Cerebral blood flow and metabolism in comatose patients with acute head injury

Relationship to intracranial hypertension

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✓ Cerebral blood flow (CBF) measurements were made in 75 adult patients with closed head injuries (mean Glasgow Coma Scale score 6.2), using the xenon-133 intravenous injection method with eight detectors over each hemisphere. All patients were studied acutely within 96 hours of trauma, and repeatedly observed until death or recovery (total of 361 examinations). Arteriojugular venous oxygen differences (AVDO2) were obtained in 55 of the patients, which permitted assessment of the balance between metabolism and blood flow, and provided estimates of cerebral metabolic rate for oxygen (CMRO2).

Based on mean regional CBF, the patients were classified into two groups: those who exhibited hyperemia on one or more examinations, and those who had a consistently reduced flow during their acute illness. “Hyperemia” was defined as a normal or supernormal CBF in the presence of coma, a definition that was independently confirmed by narrow AVDO2's indicative of “luxury perfusion.” During coma, all patients showed a significant depression in CMRO2.

Forty-one patients (55%) developed an acute hyperemia with an average duration of 3 days, while 34 patients (45%) consistently had subnormal flows. Although more prevalent in younger patients, hyperemia was found at all age levels (15 to 85 years). There was a highly significant association between hyperemia and the occurrence of intracranial hypertension, defined as an intracranial pressure above 20 mm Hg. Patients with reduced flow showed little or no evidence of global cerebral ischemia, but instead revealed the expected coupling of CBF and metabolism. The CBF responses to hyperventilation were generally preserved, with the hyperemic patients being slightly more reactive. In 10 patients with reduced flow, hyperventilation resulted in wide AVDO2's suggestive of ischemia.

Abstract

✓ Cerebral blood flow (CBF) measurements were made in 75 adult patients with closed head injuries (mean Glasgow Coma Scale score 6.2), using the xenon-133 intravenous injection method with eight detectors over each hemisphere. All patients were studied acutely within 96 hours of trauma, and repeatedly observed until death or recovery (total of 361 examinations). Arteriojugular venous oxygen differences (AVDO2) were obtained in 55 of the patients, which permitted assessment of the balance between metabolism and blood flow, and provided estimates of cerebral metabolic rate for oxygen (CMRO2).

Based on mean regional CBF, the patients were classified into two groups: those who exhibited hyperemia on one or more examinations, and those who had a consistently reduced flow during their acute illness. “Hyperemia” was defined as a normal or supernormal CBF in the presence of coma, a definition that was independently confirmed by narrow AVDO2's indicative of “luxury perfusion.” During coma, all patients showed a significant depression in CMRO2.

Forty-one patients (55%) developed an acute hyperemia with an average duration of 3 days, while 34 patients (45%) consistently had subnormal flows. Although more prevalent in younger patients, hyperemia was found at all age levels (15 to 85 years). There was a highly significant association between hyperemia and the occurrence of intracranial hypertension, defined as an intracranial pressure above 20 mm Hg. Patients with reduced flow showed little or no evidence of global cerebral ischemia, but instead revealed the expected coupling of CBF and metabolism. The CBF responses to hyperventilation were generally preserved, with the hyperemic patients being slightly more reactive. In 10 patients with reduced flow, hyperventilation resulted in wide AVDO2's suggestive of ischemia.

Recent studies on acute head injury7,11,13,53 have revealed wide variations in cerebral blood flow (CBF), such that very high as well as low flows may occur in comatose patients with similar neurological findings, or even within the same patient over time. In contrast, the cerebral metabolic rate for oxygen (CMRO2) is consistently depressed following brain trauma,4,59,66,69 the magnitude of depression being roughly proportional to the depth of coma. Since under most conditions blood flow is functionally coupled with metabolism,57,60 the occurrence of a high CBF during coma suggests an uncoupling of the two.

Such a dissociation of CBF and metabolism was postulated by Lassen,34 who described a “luxury perfusion syndrome” in patients with acute brain disorders. This syndrome is characterized by cerebral hyperemia, defined as excessive blood flow relative to the brain's metabolic requirements. Lassen argued that the hyperemia was due to impaired CBF autoregulation secondary to ischemia or hypoxia, and speculated that it could lead to disruption of the blood-brain barrier and edema formation. Since then, hyperemia has been observed in a number of acute clinical conditions, including ischemic stroke35,51 and head injury.7,11,13,53

Of particular relevance to head injury is the related concept of “vasomotor paralysis” introduced by Langfitt and coworkers31–33 to explain brain swelling and intracranial hypertension in experimental studies of cerebral compression and trauma. They postulated an acute reduction in vasomotor tone that resulted in cerebral vasodilatation, increased blood volume, and elevated intracranial pressure (ICP). When arterial hypertension followed trauma, massive brain swelling occurred that was associated with both hyperemia and edema.38,64 These findings suggested that brain trauma impairs CBF autoregulation, which was subsequently confirmed.36,42,62

It is apparent that the concepts of luxury perfusion and vasomotor paralysis refer to different aspects of the same phenomenon; namely, an acute derangement of the cerebral circulation manifested by hyperemia and a potential for brain swelling. Although repeatedly observed in human and animal studies, the pathophysiological significance of this syndrome remains obscure, including its relevance to the management of clinical head injury. Thus, the incidence and time course of hyperemia following head injury is not fully known, nor is its relationship to intracranial hypertension. Furthermore, it is not clear whether therapy should be aimed at reducing the hyperemia. Although hyperventilation therapy has been widely used to control ICP, its effect on acute hyperemia has not been systematically evaluated.

The present study was undertaken to elucidate the role of acute CBF alterations in the pathophysiology of clinical head injury. Special emphasis was placed on the occurrence of hyperemia, its time course and relationship to ICP, and its response to hyperventilation. Serial observations were made in 75 comatose patients studied as soon as possible after trauma. Advantage was taken of the noninvasive intravenous xenon-133 (Xe133) technique, which allowed repeated bilateral determinations of CBF in the intensive care unit. This was supplemented by measurements of arteriojugular venous oxygen difference (AVDO2), from which global estimates of CMRO2 were derived. Because AVDO2 represents the ratio of metabolism to blood flow, it also provided independent confirmation of cerebral ischemia and hyperemia.

Clinical Material and Methods
Patient Population

Seventy-five acutely comatose patients with closed head injury were selected from a total of 110 consecutively studied cases. The criteria for selection were that the first CBF examination was performed within 96 hours of injury, and that the patient was completely unresponsive to verbal commands at that time. The remaining 35 patients were excluded for the following reasons: the first CBF examination was later than 96 hours postinjury (14 cases), recovery of consciousness occurred prior to the first study (14 cases), brain death intervened before the studies could be initiated (five cases), and early administration of barbiturates precluded baseline CBF observations (two cases).

