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(Stroke. 1996;27:303-310.)
© 1996 American Heart Association, Inc.

Articles

Heparin Reduces Neurological Impairment After Cerebral Arterial Air Embolism in the Rabbit

Keon Hee Ryu, MD, PhD; Bradley J. Hindman, MD; Daniel K. Reasoner, MD Franklin Dexter, MD, PhD

From the Department of Anesthesiology, Catholic University Medical College, Kangnam Saint Mary's Hospital, Seoul, Korea (K.H.R.), and the Department of Anesthesia, University of Iowa, College of Medicine, Iowa City.

Correspondence to Bradley J. Hindman, MD, Department of Anesthesia, University of Iowa, College of Medicine, Iowa City, IA 52242.

	Abstract

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Background and Purpose Neurological injury after cerebral air embolism may be due to thromboinflammatory responses at sites of air-injured endothelium. Because heparin inhibits multiple thromboinflammatory processes, we hypothesized that heparin would decrease neurological impairment after cerebral air embolism.

Methods To first establish a dose of air that would cause unequivocal neurological injury, anesthetized New Zealand White rabbits received either 0, 50, 100, or 150 µL/kg of air into the internal carotid artery (n=5 in each group). One hour later, anesthesia was discontinued. Animals were neurologically evaluated at 24 hours with the use of a scale ranging from 0 (normal) to 97 (coma) points. In a subsequent experiment, anesthetized rabbits received either heparin (n=17) or saline (n=15) 5 minutes before air injection (150 µL/kg). Heparin was given as a 200-IU/kg bolus and followed by a constant infusion of 75 IU · kg^-1 · h^-1 for 2 hours. Equal volumes of saline were given to control rabbits. Two hours later, anesthesia was discontinued. Animals were neurologically evaluated 24 hours after air embolism.

Results There was a monotonic relationship between dose of air and severity of neurological impairment at 24 hours (P=1.1x10^-7). Animals receiving 150 µL/kg of air were unequivocally injured (score, 60±16). In the second experiment, heparin animals had significantly less neurological impairment at 24 hours (34±14) than saline controls (52±8) (P=.0013).

Conclusions When given prophylactically, heparin decreases neurological impairment caused by severe cerebral arterial air embolism.

Key Words: air embolism • fibrin • heparin • leukocytes • thrombin • rabbits

	Introduction

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Cerebral arterial air embolism can occur in many settings, including angiography, decompression sickness, and cardiac surgery. Although long recognized as a potentially devastating entity, there are no established therapies for cerebral air embolism other than hyperbaric oxygenation.¹ Although air emboli occlude cerebral blood vessels, the duration of occlusion can often be quite short (1 to 3 minutes at the arteriolar level).^{2 3 4 5} Accordingly, it has been suggested that neurological injury from cerebral air embolism may not be the result of temporary vessel occlusion but rather is more likely the result of secondary thromboinflammatory responses at sites of air-injured endothelium.^{4 5 6 7 8 9 10} Both ultrastructural^{11 12 13 14} and functional ^{6 7 9 15 16 17} studies indicate that there is a complex interaction among bubbles, blood elements (platelets, fibrinogen, and leukocytes), and endothelium, which results in local fibrin deposition^{11 12} and adherence of platelets^{10 17} and leukocytes^{6 7 16} to both bubbles and air-injured endothelium. Hence, cerebral air embolism has elements of both thrombosis and inflammation.

Thrombin is a key mediator of both thrombotic and inflammatory responses to ischemia, reperfusion, and vessel injury.^{18 19 20} Thrombin converts fibrinogen to fibrin. Fibrin obstructs vascular beds²¹ and can serve as a substrate for the adherence of leukocytes to damaged endothelium.^{22 23} Furthermore, thrombin causes endothelial expression of P-selectin^{19 20 24 25} and intercellular adhesion molecule-1,¹⁹ promoting adhesion of leukocytes to damaged endothelium. Because heparin inhibits (1) fibrin formation,²⁶ (2) thrombin binding to endothelium,²⁷ and (3) the binding of P-selectin to neutrophils,²⁸ we hypothesized that heparin would attenuate the injurious effects of cerebral arterial air embolism. To test this hypothesis, we modified the rabbit model of cerebral air embolism of Helps et al,⁵ gave heparin both before and after air embolism, and assessed neurological outcome 24 hours later.

	Materials and Methods

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Experimental protocols were approved by the Animal Care and Use Committee of the University of Iowa in accordance with the Guide for the Care and Use of Laboratory Animals, National Institutes of Health publication No. 85-23, revised 1985.

