Potassium and the pathogenesis of cerebral arterial spasm in dog and man. intraeranial arterial spasm cerebrospinal fluid

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1 Potassium and the pathogenesis of cerebral arterial spasm in dog and man ROBERT H. WILKINS, M.D., AND PHILIP LEVITT, M.D. Division of Neurosurgery, Duke University Medical Center attd the Durham Veterans A dministration Hospital, Durham, North Carolina This study investigates the possibility that the intracranial arterial spasm occurring in patients with subarachnoid hemorrhage might be due to potassium released from blood clots surrounding the involved cerebral arteries. Although cerebral arterial spasm could be induced in the dog by the injection of potassium into the chiasmatic cistern, it only occurred with potassium concentrations higher than those expected to result from hemolysis of subarachnoid clots. Furthermore, the potassium concentrations were not elevated in the cerebrospinal fluid of human patients with subarachnoid hemorrhage, and the individual potassium values could not be correlated with the presence or degree of spasm encountered in these patients. KEY WORDS potassium intraeranial arterial spasm cerebrospinal fluid suharaehnoid hemorrhage I T has been postulated that the intracranial arterial spasm associated with subarachnoid hemorrhage may be initiated by some chemical agent or agents released from the blood clot surrounding the involved cerebral arteries. Logically, one such substance might be potassium, since potassium is liberated from erythrocytes during hemolysis, and is known to have vasomotor effects. 6''4'6'~s In addition, it has been reported that the potassium level is significantly elevated in the xanthochromic cerebrospinal fluid from patients with "h~morragies m6ningo-enc6phalique. '' We have investigated this possibility in two ways. First, we have induced cerebral arterial spasm in dogs by injecting potassium solutions of varying concentrations into the chiasmatic cistern, and, second, we have measured the potassium levels in the cerebrospinal fluid (CSF) of a series of patients with subarachnoid hemorrhage. Materials and Methods Mongrel dogs of both sexes, weighing between 3 and 45 lbs. were anesthetized with intravenous sodium pentobarbital ( mg per lb body weight). After endotracheal intubation, the dogs either were allowed to breathe spontaneously or were paralyzed with intravenous succinylcholine chloride and ventilated with a respirator. Injections of sterile fluid were made into the chiasmatic cistern over to 5 sec by the method of McQueen and Jeanes 9 or that of Lougheed and Tom. 7 Evans blue* was added to the injected fluids to permit postmortem verification that each injection had reached its intended destination. The few animals in which the needle insertion accidentally caused subarachnoid hemorrhage were discarded from the study, as were the dogs in * Evans Blue Injection, USP, Warner-Chilcott, Morris Plains, New Jersey. Y. Neurosurg. / Volume 35 / July, 97 45

2 Robert H. Wilkins and Philip Levitt which the fluid injections did not enter the chiasmatic cistern. In the first series of experiments (Group A), the ml of injected fluid consisted of distilled water (containing no preservatives) to which a potassium chloride (KC) solution* and. to. ml of Evans blue dye were added just prior to injection. In the second series of experiments (Group B), the fluid for injection was also prepared just prior to injection. Approximately 7 to mg of human fibrinogent were dissolved in 5 ml of water, and units of bovine thrombin~ were dissolved in ml of water. Then. to. ml of KC and. ml of Evans blue were added to the fibrinogen solution. During the experiment, the following solutions were injected into the chiasmatic cistern in sequence:. ml of fibrinogen (with KC and Evans blue),.5 ml of distilled water,.5 ml of thrombin, and.5 ml of distilled water. In vitro, this resulted in a blue fibrin clot within rain. The dogs were monitored for hours with repeated carotid arteriography and continuous systemic arterial blood pressure measurements, electroencephalography, and electrocardiography, and were examined pathologically, as described previously. ~3 The potassium concentrations in human and canine fluids were determined by flame photometry. 3 By the same technique, the solutions of fibrinogen, thrombin, and Evans blue used in the cisternal injections were found to contain less than. meq/l of potassium. Results Injection of Potassium Solutions into the Chiasmatic Cistern of Dogs Group A: Potassium Chloride in Distilled Water. Thirteen dogs received chiasmatic injections of distilled water containing potassium chloride and Evans blue. Usually there was a transient bradycardia and hypotension of moderate degree near the end of the injec- * Potassium Chloride 4 meq; Abbot Laboratories, North Chicago, Illinois. t Fibro-AHF: Merck Sharp & Dohme, West Point, Pennsylvania. Thrombin, Topical; Parke, Davis & Company, Detroit, Michigan. tion, with a gradual return of the pulse rate and blood pressure to normal over