardiac cycle, to either improve CBF or reduce ICP dose. In this study, we present our initial experience with the cardiac-gated ICBP in a swine model of gradually elevated ICP.

Methods

Cardiac-Gated Intracranial Balloon Pump

The experimental system, designed and constructed in our laboratory, is composed of a linear motor that drives a syringe pump connected to a balloon via a high-pressure catheter (Fig. 1). The pump, an FRLS-AC servo motor (HIWIN Technologies Corp.), is controlled by a computer. The computer receives signals from a data acquisition system (USB-6002 16-Bit, National Instruments), using a digital control card (DCC), designed to acquire data from several sensors: 1) two Millar pressure probes (3.5F Millar Mikro-Tip pressure catheter), one for measurement of ICP and the other for monitoring arterial carotid pressure, 2) a cerebral thermal diffusion blood flow probe (Bowman Q Flow 500 probe, Hemedex, Inc.), and 3) an ECG monitor (Philips). The software synchronizes the forward and backward motion of the piston to the cardiac cycle on a beat-to-beat basis at specified timings. The motor was preset to inflate and deflate the balloon, at a specific delay time relative to the ECG R-wave, detected by a real-time R-wave detection algorithm. The prototype balloons were made from a flexible, elastic, biocompatible polyurethane, modified from commercial parenchymal ICP probes (Spiegelberg GmbH & Co. KG), which allow for small (up to 2.0 ml), nontraumatic inflation and deflation, designed for intracranial insertion into the ventricular space via burr hole. The balloons were connected to a rigid catheter that was attached to an all-glass 10-ml syringe, with a luer-lock tip (Poulten & Graf GmbH), driven by the motor (Fig. 1).

FIG. 1.
FIG. 1.

The ICBP system. Left section: Data acquisition unit, made of a digital control card that receives physiological analog signals from the sensors implanted in the animal model. Middle section: Computer acting as a control unit activating the pump. Right section: Computer-controlled syringe pump connected to a balloon catheter.

The system parameters that were altered between different intervention protocols were inflation time delay from the R-wave (at the millisecond level), deflation time delay from R-wave, piston displacement velocity (determining the profile of volume change with a speed of up to 4000 cm/sec), and balloon volume. By changing these parameters, different profiles of balloon inflation and deflation relative to the cardiac cycle, as well as percent of the cardiac cycle through which the balloon is deflated or inflated, could be manipulated, and theoretically a multitude of ICP waveforms could be generated. The acquisition system enabled us to continuously measure CBF, carotid arterial pressure, and ICP (at 16-bit resolution and a sampling rate of 200 Hz), synchronous to any volumetric change induced by the pump.

Preparation of the Animal

The study was performed in female Yorkshire swine weighing from 38 to 42 kg from the large-animal sterile surgical facility available in our institution. All swine were obtained from licensed suppliers, quarantined for a minimum of 7 days before study entry, and maintained in an accredited animal care facility under the guidelines of the Guide for the Care and Use of Laboratory Animals after the study received IRB approval (Ein Kerem Campus, Hebrew University, Jerusalem, Israel).

Anesthesia was induced using sodium pentothal (20 mg/kg, intravenously) and the animals were then intubated and placed on a ventilator with isoflurane gas (1.0%–1.5%) used to maintain anesthesia throughout the study. Animals were placed in a supine position, immediately after intubation, and a carotid 5F arterial line (micropuncture access kit, Cook Medical) was inserted under ultrasound guidance. ECG, carotid arterial blood pressure (ABP), respiration, temperature, arterial blood gases, and pH were monitored. All swine had a Foley catheter inserted. Blood gases and pH were maintained within normal ranges (pH 7.4, partial pressure of carbon dioxide 35–45 mm Hg, partial pressure of oxygen 95–100 mm Hg) mechanically by controlling the ventilation volume and frequency, and body temperature was maintained with a thermal blanket (37°C ± 3°C) and intravenous infusion of a saline solution of Ringer’s lactate at a rate of 25 ml/hour throughout unless otherwise dictated by protocol as described below.

The animals were then carefully rolled into prone position. Transverse and sagittal incisions were made posterior to the eye and at the midline, and the skin, fascia, and temporalis muscle were retracted to expose the skull. An automatic drill (Summex, Stryker) was used to drill 3 separate burr holes located 1 cm to the right of the midline and 1 cm posterior to the coronal suture, 1 cm to the left of the midline and 1 cm posterior to the coronal suture, and 1 cm to the right of the midline and 1 cm anterior to the coronal suture. The balloon catheter, Hemedex monitor, and intracranial ICP sensors were then implanted in these burr holes, respectively, under sterile conditions (Fig. 2). ICP and CBF probes were inserted into the parenchyma (at a depth of about 1–2 cm). The balloon was inserted into the ventricle, under ultrasound guidance. The burr holes were closed with bone wax (Bonewax, Aesculap).

FIG. 2.
FIG. 2.

Animal procedure. A: Skin incisions: skull exposure and probe instrumentation (clockwise from top right—balloon catheter, ICP probe, CBF probe, and intraventricular infusion cannula). B: Partially deflated balloon, preinsertion. C: Swine positioning after carotid instrumentation and connection of balloon catheter to the pump. Figure is available in color online only.

