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(Stroke. 1996;27:906-912.)
© 1996 American Heart Association, Inc.

Articles

Optimal Timing of Hemodilution for Brain Protection in a Canine Model of Focal Cerebral Ischemia

Kiyoyuki Yanaka, MD, PhD; Paul J. Camarata, MD; Stephen R. Spellman, BA; Drew E. McDonald, BA Roberto C. Heros, MD

From the Department of Neurosurgery, University of Minnesota Medical School, Minneapolis.

Correspondence to Paul J. Camarata, MD, Department of Neurosurgery, University of Minnesota, Box 96 UMHC, 420 Delaware St SE, Minneapolis, MN 55455. E-mail camarpj@maroon.tc.umn.edu.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose Hemodilution is known to ameliorate the effects of focal ischemia when used shortly after cerebral arterial occlusion; however, it remains to be proved whether hemodilution will be effective when used at more clinically relevant times, ie, with some delay between the onset of ischemia and initiation of therapy.

Methods Thirty-two dogs were selected for inclusion in this study. Cerebral infarction was induced by permanent occlusion of the middle cerebral and the azygos anterior cerebral arteries. The animals were allocated to 1 of 4 groups of eight animals each: arterial occlusion without hemodilution (group 1); hemodilution immediately after occlusion (group 2); hemodilution 3 hours after occlusion (group 3); and hemodilution 6 hours after occlusion (group 4). Isovolemic hemodilution to a hematocrit of 30% was performed. The animals were killed 6 days after induction of ischemia, and the infarct size was determined.

Results Groups 2 and 3 showed significant reduction of infarct size (P<.0001) when compared with group 1. The neurological grade of group 3 on postoperative days 4, 5, and 6 was significantly better than those of groups 1 and 4 (P<.01). Group 4 showed a significant increase in the incidence of hemorrhagic infarction when compared with groups 1 and 2 (P<.01).

Conclusions The current study indicates that hemodilution administered as much as 3 hours after ischemia is effective in reducing infarct size and improving neurological status. When administered 6 hours after ischemia, hemodilution is not helpful and may be harmful.


Key Words: cerebral ischemia, focal • hemodilution • neuroprotection • dogs


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Experimental studies in this laboratory and others have left little doubt that when applied under optimal conditions, hemodilution is effective in reducing stroke size and its neurological sequelae.1 2 3 4 5 Hemodilution is believed to improve rheological conditions at the microcirculatory level, thus increasing regional cerebral blood flow in normal brain and ischemic brain.4 6 7 Despite this, two large multi-institutional trials failed to show a clinical benefit for hemodilution.8 9 10 However, patients were entered into these trials relatively late after their strokes and hemodilution was carried out to a modest degree only. Recent work in our laboratory has demonstrated that the optimal degree of hemodilution in a canine model of focal ischemia is achieved when the hematocrit is lowered to {approx}30% immediately after occlusion.2 However, it is highly unlikely that in the clinical setting hemodilution can be started immediately after the onset of cerebral ischemia. The "window of opportunity" during which reperfusion or protective measures must be instituted to salvage ischemic brain tissue is generally thought to be less than 6 hours, but this is highly dependent on the adequacy of collateral circulation.11 12 13 14 It remains to be proved whether hemodilution will be effective when used at clinically relevant times, ie, with some delay between ischemia onset and initiation of therapy. This study was designed to determine the effectiveness of isovolemic hemodilution to a hematocrit of 30% carried out at different times after the onset of focal ischemia and to determine the time beyond which hemodilution will no longer be effective.


*    Materials and Methods
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 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
General Protocol
Forty-two conditioned adult mongrel dogs weighing 15 to 20 kg were used for this study. The experiment was approved by the Animal Care Committee at the University of Minnesota and carried out under the auspices of Research Animal Resources, an American Association for the Accreditation of Laboratory Animal Care (AAALAC)–approved facility. Ten animals were excluded from the study; 5 did not meet the selection criteria, on the basis of SSEP monitoring as described below, and 5 were killed before the end of the study because of postoperative complications. The remaining 32 animals were allocated to 1 of 4 groups of 8 animals each: arterial occlusion without hemodilution (group 1), hemodilution immediately after occlusion (group 2), hemodilution 3 hours after occlusion (group 3), and hemodilution 6 hours after occlusion (group 4).

