Recurrent spreading depolarizations after subarachnoid hemorrhage decreases oxygen availability in human cerebral cortex

Abstract

Objective: Delayed ischemic neurological deficit (DIND) contributes to poor outcome in subarachnoid hemorrhage (SAH) patients. Because there is continuing uncertainty as to whether proximal cerebral artery vasospasm is the only cause of DIND, other processes should be considered. A potential candidate is cortical spreading depolarization (CSD)-induced hypoxia. We hypothesized that recurrent CSDs influence cortical oxygen availability.

Methods: Centers in the Cooperative Study of Brain Injury Depolarizations (COSBID) recruited 9 patients with severe SAH, who underwent open neurosurgery. We used simultaneous, colocalized recordings of electrocorticography and tissue oxygen pressure (p(ti)O(2)) in human cerebral cortex. We screened for delayed cortical infarcts by using sequential brain imaging and investigated cerebral vasospasm by angiography or time-of-flight magnetic resonance imaging.

Results: In a total recording time of 850 hours, 120 CSDs were found in 8 of 9 patients. Fifty-five CSDs ( approximately 46%) were found in only 2 of 9 patients, who later developed DIND. Eighty-nine ( approximately 75%) of all CSDs occurred between the 5th and 7th day after SAH, and 96 (80%) arose within temporal clusters of recurrent CSD. Clusters of CSD occurred simultaneously, with mainly biphasic CSD-associated p(ti)O(2) responses comprising a primary hypoxic and a secondary hyperoxic phase. The frequency of CSD correlated positively with the duration of the hypoxic phase and negatively with that of the hyperoxic phase. Hypoxic phases significantly increased stepwise within CSD clusters; particularly in DIND patients, biphasic p(ti)O(2) responses changed to monophasic p(ti)O(2) decreases within these clusters. Monophasic hypoxic p(ti)O(2) responses to CSD were found predominantly in DIND patients.

Interpretation: We attribute these clinical p(ti)O(2) findings mainly to changes in local blood flow in the cortical microcirculation but also to augmented metabolism. Besides classical contributors like proximal cerebral vasospasm, CSD clusters may reduce O(2) supply and increase O(2) consumption, and thereby promote DIND.

Figures

FIGURE 1

X-ray topographic images and cranial computed tomography (CT) slices of Patients 1 and 2 with individual locations of the electrocorticography (ECoG) strip electrodes (arrows, CT artifacts of electrodes) and the oxygen partial pressure probes (arrowheads) adjacent to strip electrodes. Please note that levels of axial sections differ somewhat among scans. The upper level shows Patient 1, with subarachnoid hemorrhage predominantly in the sylvian fissure with additional intraparenchymal hemorrhage and perifocal space-occupying edema. (A-D) A CT scan was performed after decompressive craniectomy with ECoG and tissue oxygen pressure (ptiO2) probe implantation 2 days after subarachnoid hemorrhage (SAH). (A) In the topogram, the arrows represent 6 single electrodes of the ECoG strip electrode. The arrowhead demarcates the ptiO2 probe. (B) The arrow indicates electrode 2. (C) Arrows indicate electrodes 3 and 4, respectively. (D) The arrow indicates electrode 5, and the arrowhead demarcates the ptiO2 probe. (E) Perfusion-weighted (PW) magnetic resonance imaging (MRI) and (F) diffusion-weighted (DW) MRI show no perfusion deficit or signs of cortical ischemia 4 days after SAH. The area of intracranial hemorrhage displays disturbance of the diffusion signal. (G) PW MRI and (H) DW MRI demonstrate areas of hypoperfusion and signs of cortical ischemia predominantly of the right frontal lobe, but also of the left frontal lobe 9 days after SAH. (I) MRI (T1 weighted) shows infarcted cortical tissue. (J) A T2-weighted MRI cross-section (more rostral) gives a detailed picture of the distribution of cortical infarcts with right frontoparietal and bifrontal representation. The lower level shows Patient 2, who suffered a subarachnoid hemorrhage from a ruptured aneurysm, which was clipped surgically 2 days after SAH. Cranial CT scan was performed 1 day after the craniotomy and ECoG and ptiO2 probe implantation. (K) X-ray topogram and (K-M) 2 different slices are depicted. (K) Six arrows indicate the ECoG strip with 6 single electrodes. The arrowhead demarcates the ptiO2 probe. (L) The arrows indicate electrodes 1, 2, and 3; the arrowhead indicates the ptiO2 probe between electrodes 2 and 3. (M) All 6 electrodes are displayed; however, the ptiO2 probe is not visible on this cross section. (N) Seven days after SAH, PW MRI showed no hypoperfusion, and (O) DW MR imaging revealed no signs of ischemia (disturbance of diffusion). (P) The same was true for the T1-weighted MRI and also (Q) for T2-weighted MRI (see Supplementary Clinical Results online for a more detailed description of the 2 individual clinical courses).

