Temporal Dynamics of Cerebral Blood Flow During the Acute Course of Severe Subarachnoid Hemorrhage Studied by Bedside Xenon-Enhanced CT

Unconscious patients with SAH, treated in our neuro-intensive care (NIC) unit, are as a routine scheduled for measurement of CBF using bedside xenon-enhanced computed tomography (XeCT) at day 0–3, 4–7, and 8–12. As mechanical ventilation is mandatory for the bedside XeCT procedures in our setting to ensure patient safety and image quality, only unconscious patients with severe SAH requiring intubation are examined. Patients who improve sufficiently to be extubated in the early course have no further CBF measurements.

During the time period 2013–2016, patients with CT verified spontaneous SAH and a valid baseline XeCT CBF measurement within day 0–3 were prospectively included in this study, and clinical data and measurements were collected accordingly. Patients with further XeCT procedures also at day 4–7 or at day 4–7 and 8–12 were allocated into subgroups (subgroup 04 and 048, respectively) to enable comparison of CBF over time. Exclusion criteria were severe intracranial hypertension, deep sedation with thiopental, respiratory problems requiring FiO2 > 0.6 (which precludes XeCT), futility or “do not resuscitate” order, and inability to obtain consent from the patients next of kin.

The standardized NIC protocol for management of SAH in our unit was applied for all patients, including continuous monitoring of physiological and biochemical parameters and clinical surveillance for early identification of avoidable factors with prompt interventions to minimize secondary brain injury [8]. All patients included were intubated due to their neurological state at admission or following deterioration day 0–1. Sedation with propofol (Propolipid^®, Fresenius Kabi AB, Uppsala, Sweden) was titrated in the interval 0–4 mg/kg/h, and morphine (Morfin, Meda AB, Solna, Sweden) administered as needed. As all patients had altered level of consciousness, they all received a ventriculostomy catheter to enable monitoring of intracranial pressure (ICP) and drainage of CSF. Elevated ICP (> 20 mmHg) was treated with open ventricular drainage against a pressure level of 15 mmHg. Aneurysms were treated early, preferably with endovascular coil embolization if feasible, or with surgical clipping.

After securing of the aneurysm, patients were kept mildly hypervolemic if not contraindicated by intracranial mass effect or elevated ICP. The volume status was maintained by fluid administration in the higher normal range with the addition of albumin infusion (Flexbumin^® 200 mg/ml, Baxter AG, Vienna, Austria) if needed and monitored by clinical evaluation, central venous pressure, and attentive fluid balance calculation. The mean arterial pressure (MAP) was kept above 85 mmHg using dobutamine (Hospira, Lake Forest, IL, USA) as inotrope or, if insufficient, norepinephrine (Noradrenalin, Hospira Nordic AB, Stockholm, Sweden) as vasopressor. Nimodipine (Nimotop^®, Bayer Pharma AG, Berlin, Germany) was administered from admission and onward as iv infusion 2 mg/h and later orally 60 mg every 4 h if the patient improved. Repeated wake-up tests were performed to monitor patients for general or focal neurological changes [9]. Transcranial Doppler measurement was not part of the clinical routine.

In the case of neurological deterioration (new focal deficits or reduced level of consciousness), clinical diagnose of DCI was concluded if other causes were ruled out, and HHH therapy was initiated for 5 days. The HHH therapy in our NIC protocol is cautious with a moderately elevated blood pressure target while keeping the patient in supine position, and with further attention on ensuring adequate intravascular volume status under careful re-evaluation of side effects. In addition to standard therapy, daily infusions of 500 ml dextran solution (Rheomacrodex^®, Meda AB, Solna, Sweden) and 200 ml albumin 200 mg/ml were administered if tolerated, targeting CVP 8–12 mmHg. Vasoactive agents were used if needed to maintain a systolic blood pressure above 140 mmHg (preferably dobutamine or, as second-line, norepinephrine).

Following our NIC protocol, all patients with confirmed diagnose of SAH and mechanical ventilation should undergo XeCT for mapping of CBF at day 0–3, 4–7, and 8–12 if logistically possible. As an advantage over several other methods, XeCT allows repeated high-resolution measurements of regional CBF at the bedside in the NIC unit [10]. The XeCT procedures are performed following the principles described by Gur et al. and Yonas et al. [11‐14]. Inhaled xenon gas is rapidly dissolved in blood and tissues and acts as an inert contrast agent during the CT scans. The subsequent calculation of CBF is based on Kety’s [15, 16] application of the Fick principle; blood flow is proportional to inert gas uptake in tissue. The Enhancer 3000 xenon delivery system (Diversified Diagnostic Products Inc, Huston, USA) is connected to the ventilator and breathing circuit. Ventilator settings are adjusted to compensate for increased compressible volume and titrated to normal PaCO2. Non-radioactive Xe¹³¹ at a concentration of 28% is administered to the breathing circuit for about 4 ½ min, and CT scans synchronized to the xenon inhalation are obtained by a bedside CereTom scanner (Neurologica, Boston, USA). Local CBF in each pixel of the CT image is calculated (ml/100 g/min) and plotted as color-coded maps at four different levels of the brain, with eight scans per level—two at baseline and six enhanced during xenon wash-in. Levels with extensive artifacts from bone structures or coils/clips were excluded from calculation. Typically, three scan levels could be used for further calculations in each patient.

