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Anesth Analg 2002;94:393-399
© 2002 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

In Nonhuman Primates Intracarotid Adenosine, but Not Sodium Nitroprusside, Increases Cerebral Blood Flow

Shailendra Joshi, MD*, Houng Duong, MD{dagger}, Sundeep Mangla, MD{dagger}, Mei Wang, MS*, Adam D. Libow, BA*, Sulli J. Popilskis, DVM*{ddagger}, Noeleen D. Ostapkovich, R.EEG/EPT§, Theodore S. Wang, PhD{dagger}, William L. Young, MD||, and John Pile-Spellman, MD{dagger}

Departments of *Anesthesiology, {dagger}Radiology, §Neurology, and ¶Neurological Surgery and the {ddagger}Institute of Comparative Medicine, College of Physicians and Surgeons of Columbia University, New York, New York; and ||Departments of Anesthesiology, Neurology, and Neurosurgery, University of California, San Francisco, California

Address correspondence to Shailendra Joshi, MD, Department of Anesthesiology, P&S P 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
 
Intracarotid infusion of short-acting vasodilators, such as adenosine and nitroprusside, in doses that lack significant systemic side effects, may permit controlled manipulation of cerebrovascular resistance. In this experiment we assessed changes in cerebral blood flow (CBF) after intracarotid infusion of nitroprusside and adenosine. The study was conducted on six adult baboons under isoflurane anesthesia and controlled ventilation. Intracarotid drug infusion protocol avoided hypotension during nitroprusside infusion and tested for autoregulatory vasoconstriction. CBF (intraarterial 133Xe technique) was measured four times during infusions of 1) intracarotid saline, 2) IV phenylephrine (0.2 µg · kg-1 · min-1) aimed to increase mean arterial pressure by 10–15 mm Hg, 3) IV phenylephrine and intracarotid nitroprusside (0.5 µg · kg-1 · min-1), and 4) intracarotid adenosine (1 mg/min). IV phenylephrine increased mean arterial pressure (69 ± 8 to 91 ± 9 mm Hg, P < 0.0001, n = 6), and concurrent infusion of intracarotid nitroprusside reversed this effect. However, compared with baseline, CBF did not change with IV phenylephrine or with concurrent infusion of IV phenylephrine and intracarotid nitroprusside. Intracarotid adenosine profoundly increased CBF (from 29 ± 8 to 75 ± 32 mL · 100 g-1 · min-1; P < 0.0001). In nonhuman primates, intracarotid adenosine increases CBF in doses that lack significant systemic side effects, whereas intracarotid nitroprusside has no effect. Intracarotid adenosine may be useful for manipulating cerebrovascular resistance and augmenting CBF during cerebral ischemia.

IMPLICATIONS: Intraarterial 133Xe cerebral blood flow (CBF) measurements suggest that intracarotid adenosine, in a dose that lacks significant systemic side effects, profoundly increases CBF, whereas nitroprusside has no effect.(5–12)


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Intracarotid infusions of vasodilators, such as papaverine, have been used to treat cerebrovascular insufficiency (1). Intracarotid infusion of drugs limits the initial distribution of drugs to one cerebral hemisphere. The internal carotid artery (ICA) blood flow volume is only a fraction of the total cardiac output. Therefore, large cerebral arterial blood concentrations of drugs can be achieved by intracarotid administration at a fraction of systemic doses. A decrease in the total dose minimizes the chances of systemic side effects. Adenosine and sodium nitroprusside are two potent cerebral vasodilators with short biological half-lives (2,3). In theory, short-acting vasodilators may have even greater selectivity for regional effects when given by the intracarotid route. For example, adenosine, which is extensively metabolized by the vascular endothelium and red blood cells, has a biological half-life of <10 s (2). The normal cerebral transit time after an intracarotid injection is approximately 5–6 s (4). Therefore, a significant proportion of adenosine will be cleared from the cerebral arterial blood as it transits the brain, to further minimize systemic effects. Intraarterial infusion of drugs with short biological half-lives is therefore particularly suited for controlled manipulation of cerebrovascular resistance (CVR) when given by the intracarotid route.

Although cerebrovascular effects of both adenosine (Table 1) and nitroprusside have been extensively investigated, these effects remain controversial, particularly after intracarotid administration. The aim of this experiment was to assess changes in cerebral blood flow (CBF) after intracarotid infusion of nitroprusside and adenosine. The experiment was also designed to test the physiologic autoregulatory response to induced hypertension and to avoid systemic hypotension during nitroprusside infusion. We hypothesized that in healthy nonhuman primates, intracarotid infusion of both nitroprusside and adenosine would augment CBF in doses that lack significant systemic side effects during recirculation of the drug.