Experimental Protocol

To create a gradual elevation in ICP, we used a slow intraventricular NaCl 0.9% infusion, mimicking hydrocephalus.10 An additional burr hole was drilled contralateral to the device-instrumented hemisphere, 1 cm to the left of the midline and 1 cm anterior the coronal suture. A 16-gauge continuous-drainage tube (Lumbar External Drainage Catheter, Codman Neuro) was inserted into the ventricle, until clear CSF was seen in the lumen. This tube was connected to an automatic syringe programmable pump (KDS 510, Dual Syringe Pump System, KS Scientific) that infused saline at a slow fixed rate (between 0.02 and 0.05 ml/min, depending on the tested protocol and stage of experiment) and gradually raised the ICP. All probes were kept in position throughout the experiment. CBF was measured continuously by assessing perfusion in a volume < 0.3 mm3 at a sampling frequency of 200 Hz for thermal diffusion CBF (CBFTD; absolute units of ml/min/100 g tissue).

ICP was raised in a graded fashion, as described above, in order to test the device’s function and efficacy at both normal and pathological ICP levels.

The balloon was inserted in a partially inflated form and was left inflated for a few minutes, until a new equilibrium was reached and ICP returned to its preinsertion level. The device was then tested, first at the baseline ICP level, and later, sequentially with every ICP increase of 5 mm Hg.

Protocols consisted of sequential balloon volume increase, as well as sequential changes in inflation and deflation time.

Prior to device activation, we verified that ICP and CBF levels were stable. Specifically, after balloon introduction with initial minimal volume, as well as before every activation protocol where balloon volume was changed, a 10-minute stabilization period was allowed. Data analyzed in every measurement included 10 minutes of preactivation, followed by 10 minutes of device activation and 10 more minutes of postactivation. ICP and CBF measurements were averaged over the selected time periods. The postactivation period was compared to the preactivation period in the same way to assess whether parameters returned to baseline following activation. At every activation, ICP and CBF changes before and after device activation relative to baseline were recorded and percent change was calculated.

At the end of the experimental protocol, animals were euthanized by injection of potassium chloride. Each animal’s brain was removed and sent for gross pathological inspection and histological studies (cresyl violet acetate, Polysciences Inc.; H & E, Abbey Color) and immunohistochemical studies, including glial fibrillary acidic protein (GFAP; Immunostar), neuron-specific enolase (NSE; Lee Biosolutions), and S-100B (Kamiya Biomedical Company).

Methods of Device Activation

Two modes of activation were explored. In the first method (protocol A), balloon inflation was carried out during diastole in order to elicit a temporary pressure rise, which in theory might augment the exit of venous blood as well as CSF from the cranium but would not be high enough to affect the arterial vasculature. The balloon was then deflated just prior to systole, with the aim of decreasing resistance to incoming arterial blood and potentially allowing greater arterial inflow to enter the cranium.

A second protocol of activation (protocol B) relies on the differential characteristics of the pressure-volume curve at different time points along the cardiac cycle, i.e., pressure-dependent cerebral compliance. In this protocol, balloon inflation was performed at end-diastole, where the pressure is low and compliance high, followed by balloon deflation around peak systolic pressure, where compliance is lower, with the aim of causing a sudden reduction of the intracranial volume at peak systolic pressure.

A preliminary study was done in 3 swine, to calibrate ICBP parameters and to assess the initial response and change in ICP waveform as a function of balloon volume (0.2–1.2 ml), inflation/deflation timing (milliseconds past the ECG R-wave), and duty cycle (percentage of the cardiac cycle in which the balloon is in its inflated form). After identifying an optimal range of working points, protocols A and B were defined and activated. In all swine that were studied after protocol A and B were defined, each swine underwent sequential activation of protocols A and B at each ICP level studied.

Data Processing

Data were analyzed with an automated algorithm using MATLAB (R2014b, MathWorks, Inc.). For waveform analysis, ICP, arterial carotid pressure, and thermal blood flow signals were high-pass filtered (second-order high-pass Butterworth filter, cutoff frequency [fc] = 30 Hz) to eliminate power line noise effects. Single ICP and CBF values, as well as mean values, were determined from unfiltered data.

All estimations of ICP and CBF parameters were performed on nonaveraged data. Comparisons were made between data segments immediately before and after pump activation and deactivation, and the 10-minute segments of the continuous activity were analyzed for trends. Segments were excluded in which the balloon cycle delay or “missed” beats occurred in more than 10% of the points due to R-wave detection failure or the heart rate differed more than 10% from the median for more than 25% of the cardiac cycles.

To assess significant changes in CBF and ICP levels, physiological parameters measured during the device activation period were compared to those measured during the preactivation period. An ANOVA test was used to assess whether the changes were significant.