The 75 selected patients ranged in age from 15 to 85 years, with a median of 28 years; 56 of them were males. The first CBF study was performed on the day of injury in 47 cases, and within 48 hours of injury in 62 cases. The average Glasgow Coma Scale (GCS)70,71 score at the time of the first study was 6.2 ± 1.7 (mean and standard deviation (SD)). By 6 months, 30 (40%) of the patients had died and two were in a persistent vegetative state. The remaining patients either made a good recovery (19 cases) or showed varying degrees of neurological or neuropsychological disability (24 cases).

All patients were initially intubated and mechanically ventilated. Twenty-seven of them underwent surgery prior to the CBF studies, 25 for evacuation of mass lesions. Intracranial hypertension was treated by hyperventilation which, when necessary, was supplemented by mannitol and/or pentobarbital infusion. Each patient had one or more acute CBF studies in the absence of mannitol or barbiturate therapy.

Computerized Tomography Scans

Computerized tomography (CT) of the brain was performed in all patients upon hospital admission, and repeated when clinically indicated. Whenever possible, follow-up scans were scheduled in close temporal proximity to the CBF studies. Forty-one patients (55%) revealed focal findings on CT scan, consisting of hematomas (subdural, intracerebral, epidural) and/or hemorrhagic contusions, which were believed to be the principal lesions. The remaining 45% of the lesions were classified as diffuse, based on the CT appearance of diffuse cerebral swelling, extensive subarachnoid hemorrhage, or small hemorrhages in the white matter suggestive of diffuse axonal injury. These figures agree well with the incidence of lesion type in a larger series of 1107 adult cases compiled by seven head injury centers,15 suggesting that the present sample is reasonably representative of such patients. A preliminary description of the CT scans has appeared elsewhere;76 their correlation with CBF findings will be reported separately.

Cerebral Blood Flow Measurements

Regional CBF was measured by the intravenous 133Xe method47,49 from 16 extracranial detectors, eight placed over each hemisphere. A total of 361 examinations were performed, averaging five per patient. Each patient was followed longitudinally until death or recovery of consciousness. A 6- to 12-month follow-up study was obtained in most survivors.

The 133Xe clearance curves were subjected to a two-compartment analysis from which two CBF indices were derived: CBF15, the mean blood flow of the fast- and slow-clearing compartments; and F1, an estimate of blood flow in the fast-clearing, primarily gray matter compartment. The CBF15 value was determined by a modified height-over-area method in which the clearance curve was integrated to 15 minutes,50 a procedure that reduces the influence of extracerebral contamination. All statistical analyses were based on CBF15, which is inherently more stable than compartmental parameters in pathological conditions. The F1 index was used to confirm the existence of hyperemia, being particularly sensitive to higher flows.

Forty-two healthy young adults provided control data for evaluation of the CBF findings. Variations between subjects were used to define the upper and lower limits of normal, as well as the expected range of hemispheral and regional differences. Although the norms were not adjusted for age, this variable was taken into consideration when interpreting the results.

Forty-nine of the head-injured patients (65%) revealed significant hemispheral asymmetries, usually accompanied by statistically reliable regional differences. A full description of the regional CBF findings will be published separately along with follow-up observations; preliminary reports have appeared previously.45,46

Because of wide variations in arterial CO2 tension (PaCO2), both within- and between-subject comparisons were based on CO2-corrected blood flow measurements. The correction factor used for CBF15 was 3.0% per mm Hg of PaCO2 change, which is similar to the mean value obtained from 29 CO2-reactive patients in the present series. In order to minimize the magnitude of the correction, however, CBF measurements were adjusted to a patient's median PaCO2 when comparing his results over time. Between-subject comparisons were based on a PaCO2 of 34.0 mm Hg, the mean value for all acute CBF studies excluding those during hyperventilation therapy.

ICP and Blood Pressure Monitoring

Intracranial pressure was continuously monitored during the acute illness by means of a subarachnoid bolt,72 except in three cases where an intraventricular catheter (Scott cannula) was used. Depending on the patient's neurological status, ICP monitoring was discontinued when pressures of less than 10 mm Hg were recorded for 2 consecutive days. Arterial blood pressure was monitored from an indwelling radial or brachial artery catheter, which was also used to obtain samples for blood gas analysis.

AVDO2 and CMRO2 Determinations

The oxygen content of peripheral arterial and jugular venous blood was determined at the time of most acute CBF studies. A thin radiopaque catheter was introduced percutaneously into the common (usually right) jugular vein and threaded upward to the level of the jugular bulb or beyond. X-ray verification of the placement was obtained in approximately half of the cases; four studies were rejected because of poor catheter position. Jugular catheterization was not attempted if the patient was physiologically unstable or otherwise considered at risk. In some cases, the catheter was left in place for 48 hours with appropriate flushing; there were no complications.

Values for blood oxygen content were derived from estimates of O2 saturation, which were determined in two ways: directly by measurement with a co-oximeter,* and indirectly by calculation from measured blood gas tensions. The two methods served to cross-validate one another and, with few exceptions, were in excellent agreement. A total of 164 technically satisfactory determinations of both arterial and jugular venous O2 content were obtained in 55 of the patients.

The AVDO2 was calculated as the difference in O2 content between simultaneously drawn arterial and jugular venous samples. The CMRO2 was estimated from the product of AVDO2 and the mean value of CBF15, averaged across 16 brain regions. Although it was recognized that CBF15 is not strictly comparable to AVDO2, being based on regional rather than global information, the mean value of CBF15 was nevertheless considered a good approximation of global blood flow.

CO2 Reactivity

Responses of CBF to hyperventilation were tested 48 times in 35 patients. The present analysis is based on findings in 31 patients who met the following criteria: one or more tests were administered during the acute illness (< 96 hours postinjury), a physiological steady state was maintained during the procedure, and the results were not confounded by simultaneous administration of mannitol or barbiturate therapy. Each CO2 test consisted of two CBF examinations, one during hyperventilation (PaCO2 18 to 26 mm Hg), and one during a “normocapnic” control condition. Because of intracranial hypertension, however, only a relative degree of normocapnia could be achieved in 15 of the patients (PaCO2 28 to 32 mm Hg); the remainder had normocapnic CO2 levels of 34 to 44 mm Hg. Order effects were minimized by counterbalancing: hyperventilation preceded the control condition in half of the cases, and followed it in the remaining half.

