High ICP is a common clinical concern in dogs with intracranial disease. Although ICP can be measured safely in dogs,^{1} measurement of ICP is rarely performed because of the expense and fragility of fiberoptic monitors and the requirement for anesthetizing subjects. Diagnosis of high ICP is therefore based on clinical signs such as altered mentation, bradyarrhythmia, pupillary size (eg, pinpoint, mydriatic, or anisocoric), poor responsiveness of the pupils to light, and presence of systemic hypertension (the Cushing response); however, when present, these clinical signs usually indicate imminent death.^{2} Systemic hypertension associated with the Cushing response is more closely correlated with brainstem ischemia than ICP,^{3} which limits the clinical usefulness of systemic hypertension as a specific indicator of high ICP. The large range in ICP at the onset of systemic hypertension due to an increase in ICP further minimizes the clinical value of measuring MAP to diagnose that increase.^{3} There is therefore a need for a sensitive and specific method for identifying the presence of high ICP in dogs with intracranial lesions.

The presence of papilledema is considered a specific indicator of high ICP in young cattle with cerebral edema due to hypovitaminosis A.^{4} In dogs, however, papilledema is nonspecific, and the cause (ie, whether the papilledema is a result of ICP or other causes) cannot be accurately differentiated on the basis of retinal examination alone. Furthermore, papilledema is a qualitative rather than a quantitative clinical finding.

Magnetic resonance imaging has been used in humans and baboons to noninvasively measure ICP.^{5} Little data exist to aid the assessment of ICP in dogs with an intracranial mass. Venous ophthalmodynamography has been investigated in humans as a noninvasive method for measuring ICP,^{6–8} although the method does not appear to have immediate application and species differences in central retinal vein anatomy may preclude application in other species. Intraocular pressure is reportedly correlated with ICP^{9} in humans, but whether a similar relationship exists in other animals has not been investigated.

We hypothesized that the volume of an intracranial mass would be associated in an exponential manner with ICP in dogs and that estimation of the volume of an intracranial mass would be clinically helpful in determining whether an increase in ICP was present. The purpose of the study reported here was to characterize the ICPVR by use of an expanding epidural balloon model that mimicked an acute epidural mass in the frontal-parietal region. This region was selected because it is a common site for craniectomy and brachytherapy catheter placement in dogs undergoing brain tumor treatment.

## Materials and Methods

**Animals**—Seven healthy adult female Beagles^{a} weighing 12.2 to 16.6 kg, with unremarkable results of physical and neurologic examinations, were used for this study. Ages ranged from 4 years 8 months to 5 years 6 months. The study protocol was approved by the Purdue University Institutional Animal Care and Use Committee. Data were collected at the same time our research group was conducting another study regarding the calibration of a novel device for the noninvasive measurement of ICP. Those results are not reported here.

**Experimental procedure**—Food was withheld from all dogs for 8 to 12 hours prior to premedication for ICP measurement; water was available until the time of premedication. For premedication, dogs received an IM injection of glycopyrrolate^{b} (0.01 mg/kg) in combination with acepromazine maleate^{c} (0.02 to 0.05 mg/kg) and butorphanol tartrate^{d} (0.2 to 0.4 mg/kg). Anesthesia was subsequently induced by IV injection of 2.5% sodium pentothal^{e} (15 mg/kg), and the dogs were endotracheally intubated and positioned in sternal recumbency, with the head resting securely on a craniotomy head stand. Anesthesia was maintained with isoflurane^{e} in oxygen that was delivered by mechanical ventilation^{f} and by use of an out-of-circle, agent-specific vaporizer in a semiclosed anesthetic circle rebreathing system.