Animal Preparation
All animals were splenectomized 1 week before craniotomy to abolish the volume reservoir function of the spleen15 and to maintain an isovolemic condition during the study. On the day of craniotomy, anesthesia was induced with an intravenous injection (10 mg/kg) of methohexital sodium (Eli Lilly & Co) and maintained with 1% to 2% halothane. The animals were intubated with a 5F cuffed endotracheal tube and mechanically ventilated with a Harvard ventilator. Arterial PCO2 was kept between 30 and 35 mm Hg. A heating blanket was used to maintain rectal temperature between 37.5°C and 38.5°C. Brain temperature was not routinely monitored because, although maintaining constant temperature has been essential in studies of cerebral ischemia, in previous experiments we found that it remained within 1°C of rectal temperature.2 4 6 16 Pancuronium bromide was administered intravenously (0.1 mg/kg), and enrofloxacin (2.5 mg/kg, Miles Inc) was administered intramuscularly at the beginning of the procedure. In all animals, the right femoral artery was cannulated with a 16-gauge catheter for monitoring of blood pressure and blood gases. Another 16-gauge catheter was placed into the inferior vena cava through a side branch of a femoral vein for administration of fluid, monitoring central venous pressure, and performing hemodilution.

A 2x2-cm craniectomy was made over the left frontoparietal cortex and a silicone elastomer leaflet with four electrodes (4-mm diameter platinum disk electrode with 6-mm separation, PMT Corp) was positioned subdurally over the somatosensory cortex (C3 position) for SSEP measurement. The electrode was then fixed to the dura and the overlying bone at its base so that it could pivot along its long axis and maintain cortical contact as the brain relaxed with cerebrospinal fluid drainage. Serum glucose and hematocrit levels were measured after induction of anesthesia, after vessel occlusion, after hemodilution, and on postoperative days 1, 4, and 6. Serum sodium and potassium were also measured on the first postoperative day.

The animals were kept alive for 6 days after craniotomy, and a daily neurological assessment was performed.

Permanent Arterial Occlusion
Through a left retro-orbital craniectomy, the left MCA and the azygos ACA were exposed.17 The animals underwent permanent arterial occlusion of the left MCA at a point before its bifurcation, followed by occlusion of the azygos ACA with a Scoville-Lewis clip, and SSEP was monitored to allow selection of animals with uniform, moderately severe cerebral infarction as described below.

SSEP Monitoring
Platinum needle electrodes (Grass Instruments) were placed on the right trigeminal innervated area of the nose, and stimuli were given as 200-ms–duration square waves at one per second with voltage adjusted to twice threshold levels (8 to 10 V) for facial twitch. The potentials were recorded from the most posterior subdural electrode of the subdural silicone elastomer strip with an ipsilateral temporalis muscle reference electrode. The recording system was adjusted to a bandwidth of 1 to 1000 Hz, and averaging was performed over 20 responses. Amplitude was measured from the top of the major positive peak to the bottom of the major negative peak. The selection criteria for animals likely to have uniform, moderately severe cerebral infarctions, determined in a recent study in our laboratory,18 are as follows: after MCA occlusion, SSEP amplitude should not fall below 25% of baseline amplitude and, after subsequent azygos ACA occlusion, the SSEP amplitude should fall below 15% of baseline amplitude. In our previous study,18 animals in which the SSEP amplitude fell below 25% of baseline value after MCA occlusion alone had massive cerebral infarctions and did not survive for 1 week after craniotomy. Conversely, animals in which the SSEP amplitude did not fall below 15% of baseline value after both the MCA and the azygos ACA occlusions had either no cerebral infarction or only minimal cerebral infarction. We have shown that, by using these criteria a priori, animals can be selected that will have a relatively uniform infarct size.18

