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Anesth Analg 2003;97:231-237
© 2003 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

The Acute Cerebrovascular Effects of Intracarotid Adenosine in Nonhuman Primates

Shailendra Joshi, MD*, Roger Hartl, MD{dagger}, Mei Wang, MS*, Lei Feng, MD{ddagger}, Daniel Hoh, BA§, Robert R. Sciacca, EngScD||, and Sundeep Mangla, MD{ddagger}

Departments of *Anesthesiology, {ddagger}Radiology, §Neurological Surgery, and ||Medicine, College of Physicians and Surgeons of Columbia University, New York, New York; and {dagger}Department of Neurosurgery, Weill Medical College, Cornell University, New York, New York

Address correspondence to Shailendra Joshi, MD, Department of Anesthesiology, P&S Box 46, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, NY 10032. Address e-mail to sj121{at}columbia.edu No reprints will be available.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
In this study we sought to determine the acute cerebrovascular effects of intracarotid adenosine by using real-time cerebral blood flow (CBF) measurements in nonhuman primates. The internal carotid arteries of healthy anesthetized baboons were transfemorally cannulated. Changes in CBF were continuously measured at baseline and with 6 increasing doses of adenosine (0.002 to 1.5 mg/min) by use of an intraparenchymal thermal diffusion (TD) probe. Each infusion lasted 5 min. At baseline and at the largest dose of adenosine, CBF was also determined by the intraarterial 133Xe technique. TD measurements revealed a dose-dependent increase in CBF from 32 ± 6 mL · l00 g-1 · min-1 at baseline to 90 ± 38 mL · l00 g-1 · min-1 with the largest dose of adenosine (n = 5; P < 0.0001). A similar magnitude of increase in CBF was also observed with 133Xe CBF measurements. No significant increases in intracranial pressure or adverse systemic hemodynamic side effects were observed during adenosine infusion. The increase in CBF after adenosine lasted only for the duration of drug infusion. In conclusion, the transient cerebrovascular effects of intracarotid adenosine make it suitable for a trial of intraarterial vasodilator therapy and for controlled manipulation of cerebrovascular resistance.

IMPLICATIONS: Using a real-time cerebral blood flow (CBF) measurement technique, we evaluated the acute cerebrovascular effects of intracarotid adenosine in anesthetized baboons. The increase in CBF lasted only for the duration of the adenosine infusion. Adenosine might be a suitable drug for trial as an intraarterial vasodilator for the treatment of cerebral vasospasm.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Significant neurological complications have been reported with intraarterial infusion of papaverine for the treatment of cerebral vasospasm (1–3). The exact etiology of these neurological side effects is unclear. However, some of them have been attributed to an increase in intracranial pressure (ICP) or cerebral steal (4,5). Compared with the elimination half-life of papaverine (107 min), the half-life of adenosine is exceedingly short (1–10 s) (6,7). Because of its short half-life and potent vasodilator properties, adenosine is an ideal drug for a trial of intraarterial vasodilator therapy before the use of longer-acting vasodilators, such as papaverine. There are limited human data with regard to the cerebrovascular effects of intracarotid adenosine (Table 1) (11). Therefore, there is a clinical need to investigate the cerebrovascular effect of intracarotid adenosine.


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  		Table 1. Effect of Adenosine on Human Cerebral Blood Flow (CBF)
 
The effects of intracarotid adenosine on ICP and the duration of its cerebrovascular effects have not been reported. The effects of intracarotid adenosine vary considerably across experimental models (Table 2), although most nonhuman primate studies show a robust increase in cerebral blood flow (CBF) (13,14,20,21). The aim of our study was to investigate the effect of intracarotid adenosine on the cerebrovascular variables of healthy baboons. We measured CBF by an intraparenchymal thermal diffusion (TD) probe that measures tissue perfusion in real time. We hypothesized that, because of its exceedingly short half-life, intracarotid adenosine would have transient cerebrovascular effects. Furthermore, we hypothesized that, because of rapid metabolism of the drug during transit through the brain, the increase in CBF with intracarotid adenosine would not be associated with systemic side effects.