SPSS statistics 23.0 software (IBM Corp, Armonk, NY, USA) was used for statistical analyses of the collected data. CBF data for groups of patients are presented as median values with interquartile range because of non-normal distribution. Statistical differences in CBF parameters between unrelated groups were tested with Mann–Whitney U test. In the analysis comparing measurements for patients with paired data from two different time windows, Wilcoxon signed ranks test was used (related samples). Friedman’s test was used to analyze data comparing measurements from multiple time windows. The Chi-squared test or Fisher’s exact test was used to compare proportions between groups. Statistical significance level was set at P < 0.05, and only p values below this level are displayed in text and figures.

During the study period, a total of 136 SAH patients underwent one or several XeCT procedures at different time windows in our NIC unit and were screened for inclusion. Eighty-one patients had valid baseline XeCT measurements at day 0–3 and were finally eligible for inclusion in the study. Fifty-one of these patients also had XeCT CBF measurements at day 4–7 (subgroup 04), and among those a further subgroup consisting of 27 patients had sequential measurements at both days 4–7 and 8–12 (subgroup 048). The clinical characteristics of the included patients are presented in Table 1. Mean age was 60 years (range 28–84) and 72% of the patients were female. Concerning the neurological state, 48% of the patients were in Hunt and Hess grade IV–V at admission, and as a number of patients deteriorated during day 0–1, 64% were in Hunt and Hess grade IV–V when graded at the time of the first XeCT. It was noted that the subgroup 048 had the highest proportion of patients in Fisher grade 4 (78%) and in Hunt and Hess grade IV-V (74%) at the time of the baseline XeCT procedure.

Hemodynamic and respiratory parameters were clinically stable with small alterations from start to end in the XeCT procedures performed (n = 159). The use of vasoactive support was generally low; dobutamine was used at the time of measurement in 24 XeCT procedures (dose range 1–12 μg/kg/min) and norepinephrine (separately or combined) in 24 procedures (dose range 0.01–0.38 μg/kg/min). No adverse events were observed in relation to the procedures.

Comparison of the conditions over time at XeCT day 0–3 and 4–7 for the subgroup 04 (n = 51) showed MAP 89.9 (CI 87.3–92.6) mmHg versus 94.3 (CI 90.9–97.7) (P = 0.014), mean pCO₂ 5.20 (CI 5.08–5.33) kPa versus 5.60 (CI 5.43–5.76) (P < 0.001), and mean dose of propofol sedation 2.6 (CI 2.2–2.9) mg/kg/h versus 2.50 (CI 2.12–2.87).

When comparing the groups with high or low initial CBF at baseline (day 0–3), mean MAP was 89.9 (CI 86.0–93.9) mmHg versus 89.9 (CI 86.3–93.6), mean pCO₂ 5.05 (CI 4.82–5.29) kPa versus 5.28 (CI 5.13–5.43), and mean dose of propofol sedation was 2.4 (CI 1.9–3.0) mg/kg/h versus 2.7 (CI 2.2–3.1) for the high- and low-CBF groups, respectively, and the differences were nonsignificant.

Details of the systemic physiological parameters, sedation dose, and neurological grade for the different groups and time windows compared are presented in conjunction with CBF measurements in Table 2 and 3 as described in the sections below.

As shown in Fig. 2, median global cortical CBF at day 0–3 for all patients (n = 81) was 34.5 (IQR 27.9–41.0) ml/100 g/min, and the median proportion of ROI area with local CBF below the threshold of 20 ml/100 g/min was 12.9% (IQR 5.5–28.3%).

For the subgroup 04 with measurements at day 0–3 and 4–7 (n = 51), median global cortical CBF was 32.8 (IQR 28.0–40.1) ml/100 g/min at day 0–3 versus 35.0 (IQR 25.4–41.3) at day 4–7. The proportion of low-flow ROI area was 16.7% (IQR 6.7–26.1) versus 16.7% (IQR 2.3–34.1) for day 0–3 and 4–7, respectively (Fig. 2).

For the subgroup 048 with measurements at all three phases, day 0–3, 4–7 and 8–12 (n = 27), global cortical CBF was 32.9 (IQR 31.5–39.8) ml/100 g/min at day 0–3 versus 37.0 (IQR 25.2–41.7) day 4–7 versus 33.6 (IQR 30.8–39.6) ml/100 g/min at day 8–12. Low-flow ROI area at the different time intervals for this subgroup constituted 11.3% (IQR 3.3–25.0) versus 7.7% (IQR 1.6–34.7) and 10.8% (IQR 5.0–18.8), respectively (Fig. 2).

The differences in CBF parameters comparing measurements between the different time windows for patients in both subgroup 04 and subgroup 048 showed a wide range and did not reach statistical significance.

