Blood-Brain Barrier Integrity During Cardiopulmonary Resuscitation in Dogs

Transcription

1 1185 Blood-Brain Barrier Integrity During Cardiopulmonary Resusitation in Dogs Charles L. Shleien, MD, Raymond C. Koehler, PhD, D. Hal Shaffner, MD, and Rihard J. Traystman, PhD Blood-brain barrier integrity during ardiopulmonary resusitation may be important beause of the potential effets of adrenergi agonists administered during arrest on erebral metabolism and the erebral vasulature. As an index of blood-brain barrier permeability to small moleules, we measured the brain uptake of [ I4 C]«-aminoisobutyri aid during a 10-minute period in 25 anesthetized dogs. To orret for the amount of arbon-14 label in the plasma spae, we administered [ 3 H]inulin 2 minutes before death. The mean transfer oeffiient in 14 brain regions of five ontrol dogs ranged from to ml/g/min. After 8 (n = 15) or 15 (n=5) minutes of ardia arrest, external hest ompression was instituted to maintain aorti blood pressure above 60 mm Hg. The transfer oeffiient was not elevated during hest ompression (n=10), immediately following defibrillation (n=5), or 4 hours after resusitation (n=5); in some brain regions the transfer oeffiient dereased. However, the derease in the transfer oeffiient was proportional to the derease in the erebral plasma volume as measured by the ratio of the [ 3 H]inulin onentration in the tissue to that in the plasma. Thus, it is unlikely that a derease in apillary surfae area masked an inrease in blood-brain barrier permeability. Therefore, we found no evidene of blood-brain barrier disruption during or after ardiopulmonary resusitation in dogs. Despite the large phasi inreases in sagittal sinus pressure assoiated with external hest ompression, onurrent inreases in erebrospinal fluid pressure apparently protet the miroirulation from inreased transmural pressure. (Stroke 1990;21: ) Integrity of the blood-brain barrier (BBB) during ardiopulmonary resusitation (CPR) is important due to the potential effets on erebral metabolism and vasular smooth musle evoked by a host of humoral substanes released after ardia arrest and by administered drugs suh as adrenergi pressor agents. Blood-brain barrier dysfuntion ould arise from either the mehanial vasular effets assoiated with CPR or from the biohemial effets assoiated with omplete erebral ishemia during ardia arrest. During hest ompression there are large phasi flutuations in both arterial and erebral venous pressures 1 that ould mehanially disrupt the BBB, partiularly in the maximally vasodilated bed. Immediately following CPR, rapid restoration of blood From the Departments of Anesthesiology/Critial Care Mediine (C.L.S., R.C.K., D.H.S., R.J.T.) and Pediatris (C.L.S.), Division of Pediatri Intensive Care, The Johns Hopkins Medial Institutions, Baltimore, Maryland. Supported by United States Publi Health Servie National Institutes of Health grants P01-NS20020 and K08-NS Address for orrespondene: Charles L. Shleien, MD, Department of Anesthesiology/Critial Care Mediine, The Johns Hopkins Hospital, 600 North Wolfe Street-Halsted 842, Baltimore, MD Reeived January 17, 1990; aepted April 10, pressure in a vasodilated bed may also inrease BBB permeability, as observed in some models of foal ishemia. 2 In addition, following prolonged global ishemia BBB permeability may inrease several hours into the reperfusion period. 3 Thus, there are several ritial periods assoiated with CPR during whih inreased BBB permeability might be antiipated: during hest ompression, during the hyperemi phase immediately after defibrillation, and during the delayed hypoperfusion phase. In one study, extravasation of vans blue was observed during the transient hypertensive period following defibrillation. 