Results

Optimization of Balloon Inflation and Deflation Parameters

In preliminary studies in 3 swine, escalating volumes from 0.2 to 1.2 ml were used for balloon inflation and the timing in relation to the cardiac cycle was varied. For protocol A, the greatest improvement in CBF resulted from a balloon inflation volume of 1–1.2 ml occurring during the last third of diastole, with deflation just prior to systole and a duty cycle of 15%–25%. For protocol B, the greatest reduction of ICP dose occurred with a balloon inflation volume of 1–1.2 ml, inflation during the last third of diastole with peak systolic deflation, and a duty cycle of 25%–35%. Once parameters for protocol A and B were defined, we studied 8 swine using these defined protocols.

Systemic and Cerebral Physiological Parameters

As seen in Table 1, ICP was increased in a graded fashion over the experimental protocol. No significant changes were observed in the ECG signal or heart rate, or in the ABP. As ICP and CBF were changing, no hemodynamic systemic changes were observed. PaCO2 and pH levels were kept within the normal range. Table 1 shows mean values of ABP, heart rate, and CBF at different ICP levels without pump activation.

TABLE 1.

Systemic and cerebral physiological parameter changes with gradual increase in ICP and no pump intervention

ICP Level (mm Hg) (n = 8)
Physiological Parameter10–1516–2021–2525–30
ABP (mm Hg)68.6 ± 4.365.9 ± 4.170.6 ± 5.169.6 ± 3.2
Heart rate (bpm)72.5 ± 6.474.5 ± 5.871 ± 3.270 ± 2.4
CBF (ml/min/100 g tissue)52.22 ± 12.343.53 ± 11.426.22 ± 9.618.12 ± 8.3

Values are presented as mean ± SD.

Effect on ICP Waveform

ICP waveform changes were evident immediately with device activation, and activation termination resulted in relatively swift return of the ICP waveform to its baseline pattern, usually within 5 to 10 cardiac cycles (Fig. 3). In all animals, balloon-induced ICP changes had several characteristic features. Diastolic balloon inflation caused a sharp ICP rise relative to the native ICP waveform, and presystolic (protocol A) or peak systolic (protocol B) deflation elicited a sharp drop in ICP (Fig. 4).

FIG. 3.
FIG. 3.

ECG, ABP, ICP, balloon activation graph showing balloon volume (Bal. Vol.), and CBF are shown. With device activation, immediate change is noted in the ICP waveform with later changes in CBF. Figure is available in color online only.

FIG. 4.
FIG. 4.

Upper: Characteristic waveforms for protocol A and B. Lower: Characteristic ICP waveform change as balloon duty cycle (BDC) increased gradually from 10% to 30%. Figure is available in color online only.

Another key parameter affecting the pump-induced ICP waveform, and as a result area under the ICP curve (ICP-AUC) was the duration of time in which the balloon was inflated relative to the entire cardiac period (duty cycle). Lasting between 10% and 30% of the total cardiac cycle, longer duty cycle led to greater ICP-AUC reduction.

Effect on CBF and ICP Dose

Data were analyzed at each ICP level as ICP gradually increased with slow intracranial fluid injection (10–15, 16–20, 21–25, and 26–31 mm Hg). As seen in Table 2, protocol A activation led to a significant improvement in CBF of up to 25% (p < 0.0001). Importantly, there was a lasting effect after pump termination before an eventual return to baseline after approximately 10 minutes. In protocol A, during and after balloon activation, ICP did not change significantly when ICP levels were greater than 15 mm Hg (Fig. 5). The degree of improvement in CBF was greater at lower ICP levels (Table 2).

TABLE 2.

Protocol A: effect on CBF and ICP (n = 8)

ICP Level (mm Hg)
10–1515–2121–2525–31
CBF level
 Activation (average % change)+25.34%+16.19%+13.00%+8.05%
 p value<0.0001<0.0001<0.0001<0.0001
 Postactivation (average % change)+2.90%+3.10%+22.74%+6.76%
 p value<0.01<0.05<0.01<0.05
ICP level
 Activation (average % change)−10.96%−1.08%+1.43%−0.19%
 p value<0.00010.120.260.3
 Postactivation (average % change)−1.12%+4.01%+3.47%+0.56%
 p value0.310.430.20.5

Percent changes in CBF and ICP for every ICP level tested. Data were processed as the average change between identical experimented trials using activation protocol A, relative to baseline measurements. Significant relative improvement in CBF was noted in any given ICP level, without concomitant significant change in ICP. CBF continued to remain significantly higher compared to baseline after 10 minutes of the postactivation period, and only later (15–20 minutes) returned to baseline (not shown).

FIG. 5.
FIG. 5.

Data overview, a single activation trial, protocol A type, at an ICP level of 18 mm Hg. ECG, ABP, ICP, balloon activation graph showing balloon volume (Bal. Vol.), and CBF are shown over a 12-minute period. With device activation, an immediate ICP waveform change is visible, without significant changes in heart rate or ABP. CBF increases with return to baseline some minutes after activation termination. ICP is transformed immediately with device activation and returns to baseline immediately after device activation termination. Figure is available in color online only.

Protocol B activation demonstrated a significant reduction in ICP during device activation, with concomitant CBF improvement, and return to baseline following deactivation (Table 3). A modest reduction in ICP (−8.6% to −11.1%, p < 0.0001) was noted at each ICP level examined and the improvement in CBF was less than that achieved in protocol A.