Anesthesia was induced in nonfasted New Zealand White rabbits (weight, 2.5 to 3.4 kg) by inhalation of 4% halothane in oxygen. After cannulation of an ear vein and orotracheal intubation with a 3.0-mm-ID cuffed tube (Mallinckrodt), animals were paralyzed with 1 mg/kg succinylcholine. Animals were ventilated with 1.4% halothane in 30% oxygen/balance nitrogen to achieve normocarbia and monitored with a calibrated anesthetic agent analyzer (Datex, Puritan-Bennett). During surgery, paralysis was maintained with succinylcholine added to an infusion of normal saline (4 mL · kg^-1 · h^-1). Esophageal temperature was maintained at 37°C to 38°C with a servo-controlled heating pad.

All surgery was performed under sterile conditions. Animals were placed prone and the scalp shaved. After skin incision, a 2-mm burr hole was drilled over the left frontoparietal cortex to expose dura. A 1-mm thermocouple (K-type, L-08419-02, Cole Parmer) was placed between the cranium and dura to monitor brain temperature. The bone defect was filled with sterile bone wax. Animals were turned supine and, via the left femoral artery, a saline-filled polyethylene catheter (PE-90, Intramedic) was advanced into the abdominal aorta for monitoring arterial pressure and blood sampling. Through a midline neck incision, the left external, internal, and common carotid arteries were isolated, and a branch of the external carotid (usually the facial) was selected for cannulation. Other branches of the external carotid were ligated with 4-0 silk, and all bleeding points were carefully cauterized to obtain a completely bloodless field. At this point succinylcholine was discontinued. The following baseline physiological measurements were obtained: mean arterial pressure, epidural temperature, expired halothane concentration, arterial pH, PO₂, PCO₂ (IL1304, Instrumentation Laboratory), and hemoglobin concentration (OSM3 [rabbit absorption coefficients], Radiometer). After this basic preparation, experimental protocols were followed as described below.

Air Dose-Response: Experiment A
Before testing the effect of heparin on neurological injury after cerebral air embolism, we established the relationship between dose of injected air and subsequent neurological outcome.

Twenty animals were prepared as described and randomly assigned to receive one of four doses of air into the internal carotid artery: 0 (saline), 50, 100, or 150 µL/kg. After isolation of the carotid arterial system, a temporary aneurysm clip was placed across the left common carotid, just proximal to its bifurcation. A saline-filled PE-50 catheter was introduced retrogradely via the facial branch of the external carotid and directed into the proximal 1 to 2 mm of the internal carotid. Care was taken to avoid entrapment of air in either the facial or internal carotid arteries. Air was injected through this catheter into the internal carotid artery at approximately 25 µL/s,⁵ followed by a flush of 0.5 mL of normal saline. Thereafter, the aneurysm clip was removed and the injection catheter withdrawn, reestablishing continuity between the internal and common carotid arteries. The injection catheter was subsequently removed from the facial artery and the external carotid artery ligated at its origin. Systemic physiological measurements were repeated 30 minutes after air injection.

One hour after air injection, halothane was discontinued. The femoral arterial catheter and epidural thermocouple were removed. Incisions in the scalp, groin, and neck were closed with 4-0 silk, infiltrated with 0.25% bupivacaine (1 mL/kg), and covered with transparent plastic dressings. Animals were extubated when they regained spontaneous ventilation and protective airway reflexes (eg, coughing), usually 30 to 40 minutes after discontinuation of halothane. After extubation, animals received supplemental oxygen by mask. Neurological status was assessed 1, 2, 3, and 4 hours after discontinuation of halothane, ie, 2, 3, 4, and 5 hours after air injection, respectively. The neurological scoring system was a modification of that described by Baker et al,²⁹ in which the best possible neurological score equaled zero and worst equaled 97 (Table 1). In this experiment, the neurological examiner was not blinded to group assignment. After the 5-hour evaluation, animals were returned to their cages, where food and water were available. Animals underwent a final neurological evaluation 24 hours after air injection, after which they were anesthetized with 5% halothane in oxygen and killed by pentobarbital overdose (150 mg/kg IV).

