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Anesth Analg 1999;88:1-7
© 1999 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

The Effects of Aprotinin on Outcome from Cerebral Ischemia in the Rat

Hilary P. Grocott, MD, FRCPC, Huaxin Sheng, MD, Yoshihide Miura, MD, Shiva Sarraf-Yazdi, BSE, G. Burkhard Mackensen, MD, Robert D. Pearlstein, PhD, and David S. Warner, MD

Neuroanesthesia Research Laboratory, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina

Address correspondence and reprint requests to Hilary P. Grocott, MD, Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710. Address e-mail to h.grocott{at}duke.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The administration of aprotinin has been associated with a reduction in cardiac surgery-related stroke. Intrinsic neuroprotective properties of this drug have not been evaluated in laboratory outcome models of cerebral ischemia. The purpose of this study was to determine whether aprotinin exhibits neuroprotective effects against either global or focal cerebral ischemia in the rat. Fasted rats were administered aprotinin (30,000 or 60,000 KIU/kg) or vehicle (0.9% NaCl) IV before global ischemia (10 min bilateral carotid occlusion with mean arterial pressure 30 mm Hg) or focal ischemia (75 min of transient middle cerebral artery occlusion [MCAO]). Five days after global ischemia, the percentage of dead hippocampal CA1 neurons (mean ± SD) was similar among the groups (small-dose aprotinin: 49 ± 31, n = 15; large-dose aprotinin: 55 ± 31, n = 13; vehicle: 47 ± 31, n = 16; P = 0.74). After 7 days' recovery from MCAO, no difference among the groups was observed for either neurologic score (P = 0.99) or cerebral infarct volume (small-dose aprotinin: 136 ± 80 mm3, n = 23; large-dose aprotinin: 132 ± 101 mm3, n = 11; vehicle: 121 ± 81 mm3, n = 21; P = 0.87).

Implications: Aprotinin offers no neuroprotection against either global or focal cerebral ischemia in the rat when administered as a single preischemic bolus.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Aprotinin is a bovine lung-derived polypeptide belonging to a family of serine protease inhibitors. Aprotinin is commonly used during cardiac surgery, in which it has been shown to reduce blood loss and transfusion requirements (1,2). Aprotinin also reduces generalized inflammation associated with cardiopulmonary bypass (CPB). This has been attributed to inhibition of several mediators of inflammation, including tumor necrosis factor-{alpha}, neutrophil CD11b integrin, and interleukin-6 (3,4).

A prospective multicenter study was performed to evaluate effects of aprotinin on reducing blood loss and transfusion requirements during repeat coronary artery bypass graft surgery (5). The incidence of stroke, examined as a secondary end point, was reduced in the groups that received aprotinin. Furthermore, in a larger retrospective assessment of all the studies performed in the United States that involved the use of aprotinin in the cardiac surgery setting, the administration of aprotinin was again associated with a significant reduction in the stroke rate (6).

The neuroprotective effects of aprotinin, however, have not undergone specific evaluation in laboratory recovery models of cerebral ischemia. Accordingly, we examined the effect of aprotinin on histologic and neurologic outcome in standard rat models of global and focal cerebral ischemia. We hypothesized that aprotinin would decrease the number of dead hippocampal CA1 neurons resulting from transient global ischemia and decrease infarct size resulting from reversible middle cerebral artery occlusion (MCAO).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This study was approved by our animal care and use committee. Male Sprague-Dawley rats (8–10 wk old; Harlan, Indianapolis, IN) were fasted from food but allowed free access to water for 12–16 h before experimentation. Rats were anesthetized with 3% halothane. The trachea was intubated, and the lungs were mechanically ventilated with 50% oxygen/50% nitrogen. Ventilation was adjusted to maintain normocapnia. Anesthesia was maintained with 0.5%–1.5% halothane (inspired). Pericranial temperature was monitored and servoregulated to 37.5 ± 0.1°C using a heat lamp and cooling fan controlled by a temperature regulation system (22-gauge needle thermistor and indicating controller; YSI Inc., Yellow Springs, OH). The tail artery was cannulated for blood pressure monitoring and arterial blood sampling. The right internal jugular vein was cannulated for drug administration, as well as induction of hypotension by blood withdrawal. Through a neck incision, both carotid arteries were encircled with sutures. Electroencephalographic (EEG) activity was monitored with active needles placed adjacent to the skull (below the temporalis muscle bilaterally) and a ground lead in the tail.

