Feasibility of improving cerebral autoregulation in acute intracerebral hemorrhage (BREATHE-ICH) study: Results from an experimental interventional study

Abstract

Background Cerebral autoregulation is impaired in a multitude of neurological conditions. Increasingly, clinical studies are correlating the nature of this impairment with prognostic markers. In acute intracerebral hemorrhage, impairment of cerebral autoregulation has been associated with worsening clinical outcomes including poorer Glasgow Coma Score and larger hematoma volume. Hypocapnia has been shown to improve cerebral autoregulation despite concerns over hypoperfusion and consequent ischemic risks, and it is therefore hypothesized that hypocapnia (via hyperventilation) in acute intracerebral hemorrhage may improve cerebral autoregulation and consequently clinical outcome. Aims To assess the feasibility and acceptability of the first cerebral autoregulation-targeted intervention in acute intracerebral hemorrhage utilizing a simple bed-side hyperventilatory maneuver. Methods Twelve patients with acute intracerebral hemorrhage within 48 h of onset were enrolled. The experimental setup measured cerebral blood flow velocity (transcranial Doppler), blood pressure (Finometer), and end-tidal CO2 (EtCO2, capnography) at baseline, and in response to hypocapnia (−5 mmHg below baseline) achieved via a 90-s hyperventilatory maneuver. Cerebral autoregulation was evaluated with transfer function analysis and autoregulatory index calculations. Results We observed tolerance to the protocol in a cohort of mild (National Institutes of Health Scale 4) supratentorial intracerebral hemorrhage patients with small volume hematomas without intraventricular extension. Importantly, a significant difference was noted between ipsilateral autoregulatory index at baseline 4.8 (1.7) and autoregulatory index during hypocapnic intervention 7.0 (0.8) (p = 0.0004), reflecting improved cerebral autoregulation, though a dose-dependent effect of EtCO2 on autoregulatory index was not observed. Conclusions In this small study, there was no observed effect on 14-day death and disability in recruited participants. This is the first report of improvement in cerebral autoregulation in acute intracerebral hemorrhage using a non-invasive interventional maneuver, through induction of hypocapnia via hyperventilation. ClinicalTrials.gov Identifier: NCT03324321 URL: https://clinicaltrials.gov/ct2/show/NCT03324321

The Effects of Hypocapnia on Brain Tissue Pulsations

“…This study found that MAP decreased with hypocapnia. This was an anticipated result and agrees with previous CO 2 studies which found a similar association [2,3,16]. Interestingly, this decrease in MAP was observed with the mild degree of hypocapnic change generated in this study.…”

“…Our findings suggest that a period of hypocapnia (even as short as 90 s) has the potential to cause a vasoconstrictive response that continues even beyond re-instatement of normocapnia, or indeed hypercapnia. This phenomenon was recently demonstrated in both healthy volunteers [2] and patients suffering intracerebral haemorrhage [3]. Animal studies have shown that the vasoconstrictive effect continues even after ischaemia and/or reperfusion is reversed [14].…”

“…Carbon dioxide (CO 2 ) levels affect vascular smooth muscle tone and hence play a pivotal role in cerebral autoregulation [1][2][3]. However, the impact of CO 2 on brain tissue pulsations (BTPs) is poorly understood.…”

Arterial carbon dioxide and bicarbonate rather than pH regulate cerebral blood flow in the setting of acute experimental metabolic alkalosis

“…Although recent work has shown promise by a hyperventilatory (hypocapnic) intervention in acute intracerebral haemorrhage (Minhas et al . 2020 a ), there are no available prospective studies on the use of NaHCO 3 – to generate an equivalent effect in acute ischaemic stroke patients (Minhas et al . 2020 b ).…”

“…Akin to our study design, slower rates of infusion (over >30 min), accompanied by dilution with sodium chloride, avoided adverse events possibly propagated by transient rises in intracranial pressure associated with a rapid rise in CO 2 during an infusion over minutes (Brown et al 2018). Although recent work has shown promise by a hyperventilatory (hypocapnic) intervention in acute intracerebral haemorrhage (Minhas et al 2020a), there are no available prospective studies on the use of NaHCO 3 to generate an equivalent effect in acute ischaemic stroke patients (Minhas et al 2020b).…”