(Stroke. 1997;28:1445-1450.)
© 1997 American Heart Association, Inc.
Articles |
Cushing's `Variant' Response (Acute Hypotension) After Subarachnoid Hemorrhage
Association With Moderate Intracranial Tensions and Subacute Cardiovascular Collapse
From the Departments of Neurosurgery and Experimental Medicine, Royal Hallamshire Hospital, Sheffield, UK.
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Abstract |
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Background and Purpose Hypertension is considered common and appropriate with subarachnoid hemorrhage (SAH), maintaining cerebral perfusion. Hypotension, in contrast, is considered rare and detrimental. This study was designed to assess the frequency of each in both acute and subacute phases of primary SAH.
Methods SAH was created by arterial rupture in spontaneously breathing rats under urethane anesthesia without craniotomy (n=32). Arterial pressure and intracranial pressure (ICP) were monitored invasively.
Results After extensive extravasation, the mean ICP rose
acutely from 8±1 to 53±4 mm Hg over 2.4±0.3 minutes. Acute
pressor changes occurred transiently in 71%. The most common acute
response was hypotension (63%). Hypertension, in contrast, was rare
(6%); the remainder was invariant (29%). Hypertension was associated
with significantly lower maximum ICP values (39±4 versus 69±4
mm Hg, P<.001) with a negative correlation between
hypotension and 
ICP (r=-.7, P<.01). Distinct
and independent of acute responses, hypotension also occurred
subacutely as a cardiovascular collapse (38%).
Conclusions In contrast to popular belief, the most common
acute response with SAH is hypotension; hypertension is rare. This, in
fact, is in full agreement with Cushing: hypertension was seen only
with gradual ICPs. In contrast, a "variant" to the classic
response (hypotension) occurred with sudden ICPs. In the present
study, hypotension stanched SAH at lower maximum ICP values, and thus
with less cerebral compression. Despite this,
cardiovascular collapse developed in a large proportion
irrespective of acute change. Such collapse without prior hypertension
(94%) implies a nonadrenergic etiology.
Key Words: hypotension • subarachnoid hemorrhage • rats
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Introduction |
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Acute hypertension is commonly considered to accompany acute SAH. This is probably because it is often present in the subacute post-SAH period.1 2 However, it may also be because it is conceptually compatible with a CHR.3 Thus, ICP remains elevated, at lower levels, for several minutes after SAH.4 5 6 7 A CHR may therefore appear appropriate, restoring cerebral perfusion.3 Hypotension, however, has only rarely been documented with SAH. Where seen, it has only occurred subacutely, as an SCC with a poor prognosis.8 9
Primary SAH cannot, of course, be clinically monitored. Evidence from secondary SAH appears to confirm a CHR.1 2 10 However, it may be that secondary SAH is entirely different: it may especially favor hypertension.8 A high ICPmax in this scenario may thus activate hypothalamic and brain stem centers, producing catecholamine activation and hypertension.11 12 13 14 15 SCC is thought to follow such catecholamine overload.13 15 Whatever its trigger, SCC appears to follow the acute ictus with temporal delay.8 9
The characteristics of primary SAH were explored in a model closely resembling that of the acute ictus. Shigeno et al16 have listed the major requirements for any putative model as (1) intracranial bleeding from acute vessel rupture, (2) acute pressure loading within a closed skull, and (3) the production of a sufficient amount of blood; to these we would add (4) endovascular source of rupture without prior craniotomy.17
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Materials and Methods |
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Adult male Wistar rats (n=40) of similar age in the weight range of 350 to 450 g were used. All animals were anesthetized with 25% urethane injected intraperitoneally (1 g/kg). A saline-pressurized arterial cannula was inserted into the lower abdominal aorta through the left femoral artery. Through this, MAP and blood gases were continuously monitored and saline was infused. No heparinization was used. The animals breathed air spontaneously. All procedures were performed on a warming plate; rectal temperatures were maintained at close to 38°C throughout the experiment.
After the rat was turned to the prone position and following careful microdissection in the suboccipital region, a small plastic cannula was inserted into the cisterna magna through a nick in the suboccipital membrane. This was then connected through a column of saline to the transducer of an oscilloscope to record the ICP, with a sinuous waveform indicating ideal positioning. This was "fixed" by the pouring of dental acrylate into the wound and by tying over the suboccipital muscles as the acrylate set, after which the animal was then returned to the supine position.