TABLE 3.

Protocol B: effect on CBF and ICP (n = 8)

ICP Level (mm Hg)
10–1616–2121–2525–31
CBF level
 Activation (average % change)+8.33%+1.46%+13.23%+8.50%
 p value<0.0001<0.0001<0.0001<0.0001
 Postactivation (average % change)+1.01%+2.61%+16.8%+18.95%
 p value0.30.220.14<0.05
ICP level
 Activation (average % change)−11.1%−10.31%−10.36%−8.58%
 p value<0.0001<0.00010.03<0.0001
 Postactivation (average % change)+0.33%+0.56%+0.19%−4.65%
 p value0.20.180.090.13

Percent changes in CBF and ICP for every ICP level tested. Data were processed as the average change between identical experimented trials using activation protocol B, relative to baseline measurement. Significant relative improvement in ICP was noted in in the top and bottom (10–16, 16–21, 21–25, and 25–31 mm Hg) ICP levels, with concomitant significant change in CBF. ICP returned to baseline during the 10-minute postactivation period.

Effect on Systemic Physiological Parameters

No significant changes were observed in the ECG signal, heart rate, or ABP (Table 4) with gradual elevation of ICP. Balloon activation did not lead to a change in these systemic physiological parameters relative to baseline (Fig. 5).

TABLE 4.

ICBP effect on physiological hemodynamic parameters

ICP Level(mm Hg)Average HR Change at Activation (n = 8)p ValueAverage ABP Change at Postactivation (n = 8)p Value
Protocol A
 10–16−1.1%0.77+0.33%0.66
 16–21−0.31%0.18+0.56%0.48
 21–25−2.76%0.25+0.19%0.29
 25–31+1.58%0.47−1.65%0.13
Protocol B
 10–16−1.2%0.45+0.13%0.5
 16–21−0.67%0.51+0.22%0.38
 21–25−1.72%0.35+0.17%0.65
 25–31+1.09%0.2+1.03%0.37

HR = heart rate.

Device activation effects of protocol A and protocol B on physiological hemodynamic parameters. Heart rate and mean blood pressure, for every ICP level tested, did not change significantly throughout the activation period.

Gross Pathology and Histology

Postmortem head CT did not demonstrate gross changes within the cerebral tissue, such as hemorrhage or hematoma. Brain histological (cresyl violet, H&E) and immunohistochemical studies (glial fibrillary acidic protein, neuron-specific enolase, S100B) showed no signs of cell death, apoptosis, glial scarring, or infection in the cortex adjacent to the balloon location.

Discussion

In this study, we present initial results with a cardiac-gated intracranial pulsating balloon pump in a swine model of elevated ICP. The ICP elevation observed in this study (mean 30.5 mm Hg) is high.14,15 Only recently have swine models using rotational injury or water intoxication leading to severe cerebral edema achieved consistent and prolonged elevation of ICP beyond the 20-mm Hg threshold considered clinically relevant in human brain injury.5,17 By inducing changes in the relative volumes within the intracranial space that are precisely timed to the cardiac cycle, we sought to affect intracranial physiological parameters. Not surprisingly, activation of the cardiac-gated intracranial balloon pump led to clear changes in the ICP waveform. Our results indicate that specific protocols of ICBP activation can lead to improvements in cerebral blood flow or in a reduction in ICP dose. Importantly, these changes are achieved without altering systemic physiological parameters.

Previous studies attempted to manipulate the ICP waveform in a cardiac-gated manner.4,13 Di Rocco et al. created an experimental model of hydrocephalus by timed increase of the amplitude of intraventricular CSF oscillations related to arterial pulsations, without concomitant changes of the mean CSF pressure, showing that CSF pulsations can cause ventricular dilatation and hydrocephalus.4 This early landmark study established the important principle of cardiac-gated manipulation of the ICP waveform, but did not seek to improve cerebral physiology. In a recent study, Luciano et al. attempted to improve cerebral physiological parameters by flattening the ICP waveform.13 They did so by gradual balloon deflation during systole followed by balloon inflation and successfully manipulated the ICP waveform at normal ICP. Our study confirms these results and builds upon them in important ways. First, we developed a protocol consisting of a short pulse of balloon inflation at end-diastole to enable synchronized changes in ICP that in theory may lead to a “squeezing out” of more venous blood during diastole. In this regard, we seek to use the coupling of cerebral venous pressure with ICP to advantage, since the increase in ICP caused by balloon inflation during diastole might potentially lead to an increase in venous outflow from the cranium. Protocol A optimized the balloon inflation volume, timing, and duty cycle with the goal of forcing out more venous blood during diastole, which in theory might lead to a subsequent decrease in resistance to arterial inflow as the balloon is deflated during systole (Fig. 6). Unfortunately, we did not have the means to measure cerebral blood volume at a high-resolution time course in order to determine whether ICBP activation leads to precisely timed changes in cerebral venous blood volume as we postulate. However, we hypothesized that a precisely timed decrease in resistance to arterial flow into the cranium might lead to an increase in CBF, a result supported by our data. Second, our experimental protocol that included raising ICP to pathological levels demonstrates that the cerebral physiological improvements attained with the cardiac-gated ICBP are maintained even when ICP is elevated.

