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NEUROSURGICAL ANESTHESIA

Reducing Cerebral Blood Flow Increases the Duration of Electroencephalographic Silence by Intracarotid Thiopental

Shailendra Joshi, MD^*, Mei Wang, MS^*, Joshua J. Etu, BA^*, and John Pile-Spellman, MD

Departments of *Anesthesiology, Radiology, and Neurosurgery, College of Physicians and Surgeons of Columbia University, New York, New York

Address correspondence and reprint requests to Shailendra Joshi, MD, Department of Anesthesiology, P&S Box 46, College of Physicians and Surgeons of Columbia University, 630 West 168th St., New York, NY 10032. Address e-mail to sj121{at}columbia.edu.

	Abstract

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The effects of IV anesthetics are enhanced by increased cerebral blood flow (CBF) because of a greater delivery of drugs to the brain. In contrast, mathematical simulations suggest that a decrease in CBF, by increasing regional drug uptake and decreasing drug washout, enhances the efficacy of intraarterial drugs. We hypothesized that administrating intracarotid anesthetics during cerebral hypoperfusion will significantly prolong the duration of electroencephalographic (EEG) silence. We tested our hypothesis on New Zealand White rabbits. In the first group of 7 animals, we observed that decreasing CBF by approximately 70% attenuated, but did not abolish, EEG activity. Subsequently, 9 animals received 3 intracarotid injections of 3 mg of thiopental (thiopental-1, thiopental + hypoperfusion, and thiopental-2). The first and third injections were made under physiological conditions. The second drug injection was made during cerebral hypoperfusion. Compared with injection of thiopental-1 and -2, thiopental + hypoperfusion resulted in a profound increase in EEG silence (from 45 ± 5 and 67 ± 27 s, to 206 ± 46 s, respectively, n = 9, P < 0.0001). The EEG recovery profile was similar during all three thiopental challenges. The study suggests that modulation of CBF is an important tool for enhancing intraarterial drug delivery to the brain.

	Introduction

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Intracarotid drugs have been administered to humans for a variety of indications, such as localization of brain functions (1–4), treatment of cerebral vasospasm (5–9), intraarterial thrombolysis (10,11), intractable increased intracranial pressure (12), severe intracranial infections (13), and brain neoplasms (14–16). Yet, this route of drug administration is seldom a treatment of choice because of the potential risks of stroke and the relative ineffectiveness in achieving tissue concentrations to justify the risks (17). Mathematical simulations suggest that intraarterial drug delivery is particularly suitable in three specific situations: (a) high brain extraction, (b) high systemic clearance, and (c) low regional blood flow states. In a direct contrast to IV administration, an increase in cerebral blood flow (CBF) adversely affects intraarterial regional drug delivery (18). With IV injections, an increase in CBF results in a greater delivery of drugs to the brain (19,20). However, with intraarterial delivery, an increase in CBF limits the uptake of the drugs by decreasing the cerebral transit time, and it also increases the regional washout of the drugs. Advances in neuroradiology now permit us to modulate CBF with distal balloon occlusion catheters (21). In rare instances, severe systemic hypotension (cardiac pause/flow arrest) is also used to target intraarterial therapeutic drugs (22,23). These recent advances in interventional radiology make it feasible to safely modulate CBF, and could be used to enhance intraarterial drug delivery to the brain.

We hypothesized that concurrent administration of intracarotid anesthetics during cerebral hypoperfusion will significantly prolong the duration of electroencephalographic (EEG) silence. To test our hypothesis, we evaluated the effects of intracarotid thiopental (1%) on the duration of electrocerebral silence in New Zealand White rabbits. We conducted our study on rabbits because they have a primate-like separation of the internal and external carotid circulation (24,25). We selected thiopental because electrocerebral activity of anesthetic drugs is directly linked to arterial blood and tissue concentrations (26). Recording electrocerebral activity provides us with a surrogate real-time measure of tissue concentrations that can be used to assess rapid changes in tissue concentrations. Within the constraints imposed by factors such as acute tolerance and hysteresis, the electrocerebral response to intracarotid anesthetics can help us understand the kinetics of intracarotid drugs particularly with bolus injections (27). Bolus intraarterial injections are necessary to evenly distribute intraarterial drugs so as to minimize the effect of streaming (28,29). However, bolus injections result in rapid changes in drug concentrations that defy conventional kinetic measurements, such as microdialysis for which time is required to equilibrate and obtain sufficient volume of dialysate for analysis (30,31).

