Early abnormal transient hyperemic response test can predict delayed ischemic neurologic deficit in subarachnoid hemorrhage

To prevent DIND related cerebral damage, it is recommended to commence a decisive treatment within 2 h of the onset of the symptoms [12]. This proves difficult to achieve in a clinical setting; firstly, due to the subtlety of the initial manifestation of DIND symptoms; and secondly, due to the difficulty of detecting a worsening neurological function in the presence of a major primary deficit. Therefore, this might not be a realistic endeavor in a lot of healthcare systems leaving many patients at a heightened risk of permanent deficits [2, 4].

The gold standard for the diagnosis of DIND is a cerebral angiogram [6]. It is an invasive procedure with inherent risk, including injury of the access artery and thromboembolic ischemic stroke [13]. Transcranial Doppler applications (TCD) have been used frequently as a non-invasive diagnostic method of DIND. The measurements are based on trends of increased systolic velocities and increased Lindegaard ratio (mean velocity in the middle cerebral artery/mean velocity in ipsilateral extracranial internal carotid artery ratio (MCA/ICA) to improve the specificity of diagnosis) [7, 8]. TCDs are a popular method because of their non-invasive nature and the fact that they do not have the side effects associated with the use of contrast agents and radiation. Moreover, they are easily accessible and pose no risk to the patient in terms of transportation while critically ill [7, 8].

Another method frequently used in the clinics is computed tomography perfusion (CTP) [9, 10]. Improvement in the imaging capabilities of CTP does allow for a non-invasive assessment of the cerebral circulation dynamics, but it is liable to the inter-evaluator variability and lack of clear interpretation paradigms given the multiplicity of variables involved in generating and influencing these images [9, 10]. To add to the complexity of this issue, we frequently find areas of clinical deterioration that do not match the areas of vascular spasm detected on vascular imaging, a phenomenon called “clinico-radiological dissociation”. Another early detection method is continuous electroencephalography (cEEG); able to detect changes suggestive of vasospasm [14]. However, for the most part, these applications are non-diagnostic of DIND. Another major concern with these imaging modalities is that irrespective of how informative they are, the radiation doses and contrast material involved in their generation limit their utility as dynamic tests to go along with the clinical evolution in the short-term or better still, in real time. This has major drawbacks for the very nature of the decision-making process required in a critical care setting. This raises the need for a test that can be safely repeated and is informative in the realm of parameters affecting clinical care decisions.

An invasive cerebral blood flow monitoring has the ability to detect changes conducive of vasospasm 24–48 h earlier than the onset of clinical vasospasm. This is suggestive of a failure of an initial autoregulatory mechanism that, if detected early, can be valuable in identifying patients at risk of developing DIND [15–18]. Transient hyperemic response test (THRT), also known as carotid compression test, is a type of TCD examination of the cerebral vessels. It was described for the first time by Giller in 1991 as a bedside test for the assessment of cerebral autoregulation with the basic premise that, in the presence of an intact autoregulation, the cerebral vessels will be able to contract in response to a hyperemic challenge generated by a brief carotid occlusion [11]. This would be translated in the TCD signal as an increase in systolic velocity. In a normal response, the velocity should increase by a minimum of 9% from the baseline velocity. Any value less than that or reduction of the velocity denoted a global failure of autoregulation. Since then, several studies have confirmed this concept in animal models, human subjects as well as several diseases including traumatic brain injury (TBI) and SAH [19–21] THRT has been used to predict autoregulation failure in traumatic brain injury as well as the development of autoregulation failure conducive of DIND in patients with SAH [20–22].

In our study, THRT was performed in the first 24–48 h and was abnormal in 83% of patient who subsequently developed DIND. Of interest, the two patients with radiological vasospasm also exhibited an abnormal THRT. This raises the possibility that the stress of SAH can prime the cerebral circulation into a deregulatory process that leads to the development of vasospasm, whether clinically overt or silent. Moreover, this predictability was not influenced by the clinical grade of the SAH, an observation that can lead to an unbiased and more attentive attitude toward patients at theoretical risk of DIND and establish lower threshold for their investigation and escalation of therapy when necessary. Although not reported in this study results, we occasionally detected the resolution of the autoregulation failure by the return of the normal response despite the aggressive therapy for vasospasm. This at least in theory can guide the timing of weaning of DIND treatment with an aim to reduce treatment morbidity.

Lam et al. reported the use of THRT in post-clipping patients performed 0–5 days post bleed, with five out of six patients exhibiting abnormal THRT [20]. Another study compared three autoregulatory parameters: THRT, Sxa (based on TCD), and TOxa (based on near-infrared spectroscopy) and found equivalent reliability between the three parameters in predicting DIND, favoring THRT due to the time consuming nature of the latter two [22].

Another interesting observation emerging from our small retrospective cohort study is that the systolic velocity in the MCA was elevated in five patients from their ictus; however, it did not translate into the development of DIND. We hypothesize that this could be a secondary response to either aggressive initial management or to the systemic stress response seen in SAH patients.

The analysis and comparison of the data obtained from THRT and radiological imaging measurements suggests that the latter methods are only moderately predictive of subsequent DIND development. We found that of all the CTP maps the MTT and TTP were the most predictive. These observations will have to be validated in a larger cohort studies.

This study suffers from the inherent drawbacks of any retrospective review. Our sample size is small but illustrative to this test. Longitudinal THRT testing was not done in all patients and would be considered in future projects.

Our results suggest the utility of THRT in detecting patients at increased risk of DIND from the time of admission, which if supported by prospective trials, will allow supporting a watchful clinical approach to their clinical course of investigation and management. It can also lead us to better select patients for trials involving early interventions in SAH and DIND, as it might serve as discriminatory test to stratify high versus low risk candidates. Understanding the trend of THRT during the period of DIND and its resolution might prove useful as well.