FIG. 6.
FIG. 6.

Protocol A concept. Upper: Balloon inflation late in diastole causing “squeezing” effect on the venous tree, pushing venous blood outside the cranium. Lower: Balloon deflation later prior to systolic upstroke, causing instantaneous reduction ICP and in resistance to arterial blood inflow, augmenting the incoming arterial pulsation. Figure is available in color online only.

In protocol B, a volume pulse was applied during early systole, i.e., the balloon was inflated at end-diastole and deflated around the time of peak systolic pressure. This protocol produced a distinctly different ICP waveform. The pressure rise that was caused by balloon diastolic inflation was countered by an ICP drop once the balloon was deflated during systolic peak pressure. The theory behind the timing of protocol B is based on the nonlinearity of the cranial pressure-volume (P-V) curve as illustrated in Fig. 7. Balloon inflation leads to a change in volume (ΔV) resulting in a small increase in pressure, ΔP, in the diastolic low-pressure portion of the P-V curve due to higher compliance. Balloon deflation of the same ΔV will cause a larger reduction in pressure, ΔP, in the systolic high-pressure portion of the P-V curve due to lower compliance. By gating deflation to peak ICP pressure, we induced a unique ICP pattern that differs from the flattened ICP pattern described by Luciano et al.13 Our protocol and that of Luciano and colleagues achieved similar results in decreasing ICP dose by a moderate amount. In the current study, we demonstrate that this effect is maintained even when ICP is pathologically elevated. A reduction in ICP dose may offer clinical benefit, as previous studies have demonstrated the prognostic significance of ICP dose.21 Although we did not observe any evidence of untoward ICP elevations with balloon activation in the current study, previous studies in swine that were specifically aimed to increase ICP demonstrate a “pressure resonance” phenomenon in which ICP progressively increased with balloon inflation.4 In future studies in a swine model and in any potential translation to clinical studies great vigilance will be required to ensure that no such pressure resonance leads to unexpected ICP elevation.

FIG. 7.
FIG. 7.

Protocol B concept. The nonlinear cranial P-V curve is shown. Balloon inflation during diastolic low pressure will result in a small pressure increase, while balloon deflation at high systolic pressure will result in a large pressure decrease.

The major parameters affecting ICBP effectiveness were pulsation phase relative to the cardiac cycle and the duration of balloon inflation in relation to the cardiac cycle (duty cycle). CBF improved between 8% and 25% with balloon inflation volumes between 0.6 and 1.2 ml and a duty cycle of 20%–30%.

Through the basic mechanism of synchronized intracranial volume manipulation, we managed to augment CBF or, alternately, reduce ICP dose. In common clinical practice, cerebral perfusion pressure (CPP) is elevated in order to raise or maintain CBF. Augmenting CBF with an ICBP as we describe may be advantageous since CBF elevation can be achieved without a need to alter CPP. This approach may offer clinical benefit by reducing the need for systemic interventions that have potentially adverse systemic consequences. In future studies in our swine model, we plan to use brain tissue oxygen monitoring to assess the physiological effects of the cardiac-gated intracranial balloon pump on this important measure of cerebral oxygenation. This may be useful since the response of brain tissue oxygen tension to physiological manipulations has been well described in previous swine models6,7 and in patients.8,9,12,18–20 Other monitoring technologies such as microdialysis may also be helpful in assessing a potential improvement in cerebral metabolism with the cardiac-gated ICBP. Another notable observation was that ICBP activation leads to an increase in CBF even when ICP is not elevated. As such, future studies may seek to study ICBP in other disease models, such as stroke or cerebral vasospasm, where ICP is usually within the normal range while CBF is reduced.

Concerns Regarding Translation to Clinical Studies

We hope that future development of this technology will lead to studies in brain-injured patients that may determine whether it is feasible and safe to use this device in patients, and whether its use may lead to an improvement in cerebral physiological parameters. A key concern regarding the potential use of this technology in patients will be to establish a high level of proof regarding safety. This will be the case especially in patients with traumatic brain injury, in whom precise placement in the small ventricles that are often associated with brain swelling may make accurate placement technically challenging and may require image-guided placement. Special care will be needed to ensure that no damage to the fornices or venous structures that abut the ventricles is caused by balloon inflation and deflation. A postinsertion CT scan to verify optimal balloon placement within the ventricle and to rule out a bleed in the placement tract will be of crucial importance. Another concern is that balloon activation inevitably leads to a short-lived elevation in ICP lasting several microseconds at the specific point at which it occurs in the cardiac cycle. This elevation, even if short-lived, raises potential safety concerns in any translation to clinical studies. Importantly, in the current study we did not observe any untoward or cascading elevation in ICP in any swine at any ICP levels. In addition, with termination of device activation ICP usually returned to preactivation baseline within 5–10 cardiac cycles, indicating that stopping the device may be a good first-step safety measure if any untoward effect is observed. Clearly, in any future studies of this technology in patients, a robust and reliable method to prevent an unexpected elevation of ICP that includes an automatic shutdown function will need to be an integral part of this system. Investigators will need to be cognizant of these challenges if this technology moves forward to studies in patients. In addition to being mindful of these safety issues, future clinical studies will need to evaluate functional outcomes to assess the possible clinical significance of alterations in CBF and ICP that may be achieved.