View this table: [in this window] [in a new window]   Table 1. Neurological Scoring System

Heparin Effect: Experiment B
In this experiment, 150 µL/kg was chosen as the air dose because, in experiment A, it resulted in unequivocal neurological injury but was survivable for 24 hours (see "Results"). Thirty-two animals were prepared for air injection as described. With the use of a random number generator, animals were randomized to receive in blinded fashion either heparin (group 1, n=17) or saline (group 2, n=15) before cerebral air embolism. In group 1, heparin (1000 IU/mL, Elkins-Sinn, Inc) was administered as a bolus of 200 IU/kg IV, followed by a continuous intravenous infusion in normal saline (4 mL · kg^-1 · h^-1) to give 75 IU kg^-1 · h^-1. In group 2, saline rather than heparin was given in volumes identical to those in group 1. Group assignment was concealed from the experimenter; heparin or saline was prepared by another researcher. Five minutes after heparin (or saline) had been given, physiological measurements were repeated and arterial blood was collected for measurement of activated clotting time (ACT) (Hemotec Inc) and plasma glucose (see below). The internal carotid artery was cannulated as described above, and 150 µL/kg of air was injected, followed by the saline flush. As before, the aneurysm clip and injection catheter were removed. For the next 2 hours, no other interventions were made other than maintaining the (blinded) heparin or saline infusions. Physiological variables were measured at 1 and 2 hours after air injection.

After final data collection, halothane and heparin (or saline) were stopped. Wounds were closed, infiltrated with local anesthetic, and dressed as described above. After extubation, neurological status was assessed at 1, 2, and 3 hours after discontinuation of halothane, ie, 3, 4, and 5 hours after air injection, respectively. After the 5-hour assessment, animals were returned to their cages, where food and water were available. Animals underwent a final neurological evaluation 24 hours after air injection. In this experiment, the neurological examiner (K.H.R.) was blinded to group assignment and coagulation data until all animals (n=32) had completed the entire 24-hour protocol. After the last examination, animals were anesthetized with 5% halothane in oxygen, and blood was collected from an ear vein for measurement of plasma glucose. Animals were then killed by pentobarbital overdose (150 mg/kg IV). All plasma samples for glucose concentration were stored frozen at -20°C until analyzed (YSI model 27, Yellow Springs Instrument Co).

In experiment A, Jonckheere's nonparametric trend test was used to assess the presence of a dose-response relationship between air dose and neurological outcome at 24 hours.³⁰ Tied neurological scores were counted in favor of the null hypothesis to ensure that the reported probability value exceeded the actual value. In experiment B, mean neurological scores at 24 hours were compared between groups with the two-sided Mann-Whitney test. All data are expressed as mean±SD. As we planned a priori, systemic physiological variables were compared qualitatively to preserve statistical power to detect differences in neurological scores between control and heparin groups.

	Results

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Systemic physiological variables for experiment A (dose-response) are summarized in Table 2. There were no physiologically important differences between groups in any systemic variable at baseline or 30 minutes after air embolism. As shown in Fig 1, injection of air caused a dose-dependent increase in neurological impairment. Neurological scores tended to improve for the first 2 to 3 hours after discontinuation of halothane. To eliminate the effect of residual halothane, only 24-hour scores were compared between groups. A dose-response relationship was observed between dose of air and degree of neurological impairment (P=1.1x10^-7).

View this table: [in this window] [in a new window]   Table 2. Experiment A: Systemic Physiological Variables

View larger version (21K): [in this window] [in a new window]   Figure 1. Experiment A. Neurological scores over time in animals receiving 0, 50, 100, or 150 µL/kg of air into the internal carotid artery (n=5 in each group). Worst possible score equals 97; best possible score equals zero (see Table 1). Halothane was discontinued 1 hour after air embolism. At 24 hours, there was a dose-response relationship (P=1.1x10-7). Missing data points are due to overlap.

In experiment B (effect of heparin), a total of five animals were excluded from analysis (three from the heparin group and two from the saline group). Two animals (one from each group) were severely hypotensive and had no spontaneous respiration 1 hour after discontinuation of halothane. Two animals randomized to heparin were excluded because of severe anemia, hypotension, and acidosis before heparin administration and air embolization. One animal from the saline group was excluded because of persistent hyperglycemia (glucose, 28 mmol/L). Data from the remaining animals (heparin, n=14; saline, n=13) were used for analysis.