4 However, BBB integrity during a stable period of ontinuous external hest ompression after ardia arrest has not been well quantified. We used the [ 14 C]a-aminoisobutyri aid (AIB) tehnique 5 in dogs to assess BBB integrity during a hemodynamially stable and reproduible period of external hest ompression. We also examined BBB integrity during the hyperemi phase immediately following defibrillation and during the delayed hypoperfusion period 4 hours after CPR. Materials and Methods Twenty-five mongrel dogs weighing kg were anesthetized with 50 i^g/kg i.v. fentanyl and 10 mg/kg

2 1186 Stroke Vol 21, No 8, August 1990 i.v. pentobarbital and then ventilated through an endotraheal tube seured by a traheostomy. Frational inspired O 2 was 30-50%. nd-tidal CO 2 was monitored to maintain Pao 2 at mm Hg. If the dog began to move, additional pentobarbital was given; generally 5-10 mg/kg i.v. was required to maintain a depth of anesthesia adequate for surgery. Saline-filled atheters were advaned through a femoral artery into the thorai aorta and through a femoral vein into the right atrium. A 4-Frenh paing wire was passed into the right heart for indution of ventriular fibrillation. Catheters were also passed through the axillary artery and vein into the sublavian artery and vein for sampling of blood and infusion of epinephrine, respetively. At the end of surgery the dog was paralyzed with 0.1 mg/kg panuronium, and 4,000 units heparin was administered. Ventriular fibrillation was indued by passing a 60-Hz urrent through the paing wire in the right heart. xternal hest ompression to maintain aorti blood pressure above 60 mm Hg was performed over the sternum with a pneumati hest ompressor (Thumper, Mihigan Instruments, Grand Rapids, Mih.). Chest ompressions were performed at a rate of 40/min, with ompressions lasting 50% of the total yle time. Compression fore was set at N to produe a yli sternal displaement equivalent to 15-20% of the anteroposterior diameter. Simultaneous ventilation at high airway pressure (75-85 mm Hg) was provided by a pressure-limited ventilator during the first 40% of eah yle. The dogs were ventilated with a mixture of 95% O 2 and 5% CO 2 during CPR to prevent hypoxia and avoid hypoapnia. We studied five groups. In group 1 («=5), the ontrol group, measurements were made during spontaneous irulation without prior ardia arrest. In group 2 (n=5), ardia fibrillation, doumented by the aorti blood pressure traing, lasted 8 minutes before CPR ommened; CPR was then ontinued for 10 minutes without attempting ventriular defibrillation. In group 3 (n=5), 8 minutes of ardia fibrillation was followed by 6 minutes of CPR. Ventriular defibrillation was ahieved within four attempts by external ountershok, and the dogs were killed 10 minutes after defibrillation by the intravenous injetion of KC1. In group 4 («=5), 8 minutes of ardia fibrillation was followed by 6 minutes of CPR and then by defibrillation; the dogs were killed 4 hours later by the intravenous injetion of KC1. In group 5 (n=5), ardia fibrillation lasted 15 minutes before CPR ommened; CPR was performed for 10 minutes without attempts at defibrillation. pinephrine was given as a 10 fig/kg bolus into the right atrium at the onset of CPR in groups 2-5. For the duration of CPR an infusion of 4 /LAg/kg/min i.v. epinephrine in saline was administered at a volumetri rate of 3.9 ml/min. This dose maintains erebral perfusion pressure at levels suffiient for nearnormal erebral blood flow. 1 Following defibrillation, the epinephrine infusion was dereased in halflogarithmi steps at 1-minute intervals when the mean aorti blood pressure was >90 mm Hg. Infusion was stopped by 12 minutes after defibrillation in all dogs. To test the sensitivity