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Journal of Cerebral Blood Flow and Metabolism 12:802--S08 © 1992 The International Society of Cerebral Blood Flow and Metabolism Published by Raven Press, Ltd., New York
Uncoupled Cerebral Blood Flow and Metabolism After Severe Global Ischemia in Rats
*tNarendra C. Singh, *tPatrick M. Kochanek, *tJoanne K. Schiding, *John A. Melick, and *Edwin M. Nemoto *Departments of Anesthesiology/Critical Care Medicine and tPediatrics, University of Pittsburgh, Pittsburgh, U.S.A.
Summary: In a rat model of complete global brain isch emia (neck tourniquet) lasting either 3 min or 20 min, we monitored global CBF (sagittal sinus H2 clearance) and CMR02 for 6 h to test the hypothesis that delayed post ischemic hyperemia and uncoupling of CBF and CMR02 occur depending on the severity of the insult. Early post ischemic hyperemia occurred in both the 3-min and 20min groups (p < 0.05 vs. baseline values) and resolved by 15 min. Hypoperfusion occurred in the 3-min group be tween 15 and 60 min postischemia (=23% reduction), and in the 20-min group from 15 to 120 min postischemia (=50% reduction) (p < 0.05), and then resolved. CMR02 was not significantly different from baseline at any time after ischemia in the 3-min group. After 20 min of isch emia, however, CMR02 was decreased (=60%) through-
out the postischemic period (p < 0.05). At 5 min after ischemia, CBF/CMR02 was increased in both groups but returned to baseline from 60 to 120 min postischemia. In the 3-min group, CBF/CMR02 remained at baseline throughout the rest of the experiment. However, in the 20-min group, CBF/CMR02 once again increased (=100%), reaching a significant level at 180 min and re maining so for the rest of the 6-h period (p < 0.05). These data demonstrate biphasic uncoupling of CBF and CMR02 after severe (20 min) global ischemia in rats. This relatively early reemergence of CBF/CMR02 uncoupling after 180 min of reperfusion is similar to that observed after prolonged cardiac arrest and resuscitation in hu mans. Key Words: Cerebral ischemia-Cerebral blood flow-Cerebral metabolism-Rat.
Animal models of global brain ischemia (GBI) show transient hyperemia immediately after isch emia, followed by a variable period of cerebral hy poperfusion (Snyder et aI. , 1975; Hossmann, 1982; Pulsinelli et aI. , 1982b; Steen et aI., 1983). Few in vestigators, however, have examined CBF beyond 4 h after ischemia, and even fewer have evaluated CBF and cerebral metabolic rate (CMR). Rats sub jected to 30 min of incomplete GBI showed a period of hypoperfusion in the hippocampus and striatum which was followed by normalization of CBF at 6 h and hyperemia at 24 h, while CMRglc remained be low normal values throughout (Pulsinelli et al. , 1982b). Similarly, in patients suffering prolonged cardiac arrest, CBF and CMR02 are uncoupled af ter 6 h of reperfusion, which is a poor prognostic
sign (Beckstead et aI., 1978; Cohan et aI. , 1989), especially when accompanied by loss of the cere brovascular CO2 reactivity (Love et al. , 1989). These data are consistent with postischemic uncou pling of CBF and CMR after ischemic insults of sufficient duration or severity. Recently, Michenfelder and associates (Michen felder and Milde, 1990; Michenfelder et al., 1991) reported that CBF remained coupled to CMR02 be tween 5 and 90 min after 3 to 18 min of CSF com pression ischemia in dogs. These investigations fo cused on the postischemic hypoperfusion period (the first 90 min after the insult); however, a de layed uncoupling of CBF and CMR may occur after such time. We hypothesized that delayed hyperemia and un coupling of CBF and CMR02 occur after GBI, de pending upon the severity of ischemic insult.