Isovolemic Hemodilution
The volume of low-molecular-weight dextran needed to maintain the isovolemic state is {approx}70% of the volume of blood withdrawn19 20 ; therefore, isovolemic hemodilution was accomplished by the repeated withdrawal, over a short period of time, of 50 mL of blood from the femoral arterial line with the simultaneous intravenous administration of 35 mL of low-molecular-weight dextran. This procedure was repeated until the hematocrit reached 30%. For groups 2 and 3, hemodilution was carried out under general anesthesia. However, the animals in group 4 (hemodilution 6 hours after ischemia) underwent hemodilution while under sedation with diazepam (0.3 mg/kg IV) due to institutional regulations. The University Animal Care Committee required us to perform hemodilution in the postoperative unit for group 4 to avoid postoperative complications, and it was obligatory that animals admitted to the postoperative unit be extubated and lucid.

Postoperative Care and Monitoring
The animals were cared for in a postoperative intensive care facility by veterinarians and veterinary technicians at Research Animal Resources at the University of Minnesota for 6 days after induction of ischemia. During this period they were given free access to food and water. On any day that an animal was not able to drink, 500 mL of Ringer's lactate solution was administered subcutaneously. Prophylactic antibiotics were given daily for 6 days. Neurological assessment was performed daily by a neurosurgeon and a veterinary technician in a blinded fashion according to the following modification16 of the criteria of Crowell and Olsson21 : grade 1, normal; grade 2, mild hemiparesis, occasionally circles toward operated side, stands without assistance; grade 3, moderate hemiparesis, circles toward operated side, stands only with assistance, no impairment of consciousness; grade 4, severe hemiparesis with decreased level of consciousness, unable to stand; and grade 5, dead.

Measurement of Infarct Size
On the sixth postoperative day, the animals were given 15 mL (100 mg/mL) of fluorescein (Alcon Laboratories) and were killed after 30 minutes. The brains were then removed for determination of infarct volume. The brains were placed in 10% formalin for 48 hours and then coronally sliced into 3.5-mm sections. Macroscopic observation of brain sections was carried out blindly. Each slice was then examined under UV light at a wavelength of 366 nm, and the areas of fluorescence were considered to be infarcted.16 22 Fluorescein has been used to investigate protein movement in brain edema and infarction. Movement of protein-bound fluorescein into brain parenchyma proceeds because of a disrupted blood-brain barrier. It is possible that fluorescent extravasation beyond the infarcted areas may occur due to vasogenic edema surrounding the infarction. However, in this model, this extravasation would be expected to be small because the animals are allowed to survive only 30 minutes after injection. In this short period of time, it is unlikely that the dye or protein to which it is attached would diffuse into the edema fluid to any significant degree. In addition, we would not expect the fluorescein in the newly formed edema to spread beyond the bounds of the infarcted tissue. Although there is no doubt of some leakage of fluorescein into surrounding viable tissue, previous work in our laboratory has confirmed a very tight correlation between microscopically verified infarct size and the amount of tissue stained by fluorescein in both untreated and hemodiluted brains.16 23 Therefore, in a chronic study, infarct areas measured by fluorescein can be considered a good approximation of the infarct volume. The surface of each slice was digitized, and the total surface area and the infarcted surface area were calculated with the use of three-dimensional reconstruction software (Jandel PC3D, Jandel Scientific). The total and infarcted volumes were calculated for each slice by multiplying the surface area by the slice thickness. The total and infarcted volumes of the hemisphere were calculated by adding the volumes of the individual slices. This procedure was carried out four times and the values were then averaged to minimize bias.

Statistical Analysis
All values are expressed as the mean±SD. Comparisons among two or more groups were accomplished with the use of single factor ANOVA. Analysis of discrete values was accomplished with the use of the {chi}2 test.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 *Results
down arrowDiscussion
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General Physiological Parameters
The mean infused dextran volume and withdrawn blood were 287.0±95.0 and 412.5±65.8 mL, respectively, and the mean duration for hemodilution was 64.8±12.4 minutes. The mean duration of general anesthesia was as follows: group 1, 243.8±23.7 minutes; group 2, 268.1±54.0 minutes; group 3, 420.8±24.1 minutes; and group 4, 230.0±25.8 minutes. The difference in duration of general anesthesia for groups 1, 2, and 4 was not statistically significant, but group 3 underwent a significantly longer peroid of halothane anesthesia. Mean serum glucose levels, blood pressure, and rectal temperature did not show any significant differences between the various groups (TableDown). The hematocrit after hemodilution did not change significantly throughout the study (TableDown).