Tidal volume and ventilation rate were altered in response to thoracic compliance and airway pressure to maintain a Paco_{2} between 35 to 40 mm Hg and an airway pressure < 20 cm H_{2}O. Ventilation rate was altered from 10 to 15 respirations/min to maintain Paco_{2} within the target range. Once a surgical plane of anesthesia was attained, neuromuscular blockade was induced by IV administration of atracurium besilate at an initial loading dose of 200 μg/kg and maintained with a constant rate infusion of atracurium at 7.0 to 8.4 μg/kg/min. Maintenance was ensured by continuous monitoring of heart rate, MAP, and end-tidal isoflurane concentration, which was kept between 1.5% and 2.0%, representing 1.1 to 1.5 times the minimum alveolar concentration (1.32%) for isoflurane in Beagles.^{10} If heart rate increased > 20% and MAP did not decrease relative to initial values, butorphanol (0.2 to 0.4 mg/kg, IV or IM) was administered at least 2 hours after anesthetic induction to provide additional intraoperative analgesia.

A dorsal midline incision was made with a No. 10 scalpel blade from the level of the nasion caudally to the inion in each dog. The temporal fascia was incised from the zygomatic process caudally along the curvature of the frontal bone to the external occipital protuberance of the sagittal crest. The temporalis muscles were elevated from the parietal and temporal bone by use of electrocautery and a periosteal elevator.

**Epidural mass model**—A 1-cm-diameter burr hole was made by use of an electric drill^{g} with a 5-mm-diameter round burr on the left side of the exposed skull of each dog, approximately midway between the bregma and inion and approximately 1 cm sagittal to the midline. A 10F Foley balloon catheter was placed through this burr hole into the epidural space with the balloon positioned rostral to the burr hole. The catheter was secured with a Chinese finger trap suture of 2-0 polydioxanone.^{h}

**ICP monitor placement**—The hand drill included in the fiberoptic ICP monitor package^{i} was used to create a burr hole on the right side of the exposed skull of each dog, approximately 1 cm sagittal to the mid-line and approximately 1 cm caudal to the bregma. The dura was incised with a dural probe also included with the ICP monitor.^{i} The fiberoptic probe was inserted to a depth of 1 cm in the rostral aspect of the right parietal lobe. The skin was loosely apposed by suturing with 3-0 polydioxanone in a simple continuous pattern.

**Measurement and alteration of ICP**—The fiberoptic ICP monitor was zeroed to atmospheric pressure after the surgery. This ICP sensor is widely used to measure ICP in critical neurosurgical patients.^{11} The ICPVR was obtained by sequential inflation of the intracranial balloon catheter.^{12–14} With the catheter balloon deflated, a baseline ICP measurement was obtained (time 0). The balloon was gradually inflated by injection of 0.5 mL of 0.9% NaCl solution every 10 minutes, and ICP was measured at each of these points until the ICP equaled or exceeded the MAP, at which point data collection was stopped because of cessation of cerebral blood flow according to the definition of cerebral perfusion pressure (cerebral perfusion pressure = MAP - ICP).^{15} The interval for incremental increases in volume was based on the results of previous studies^{16,17} in dogs that indicated ICP stabilizes within 3 to 10 minutes in response to an increase in balloon volume.

Several variables were monitored continuously during anesthesia for each dog. Continuous ICP was monitored by use of the fiberoptic ICP monitor. A multiparameter patient monitor^{j} was used to continuously monitor heart rate and ECG rhythm, directly measured blood pressure and waveforms, respiratory rate and pressure wave forms, end-tidal CO_{2} concentration, Spo_{2}, and rectal temperature. The following data were collected at each incremental balloon volume: ICP, heart rate, directly measured MAP, ventilatory rate, end-tidal CO_{2} concentration, Spo_{2}, and rectal temperature. Arterial blood samples were obtained at the first and final measurement points of the study. Blood pH, Paco_{2}, and Pao_{2} and the plasma concentrations of Na^{+}, K^{+}, Ca^{2+}, glucose, and hemoglobin were measured and base excess and blood HCO_{3}^{−} concentration were calculated by use of a point-of-care analyzer.^{k} At completion of the study, dogs were humanely euthanatized by bolus administration of sodium pentobarbital (60 mg/kg, IV).