After surgical preparation (approximately 20 min), local anesthetic (1% lidocaine) was instilled in the wounds, 50 IU of heparin IV was administered, and the inspired halothane concentration was reduced to 0.5%. A stabilization interval of 20 min was allowed. Before onset of ischemia, 1 mg of succinylcholine was given IV. Rats were randomly allocated to one of three groups (n = 13–16 per group): vehicle = 3.0 mL/kg 0.9% NaCl IV over 10 min immediately before ischemia; small-dose aprotinin = 30,000 KIU/kg aprotinin IV over 10 min immediately before ischemia; and large-dose aprotinin = 60,000 KIU/kg IV over 10 min immediately before ischemia.

The aprotinin used throughout the experimental series was a commercially available preparation (Trasylol®; Bayer Corporation, West Haven, CT) containing 10,000 KIU, 9 mg of sodium chloride, and hydrochloric acid and/or sodium hydroxide (added to adjust the pH to 4.5–6.5) per milliliter of water. Investigators were blinded to group assignment until after the neurologic and histologic analyses were completed.

Global ischemia was induced by blood withdrawal from the venous catheter to reduce the mean arterial pressure (MAP) to 30 mm Hg according to previously published methods (7). Both carotid arteries were then temporarily occluded with cerebral aneurysm clips. EEG isoelectricity occurred after carotid clamping, thereby defining the global ischemic state. Continued withdrawal of blood was performed as required to maintain MAP 30 mm Hg. After 10 min, the aneurysm clips were removed, blood withdrawn via the venous catheter was reinfused, and 0.4 mEq of sodium bicarbonate was infused IV.

Rats remained anesthetized with 0.5% halothane for 120 min postischemia with continued pericranial temperature servoregulation to 37.5 ± 0.1°C. Anesthesia was then discontinued, and the trachea was extubated. Animals were allowed to recover in an enriched oxygen environment (50% fraction of inspired oxygen) for 3 h before being returned to cages with free access to water and food for the next 5 days.

Blood pressure, EEG, and pericranial temperature were continuously recorded during the experiment on a computer using an analog to digital converter.

On the fifth postoperative day, motor function tests were performed by a blinded observer according to an established protocol, including assays of prehensile traction and balance beam performance (8,9). The motor score was graded on a 0–9 scale (best score = 9). Rats were then anesthetized with halothane, and they underwent in situ brain fixation by an intracardiac injection of buffered 4% formalin. After overnight stabilization, the brains were removed and stored in 4% formalin. Paraffin-embedded brain sections were serially cut (5-µm sections) and stained with acid fuschin/celestine blue. Injury to the CA1 hippocampus was evaluated by a blinded observer using light microscopy; viable and nonviable neurons were counted, and the percentage of nonviable neurons was calculated (%CA1 dead). The side of the brain with the worst damage was used for the final analysis.

Physiologic values were compared among groups by using one-way analysis of variance. The Kruskal-Wallis H statistic was used to compare both %CA1 dead neurons among groups and neurologic scores. A P value <=0.05 was considered significant.

Male Wistar rats (8–10 wk) were fasted from food but allowed free access to water for 12–16 h before the experiment. The animals were then anesthetized with halothane (2%–3%) in 50% O2/50% N2. After tracheal intubation, the lungs were mechanically ventilated to maintain normocapnia. The halothane concentration was then reduced to 1.0%–1.5%. The tail artery was catheterized to monitor MAP and sample blood. The right internal jugular vein was cannulated for drug administration. Pericranial temperature was monitored and servoregulated to 37.5 ± 0.1°C using a heat lamp and cooling fan controlled by a temperature regulation system.