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  		Table 1. Effect of Intravenous and Intracarotid Adenosine on Cerebral Blood Flow (CBF) of Primates
 

   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval by the institutional animal care and use committee, studies were conducted on adult male baboons (Papio anubis). The animals were fasted overnight and then sedated with IM ketamine (20 mg/kg) for intravascular access and tracheal intubation. Anesthesia was maintained with air, oxygen, and isoflurane 1%–1.3%. The lungs were mechanically ventilated to maintain an arterial carbon dioxide tension (PaCO2) of 30–35 mm Hg. Electrocardiogram, intraarterial blood pressure, transcutaneous oxygen saturation, ETCO2, and isoflurane concentrations, as well as urinary output, were monitored.

The groin puncture site over the femoral artery was infiltrated with 0.5% bupivacaine. A 4.5F introducer sheath (Check-Flo; Cook Co., Inc., Bloomington, IN) was placed into the artery. The side arm of the introducer sheath was transduced to continuously monitor systemic mean arterial pressure (MAP). Through the femoral introducer sheath, a 4F coaxial catheter (Cook Co. Inc.) was placed into the common carotid artery. Finally, a microcatheter (2.0F, Fastrack; Boston Scientific Corp., Natick, MA) was advanced via the coaxial sheath into the ICA. Satisfactory positioning of the catheter was verified by biplane angiograms. The microcatheter was used to measure pressure in the ICA and for delivery of drugs and the 133Xe isotope.

To eliminate any catheter-induced vasospasm, the placement of the ICA catheter was considered satisfactory if 1) there was free flow of angiographic contrast, 2) a pressure wave form could be recorded through the microcatheter, and 3) mean pressure recorded through the microcatheter was within 10% of the mean femoral artery pressure. To minimize the chances of embolic complication, 1000 U of heparin was administered IV after placement of the microcatheters.

CBF was determined by the intraarterial 133Xe injection technique (13). The technique involved injection of 0.8–1.5 mCi of 133Xe isotope that was flushed with a bolus of normal saline ({approx}3 mL/3–5 s). This resulted in an instantaneous input function and thus avoided the need for determining arterial concentration and deconvolution analysis of the washout curve. The washout of the tracer was recorded over the next 90 s. Tracer washout was recorded by a scintillation detector (Carolina Medical, King, NC) that was placed over the middle cerebral artery territory. Satisfactory placement of the detector was confirmed by angiography. CBF was determined by analyzing the slope of the 133Xe washout curve between 20 and 80 s after tracer injection to determine the initial slope index (ISI). The ISI yields a value of CBF (mL · 100 g-1 · min-1) that is biased toward the gray matter.

Intracarotid drug or saline infusions were delivered at a preset rate of 1 mL/min by a calibrated infusion pump (IVAC, Santa Clara, CA). Drug or saline was infused for approximately 5 min. Three and a half minutes after the start of drug infusion, a bolus of 133Xe was injected and flushed with saline. Intracarotid infusions were resumed immediately after bolus injection of 133Xe and were continued for the next 90 s. Injection of 133Xe resulted in a bolus (0.3 mL) delivery of drugs contained in the dead space of the microcatheter. Rapid aspiration of the microcatheter to remove the drug in the dead space of the catheter was technically difficult. Therefore, we elected to ignore this small bolus of drug that was injected at the time of 133Xe CBF measurement. Hemodynamic variables were recorded at the end of 90 s of tracer washout. A sample of arterial blood was obtained for each CBF measurement to determine PaCO2 and hematocrit. CVR (mm Hg · mL-1 · 100 g-1 · min-1) was calculated by dividing the mean ICA pressure by CBF.

For the preliminary dose-ranging study, doses of adenosine were selected on the basis of previous human experience (12). In humans, a 1- to 2-mg intracarotid bolus of adenosine results in a transient increase in CBF that is not associated with any adverse effects. Assuming that primate CBF is proportional to their body weight, the projected intracarotid drug doses in baboons would be approximately one-fifth of human doses. During the preliminary study, CBF was determined at four times: baseline and after infusion of 0.5, 1.0, and 1.5 mg/min of adenosine (Adenocard; Fujisawa Healthcare Inc., Deerfield, IL). Intracarotid drugs and 133Xe were injected as described previously. The dose of nitroprusside (0.5 µg · kg-1 · min-1, Nitropress; Abbott Laboratories, North Chicago, IL) was selected on the basis of previous human studies (14). On systemic recirculation, this dose of nitroprusside is sufficient to decrease MAP by 10–15 mm Hg.