of the AIB tehnique to elevations in erebral venous pressure, we used the venous outflow tehnique of Rapela and Green 6 to isolate the erebral venous drainage in two additional dogs. A srew lamp on the venous outflow side of the iruit was used to raise the erebral venous pressure to 30 mm Hg in one dog and 75 mm Hg in the other. In addition, a 16-gauge atheter was inserted into the isterna magna to drain erebrospinal fluid. After 3-4 minutes of stable pressures, AIB was injeted. The dogs were killed 10 minutes later. Pressures were reorded from the intrathorai aorta and right atrium with Statham 23 Db transduers (Hato Rey, Puerto Rio) referened to the level of the right atrium. Arterial blood gases and ph were obtained before ardia arrest in all five groups, during CPR in groups 2-5, and after defibrillation in groups 3 and 4. Ten minutes before death, 250 ^,Ci of the lowmoleular-weight traer AIB (moleular weight 104, speifi ativity mci/mmol; Du Pont-New ngland Nulear Produts, Boston, Mass.) was injeted intravenously. In groups 2 and 5 AIB was given at the onset of CPR after vasular pressures stabilized (within 20 seonds), in group 3 it was given immediately after defibrillation, and in group 4 it was given 4 hours after defibrillation. To orret for the amount of AIB in the plasma spae, 250 fid (0.25 ml) [ 3 H]inulin (Du Pont-New ngland Nulear Produts) was injeted intravenously exatly 8 minutes after the injetion of AIB. Arterial blood samples were drawn from the axillary artery atheter 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, and 10 minutes after the injetion of AIB. Two tissue samples weighing 200 mg apiee were disseted from the hippoampus, audate nuleus, ervial spinal ord, medulla, pons, midbrain, and dienephalon; one sample eah was disseted from the superior olliulus and pituitary gland; and four samples were disseted from the erebellum. ight ortial samples were obtained from eah of the primary supply regions of the anterior, middle, and posterior erebral arteries and from the seondary anterior-middle and posterior-middle erebral artery watershed regions. All samples were plaed in glass vials. Two milliliters of Protosol (Du Pont-New ngland Nulear Produts) was added to eah vial to dissolve the tissue sample, and the vials were plaed in a water bath at C overnight. Ten milliliters of Bioount (Researh Produts International Corp., Mt. Prospet, 111.) was used for this double-label sintillation oktail on 50-^.1 aliquots of tissue and plasma. Glaial aeti aid (0.05 ml) was added to neutralize the solution and minimize hemiluminesene. Samples were kept at room temperature overnight before ounting fi emissions (LS 3801, Bekman Instruments, In., Shiller Park, 111.).

3 Shleien et al Blood-Brain Barrier During Resusitation f ~ 60- S o o m \ CD ~O ^ K) D in O O Control * 8 min ishemia+cpr T-- TPost-defibrillation A A 4 hr post defibrillation»15 min ishemia+cpr T Control 2-8 min ishemia+cpr 3 Post defibrillation 4-4 hr post-defibrillation 5-15 min ishemia+cpr TIM (minutes) FIGUR 1. Profiles of f' 4 C]a-aminoisobutyri aid (AIB) plasma onentrations for five groups of dogs (n=5). CPR, ardiopulmonary resusitation. Disintegrations per minute (dpm) of both ^-emitting substanes were obtained using a double-isotope tehnique orreted for quenh and bakground by the external standard method. Using the equation of Ohno et al 7 as modified by Blasberg et al, 5 the transfer oeffiient (Kj, in milliliters per gram per minute) for AIB was alulated as [ 14 C(T)-( 3 H(T)x 14 C(P)/ 3 H(P))]H C(P)dt, where 14 C(T) is the onentration of AIB in the tissue sample at the end of the experiment (dpm per gram), 3 H(T) is the onentration of [ 3 H]inulin in the tissue sample at the end of the experiment (dpm per gram), 