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  		Table 2. Effect of Intraarterial Adenosine on Cerebral Blood flow (CBF)
 

   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval by the institution’s animal care and use committee, the studies were undertaken on adult male baboons (Papio anubis). The anatomical organization of cerebral circulation of these nonhuman primates is fairly similar to that of humans (22,23). The animals were sedated with IM ketamine (20 mg/kg). After IV access was obtained, the animals were intubated and mechanically ventilated. Anesthesia was maintained with an end-tidal isoflurane (ETiso) concentration of 1%–1.5%. A femoral arterial line was placed to continuously monitor the systemic blood pressure. A nasopharyngeal probe was used to monitor temperature. The nasopharyngeal temperature was kept constant between 35.0°C and 36.0°C by using a Bair Hugger® (Augustine Medical Inc., Eden Prairie, MN) (24).

The animals were subsequently placed prone on a stereotactic frame. Under sterile surgical conditions, 2 5-mm frontal burr holes were drilled approximately 1.5 cm lateral to the midline. The dura was carefully penetrated with a spinal needle and irrigated to ensure that there was no bleeding. Two bolts were inserted into the skull. Through one bolt, an intraparenchymal TD probe (Q flow-400®; Thermal Technologies Inc., Cambridge, MA) was advanced approximately 1 cm beyond the dura, so as to be embedded deep within the gray matter. Through another bolt, a fiberoptic ICP probe (Camino®; Integra Life Sciences Corp., Plainsboro, NJ) was advanced to approximately the same distance (Fig. 1).



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  		Figure 1. An oblique radiograph of a baboon head showing the placement of thermal diffusion (TD), intracranial pressure (ICP), and nasopharyngeal temperature (NP) probes. The probes were positioned in the distribution of the middle cerebral artery. The cerebral blood flow detector is located in close proximity to the ICP and TD probes.

 
The Q flow-400 TD probe can quantify tissue perfusion (mL · l00 g-1 · min-1) in a small volume of tissue (30–100 µL) in real time. The flexible probe is {approx}2 mm in diameter. The advantage of this TD technique is that it quantifies perfusion without the need for a no-flow calibration. It does so by determining the conductive properties of the tissue from the initial rate of propagation of the thermal field when the heat to the probe is first turned on, and it uses the measure of conduction to determine the thermal convection (blood flow) component of the heat transfer. The performance of the Q flow-400 probe has been validated in experimental and clinical settings (25,26).

Once both the Q flow-400 and ICP devices were functioning optimally, as judged by the stability of the reading and the quality of the wave forms, the animals were turned supine. The skin over the contralateral femoral artery was infiltrated with 0.5% bupivacaine. A 4.5F introducer sheath (Check-Flo®; Cook Co. Inc., Bloomington, IN) was placed in the femoral artery. Through the introducer sheath, a 4F coaxial catheter (Cook Co. Inc., Bloomington, IN) was advanced into the common carotid artery. A microcatheter (1.8F, Fastracker-10®; Target Therapeutics, Boston Scientific International, Cedex, France) was then guided, via the coaxial sheath, into the internal carotid artery (ICA). Satisfactory positioning of the ICA catheter was angiographically verified. We used the following criteria for satisfactory placement of the microcatheter in the ICA to eliminate vasospasm: 1) there was free flow of angiographic contrast after intraarterial injections; 2) a pressure wave could be recorded through the microcatheter; and 3) the pressure recorded in the ICA (Pica) was within 10% of the mean arterial blood pressure (MAP) recorded in the femoral artery. To minimize the risks of thromboembolism, heparin (1000 U) was administered IV after placement of endovascular catheters.