Drug challenge studies were designed to test for pressure autoregulation and avoid hypotension during intracarotid nitroprusside infusion. Except for the use of adenosine as the control drug, the drug infusion protocol is identical to our human studies (15). These studies involved four CBF determinations: first, at baseline during intracarotid infusion of normal saline, and second, during induced hypertension with IV phenylephrine (20-µg bolus followed by 0.2 µg · kg-1 · min-1). This dose of phenylephrine increases the MAP by 10–15 mm Hg and is therefore sufficient to reverse the systemic effects of intracarotid nitroprusside. We selected IV phenylephrine to increase blood pressure because the drug lacks direct cerebrovascular effects (16). The third determination was performed during concurrent infusions of IV phenylephrine and intracarotid nitroprusside and the fourth during intracarotid infusion of adenosine. The four stages of the experiment were not randomized. The sequence of drug challenges was designed to ensure smooth transition from one stage of the experiment to another with minimal delay. Thus, four CBF measurements could be completed in less than 25 min to minimize any time-dependent increase in CBF caused by background isoflurane anesthesia (17).

On completion of the experiments, the vascular catheters were removed. Pressure was applied on the femoral puncture site to control local bleeding. Animals were monitored for 24 h in a postoperative care facility.

The data are presented as mean ± SD. The data were analyzed by repeated-measures analysis of variance, and post hoc testing was performed with the Bonferroni-Dunn test.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Seven studies were conducted on six adult male baboons weighing 14 ± 4 kg. Satisfactory placement of the catheter was achieved in all cases, and there was no evidence of cerebral vasospasm during any of the studies.

Dose-response to adenosine was studied in a single animal weighing 15 kg. The three doses of intracarotid adenosine (0.5, 1, and 1.5 mg/min) increased CBF from 21 at baseline to 29, 44, and 58 mL · 100 g-1 · min-1, respectively. MAP and heart rate did not change during intracarotid adenosine infusions. We selected the intermediate dose of 1 mg/min for further studies because of concerns that excessive doses may result in an increase in intracranial pressure (ICP) or systemic side effects such as hypotension or atrio-ventricular block (18).

Complete data were available from all six drug-challenge experiments (Table 2). Each animal participated in one drug-challenge experiment. PaCO2, end-tidal isoflurane, and hematocrit remained stable throughout the study. IV phenylephrine increased MAP from 69 ± 8 mm Hg at baseline to 91 ± 9 mm Hg (P < 0.0001). Concurrent infusion of IV phenylephrine and intracarotid nitroprusside decreased the MAP from 91 ± 9 to 75 ± 7 mm Hg (P < 0.001), but it remained at a level that was slightly higher than baseline (Table 2). MAP was comparable to baseline during intracarotid infusion of adenosine (69 ± 8 and 71 ± 10 mm Hg, respectively; not significant). Changes in pressure in the ICA mirrored those in MAP at each stage of the experiments.


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  		Table 2. Changes in Physiological Variables During Intracranial Infusion of Nitroprusside and Adenosine
 
Compared with baseline, CBF did not change significantly during infusion of IV phenylephrine or with concurrent infusions of IV phenylephrine and intracarotid nitroprusside (27 ± 6 vs 27 ± 7 and 29 ± 8 mL · 100 g-1 · min-1, respectively). However, adenosine infusion resulted in an increase in CBF, from 29 ± 8 to 75 ± 32 mL · 100 g-1 · min-1; P < 0.0001). Figures 1 and 2 show individual changes in MAP and CBF during the four stages of each of the six experiments. IV phenylephrine infusion resulted in an increase in CVR from 2.7 ± 0.6 to 3.5 ± 0.7 mm Hg · mL-1 · 100 g-1 · min-1 (P < 0.001). CVR was comparable to baseline during concurrent infusion of IV phenylephrine and intracarotid nitroprusside (2.7 ± 0.6 and 2.8 ± 0.8 mm Hg · mL-1 · 100 g-1 · min-1, respectively). Infusion of intracarotid adenosine after concurrent infusions of IV phenylephrine and intracarotid nitroprusside decreased CVR (from 2.8 ± 0.8 to 1.1 ± 0.5 mm Hg · mL-1 · 100 g-1 · min-1; P < 0.001).



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  		Figure 1. Individual changes in mean arterial pressure (mm Hg) at four stages of six animals at baseline (Base), during IV infusion of phenylephrine (IV-PE), during concurrent infusion of IV-PE and intracarotid (IC) nitroprusside (IV-PE + IC-NP), and during IC infusion of adenosine (IC-ADO).