14 C(P) is the onentration of AIB in the 10-minute plasma sample (dpm per milliliter), 3 H(P) is the onentration of [ 3 H]inulin in the 10-minute plasma sample (dpm per milliliter), and C(P)dt is the integrated arterial plasma onentration of AIB during the 10-minute sampling time (minutes x dpm per milliliter). We also alulated a orreted Kj (Kj') that normalized for differenes in plasma volume among groups as (a/ft)kj, where a is the mean ratio of the onentration of [ 3 H]inulin in the tissue to that in the plasma for the five dogs in group 1 and b is the [ 3 H]inulin tissue-to-plasma ratio in eah dog in the experimental group. This normalization assumes a simple linear relation between apillary surfae area and plasma volume among dogs, whih is a reasonable first approximation if the predominant mehanism of dereased plasma volume is a derease in perfused apillary density and if the hanges in mirovasular diameter and hematorit are small. For eah brain region, Kj is expressed as mean±sm. Differenes among groups were evaluated by one-way analysis of variane. Comparisons with group 1 were made using Dunnett's test with a probability value of Results The profiles of AIB plasma onentrations for the five groups generally had similar shapes (Figure 1). However, as a result of the low ardia output during CPR, peak plasma onentrations of AIB were higher and the subsequent delines were slower in , **** * **» * *»*«**** * * AC MC PC AMW PMW HIP CAUD *» ** * * SC CR MD PONS MID COLL DI FIGUR 2. Mean (bars) and individual (dots) transfer oeffiient (Kj) for anterior erebral artery (AC), middle erebral artery (MC), posterior erebral artery (PC), anterior-middle erebral artery watershed (AMW), and posterior-middle erebral artery watershed (PMW) regions, hippoampus (HIP), audate nuleus (CAUD), ervial spinal ord (SC), erebellum (CR), medulla (MD), pons (PONS), midbrain (MID), superior olliulus (COLL), and dienephalon (DI) of dogs. CPR, ardiopulmonary resusitation. *p<0.05 different from group 1 for that brain region by one-way analysis of variane and Dunnett's test. groups 2 and 5. These higher plasma onentrations of AIB theoretially have no effet on Kj beause they are suffiiently low to remain on the linear portion of the uptake-onentration urve and beause the greater amount of residual arbon-14 label in plasma at 10 minutes is orreted for by the [ 3 H]inulin tissue-to-plasma ratio. The latter assumes that the uptake of [ 3 H]inulin is negligible ompared with that of AIB. This assumption appears reasonable beause the moleular weight of inulin is 300 times that of AIB and beause the exposure to [ 3 H]inulin lasted only 2 minutes. Mean and individual Kj values for 14 brain regions in the five groups are shown in Figure 2. For eah brain region the mean Kj values for individual dogs in groups 2-5 was not higher than the mean Kj value in group 1. Only one dog (in group 3) had an individual Kj value higher than the mean Kj value in group 1 for any brain region. This ourred in the spinal ord,

4 1188 Stroke Vol 21, No 8, August 1990 TABL 1. Region [ 3 H]InuIin Tissue-to-Plasma Ratio for 14 Brain Regions in Dogs ACA MCA PCA ACA-MCA watershed PCA-MCA watershed Hippoampus Caudate nuleus Spinal ord Cerebellum Medulla Pons Midbrain Colliulus Dienephalon ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.003* 0.017± ± ±0.002 Group ± ± ± ± ±0.002* 0.012± ± ±0.002* 0.018± ± ± ± ±0.002* 0.014±0.002* 0.013± ± ± ±0.002* 0.015± ± ±0.002* 0.017± ± ±0.003* 0.013± ±0.002* 0.015± ± ±0.001* 0.010±0.002* 0.019± ± ±0.002* 0.014± ±0.002* 0.012±0.002 Values are mean±sm of ([ 3 H]inulin dpm/g tissue)/([ 3 H]inulin dpm/ml plasma) (n=5). 