Patient Classification

Patients were classified according to the level of their CBF during acute coma. The classification was based on CBF examinations performed within 96 hours of injury, when the patient was unresponsive to verbal commands. Two groups were formed comprising: 1) patients who showed clear evidence of hyperemia on one or more occasions, and 2) those who consistently revealed a reduced flow. Hyperemia was defined as a CBF within or above the normal range for conscious healthy adults. Reduced flow was defined as a CBF below the lower limit of normal; that is, more than two standard deviations less than the normal mean.

This classification was based on the premise suggested by earlier work4,59,66,69 that head-injured patients in coma have a diminished CMRO2. A corresponding reduction in CBF would be expected if blood flow and metabolism were functionally coupled. On the other hand, a normal or supernormal CBF during coma would constitute a hyperemia, since blood flow would exceed the brain's metabolic requirements.

The association of coma with a low CMRO2 was confirmed in the present series. Figure 1 shows the relationship between the GCS score and CMRO2, based on 186 observations in 65 patients. Ten semicomatose head-injured patients (not in the present sample) were included in order to extend the range of observations.

Fig. 1.
Fig. 1.

Mean and standard error (SE) of cerebral metabolic rate (CMRO2) plotted against the Glasgow Coma Scale (GCS) score.70,71 The CMRO2 is expressed in ml/100 gm/min. The findings are based on 186 studies in 65 patients. The number of observations at each GCS score level is: 36, 74, 34, 30, and 12, respectively, from left to right. Patients with GCS scores of 8 or less had CMRO2's below 1.6 (dashed line), which is less than half of the normal mean value of 3.3 ml/100 gm/min.28

As shown in Fig. 1, patients with GCS scores of 8 or less had a 50% reduction in CMRO2 relative to the normal waking value.28 Since the lower limit of normal for CBF is approximately 25% below its mean, a conservative definition of hyperemia during coma is a CBF within or above the normal range. Such a level would clearly suggest a dissociation of CBF and metabolism. Although the classification of patients was based exclusively on CBF criteria, measurements of AVDO2 provided independent confirmation of the presence or absence of hyperemia in most patients (see Results).

The mean value of CBF15 for 16 brain regions was used to determine blood flow level. In spite of significant hemispheral and/or regional CBF differences in 65% of the cases, both hyperemia and reduced flow were usually global in distribution; that is, focal changes were of smaller magnitude than generalized increases or decreases in flow. When classifying CBF, appropriate allowance was made for the patient's PaCO2. Most patients had one or more studies in the normocapnic range, so that only a minimal correction for PaCO2 was necessary. In some cases, the patient's measured CO2 reactivity could be used to adjust the CBF values.

The presence of coma during the CBF studies was defined as failure to respond to verbal commands, a criterion that proved to be both reliable and operationally simple. Unresponsiveness to commands was associated with a GCS score of 8 or less in 67 patients; GCS scores of 9 or 10 were obtained in the remaining eight cases.

Results
Incidence and Time Course of Hyperemia

In accordance with the criteria described above, acute hyperemia was observed in 41 (55%)of the 75 comatose patients, while a consistently reduced flow was found in the remaining 34 patients (45%). Among the hyperemic cases, 15 revealed an absolute hyperemia, defined as CBF above the upper limit of normal, while 26 had a relative hyperemia, defined as CBF within the normal range. By definition, all patients with a reduced flow had subnormal CBF values.

Hyperemia was transient in nature, with an average duration of 3 days and a range of 1 to 8 days. Thirty-seven of the 41 patients with hyperemia also experienced significant blood flow reductions, either preceding or following the hyperemic phase. The remaining four cases were young adults (aged 15 to 19 years) whose blood flow declined with recovery of consciousness, but never dropped below the normal range.

In two-thirds of the hyperemic patients (27 cases), the hyperemia appeared and was maximal on the initial blood flow examination. In one-third of the cases, the onset of hyperemia was delayed until later examinations, although still occurring in acute coma. Figure 2 illustrates these two distinct CBF patterns involving an initial and a delayed hyperemia. Temporal profiles of this type lend support to the diagnosis of hyperemia, since they provide evidence of CBF changes in the same individual, who in essence serves as his own control.

Fig. 2.
Fig. 2.

Left: Case 23. Serial cerebral blood flow (CBF) measurements plotted against days postinjury in a patient with a large left epidural hematoma that was surgically evacuated prior to the first study. F1 = fast compartment blood flow; CBF15 = mean blood flow for the fast and slow compartments. The CBF estimates were averaged across eight regions in each hemisphere and adjusted to the patient's median PaCO2 of 37.0 mm Hg. An initial hyperemia was followed by a reduction in flow that returned to the normal range as recovery progressed. An acute hemispheral asymmetry (left > right) was reversed on the final examination (right > left), at which time the patient had a mild residual aphasia. See text for further details. Right: Case 16. Serial CBF measurements plotted against time (hours and months) in a patient with a small left subdural hematoma that was not surgically evacuated. A delayed hyperemia at 36 to 82 hours was preceded and followed by a reduction in flow that remained subnormal in association with hydrocephalus and dementia. Administration of 100 gm mannitol (MANN) at 14 hours yielded a small but significant increase in CBF compared with the control value (CTRL). Cerebrospinal fluid drainage via lumbar puncture (LP) at 5 months failed to produce a change in flow. See text for further details.

Figure 2 left is an example of hyperemia 2 days after evacuation of a large left epidural hematoma, at which time the patient was unresponsive to commands (GCS score 9) and had a mild elevation of ICP. The CBF subsequently declined to subnormal levels as consciousness returned (GCS score 12), reaching its lowest point on the 24th day postinjury. Further improvement in neurological status (GCS score 15) was associated with an increase in blood flow, which by 125 days after injury was within normal limits. Such a U-shaped pattern is typical of hyperemic patients undergoing moderate to good recovery.

Figure 2 right illustrates delayed hyperemia in a patient with a left subdural hematoma that was considered too small for surgical evacuation. The initial study, obtained 13 hours postinjury, showed a reduced blood flow during coma (GCS score 5). By 36 hours the patient developed hyperemia, which persisted for 2 days and was accompanied by a significant increase in ICP. Subsequently, CBF declined when consciousness returned (GCS score 14), but remained subnormal in association with communicating hydrocephalus and impaired cognitive function.