seconds to minutes. ~ Typically, if the dog had not been paralyzed with succinylcholine chloride, it had a tonic seizure that began during the injection and lasted from to 6 sec. During this period the electroencephalogram (EEG) was marred by muscle contraction artifact. The EEG tracings of the dogs that received to 5 meq/l of potassium were wise unchanged, but the tracings of the dogs given to meq/l also frequently showed a transient diminution of wave frequency and amplitude for a few minutes after the muscle artifact had subsided. The most frequent change on the electrocardiogram (EKG), aside from bradycardia, was transient depression or elevation of the T waves. Occasional changes in the configuration of the P waves and QRS complex were also noted, and U waves appeared in the tracing of one dog. Two dogs had premature ventricular contractions, leading in one to a temporary run of ventricular tachycardia followed by a bigeminy rhythm. These various electrocardiographic abnormalities occurred only in the dogs given potassium in a concentration of or meq/l. Cerebral arterial spasm was produced primarily by solutions containing or meq/l of potassium chloride. The spasm ordinarily was maximal within 5 min after the injection, and diminished within hours. Pathological examination showed that the Evans blue disappeared from the subarachnoid spaces within a few hours as the dura mater lining the base of the skull became stained blue. None of the animals was found to have subarachnoidal, intracerebral, or intraventricular hemorrhage as a result of the injection. Group B: Potassium Chloride in an Artificial Fibrin Clot. In Group A, discussed above, the Evans blue (and probably the potassium as well) disaopeared from the basal cisterns relatively quickly, and the arterial soasm regressed at the same time. In Group B, an attempt was made to keep the potassium localized about the circle of Willis by adding it to an artificial fibrin clot formed bv the sequential injection of fibrinogen and thrombin solutions into the chiasmatic cistern. Evans blue was added to mark the lo- 46 d. Neurosurg. / Volume 35 / duly, 97

3 Potassium and cerebral arterial spasm cation of the fibrin clot so that it could be recognized more easily at postmortem examination. Autopsies of the 7 dogs in Group B showed the blue clot to be well localized in the subarachnoid spaces about the circle of Willis initially. However, the clot usually was dissolved within to days. Control Animals. Nine dogs received the fibrinogen, thrombin, and Evans blue solutions to which no potassium chloride was added. Of the three dogs given 3.5 ml injections, each had a striking tonic seizure during the injection with deviation of the head to the side and with marked salivation. Each developed an immediate bradycardia and hypotension, as in Group A, but this was followed in two dogs by a period of marked hypertension, lasting 8 and 3 min respectively. On EKG, one of the three dogs developed peaked T waves, premature ventricular contractions, and a bigeminy rhythm. An developed a bigeminy rhythm without the changes. None of the nine control dogs developed cerebral arterial spasm. At autopsy, none was found to have intracraqial hemorrhages as a result of the injection. In four of them, sacrificed a few hours after injection, cross sections of the cerebral arteries were examined microscopically. No abnormalities were noted aside from very mild adventitial inflammation. Experimental Animals Receiving Potassium Chloride. These 8 dogs were given KC in varying concentrations in addition to the fibrinogen, thrombin, and Evans blue. Typically, each dog had a tonic seizure during and shortly after the injection, sometimes with tonic head deviation and hvpersalivation. Their EEG patterns and cardiovascular responses were similar to those of the does. However, their EKG tracings showed more striking changes. With increasing potassium concentrations there was a tendency toward the increased occurrence of T wave changes, ST segment depression, premature ventricular contractions, bigeminy rhythm, and ventricular tachvcardia. Arteriographic evidence of spasm was not seen in the two does that were given potassium in a concentration of meq/l, and in only three of the seven given 6 meq/l. In comparison, spasm was noted in all of the nine dogs given to meq/l of potassium. As in the dogs, no intracranial hemorrhages were noted at autopsy. In five of the 8 dogs, sacrificed a few hours after the injection, cross sections of the cerebral arteries were examined microscopically. During life, four of these five had developed cerebral arterial spasm. Histologically the arteries appeared normal aside from mild adventitial inflammation (i.e., they appeared the same as the arteries from the four control dogs). Potassium Determinations in Dogs In 8 dogs, the potassium concentrations of whole blood were determined after the red blood cells had been hemolyzed by the addition of distilled water. The values, corrected for dilution, varied between 3.6 and 7. meq/l. The blood potassium levels were again