Prolonged hypoperfusion in the cerebral cortex following cardiac arrest and resuscitation in dogs

ORIGINAL CONTRIBUTION brain, blood flow; brain, ischemia; cardiac arrest; resuscitation

Prolonged Hypoperfusion in the Cerebral Cortex Following Cardiac Arrest and Resuscitation in Dogs Increasing cerebral vascular resistance and brain perfusion failure occur within 90 minutes following cardiac arrest and resuscitation. This study followed cortical perfusion for 18 hours after a 15-minute cardiac arrest. Six dogs were anesthetized with ketamine and gallamine and then mechanically ventilated. They were instrumented for arterial pressure, central venous pressure, and regional cerebral cortical blood flow (rCCBF) determined by thermodilution. A left thoracotomy and pericardiotomy were done. 7~vvo dogs served as non-arrest controls. Cardiac arrest was produced in four dogs with an intravenous bolus of KC1 at I mEq/kg. After 15 minutes of cardiac arrest, the animals were resuscitated with internal massage, NaHC03, epinephrine, and internal defibrillation. Cortical blood flow was followed for 18 hours. Arterial core temperature was never less than 35 C. Pre-arrest cortical blood flows were 0.86 cc/min/g (+_ 0.11). The two control animals had stable rCCBF (0.74 +- 0.17) for all determinations during the 18-hour follow-up period. Determinations of rCCBF from 6 to 18 hours in post-arrest animals were 7% to 14% of pre-arrest values. We conclude that the postresuscitation perfusion failure in the cortex is prolonged. A n y potential for neuronal recovery, unless perfusion is protected, would not be realized given this phenomenon. [White BC, Winegar CP, Henderson O, Jackson RE, Krause G, O'Hara T, Goodin T, Vigor DN: Prolonged hypoperfusion in the cerebral cortex following cardiac arrest and resuscitation in dogs. Ann Emerg Med 12:414-417, July 1983.]

INTRODUCTION Recognition of the constant p h e n o m e n o n of progressive and deep hypoperfusion of the cerebral cortex after ischemic-anoxic insults 1-s has been important in the development of new approaches to cerebral resuscitation. 6y We previously demonstrated this phenomenon to be most clearly related to increased vascular resistance, resulting in near-zero cortical perfusion by 90 minutes post-resuscitation following a 20-minute perfusion arrest, s This study was conducted to evaluate cortical perfusion during longer post-resuscitation follow up to determine whether the cortical hypoperfusion syndrome persists over many hours or whether it is a transient phenomenon.

Blaine C. White, MD, FACEP Carl P. Winegar, MD Orzie Henderson, MD Raymond E. Jackson, MD Gary Krause, MD Thomas O'Hara, MD Thomas Goodin, MD David N. Vigor Detroit, Michigan From the Section of Emergency Medicine, Department of Surgery, Wayne State University College of Medicine, Detroit, Michigan. This work was supported in part by Knoll Pharmaceuticals and Jannsen Research Foundation. Submitted for publication April 28, 1982. Revision received March 7, 1983. Accepted for publication March 23, 1983. Address for reprints: Blaine C. White, MD, FACEP, Associate Professor, Section of Emergency Medicine, A-214-D East Fee Hall, Michigan State University College of Medicine, East Lansing, Michigan 48823.

MATERIALS AND METHODS Six mongrel dogs weighing between 20 and 25 kg were anesthetized with intravenous (W)ketamine (7 mg/kg) and gallamine (1 mg/kg). Intubation and volume-controlled ventilation were instituted immediately following anesthetic induction. Anesthesia was maintained with an IV drip of ketamine (2 g) and gallamine (100 mg) in 500 cc normal saline. Procaine penicillin (750,000 U) and streptomycin (250 mg) were given intramuscularly preoperatively. The animals were instrumented for intra-arterial pressure monitoring. Arterial blood gases were determined on an IL-313 blood gas analyzer. Urinary output was monitored by means of an indwelling catheter. Pulmonary arterial (PA) pressures were monitored through a PA catheter inserted via the right jugular vein.