Of particular interest in these two cases is the occurrence of significant hemispheral asymmetries (Fig. 2). During hyperemia, both patients showed a higher flow on the side of the lesion defined by CT scan, a phenomenon described previously.46 This is contrary to findings in patients with reduced flow, who usually have a lower CBF on the side of the lesion. It should be noted that the magnitude of the asymmetries is small relative to the large global CBF changes occurring over time.

Relationship of CBF to ICP

During the acute illness, 35 patients (47%) developed intracranial hypertension, defined as an ICP greater than 20 mm Hg recorded on at least two occasions, but usually involving sustained or repeated elevations ranging from 20 to 40 mm Hg. The remaining 40 cases (53%) did not have intracranial hypertension; that is, their ICP never exceeded 20 mm Hg. In classifying the patients, care was taken to exclude spuriously high ICP recordings attributable to suctioning, coughing, gross head movement, or improper transducer calibration.

Table 1 presents the CBF findings in these two ICP groups. Whereas 77% of the patients with ICP's greater than 20 mm Hg revealed hyperemia, only 23% had a consistently reduced flow. The reverse trend was found in patients with ICP's below 20 mm Hg: 35% of them showed hyperemia, while 65% had a reduced flow. The differences were highly significant statistically.

TABLE 1

CBF findings in two groups of head-injured patients classified according to ICP*

Acute CBF FindingsTotal CasesICP > 20 mm HgICP < 20 mm Hg
No.PercentNo.Percent  
hyperemia4127771435
reduced flow348232665
totals753510040100

The two intracranial pressure (ICP) groups differed significantly with respect to cerebral blood flow (CBF) (p < 0.001, chi-square test).

Although hyperemia was clearly associated with increased ICP, it also occurred in one-third of the patients with normal pressures. It should be noted, however, that many patients in the latter group were being vigorously treated for prevention of intracranial hypertension. In the absence of such therapy, the correlation between hyperemia and increased ICP might have been even higher.

Relationship of CBF to Age

Preliminary reports from this laboratory6,47 have suggested a relationship between CBF and age, specifically a higher incidence of hyperemia in young head-injured patients. Table 2 compares the CBF findings at three age levels in the present sample. Although there is a distinct predilection for younger patients to have hyperemia and for older patients to have reduced flow, hyperemia is not confined to the younger age group. Not only is there a relatively high incidence of hyperemia in the 21 to 39 year-old group, but two of the four oldest patients (over 70 years) revealed an absolute hyperemia in which CBF exceeded the upper limit of normal.

TABLE 2

CBF findings in three groups of head-injured patients classified according to age*

Acute CBF FindingsTotal Cases15–20 Yrs21–39 Yrs≥ 40 Yrs
hyperemia4119139
reduced flow3481115
total cases75272424

The three age groups differed significantly with respect to cerebral blood flow (CBF) (p < 0.02, chi-square test).

Arteriovenous Oxygen Differences

The difference between arterial and jugular venous O2 content provides a means of assessing the overall balance between cerebral metabolism and blood flow, thereby indicating the presence of global ischemia or hyperemia. This is evident from rearrangement of the Fick equation: AVDO2 = CMRO2/CBF.27 Thus, when CBF is low relative to the brain's metabolic needs (ischemia), a wide AVDO2 is obtained. Conversely, when CBF is high relative to metabolism (hyperemia), a narrow AVDO2 is obtained. The normal coupling of CBF and CMRO2 yields intermediate values.

As in the case of blood flow, AVDO2 varies with arterial CO2 tension. As long as CMRO2 remains constant, a reasonable assumption for most CO2 changes,39 CBF and AVDO2 will be reciprocally related. This permits an adjustment of AVDO2 which, although opposite in direction to CBF, is of the same magnitude; that is, approximately 3% change per mm Hg PaCO2. Such an adjustment was utilized in the present study to facilitate comparison of AVDO2 values at different CO2 levels. All values were adjusted to 34.0 mm Hg, the mean PaCO2 of the sample.

In order to identify global ischemia and hyperemia, it is necessary to define the normal limits of AVDO2. At a PaCO2 of 40.0 mm Hg, the normal mean AVDO2 is 6.3 vol%,28 with a range of 3.9 to 8.7 vol% (± 2 SD). Interpretation of the present results, however, requires an upward adjustment of these values, consistent with the lower mean PaCO2 of the sample. At a PaCO2 of 34.0 mm Hg, the normal AVDO2 is approximately 7.4 vol%, with a range of 5.0 to 9.8 vol%.

Evidence for Global Ischemia

In 164 determinations on 55 patients, only three cases had adjusted AVDO2 values exceeding 9 vol%, and only one was greater than 10 vol%. This result argues against significant ischemia, being well within chance deviation from normal. Even when raw (unadjusted) arteriovenous (AV) differences were considered, only 11 values exceeded 9 vol%, and all but one of these could be attributed to hyperventilation induced for therapeutic reasons (see Discussion).

The highest adjusted AVDO2 (10.7 vol%) occurred in an elderly head-injured patient with cerebrovascular disease, who at the time of the study had vasospasm on angiography. With this single exception, none of the AVDO2 measurements showed clear evidence of ischemia, in spite of significant CBF reductions in more than half of the cases. It should be emphasized, however, that these global findings do not rule out local or regional cerebral ischemia, nor do they preclude the occurrence of global ischemia prior to intensive care management or during periods of physiological instability when AVDO2 measurements were not obtained.

Evidence for Global Hyperemia

In contrast to the relative absence of wide AV differences indicative of ischemia, 34% of the adjusted AVDO2 values were below 4.0 vol%, which is suggestive of hyperemia. This finding is consistent with the high incidence of hyperemia defined independently by CBF, and argues for a correlation between AVDO2 and blood flow. A comparison was therefore made between AVDO2 measurements at two CBF levels: hyperemia and reduced flow, as previously defined.

Figure 3 and Table 3 present such a comparison based on a total of 73 examinations in 24 patients with hyperemia and 21 patients with reduced flow, there being no overlap between groups. To assure independence of the two groups, only studies during acute hyperemia were included in the hyperemic sample; measurements of reduced flow in these patients were excluded. Comparability of neurological status was achieved by limiting the studies to acute coma; all subacute and follow-up examinations were excluded.

Fig. 3.
Fig. 3.

Cerebral arteriojugular venous oxygen differences (AVDO2), expressed in vol%, for two groups of head-injured patients classified according to cerebral blood flow. Patients with reduced flow had normal AVDO2's, while those with hyperemia had significantly lower values. Means and standard deviations are presented in Table 3.