	Methods

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After approval of the protocol by the institution’s animal care and use committee, the study was conducted on New Zealand White rabbits (3–4 lbs. in weight). The animals were given full access to food and water before the experiment. The animals were sedated with intramuscular ketamine (50 mg/kg). IV access was obtained through an earlobe vein. Hydrocortisone 10 mg was given after placement of an IV catheter because it prevents hypotension that sometimes occurs after surgical intervention in this animal species. Subsequently, the animals received 0.2-mL boluses of IV propofol (Diprivan® 1%; AstraZeneca Pharmaceutical LP, Wilmington, DE) as needed for maintaining adequate depth of anesthesia before tracheotomy. After infiltration of the incision site with 0.25% bupivacaine with 1:200,000 epinephrine, a tracheotomy was undertaken for placement of an endotracheal tube for mechanical ventilation by a Harvard small animal ventilator (Harvard Apparatus Inc., South Natick, MA). End-tidal CO₂ (ETco₂) was continuously monitored with a Novametrix Capnomac monitor (Novametrix Medical Systems Inc., Wallingford, CT). After securing the airway, anesthesia was maintained with an IV infusion of propofol 1–2 mL · kg^–1 · h^–1, and fentanyl 1–2 µg · kg^–1 · h^–1. A femoral arterial catheter was placed for monitoring mean arterial blood pressure (MAP). This anesthetic regimen provides stable hemodynamic conditions and permits recording of electrocerebral activity over several hours (32).

The right common carotid artery was dissected in the neck and cannulated using a 20-cm-long PE-50 tubing (Becton Dickinson and Co., Sparks, MD). The dead space of the catheter and the stopcock was approximately 0.2 mL. The catheter tip was located at 3–5 mm below the putative origin of the internal carotid artery (ICA). We have observed that the ICA occlusion in rabbits tends to decrease distal cerebral arterial blood pressure by not more than 20% less than MAP and is clearly within the normal autoregulatory range. Experiments suggest that although occlusion may decrease hemispheric blood flow, unilateral ICA occlusion alone in these animals is unlikely to cause injury (33). There are profound anatomical variations in the size and origin of rabbit ICA (24). Therefore, rather than attempt retrograde cannulation, our approach was to isolate the ICA by cannulating the common carotid and ligating all branches other than the ICA. Correct identification of the ICA and its isolation were confirmed by the retinal discoloration test (34). Briefly, this test entails injection of 0.1–0.2 mL of 0.05% indigocarmine-blue. Injection of indigocarmine-blue changes the retinal reflex from red to blue when the ICA is correctly identified.

An esophageal temperature probe was used to monitor core temperature (Mon-a-therm, 400H; Mallinckrodt Anesthesia Products, St. Louis, MO). The animal’s temperature was kept constant at 37° ± 1.0°C using an electrically heated blanket. IV fluid was infused at 10 mL · kg^–1 · h^–1. The IV infusion consisted of 3 fluids: Ringer’s lactate solution, 5% dextrose, and 5% albumin mixed in a ratio of 3:1:1, respectively. EEG recording, MAP, ETco₂, and laser Doppler flows were continuously recorded on a computer using Powerlab software (AD Instruments Inc., Grand Junction, CO).

To measure local CBF, one probe (Probe 407-1; Perimed Inc., Jarfalla, Sweden) was placed on each hemisphere. For probe placement, the animals were turned prone and positioned on a stereotactic frame. The skull was exposed through a midline incision. A 5 x 4 mm² area of the skull was shaved with an air-cooled drill, slightly anterior to bregma and 1 mm lateral to the midline. The skull was shaved to expose the inner table, such that the cortical vessels could be seen through a fine layer of bone. The probes were maneuvered to obtain a laser Doppler blood flow value of 50–250 perfusion units (PU). Once the optimum site of placement was identified, the probes were secured within plastic retainers, and glued to the skull. Satisfactory probe placement was judged by an abrupt increase in probe reading during intracarotid injection of a small volume of saline (0.2 mL). Laser Doppler blood flow measurement technique provided a relative measure of blood flow changes in the tissue; therefore, laser Doppler blood flow values were normalized to the baseline value and are expressed as percent change from baseline value.