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  		Table 1. Physiological Parameters in a Canine Model of Focal Cerebral Ischemia

Infarct Volume
The mean infarct size, expressed as a percentage of the total hemispheric volume±SD, was as follows: group 1, 29.9±0.8%; group 2, 15.8±0.9%; group 3, 19.6±2.5%; and group 4, 36.8±10.5%. Groups 2 and 3 showed a significant decrease in the size of infarction when compared with group 1 (P<.0001). Group 4 showed a trend toward a larger infarction than group 1 (Fig 1Down).



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  		Figure 1. Graph shows mean infarct volume expressed as a percentage of the total hemisphere for each study group. Vertical bars indicate SD. Groups 2 and 3 showed significant reductions of infarction size when compared with group 1 (*P<.0001).

Neurological Assessment
The daily neurological grades of the animals are summarized in Fig 2Down. The neurological grade of group 2 was significantly better than those of groups 1 and 4 throughout the study (P<.01). The neurological grade of group 3 on postoperative days 4, 5, and 6 was significantly better than those of groups 1 and 4 (P<.01). The neurological grade of group 4 showed a trend to be worse than that of group 1, but it was not statistically significant.



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  		Figure 2. Graph shows the clinical outcome of the animals in each study group. See text for definition of grades. The neurological grade of group 2 was significantly better than those of groups 1 and 4 throughout the study (*P<.01).

Hemorrhagic Infarction
The incidence of hemorrhagic transformation of each group is summarized in Fig 3Down. Group 4 showed a significant increase in the incidence of hemorrhagic infarction when compared with groups 1 and 2 (P<.01).



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  		Figure 3. Graph shows incidence of hemorrhagic infarction. The incidence of hemorrhagic infarction in group 4 was significantly higher than those of groups 1 and 2 (P<.01).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
Background and Rationale for Hemodilution
There would be little hope for amelioration with therapeutic intervention if irreversible cerebral infarction occurred in an entire arterial distribution immediately after arterial occlusion. However, there is thought to be a surrounding "ischemic penumbra" in which blood flow is reduced enough to result in electrophysiological disturbance of cells but not enough to produce irreversible cell death.24 This "penumbra" may persist for hours or days and offers a window of therapeutic opportunity to improve the CBF, which could be effective in preventing irreversible cell death.12 Even a slight improvement in perfusion may be capable of preventing irreversible cell death in the penumbra until reperfusion occurs by spontaneous increase in collateral circulation through therapeutic maneuvers.

One approach to increase CBF to protect and salvage ischemic cells is to improve the hemorheological properties of blood by lowering its viscosity. Hemodilution as a potential therapeutic technique for ischemic stroke has been extensively studied. It is well known that hemodilution increases CBF in both normal and ischemic brain tissues.25 26 27 28 The rationale for the use of hemodilution in the treatment of cerebral ischemia is given by the well-known Hagen-Poiseuille equation, which indicates that when other factors remain constant, flow is inversely proportional to viscosity.29 Under normal conditions in the healthy brain, the pressure gradient and the radius of resistance vessels are the major factors that determine blood flow. However, in areas of focal cerebral ischemia in which vessels are maximally dilated and the capacity for pressure autoregulation is impaired, blood viscosity becomes a major determinant of blood flow, and hematocrit is the major factor influencing blood viscosity.30 31 Blood viscosity is a particularly important determinant of flow at the low velocity gradients (shear stress rates) present in the ischemic microcirculation.28 32 33 34 35 36 37 It has been established in our experimental studies2 16 23 25 as well as in others,5 7 38 39 40 41 42 43 that hemodilution when used under optimal conditions is very effective in improving neurological condition and reducing the size of infarction.