Besides the TD measurements, at baseline and at the largest dose of adenosine, CBF was also determined by the intraarterial 133Xe injection technique. The technique involved a bolus injection of 0.8–1 mCi of 133Xe dissolved in 1 mL of saline that was rapidly flushed with a 3- to 4-mL bolus of normal saline. This resulted in an instantaneous input function, thus avoiding the need to determine arterial concentration for deconvolution analysis of the washout curve (27). The washout of the tracer was recorded over the middle cerebral artery distribution by a collimated cadmium telluride scintillation detector (Carolina Medical Inc., King, NC), in proximity of the TD and ICP probes as confirmed by angiography (Fig. 2). Blood flow was determined by analyzing the slope of the 133Xe washout curve (initial slope index) from 20 to 80 s after tracer injection. This method yields a value of CBF that is biased toward the gray matter (28). Given a blood-brain partition coefficient of 1 for the gray matter, initial slope index can be expressed in milliliters per 100 g per minute (29). Bolus injection of 133Xe was delivered approximately 3.5 min after an intracarotid infusion was started. The intracarotid infusions were resumed immediately after 133Xe injection. Tracer washout was recorded for 90 s. Hemodynamic variables, such as heart rate and MAP, were recorded at the end of tracer washout. A sample of arterial blood was obtained for each 133Xe CBF measurement for determination of the PaCO2 (mm Hg) and hematocrit (Hct; %). Cerebrovascular resistance (CVR; mm Hg · mL-1 · 100 g-1 · min-1) was calculated by dividing the Pica by CBF.



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  		Figure 2. Line chart showing the changes in cerebral blood flow (CBF) as measured by thermal diffusion at the three largest doses of adenosine in one animal. The CBF values have been averaged for each minute. The horizontal bars indicate the duration of adenosine (ADO) infusions of 5 min each. ADO 0.5, ADO 1.0, and ADO 1.5 correspond to intraarterial infusions of adenosine 0.5, 1.0, and 1.5 mg/min, respectively. Note that the rapid onset and offset of the effect of intracarotid adenosine tissue perfusion returns to near-baseline values after each dose.

 
A preliminary study was conducted on one adult baboon. These data were not included in the final dose-response analysis. During this experiment, we tested only one dose of adenosine (1 mg/min). This dose was based on our previous experience with adenosine (21). In this animal, the hemodynamic variables were not affected by intracarotid adenosine, but CBF, measured both by TD and the 133Xe technique, nearly doubled. Other investigators had reported a significant increase in baboons with 0.3 and 0.5 mg/min (13,14). We therefore elected, for the final dose-response studies, to test 3 smaller (0.002, 0.02, and 0.2 mg/min) and 3 larger (0.5, 1.0, and 1.5 mg/min) doses of intracarotid adenosine. All drugs were freshly prepared in normal saline, and the infusion rate was kept constant at 1 mL/min. On the basis of a molecular weight of 267.24, these doses corresponded to molar concentrations of 0.007, 0.07, 10.7, 2, 4, and 6 mM, respectively.

Although the effect of adenosine appeared to be transient, we were not certain at the start of the study that all cerebrovascular effects of intracarotid adenosine would be immediately reversed on cessation of infusion. Thus, to minimize the time required for all seven measurements, we escalated the doses of the drug, rather than administering the doses in a random manner. It was also noted during the preliminary study that bolus injection of 133Xe resulted in an increase in the TD values. Whether this was due to bolus drug delivery or an interference with thermal equilibrium after 133Xe injection can only be speculated. Thus, in the subsequent studies, TD values were averaged for 30 s before 133Xe injection.

The experimental protocol involved seven sequential CBF measurements. The first CBF value was determined during intracarotid infusion of normal saline (baseline). Subsequently, six doses of adenosine were infused into the ICA. Each intracarotid infusion lasted for approximately 5 min. To minimize the time for the study, we used progressively increasing doses of the drug. All measurements were completed within 35–45 min to avoid the time-dependent effects of prolonged isoflurane anesthesia on the CBF of primates (30).