Frontoparietal leads were placed and used to monitor the bilateral EEG activity. EEG activity was monitored using standard stainless steel needle electrodes (impedance is <10 k). The frontal and the parietal needle electrodes were secured to the skull by small stainless steel screws. The neutral electrode was placed behind the ear. Frontoparietal EEG signals were recorded using a bioamplifier (ML136; AD Instruments), with a range of 100 mV, and the EEG activity recording mode having a pass-band 0.3–60 Hz. Analog data were sampled at 100 Hz per channel with an analog to digital converter and displayed using the Chart 4.0 program (AD Instruments).

EEG silence was defined operationally, using a reference recording obtained with an identical recording technique from a known brain-dead preparation after administration of IV KCl (35). A burst suppression pattern was evident during recovery from EEG silence that was characterized by transient bursts of EEG activity in the 30- to 50-µV range spaced with an intervening period of EEG silence. The intracarotid drug effects are essentially unilateral and therefore we performed our measurements on the hemisphere of injection. The other hemisphere did receive a portion of the drug as we observed a smaller effect. EEG recovery was defined as the return of EEG activity with amplitudes and frequency composition comparable to baseline as judged by visual inspection (36). Recovery time was defined as time between onset of EEG silence after thiopental injection to EEG activity recovery comparable to baseline amplitude and morphology (Fig. 1). Silence time was the duration of time between injection of the last bolus and return of detectable EEG activity, generally a burst suppression pattern. Hemodynamic and CBF variables for each drug were evaluated at three points of time: (i) baseline, (ii) EEG silence, and (iii) recovery of EEG activity, respectively.

View larger version (61K): [in this window] [in a new window]   Figure 1. Changes in electroencephalographic (EEG) activity at baseline, during hypoperfusion or/and intracarotid (IC) thiopental and at recovery. X-axis in each figure represents time lapse of 5 s. The Y-axis represents EEG of 0.5 mV. Top panel shows that hypotension alone did not produce EEG silence. The bottom two panels show comparable EEG recovery from EEG silence with or without hypoperfusion. EEG activity was comparable to baseline after all three challenges.

Group I
Preliminary studies were undertaken in seven animals to assess cerebrovascular and electrocerebral effects of cerebral hypoperfusion. Cerebral hypoperfusion was produced by severe systemic hypotension by tandem boluses of IV esmolol 10 mg and adenosine 30 mg. During cerebral hypoperfusion, our aim was to decrease laser Doppler blood flow to 25% of the baseline values. Hypotension was comparable in all groups. In these animals, measurements were made at the three points of time as described above. Because this group did not experience EEG silence, data were collected at the peak of hypotension, after a bolus of saline (0.5 mL) injected in the carotid artery.

Group II
The study required comparisons between the effects of intracarotid thiopental (Pentothal®; Abbott Laboratories, North Chicago, IL) with normal CBF and during hypoperfusion in the brain. There was a possibility that severe hypotension with the concurrent use of intraarterial thiopental could injure the preparation. Because of the possibility of injury, we did not randomize the two interventions, but assessed the effects of thiopental before and after the hypotensive challenge. This helped assess the time-dependent, post-arrest, and residual drug effects on the preparation. In the first challenge, we obtained baseline measurements of physiological variables under normocapnic conditions. Thereafter, the animal received a standard injection of 0.5 mL of 1% thiopental. Considering that the dead-space of the catheter and the stopcock was 0.2 mL, a 3-mg bolus of thiopental was effectively delivered with each injection. Systemic hemodynamic, cerebrovascular variables and the EEG activity effects of the drugs were recorded continuously, before, during, and after thiopental injection. The preparation was allowed to recover for 45 min. In the next challenge, IV esmolol (10 mg) and adenosine (30 mg) were injected IV, and at the peak of hypotension, 3 mg of 1% thiopental injection was given through the ICA. Electrophysiological and hemodynamic variables were assessed thereafter. The third challenge was similar to the first challenge that was undertaken 45 min later when a repeat bolus of thiopental 3 mg was injected via the intracarotid route.