FIGURE 2

Subdural electrocorticography (ECoG). (A) A representative electrocorticogram 5 days after subarachnoid hemorrhage (SAH) over a time period of 40 minutes (Patient 2). The upper 4 traces (channels A, B, C, and D) demonstrate the high-passed filtered ECoG data. The ECoG displays a cortical spreading depression (CSD, arrows) propagating from channel B through C to D. The middle 4 traces show the integrals of each ECoG channel, with the corresponding integral changes indicated with arrows. The lowermost 4 show the power of ECoG and the rapid reduction of power due to the CSD. Time period from arrows to hash symbols represents the duration of the CSD4; channel D shows the longest duration of this typical CSD. Scales shown in channel D are also representative for the channels A, B, and C, respectively. (B) Schema of ECoG electrode strip: 5 bipolar electrodes generate the 4 channels: A, B, C, and D. The 6th electrode can be used as ground. (C) Histogram of CSD occurrence in SAH patients (n = 8; for day 1, n = 6) demonstrates that most CSDs (89 of 120 CSDs, ∼75%) occur between the 5th and 7th day after SAH.

FIGURE 3

Coregistration of electrocorticography (ECoG) and tissue oxygen pressure (ptiO2). (A) A cluster of repetitive cortical spreading depolarizations (CSDs) in association with transient biphasic ptiO2 responses demonstrated in the coregistration of ECoG (lower line) and ptiO2 measurement (upper line) of a subarachnoid hemorrhage patient over a time period of 10 hours (Patient 5). Channel D (integral [int.]) is shown. The 3 CSDs are marked by the arrows; arrowheads demonstrate the corresponding biphasic ptiO2 responses. The long time period and the low baseline level of the ECoG integral reveal the spatial and temporal association with ptiO2 responses. (B) The enlargement of temporal resolution of a certain time period (rectangle in part A) and the addition of a second ECoG channel (C) (raw data and integral) reveal the exact CSD propagation (arrows) from channel D to C and the clear temporal relationship with the corresponding biphasic ptiO2 response (arrowhead).

FIGURE 4

Three different types of tissue oxygen pressure (ptiO2) responses are found in the cortex of subarachnoid hemorrhage (SAH) patients in spatial and temporal association with cortical spreading depolarizations (CSDs). (A) Biphasic ptiO2 response with an initial decrease and a secondary increase, monophasic ptiO2 decrease, and monophasic ptiO2 increase. Arrows indicate the start of CSD in the electrocorticography (ECoG) channel next to the ptiO2 probe. (B) Magnification of the biphasic ptiO2 response of part A. Further detailed ptiO2 response analyses reveal values of specific features, integrals, and subareas of the ptiO2-curve: BASE = ptiO2 at baseline (30.60 [25.25, 36.70] mmHg), MINhypo= the minimum (23.90 [16.75, 32.38] mmHg), DURhypo= the duration (345 [207.5, 502.5] seconds), and INThypo= the integral (12.76 [3.87, 18.94] arbitrary units [aU]) of the initial hypoxic phase. descINThypo= (grey-shaded) integral representing the phase we designate “descent area,” that is, the area under the curve from start to minimum of the hypoxic phase. MAXhyper= the maximum (38.00 [28.30, 45.00] mmHg), DURhyper= the duration (720.0 [540.0, 1090.0] seconds), and INThyper= the integral (40.00 [12.50, 124.28] aU) of the secondary hyperoxic phase; ascINThyper= second (grey-shaded) integral depicting an ascent area, that is, the area from start to maximum of the secondary hyperoxic phase. In some cases (compare with Fig 4A), ptiO2 shows an asymptotic return to ptiO2 baseline, which may distort curve analysis; thus the grey-shaded areas are additionally scrutinized to avoid this distortion. (C) Relative percentage frequencies of different ptiO2 responses to ECoG events (90 CSDs). Clear spatial and temporal associations of ptiO2 responses with EcoG events are found in 53.3 (42.7, 67.1)% of the CSDs (in total 47 of 90 CSDs, with association rates up to 90% in single individuals). The differentiation of all CSD-associated ptiO2 response types demonstrates that the biggest portion is contributed by biphasic ptiO2 responses (Bi); monophasic increases (MI) were rare in the severe SAH patients, and monophasic decreases (MD) were more frequent. (D) The 3 different ptiO2responses (compare with part C) in total ∼100% and their distribution of SAH patients with no ischemic neurological deficit (DIND) (white bars) versus SAH patients with DIND (black bars). All monophasic ptiO2 increases were found in SAH patients with no DIND and good outcome (extended Glasgow Outcome Scale ≥ 6). Biphasic ptiO2 responses were approximately similar in both patient groups, whereas monophasic decreases were typically found in patients developing DIND.