Systemic physiological variables for experiment B are summarized in Table 3. At baseline, there were no important differences between groups in any physiological variable other than mean arterial pressure, which was greater in the saline group than in the heparin group (72±9 versus 64±4 mm Hg, respectively). The saline group continued to have a slightly (5 to 10 mm Hg) greater arterial pressure than the heparin group for the remainder of the experiment. Baseline ACT (~80 seconds) exceeded normal human values (110 to 130 seconds) but did not differ between groups. After drug administration, animals in the heparin group maintained much greater ACT values (450 to 600 seconds) than those in the saline group (~200 seconds). Groups did not differ with respect to arterial blood gases or hemoglobin concentration, epidural temperature, plasma glucose concentration, or expired halothane concentration over the course of the experiment. At 24 hours after cerebral air embolism, groups did not differ with respect to plasma glucose concentration.

View this table: [in this window] [in a new window]   Table 3. Experiment B: Systemic Physiological Variables

Neurological outcome scores from experiment B are shown in Fig 2. One animal in each group died between the 5- and 24-hour evaluations and were therefore not included in the analysis of neurological outcome. At 24 hours, animals in the heparin group had less neurological impairment (total score, 34±14) compared with those in the saline group (total score, 52±8) (P=.0013). The difference in total score was accounted for by differences in several components of the neurological exam (respiration, gait, and behavior).

View larger version (20K): [in this window] [in a new window]   Figure 2. Experiment B. Neurological scores over time in animals receiving 150 µL/kg of air randomized to either heparin or saline (see text). Halothane was discontinued 2 hours after air injection. At 24 hours, animals in the heparin group had less neurological impairment (34±14, n=13) than those in the saline group (52±8, n=12) (P=.0013). Missing data points are due to overlap.

	Discussion

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We chose neurological status as our end point because we wanted to study neurological impairment analogous to that encountered clinically after severe cerebral air embolism. Prior animal studies of cerebral air embolism have used sensory evoked potential (SEP),^{6 7 8 9 10 15 31 32 33} cerebral blood flow,^{6 7 8 9 10 31 32 33} or survival³⁴ as indexes of neurological outcome. For this experiment, we did not consider any of these end points to be entirely satisfactory. In cats undergoing 2 hours of temporary or 6 hours of permanent middle cerebral artery occlusion, persistent abolition of SEPs has been shown to correlate with development of cortical edema³⁵ and severe ischemic neuronal changes,³⁶ respectively. Nevertheless, in both studies, whenever SEP amplitude was greater than zero, there was no correlation between SEP amplitude and either brain edema³⁵ or moderate to severe ischemic changes.³⁶ In other words, whenever SEP amplitude was greater than zero, there did not appear to be a proportional relationship between the magnitude of SEP recovery and extent of neuronal injury. Because air emboli have elements of both temporary and permanent ischemia and because secondary thromboinflammatory processes are likely to evolve over time, we questioned whether early indexes of neurological injury/recovery, such as SEP, would necessarily correlate with neurological outcome. With regard to cerebral blood flow, Helps et al⁵ found no correlation between SEP amplitude and local cerebral blood flow after injection of 150 µL/kg of air into the rabbit internal carotid. Finally, survival alone is not a reliable index of neurological injury because postprocedural deaths may not necessarily be due to neurological causes. For this reason, we did not use survival as an outcome measure, and we excluded animals that died before the 24-hour examination.

Rather than producing a distinct focal deficit, cerebral air embolism results in a widely disseminated multifocal pattern of neurological injury.^{13 14 32} For this reason, we used a neurological outcome scale developed to assess recovery after global cerebral ischemia in the rabbit. Using this scale, Baker et al²⁹ found that rabbits undergoing 10 minutes of global cerebral ischemia under hypothermic (29°C) conditions had better neurological status, less histopathologic change, and less glutamate release than rabbits made ischemic while normothermic. Hence, the neurological scoring system used in the present study corresponds to both histopathologic and biochemical indexes of neurological injury after a diffuse neurological insult.

We observed a clear relationship between dose of air and severity of neurological impairment. As shown in Fig 1, neurological scores improved in all groups during the first few hours after discontinuation of halothane, with less improvement as the dose of air increased. It appears that early neurological status was influenced by both residual halothane and dose of air. To eliminate the effect of residual anesthesia, we limited our statistical analysis to neurological status at 24 hours. Control rabbits, which received no air, appeared essentially normal. Rabbits receiving 50 µL/kg of air were also minimally affected and were often difficult to distinguish from controls. In contrast, rabbits receiving 150 µL/kg of air were uniformly and unequivocally injured. The best neurological score in the 150-µL/kg group was worse than the worst score in any other group. At 24 hours, animals in the 150-µL/kg group were impaired in several subcategories of the neurological exam, whereas animals in other groups usually demonstrated impairment (if present) only in the behavioral subcategory. Hence, for experiment B we chose 150 µL/kg as the dose of air that would reliably produce marked and unequivocal but survivable neurological impairment.