The data are presented as mean ± sd. The hemodynamic and laser Doppler flow data recorded at the three points of time (baseline, silence, and recovery) were normalized to baseline value. A P value < 0.05 was considered significant among the 3 challenges (thiopental-1, thiopental + hypoperfusion, and thiopental-2; analysis of variance factorial). P < 0.0167 was considered significant among the 3 stages of each challenge (baseline, drug, and recovery). All data points were evaluated by analysis of variance repeated measures with Bonferroni-Dunn test for multiple comparisons.

	Results

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Group I
Preliminary studies evaluated the effects of severe hypotension by esmolol and adenosine on electrophysiological and hemodynamic variables. The control studies were conducted on seven animals to evaluate the cerebrovascular and electrophysiological effects of severe systemic hypotension. Injection of adenosine and esmolol decreased the MAP from 97 ± 11 to 30 ± 8 mm Hg, P < 0.0001. Heart rate (HR) decreased from 252 ± 17 to 129 ± 20 bpm, P < 0.002, during hypotension. The EEG activity showed a decrease in amplitude and frequency during hypotension in all seven animals (Fig. 1). Blood flow decreased from 127 ± 75 to 40 ± 24 PU, P < 0.002, i.e., to 32% of baseline values during hypotension. MAP and HR returned to 90% of baseline values within 3–4 min of drug injection in all cases. No inotropic support was required during recovery.

Group II
Nine of the 10 animals in this arm of the study completed the protocol. Data from one animal were lost because of arterial hemorrhage. Data from the other nine animals were included in the final analysis.

Intracarotid injection of thiopental before hypoperfusion (thiopental-1) produced 45 ± 5 s of electrocerebral silence. Post-hypoperfusion injection of thiopental (thiopental-2) produced 67 ± 27 s of electrocerebral silence that was not significantly different from thiopental-1 (n = 9, P = 0.132; Table 2). Injection of thiopental during hypoperfusion produced 206 ± 46 s of silence that was significantly different from thiopental-1 (46 ± 5 s, P < 0.0001) and thiopental-2 (67 ± 27 s, P < 0.0001). MAP, HR, ETco₂, and laser Doppler flows were significantly lower during thiopental-hypoperfusion (Tables 3 and 4). Ipsilateral laser Doppler flow during thiopental-1 was 147 ± 83 PU and during thiopental-hypoperfusion was 33 ± 11 PU, i.e., flow decreased to 27% of baseline values. All these variables were comparable between the two thiopental challenges. The recovery time was significantly prolonged during thiopental-hypoperfusion (291 ± 59 s) but was comparable between thiopental-1 (126 ± 29 s) and thiopental-2 (161 ± 71 s). However, the time between the ends of silence to recovery was similar in the 3 groups, thiopental-1, thiopental + hypoperfusion, and thiopental-2 (81 ± 27, 85 ± 27, and 94 ± 55 s, respectively).

	Discussion

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Previous experiments with intraarterial drug delivery revealed a significant dose advantage of intraarterial drugs (18). One of the major concerns with intraarterial infusions of drugs, particularly at slow flow rates, has been the uneven distribution of the drug caused by streaming (37). Streaming of drugs can result in regional tissue toxicity and can be overcome with rapid rates of drug infusions, or with bolus drug delivery. However, it is difficult to investigate the kinetics of intraarterial drug delivery with bolus drug injections. Bolus injections of drugs, which last only 1–2 seconds, cause rapid changes in drug concentrations and, in the case of intracarotid anesthetics, the electrocerebral activity recovers in less than a minute. Classical techniques such as microdialysis that require time for equilibrium across the dialysis membrane will be ineffective in such setting (30). Jones et al. (31) decapitated rats within 15 seconds of bolus injection and determined the brain concentrations. The tissue drug concentrations were found to be 5- to 25-fold larger than theoretical predictions. As an alternate approach, we used EEG changes in response to bolus intracarotid anesthetics as surrogate real-time measure of tissue concentrations. Electrocerebral activity changes as a function of the concentrations of thiopental in the brain and in arterial blood. In rats, for example, electrocerebral silence occurs with a tissue concentration of thiopental of about 0.13 mg/g (26). Arguably, monitoring EEG changes after intracarotid anesthetics can give us insight into the kinetics of highly lipid soluble drugs with a kinetic profile similar to IV anesthetics.