Limitations

Our study has several limitations. In this preliminary work in an animal model of raised ICP, we attempted to assess the feasibility of using a cardiac-gated ICBP to affect cerebral physiological parameters. Further work will be needed to validate our results. We assessed CBF with a local CBF probe. Future studies may seek to assess hemispheric or global measurements of CBF using other technologies or to use measures of brain tissue oxygenation as a physiological marker of efficacy. Studies that are able to measure cerebral blood volume with balloon inflation and deflation would be useful to assess whether the hypothesis that ICBP activation leads to precisely timed changes in cerebral venous blood volume is correct. We used an intracranial infusion model, leading to a gradual elevation in ICP without creating focal pathology. Future studies may seek to investigate the use of an ICBP in a traumatic model of brain injury or in other disease states such as models of stroke or cerebral vasospasm. Lastly, further studies should explore different protocols of balloon volume, timing, and duty cycle to identify other protocols that may be efficacious in different pathological states.

Conclusions

In this preliminary large-animal study, we show that a novel, cardiac-gated, intracranial pulsating balloon can improve cerebral physiological parameters, including CBF and ICP dose, without affecting systemic physiological parameters. Further study to assess the potential utility stemming from cardiac-gated controlled ICP manipulation is warranted, with the goal of evaluating whether this technology may one day offer clinical benefit to brain-injured patients.

Acknowledgments

The authors wish to thank Erez Nossek, MD, Director of Vascular Neurosurgery, Maimonides Medical Center, Brooklyn, New York, for his critical review of this work. This study was funded by a KAMIN research grant, issued by the Israeli Innovation Authority, awarded to Dr. Doron and Professor Barnea (KAMIN grant 56350).

Disclosures

Dr. Doron and Professor Barnea are listed as inventors on a patent of the device presented in this work.

Author Contributions

Conception and design: Doron, Rosenthal, Barnea. Acquisition of data: Doron, Or, Battino, Barnea. Analysis and interpretation of data: all authors. Drafting the article: Doron, Rosenthal, Barnea. Critically revising the article: Doron, Rosenthal, Barnea. Reviewed submitted version of manuscript: Doron, Rosenthal, Barnea. Approved the final version of the manuscript on behalf of all authors: Doron. Statistical analysis: Doron, Or, Barnea. Administrative/technical/material support: all authors. Study supervision: Doron, Rosenthal, Barnea.

Supplemental Information

Previous Presentations

Preliminary data from this work were presented as an oral presentation at the Annual Meeting of the Israeli Neurosurgical Society, May 2018, Upper Galilee, Israel.

References

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    Ambarki K, Baledent O, Kongolo G, Bouzerar R, Fall S, Meyer ME: A new lumped-parameter model of cerebrospinal hydrodynamics during the cardiac cycle in healthy volunteers. IEEE Trans Biomed Eng 54:483491, 2007

    • Crossref
    • PubMed
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  • 2

    Bederson JB, Connolly ES Jr, Batjer HH, Dacey RG, Dion JE, Diringer MN, et al.: Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 40:9941025, 2009

    • Crossref
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  • 3

    Carney N, Totten AM, O’Reilly C, Ullman JS, Hawryluk GW, Bell MJ, et al.: Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery 80:615, 2017

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  • 4

    Di Rocco C, Pettorossi VE, Caldarelli M, Mancinelli R, Velardi F: Experimental hydrocephalus following mechanical increment of intraventricular pulse pressure. Experientia 33:14701472, 1977

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Friess SH, Ralston J, Eucker SA, Helfaer MA, Smith C, Margulies SS: Neurocritical care monitoring correlates with neuropathology in a swine model of pediatric traumatic brain injury. Neurosurgery 69:11391147, 2011

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Hawryluk GW, Phan N, Ferguson AR, Morabito D, Derugin N, Stewart CL, et al.: Brain tissue oxygen tension and its response to physiological manipulations: influence of distance from injury site in a swine model of traumatic brain injury. J Neurosurg 125:12171228, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Hemphill JC III, Knudson MM, Derugin N, Morabito D, Manley GT: Carbon dioxide reactivity and pressure autoregulation of brain tissue oxygen. Neurosurgery 48:377384, 2001

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Hlatky R, Valadka AB, Gopinath SP, Robertson CS: Brain tissue oxygen tension response to induced hyperoxia reduced in hypoperfused brain. J Neurosurg 108:5358, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Kiening KL, Unterberg AW, Bardt TF, Schneider GH, Lanksch WR: Monitoring of cerebral oxygenation in patients with severe head injuries: brain tissue PO2 versus jugular vein oxygen saturation. J Neurosurg 85:751757, 1996

