JOURNAL OF SURGICAL RESEARCH 18, 447-450 (1975)

Intracranial Pressure, Behavioral and Electrophysiological

Observations in Experimental Intracranial Hypertension

L. F. MARSHALL, M.D., F. DURITY, M.D., F. WELSH, PH.D., H. E. JAMES, M.D., AND T. W. LANGFITT, M.D.

Division of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Submitted for publication November 14, 1974

Recent investigations of cerebral ischemia produced by intracranial hypertension or systemic circulatory arrest have delineated the metabolic and morphologic conse- quences of cerebral ischemia [l-5, 121. But little attention has been paid to the be- havioral consequences of these ischemic in- sults. Neeley and Youmans [ 111 found that dogs which had been subjected to an ele- vation of the intracranial pressure above the systemic arterial pressure survived more than 48 hr. They were able to see, stand, and hear the day after the insult. Kramer and Tuyman [8] using an identical preparation presented evidence that if the period of com- plete cerebral ischemia was limited to less than 15 min a few animals would recover almost complete neurological function. However, if the period of ischemia was car- ried even 1 or 2 min beyond 15 min, recovery of function did not occur in any animal and restitution of electrical activity was poor. In contrast to these findings, Hossman and Kleihues [7] using cephalic vessel clamping, produced complete cerebral ischemia for as long as 60 min and reported recovery of complete neurological function in one animal and good recovery in several others. Furthermore, in that same series of experi- ments, the authors also suggested that ani- mals in which the ischemic insult was not complete (accidental cerebral oligemia) did more poorly than animals subjected to com- plete cerebral ischemia. Since this finding was at such variance with the traditional view of the brain’s vulnerability to ischemia,

it seemed important as part of a larger study of the effects of cerebral oligemia and isch- emia produced by intracranial hyperten- sion, to examine the behavioral and elec- trophysiological consequences of an oligemic or ischemic insult.

MATERIALS AND METHODS Fifteen albino, adult rabbits weighing 2.5-

4 kg were anesthetized with pentobarbital20 mg/kg. After tracheostomy the animals were ventilated with a Harvard small-animal respirator using a mixture of 50% oxygen and 50% nitrous oxide. Silastic femoral arterial and venous catheters were inserted and the SAP was continuously recorded on a Hewlett Packard multichannel recorder. The animals were paralyzed with Flaxedil (galamine triethyl iodide) triethiodide 4.50 mg/kg and placed prone with the head sup- ported in the stereotaxic head holder. A 22- gauge double-lumen needle was introduced into the cisterna magna for measurement of the ICP and for infusion of mock CSF. The EEG was continuously recorded on a Grass 8 channel inkwriting electroencephalograph from four bipolar needle electrodes placed in the frontal and parietal regions bilaterally. During the experiments the arterial PCo, was maintained between 38 and 42 torr ex- cept in those animals permitted spontaneous hyperventilation during the first hour of restitution after cerebral oligemia or isch- emia. The arterial PO, was maintained at greater than 90 torr throughout the entire experiment.

447 Copyright 0 1975 by Academic Press, Inc. All rights of reproduction in any form reserved.

448 JOURNAL OF SURGICAL RESEARCH VOL. 18, NO. 4, APRIL 1975

The mock CSF used was warmed to 37°C and buffered to a pH of 7.4 prior to infusion and the volume required to produce oligemia or ischemia recorded. The arterial pressor response which occurred in every animal at initiation of a rising ICP was controlled with Arfonad (trimethapan camphor-sulfonate), and when necessary the SAP was supported with intravenous angiotensin. Animals in which the systolic SAP fell below 80 torr were excluded and care was taken to avoid systemic hypertension which was defined as a blood pressure greater than 160 torr during restitution.

Group I (n = 3) served as controls. Oligemia (Group II, n = 6) was produced by abruptly elevating the ICP to within 20 torr of the systolic SAP and maintaining this level of perfusion for 15 min. The infusion was abruptly terminated at 15 min and the ICP allowed to fall spontaneously. In three oligemic animals a normocapnic state was maintained by unparalyzed controlled venti- lation to a near normal PACO, for the first hour after the insult. In three other oligemic animals spontaneous hyperventilation was permitted during the first hour of restitution, and the animals were taken off the ventilator as soon as satisfactory spontaneous venti- lation occurred. Complete ischemia (Group III, n = 6) was produced by rapidly elevating the ICP to 20 torr above systolic SAP for 15 min followed by restitution of a normal cere- bral perfusion pressure as in Group II. The ischemic animals were also divided into two groups. In three ischemic animals a normocapnic state was maintained by un- paralyzed controlled ventilation and in the remaining three animals spontaneous hyper- ventilation was permitted during the first hour of restitution. The cornea1 reflex, pupillary light reflex and response to painful stimulation were assessed and any spon- taneous movements were noted every 15 min during the hour of controlled ventilation, and for 3 hrs of restitution under conditions of spontaneous ventilation, if possible. Ani- mals that did not require respiratory or arterial pressure support after 4 hr of

recovery were observed continuously for righting movements, feeding and drinking behavior, and response to auditory stimuli until death occurred.