Animals receiving heparin had less neurological impairment at 24 hours compared with nonheparinized controls. Randomly, heparin animals happened to have slightly lower arterial pressure than controls. However, this difference would only tend to increase the residence time of bubbles and exacerbate the effect of air.³ Hence, arterial pressure differences between groups would tend to bias the results against a protective effect of heparin.

Our findings are in contrast to those of the Hallenbeck group,^{15 32 33} which, using SEP as the end point, observed no evidence of a protective effect of heparin, either alone or when combined with either indomethacin or prostaglandin I₂, in their dog model of cerebral air embolism. Several differences in study design may explain this disparity. Perhaps the most important difference is that we administered heparin before air embolism. Animals given heparin achieved ACT values of 450 to 600 seconds, a level of anticoagulation considered adequate for cardiopulmonary bypass (additional discussion below).³⁷ Conversely, in prior dog experiments, heparin and other agents were not administered until 1 hour after cerebral air embolism had begun.^{32 33} Because secondary effects of air emboli (cerebral blood flow and SEP deterioration) have their onset within 20 minutes after clearance of air,^{4 5} it is likely that interventions to inhibit these secondary effects must start either before or concurrent with air embolism. In addition, it is possible that interventions need to be continued for some time afterward. In this study we maintained steady state heparin therapy for 2 hours after embolization. In contrast, in the cited dog studies heparin was not continued after the initial bolus.^{15 32 33} In the Hallenbeck dog model, a three-drug combination of heparin, indomethacin, and prostaglandin I₂ did appear to improve SEP amplitude compared with untreated controls.^{32 33} However, in subsequent experiments the effect was either not sustained¹⁰ or did not achieve statistical significance.⁹ As before, therapy was not started until 1 hour after cerebral air embolism had begun, and with one exception¹⁰ heparin was not continued beyond the single bolus. The importance of continuous heparin in the presence of vessel injury has recently been confirmed by Frebelius et al.³⁸ Using an aortic injury model in the rabbit, these investigators showed that a continuous heparin infusion (75 IU · kg^-1 · h^-1) inhibited thrombin activity on injured vessels and completely prevented fibrin deposition. In contrast, heparin infusion for only 1 hour decreased neither vessel thrombin activity nor fibrin deposition. Our experiment cannot address the minimum duration of heparin therapy required to provide neurological protection in the setting of air embolism.

Another major difference in study design between this experiment and prior dog studies relates to the method of air delivery. In this experiment, air was given as a single discrete bolus that, as Helps et al^{4 5} have shown, is cleared from the pial vasculature within 2 to 4 minutes. In contrast, in the cited dog experiments, air was given as repeated boluses over 60 minutes titrated to maintain SEP amplitude at 10% to 20% of the baseline. Thus, in the dog experiments, the brain experienced repeated episodes of temporary vessel occlusion, which may have potentiated the effect of air and/or affected its subsequent distribution. Indeed, Hallenbeck et al³² reported that the dose of air required to maintain SEP suppression progressively decreased over the 60-minute infusion interval. Thus, although the total dose of air in prior dog experiments was far less than in this study (~20 µL/kg versus 150 µL/kg, respectively), it is possible that the effect and/or distribution of the insult may actually have been greater in the former.

The heparin dose used in this experiment was based on pharmacokinetic and pharmacodynamic studies of heparin in the New Zealand White rabbit.^{38 39 40} These studies indicate that a heparin infusion of 75 IU · kg^-1 · h^-1 results in a steady state heparin concentration of 1 to 1.5 IU/mL (7 to 11 µg/mL). At this concentration, inhibition of fibrin formation (ie, inhibition of thrombin activity) is 90% of maximum.³⁹ With heparin concentrations in this range, the most common measure of heparin effect, the activated partial thromboplastin time, becomes markedly prolonged (>>150 seconds) and becomes an inconvenient index of heparin concentration/effect.⁴¹ For this reason, we chose to use the ACT to monitor heparin effect. The ACT is less sensitive to heparin than the activated partial thromboplastin time,⁴¹ varies linearly with heparin concentration,⁴¹ and is used clinically when very high doses of heparin are used (eg, for cardiopulmonary bypass, 300 to 400 IU/kg).⁴²