At the end of the experiment, the location of the catheter and the integrity of the cerebral arteries were confirmed by angiography. The animals were killed with a pentobarbital/potassium chloride mixture. At autopsy, the brain was inspected for any injury at the site of probe placement.

All data are presented as mean ± SD and were analyzed by repeated-measures analysis of variance. Post hoc testing was performed by using Tukey’s procedure. Simple regression analysis was used to compare the correlation between the results obtained by TD and 133Xe CBF measurements. Saline and adenosine were used as the grouping variable.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The study was conducted on five adult male baboons weighing 14 ± 4 kg. In all animals, the ICA catheters were placed satisfactorily, and there was no evidence of vasospasm during angiography. Data from the preliminary study were excluded from dose-response and correlation analysis.

A preliminary study was conducted on one animal weighing 10.5 kg, in whom CBF measurements were performed at baseline and after intracarotid adenosine (1 mg/min). The TD measurements in this animal showed an increase in CBF from 76 to 136 mL · l00 g-1 · min-1 after adenosine. The corresponding increase in CBF by 133Xe measurements was from 62 to 111 mL · l00 g-1 · min-1. MAP increased from 66 to 74 mm Hg, and heart rate increased from 117 to 120 bpm. The ICP increased from 15 to 18 mm Hg. PaCO2 did not change during adenosine infusion.

Temperature, Hct, PaCO2, and ETiso concentrations did not change during the study (Table 3). TD measurements revealed a dose-dependent increase in CBF after intracarotid infusion of adenosine at doses >0.2 mg/min. The increase in CBF was exceedingly transient and lasted for only the duration of drug infusion (Fig. 2). At the smaller doses (<0.2 mg/min), adenosine did not increase CBF. At the largest dose of 1.5 mg/min, CBF increased from the baseline value of 32 ± 6 mL · l00 g-1 · min-1 to 90 ± 38 mL · l00 g-1 · min-1 (n = 5; P < 0.001). TD measurements also revealed that the increase in blood flow after intracarotid adenosine was promptly reversed on cessation of infusion. Corresponding to the changes in TD was an increase in CBF, evident by 133Xe CBF measurements, from 28 ± 9 mL · l00 g-1 · min-1 to 76 ± 34 mL · l00 g-1 · min-1 (n = 5; P < 0.03) at the largest dose. The MAP, Pica, and cerebral perfusion pressure (CPP) did not change significantly during intracarotid adenosine infusion. Three animals showed no change in ICP during adenosine infusions. In the remaining two animals, ICP increased from 7 to 16 mm Hg and from 19 to 30 mm Hg. The increase in ICP (13 ± 5 mm Hg to 17 ± 7 mm Hg; P = 0.8; n = 5; Table 3) and the decrease in CPP (61 ± 13 mm Hg to 54 ± 16 mm Hg; P = 0.9; n = 5) with intracranial adenosine were not statistically significant. Furthermore, with the largest dose of adenosine (1.5 mg/min), there was no correlation between the percentage increase in ICP from baseline and the percentage increase in TD CBF: %{Delta} TD CBF = 262 - 1.5%{Delta} ICP (r = 0.44; P = 0.45; n = 5). A dose-dependent decrease in CVR was evident with doses of adenosine ≥0.2 mg/min. The CVR decreased from 2.8 ± 0.9 mm Hg · mL-1 · 100 g-1 · min-1 at baseline to 1.1 ± 0.5 mm Hg · mL-1 · 100 g-1 · min-1 at the largest dose of the drug. At the largest dose of adenosine, the decrease in CVR was also evident with 133Xe CBF measurements, from 3.4 ± 1.4 mm Hg · mL-1 · 100 g-1 · min-1 to 1.3 ± 0.7 mm Hg · mL-1 · 100 g-1 · min-1 (n = 5; P < 0.02).