Received September 17, 1991; final revision received March 26, 1992; accepted March 27, 1992. Address correspondence and reprint requests to Dr. P. M. Kochanek at Department of Critical Care Medicine, Children's Hospital of Pittsburgh, 3705 5th Avenue at DeSoto St. , Pitts burgh, PA 15213, U.S.A. Abbreviations used: OBI, global brain ischemia; PEEP, posi tive end expiratory pressure.
MATERIALS AND METHODS The protocol was approved by the Animal Care and Use Committee of the University of Pittsburgh School of
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UNCOUPLED POSTISCHEMIC CBF AND CMR02 Medicine. Sixteen barrier-bred, virus-free, male Wistar rats (Hilltop Laboratories, Scottdale, PA, U.S.A.) were used.
Anesthesia and surgical preparation Anesthesia was induced in a plastic jar insufflated with 5% halothane/95% 02' The rats' tracheas were intubated with a 14-gauge catheter and their lungs were mechani cally ventilated with 0.5% halothanel70% N20/30% O2 at 60 breaths/min, tidal volume of 5 ml, and 5 cm H20 pos itive and expiratory pressure (PEEP). The rats were im mobilized with pancuronium bromide (Elkins-Sinn, Cherry Hill, NJ, U.S.A.), 0.3 mg h-I, i.v. Two femoral artery catheters and one femoral vein catheter (PE-50) were inserted. The dorsal aspect of the skull was exposed via a midline incision. The rats were fixed in a stereotaxic device (David Kopf, Tujunga, CA, U.S.A.) in a Faraday cage. Rectal temperature was continuously monitored (Telethermom eter, Yellow Springs, OH, U.S.A.) and controlled with a heating pad. Arterial blood pressure and heart rate were recorded on a polygraph (Grass, Quincy, MA, U.S.A.). A platinum microlelectrode (25-50-fLm-tip diameter) was in serted through a burr hole 0.5 cm anterior to the torcular into the sagittal sinus. Microelectrodes were connected to chemical microsensors (Diamond Electro-Tech, model 1201, Ann Arbor, MI, U.S.A.). A short-bevel, 27-gauge stainless steel needle was inserted into the torcular through a second burr hole for cerebral venous blood sampling. Heparin (Upjohn, Kalamazoo, MI, U.S.A.), 100 units, i.v., was administered to prevent clotting. The burr holes and skull were then covered with agar to pre vent diffusion of H2 from the tissue and to facilitate tem perature homeostasis.
CBF and CMR02 measurements CBF was measured using a previously described tech nique for sagittal sinus H2 clearance (Young, 1980; Kochanek et al., 1988). Briefly, H2 gas (5-6%) was added to the inspired gas mixture, and after equilibration, H2 washout was effected and global CBF (miIOO g-I min-I) was calculated from the entire clearance curve by the T I2 I method. For CBF determinations at the 5-min post ischemia time point, saturation with H2 was achieved be fore ischemia and clearance was initiated precisely at 5 min of reperfusion. Cerebral venous and systemic arterial O2 contents were determined in 0.25-ml blood samples using a CO-Oximeter (Instrumentation Laboratory, model 282, Lexington, MA, U.S.A.). CMR02 (mliOO g-I min - I) was calculated as the product of CBF and the systemic arterial minus cerebral venous difference in O2 content.
Global brain ischemia GBI was produced by a combination of arterial hy potension (50 mm Hg) and a high-pressure neck tourni quet (Nemoto et al., 1977; Siemkowicz and Hansen 1978; Siemkowicz, 1980). The effectiveness of the method in producing complete GBI was verified in two ways. A tourniquet inflation pressure of 25 psi produced complete GBI as verified in two pilot rats by increasing MABP to 180 mm Hg and then removing the brain for direct inspec tion of the cranial vault for the appearance of perfusion. In addition, the complete absence of H2 clearance during ischemia was verified in each study. Complete GBI was initiated by trimethaphan camsylate (Roche Laborato-
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ries, Nutley, NJ, U.S.A.), 2.0 mg i.v. administered to de crease MABP to about 50 mm Hg when the tourniquet was inflated to 25 psi. To prevent the hypertensive re sponse to tourniquet inflation, PEEP was increased from 5 to 15 cm H20 and blood (5-10 m!) was withdrawn to maintain the MABP between 50 and 60 mm Hg during GBI. In the 20-min group, blood gases were measured after 10 min of ischemia, and sodium bicarbonate (1 mg kg-I, i.v.) was administered to maintain a base excess > - 5 mmol L- 1 • Before tourniquet deflation, PEEP was reduced to 5 cm H20. After deflation, shed blood was infused slowly to maintain MABP > 100 mm Hg. If after 2 min, MABP was 100 mm Hg.