After tracheostomy, the right CCA was dissected free from its vagus
nerve, with the ECA being divided to a small stump. The pterygopalatine
branch of the ICA was then temporarily clipped, as were both the distal
ICA and the proximal CCA; within this isolated segment, a small length
of 3/0 prolene (about 3 cm) was introduced via the ECA stump (Fig 1
). The ICA clip was then removed, and the thread was
passed intracranially within the lumen of the ICA until, on passing
through a small resistance, it ruptured through the wall of the
anterior circle of Willis, thus causing acute SAH.17 This
was confirmed by a sudden elevation in the ICP to a peak value, from
which it then fell to a lower plateau (Figs 2 through 4). Frequently,
respiratory irregularities occurred at this stage, but these were
usually only transient, and respiratory support (Harvard
Apparatus Ltd) was rarely required (but hence the prior
tracheostomy). The thread was then immediately withdrawn, and after
coagulation of the ECA stump, reperfusion was attempted by release of
the CCA clip: if the ICP showed a significant re-rise, then the clip
was repositioned for a few minutes more. After an arbitrary period of 3
hours, the animal was killed by exsanguination.
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Control Group
In an additional 8 animals, the above procedure was performed in
exactly the same manner but without the production of SAH,
since the thread was passed only a short distance within the ICA before
its abrupt removal.
All procedures performed were in accordance with British Home Office guidelines.
Statistics
All mean values are expressed as mean±SE. Statistical
analysis between groups was performed by one-way ANOVA, with
values of P<.05 being considered significant.
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Results |
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Control Group
Satisfactory MAP and ICP values were obtained in 8 of 8 rats and are summarized in Table 1
. Results of
arterial blood gas analysis were normal (Table 2), and rectal temperatures were maintained at 38°C
throughout. At no point was any blood observed in the ICP cannula, nor
was any found within the subarachnoid space at postmortem.
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SAH Group
Satisfactory blood pressure recordings were obtained in 32
of 32 rats, and satisfactory ICP values in 25 of 32. Mean blood gas
values were similar to those in the controls (Table 2
). After acute
SAH, the mean ICP rose nearly sevenfold from 8±1 to 53±4 mm Hg
over 2.4±0.3 minutes. Thereafter, it gradually fell to a lower plateau
significantly above baseline value (Figs 2 through 4). Respiratory
irregularities and extensor posturing were characteristically
transient, with the mean PO2 falling from
11.9±0.2 to 10.1±0.3 with rapid spontaneous recovery. On one
occasion, ventilation with 100% oxygen was required. Pressor changes
occurred both acutely and subacutely. Acute pressor changes were
always transient and spontaneously reversible. Subacute change
always took the form of inexorable SCC, following significant temporal
delay.
Acute Pressor Change
There were three clearly defined acute pressor responses:
hypotension, hypertension, and invariant tension. Hypotension occurred
acutely in 20 of 32 cases (63%) and resulted in a fall of MAP of
41±5 mm Hg over 2.1±0.3 minutes. This usually recovered with
the ICP pari passu (Fig 2); however, on occasion this was more
prolonged (Fig 3). The ICPmax (39±4 mm Hg) was
significantly lower than that in the other groups (69±4 mm Hg,
P<.001), as was the rate (
ICP/t, 2.1±0.3 minutes). A
negative correlation was demonstrated between hypotension and the
ICP (r=-.7, P<.01) (Fig 5).
The effect of hypotension was to increase the ratio of
ICPmax to MAP from 38% to 60% after SAH.
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In 10 rats (31%), the MAP was invariant during SAH (not shown). In 2
rats (6%), a classic CHR was demonstrated (Fig 4). In contrast to
hypotension, both ICPmax and ICP/t were significantly
greater in these groups (Fig 4), with the ICPmax
representing 56% and 58% that of the pre-SAH MAP,
respectively. Furthermore, the ICPmax attained after CHR
was significantly higher still (84 mm Hg) relative to invariant
and hypotension groups (51 mm Hg, P<.05).
Subacute Cardiovascular Collapse
SCC occurred in 12 rats (38%) overall. It was temporally distinct
from any acute pressor change and resistant to routine
supportive measures. Hypoxia was not allowed to influence its
course. SCC occurred in 7 of 20 cases (35%) with prior acute
hypotension and in 5 of 12 cases (42%) with prior hypertension or
invariant tension.
Postmortem Confirmation of SAH
Extensive SAH was confirmed at postmortem by blood in the (1) ICP
cannula, (2) cisterna magna, (3) convexities, and (4) basal cisterns.