TABLE 3

Relationship between cerebral blood flow (CBF) and metabolism in comatose patients with acute head injury*

CBF GroupGCS ScoreCMRO2CBF15AVDO2
hyperemia6.3 ± 1.61.6 ± 0.547.4 ± 7.73.5 ± 1.1
reduced flow6.4 ± 1.91.4 ± 0.423.5 ± 5.46.1 ± 1.1
significance of differenceNSNSp < 0.001p < 0.001

Based on 38 studies in 24 patients with hyperemia and 35 studies in 21 patients with reduced flow. Values are means ± standard deviations. Cerebral metabolic rate for oxygen (CMRO2) and mean CBF for the fast and slow compartments (CBF15) are expressed in ml/100 gm/min; arteriojugular venous oxygen difference (AVDO2) is in vol%. Both CBF15 and AVDO2 were corrected to a PaCO2 of 34.0 mm Hg; no correction was applied to CMRO2. GCS = Glasgow Coma Scale; NS = not significant by t-test.

As shown in Table 3, the two CBF groups were equivalent with respect to both depth of coma (GCS score) and CMRO2, in spite of marked differences in CBF15 and AVDO2. By definition, the patients with hyperemia had CBF's above the lower limit of normal, while those with reduced flow had subnormal values. At the assumed PaCO2 of 34.0 mm Hg, the normal value for CBF15 is 44.1 ± 5.6 ml/100 gm/min (mean and SD). Of special interest in Table 3 is the significant difference in AVDO2 between blood flow groups. This difference is of the same magnitude but opposite in direction to the difference in CBF15. Because AVDO2 and CBF15 vary inversely, their product yields a relatively constant CMRO2.

Figure 3 compares the distribution of adjusted AV differences in the two CBF groups. While most of the hyperemic patients had AVDO2's less than 4.0 vol%, which is below the normal range, the majority of patients with reduced flow had values between 6.0 and 9.0 vol%, which is within the normal range.

The finding of a narrow AV difference in the hyperemic group offers confirmation of the original CBF diagnosis of hyperemia. Because AVDO2 and CBF15 were independently derived, being based on different methodologies, their substantial agreement provides a cross-validation of the techniques.

Relationship of CBF to Metabolism

As noted earlier, the occurrence of a high CBF in comatose patients with depressed metabolism suggests an uncoupling of the two variables. On the other hand, a proportional reduction of blood flow and metabolism would be consistent with normal coupling. Figure 4 shows the relationship between CBF15 and CMRO2, plotted separately for patients with hyperemia and reduced flow. The sample is the same as described in Table 3.

Fig. 4.
Fig. 4.

Cerebral blood flow (CBF15) plotted against cerebral metabolic rate for oxygen (CMRO2), both expressed in ml/100 gm/min. The reduced flow group shows coupling between CBF and metabolism (r = +0.79, p < 0.001), as revealed by the data points around the regression line. In contrast, the hyperemic group clearly shows uncoupling (r = +0.16, not significant). Means and standard deviations are presented in Table 3.

It is apparent from Fig. 4 that little or no correlation exists between CBF and metabolism in the hyperemic group. A product-moment correlation of +0.16 was obtained, which is not significantly different from zero. In contrast, patients with reduced flow gave a highly significant correlation of +0.79, as revealed by the approximation of data points to the regression line.

These results, in combination with the AVDO2 findings, support the hypothesis that reduced CBF in comatose head-injured patients is a consequence of normal metabolic coupling, rather than an indication of cerebral ischemia. The results also suggest that normal or supernormal flows in this condition constitute a luxury perfusion in which CBF and metabolism become uncoupled.

CBF Response to Hyperventilation

Responses of CBF to a change in arterial pCO2 (Δ PaCO2) were determined acutely in 31 patients, 20 of whom were tested within 24 hours of injury. Seventeen patients were undergoing hyperventilation therapy at the time. Because of intracranial hypertension, some patients were unable to tolerate large PaCO2 increases; nevertheless, a minimum change of 5 mm Hg was induced in all cases. The mean Δ PaCO2 for the group was 10.6 mm Hg, with a range of 5 to 20 mm Hg. Although 14 patients showed mean arterial pressure changes of 5 to 15 mm Hg, there was no systematic difference between PaCO2 levels, since blood pressure increases equaled decreases.

Both absolute and relative CBF responses to hyperventilation were calculated.1 Absolute reactivity was defined as CBF change (Δ CBF15) per mm Hg of Δ PaCO2. Relative reactivity was defined as percent CBF change (Δ CBF15/CBF15) per mm Hg of Δ PaCO2.

Compared to the normocapnic condition, CBF declined with hyperventilation in 29 patients, all of whom had a relative reactivity greater than 1.0%. The remaining two cases showed no response, there being a slight increase in CBF with hyperventilation. Both of these patients underwent neurological decompensation and died within a few days. A decrease in ICP of 3 to 11 mm Hg was produced by hyperventilation in 15 cases; the remaining patients showed no change during the test.

In order to determine the effectiveness of hyperventilation at different blood flow levels, CBF responses were compared in two separate groups of patients: those with acute hyperemia, and those with reduced flow. Table 4 presents such a comparison in the 29 CO2-reactive cases. One unresponsive patient in each group was excluded. As shown in Table 4, absolute CO2 reactivity was significantly greater during hyperemia than during reduced flow. Although there is a trend in the same direction, relative reactivity was not significantly different between groups. For the combined sample, the mean relative reactivity was 2.9%, which compares favorably with average values reported in the literature.1

TABLE 4

CBF reactivity to hyperventilation in acute head injury: comparison of two CBF groups*

CBF GroupNo. of CasesAbsolute Reactivity (Δ CBF15/Δ PaCO2)Relative Reactivity (% Δ CBF15/Δ PaCO2)
hyperemia161.4 ± 0.43.3 ± 1.1
reduced flow130.7 ± 0.32.4 ± 0.9

Absolute, but not relative, reactivity was significantly greater in the hyperemic group (p < 0.002, Mann-Whitney U-test). The symbol Δ denotes changes associated with hyperventilation. CBF = cerebral blood flow. Δ CBF15 is expressed in ml/100 gm/min. The mean Δ PaCO2 for the sample was 10.6 mm Hg.

These results indicate that hyperventilation is effective in reducing CBF in acute head injury, especially in patients with hyperemia. Four hyperemic patients retested after 48 hours of prolonged hyperventilation showed no adaptation of the response. The incidence of impaired CO2 reactivity appears to be low, and probably occurs only as a preterminal phenomenon.