**ICP-volume relationship**—Two-factor and 3-factor exponential equations were chosen to model the ICPVR because the relationship is more appropriately modeled with an exponential equation rather than a linear equation.

^{18}The relationship between ICP (in mm Hg) and balloon volume (in mL) was analyzed by use of nonlinear regression

^{l}and the following 2-factor exponential equation:

_{0}is the ICP when balloon volume equals 0 mL, k is the nonlinear stiffness constant (mL

^{−1}) for the pressure-volume relationship, and V is the balloon volume. Taking the derivative of equation 1 with respect to V produces the following equation:

^{5}; however, the equation assumes that the asymptotic pressure (P

_{asymptote}) approximates 0. It is much more likely that the value for P

_{asymptote}approximates the value for venous pressure near the external auditory canal.

^{16,19}Accordingly, the ICPVR was also modeled by use of a 3-factor exponential equation:

_{asymptote}is the ICP at infinite negative volume. Taking the derivative of equation 3 with respect to V produces the following equation:

_{asymptote}), with gradient k and intercept equal to 0. Equation 3 has been widely used to model the end-diastolic pressure-volume relationship in the left ventricle

^{20}and on this basis was adapted for use to characterize the ICPVR. It should be noticed that equation 3 reduces to equation 1 and equation 4 reduces to equation 2 when P

_{asymptote}equals 0 mm Hg.

Initial estimates for P_{0} (0 to 20 mmHg in increments of 5 mm Hg), P_{asymptote} (-2 to +6 mm Hg in increments of 2 mm Hg), and k (0.2 to 0.8 mL^{−1} in increments of 0.2 mL^{−1}) were used when applying the nonlinear regression procedure to equations 1 and 3. The accuracy of the estimated values for P_{0}, P_{asymptote}, and k for each dog was evaluated by use of the number of iterations required to converge to a solution, by calculating the *R*^{2} value, by comparing actual with predicted values for ICP, and by examining residual plots.

**Statistical analysis**—Data are reported as mean ± SD. Repeated-measures ANOVA^{m} and an autoregressive covariance structure were used to investigate whether study variables changed with increasing balloon volume. Equations 1 and 3 for modeling the ICPVR were compared through goodness of fit as quantified by sum of squares.^{21} Estimated values for P_{0}, P_{asymptote}, and k from the steady state and peak pressure-volume relationship data were compared by use of paired *t* tests. A value of *P* < 0.05 was considered significant for all analyses.

## Results

The mean ± SD value for the ICP of the 7 dogs with the balloon deflated was 13.0 ± 8.0 mm Hg. A curvilinear ICPVR was evident for all 7 dogs when steady-state ICP values were graphically displayed (Figure 1). An excellent fit to equations 1 (involving P_{0} and k) and 3 (involving P_{0}, P_{asymptote}, and k) was obtained for all dogs as determined by examination of residual plots and the *R*^{2} value exceeding 0.93 for the data from each dog. Estimated mean values for P_{0} and k were similar for equations 1 and 3 (Table 1).

Mean ± SD values for variables used in modeling the ICP-volume relationship by use of 2 types of equations^{*} in healthy adult anesthetized female Beagles.

Factor, by pressure condition | 2-factor equation value | 3-factor equation value | P value |
---|---|---|---|