Experimental protocol Halothane was discontinued after preparatory surgery and the rats were allowed to equilibrate on 70% N20/30% O2 for 30 min. Baseline CBF and CMR02 were measured and the following physiologic variables were controlled. MABP was maintained above 100 mm Hg, temperature at 37.0 ± O.soC, pH between 7.35 and 7.45, Pac02 between 32 and 38 mm Hg, Pa02 between 100 and 150 mm Hg, base excess at greater than - 5 mmol L-I, and hemoglobin between 13 and 15 g dl- 1 by replacing withdrawn blood with heparinized blood from donor Wistar rats. GBI for either 3 min (n = 6) or 20 min (n = 10) was then induced as described above. CBF and CMR02 were measured at 5 min, 15 min, 1 h, 2 h, 3 h, 4 h, 5 h, and 6 h after ischemia. CBF and CMR02 measurements after I h of reperfusion were averaged from two samples.
Data analysis Controlled and experimental variables were compared at baseline between groups using Student's unpaired t-test. To examine the effect of time postischemia on the experimental variables in each group, a two-way analysis of variance for repeated measures was used (multivariate model with data estimation for missing values, BMDP P5V) followed by comparison to respective baseline val ues using Scheffe's post-hoc procedure. All values are expressed as mean ± SD. A p value 0 0 T"-
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(9.80 ± 3.15 ml 100 g-I min -1 and 10.06 ± 3.50 ml 100 g-l min-1 in the 20-min and 3-min groups, re spectively). In the 3-min group, CMR02 was un changed from baseline at all times after ischemia (Fig. 2). In the 20-min group, however, CMR02 re mained below baseline values for up to 6 h (p < 0.05; Fig. 2). Baseline CBFICMR02 was similar in the 20-min and 3-min groups (12.8 ± 2.3 and 16.9 ± 6.3, re spectively). At 5 min after ischemia, CBFICMR02 was increased in both groups (Fig. 3, p < 0.05). In the 3-min group, CBFICMR02 decreased to base line by 15 min after ischemia and remained un changed to 6 h (Fig. 3). In the 20-min GBI group,
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FIG. 1. Global CBF in ml 100 g -1 min -1 versus time (min) in rats before (baseline, B) and after 20 min (e) or 3 min (0) of complete global brain ischemia (GBI). Transient hyperemia occurred in both groups at 5 min after ischemia. Hypoperfusion developed at15 min and 60 min after ischemia in both groups. CBF remained decreased at120 min after ischemia in the 20-min GBI group. n = sample size at each time point. *p < 0.05 versus respective baseline value.