Discussion
Methodological Considerations

An important feature of the present study was the simultaneous determination of CBF and AVDO2. Since blood flow varied widely from very low to high values, knowledge of AVDO2 was crucial in its interpretation. Thus, most low CBF's did not indicate ischemia, as evidenced by normal AV differences, while most normal CBF's indicated hyperemia, as evidenced by narrow AVDO2's (Table 3). Without the AVDO2 data, entirely different interpretations might have been made.52

Serial studies also contributed to the interpretation of results by providing insight into the time course of hemodynamic changes. Thus, twofold differences in CBF over short time intervals were used to identify transitions between hyperemia and reduced flow (Fig. 2). Although transient, the average duration of hyperemia was 3 days, making it unlikely that instances of high CBF were left undetected by serial examination. The irregular timing of the studies, however, precluded accurate determinations of the onset and resolution of hyperemia, as well as assessment of its maximum value. For this reason, the proportion of both delayed and absolute hyperemias may have been greater than the one-third cases observed.

It should be emphasized that the overall incidence of hyperemia (55%) is a function of patient selection; that is, the analysis was limited to patients who were acutely comatose. Patients who were not in coma or who were initially studied later than 96 hours after injury showed little evidence of hyperemia. In 28 such cases (excluded from the sample), 24 had reduced flows.

Both the CBF classification of patients and CMRO2 determinations were based on bilateral blood flow measurements averaged across 16 brain regions. The use of such an average appears justified, since CBF changes in these patients were primarily global. Although significant regional and hemispheral differences occurred in 65% of the cases, they were of lesser magnitude, being superimposed on more generalized increases or decreases in flow. Similar generalized CBF changes have been observed by others in both acute head injury13,54 and stroke.40,55 To some extent, however, the predominance of global findings can be attributed to the limited spatial resolution of the present blood flow method.

Since variations in PaCO2 are normally a critical determinant of both CBF and AVDO2,39 differences in CO2 level between and within patients could easily override the influence of pathophysiological factors and obscure significant relationships. Meaningful interpretation of the results therefore required an adjustment of these variables for PaCO2. The validity of such an adjustment was supported by the normal CO2 reactivity observed in 29 of 31 tested patients. Individual differences in reactivity, however, made it desirable to minimize the magnitude of the CO2 correction. This was accomplished by adjusting both CBF15 and AVDO2 to the mean PaCO2 of the sample (34.0 mm Hg), rather than to some arbitrary level. In all but nine patients, serial studies provided one or more acute observations in the normocapnic range that required only small adjustments.

Significance of Reduced Flow

The most common finding in the present study was a low CBF, which occurred not only in patients classified as having reduced flow, but also preceding and following the high-flow phase in patients with hyperemia. Yet in spite of this finding, only one of 55 cases with metabolic determinations had a wide AVDO2 indicative of global cerebral ischemia, and this was an elderly patient with concurrent cerebrovascular disease. The presence of normal AV differences in patients with reduced flow (Fig. 3), along with the significant correlation between CBF and CMRO2 in such patients, strongly suggests that the observed CBF reductions are secondary to a depressed metabolism, rather than a sign of cerebral ischemia.

The lack of evidence for global ischemia would appear to be inconsistent with the high incidence of postmortem ischemic brain damage described by Adams and Graham2 in patients with severe head injury. The frequent occurrence of systemic ischemia and hypoxia before hospital admission43 offers a possible explanation. Indeed, 12 patients in the present series experienced profound episodes of hypotension/hypoxemia prior to intensive care, and other undocumented cases undoubtedly occurred. All of the patients, however, were physiologically stable by the time of their CBF examinations. In some cases, ICP elevations of 20 to 40 mm Hg were present during the studies, but adequate cerebral perfusion pressures were always maintained. Additional episodes of agonal cerebral ischemia (hypotension/elevated ICP) were documented in eight preterminal cases, but CBF studies were not performed at that time. Although observed in only one case, the occurrence of vasospasm in the early posttraumatic period74 is yet another possibility that could explain the production of ischemic brain damage.

The extent to which cerebral ischemia occurs during intensive care management is not clear. The present finding of normal AV differences in patients with reduced flow is based on steady-state values adjusted for PaCO2. During routine care, however, some patients may experience wide AV differences approaching ischemic levels, particularly at times of physiological instability or during the course of hyperventilation therapy. Frequent serial observations obtained in five of the patients revealed large perturbations in AVDO2, primarily in association with PaCO2 changes. These results will be reported separately.

Even in the absence of global ischemia, the possibility remains that purely regional ischemia exists which is not detectable by AV differences across the entire brain. The ischemic foci may be too small, or their effect on AVDO2 may be cancelled by coexisting hyperemic foci. Heterogeneous perfusion of the type found in animal models of ischemia16 might well occur following acute head injury. This would seem most likely in patients with ICP elevations who have focal swelling that produces brain compression and distortion. It remains for positron emission tomography (PET), and possibly nuclear magnetic resonance studies, to reveal the extent of local ischemic changes. Focal increases in oxygen extraction ratio, indicative of ischemia, have been reported in PET studies of acute stroke,35 which raises the possibility of comparable findings in acute head injury.

Significance of Hyperemia

Perhaps the most relevant clinical finding in the present study is the occurrence of acute hyperemia in over half of the patients and its association with intracranial hypertension (Table 1). The observation that a normal or supernormal CBF during coma is accompanied by a narrow AVDO2 argues strongly that such flows are a luxury perfusion. The high incidence of hyperemia is not surprising, however, since most previous CBF studies on head injury have made similar observations.7,9,11,53,54 Indeed, Fieschi and coworkers13 anticipated the present findings by noting that high CBF's were associated with both an elevated ICP and increased jugular venous pO2 (narrow AV difference).

No attempt was made here to obtain correlations between CBF and ICP in the same patient over time, which would have required more frequent blood flow examinations. Rather, an overall relationship between these variables was found, such that most cases who developed intracranial hypertension (77%) had hyperemia, while most cases whose ICP remained normal (65%) had reduced flow. The occurrence of hyperemia in 35% of patients with normal ICP probably reflects the vigorous attempt to control intracranial hypertension. Even though ICP never exceeded 20 mm Hg in these patients, a number of them showed evidence of low brain compliance during routine postural manipulation and CO2 reactivity tests. It seems likely that under conditions of therapy, an abnormal volume-pressure relationship41 would be more predictive of hyperemia than ICP level per se.