Patients were dichotomized into a high- and a low-CBF group depending on the baseline global cortical CBF day 0–3, cutoff 30 ml/100 g/min. Among the 51 patients with two or more XeCT measurements, there were 17 patients with low initial CBF and 34 with high CBF. Global cortical CBF, regional CBF of the worst vascular territory, and the proportion of low-flow area for these groups are presented in Fig. 3a, b and Table 2.

Day 0–3 versus day 4–7—Median global cortical CBF for the high-CBF group was 37.7 (IQR 32.6–46.7) ml/100 g/min at day 0–3 compared to 36.8 (IQR 29.5–44.8) at day 4–7 (Fig. 3a, b). In the low-CBF group, CBF increased from 23.6 (IQR 21.0–28.1) ml/100 g/min to 28.4 (IQR 22.7–38.3) at day 4–7 (P = 0.025), still markedly lower compared to the high-CBF group (P = 0.016). The rCBF of worst vascular territory (Table 2) followed a similar pattern and was unchanged over time for the high-CBF group but increased from 16.2 (IQR 11.2–19.8) ml/100 g/min to 20.0 (IQR 16.8–29.1) at day 4–7 for the low-CBF group (P = 0.017). The proportion of ROI area with CBF below 20 ml/100 g/min also remained statistically unchanged for the high-CBF group, 10.0% (IQR 2.8–17.3) day 0–3 versus 8.3% (IQR 1.2–30.4) day 4–7. The low-CBF group showed a decrease in the proportion of low-flow ROI area from 39.4% (IQR 25.7–50.3) day 0–3 to 25.6% (IQR 8.9–41.0) day 4–7 (P = 0.042).

Day 0–3 versus day 4–7 versus day 8–12—In the subset of 27 patients who had measurements at all three time windows, six patients had low initial CBF. In the high-CBF group, global cortical CBF and proportion of ROI area with CBF below 20 ml/100 g/min were statistically unchanged through the three measurements; median CBF 35.2 (IQR 32.0–41.8) ml/100 g/min versus 38.1 (IQR 28.6–45.0) versus 36.9 (IQR 31.1–42.2) (Fig. 3c, d). In the low-CBF group in this subset of patients, median CBF was 21.3 (IQR 20.5–28.2) ml/100 g/min versus 22.7 (20.5–28.2) versus 31.6 (IQR 29.8–34.4), but the increase did not reach statistical significance when analyzed with time window as independent variable. A corresponding numeric decrease in proportion of low-flow ROI area for this group from day 0–3 to day 8–12 was also found statistically nonsignificant (Fig. 3d).

Twenty-two of the 51 patients with repeated XeCT procedures were receiving HHH therapy due to clinical suspicion of DCI. As the clinical course and CBF dynamics may differ from the natural course of patients with “standard treatment”, patients were further divided into subgroups according to whether HHH therapy was given or not. The more detailed CBF data and physiological parameters for these subgroups are presented in Table 3.

In the group of patients with low initial CBF (< 30 ml/100 g/min) at day 0–3, thirteen of 29 patients (45%) had poor clinical course outcome at discharge from NIC (unconscious, GCS motor ≤ 5, or dead) compared to 18 of the 52 patients (35%) with high initial CBF. In the subgroup 04 with repeated XeCT procedures, poor outcome was concluded in 11 of the 20 patients (55%) who still had low CBF at XeCT day 4–7 compared to 11 of 31 patients (35%) with high CBF at day 4–7. The differences in proportion of patients with poor outcome between the low- and high-CBF groups did not reach statistical significance.

Radiologically, the proportion of patients with infarcts with a largest diameter exceeding 20 mm at follow-up CT was 34% in the group with low baseline CBF compared to 44% in the high-CBF group. For the subgroup 04, when CBF at day 4–7 was considered, the occurrence of infarcts > 20 mm was 60% in low-CBF patients and 35% in high-CBF patients. Neither of these differences reached statistical significance.

Despite the intention to consecutively include all intubated SAH patients, there is always a risk of selection bias. The main reasons for not including patients were logistic factors and medical priorities, so it is unlikely that the selection of patients influenced the results in an improper way. It should, however, be stressed that only poor-grade SAH patients in need of mechanical ventilation were studied, and the results are not generalizable to the entire population of SAH patients.

We used data from patients who had valid XeCT procedures at one, two, or three consecutive time windows. From the clinical characteristics (Table 1), it is noted that the proportion of patients with higher severity grade is slightly larger in the subset of patients (n = 27) who were examined three times. This is expected, as only patients still in need of ventilation day 8–12 had a third XeCT, and data for this group may thus represent the patients with most severe SAH. Accordingly, the study lacks information about CBF dynamics in patients who improved sufficiently to be extubated before the second or third time window.

There were generally small differences in systemic physiological conditions between the groups and time windows studied. For the subgroups with measurements also at day 4–7 and 8–12, there were statistically significant differences in mean MAP and pCO₂ between the time windows. The differences were modest from a clinical view, but influence on CBF from these factors is possible. There were, however, no significant differences in these parameters between the groups defined by high or low initial CBF.