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Krishnamurthy S, Li J, Schultz L, McAllister JP II: Intraventricular infusion of hyperosmolar dextran induces hydrocephalus: a novel animal model of hydrocephalus. Cerebrospinal Fluid Res 6:16, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Löfgren J, von Essen C, Zwetnow NN: The pressure-volume curve of the cerebrospinal fluid space in dogs. Acta Neurol Scand 49:557574, 1973

  • 12

    Longhi L, Pagan F, Valeriani V, Magnoni S, Zanier ER, Conte V, et al.: Monitoring brain tissue oxygen tension in brain-injured patients reveals hypoxic episodes in normal-appearing and in peri-focal tissue. Intensive Care Med 33:21362142, 2007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Luciano MG, Dombrowski SM, Qvarlander S, El-Khoury S, Yang J, Thyagaraj S, et al.: Novel method for dynamic control of intracranial pressure. J Neurosurg 126:16291640, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Nilsson F, Akeson J, Messeter K, Ryding E, Rosén I, Nordström CH: A porcine model for evaluation of cerebral haemodynamics and metabolism during increased intracranial pressure. Acta Anaesthesiol Scand 39:827834, 1995

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Odland RM, Venugopal S, Borgos J, Coppes V, McKinney AM, Rockswold G, et al.: Efficacy of reductive ventricular osmotherapy in a swine model of traumatic brain injury. Neurosurgery 70:445455, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Preuss M, Hoffmann KT, Reiss-Zimmermann M, Hirsch W, Merkenschlager A, Meixensberger J, et al.: Updated physiology and pathophysiology of CSF circulation—the pulsatile vector theory. Childs Nerv Syst 29:18111825, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Ramirez de Noriega F, Manley GT, Moscovici S, Itshayek E, Tamir I, Fellig Y, et al.: A swine model of intracellular cerebral edema—cerebral physiology and intracranial compliance. J Clin Neurosci 58:192199, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Rosenthal G, Hemphill JC III, Sorani M, Martin C, Morabito D, Meeker M, et al.: The role of lung function in brain tissue oxygenation following traumatic brain injury. J Neurosurg 108:5965, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Rosenthal G, Hemphill JC III, Sorani M, Martin C, Morabito D, Obrist WD, et al.: Brain tissue oxygen tension is more indicative of oxygen diffusion than oxygen delivery and metabolism in patients with traumatic brain injury. Crit Care Med 36:19171924, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Scheufler KM, Röhrborn HJ, Zentner J: Does tissue oxygen-tension reliably reflect cerebral oxygen delivery and consumption? Anesth Analg 95:10421048, 2002

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Vik A, Nag T, Fredriksli OA, Skandsen T, Moen KG, Schirmer-Mikalsen K, et al.: Relationship of “dose” of intracranial hypertension to outcome in severe traumatic brain injury. J Neurosurg 109:678684, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Wagshul ME, Eide PK, Madsen JR: The pulsating brain: a review of experimental and clinical studies of intracranial pulsatility. Fluids Barriers CNS 8:5, 2011

  • Collapse
  • Expand

Illustration from Ivan et al. (pp 1517–1528). Copyright Kenneth Probst. Published with permission.

  • FIG. 1.

    The ICBP system. Left section: Data acquisition unit, made of a digital control card that receives physiological analog signals from the sensors implanted in the animal model. Middle section: Computer acting as a control unit activating the pump. Right section: Computer-controlled syringe pump connected to a balloon catheter.

  • FIG. 2.

    Animal procedure. A: Skin incisions: skull exposure and probe instrumentation (clockwise from top right—balloon catheter, ICP probe, CBF probe, and intraventricular infusion cannula). B: Partially deflated balloon, preinsertion. C: Swine positioning after carotid instrumentation and connection of balloon catheter to the pump. Figure is available in color online only.

  • FIG. 3.

    ECG, ABP, ICP, balloon activation graph showing balloon volume (Bal. Vol.), and CBF are shown. With device activation, immediate change is noted in the ICP waveform with later changes in CBF. Figure is available in color online only.

  • FIG. 4.

    Upper: Characteristic waveforms for protocol A and B. Lower: Characteristic ICP waveform change as balloon duty cycle (BDC) increased gradually from 10% to 30%. Figure is available in color online only.

  • FIG. 5.

    Data overview, a single activation trial, protocol A type, at an ICP level of 18 mm Hg. ECG, ABP, ICP, balloon activation graph showing balloon volume (Bal. Vol.), and CBF are shown over a 12-minute period. With device activation, an immediate ICP waveform change is visible, without significant changes in heart rate or ABP. CBF increases with return to baseline some minutes after activation termination. ICP is transformed immediately with device activation and returns to baseline immediately after device activation termination. Figure is available in color online only.

  • FIG. 6.

    Protocol A concept. Upper: Balloon inflation late in diastole causing “squeezing” effect on the venous tree, pushing venous blood outside the cranium. Lower: Balloon deflation later prior to systolic upstroke, causing instantaneous reduction ICP and in resistance to arterial blood inflow, augmenting the incoming arterial pulsation. Figure is available in color online only.

  • FIG. 7.