Clinical Studies
Some recent clinical studies have shown a benefit with hemodilution, even though patients were entered into these studies as much as 72 hours after the onset of ischemia.38 42 However, two large multi-institutional studies undertaken to study the effect of hemodilution in acute stroke failed to show benefit. The first prospective controlled trial of isovolemic hemodilution was conducted in Scandinavia.9 This study, involving 15 centers and 363 patients (183 patients treated with hemodilution and 180 control subjects), found no advantage for hemodilution. Critics of this study have noted that these patients were entered into the trials as much as 48 hours after ischemic stroke, that there was substantial heterogeneity of the patient population, and that the hematocrit was lowered only modestly to an average of 37%.25 44 In subgroup analyses, there was no evidence that hemodilution improved clinical outcome, even when initiated within 12 hours after the onset of symptoms10 ; however, the number of patients treated within that period was relatively small. Another recent large Italian study of 1266 randomized patients with hemispheric stroke also showed no benefit for hemodilution.8 Patients were entered into this study as much as 12 hours after the ischemic event, but again hemodilution was carried out slowly and to a modest degree only. In the current study, we found that hemodilution when initiated within 3 hours after ischemia significantly reduced infarction size and improved the neurological status; when initiation of the treatment was delayed for 6 hours, however, hemodilution was ineffective and might have been detrimental. In view of our findings, it is not surprising that recent controlled studies have had negative results, because only a very small minority of patients received hemodilution within 3 hours of stroke onset.

In the current study, macroscopic hemorrhagic transformation occurred significantly more frequently in group 4 than in groups 1 and 2 (P<.01). Group 4 also showed a trend to have larger infarction than did group 1; the infarction may have been exacerbated by hemorrhagic transformation. No hemorrhagic transformation of infarction was reported in the Scandinavian and Italian studies. Strand42 reported that hemorrhagic cerebrospinal fluid was less common in the hemodiluted group and concluded that the risk of converting an ischemic infarct to a hemorrhagic one by hemodilution seemed small. However, limited experimental evidence suggests that if reperfusion occurs after a critical period of ischemia, hemorrhagic transformation may ensue.45 46 47 48 49 50 Even restoration of blood flow through leptomeningeal collaterals is thought to be sufficient to cause hemorrhagic infarction in some cases in which direct reperfusion does not occur.49 51 52 Hemodilution does not directly reopen occluded vessels as is the case with thrombolysis but rather increases collateral CBF in ischemic brain tissue.27 53 Our data suggest that late institution of hemodilution (after as much as 6 hours) increases the incidence of hemorrhagic transformation after ischemia, perhaps by increasing collateral flow to dysautoregulated brain tissue, subjecting damaged capillaries to abnormally high pressures or flows.

The duration of general inhalation anesthesia for groups 1, 2, and 4 was not significantly different, but animals in group 3 underwent a significantly longer period of anesthesia. Ideally it would have been beneficial to keep all animals anesthetized for the duration of the experiment, including hemodilution, in the group in which hemodilution was to be administered for the longest time after ischemia. In the initial experiment design, we had thought to include a group at 12 and possibly 24 hours, and maintenance of halothane anesthesia for that time period was clearly not feasible. In addition, because of logistical problems involving transportation and care of the animals in a critical care facility remote from the site of the operative procedure, we were unable to keep the group 4 animals anesthetized for the duration of the waiting period before the 6 hour hemodilution was to occur. We opted, therefore, to compromise by keeping the experimental conditions identical (ie, halothane anesthetic during hemodilution) for the groups treated with hemodilution within the most likely window of opportunity according to other studies. The duration of halothane anesthesia, however, does introduce a confounding variable into the treatment of this group. Others have found that exposure to halothane has no neuroprotective effect in a canine model of focal cerebral ischemia.54 55 If one were to postulate that halothane has a neuroprotective effect and that hemodilution is ineffective in decreasing infarction size, infarctions in group 3 animals would be expected to be smaller than in group 2 rather than larger. Likewise, intravenous administration of diazepam has been found to decrease CBF and CMRO2 in dogs but not to reduce the size of infarction.56 Nevertheless, the results for the 6-hour group must be interpreted in light of this difference (hemodilution under diazepam anesthesia versus halothane).

