In the current study including 148 patients with aSAH, the associations among neuro-ICUvariables with CBF and CDO2 were weak. Lower hematocrit correlated with higher CBF, but not with increased CDO2, indicating therapeutic limitations for the hemodilution component of HHH-therapy. Higher body temperature was associated with increased CBF and CDO2, but this likely reflected a compensatory increase to meet energy metabolic demand. ICP, CPP, and PRx only had modest associations with CBF and CDO2. Cerebral hypoperfusion and poor oxygen delivery were still frequent and particularly low CDO2 in the early phase was independently associated with unfavorable outcome. This indicates that common neuro-ICUvariables such as ICP and CPP were poor surrogates of CBF and CDO2, and this corroborates the indication for CBF imaging to better detect development of both global and focal secondary brain injury.
Neurointensive Care Targets in Relation to CBF and Oxygen Delivery
In the current study, the association among neuro-ICU variables and CBF and CDO
2 was limited. The absolute CPP was not significantly associated with CBF. This was to some extent expected, since CPP was kept within 60–100 mm Hg and cerebral autoregulation normally keeps CBF constant within these limits. However, cerebrovascular resistance may increase following vasospasm and most patients exhibited disturbed pressure autoregulation with PRx more than 0, predisposing for cerebral ischemia [
38]. Considering the variable degree of such disturbances among patients, fixed CPP may not reliably rule out hypoperfusion/ischemia. Instead, more disturbed pressure autoregulation (higher PRx) and CPP below the autoregulatory CPPopt-target correlated better with cerebral hypoperfusion and poor CDO
2, indicating that these measures may be superior to fixed/absolute CPP targets. This was consistent with previous studies by our group on similar but smaller cohorts of patients with aSAH [
6,
39]. However, these associations were only found in the early phase after aSAH and did not hold true in multiple linear regressions. The role of CPPopt in aSAH has also been questioned because outcome studies have rather supported high fixed CPP targets than dynamic CPPopt targets [
2]. Hence, much future work is still needed to determine whether CPPopt has a place in aSAH management. One major limitation include that PRx and CPPopt are global measures and may not be sensitive for focal vascular events. They may particularly be invalid in a scenario with asymmetrical vascular disturbances, such as when there is severe vasospasm in one hemisphere and vasodilation in the other. Another explanation is that the true CPPopt may be too high in the vasospasm phase to be fully explored on the
U-shaped curve, which leads to an invalid underestimation.
Higher pCO
2 correlated with higher CBF and was marginally associated with higher CDO
2 in univariate, but not the multiple linear regression analyses in the early phase. This was in line with previous studies indicating that hypercapnia increases CBF and brain tissue oxygenation [
7], reduces DIND [
8], and improves clinical outcome in aSAH [
8,
40,
41]. There was no association of pO
2 with CBF and CDO
2, despite previous findings supporting an association among hyperoxia with cerebral vasospasm [
13], DIND [
14,
15], and unfavorable outcome in aSAH [
14,
15]. One explanation could be that both pCO
2 and pO
2 were tightly regulated at the time when the Xe-CT was performed, which reduced the chances to detect any effect on CBF and CDO
2.
Furthermore, lower hematocrit was strongly associated with higher CBF and lower percent of hypoperfusion and critical hypoperfusion in the vasospasm phase. However, this did not translate into better CDO
2, as a consequence of the corresponding reduction in CaO
2 from the lower hematocrit value. The increase in CBF may be related to a reduction in blood viscosity or successful hypervolemia treatment leading to both higher intravascular volume and CBF, but others suggest that it is solely a partially compensatory increase in CBF to meet CDO
2 demand [
16]. Nevertheless, despite the lack of improvement in CDO
2, higher CBF from hemodilution could improve cerebral microcirculation, glucose delivery, and clearance, but this argument is only speculation. Increased glucose delivery could be particularly important considering that mitochondrial dysfunction with a reduced capacity to use oxygen is common after aSAH [
42]. However, others have rather discussed the possibility to improve CDO
2 by means of hypervolemia and higher hematocrit using red blood cell transfusion [
43]. Overall, this still questions the therapeutic effect of hemodilution in HHH therapy. Previous experience from our group is that HHH therapy for DIND increases CBF and is neither associated with a worsening nor an improvement in cerebral energy metabolism, as assessed with a microdialysis [
24]. The results could either be interpreted as that a more severe energy metabolic worsening was prevented or that it had no beneficial effect on the brain. It is also difficult to isolate the hemodilution component from the HHH therapy. Altogether, multimodality monitoring studies combining CBF imaging, brain tissue oxygenation, and microdialysis could further elucidate the cerebral effects of different components of HHH in aSAH care.