1, ontrol; 2, 8 min ishemia plus ardiopulmonary resusitation (CPR); 3, post-defibrillation; 4, 4 hr post-defibrillation; 5, 15 min ishemia+cpr; ACA, anterior erebral artery; MCA, middle erebral artery; PCA, posterior erebral artery. */?<0.05 different from group 1 value by one-way analysis of variane and Dunnett's test. erebellum, medulla, pons, and midbrain. For some brain regions mean Kj in an experimental group was signifiantly lower than that in group 1. During CPR in groups 2 and 5, mean Kj was signifiantly lower for all primary and seondary erebral artery regions, the hippoampus, midbrain, and dienephalon. In group 5, mean Kj for the erebellum was also signifiantly lower. Immediately after defibrillation in group 3, mean Kj was signifiantly lower for the anterior and posterior erebral artery regions and the anteriormiddle and posterior-middle erebral artery watershed areas. Four hours after CPR in group 4, mean Kj was signifiantly lower for all primary and seondary erebral artery regions, the midbrain, and the superior olliulus. Mean Kj for the pituitary gland ranged from ±0.017 to ±0.005 in the five groups (data not shown). These values are times those for the other brain regions. This result was expeted beause of the lak of a BBB in the pituitary gland and indiates that the radiolabel was delivered intraranially in eah dog. Kj depends not only on BBB permeability but also on apillary surfae area; hene, a derease in surfae area may aount for the low postishemi Kj. Capillary surfae area is a funtion of the number of perfused mirovessels and the square of their diameter, and thus, surfae area may be expeted to vary as a nonlinear funtion of plasma volume. We estimated plasma volume for eah brain region using the [ 3 H]inulin tissue-to-plasma ratio. Mean values for 14 brain regions in the five groups are shown in Table 1. For eah brain region, this ratio in the experimental groups was less than that in group 1. For example, for the middle erebral artery region, the [ 3 H]inulin tissue-to-plasma ratio in groups 2-5 ranged from 58% to 75% of that in group 1. Kj for that region in the experimental groups had a similar range of 42-78% of the group 1 value (Figure 2). Values of Kj' are plotted in Figure 3; Kj' of group 1 equals Kj. In ontrast to Kj, mean Kj' in the four experimental groups was not less than that in group 1 for any brain region. During CPR in groups 2 and 5, mean Kj' for the medulla was signifiantly greater than that in group 1. Mean aorti blood pressure and arterial blood gases during the 2 minutes of AIB irulation are shown in Table 2. Immediately following defibrillation in group 3, aorti systoli blood pressure inreased to a mean peak of 297 ±23 mm Hg. However, this peak was short-lived, and systoli pressure dereased to a mean of 216±18 mm Hg by 1 minute after the peak and 183±20 mm Hg by the next minute. In the two dogs in whih the venous outflow tehnique was used to elevate erebral venous pressure (to 38 mm Hg in one and 75 mm Hg in the other), erebral perfusion pressure averaged 27 and 45 mm Hg, respetively, during the 10 minutes following AIB injetion. In these two dogs, Kj was higher for all brain regions than in group 1 (Table 3). Disussion We found no diret evidene of inreased BBB permeability to a small moleule suh as AIB in any experimental protool tested in this dog model of CPR. During CPR, there are large phasi inreases in both arterial and jugular venous blood pressures, 8 with peak sagittal sinus pressure reahing mm Hg. 1 Thus, we antiipated that postishemi disruption of the BBB would be enhaned by large flutuations of erebral venous pressure. The reason we did not find disruption may be related to the simultaneous inrease in erebrospinal fluid pressure