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PROLONGED HYPOPERFUSION White et al

J

Arterial thermal p r o b e - -

Volume = 1 cc Mass = 1 g

~,h

I

Tissue thermal probe

--> Venous blood out

1. The law of specific heat capacity: Heat in an object = temperature of object x mass x K (Kelvin degrees) where K is the specific heat capacity of the object. 2. Tissue mass is overwhelmingly composed of H20, for which K = 1. Therefore in our model: Tissue heat (H T in cal) = Tissue temp (TT in K) x 1 g. 3. By conservation of energy, change in tissue heat (dHT) in an instant of time (dt) is equal to: a. Heat brought in by arterial blood (dHBI), b. Plus heat produced in the tissue by metabolism (Ha x dt where HM is cal/sec/g), c. Minus heat carried out in the venous blood (dHao). 4. From equation (F x dt where 5. Therefore dHT 6. AS before 8 we

Thus dHT = dHBi + (HM X d t ) - dHBo. 1 the heat carried in by the arterial blood is the arterial temperature (TA) multiplied by its mass F is flow rate in cc/sec/g). This statement also holds for venous blood temperature (Tao) and dHBo. = TA X F x dt + (HM X dt) - TBO X F × dt. assume that thermal equilibration occurs instantaneously between the tissue and perfusing blood and

TBO = TT. 7. Because equation 5 cannot be solved for flow with HM an unknown variable, we will examine this constant in the steady state before the cold saline infusion. At this time, with dHT = 0, HM = F × (TTo -- TAo). 8. Substituting equations 6 and 7 into equation 5 and dividing both sides by the 1-g mass yields: dTT = (F/g x TA × dt) + (F/g x [TTo -- TAo] × tit) - (F/g x TT X dt) 9. Integrating both sides of equation 8 between the limits of time 0 (t = 0) before the beginning of the saline infusion and time n (t = n) at the end of the saline infusion yields: TTn -- TT 0 = F/O x (ATA + tn X (TT0 -- TA0 ) -- ATF) where (see Figure 2): a. ATA = area under arterial temp curve during infusion, b. ArT = area under tissue temp curve during infusion, and c. tn x (TTo - TAo) is the area between the two curves resulting from the metabolic heat produced by the brain.

10. F (in cc/sec/g) =

TTo -

TTn

A ~ - ATA -- (tn + (TTo -- TA0)) This equation for organ perfusion is equivalent to: F =

Drop in brain temperature

Area opened between the brain and arterial temperatures and is similar to that used for dye dilution cardiac output, except that here the indicator is temperature instead of dye concentration.

Fig. 1. M a t h e m a t i c a l model. This mathematical model was developed to determine tissue blood flow using simultaneous measurement of arterial and tissue temperature during an IV infusion of cold saline. The model examines heat exchange and blood flow in the 1 g of tissue under the tissue thermal probe, as illustrated. 14/415

Determination of rCCBF We have previously described a t h e r m o d i l u t i o n t e c h n i q u e for determination of regional cerebral cortical blood flow (rCCBF) in the parietal cortex, s This technique was m o d i f i e d (Figure 1) to a l l o w determination of rCCBF by venous infusion of cold saline (rather than by carotid arterial injection s ) in this proAnnals of Emergency Medicine

longed study of post-arrest cortical perfusion. A Yellow Springs Instrument (YSI) #511-X thermistor was introduced into a femoral artery through a 20gauge angiocath. A YSI #532 brain thermal probe was incorporated into a Richmond head bolt with the thermistor extending 4 m m beyond the tip of t the bolt. A standard bolt hole was 12:7 July 1983

Brain Temperature -

Fig. 2. Schematic of data from rCCBF determination using cold saline infusion from a peripheral vein, and simultaneous recording of arterial and cerebral cortical temperatures. The f l o w (F) is inversely related to the area which is crosshatched, and directly related to the difference between TTo and TT at "n." T_To = brain temperature just before the beginning of the infusion. TAo = arterial temperature just before the beginning of the infusion. The clear area between the two data curves is due to the heat of cerebral metabolism. ATA denotes the area under the arterial curve.

-

Arterial Temperature 38 C

37 C

~

~

~

'

'

"

~

Area = ATA ] /

36 C

Fig. 3. Flow and arterial brain temperature difference (ABTd).

i

60 120 Seconds of 0 Degree Saline Infusion (4 cc/kg)

180 2

1. Pre-arrest: Flow -- 0.86 mL/min/g _+ 0 . 1 1

ABTd = 0.18 C _+ 0.03

2. Mean control animal values for all measurements during the 18-h observation period: Flow = 0.74 _+ 0.17 mL/min/g ABTd = 0.16 C _+ 0.05 3. Post resuscitation: Time (h) Flow 6 0.09 mL/min/g _+ 0.06 12 0.12 mL/min/g _+ 0.08 18 0.06 mL/min/g _+ 0.04

drilled in the parietal skull. Bone bleeding was carefully controlled with bone wax, and the dura was then opened 2 m m under direct vision. The blunt brain thermistor was then introduced into the surface of the cortex by installation of the bolt. Both the thermistors were connected to calibrated YSI thermocomputers. Temperatures from both brain and arterial probes were recorded initially and then during a three-minute IV infusion by Harvard pump of 4 cc/kg of saline at 2 C (Figure 2). The thermal data were integrated by an Apple II computer which was programmed to solve the differential equation (Figure 1) for blood flow {mL/min/g).