    Protocol B concept. The nonlinear cranial P-V curve is shown. Balloon inflation during diastolic low pressure will result in a small pressure increase, while balloon deflation at high systolic pressure will result in a large pressure decrease.

  • 1

    Ambarki K, Baledent O, Kongolo G, Bouzerar R, Fall S, Meyer ME: A new lumped-parameter model of cerebrospinal hydrodynamics during the cardiac cycle in healthy volunteers. IEEE Trans Biomed Eng 54:483491, 2007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Bederson JB, Connolly ES Jr, Batjer HH, Dacey RG, Dion JE, Diringer MN, et al.: Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 40:9941025, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Carney N, Totten AM, O’Reilly C, Ullman JS, Hawryluk GW, Bell MJ, et al.: Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery 80:615, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Di Rocco C, Pettorossi VE, Caldarelli M, Mancinelli R, Velardi F: Experimental hydrocephalus following mechanical increment of intraventricular pulse pressure. Experientia 33:14701472, 1977

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Friess SH, Ralston J, Eucker SA, Helfaer MA, Smith C, Margulies SS: Neurocritical care monitoring correlates with neuropathology in a swine model of pediatric traumatic brain injury. Neurosurgery 69:11391147, 2011

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Hawryluk GW, Phan N, Ferguson AR, Morabito D, Derugin N, Stewart CL, et al.: Brain tissue oxygen tension and its response to physiological manipulations: influence of distance from injury site in a swine model of traumatic brain injury. J Neurosurg 125:12171228, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Hemphill JC III, Knudson MM, Derugin N, Morabito D, Manley GT: Carbon dioxide reactivity and pressure autoregulation of brain tissue oxygen. Neurosurgery 48:377384, 2001

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Hlatky R, Valadka AB, Gopinath SP, Robertson CS: Brain tissue oxygen tension response to induced hyperoxia reduced in hypoperfused brain. J Neurosurg 108:5358, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Kiening KL, Unterberg AW, Bardt TF, Schneider GH, Lanksch WR: Monitoring of cerebral oxygenation in patients with severe head injuries: brain tissue PO2 versus jugular vein oxygen saturation. J Neurosurg 85:751757, 1996

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Krishnamurthy S, Li J, Schultz L, McAllister JP II: Intraventricular infusion of hyperosmolar dextran induces hydrocephalus: a novel animal model of hydrocephalus. Cerebrospinal Fluid Res 6:16, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Löfgren J, von Essen C, Zwetnow NN: The pressure-volume curve of the cerebrospinal fluid space in dogs. Acta Neurol Scand 49:557574, 1973

  • 12

    Longhi L, Pagan F, Valeriani V, Magnoni S, Zanier ER, Conte V, et al.: Monitoring brain tissue oxygen tension in brain-injured patients reveals hypoxic episodes in normal-appearing and in peri-focal tissue. Intensive Care Med 33:21362142, 2007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Luciano MG, Dombrowski SM, Qvarlander S, El-Khoury S, Yang J, Thyagaraj S, et al.: Novel method for dynamic control of intracranial pressure. J Neurosurg 126:16291640, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Nilsson F, Akeson J, Messeter K, Ryding E, Rosén I, Nordström CH: A porcine model for evaluation of cerebral haemodynamics and metabolism during increased intracranial pressure. Acta Anaesthesiol Scand 39:827834, 1995

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Odland RM, Venugopal S, Borgos J, Coppes V, McKinney AM, Rockswold G, et al.: Efficacy of reductive ventricular osmotherapy in a swine model of traumatic brain injury. Neurosurgery 70:445455, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Preuss M, Hoffmann KT, Reiss-Zimmermann M, Hirsch W, Merkenschlager A, Meixensberger J, et al.: Updated physiology and pathophysiology of CSF circulation—the pulsatile vector theory. Childs Nerv Syst 29:18111825, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Ramirez de Noriega F, Manley GT, Moscovici S, Itshayek E, Tamir I, Fellig Y, et al.: A swine model of intracellular cerebral edema—cerebral physiology and intracranial compliance. J Clin Neurosci 58:192199, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Rosenthal G, Hemphill JC III, Sorani M, Martin C, Morabito D, Meeker M, et al.: The role of lung function in brain tissue oxygenation following traumatic brain injury. J Neurosurg 108:5965, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Rosenthal G, Hemphill JC III, Sorani M, Martin C, Morabito D, Obrist WD, et al.: Brain tissue oxygen tension is more indicative of oxygen diffusion than oxygen delivery and metabolism in patients with traumatic brain injury. Crit Care Med 36:19171924, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Scheufler KM, Röhrborn HJ, Zentner J: Does tissue oxygen-tension reliably reflect cerebral oxygen delivery and consumption? Anesth Analg 95:10421048, 2002

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Vik A, Nag T, Fredriksli OA, Skandsen T, Moen KG, Schirmer-Mikalsen K, et al.: Relationship of “dose” of intracranial hypertension to outcome in severe traumatic brain injury. J Neurosurg 109:678684, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Wagshul ME, Eide PK, Madsen JR: The pulsating brain: a review of experimental and clinical studies of intracranial pulsatility. Fluids Barriers CNS 8:5, 2011

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