measured several times in four of these dogs over a -hour period after the injection of 6,, or meq/l of potassium (with fibrinogen, thrombin, and Evans blue) into the chiasmatic cistern. There was a transient mild rise in the blood potassium value of to meq/l associated with the cisternal injection. In four normal dogs, the potassium concentrations in the CSF (removed by antemortem puncture of the cisterna magna) were 3., 3., 3., and 3. meq/l. Potassium Determinations in Humans The potassium concentrations in the whole blood of five patients with various disorders were 38, 38, 4, 4, and 43 meq/l. Potassium concentrations were measured in the CSF of 7 patients (Table ). The bloody CSF samples were centrifuged first, and only the supernatant fluid was tested. There appeared to be no correlation between the CSF or serum ootassium concentration and the presence or degree of CSF xanthochromia or cerebral arterial spasm. In one patient, the CSF potassium levels were measured daily for 7 days. Initially the CSF was slightly xanthochromic; it became clear and colorless after days. The potassium values varied between.4 and.8 meq/l, with no apparent relationship to the degree of xanthochromia. I. Neurosurg. / Volume 35 / July, 97 47

4 m m m Robert H. Wilkins and Philip Levitt TABLE Potassium levels in human CSF Diagnosis Degree of CSF Xanthochromia* Degree of Cerebral Arterial Spasm*~ CSF K + (meq/l) Serum K + (meq/l) t Controls (5 patients) dementia dementia hydrocephalus m yelopathy seizures brachial plexus injury headaches psychoneurosis 3, ~ubarachnoid Hemorrhage patients) * Degree ofcsf xanthochromia and of cerebral arterial spasm was graded according to the following system: =none; I =slight trace; =mild; 3 =moderate; and 4 =marked. t Evaluation was done within day of lumbar puncture. Discussion. Is the intracranial arterial spasm that occurs in patients with subarachnoid hemorrhage caused by potassium released from blood clots in the basal subarachnoid cisterns? The concentrations of potassium found in canine and human blood and CSF in the present experiments are consistent with the values reported by investigators.,3,~,7,8a~76 The canine red blood cell contains only about meq/l of potassium, ~ so hemolysis of dog blood does not raise its potassium level much above the meq/l level found in canine plasma.,~ In contrast, the human erythrocyte contains an estimated 36 meq/l, 5 and hemolysis of human blood will raise the potassium level approximately times higher than the 3.6 to 5.5 meq/l levels found in normal human plasma? In our dogs, cerebral arterial spasm could be induced by the injection of potassium solutions into the chiasmatic cistern. This spasm was arteriographically identical to that caused by the similar injection of autogenous whole blood. 3 However, in order to produce significant arterial spasm, we had to 48 J. Neurosurg. / Volume 35 / July, 97

5 Potassium and cerebral arterial spasm inject potassium concentrations in excess of 5 meq/l. Furthermore, the CSF potassium values in our patients could not be correlated with the presence or degree of CSF xanthochromia (in disagreement with results of one previous study, ~ but consistent with the results of an ~~ or cerebral arterial spasm. These facts make it unlikely that cerebral arterial spasm is due to the liberation of potassium from dissolving blood clots about the major cerebral arteries. This is especially true in the dog, in which whole blood contains relatively little potassium. However, in the human this mechanism still cannot be discounted entirely since hemolysis within the depths of a periarterial clot might release potassium in local concentrations up to 36 meq/l without influencing the level of potassium in the CSF.. Are the EKG changes that occur in patients with subarachnoid hemorrhage caused by potassium released from subarachnoid blood clots? Potassium is essential to the normal function of the heart, and abnormal levels of circulating potassium have profound effects on cardiac physiology and the electrocardiogram. 4,4,ls,4 With increasing levels of serum potassium, the canine EKG changes in predictable steps. For example, in lead II, the T waves become tall in amplitude and short in duration at serum potassium concentrations of 5 to 7 meq/l. Depression of the ST segment appears at 8 to meq/l, intraventricular block begins at about meq/l, the P waves disappear at 9 to meq/l, and cardiac arrest occurs at 4 to 6 meq/ L. 4 Characteristically, as the intraventricular block develops, rapid ectopic rhythms and a fast or slow idioventricular rhythm with QRS widening also occur. Some of these changes were observed in our dogs, especially in those given subarachnoid potassium injections of or meq/l. However, these changes occurred more frequently and to a greater degree in the dogs given fibrinogen and thrombin (which contains virtually no potassium) in addition to the KC, and they also occurred in the control dogs given only fibrinogen and thrombin. Therefore, we could not establish a direct relationship between the potassium injected and the EKG