Increased body temperature was associated with higher CBF and CDO
2. This was likely a compensatory mechanism to meet increased energy metabolic demand [
44]. This increase is often usually only partially compensatory to energy demand and is not a viable treatment option to counteract ischemia, since hyperthermia has previously been associated with DIND, and worse clinical outcome in aSAH [
2,
45].
Older age was a clinical variable associated with lower CBF and particularly lower CDO
2. Although older patients are not more prone to develop vasospasm or DIND [
46], they are fragile and often exhibit a combination of arterial hypotension and hypoxemic insults [
47]. This could explain the increased susceptibility for secondary ischemic/hypoxic brain injury as was evident in our study. Furthermore, increased PTT was independently associated with higher CBF and CDO
2. This suggests an association between a higher SVR and higher risk of cerebral hypoperfusion and hypoxia. The underlying factor for SVR could be arterial stiffness from atherosclerosis, but also from stress-induced and vasopressor-induced vasoconstriction. This also suggests that an attempt to increase MAP/CPP by vasopressors, which potentially increases SVR/PTT, may exert a negative effect on CBF and CDO
2, whereas measures made to increase intravascular volume and cardiac output might be more favorable approaches.
Altogether, the associations among neuro-ICU variables with CBF and CDO2 were weak, but cerebral hypoperfusion and poor CDO2 were relatively frequent at 15% and 30%, respectively. This supports the role of Xe-CT imaging to detect secondary brain injury development, not evident by standard neuro-ICU variables such as high ICP and low CPP. Also focal, continuous CBF monitoring such as thermal dilution methods could be of value and may be explored in future studies. Although the associations between neuro-ICU variables and CBF/CDO2 were weak when evaluated as absolute values, interventions that change systemic variables such as CPP augmentation or pCO2 elevation would be expected to at least exert some effect on CBF/CDO2. However, our study was not designed to determine whether any specific treatment intervention would be superior to another in this scenario.
CBF and Oxygen Delivery in Relation to Clinical Outcome
Low CBF and CDO
2 in the early phase were associated with unfavorable outcome, but this did only hold true for CDO
2 in multiple logistic regressions and not in the vasospasm phase. The association among CBF and CDO
2 with outcome was hence stronger in the early phase than the vasospasm phase. One explanation could be that early CBF disturbances also predicts a worse neuro-ICU course, as early cerebral hypoperfusion tends to persist in the late course [
23] and has been associated with DIND [
48]. Apparently, early assessment of CBF and CDO
2 may be valuable to identify patients at risk of having poor outcome with the intention to individualize their treatment and change their destined clinical course. Another explanation for the association between low CBF and CDO
2 and worse outcome could be that the former two were metabolically downregulated following a more severe brain injury, although this was taken into account to some extent by adjusting for WFNS grade. However, overall, the weak association between CBF and CDO
2 and clinical outcome was expected, considering that the measurement only reflected a snapshot of the acute phase after aSAH.
Limitations
First, the associations between systemic and cerebral physiological variables and CBF and CDO2 were generally weak. This may be explained by that these latter two variables are regulated by a complex plethora of mechanisms that interact with each other rather than being determined by one single variable. It was also evident that severely deranged physiological variables were infrequent, which likely reduced any chance to detect an effect of these variables on CBF and CDO2. Second, PTT, ICP, CPP, CPPopt, PRx, and body temperature were calculated for 30 min centered on the time point of the Xe-CT. The reason for such a long interval was to get a stable value, particularly for CPPopt and PRx. However, if the physiological variables were calculated only for 1 min at the time point of the Xe-CT (data not shown), similar, but slightly weaker associations were found for CPPopt/PRx and CBF and CDO2. Third, the study group was highly selected to be patients in a bad clinical situation, who were intubated and with specific requirements on the monitoring for inclusion in the study. This, together with the limited number of individuals could explain why some tests did not reach statistical significance. Fourth, reduced CBF may be explained a reduction in energy metabolic demand by, e.g., concurrent brain injury, hypothermia and sedation rather than ischemia. However, the burden of hypoperfusion and critical hypoperfusion was calculated as the percent of cortical brain areas with CBF < 20 mL/100 g/min and CBF < 10 mL/100 g/min, respectively. These measures rather reflect the proportion of focal hypoperfusion rather than global changes related to sedation, etc. Fifth, including the patients treated with DIND may have influenced the overall results but excluding the patients with DIND from the univariate correlation analyses did not affect the associations. Sixth, DIND was diagnosed based on clinical ground by experienced clinicians, although it was possible that false positives and negatives (silent brain infarctions) occurred to some extent. Seventh, ABP was measured at heart level which overestimates CPP to some extent when the head of the bed is elevated but this did not affect the calculation of ∆CPPopt because it is the difference between CPP and CPPopt. The results may have been confounded by that a smaller group of patients receiving HHH therapy was placed in supine position but the results did not change when those patients were excluded from the analysis.