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  		Table 3. Change in Cerebral Hemodynamic Variables After Intracarotid Infusion of Adenosine
 
Collectively, there was some correlation between all 10 CBF measurements (baseline and adenosine) with both the TD and intraarterial 133Xe techniques: TD = 27 + 0.7 133Xe (r2 = 0.318; n = 10; P = 0.08) (Fig. 3). However, only the baseline CBF values showed a statistically significant correlation: TD (baseline) = 14 + 0.63 133Xe (r2 = 0.976; n = 5; P = 0.001). There was no correlation between the CBF values obtained by the TD and 133Xe CBF methods after intracarotid infusion of adenosine: TD (adenosine) = 92 - 0.03 133Xe (r2 = 0.001; n = 5; P = 0.96).



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  		Figure 3. Bivariate scattergram showing individual measurements of cerebral blood flow (CBF) by two different techniques—1) thermal diffusion (y axis) and 2) intraarterial 133Xe injection technique (x axis)—during intracarotid infusion of saline (x) and adenosine 1.5 mg/min ({circ} in five animals.

 
Autopsy revealed normal brains that showed no gross injury or bleeding along the track of the ICP or the TD probe.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
There were three significant results of this study. First, two independent flow-measurement techniques demonstrated a robust increase in CBF after intracarotid adenosine in nonhuman primates. A clear dose-dependent increase in CBF and a decrease in CVR were evident by TD measurements. Second, intracarotid adenosine did not result in a significant increase in ICP. Thus, CPP was maintained during intracarotid adenosine infusion. Third, the cerebrovascular effects of intracarotid adenosine were exceedingly transient, and the blood flow promptly returned to near-baseline values immediately after cessation of infusion. Collectively, these results suggest that in nonhuman primates, intracarotid adenosine (0.5–1.5 mg/min) significantly decreases CVR. The decrease in CVR is transient and is not associated with systemic side effects.

Most previous studies demonstrating the effect of adenosine on CBF used the 133Xe-injection technique. 133Xe CBF measurement averages CBF over several minutes. Therefore, 133Xe measurements do not reflect the onset and offset of a drug such as adenosine. In contrast, TD measurements quantify tissue perfusion in real time. TD measurements provide an ideal tool for measuring the response to multiple doses of drugs or for investigating the speed of onset and offset of drug effects, such as with intracarotid adenosine. In human subjects, for example, we had observed a very robust (>150%), although exceedingly transient (<25 seconds), increase in CBF after intraarterial adenosine that was not evidenced by the conventional analysis of the 133Xe washout curve (11). In previous studies with intracarotid adenosine, we had measured CBF by monocompartmental analysis by determining the initial slope of 133Xe washout (20,21). Although such CBF measurements have been validated (29), the monocompartmental analysis primarily reflects flow changes in the gray matter. Differences in vasodilator response to adenosine in different regions of the brain have been observed in small animals (17) and in human subjects (8). Thus, on the basis of intraarterial 133Xe CBF measurements, the possibility that adenosine was selectively affecting a specific anatomical site, such as the caudate nucleus, could not be excluded. Therefore, in this study, as shown in Figures 1 and 2, we positioned the TD deep within the gray matter—the region of the brain that is most likely to benefit from the increase in blood flow and the neuroprotective properties of adenosine.

During this study, we observed that the baseline CBF values obtained by the intraarterial 133Xe and TD techniques correlated well with each other: TD (baseline) = 14 + 0.63 133Xe (r2 = 0.976; n = 5; P = 0.001). Further, collectively for all animals, CBF measurements by the two techniques revealed a nearly identical increase in flow after intracarotid adenosine (Table 3). However, individually there was no correlation between the 133Xe CBF and TD values obtained after adenosine infusion: TD (adenosine) = 92 - 0.03 133Xe (r2 = 0.001; n = 5; P = 0.9). This could, in part, be explained by our inability to aspirate the microcatheter before 133Xe injection, which probably resulted in a bolus (approximately 0.5 mL) of the drug. The dramatic changes in CBF due to adenosine, as shown in Figure 3, might have interfered with 133Xe CBF mea-surements and could explain the lack of correlation between the CBF values obtained by the two methods after intracarotid adenosine infusion in individual animals.