Steady-state pressure (n = 7 dogs) | |||

k (mL^{−1}) | 0.536 ± 0.143 | 0.615 ± 0.137 | 0.16 |

P_{0} (mm Hg) | 10.1 ± 4.4 | 11.1 ± 4.5 | 0.12 |

P^{asymptote} (mm Hg) | ND | 2.8 ± 4.9 | ND |

Peak pressure (n = 6 dogs) | |||

k (mL^{−1}) | 0.570 ± 0.170 | 0.682 ± 0.262 | 0.06 |

P_{0} (mm Hg) | 19.3 ± 9.3^{†} | 18.6 ± 9.9^{†} | 0.13 |

P^{asymptote} (mm Hg) | ND | 5.2 ± 5.4 | ND |

^{*}The relationship between ICP and balloon volume was analyzed with a 2-factor exponential equation (*P* = P_{0} × e^{k × V}) and a 3-factor exponential equation (*P* = [P_{0} - P_{asymptote}] × e^{k × V} + P_{asymptote}), in which P is the ICP, P_{0} is the ICP when balloon volume equals 0 mL, k is the nonlinear stiffness constant for the pressure-volume relationship, V is the balloon volume, and P_{asymptote} is the ICP at infinite negative volume. *P* values are for the comparison of the estimated values between the 2-factor and 3-factor equation models.

^{†}*P* < 0.05 compared with steady-state value for P_{0}.

ND = Not determined.

Equation 3 provided a better fit than equation 1 for only 1 of the 7 dogs, as indicated by a *P* value < 0.05 for the comparison of the difference in the estimated value for P_{0} between the 2– and 3-factor equations (Table 2). However, as expected, the *P* value for equation comparisons was dependent on the number of data points used in the nonlinear regression analysis.

Individual dog data used in modeling the ICP-volume relationship by use of 2 types of equations^{*} in 7 healthy adult anesthetized female Beagles.

2-factor equation | 3-factor equation | ||||||
---|---|---|---|---|---|---|---|

Variable | No. of measurements | P_{0} (mm Hg) | k (mL^{−1}) | P_{0} (mm Hg) | P_{asymptote} (mm Hg) | k (mL^{−1}) | P value |

Steady-state pressure, by dog | |||||||

1 | 6 | 6.5 | 0.388 | 7.5 | 4.6 | 0.559 | 0.23 |

2 | 12 | 10.6 | 0.379 | 11.7 | 3.2 | 0.414 | 0.03 |

3 | 6 | 16.8 | 0.659 | 16.5 | −1.5 | 0.637 | 0.26 |

4 | 9 | 9.3 | 0.386 | 12.1 | 10.0 | 0.703 | 0.07 |

5 | 6 | 13.7 | 0.668 | 16.3 | 6.7 | 0.767 | 0.23 |

6 | 9 | 3.4 | 0.608 | 4.1 | 1.1 | 0.631 | 0.10 |

7 | 6 | 10.3 | 0.663 | 9.2 | −4.2 | 0.591 | 0.23 |

Peak pressure, by dog | |||||||

1 | 6 | 12.3 | 0.659 | 13.0 | 5.3 | 0.832 | ND |

2 | 12 | 15.1 | 0.410 | 16.1 | 4.5 | 0.463 | ND |

3 | 6 | 20.8 | 0.905 | 23.5 | 11.2 | 1.129 | ND |

4 | 9 | 13.0 | 0.581 | 13.6 | 2.8 | 0.631 | ND |

5 | 6 | 34.7 | 0.516 | 36.2 | 10.9 | 0.608 | ND |

6 | 9 | 10.2 | 0.464 | 9.1 | −3.4 | 0.428 | ND |

7 | 6 | 28.8 | 0.459 | ND | ND | ND | ND |

*P* values are for the comparison of the estimated value for P_{0} between the 2-factor and 3-factor equation models. Such values were not generated for peak pressure because of the lower biological relevance of modeling peak pressure rather than steady-state pressure.

*See* Table 1 for remainder of key.

Nonlinear regression modeling in which peak pressure values were used could only be applied to the ICP-volume data for 6 of the 7 dogs. The estimated value for the stiffness constant (k) was similar for peak pressure and steady-state pressure analyses (*P* = 0.59 for the 3-factor equation; *P* = 0.67 for the 2-factor equation), as was the value for P_{asymptote} (*P* = 0.69 for the 3-factor equation). In contrast, as expected, P_{0} was higher (*P* = 0.041 for the 3-factor equation; *P* = 0.016 for the 2-factor equation) when calculated from peak-pressure values.