 


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  		Figure 2. Individual changes in cerebral blood flow (mL · 100 g-1 · min-1) at four stages of six animals at baseline (Base), during IV infusion of phenylephrine (IV-PE), during concurrent infusion of IV-PE and intracarotid (IC) nitroprusside (IV-PE + IC-NP), and during IC infusion of adenosine (IC-ADO).

 
At the end of the drug infusion studies, angiography revealed that the microcatheter was still located in the ICA and that there was a normal flow of contrast in anterior and middle cerebral arteries. Catheters were removed under fluoroscopic control. Protamine was not required to reverse the effect of IV heparin. Bleeding from the groin puncture site was controlled by local pressure. All animals were active in their cages within an hour of recovery from anesthesia. No neurologic complications were encountered during any study.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
There are two significant results of this study. First, in the absence of cerebral vasospasm, intracarotid nitroprusside in doses that decrease systemic vascular resistance on recirculation of the drug, as is evidenced by a decrease in MAP, fails to augment CBF. Second, in contrast to nitroprusside, intracarotid adenosine profoundly increases CBF without any adverse hemodynamic side effects. The study underscores the potential efficacy of intracarotid adenosine in augmenting CBF and questions the therapeutic potential of intracarotid nitroprusside in manipulating CVR.

The effects of nitroprusside on CBF seem to be inconsistent across animal species. In rodents and goats, intracarotid nitroprusside increases CBF (19,20). On the basis of such observations, Zhang et al. (21) suggested the therapeutic usefulness of intracarotid nitroprusside in attenuating ischemic cerebral injury. These observations are also supported by experiments on rodent brain slices that demonstrate a dose-dependent increase in arteriolar diameter after incubation with nitroprusside (22,23). Although there is little direct evidence that in humans nitroprusside augments CBF, several studies have demonstrated that IV nitroprusside does not generally increase CBF (24–27). There are only two studies that have investigated the effects of intracarotid nitroprusside on human CBF (14,26). Both of these studies failed to demonstrate an increase in CBF after intracarotid nitroprusside. These studies were conducted on patients with suspected cerebrovascular diseases undergoing angiography, and a confounding effect of intracranial pathology could not be excluded.

In theory, three other factors could explain the failure of nitroprusside to augment CBF: 1) the concurrent use of phenylephrine and nitroprusside, 2) inhibition of nitroprusside response by the radiocontrast, iohexol, that was used for angiography, or 3) the effect of background isoflurane anesthesia. We believe that these factors did not contribute to the lack of nitroprusside response in this study. For example, phenylephrine has no direct effect on CBF in the presence of an intact blood-brain barrier (16) and is frequently used to test cerebral autoregulatory response. It is therefore unlikely that phenylephrine completely abolished the response to intracarotid nitroprusside. With regard to the radiocontrast agent, preliminary reports suggest that preincubation of vascular rings from baboons in iohexol does not affect cyclic guanosine monophosphate (a marker of nitric oxide [NO] activity) generation by nitroprusside (28). Furthermore, in the coronary circulation of humans, NO-mediated vasodilation by nitroprusside can be demonstrated during angiography (29). It also seems unlikely that iohexol abolished the CBF response to intracarotid nitroprusside. With regard to background anesthesia, the use of a volatile anesthetic during experiments was primarily a preference of the veterinary team. We reasoned that the effects of anesthesia would be shared by both adenosine and nitroprusside infusions. Adenosine and nitroprusside measurements were made within 10 minutes. Although a time-dependent increase in CBF has been reported over several hours of isoflurane exposure, it was probably not a factor in this study (17).

Thus, the apparent failure of intracarotid nitroprusside to augment CBF seems to question the role of NO in regulating the CBF of higher primates. The evidence that NO plays at least some role in regulating resting cerebrovascular tone comes from studies with NO synthase (NOS) inhibition. Both IV and intracarotid infusions of NOS inhibitors in humans and in nonhuman primates modestly (13%–20%) decrease CBF (30–32). When these observations are combined with those suggesting a failure of nitroprusside, an endothelium-independent NO donor, to augment CBF, three possibilities are suggested. The first is that in higher primates, NO is not a major modulator of resting resistance arteriolar tone which normally determines CBF. The second is that the mechanism for NO-mediated vasodilation resides on the abluminal surface of cerebral arteries beyond the diffusion range of intraarterial NO. Such a conclusion could be supported by experiments on brain slices that expose the abluminal surface of the parenchymal arterioles to the drug and show a dose-dependent increase in vessel diameter after nitroprusside incubation (22,13). The third is that NO regulates the tone of large cerebral arteries but not resistance arterioles.