The second significant finding of this study was that ICP did not increase after intracarotid adenosine. Intraarterial vasodilators, such as nitroprusside and papaverine, are known to significantly increase ICP. In case of nitroprusside, large doses of the drug can double ICP without affecting the CBF of healthy monkeys (31). Few investigators have studied the effects of intraarterial papaverine on both ICP and CBF simultaneously in primates without cerebral vasospasm. Data from patients with cerebral vasospasm suggest that intraarterial papaverine can increase ICP by 100% (4). In the same population, the increase in CBF after intraarterial papaverine is relatively modest ({approx}40%) (28). However, our results suggest that in case of intracarotid adenosine, the converse seems to be true: the drug has a profound effect on CBF (>200%), but its effect on ICP appears to be relatively modest.

The lack of an increase in ICP observed in this study, however, should not be an argument against ICP monitoring during intraarterial infusion of adenosine. A strong argument can be made against the small sample size of our study. Furthermore, from a clinical standpoint, any drug that profoundly increases CBF also carries the risk of increasing ICP because of a concomitant increase in intracranial blood volume. The risks might be further increased if the cerebral venous return were obstructed, for example, if the patient’s head were malpositioned (32). During our experiments, the necks of the animals had to be maximally flexed in the midline to facilitate angiography and to provide ready access to the implanted probes. The effect of the neck flexion on ICP mea-surements during our study can only be speculated, but it could explain the increase in ICP of two animals and the absence of any change in the other three.

The third significant finding of this study was the prompt return of CBF to near-baseline values on cessation of drug infusion. As is evident from Figure 3, adenosine in modest doses ({approx}0.5 mg/min) has almost an instant onset and offset of vasodilator effect. Thus, intracarotid adenosine might be useful for evaluation of intraarterial vasodilator therapy and for controlled manipulation of CVR. Intraarterial papaverine has been extensively used to treat cerebral vasospasm. Neurological complications that have been reported after papaverine infusion have been attributed to cerebral steal, increase in ICP, cerebral embolization, preservative toxicity, and so on (5). Because the exact etiology of such neurological complications remains to be fully elucidated, a trail of intraarterial therapy by a short-acting vasodilator, such as adenosine, might be useful in identifying those at risk for such complications. Because of the complex etiology of cerebral vasospasm, systematic investigation will be required to assess the efficacy of adenosine in treating the disease (33). Doses of 1 mg/min have been proposed in the literature for such an application (34).

We therefore conclude that, in nonhuman primates, intraarterial infusion of adenosine in doses of 0.5–1.5 mg/min results in a profound increase in CBF without significant systemic hemodynamic side effects. Projected to humans on the basis of body weight, intracarotid adenosine (2.5–7.5 mg/min) might be useful in augmenting CBF. Adenosine could be useful during intraarterial treatment of ischemic stroke and for a trail of intraarterial vasodilator therapy for patients with cerebral vasospasm.


   Acknowledgments
 
Supported in part by a Foundation for Anesthesia Education and Research/Datex-Ohmeda Basic Science Starter Grant, National Institutes of Health Grant K08 00698, and an Infrastructure Support grant from the Office of Clinical Trials at Presbyterian Hospital (SJ); 133Xe cerebral blood flow equipment was provided by a previous National Institutes of Health grant (RO1 NS 27713).

We thank the following staff members of the College of Physicians and Surgeons of Columbia University: Sulli J. Popilskis, DMV, and Bohdan Spiegowski, Institute of Comparative Medicine; and Ludmila L. Karameros, Department of Anesthesiology, for her help in preparing the manuscript. The Q-Flow TD measurement equipment was loaned from Thermal Technologies Inc. (Cambridge, MA).


   Footnotes
 
Presented in part at the annual meeting of the American Society of Anesthesiologists, Orlando, FL, October, 2002.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication February 21, 2003.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press