The most probable explanation for the relationship between hyperemia and ICP is an increase in cerebral blood volume (CBV).33 If blood flow is doubled, as in some patients with absolute hyperemia, CBV might be expected to increase by 30%,21 or as much as 15 cc. Even patients with a normal CBF (those with relative hyperemia) could have increased CBV if diminished cerebral perfusion pressure induces compensatory vasodilatation. In an experimental study by Grubb, et al.,22 CBF remained at normal levels following cisternal cerebrospinal fluid (CSF) infusion, while blood volume and ICP progressively increased. When intracranial compliance is already low due to the presence of extravascular blood, cerebral edema, or poor CSF drainage, only minor increases in blood volume may be sufficient to cause significant ICP elevations.41

Although edema undoubtedly contributes to intracranial hypertension, phasic changes in ICP, including “plateau waves,”63 are probably best explained by rapid circulatory adjustments. Since edema on CT scan is not fully apparent until several days after injury,8,75 it may contribute more to later ICP elevations than to those occurring initially. There is reason to believe that edema, itself, may be exacerbated by hyperemia when CBF autoregulation fails and there is increased capillary hydrostatic pressure.38,64

Factors Relating to Hyperemia

One of the principal differences between patients with reduced flow and hyperemia is the magnitude of the correlation between CBF and metabolism (Fig. 4). Whereas patients with reduced flow showed the expected coupling between CBF and CMRO2,57,60 hyperemic patients revealed uncoupling (blood flow was no longer under metabolic control). A possible explanation for such uncoupling is a decrease in cerebral vasomotor tone, which is suggested by the consistent finding of impaired CBF autoregulation to blood pressure changes in patients with hyperemia.7,11,13,17,53 A total loss of vasomotor reactivity seems unlikely, however, since most head-injured patients retain some degree of responsiveness to PaCO2 changes. Selective impairment of this type (defective autoregulation and preserved CO2 reactivity) has been described by Paulson and coworkers,55 who referred to it as “dissociated vasoparalysis.”

Hyperemia is probably not a necessary consequence of impaired CBF autoregulation, since head-injured patients with reduced flow have also been found to have such impairment.53 Interpretation of most autoregulation studies, however, has been complicated by the absence of metabolic data needed to establish the presence of hyperemia or ischemia, and by the possible occurrence of “false autoregulation” attributed to concomitant changes in tissue pressure.12 Clearly, further research is needed to define more precisely the relationship between hyperemia and disturbed vasomotor regulation.

In his paper on luxury perfusion, Lassen34 argued that the most likely cause of hyperemia was metabolic acidosis of the brain brought about by increased lactic acid production. There is now abundant evidence that patients with acute head injury have CSF lactacidosis, as revealed by a low pH, reduced bicarbonate, and elevated lactate levels.11,29,53,65 Even more compelling is the direct association of hyperemia with CSF lactacidosis in head injury,77 and the finding of increased tissue lactate in hyperemic regions around brain tumors.24 Although other vasoactive agents or disturbances in neurogenic control undoubtedly contribute to hyperemia, metabolic acidosis appears to be an important factor.

Several conditions known to produce metabolic acidosis of the brain have been implicated in the production of hyperemia. These include cerebral ischemia,23,68 hypoxia,14 and seizures,5 all of which have been shown experimentally to result in reactive hyperemia that may last for several hours. Consistent with these findings is the occurrence of hyperemia in patients with acute stroke51 and cardiac arrest.3 In the present series, an attempt was made to identify early posttraumatic events that might trigger hyperemia. As described above, 12 patients had severe hypotensive/hypoxemic episodes, and 12 other patients had clinical seizures either before or during their CBF studies. Although prior ischemic episodes and seizures were each twice as prevalent in patients with hyperemia as opposed to reduced flow, the differences were not significant in this small sample. Furthermore, the irregular timing of the studies did not permit establishment of any temporal relationship. It is clear that further observations are needed, including more precise documentation of such episodes and earlier, more frequent CBF examinations.

Hyperemia may also be triggered by large surges in systemic arterial pressure that break through the upper limit of CBF autoregulation.67 Profound increases in arterial pressure, often accompanied by ICP elevations, have been observed immediately following experimental brain trauma.31,73 It is not unreasonable to believe that such events, although transient, may interfere with subsequent control of the cerebral circulation.

A relationship between type of brain lesion and hyperemia has been reported by Enevoldsen and coworkers,11 who found focal CBF increases primarily in regions of cortical contusion and laceration. In the present series, there was no significant difference in CT-defined lesions between patients with global hyperemia and reduced flow, other than the expected higher incidence of diffuse cerebral swelling in the hyperemic group.48 Analysis of the regional CBF data, however, suggested a possible relationship. Six hyperemic patients had small subdural hematomas that were either not evacuated or incompletely removed, and all six had significantly higher flows in the hemisphere with the lesion. The latter is consistent with the observation of Kuhl, et al.,30 who found localized increases in blood volume adjacent to subdural hematomas. Whether a particular type of lesion can produce and sustain hyperemia, or account for its evolution over time, is an intriguing question for future research.

Effects of Hyperventilation

Hyperventilation was effective in reducing CBF in 29 of 31 patients, there being only two cases with a complete loss of responsiveness. These results are in accord with previous findings of preserved CO2 reactivity following head injury,12,13,25,53 but as in the earlier studies, large individual differences were observed (Table 4). The loss of responsiveness in two preterminal cases agrees with the conclusion of Overgaard and Tweed53 that impaired CO2 reactivity is an unfavorable prognostic sign.

The significance of CO2 reactivity lies in its relevance to hyperventilation as a means of controlling ICP. The fact that CBF responsiveness is preserved in most head-injured patients argues for the effectiveness of hyperventilation therapy. Since patients with hyperemia are more likely to develop intracranial hypertension than those with reduced flow, their relatively greater responsiveness is of potential therapeutic value.

Reductions in ICP during hyperventilation can be attributed to cerebral vasoconstriction with a consequent reduction in blood volume.20,21 Because hyperventilation induces respiratory alkalosis, it may also be beneficial in reversing metabolic acidosis of the brain. Of particular interest is the finding of Paulson, et al.,55 that hypocapnia restores CBF autoregulation in patients with global hyperemia.

Previous reports have suggested that both CBF58 and ICP26 become refractory to prolonged hyperventilation. Adaptation of the CBF response may depend on accumulation of lactic acid in the brain, which occurs with intense hyperventilation and has been attributed to mild cerebral ischemia.56,61 If ischemia is in fact responsible for adaptation of the CBF response, then it follows that patients with hyperemia would be less refractory to prolonged hyperventilation. This is consistent with observations in four of the hyperemic patients, who retained their CO2 reactivity after 48 hours of hyperventilation therapy. Preservation of CO2 reactivity, however, does not assure the continued effectiveness of hyperventilation with respect to ICP, since progressively increasing edema may offset reductions in blood volume.