The third inference is supported by in vitro and in vivo studies. In vitro studies on isolated vessels suggest that large cerebral arterioles show a greater magnitude of vasoconstriction after NOS inhibition than smaller arterioles (33). In vivo, in dogs, IV nitroprusside has little effect on CBF, although the drug increases ICP (34). Michenfelder and Milde (34) therefore suggested that nitroprusside has a preferential effect on cerebral conductance rather than on resistance vessels. Furthermore, in patients with subarachnoid hemorrhage, intrathecal nitroprusside has been successfully used to treat vasospasm that affects large cerebral arteries (35,36). Similarly, in primates with experimental subarachnoid hemorrhage, intracarotid NO donors have been shown to augment CBF (37,38). It seems that under pathological conditions, when the resistance of large arteries determines CBF, then NO donors are effective in augmenting CBF.

The second significant finding of this study is that intracarotid adenosine infusion (1 mg/min) results in a robust increase in CBF of baboons. It is important to note that we did not observe any bradycardia during intracarotid adenosine that would have indicated an increase in ICP (18,39). Despite dramatic increases in CBF, all animals recovered uneventfully from anesthesia. Although a modest increase in CBF (50%–80%) after intracarotid adenosine has previously been reported in baboons, the effects of a larger dose on CBF were much more evident in this study. As reviewed by Heistad and Kontos (16), there is considerable species-related variation in intraarterial response to adenosine in cerebral circulation. In general, intraluminal application of adenosine is less effective than extraluminal application (40). However, in baboons, intracarotid adenosine seems to be an effective tool for augmenting CBF.

At the same time there are also conflicting data with regard to the effect of IV adenosine on human CBF. Not all studies with IV adenosine demonstrate a consistent increase in CBF (Table 1). Previously, in human subjects, we observed a transient increase in the slope of the 133Xe washout curve between 5 and 25 seconds (early ISI) after a 1–2 mg/min intracarotid infusion of adenosine. Analysis of tracer washout by the conventional method for determining ISI did not reveal an increase in CBF. However, if we consider the early ISI to be a measure of CBF, then in humans a 1- to 2-mg bolus of adenosine can result in a transient (<30 seconds), although profound ({approx}174%), increase in CBF (12).

One of the limitations of this study is that we used clinically relevant doses of nitroprusside and adenosine. We did not explore larger doses of nitroprusside because they were likely to result in greater systemic hypotension than the 10–15 mm Hg reduction in MAP that was evident in this study. We estimated that the dose of nitroprusside (10-5 M) used in this study generated a cerebral arterial blood concentration in the micromolar range that is sufficient to relax cerebral blood vessels (41). We therefore believe that the failure of intracarotid nitroprusside to augment CBF in higher primates is not caused by an inadequate dose of the drug, but that it represents a lack of effect of the drug when given by the intraarterial route. The normal transit time through cerebral circulation after intracarotid injection is approximately five or six seconds (4). The elimination half-life of nitroprusside (90 seconds) is much greater than that of adenosine (<10 seconds) (2). It is possible that compared with adenosine, a larger proportion of intracarotid nitroprusside reaches the systemic circulation and thus decreases the systemic vascular resistance. In the case of adenosine, we estimate that the cerebral arterial blood concentration was in the {approx}100 µM range. However, because of its exceedingly short half-life, intracarotid adenosine was adequately metabolized during transit through the brain and hence did not result in systemic side effects.

We conclude that in higher primates in the absence of cerebral vasospasm, intracarotid nitroprusside, in doses that are sufficient to decrease MAP on recirculation of the drug, fails to augment CBF. In contrast to nitroprusside, intracarotid adenosine (1 mg/min) profoundly increases CBF without any adverse effects on systemic circulation. In equivalent human doses ({approx}5 mg/min), intracarotid adenosine might be a useful drug for controlled manipulation of CVR. Neuroprotective properties of adenosine make intracarotid infusion of the drug particularly attractive in the setting of actual or threatened cerebral ischemia.(5–12)


   Acknowledgments
 
Supported, in part, by FAER/Datex-Ohmeda Research Starter, an Infrastructure Support grant from the Office of Clinical Trials of Presbyterian Hospital, and National Institutes of Health Grants K08 00698 (SJ) and K24 NS02091 (WLY).

The authors wish to thank Richard Arrington (Department of Anesthesiology) and Bohdan Spiegowski (Institute of Comparative Medicine) for their technical assistance. Thanks are also due to Ludmila L. Karameros for her help in preparing and editing the manuscript.


   Footnotes
 
Presented, in part, at the annual meeting of the American Society of Anesthesiologists, San Francisco, CA, October, 2000.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 28, 2001.




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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