The animals were then prepared for MCAO (10,11). A midline cervical incision was performed, and the right common carotid artery was identified. The external carotid artery was isolated, and the occipital, superior thyroid, and external maxillary arteries were ligated and cut. The internal carotid artery (ICA) was dissected distally until the origin of the pterygopalatine artery was visualized. Lidocaine (1%) was instilled into the surgical wounds.

Rats were then randomly assigned to one of three groups: vehicle (n = 23) = 3.0 mL/kg 0.9% NaCl IV over 10 min immediately before ischemia; small-dose aprotinin (n = 11) = 30,000 KIU/kg aprotinin IV over 10 min immediately before ischemia; and large-dose aprotinin (n = 21) = 60,000 KIU/kg IV over 10 min immediately before ischemia.

All rats then underwent 75 min of MCAO induced by placing a nylon monofilament over the middle cerebral artery (MCA) via the ICA. During ischemia and reperfusion, the inspiratory gas mixture contained 0.7% halothane, 50% O2, and balance N2. After ischemia, the animals remained anesthetized with the same inspiratory gas mixture for 2 h to allow continuous control of pericranial temperature. Vascular catheters were then removed, the anesthetic was discontinued, and the trachea was extubated after recovery of adequate spontaneous ventilation. Seven days later, the rats underwent a standardized neurologic examination designed to detect hemiparesis by a blinded observer (12). Each animal was assigned a score of 0–3 (0 = no observable deficit; 1 = forelimb flexion, 2 = decreased resistance to lateral push without circling, and 3 = same behavior as 2 with circling) (13). Neurologic tests were performed by a single observer who was blinded to the animal's group assignment.

After neurologic examination, all animals were weighed, anesthetized (4% halothane in O2), and decapitated. The brains were removed and frozen at -20°C in 2-methylbutane. Using a cryotome, quadruplicate 20-µm coronal sections were obtained at 660-µm intervals throughout the rostral-caudal extent of the infarct. The sections were then dried and stained with hematoxylin and eosin.

Infarct volume was measured by digitally sampling stained sections with a video camera controlled by an image analyzer. The image of each section was stored as a 1280 x 960 eight-bit matrix of pixel units. For each tissue section, the pixel units were calibrated to give values as millimeters squared. The digitized image was then displayed on a video monitor. With the observer blinded to experimental conditions, infarct borders in the cortex and the subcortex were individually outlined (corpus callosum and ventricular spaces excluded) using an operator-controlled cursor. The infarct area was determined automatically by counting pixels contained within the outlined regions of interest. Infarct volumes were computed as running sums of infarct area multiplied by the known interval (e.g. 660 µm) between sections over the extent of the infarct expressed as an orthogonal projection. All image analysis was performed by the same observer.

Physiologic values, infarct size, and neurologic outcome among the three groups were compared by using one-way analysis of variance. The relationship between infarct size and neurologic outcome was compared by using Spearman's rank sum correlation. Neurologic scores were compared by the Kruskal-Wallis H statistic. A P value < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Physiologic values for the global ischemia study groups are reported in Table 1. No significant differences were present among the groups. Median (± interquartile range) neurologic function scores were similar among the groups (vehicle = 8 ± 1, small-dose aprotinin = 9 ± 0.25, large-dose aprotinin = 7.5 ± 2; P = 0.08). CA1 damage (% dead neurons) is presented in Figure 1. Mean (±SD) % dead hippocampal CA1 neurons was similar among groups (vehicle = 47 ± 31, small-dose aprotinin = 49 ± 31, large-dose aprotinin = 55 ± 31; P = 0.74).


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  		Table 1. Physiologic Values for Global Ischemia
 


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  		Figure 1. {circ} = percent dead hippocampal CA1 neurons (% dead CA1) in individual rats subjected to 10 min near-complete forebrain ischemia and a 5-day recovery interval. Aprotinin (small-dose: 30,000 KIU/kg or large-dose: 60,000 KIU/kg IV) was administered 10 min before ischemia. Horizontal bars denote mean values for each group. No significant difference was observed between the vehicle and treatment groups (P = 0.74).