The possibility arises that hyperventilation in patients who already have a reduced flow may produce excessive vasoconstriction that could result in cerebral ischemia. Table 5 presents findings in 10 patients with reduced flow who developed a wide AVDO2 (9 to 12 vol%) during hyperventilation therapy. These patients had a GCS score of 4 to 9 (mean 6.4) and PaCO2 of 23.2 ± 2.8 mm Hg. Whereas CMRO2 was higher in these patients than in the series as a whole (Table 3), CBF15 was substantially lower, so that blood flow was decreased relative to metabolic requirements. Whether the CBF reduction was sufficient to cause ischemia cannot be determined with certainty. However, the values for jugular venous oxygen tension (VpO2) are in a range found to produce electroencephalographic slowing and disturbances of consciousness in normal subjects.18 Since both AVDO2 and VpO2 represent averages for the whole brain, it is reasonable to expect that some local regions may deviate even more in the direction of ischemia. Although not conclusive, these findings suggest that hyperventilation therapy should be administered selectively. Similar observations have led others19 to caution against the excessive use of hyperventilation. Fortunately, hyperemic patients in whom such therapy is most indicated stand the least risk of developing cerebral ischemia.

TABLE 5

Findings in 10 patients with wide AVDO2's*

Hemodynamic VariableHyperventilated PatientsNormal Value (PaCO2 ≈ 40)
CMRO21.9 ± 0.53.3 ± 0.4
CBF1518.6 ± 4.453.3 ± 6.8
AVDO210.5 ± 0.76.3 ± 1.2
VpO222.3 ± 1.837.5 ± 5.6

Values are means ± standard deviations obtained 10 to 85 hours postinjury. AVDO2 = arteriovenous oxygen differences (in vol%); CMRO2 = cerebral metabolic rate for oxygen (in ml/100 gm/min); CBF15 = mean cerebral blood flow of fast and slow compartments (in ml/100 gm/min); VpO2 = jugular venous oxygen tension (in mm Hg).

Normal values were obtained as follows: CMRO2 and AVDO2 from Kety and Schmidt,28 VpO2 from Dastur, et al.,10 and CBF15 from the present control series.

Implications for Patient Management

Intracranial hypertension is perhaps the most critical problem in the management of acute head injury, as evidenced by the substantially poorer outcome of patients with an elevated ICP.37,44,48 Because even modest increases in ICP can have serious consequences due to herniation and resulting brain-stem compression, control of ICP becomes a primary therapeutic goal.

The present findings suggest that cerebral circulatory factors exert an important influence on ICP, particularly the presence or absence of acute hyperemia. Information on CBF and AVDO2 has provided insight into the pathophysiology of head injury, which has clear implications for control of ICP. The question arises whether such information, obtainable by simple bedside procedures, can be useful in routine patient management.

Certainly in the case of hyperventilation, knowledge of hemodynamic variables could contribute to decisions regarding the appropriateness, magnitude, and timing of the therapy. This subject will be addressed in a separate paper by the authors (J Cruz, et al., in preparation, 1984). Application of CBF and AVDO2 methodology to other therapies, such as administration of mannitol or barbiturates, is currently underway in this laboratory and elsewhere. Its value in the broader spectrum of patient management awaits further investigation.

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    Wilkins RH: Intracranial vascular spasm in head injuriesVinken PJBruyn GW (eds): 23. Amsterdam: North-Holland1975163197

  • 75.

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  • 76.

    Zimmerman RABilaniuk LTGennarelli TAet al: Cranial computed tomography in diagnosis and management of acute head trauma. AJR 131:27341978AJR 131:

  • 77.

    Zupping R: Cerebral acid-base and gas metabolism in brain injury. J Neurosurg 33:4985051970Zupping R: Cerebral acid-base and gas metabolism in brain injury. J Neurosurg 33:

Co-oximeter manufactured by Instrumentation Laboratory, Inc., 113 Hartwell Avenue, Lexington, Massachusetts.

This research was supported by Grant NS 08803 from the National Institute of Neurological and Communicative Disorders and Stroke.

Article Information

Address reprint requests to: Walter D. Obrist, Ph.D., Division of Neurosurgery, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Mean and standard error (SE) of cerebral metabolic rate (CMRO2) plotted against the Glasgow Coma Scale (GCS) score.70,71 The CMRO2 is expressed in ml/100 gm/min. The findings are based on 186 studies in 65 patients. The number of observations at each GCS score level is: 36, 74, 34, 30, and 12, respectively, from left to right. Patients with GCS scores of 8 or less had CMRO2's below 1.6 (dashed line), which is less than half of the normal mean value of 3.3 ml/100 gm/min.28

  • View in gallery

    Left: Case 23. Serial cerebral blood flow (CBF) measurements plotted against days postinjury in a patient with a large left epidural hematoma that was surgically evacuated prior to the first study. F1 = fast compartment blood flow; CBF15 = mean blood flow for the fast and slow compartments. The CBF estimates were averaged across eight regions in each hemisphere and adjusted to the patient's median PaCO2 of 37.0 mm Hg. An initial hyperemia was followed by a reduction in flow that returned to the normal range as recovery progressed. An acute hemispheral asymmetry (left > right) was reversed on the final examination (right > left), at which time the patient had a mild residual aphasia. See text for further details. Right: Case 16. Serial CBF measurements plotted against time (hours and months) in a patient with a small left subdural hematoma that was not surgically evacuated. A delayed hyperemia at 36 to 82 hours was preceded and followed by a reduction in flow that remained subnormal in association with hydrocephalus and dementia. Administration of 100 gm mannitol (MANN) at 14 hours yielded a small but significant increase in CBF compared with the control value (CTRL). Cerebrospinal fluid drainage via lumbar puncture (LP) at 5 months failed to produce a change in flow. See text for further details.

  • View in gallery

    Cerebral arteriojugular venous oxygen differences (AVDO2), expressed in vol%, for two groups of head-injured patients classified according to cerebral blood flow. Patients with reduced flow had normal AVDO2's, while those with hyperemia had significantly lower values. Means and standard deviations are presented in Table 3.

  • View in gallery

    Cerebral blood flow (CBF15) plotted against cerebral metabolic rate for oxygen (CMRO2), both expressed in ml/100 gm/min. The reduced flow group shows coupling between CBF and metabolism (r = +0.79, p < 0.001), as revealed by the data points around the regression line. In contrast, the hyperemic group clearly shows uncoupling (r = +0.16, not significant). Means and standard deviations are presented in Table 3.

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