5 Shleien et al Blood-Brain Barrier During Resusitation 1189 \ o> \ n Control 2-8 min ishemia + CPR 3-Post-defibrillation 4 4 hr post defibrillation 5-15 min ishemia + CPR AC MC PC AMW PMW HIP CAUD * SC CR MD PONS MID COLL DI FIGUR 3. Mean±SM orreted transfer oeffiient (K/) for anterior erebral artery (AC), middle erebral artery (MC), posterior erebral artery (PC), anterior-middle erebral artery watershed (AMW), and posterior-middle erebral artery watershed (PMW) regions, hippoampus (HIP), audate nuleus (CAUD), ervial spinal ord (SC), erebellum (CR), medulla (MD), pons (PONS), midbrain (MID), superior oluulus (COLL), and dienephalon (DI) of dogs (n=5). *p<0.05 different from group 1 for that brain region by one-way analysis of variane and Dunnett's test. during the hest ompression phase of CPR. 9 If these inreases in sagittal sinus pressure and erebrospinal fluid pressure were perfetly mathed in amplitude and time phase, there would be no dynami hange in transmural pressure. We found that elevating the erebral venous pressure without ishemia inreased Kj when the erebrospinal fluid was drained onomitantly. Thus, inreased erebrospinal fluid pressure likely protets the BBB during hest ompression. Another fator may be the presene of venous hyperapnia. Baumbah et al 10 showed less disruption of the BBB during hypertension aompanied by hyperapnia than during normoapni hypertension. Whether the mehanism of this effet is due to attenuation of the inrease in pial venular pressure by hyperapnia or to a diret effet on the BBB unrelated to venous pressure is unlear. Thus, it is possible that slow washout of CO 2 during CPR after omplete ishemia exerts a protetive effet on the BBB. The period immediately following CPR is one during whih the BBB is prone to disruption beause of erebral vasodilation in the presene of arterial hypertension. Aorti blood pressures of >160 mm Hg have been assoiated with BBB disruption, 11 and the disruption is detetable with AIB. 12 During CPR, Arai et al 4 observed extravasation of vans blue mirosopially following defibrillation in eight of nine dogs in whih the peak aorti systoli blood pressure averaged approximately 250 mm Hg. In our study, the transient inrease in aorti systoli blood pressure to a mean of 297 mm Hg may not have lasted suffiiently long to ause disruption. One dog exhibited elevated Kj in the brain stem and spinal ord but not the erebral ortex. This regional pattern is unexpeted beause during hypertension the brain stem is more resistant to BBB disruption than the erebral ortex. 13 However, the [ 3 H]inulin plasma-to-tissue ratio in this dog was inreased relative to that in group 1. Thus, this inrease in K; might have been due to only an inrease in apillary surfae area. In other models of erebral ishemia without the mehanial effets of CPR, two phases of inreased BBB permeability are sometimes observed. With reversible middle erebral artery olusion, a biphasi pattern of disruption an our, first 15 minutes and then 5 hours after ishemia. 2 With global ishemia in rats, the BBB was disrupted only during the early stages following 15 or 30 minutes of ishemia, with reovery 24 hours after the original insult. 14 With a longer ishemi period lasting 60 minutes, TABL 2. Pooled Data, Arterial Blood Gases and Mean Aorti Blood Pressure During Cirulation of [ M C]«- Aminoisobutyri Aid in 25 Dogs Arterial ph Pa>2 (mm Hg) Pa>2 (mm Hg) Mean aorti blood pressure (mmhg) Before ardia arrest (group 1, n=5) 7.40 ± ±1 174± ±7 During ardiopulmonary resusitation (groups 2+5, n = 10) 7.14± ± ±11 arly (group 3, n=5) 7.22± ±2 176±16 178±11 After defibrillation Late (group 4, n=5) 7.35 ± ±1 185 ±26 121±3 Data are mean±sm. Group 1, ontrol; group 2, 8 min ishemia plus ardiopulmonary resusitation (CPR); group 3, post-defibrillation; group 4, 4 hr post-defibrillation; group 5, 15 min ishemia + CPR.