 
Physiologic values for the focal ischemia study groups are given in Table 2. No significant differences were present among the groups. Similarly, there were no differences in neurologic outcome scores among the groups (P = 0.99) (Table 3). However, neurologic score did correlate with total infarct volume (Spearman rank correlation; P < 0.0001, r = 0.86) (Figure 2).


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  		Table 2. Physiologic Values for Focal Ischemia
 

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  		Table 3. Cerebral Infarct Volumes and Neurologic Scores for the Experimental Groups
 


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  		Figure 2. {circ} = the neurologic scores for the individual rats subject to 10 min near-complete forebrain ischemia and a 5-day recovery interval. Aprotinin (small-dose: 30,000 KIU/kg or large-dose: 60,000 KIU/kg IV) was administered 10 min before ischemia. There was a strong correlation between infarct volume and neurologic scores (Spearman rank correlation; P < 0.0001, r = 0.86).

 
Cortical, subcortical, and total infarct volumes are presented for individual rats in Figure 3. Infarct volumes for groups and regions are provided in Table 3. Differences among the groups for subcortical, cortical, and total infarct volumes were not significant.



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  		Figure 3. Infarct volumes (total—A, subcortical—B, cortical—C) in rats after 75 min of middle cerebral artery occlusion and 7 days of recovery. {circ} = values from individual animals. Horizontal lines indicate mean values for each group.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Aprotinin is a 58 amino acid polypeptide that exhibits inhibitory effects on proteins containing serine residues within their active sites, thereby defining it as a serine protease inhibitor (1). It has been shown to inhibit trypsin, kallikrein, bradykinin, plasmin, leukocyte elastase, coagulation factors XIIa and IXa, and several complement cascade enzymes (4,15–20).

Aprotinin was first developed for the treatment of clinical pancreatitis because of its antitrypsin effects (21). However, some investigations into possible neurologic effects have been performed. Early laboratory investigation using cell cultures of cerebellar explants suggested a beneficial effect in prolonging neuronal survival (22,23). In one study, cerebellar cultures from rat brain were grown in culture media containing various concentrations of aprotinin (22). Cultures with aprotinin concentrations of 1,000–50,000 KIU/mL showed a qualitative improvement in appearance compared with cultures treated with the lower concentrations or vehicle. The beneficial mechanism of action in this study was thought to be related to the inhibition of the proteolytic enzyme, cathepsin D.

Apart from cardiac surgery settings, other applications of aprotinin went largely without further study until Kamiyama et al. (24) administered aprotinin (66,000-KIU/kg IV bolus) to rats undergoing global cerebral ischemia. A reduction in cerebral edema and improvements in cerebral energetics after 3 h of global ischemia were demonstrated. Aoki et al. (25) studied the effects of aprotinin in the setting of experimental CPB and hypothermic circulatory arrest (HCA). In piglets undergoing HCA, aprotinin (1.71 x 106 KIU/m2 bolus and 4.0 x 105 KIU infusion) enhanced recovery of cerebral ATP and pH. No histologic analysis was performed in either of these studies.

Another serine protease inhibitor, nafomostat (FUT-175), has undergone investigation in a rabbit model and has shown efficacy in reducing vasospasm after subarachnoid hemorrhage (26). It has subsequently been reported that nafomostat provides some benefit in treating cerebral vasospasm in humans (27).

The most compelling reason for further study of aprotinin in the setting of cerebral ischemia came with the results of two published reports examining the effects of aprotinin during cardiac surgery. A multicenter study involving 287 patients was performed to prospectively evaluate effects of aprotinin on reducing blood loss and transfusion requirements during repeat coronary artery bypass graft surgery (5). The incidence of stroke, although examined only as a secondary end point, was reduced in the groups that received aprotinin (2.1% in the placebo group versus 0% in both the large- and small-dose aprotinin groups). Furthermore, in a retrospective report of all the studies performed in the United States that involved the use of aprotinin in the cardiac surgery setting (n = 2549), the administration of aprotinin was again associated with a significant reduction in the stroke rate. The stroke rate in the control group was 2.1% versus 0.7% in the large dose aprotinin-treated group (P = 0.03) (6).