At concentrations expected in this experiment (1 to 1.5 IU/mL, 7 to 11 µg/mL), heparin has been shown to inhibit several thromboinflammatory pathways. Using de-endothelialized rabbit aortas, Hatton and Moar²⁷ showed that heparin inhibits thrombin binding to exposed subendothelium (ED₅₀=1.8 IU/mL). This finding is consistent with that of Frebelius et al,³⁸ in which heparin (1.4 IU/mL) completely inhibited thrombin activity on injured vessel walls (see above). Thrombin inhibition would be expected to decrease local fibrin formation³⁸ and endothelial expression of platelet-activating factor²⁴ and P-selectin,^{19 24 25} thereby decreasing leukocyte adherence at sites of injured endothelium. In addition, Silvestro et al⁴³ found that pretreatment of neutrophils with heparin (ED₅₀=0.1 µg/mL) inhibits leukocyte adherence to both thrombin- and platelet-activating factor-activated endothelium. We speculate that these effects are responsible for the lesser degree of neurological impairment observed in our heparinized animals. Heparin has additional anti-inflammatory effects⁴⁴ that may have also contributed to its protective effect in this experiment. In vitro studies show that heparin concentrations of 20 to 50 µg/mL inhibit lysosomal enzyme release and production of active oxygen species from activated neutrophils.^{45 46} In vivo, heparin concentrations of 50 µg/mL inhibit leukocyte rolling.⁴⁷ Although plasma heparin concentrations in this experiment were certainly far less than those required for these latter effects, heparin efficiently binds to endothelium^{48 49} and may achieve local concentrations sufficient for these effects.⁵⁰ Heparin has also been shown, both in humans and in this experimental species (rabbit), to release endothelial-bound superoxide dismutase.⁵¹ Heparin-induced superoxide dismutase release has been shown to inhibit postischemic leukocyte adherence⁵² and free radical production.⁵³ Finally, heparin has been shown to cause release of endogenous tissue factor pathway inhibitor.⁴⁰ Blockade of tissue factor has been shown to reduce postischemic intramicrovascular fibrin deposition in a baboon model of temporary middle cerebral artery occlusion.¹⁸

Although heparin decreased neurological impairment after cerebral air embolism in this experiment, it was only partially effective. Had we used smaller doses of air, resulting in less neurological impairment, the protective effect of heparin might not have been demonstrable. It is also possible, had neurological status been evaluated at greater time intervals, eg, 48 to 96 hours after air embolism, that the protective effect of heparin might have dissipated.

Expected heparin concentrations in this experiment (1 to 1.5 IU/mL) greatly exceed those achieved with standard heparin therapy (0.2 to 0.4 IU/mL), which aims to double the activated partial thromboplastin time.²⁶ However, our observation of a protective effect of high-dose heparin may explain the apparent tolerance of cardiac surgery patients to microscopic cerebral air emboli. In preparation for cardiopulmonary bypass, these patients receive 300 to 400 IU/kg of heparin,^{42 54} achieving plasma levels of 2 to 4 IU/mL.⁵⁴ Transcranial Doppler studies demonstrate that cerebral air embolism is commonplace throughout cardiac surgery and cardiopulmonary bypass.^{55 56 57} Nevertheless, in these studies, overt signs of neurological injury that can be attributed to cerebral air embolism are quite rare.

Because heparin can modulate so many different thromboinflammatory pathways, it is possible that lesser heparin concentrations might also be protective. Nevertheless, the weight of current evidence strongly suggests that heparin is quite unlikely to be effective unless given concurrent with or immediately after air embolism. Thus, heparin is likely to be clinically useful only as a prophylactic measure. Because of bleeding risk, few clinicians would advocate marked anticoagulation as a prophylactic measure for cerebral air embolism unless otherwise required (ie, for cardiac or carotid surgery). Consequently, we think that the significance of this study for treatment of patients who have already suffered cerebral air embolism rests principally in its mechanistic implications. Our study suggests that thromboinflammatory mechanisms may indeed mediate (at least a portion of) the neurological injury that results from cerebral air embolism. On this basis, we suggest that future approaches to therapy should be directed toward inhibition of one or more thromboinflammatory pathways. Examples of potentially effective therapy in the setting of cerebral air embolism could include selective thrombin inhibition,^{58 59} inhibition of leukocyte adherence/action,^{60 61} and/or blockade of tissue factor.¹⁸

	Acknowledgments

 
This study was supported by the Department of Anesthesia Research Fund (University of Iowa, College of Medicine, Iowa City).

Received September 20, 1995; revision received October 18, 1995; accepted November 1, 1995.

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