An attempt was initially made to grade the extravasated volume;
however, the above picture was routinely apparent. Routine light
microscopy of heart (hematoxylin and eosin, Masson's trichrome) and
brain (hematoxylin and eosin) revealed no untoward parenchymal features
(not shown). Pulmonary edema was frequent after SCC.
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Discussion |
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SAH was typically heralded by acute respiratory irregularities, pressor disturbances (hypertension or hypotension), and extensor posturing: a familiar triad. All acute changes were transient and spontaneously reversible (one case, however, required ventilatory support). SCC, in contrast, was always progressive, occurring in 38% with temporal delay. Notwithstanding considerable SAH, however, both high ICPmax and CHR (hypertension) were rarely witnessed acutely (6%). Instead, the converse—a moderate ICPmax and an acute hypotension (hypotension) (63%)—prevailed. SCC, then, was most often preceded by the opposite of the catecholamine response ordinarily expected.11 12 13 14 15
Cushing presented his classic intracranial studies at the
Mütter lecture in 1902.18 Here, ICPs were created
incrementally, by either saline infusion or balloon expansion, to
gradually attain the MAP. This was to mimic the effects of
space-occupying lesions or hematomas. The major effect observed was
that of a corresponding elevation in MAP "sufficient to overcome the
high intracranial tension." Cushing emphasized that this primarily
maintained medullary respiratory center flow (it did not restore global
cerebral blood flow), with any hypertension occurring at lower ICPs
proving detrimental.18 19 Thus, the CHR did not occur
until the ICP had approached the MAP, whereafter both rose pari
passu.18 Because the mean ICP in the present study
(from 8±1 to 53±4 mm Hg) fell far short of the MAP (113±4
mm Hg:151/94 mm Hg), the rarity of the CHR may therefore appear
to be explained. However, the real explanation relates to the fact that
hypertension was never originally stated in the context of SAH; it only
related, in fact, to gradual ICPs.
In his "variants" to the classic response, Cushing clearly stated
that where ICPs were created suddenly, a complete "checking of
the heart" resulted (attributable to "vagal activation"), from
which the MAP then "gradually recovered."18 Although
he sometimes infused directly into the cisterna magna, close to
cardiorespiratory centers, Cushing also tried "many other sites,"
finding this to have little influence on the results.18
Therefore, the exact opposite to the CHR was to be expected with SAH.
This has subsequently been supported experimentally, where hypotension
has also followed arterial rupture.20 However,
another factor in the present study may have been related to the
moderate ICPmax attained. Thus, transient hypotension has
also been observed with incremental ICP studies producing submaximal
ICPmax values (see References 21 and 2221 22 ). In consequence,
hypotension may relate both to the height of the ICPmax and
to its rate (Figs 2 through 4).
The moderate ICPmax produced suggests a less severe SAH.
However, extensive extravasation was routinely apparent at postmortem.
A moderate ICPmax had therefore paradoxically occurred
along with extensive SAH. This may be explained—at least in those
cases where hypotension had occurred—by a reduced extravasating
pressure. However, hypotension did not invariably occur; hypertension
sometimes occurred instead. Hydraulic recording failure can be
ruled out because subarachnoid space injections cause
homogeneous ICPs18 and blood clearly
communicated with the cisterna magna posteriorly. Furthermore, the
continuous ICP tracings do not suggest obstructive interludes (Figs 2 and 3). In consequence, the ICPmax poorly reflected the
extravasated volume. Such disparities have in fact been frequently
alluded to.4 5 6 7
Large extravasated volumes producing moderate ICPmax
suggest efficient ICP venting. This implies unusually compliant
meninges or rapid cerebrospinal fluid displacements from the
subarachnoid space. Seiro23 in fact had found it
difficult to maintain incremental ICPs, as if due to cerebrospinal
fluid leakage. Cushing had also been warned of such displacements,
which, occurring into the venous system, might induce a cardiac
overload.18 Although this did not occur (only 100 mL was
expressed in 30 minutes), Cushing readily acknowledged this "free
communication": this was dramatically witnessed after
inadvertent bursting of mercury into "sinuses, jugulars,
right heart and lungs."18
Mechanism of Acute Pressor Response
Increased craniocaudal ischemia, with increasing
ICPmax, is thought to account for the pressor
responses seen with ICPs. In the first phase
(ICPmax<MAP), the cerebrum alone is
ischemic,15 16 resulting in decreases of heart
rate, MAP, and cardiac output14 15 22 (in some way