While designing this study, we used pharmacological means to decrease CBF rather than four-vessel occlusion that requires extensive dissection. We used adenosine and esmolol, which are exceedingly short-acting drugs. A combination of these drugs was sufficient to produce a severe reduction in laser Doppler flow to 25%–30% of baseline values. However, the use of potent hypotensive drugs made randomization difficult. Rather than randomize the drugs, we tested the response to thiopental before and after the pharmacological hypotension. The results of thiopental-1 and thiopental-2 challenges were fairly similar (Tables 3 and 4), which suggest a minimal residual effect of hypoperfusion on electrocerebral response to intracarotid thiopental.

The baseline conditions and the effects of esmolol and adenosine were comparable in Groups I and II. A slowing of electrocerebral activity, and not electrocerebral silence, was evident during systemic hypotension in Group I. In theory, one could argue that the prolongation of electrocerebral silence by intracarotid anesthetics during hypoperfusion could be the result of a synergistic electrophysiological interaction between cerebral hypoperfusion and anesthetic drugs, and not the result of a kinetic interaction. The absence of EEG silence during a similar degree of hypoperfusion and a similar pattern of EEG recovery from intracarotid thiopental argues against a pharmacodynamic interaction between hypoperfusion and thiopental. To ultimately exclude a pharmacodynamic interaction between the drug and systemic hypotension, despite technical challenges, direct tissue drug concentration measurements will be required.

Uneven concentrations of the drugs caused by streaming can also be overcome by increasing the volume of drug infusion. However, rapid rates of drug infusion (20% of arterial blood flow) required to overcome streaming may not be feasible in clinical settings or may result in systemic toxicity. To mitigate such complications, continuous intraarterial drug infusions of chemotherapeutic drugs were supplemented with hemoperfusion of jugular venous return (38,39). Despite these innovative approaches, the efficacy of intraarterial drug infusions remained low and by and large failed to justify the risks of intraarterial drug delivery, such as strokes. Thus, the results of this study are particularly significant because they offer an alternate strategy to enhance the effect of intracarotid drugs and one that is relatively independent of the rate of drug infusion. The development of small balloon occlusion catheters that can be used in distant regions of the human brain can be used in clinical settings to enhance the efficacy of intraarterial drugs.

There are two concerns for using cerebral hypoperfusion to the brain. The first is possibility of ischemic cerebral injury and the second is occurrence of reactive hyperemia. In our model, the duration of cerebral hypoperfusion was very transient, <20 seconds, and the flows rapidly returned to near baseline values within 1 minute of hypotension and the MAP returned to near baseline values within 3–4 minutes. We observed only a transient attenuation of EEG activity during hypoperfusion in the absence of thiopental. EEG activity rapidly returned to baseline amplitude and morphology with the return of normal MAP. We therefore believe that the magnitude of transient reduction of flow (to approximately 25%–30%) in our model was not associated with injury.

The second hazard of cerebral hypoperfusion is reactive hyperemia. Such an increase in flow will enhance drug elimination from the brain. We did not observe a significant increase in laser Doppler flow after transient flow arrest during our preliminary studies. Previously, we have observed significant (200%) increases in laser Doppler flows occur in our model when ischemia lasted for about 10 minutes (31). It seems that transient ischemia of <20 seconds’ duration does not result in hyperemia of a significant magnitude.

We conclude that the administration of intracarotid thiopental during cerebral hypoperfusion increases the duration of drug effect. Furthermore, modulation of blood flow might be an important tool in enhancing intraarterial drug delivery to the brain. The significance of this study might be in the intracarotid delivery of chemotherapeutic drugs. In such a high risk and high benefit situation, methods to decrease blood flow, either by systemic hypotension or occlusion catheters, may be justified to enhance delivery of chemotherapeutic drugs and improve outcome. Recent technical advances in endovascular neurosurgery, such as distal balloon occlusion catheters and flow arrest, which can manipulate blood flows in the clinical setting, could be used to enhance intraarterial drug delivery.

Acknowledgments are due to the following staff members of Columbia University: Jodi Wagman, Administrative Assistant in the Department of Anesthesiology, for her help in preparing the manuscript, and Richard Arrington, BA, Cert. AT, Manager of Anesthesiology Services, for helping with technical aspects of the experiments.

	Footnotes

 
This work was supported by National Institutes of Health Grant GM K08 00698, and Irving Clinical Research Career Award from the Irving Center for Clinical Research, New York, NY (to SJ).

Accepted for publication February 11, 2005.

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