RESULTS Intracranial Pressure

The intracranial pressure fell rapidly at the termination of the infusion. By 5 min postoligemia or postischemia the in- tracranial pressures were almost identical 14.8 f 5.2 torr in the former and 15.9 f 8.5 in the latter. By 1 hr the ICP in the post- oligemic or postischemic animals never exceeded 7 torr and thus did not differ significantly from the control animals (mean ICP = 6.1 =t 1.4 torr).

Electrophysiological Observations

The EEG became isoelectric later, 26.0 f 4.4 set in oligemic animals than in ischemic animals (9.7 f 3.2 set P < 0.05). Recovery of the EEG was defined as return of large amplitude slow-wave activity present in all four leads. Significant differences in recovery between the groups as a whole did occur (oligemia 35.7 f 6.7 min vs ischemia 71.9 f 13.1 min at P < 0.05). Although there was a trend toward earlier recovery of electrical activity in spontaneously hyperventilating animals than in those animals maintained in a normocapnic state during the first hour of restitution, these differences did not reach significance. Qualitative recovery of elec- trical activity during the 3sA-hr period of restitution from the termination of the 15- min insult was better in all the oligemia ani- mals than in the ischemia animals, and by 3 hr significantly more fast activity was pre- sent in the hyperventilating animals in both groups. In ischemic animals large-amplitude slow-wave activity persisted in the normocapnic group and secondary dete- rioration of electrical activity was noted in two of three of these animals between the third and fourth hour. In contrast, in isch- emit spontaneously hyperventilating ani- mals there was some return of low-am- plitude fast activity and no evidence of

MARSHALL ET AL.: EXPERIMENTAL INTRACRANIAL HYPERTENSION 449

secondary deterioration of electrical activity. In none of the ischemic animals, however, did the EEG ever approach normal during the entire period of observation.

Behavior Significant recovery of neurological

function was found only in those animals permitted hyperventilation (PACO, 16-24 torr, arterial pH 7.58-7.66) during the first hour of restitution. In the oligemia animals by 20 min postoligemia the cornea1 reflex could be elicited and within 90 min the ani- mals though paraplegic would attempt to right themselves. At 3 hr of restitution the hindlimb weakness had improved sufficiently so that the animals were quite mobile and they were able to chew. All three animals survived for at least 12 hr and death ap- peared to be due to respiratory obstruction. In contrast, oligemic animals in which normocapnea was maintained during the first hour of restitution were more severely damaged. The cornea1 reflex could never be elicited befor 50 min after the insult, and recovery of the level of consciousness was minimal, there being only a feeble response to pain. Only one of these three animals was able to ventilate adequately spon- taneously during the period of restitution, the other two required mechanical venti- lation throughout.

In the postischemic animals which were permitted spontaneous hyperventilation, return of the cornea1 reflex occurred 70 min after the insult and feeble movements of the lower extremities were first seen at 90 min. Though still paraplegic at 4 hr these animals were able to right themselves, move using their forelegs, and were able to drink. One animal died at 8 hr from uncontrollable hypotension, and two died at 14 and 18 hr, respectively, from respiratory obstruction and heart failure. Again, as in the oligemic animals, ischemic animals which were main- tained in the normocapnic state for the first hour of restitution recovered much more poorly. The cornea1 reflex did not return be- fore 2 hr postischemia, there was no

response to painful stimulation in any of these animals, and recovery of spontaneous ventilation was poor or absent.

DISCUSSION Secondary elevations in the intracranial

pressure were not seen in any animal. Great care was taken to avoid systemic hyperten- sion, and we have demonstrated in previous experiments with this model that the blood- brain barrier was not disrupted [9]. This probably accounts for the absence of in- tracranial hypertension as suggested by Ek- Strom-Jodal et al. [6]. Thus, intracranial hypertension is not an invariable accom- paniment of severe brain ischemia.

Hypocapnea in the immediate postinsult period was associated with significant improvement in functional recovery. It is un- likely that the normocapnic animal suffered some deleterious effect from mechanical ventilation. It is more likely that hypocapnic alkalosis is beneficial in the postinsult pe- riod.

The mechanism by which hypocapnic alkalosis might protect the brain is prob- lematical. Although Siesjo [12] has dem- onstrated that even severe acidosis has no effect on the time course of recovery of brain energy metabolism, the present study indi- cates that hypocapnea is associated with a significant improvement in functional re- covery after either oligemia or ischemia. It thus seems likely that the beneficial effects of alkalosis are related to intracellular events other than energy metabolism. Since, in previous experiments [9], we have dem- onstrated that the return of electrical activity correlates poorly with the recovery of energy metabolism, it is probable that the beneficial effects of hypocapnia are not re- lated to mitochondrial energy function. It is possible that hyperventilation might relieve some pH-inhibited step within the cell which is important for the recovery of neurological function. Seitz et al. [13] suggested this mechanism when they found that the CSF pH in brain-injured patients was acidotic and that intrathecal sodium bicarbonate pro-

450 JOURNAL OF SURGICAL RESEARCH VOL. 18, NO. 4, APRIL 1975

duced remarkable improvements in the clinical status, EEG, and cerebral blood flow in these patients. Furthermore, there is evi- dence that brain electrical activity does not recover until tissue lactate falls below a critical level [lo], again suggesting that lactate inhibits cell function. Further investi- gations are needed to determine the mechanism by which hypocapnia favorably influences brain function after oligemic and ischemic insults.

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