attributable to "vagal activation"18 ). As the
pressure wave progresses (ICPmax
MAP), the upper brain
stem becomes ischemic, causing a "mixed vagosympathetic"
output manifest as the CHR (bradycardia, hypertension, and
respiratory irregularity).15 22 Eventually
(ICPmax>MAP), the lower medulla becomes ischemic
where the parasympathetic response is somehow lost, allowing
sympathetic domination. This is manifest as a generally hyperdynamic
state of increased heart rate and MAP,14 15 22 a common
agonal feature.21
Reversible hypotension lasting several minutes (Figs 2 and 3) suggests
VVS.8 18 This is certainly not purely "vagal,"
however; such a patient may also be pale and clammy, with dilated
pupils.24 25 VVS, furthermore, can be triggered by
emotional factors and pain: stimuli that ordinarily activate
catecholamines.24 25 Bradycardia, indeed, may
be absent (as in the present study) or replaced by
tachycardia, and its rate is rarely slow enough to explain
hypotension.24 25 The hypotension most likely results from
excessive splanchnic and skeletal muscle vasodilation25 ;
that Cushing noted the opposite ("anemic bowels") with the
CHR18 suggests a fundamental link between CHR and
hypotension. The occurrence of VVS with emotional shock is of uncertain
teleological value.25 Its occurrence with SAH, however,
may be appropriate, augmenting tamponade at lower ICPmax
values (see below). In some cases of SAH where the impact sustained and
headache appeared minimal, the presentation was actually
that of syncope.26
The mean hypotension produced (41±5 mm Hg) effectively elevated
the ICPmax to MAP ratio from a possible 38% (had there
been no hypotension) to one of 60%. This is remarkably similar to that
attained in both other groups with higher ICPmax values and
suggests this to be of fundamental importance in stanching SAH. The
negative correlation between hypotension and ICP (Fig 5) conceivably
portrays VVS as an adaptation to efficient ICP venting, a lower
ICPmax, and thus a weaker tamponade. However, hypotension
per se lowers the extravasating pressure and therefore also the
ICPmax. Clearly, it would not be possible to resolve this
argument any further here. Notwithstanding, the correlation clearly
demonstrates hypotension to stanch SAH at lower ICPmax
values and thus with less compressive cerebral strain.
Subacute Cardiovascular Collapse
VVS associated with moderate ICPs has been considered
inconsequential: VVS correlating with low catecholamines
and a low mortality.11 14 The present results,
however, do not support this; a high mortality (38%) ensued
irrespective of initial pressor change (hypertension or hypotension). A
similar proportion is seen clinically with sudden death.27
Thus, hypotension does not offset SCC despite lower ICPmax
values and moderate cerebral strain. SCC was always temporally distinct
from initial pressor change, the latter having always initially fully
recovered; this resembles that seen clinically, where SCC has only
followed temporal delay.9 SAH per se, irrespective of
"severity" or initial pressor change, thus appears unusually
associated with SCC.
That SCC occurred in the majority (94%) without a CHR, however, appears contrary to the view that it necessarily follows catecholamine activation.11 12 13 14 15 This accords with other studies where an initial hypotension with rebound had finally given way to SCC, with modest ICPmax values pertaining throughout.11 21 28 29 Recent studies have promoted myocardial inductions of cytokine-mediated nitric oxide synthase in this context, the excess nitric oxide obtunding ß-mediated contractility.30 31 32 33 Indeed, elevated systemic cytokines have been observed in this state,31 as well as centrally after SAH.34 35 Whether this could explain the present findings, however, remains conjectural. The normal findings on routine myocardial sectioning are not surprising, since others have found that at least 6 hours were needed for pathological changes to develop36 ; this was beyond the scope of the present study.
Conclusion
Acute hypotension is the most common transient pressor response
with SAH in rats. This is in full accordance with Cushing: the classic
response was only stated with gradual ICPs. The effect produced was
a stanch of SAH at lower ICPmax and therefore less
compressive parenchymal strain. Despite this, SCC remained equally as
likely as, and therefore independent of, the acute response seen.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was funded by the Department of Neurosurgery, Royal Hallamshire Hospital, Sheffield, UK. I would like to thank Sophie Kirk, Parker-Stratton Design.
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Footnotes |
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Reprint requests to L. Marshman, 5 Bakers Lane, Lingfield, Surrey, RH7 6HE, UK.
Received February 11, 1997; revision received April 9, 1997; accepted April 23, 1997.
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