FIGURE 5

Cortical spreading depolarization (CSDs) within clusters and corresponding tissue oxygen pressure (ptiO2) responses. (A) An example (taken from Patient 1, 6 days after subarachnoid hemorrhage [SAH]) of 4 repetitive CSD-associated ptiO2 responses within a cluster (arrows in A–C represent start of CSD). The 1st ptiO2 response was biphasic, the 2nd and 3rd showed stepwise augmentation of primary hypoxic phases of the ptiO2 responses with subsequent small or almost nonexisting secondary hyperoxic phases, and the 4th showed a drastically enlarged hypoxic phase. Please note that particularly in the 4th ptiO2 response, the baseline level was not restored. This example shows an immediate transition from a biphasic to a monophasic decrease pattern of the ptiO2 response and may therefore reveal a change from normal to inverse neurovascular coupling and/or increased oxygen consumption, with the likelihood of secondary cortical ischemia after SAH. (B) The second example (taken from Patient 2, 7 days after SAH) of 4 repetitive CSD-associated ptiO2 responses within a cluster (arrows, see above). The primary hypoxic phases were stepwise slightly enlarged beginning with the 1st, then the 2nd, 3rd, and 4th response; however, a similar extension was seen in the secondary hyperoxic phases. In this example, all ptiO2 responses were biphasic in nature, and the ptiO2 baseline level was subsequently reestablished or even slightly exceeded, possibly representing normal (compensatory hyperemic) neurovascular coupling and/or simply transiently increased oxygen consumption not leading to ischemic transformation after SAH. (C) Examples of 2 CSD-associated ptiO2 responses with a rapid sequence of CSDs. Note that the period from 1st to 2nd CSD lasts only ∼12 minutes. The first ptiO2 response showed a biphasic pattern with a small hypoxic and a relatively large secondary hyperoxic phase, whereas the 2nd response revealed a deeper and prolonged hypoxic phase without a secondary hyperoxic phase, that is, a monophasic decrease of ptiO2. This example demonstrates a rapid transition from biphasic to monophasic decreasing ptiO2 pattern, perhaps due to the very small period between 2 repetitive CSDs. (D, E) Analysis of CSDs and corresponding ptiO2 responses within clusters. Box plots represent CSDs categorized by their specific order (1st, 2nd, 3rd, and ≥4th) showing median, quartiles, and full range of data. CSD-associated hypo- and hyperoxic ptiO2 response phases (areas of descINThypo or ascINThyper, see Fig 4B) are shown. With ascending order of CSDs within the clusters (D) areas of the initial hypoxic phase increased significantly in a stepwise fashion within clusters (n = 5, p = 0.011, Friedman test). (E) Areas of the secondary hyperoxic phase showed no significant alterations (n = 5, not significant); however, CSDs ≥4th in a cluster suggested a trend to higher areas. aU = arbitrary units.