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CBF/CMR02 was increased at 15 min after isch emia, returned to baseline between 60 and 120 min, increased again at 180 min, and remained high for the rest of the monitoring period (p < 0.05; Fig. 3). DISCUSSION The combination of arterial hypotension and a high-pressure neck tourniquet produces complete GBI (Nemoto et aI., 1977; Siemkowicz and Hansen, 1978; Siemkowicz, 1980), which we confirmed by both direct observation and the absence of H2 clear ance during ischemia. Thus, the duration and sever-
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showed severe damage (Nemoto et aI., 1977). A similar evaluation has not been performed in this rat model. The early reperfusion hyperemia seen at 5 min after ischemia in our model corroborates the find ings of previous investigators (Snyder et aI., 1975; Kagstrom et aI., 1983; Newberg et aI., 1984). The mechanism of early postischemic hyperemia is un known. However, tissue acidosis (Lassen, 1966; Rehncrona et aI., 1980; Hillered et aI., 1985) and oxygen radical formation (Kontos, 1985), among other factors, have been implicated. With early hyperemia (at 5 min after both 3 and 20 min of GBI), we observed a decrease in CMR02, as have other investigators (Kagstrom et aI., 1983; Newberg et aI., 1984). In contrast, Michenfelder and Milde (1990) reported an early increase in CMR02 at 1 min after GBI by CSF compression in dogs. We did not measure CMR02 at 1 min after ischemia and could have missed an early, transient increase in CMR02. Alternatively, the hyperemia observed by Michenfelder and Milde (1990) at 1 min after ischemia was more than twice that observed in our study at 5 min. This might indicate differences in the ischemic insult inflicted by their compression versus our neck-tourniquet method and, thereby, differences in the postischemic responses observed. The twofold higher CBF values that they obtained could also account for the increase in CMR02. Spu rious correlations by mathematical coupling can oc cur when two variables are derived as the product of the same measurement (Lucking et aI., 1990). An increased CMR02 is unlikely to be observed so early after ischemia because the brain is electrically silent at this time. After GBI and early hyperemia, classic postisch emic hypoperfusion was observed between 15 and 60 min in the 3-min ischemia group and between 15 and 120 min in the 20-min ischemia group (Figs. 1 and 2). Others have reported the occurrence of sus tained hypoperfusion even after only 2 or 3 min of GBI (Michenfelder and Milde, 1990; Kato et aI., 1990). Michenfelder and Milde (1990) suggested a correlation between duration of ischemia and de gree of hypoperfusion 90 min postischemia. In our study, the hypoperfusion was mild and transient in the 3-min ischemia group. Both the mechanism and importance of postischemic hypoperfusion remain to be established (Steen et aI., 1983; Sakabe et aI., 1986; LaManna et aI., 1988; Tortella et aI., 1989; Hallenbeck and Dutka, 1990). Although CBF/CMR02 between 60 and 120 min postischemia did not differ from baseline in our study or in studies by others, it is unclear whether actual coupling of flow and metabolism is occurring J Cereb Blood Flow Metab. Vol. 12. No.5. 1992
or whether this represents coincident hypoperfu sion and hypometabolism. Fox et aI. (1988) demon strated uncoupling of CBF and CMR02 (hyperemia with an increase in CMRglc but not CMR02) even in the normal brain after peripheral nerve stimulation. Supporting the theory of coupling of CBF and me tabolism, measurements of CMRglc and CBF at 3 h after severe (30 min) GBI also showed concurrent hypoperfusion and hypometabolism with normal CBF/CMRglc (Ueki et aI., 1988; Kocher, 1990). Strongly supporting the theory of coupling of CBF and CMR02 during the postischemic hypoperfusion period, Michenfelder et aI. (1991) showed that in creasing CMR02 via induced hyperthermia 45 min postischemia (after 12 min GBI in dogs) produced a concurrent increase in CBF with maintained CBFI CMR02. In considering whether CBF and CMR are coupled or uncoupled, it is usually assumed that parallel changes in these two variables are indica tions of coupled changes. However, a normal global CBF value does not necessarily indicate normal re gional CBF as the flow distribution may be de ranged despite normal global CBF (Ginsberg et aI., 1979; Pulsinelli et aI., 1982b; Safar, 1986). Beyond 3 h of reperfusion after 20 min of GBI, CBF returned to normal despite the persistence of CMR02 at 50% of