The mechanism of benefit from aprotinin is not clear from these studies, but an antiinflammatory role can be postulated. Inflammatory mechanisms contribute significantly to injury after cerebral ischemia (28–31). We hypothesized that the ability of aprotinin to attenuate the inflammatory response through inhibition of various serine proteases would result in a reduction in ischemic injury. Unfortunately, we did not demonstrate any neuroprotective efficacy of aprotinin in these established rodent models of either focal or global cerebral ischemia.

There are several possible explanations for our negative results. One possibility is that aprotinin simply offers no benefit. No trend was suggested in either of our trials despite a considerable history of positive outcome results from pharmacologic therapy in both models (32,33). However, if the main effect of aprotinin is to modulate inflammatory pathways, administration of the drug before ischemia may not have adequately blunted postischemic inflammatory cascades. Based on human pharmacokinetics, the distribution half-life of aprotinin is 0.7 h (34). Therefore, a prolonged infusion of the drug during reperfusion may have better blunted the continued inflammatory cascade that progresses for many hours to days after reperfusion. A study that involves prolonged infusion of aprotinin during reperfusion would be necessary to address this possible protective mechanism.

The aprotinin dose we used was similar to that which was previously shown to reduce edema and hasten recovery of high energy phosphate concentrations resulting from global ischemia in the rat (24). The doses used in our study also approximate the dose usually given to humans for CPB (30,000 KIU/kg IV bolus, approximately 30,000 KIU/kg in the CPB prime, followed by a variable length infusion of 8,000 KIU · kg-1 · h-1 IV during CPB). Aprotinin levels were not measured during our study. It has been previously shown that a level of 200 KIU/mL is necessary to inhibit kallikrein (35). The KIU level necessary to inhibit all of the serine proteases that may be involved in ischemic injury is not known. It is possible that the dose administered was insufficient to inhibit the target enzymes, particularly if blood-brain barrier penetration is poor.

Halothane was used during this study. Halothane has neuroprotective effects, particularly during focal ischemia (36,37). It is possible that, with halothane anesthesia, aprotinin was not able to exert any additional protective effects. The lack of aprotinin effect may also have been due to the ischemia severity used in this study. A protective effect from aprotinin may have been observed if a less severe ischemic insult had been used.

The discrepancy between the cardiac surgery studies by Levy et al. (5,6), which showed a positive result, and ours, which failed to identify evidence of neuroprotection, may be explained on methodologic grounds. First, our model is quite different from the complex situation of CPB. Our particular focal ischemia model used a reversible filament occlusion technique to produce a stroke. Cerebral embolic events (aortic plaque and thrombotic material) are largely responsible for stroke during cardiac surgery. A drug that reduces stroke incidence may do so either by reducing stroke size or by reducing stroke events. The protective effect observed for aprotinin in the human trial may have been attributable to a reduction in stroke events. Aprotinin affects the coagulation cascade. Even when patients are heparinized for CPB, ongoing coagulation can be demonstrated (38). It is possible that, with aprotinin in the circulation, there was inhibition of coagulation pathways and that fewer thromboembolic events occurred before, during, and/or after CPB.

In summary, we demonstrated no direct benefit from preischemic aprotinin administration in two rat models of experimental cerebral ischemia. Further work is required to determine whether aprotinin would have a beneficial effect if given for a more prolonged period during reperfusion. The application of the drug in a CPB model itself may also be of benefit in determining the beneficial mechanism seen in the clinical trials, which have indirectly suggested neurologic benefit from this drug in the setting of CPB.


   Acknowledgments
 
This work was supported by a grant from Bayer, Inc. and National Institutes of Health Grants GM08600-02 and GM39771-11.

The authors thank Carla Calvi and Ann Brinkhous for their expert technical assistance in completing these experimental protocols.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication October 7, 1998.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press