Experimental Procedure Pre-arrest flow determinations were 12:7 July 1983

ABTd 0.02 C _+ 0.01 0.01 C _+ 0.01 0.01 C _+ 0.01

carried out at a PCO2 of 40 torr and a PO2 t> 100 torr. A left lateral thoracotomy was then performed using sterile surgical technique. Two dogs were not subjected to arrest, and served as controls for stability of rCCBF. Cardiac arrest was initiated in four dogs by administration of KC1 1 mEq/kg by IV bolus. Ventilation and anesthesia were stopped, and full cardiopulmonary arrest was left untreated for exactly 15 minutes. The pericardium was opened widely early in the arrest period. After 15 minutes of cardiopulmonary arrest, ventilation with 100% O2 was resumed, and internal cardiac massage was begun. NaHCO3 was given in a dose of 10 mEq/kg IV. Epinephrine was administered by a rapid continuous drip of a solution of 3 mg epinephrine in 500 cc DsW. DeAnnals of Emergency Medicine

fibrillation using 20 to 40 joules was administered with internal paddles after five to six minutes of internal massage. After restoration of spontaneous heart beat and arterial pressure, the epinephrine drip was discontinued. Thereafter, a HALFD fluid regimen 9 and dopamine, 800 mg in 500 cc DsW (drip at less than 15 ~xg/kg/min), was used to maintain a systolic blood pressure of at least 150 m m Hg. All animals were given 40 mg gentamicin IVPB post resuscitation. A thoracostomy tube with a Heimlich valve was placed in the left thorax, and the thoracotomy was closed. P o s i t i v e end e x p i r a t o r y pressure (PEEP) at 2 to 5 cm was used together with supplemental O2 as required to support arterial PO~ at 80 torr. Ventilator volume adjustments were made as necessary to maintain PCO2 between 35 and 45 torr. Flow studies to determine rCCBF were done at 6, 12, and 18 hours post resuscitation and at the same time in controls. PEEP was discontinued by 4 to 5 hours post resuscitation in all animals. RESULTS All animals were resuscitated within seven minutes after internal massage was begun. Peak systolic pressures of 100 to 150 m m Hg were consistently produced during the internal massage. No metabolic alkalosis was ever

seen.

Flow and arterial brain temperature difference (ABTd) data from the study are shown (Figure 3).

DISCUSSION Our data demonstrate a deep and 416/15

PROLONGED HYPOPERFUSION White et al

prolonged hypoperfusion of the cerebral cortex f o l l o w i n g r e s u s c i t a t i o n from 15 m i n u t e s of c o m p l e t e cardiopulmonary arrest. As we have previously reported, s this hypoperfusion p h e n o m e n o n begins w i t h i n 20 minutes post resuscitation, and cortical perfusion rates are near zero within 90 minutes. The data reported here provide evidence that this perfusion failure persists over 18 hours. Hayward 1° has previously reported t h e n o r m a l ABTd data and demonstrated that this thermal difference is reduced w i t h increased organ perfusion rates, as our m a t h e m a t i c a l model predicts {Figure 1, equation 7). Our data post arrest, however, demonstrate both sharply decreased perfusi0n and loss of normal ABTd. Our model {Figure 1, e q u a t i o n 7) m a y be u s e d to argue t h a t the observation that the brain has become isothermic w i t h the arterial blood reflects profound failure of heat-producing m e t a b o l i s m in the cortex. Wauquier et a111 have recently reported similar observations and also protection of the n o r m a l brain heat production by the Ca2+ antagonist, flunarizine. Other investigators have been unable to detect platelet thrombi or fibrin in cerebral small vessels during the reperfusion failure following ischemic-anoxic global brain insults. 12 These data, and the failure of heparin to a m e l i o r a t e the hypoperfusion, s,13 argue against a p r i m a r y role for intravascular coagulation in the path ° o p h y s i o l o g y of t h e p o s t - i s c h e m i c anoxic cerebral hypoperfusion. A l t h o u g h w e d i d n o t m e a s u r e intracranial pressure (ICP) in these exp e r i m e n t s , other i n v e s t i g a t o r s have r e p o r t e d m i n i m a l ICP c h a n g e s for t h e first 24 h o u r s f o l l o w i n g global ischemic-anoxic brain injury. 14,1s Studies in our laboratories 16 and by Hoffmeister et al 7 and Steen et a117 d e m o n s t r a t e t h a t use of Ca2+ antagonists can p r o t e c t n o r m a l postr e s u s c i t a t i o n cortical perfusion and resistance and produce a rapid diminution of neurologic deficit. 16 Thus the aggregate data suggest that the early pathogenesis of post resuscitation cortical hypoperfusion occurs due to increased vascular resistance due to Ca 2 + entry into the vascular cells. 6'7'11'16-21 Clinicians are familiar with the rule "no flow = no organ," which arises directly from the i m p l i c a t i o n s of the second law of thermodynamics. The d e m o n s t r a t i o n of a p h e n o m e n o n of prolonged cortical hypoperfusion 16/417