changes that resulted from the injection. Furthermore, there was no indication that serum potassium levels were elevated by the subarachnoid injections to an extent capable of causing significant EKG changes. In any event, the electrocardiographic abnormalities associated with subarachnoid hemorrhage (primarily T wave distortions, U waves or TU fusion waves, prolongation of the QT interval, or elevation of the ST segment, without intraventricular block or P wave changes ) are somewhat different from those encountered in the present experiments and from those expected from hyperkalemia. Also, serum concentrations of potassium in our patients, and in those reported by s, 9 are not elevated in association with subarachnoid hemorrhage. For these reasons, we think that it is unlikely that the EKG changes occurring in patients with subarachnoid hemorrhage are due to potassium released from subarachnoid blood clots. Summary We have hypothesized that the intracranial arterial spasm that frequently occurs in patients with subarachnoid hemorrhage might be due to potassium released from blood clots surrounding the involved cerebral arteries. However, our investigations, involving 44 dogs and 3 human patients, have not supported this hypothesis. Acknowledgments The authors thank Mr. Ezra Hayes, Mrs. Nancy Bouknight, and Dr. Robert L. Habig for their technical assistance. References. Altman PL, Dittmer DS (eds): Blood and Other Body Fluids. Washington, D C, Federation of American Societies for Experimental Biology, 96, pp,, 9, 3, 35, 35. Ballif L, Gherscovici I: Le ph du liquide c~phalorachidien et dosage du potassium rachidien dans le diagnostic des h6morragies m6ningo-enc~phaliques. C R S6anc Soc Biol 9:3-33, Bekaert J, Demeester G: Influence of the potassium concentration of the blood on the potassium level of the cerebrospinal fluid. Exp Med Surg :48--5, Bellet S, Gazes PC, Steiger WA: The effect of potassium on the electrocardiogram in the normal dog and in dogs with myocardial infarction. Amer J Med Sci :37-46, Bernstein RE: Potassium and sodium balance I. Neurosurg. / Volume 35 / July, 97 49

6 Robert H. Wilkins and Philip Levitt in mammalian red cells. Science NY : , Bohr DF: Electrolytes and smooth muscle contraction. Pharm Rev 6:85-, Bradbury MWB, Stubbs J, Hughes IE, et al: The distribution of potassium, sodium, chloride and urea between lumbar cerebrospinal fluid and blood serum in human subjects. Clin Sci 5:97-5, Breyer U, Kanig K: Cerebrospinal fluid electrolyte disturbances in neurological disorders: with special reference to inorganic phosphate. Neurology (Minneap) :47-53, Buckell M, Richardson A, Sarner M: Biochemical changes after spontaneous subarachnoid haemorrhage. Pt. II. The patient on admission. $ Neurol Neurosurg Psychiat 9:93-98, 966. Cooper ES, Lechner E, Bellet S: Relation between serum and cerebrospinal fluid electrolytes under normal and abnormal conditions. Amer J. Meal 8:63-6, 955. Dees JE: Coagulum pyelolithotomy. Trans Amer Ass Genitourin Surg 46:5-, 954. Friedman SM, Friedman CL: Effects of ions on vascular smooth muscle, in Field J (ed): Handbook of Physiology: A Critical, Comprehensive Presentation of Physiological Knowledge and Concepts. Washington, D C, American Physiological Society, 963, Section, : Helmsworth JA: Potassium content of normal cerebrospinal fluid. J Lab Clin Med 3:486-49, Katz LN, Lindner E: The action of excess Na, Ca and K on the coronary vessels. Amer J Physiol 4:55-6, Kem~ny A, Boldizs~ir H, Pethes G: The distribution of cations in plasma and cerebrospinal fluid following infusion of solutions of salts of sodium, potassium, magnesium and calcium. J Neurochem 7:8-7, Levowitz BS, Kamil N, Goldson H, et al: Vascular responses to potassium ion. Surg Gyn Obstet 9: , Lougheed WM, Tom M: A method of introducing blood into the subarachnoid space in the region of the circle of Willis in dogs. Can J Surg 4:39-337, McKeever WP, Braun H, Coder D, et al: The local effect of potassium on different segments of the coronary vascular bed. Clin Res 8:88, 96 (abstract) 9. McQueen JD, Jeanes LD: Influence of hypmia on intracranial hypertension. J Neurosurg 9:77-88, 96. Shaw CW, Holley HL: Sodium and potassium concentration in human cerebrospinal fluid. I. Normal values. $ Lab Clin Med 38: , 95. Walker SM, Smolik EA, Gilson AS Jr: The effects of intracisternal injection of potassium phosphate on the rate and rhythm of the heart and on the blood pressure and on the respiration of the dog. Amer J Physiol 45:3-38, 945. Wilkins RH, Alexander JA, Odom GL: Intracranial arterial spasm: a clinical analysis. J Neurosurg 9:-34, Wilkins RH, Levitt P: Intracranial arterial spasm in the dog: a chronic experimental model. $ Neurosurg 33:6-69, Winkler AW, Hoff HE, Smith PK: Electrocardiographic changes and concentration of potassium in serum following intravenous injection of potassium chloride. Amer J Physiol 4: , 938 Received for publication July 6, 97. Address reprint requests to: Robert H. Wilkins, M.D., Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina g. Neurosurg. / Volume 35 / July, 97