normal values, indicating a dis sociation between CBF and CMR02• Delayed hy peremia at 24 h after severe (30 min) GBI, was ob served by Pulsinelli et aI. (l982b) in rats, and a nor malization of CBF despite sustained depression of CMR02 was observed in humans after cardiac ar rest (Beckstead et aI., 1978). In clinical studies it is suggested that absolute hyperemia beyond 24 h af ter GBI indicates severe neurologic damage, partic ularly when associated with a loss of CBF reactivity to changes in Pac02 (Cohan et aI., 1989; Love et aI., 1989). The time course of delayed hyperemia and its re lationship to metabolism has received little study in experimental models of GBI, particularly the period between 3 h and 24 h after ischemia. We observed that global hypoperfusion after 20 min of ischemia resolved as early as 180 min after ischemia, and that secondary uncoupling of CBF and CMR02 oc curred by 180 min (Fig. 3). To our knowledge, this is the first experimental animal study that demon strates the time course of "normalization" of global CBF after postischemic hypoperfusion with the conversion of "delayed" hypoperfusion and hypo metabolism to hyperemia and dissociation of CBF and CMR02• Numerous studies in animal models show a normal ratio of CBF and CMR between 30 min and 180 min after even severe GBI; however, almost invariably, the longest postischemic time for
UNCOUPLED POSTISCHEMIC CBF AND CMR02
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which data is reported is 2-3 h (Snyder et al., 1975; Newberg et al., 1984; Ueki et al., 1988; Michen felder and Milde, 1990). That CBF and CMR02 are again uncoupled as early as 3 h after 20 min of GBI was surprising. Similarly to the time course of the uncoupling of CBF and CMR02 observed in our study, Sims and Pulsinelli (1987) showed that altered mitochondrial respiration did not begin until 3 h after 30 min of GBI in rats. CBF and CMR02 may be coupled early postischemia with subsequent deterioration in mi tochondrial function and uncoupling of CBF and CMR02 beginning about 3-4 h after severe GBI. Although the precise mechanisms involved in the coupling of CBF with CMR remain to be deter mined, locally released metabolites (H +, adeno sine, eicosanoids, neurotransmitters) and extrinsic factors (autonomic tone, input from remote brain areas) are involved (Sokoloff, 1981; Tanaka et al., 1985; Dietrich et al., 1986; Chemtob et al., 1990). The mechanism of the progression of hypoperfusion to relative or absolute hyperemia despite sustained postischemic oxidative hypometabolism remains unknown. Secondary acidosis may contribute to this hyperemia (Kalin et al., 1975). Pulsinelli and Duffy (1983) reported delayed lactate accumulation at 6 h after 30 min of GBI in rats. However, we did not measure CMRglc, tissue pH, or lactate in our study. In conclusion, our results showed (1) the occur rence of hyperemia with hypometabolism and un coupling of CBF and CMR02 at 5 min after either 3 or 20 min of GBI; (2) the development of transient, mild postischemic hypoperfusion between 15 and 60 min after 3 min of ischemia, and delayed postisch emic hypoperfusion with concurrent hypometabo lism between 15 and 120 min in the group with 20 min of GBI; and (3) biphasic uncoupling of CBF and CMR02 during reperfusion only in the group with 20 min of GBI, with delayed recovery of CBF de spite persistent hypometabolism after 180 min. This early reemergence of CBFI CMR02 uncoupling is similar to the clinical setting of prolonged cardiac arrest and resuscitation. CBF and CMR02 are only transiently coupled after severe GBI. Further stud ies may provide additional understanding of the mechanism and prognostic significance of delayed hyperemia with uncoupling of CBF and metabolism after GBI.
editorial assistance. This work was presented at the XVth International Symposium on Cerebral Blood Flow and Metabolism (Brain 91), Miami, Florida, June 2, 1991 and at the Royal College of Physicians and Surgeons of Can ada, Quebec, Canada September 23, 1991.
Acknowledgment: The authors thank Dr. Janine Janosky, Department of Clinical Epidemiology and Pre ventive Medicine for statistical assistance, Drs. Peter Sa far, Katherine Biagas, and Shekhar Venkataraman for suggestions; Janet Santucci, Carleen Heinz, and Becky Gmuer for secretarial assistance; and Nancy Arora for
Michenfelder JD, Milde JH (1990) Postischemic canine cerebral blood flow appears to be determined by cerebral metabolic needs. J Cereb Blood Flow Metab 10:71-76
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