Heart rate (*P* = 0.38) and MAP (*P* = 0.52) did not change significantly for the various balloon volumes, indicating the absence of the Cushing response. Arterial blood pH (baseline, 7.38 ± 0.05; study end, 7.37 ± 0.04) and Paco_{2} (baseline, 35.3 ± 2.9 mm Hg; study end, 36.5 ± 4.1 mm Hg) were similar at the start and end of the study, as were PaO_{2}, blood bicarbonate concentration, base excess, and plasma concentrations of Na^{+}, K^{+}, Ca^{2+}, glucose, and hemoglobin (data not shown).

## Discussion

Accurate characterization of the ICPVR is clinically helpful in indicating the margin of safety when obtaining CSF from the atlanto-occipital space in dogs in which cerebral disease has been identified through brain imaging. Similarly, with the increasing availability of treatment options for brain tumors in dogs, there is a need to identify the safety of intracranial procedures such as implantation of brachytherapy balloon catheters that create an acute, artificial mass lesion. Although such treatments have long been used in human medicine, differences in cerebral volumes between humans and dogs suggest that the safety of brachytherapy balloon catheter techniques in dogs needs additional investigation. Characterization of the ICPVR should also be helpful in deciding when decompressive craniectomy is indicated in dogs with head trauma and acute mass lesions secondary to subdural or epidural hemorrhage.

The normal range for ICP in the isoflurane-anesthetized dogs in the study reported here, when calculated from the mean P_{0} value for the 3-factor equation (mean, 11 mm Hg; range, 2 to 20 mm Hg; n = 7), was similar to that reported elsewhere for dogs anesthetized with isoflurane,^{22,23} pentobarbital,^{16} and halothane.^{12} Our mean value for ICP was similar to that reported for mean CSF pressure in the atlanto-occipital space in conscious dogs^{24} and dogs anesthetized with morphine and ether.^{25} Our range for ICP calculated from the mean P_{0} value was lower than that obtained from the dogs immediately after instrumentation; presumably, surgical manipulation resulted in greater variation in the baseline value. Although it would be preferable to conduct studies providing ICP measurements on a larger number of dogs and involving various anesthetic protocols, until such studies are performed, it is reasonable to propose that high ICP should be suspected whenever ICP is > 20 mm Hg.

_{0}, and P

_{asymptote}obtained with the 3-factor exponential equation (Table 2). Such a calculation indicated that a balloon volume > 1.2 mL was associated with a high ICP (> 20 mm Hg) in the dogs in our study (Figure 1); a balloon volume of > 1.3 mL was calculated by use of the mean values for k and P

_{0}and the 2-factor exponential equation. These calculations suggested that high ICP should be suspected in dogs with a BW of 12 to 17 kg whenever the calculated volume of an intracranial mass exceeds 1.2 to 1.3 mL.

Allometric scaling indicates that brain weight (in g) in nonprimate mammals equals 9.3 × BW^{0.73}, with BW in kg.^{26} This equation predicts a mean brain weight of 64 g (and therefore an approx brain volume of 64 mL, based on brain tissue density of 1.05 g/mL) and a brain weight of 0.46% of BW for the 14-kg-BW dogs in the study reported here. The estimated brain weight was similar to measured mean brain weights in other studies of 0.47% of BW in 6 mongrel dogs weighing 17 to 22 kg^{16} and 0.41% of BW in 15 dogs weighing 14 to 28 kg.^{27} A calculated intracranial volume of 1.2 to 1.3 mL therefore approximates 2% of the brain volume. This represents a remarkably small percentage of the healthy brain volume and is consistent with widely held beliefs that the intracranial space has low compliance.

We believe that ours is the first study in which a 3-factor exponential equation was used to model the ICPVR. The 3-factor exponential equation has been commonly used to model the end-diastolic pressure-volume relationship in the left ventricle of the heart.^{20,28,29} Previous studies^{19,30} in which the ICPVR was modeled have involved a 2-factor exponential equation that assumes P_{asymptote} equals 0 mm Hg; however, it is likely that the true value for P_{asymptote} exceeds 0 mm Hg because this pressure should approximate that in the small veins near the external auditory canal. Our supposition was confirmed in 1 of the 7 dogs in which the 3-factor exponential equation could be fit to the data; that dog had the largest number of data points (12) available for nonlinear regression analysis. In other words, the 3-factor exponential equation (equation 3) should be regarded as the preferred equation to model the ICPVR; however, application of this equation requires more data points to provide an accurate estimate for the value of P_{asymptote} in an individual dog.