following global cerebral i s c h e m i c anoxic insults is thus by itself adequate reason for post-arrest encephalopathy. D e m o n s t r a t i o n s t h a t this h y p o p e r f u s i o n s y n d r o m e a n d acc o m p a n y i n g loss of brain m e t a b o l i c heat production can be interrupted by Ca2+ blockers, such as flunarizine, are encouraging; however, several other questions arise in view of the prolonged hypoperfusion demonstrated in this study. H o w long will a single dose of Ca2+ antagonist protect cerebral resistance and perfusion? Are repeat doses necessary? D o t h e Ca2+ antagonists have direct n e u r o n a l protective effects, apart from perfusion protection? 12,2°,21 Finally, in terms of u l t i m a t e clinical application, are we going to need routine rCCBF monitoring early in the post-resuscitation period to identify and interdict the phen o m e n o n of cerebral hypoperfusion? CONCLUSION Resuscitation from prolonged cardiopulmonary arrest is'followed by a progressive hypoperfusion s y n d r o m e in the cerebral cortex. Cerebral cortical blood flow remains less than 20% of normal through 18 hours post resuscitation. This p h e n o m e n o n is probably primarily due to increased vascular resistance, and is in itself a logically sufficient explanation for extensive damage to the cortex. The depth and duration of this p h e n o m e n o n m a y require routine cerebral m o n i t o r i n g to guide therapy directed at amelioration of ischemic-anoxic brain injury.

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arrest. Ann Emerg Med 11:119-126, 1982. 7. Hoffmeister F, Kazda S, Krause HP. Influence of nimodipine on the post ischemic changes of brain function. Acta Neurol Scand 60(Suppl 72):358-359, 1979. 8. Hoehner PJ, Krause G, White BC, et al: Determination of cerebral cortical blood flow: A thermal technique. Ann Emerg Med 12:2-7, 1983. 9. Jelenko C, Solenberg RI, Wheeler ML, et al: Shock and resuscitation III: Accurate refractiometric COP determinations in hypovolemia treated with HALFD. JACEP 8:253-259, 1979. 10. Hayward JN: Cerebral cooling during increased cerebral blood flow in the monkey. Proc Soc Exp Biol Med 124:555-560, 1967. 11. Wauquier D, Ashton C, Clinke G: Pharmacological effects in protective and resuscitative models of brain hypoxia, in Hoyer, Wiedemann (eds): Workshop on Problems and Perspectives of Brain Protection. Heidelberg, Germany, Springer Verlag, 1982. 12. Chiang J, Kowade M, Ames A, et al: Cerebral ischemia III: Vascular changes. Am J Path(}] 52:455-464, 1968. 13. Fischer EG, Ames A: Studies on mechanisms of impairment of cerebral circulation following cerebral ischemia: Effect of hemodilution and perfusion pressure. Stroke 3:538-547, 1972. 14. Safar P: Resuscitation after brain ischemia. Clinics in Critical Care Medicine 2: 155-167, 1981. 15. Langfitt TW: Increased intracranial pressure, in Youmans JP {ed}: Neurologic SurgeG Philadelphia, WB Saunders, 1973. 16. Winegar CD, Jackson RE, White BC, et al: Early amelioration of neurologic deficit by lidoflazine in clogs after 15 minutes of cardiopulmonary arrest. Ann Emerg Med, in press. 17. Steen PA, Newberg LA, Milde Aid, et al: N i m o d i p i n e i m p r o v e s CBF and neurologic recovery after complete cerebral ischemia in the dog. Journal of Cerebral Blood Flow and Metabolism, in press. 18. Borgers M: Calcium in cellular function. American Journal of Emergency Medicine, in press. 19. Van Neuten JM, Vanhoutee PM: Improvement of tissue perfusion with inhibitors of calcium ion influx. Biochem Pharmacol 29:479-483, 1980. 20. Hass WK: Beyond cerebral blood flow, metabolism and ischemic thresholds: An examination of the role of Ca2+ in the initiation of cerebral infarction, in Proceedings of the Saltzburg Conference on Cerebral Vascular Disease: Cerebral Vascular Disease, vol 3. Amsterdam, 1981. 21. Siesjo BK: Cell damage in the brain: A speculative synthesis. Journal of Cerebral Blood Flow and Metabolism 1:155-173, 1981. 12:7 July 1983