Therapeutic Window for Cerebral Ischemia
Ischemic tissue can be rescued by therapies designed (1) to establish reperfusion, such as thrombolytic therapy,46 48 surgical revascularization,57 58 59 60 61 and hemodilution, or (2) to protect brain tissue against the effects of ischemia, such as mild hypothermia,62 63 excitatory amino acid inhibitors,64 65 calcium channel blockers,66 free radical scavengers,67 68 and gangliosides.69 Correspondingly, the time period after a focal ischemic insult during which each of the above therapies must be initiated to be effective may vary to a certain degree. Reversible occlusion of the MCA has been used to characterize temporal thresholds for infarction in monkeys,11 12 14 cats,14 70 and rats.13 These studies revealed that 2 to 6 hours of focal cerebral ischemia were sufficient to attain maximal infarction in these species. Any therapies given after this time, therefore, would provide little benefit. However, Busto et al71 revealed that mild hypothermia failed to show a protective effect when administered as little as 30 minutes after the ischemia. Recent experiments in rats have shown excitatory amino acid inhibitors to be effective at reducing ischemic damage, even when given as much as 3072 and 9073 minutes after ischemia. However, reperfusion with thrombolysis in an embolic stroke model reduced the infarct volume even when given as much as 2 hours after stroke onset.74 Kaplan et al13 reported that the window of opportunity for reperfusion in rats was 3 to 4 hours after focal ischemia. In general, therapies designed to establish reperfusion such as hemodilution may have a longer window of opportunity than treatments with neuroprotective agents.

It is clear from many experimental studies that a certain amount of at-risk ischemic tissue can be rescued by maneuvers designed to establish reperfusion or to protect brain tissue against the effects of ischemia. Depending on the collateral flow, the narrow window of opportunity during which reperfusion or neuronal protection strategies must be initiated in nonhuman primates is thought to be less than 6 hours.11 12 14 Given the limitations of the current model in the dog, results of the present series of experiments suggest that an attempt to increase blood flow to collateral-dependent tissue with hemodilution will be ineffective in decreasing infarction size if administered more than 6 hours after the onset of focal cerebral ischemia. Interestingly, studies of thrombolysis for reperfusion have demonstrated similarly disappointing results when therapy was administered this late after vessel occlusion.46 48 50

Other studies have demonstrated the effectiveness of hemodilution in reducing infarct size when administered immediately or within 1 hour after the onset of ischemia.2 16 However, even in an ideal situation, it may be difficult to treat most stroke patients within 1 hour of the event.75 76 77 It is perhaps most important and promising to note that in the current study, hemodilution administered even 3 hours after ischemia was effective in reducing infarct size and improving neurological status. As physicians and patients begin to recognize the need for urgent recognition and intervention in acute ischemic stroke, and as stroke patients come to medical attention earlier after the onset of ischemia, the results of the current study suggest the need to restudy the use of hemodilution in the treatment of acute ischemic stroke.


*    Selected Abbreviations and Acronyms
 
ACA = anterior cerebral artery
CBF = cerebral blood flow
CMRO2 = cerebral metabolic rate of oxygen
MCA = middle cerebral artery
SSEP = somatosensory evoked potential


*    Acknowledgments
 
This work was supported in part by a Clinical Investigator Development Award 1K08-NS 01745-01 from the National Institute of Neurological Disorders and Stroke and National Institutes of Health training grant No. T32-NS-07361-01 (P.J. Camarata). The authors would like to thank Jerone D. Kennedy, MD, for technical assistance during surgery, and David Delong, DVM, Wendeline Wagner, DVM, and veterinary technicians of the Research Animal Resources, University of Minnesota, for excellent postoperative care of the animals.

Received October 25, 1995; revision received February 13, 1996; accepted February 22, 1996.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

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