Our mean value for k (approx 0.6 mL^{−1}) was numerically lower than the value calculated in another study^{18} for 8- to 14-kg dogs (0.94 mL^{−1}) on the basis of a 2-factor semilogarithmic model and subarachnoid volume infusion. The greater intracranial compliance in the dogs in our study (lower value for the stiffness constant k) when intracranial volume was altered by balloon inflation was expected because our experimental procedure permitted translocation of CSF from the intracranial to extracranial space and alterations in the rate of CSF formation and absorption.^{17,30,31} Translocation of CSF is likely to be altered when subarachnoid volume infusion is used. Our finding that P_{0} was significantly higher when calculated from peak-pressure rather than steady-state values indicated that the incremental change in intracranial volume was accommodated by changes in the volume of components within the intracranial space. This accommodation was most likely due to translocation of CSF from the intracranial to extracranial space, a decrease in intracranial venous volume, and alterations in the rate of CSF formation and absorption.^{18} This finding supports our hypothesis that a more accurate description of the ICPVR is obtained by incremental increase in the volume of balloon catheter rather than by injection or removal of fluid from the subarachnoid space. This finding also provides evidence that chronic or slow-growing mass lesions may result in a smaller increase in ICP than acute lesions because of accommodation, whereas acute lesions would likely yield more prominent increases in ICP. Thus, the model presented here is most accurately applied to acute lesions; extrapolation of the model to chronic or slow-growing lesions may overestimate the true ICP. A more in-depth study of the effect of accommodation on ICP for chronic lesions is needed to provide more detailed information on the limits of accommodation, but was not within the scope of our study.

A limitation of using k as an index of intracranial stiffness is that k is a dimensional constant with units of mL^{−1}. As such, caution should be exercised when our results are extrapolated to dogs with a BW much different from those in the study reported here (12 to 17 kg). An additional limitation of our study is that we used an acute expansion model for increasing ICP (balloon inflation). It is likely that a slowly enlarging mass will cause some necrosis of adjacent cerebral tissue, thereby altering the ICPVR. Our findings are therefore most accurately applied in cases of acutely occurring changes such as acute hemorrhage or trauma. Regardless of these limitations, the results of the study reported here suggested that high ICP should be suspected in dogs weighing 12 to 17 kg whenever a rapidly occurring, space occupying intracranial lesion exceeding 1.2 mL (or a mass exceeding 2% of the brain volume) is identified.

## ABBREVIATIONS

BW | Body weight |

ICP | Intracranial pressure |

ICPVR | Intracranial pressure-volume relationship |

MAP | Mean arterial blood pressure |

Marshall Farms, North Rose, NY.

American Regent Inc, Shirley, NY.

Vedco Group Intl, Houston, Tex.

Fort Dodge Animal Health, Overland Park, Kan.

Abbott Laboratories, Abbott Park, Ill.

Hallowell EMC veterinary ventilator, Model 2000, Hallowell EMC, Pittsfield, Mass.

E-pen electric pen drive, Synthes Inc, West Chester, Pa.

PDS, Ethicon Inc, Somerville, NJ.

Camino ICP V420, Camino Laboratories, San Diego, Calif.

Datascope, Passport 2, Datascope Corp, Mahwah, NJ.

i-STAT analyzer and CG8+ cartridge, Abbott Laboratories, Abbott Park, Ill.

PROC NLIN, SAS, version 9.1, SAS Institute Inc, Cary, NC.

PROC MIXED, SAS, version 9.1, SAS Institute Inc, Cary, NC.

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