6 1190 Stroke Vol 21, No 8, August 1990 TABL 3. ffet of levated Cerebral Venous Pressure on K of [ 14 C] a-aminoisobutyri Aid in Seleted Brain Regions of Two Dogs Kj (ml/g/min) Region Middle erebral artery Posterior erebral artery Spinal ord Medulla Colliulus Dogl (38 mm Hg) Dog 2 (75 mm Hg) Group 1 (n=5) (mean±sm) 0.005± ± ± ± ± seondary brain edema that developed later during reperfusion was often assoiated with inreased AIB uptake. 13 The differenes between these studies and ours may be due to differenes in speies and type, severity, and duration of ishemia. Only 8 or 15 minutes of global ishemia and 6 minutes of inomplete reperfusion during CPR may not be suffiiently long to ause BBB disruption subsequent to defibrillation. In addition, we annot exlude that BBB disruption ours after >4 hours of reperfusion. The AIB tehnique has generally been used in small animals suh as rats and gerbils but not large animals. Mean values of Kj among 14 brain regions ranged from to ml/g/min in our ontrol dogs, approximately those reported in small animals ( ml/g/min) When testing the sensitivity of the AIB tehnique using the venous outflow method to elevate erebral venous pressure, large inreases in Kj were evident (Table 3). The high Kj in the pituitary gland, where no BBB is present, also supports the validity of the AIB tehnique in dogs. There are other possibilities that explain the lak of elevated Kj. Cerebral vasular surfae area may be dereased even more than aounted for by our orretion using the [ 3 H]inulin tissue-to-plasma ratio. However, the magnitude of this error should be small and should not mask large inreases in Kj. Moreover, if surfae area varied with plasma volume raised to the two-thirds power (as would our if the hanges were due stritly to diameter and not to reruitment), then the derease in plasma volume would overestimate, not underestimate, the derease in apillary surfae area. Another possibility is that AIB uptake and sequestration by the A transport system for amino aids may be inhibited after ishemia. This might ause a falsely low Kj beause of bak-diffusion of AIB. However, the brief 10-minute exposure to this traer would not be expeted to allow for substantial bak-diffusion unless permeability were high in the first plae, whih is unlikely sine Kj remained low. Thus, transporter inhibition may affet the preise quantifiation of Kj, but it should not prevent the detetion of an inreased Kj. We found not only that Kj was not elevated, but that it was lower than ontrol for some brain regions. We suggest that the dereased Kj is due to dereased surfae area of the apillary bed beause brain plasma volume as measured by the [ 3 H]inulin spae was dereased. Although it is possible that some plasma radiolabel was lost after death when the tissue was exised, it is unlikely that there was a systemati error that ould aount for the 30-40% redution in plasma volume in the experimental groups ompared with the ontrol group. During CPR, erebral blood flow is near normal in this model. 1 Thus, if erebral blood flow is normal and erebral plasma volume is low, then omplete apillary reruitment is unlikely during CPR after ishemia, and reperfusion will be heterogeneous. Kagstrom et al 16 demonstrated the presene of reperfusion defets with normal erebral perfusion pressure immediately after 15 minutes of ishemia in rats. With CPR, reperfusion heterogeneity may be even more severe beause of subnormal erebral perfusion pressure. Reently, nnis et al 17 observed a 20% derease in the number of perfused apillaries in gerbils after 3 hours of inomplete ishemia and 11 minutes of reperfusion that partially aounted for the dereased Kj for AIB. Four hours after CPR, no inrease in Kj was noted. In parallel experiments, mean±sm erebral blood flow was only 18 ±1 ml/min/100 g 4 hours after CPR, representing a 42% derease from ontrol values. 18 The present [ 3 H]inulin tissue-to-plasma ratio was 40% lower than ontrol. Thus, erebral blood flow and plasma volume dereased equally during hypoperfusion. Similar results have been observed after ishemia in gerbils. 15 If the erebral blood volume is diminished, then Kj may be dereased beause of a dereased apillary surfae area. In onlusion, using a small amino aid to assess the integrity of the BBB in dogs after ardia arrest, we found no substantial disruption of the BBB assoiated with hest ompression during CPR, immediately following defibrillation, or 4 hours after defibrillation. Therefore, irulating hydrophili substanes suh as epinephrine typially administered in high doses during CPR are unlikely to gain aess to the vasular smooth musle or to neurons, where they ould indiretly affet erebral blood flow or metabolism. Aknowledgments We would like to aknowledge the skilled tehnial assistane by Jodi Leatherman and the fine preparation of the manusript by Nikki Womer.

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