Discussion

The main conclusion of our proof-of-principle study is that POCUS is a feasible method for screening the presence of LVO in patients with suspected acute ischemic stroke, and its preliminary favourable diagnostic performance is a suggestion that it could be used to select patients for primary admission in EVT-capable centers. Our definition of CCA flow profile compatible with LVO, which was evaluated visually by raters blinded to the presence of LVO, was shown to reliably reflect higher pulsatility and resistance indexes and lower end diastolic velocities. These characteristics are known sonographic hallmarks for the presence of an occlusion or severe stenosis distal to the examined segment of the artery.^{Reference Alexandrov15} Similar to some of the objective DUS parameters (end diastolic velocity, mean velocity, resistance index, and pulsatility index), CCA flow profile compatible with LVO was associated with presence of LVO in CTA in the univariable analysis. However, none of the parameters independently predicted the presence of LVO in the multivariable analysis, which is probably related to the small sample size and collinearity. Although our study focused on qualitative DUS analysis for prediction of LVO, objective DUS parameters may also be used to define high-risk profiles and provide the opportunity to develop automated machine-learning based methods to identify LVO, which are independent from user interpretation.

Currently, many stroke networks operate using the drip-and-ship model, where LVO is identified in primary stroke centers using CTA. The reliable identification of LVO before stroke patients reach the primary stroke center, i.e., during the prehospital phase, would allow these patients to be directly transferred to EVT-capable centers, hence shortening the time between symptom onset and groin puncture. Time delays in achieving reperfusion with EVT are associated with a significant negative impact on the patient´s functional outcome,^{Reference Kunz, Hunink and Almekhlafi16} and the eligibility for EVT reduces with the passing of time since symptom onset.^{Reference Nikoubashman, Pauli and Schurmann6} The benefit of the “mothership” strategy was recently put to test in the RACECAT trial, which showed similar results for both “mothership” and “drip-and-ship” strategies.^{Reference de la Ossa, Abilleira and Jovin7} However, the study presents several limitations, including that the results do not apply to other stroke networks with different geographical characteristics and with different organization of the health care resources,^{Reference Holodinsky, Williamson and Demchuk17} and that the RACE scale did not present an optimal accuracy for identification of LVO.

The accurate identification of acute ischemic stroke patients with LVO in a prehospital setting is of major importance for optimizing strategies to implement the “mothership” model in stroke networks. The method used in the identification of stroke patients with LVO in a prehospital setting should, in our view, have the following characteristics: 1) have an excellent sensitivity, in order not to miss patients with LVO; 2) have a good positive predictive value, in order not to overload comprehensive stroke centers with patients who otherwise could benefit more from a rapid direct admission in primary stroke centers; 3) be readily available in the prehospital setting without causing delays in patient transfer; 4) be noninvasive; 5) have a simple and rapid application; and 6) have a good reliability. DUS of the CCA appears to fulfill most of these criteria, and the main obstacle being its reliability in the setting of prehospital application. Additional advantages of POCUS as a screening method for LVO in the prehospital setting include the fact that it is a handheld portable device easy to implement in ambulances, the fact that it does not require an extensive training and does not involve radiation, the relatively low cost of these devices, and the possible use of the device for other medical emergencies.

The use of clinical stroke scales for the identification of LVO presents several limitations, mainly related to the relatively low sensitivity^{Reference Duvekot, Venema and Rozeman8} and need for training prehospital personnel in the recognition of specific neurological signs, which is sometimes challenging. The performance of the RACE scale as a screening method in the RACECAT trial, namely the proportion of patients with no LVO despite high RACE scores (which represented 54% of the study population and 33% of patients with confirmed ischemic stroke or transient ischemic attack), probably influenced the results of the trial.^{Reference de la Ossa, Abilleira and Jovin7} The implication is that a relevant proportion of stroke patients actively deviated to an EVT-capable center will ultimately not benefit from such strategy because they do not present LVO and may receive intravenous thrombolysis at a later time point. At the same time, a relevant proportion of patients with LVO despite low RACE scores (up to 1/3 of patients with LVO),^{Reference de la Ossa Pérez, Carrera and Gorchs11} who were not included in RACECAT, could potentially benefit from the “mothership” strategy.

An alternative strategy is the use of mobile stroke units with capability to perform CT and CTA, initiate intravenous thrombolysis in the ambulance, and directly transfer patients to comprehensive stroke centers in the presence of LVO.^{Reference Harris18} This strategy presents the major limitation of being highly resource demanding. The accuracy of other promising strategies for detection of LVO, such as the volumetric impedance phase shift spectroscopy device,^{Reference Kellner, Sauvageau and Snyder19} and portable devices using electroencephalography and somatosensory-evoke potentials,^{Reference Sergot, Maza and Derrick20} still needs to be established in a prehospital setting. Transcranial doppler was also shown to reliably predict ischemic stroke due to occlusion of the internal carotid or middle cerebral arteries,^{Reference Thorpe, Thibeault, Canac, Wilk, Devlin and Hamilton21–Reference Herzberg, Boy and Holscher23} but it is technically more demanding, requires more expertise than DUS of CCA, and is limited by absent acoustic temporal bone window in 20–30% of all stroke patients,^{Reference Gahn, Gerber and Hallmeyer24} which may limit its use in the prehospital setting by non-expert users.

The main limitation of our study is that it is a small-sized proof-of-concept study that needs to be confirmed in unselected patients with suspected acute ischemic stroke. The group comparisons and logistic regressions we conducted are, therefore, to be interpreted with caution. The noninclusion of patients with occlusions of smaller arteries of the anterior circulation (A1, M2, M3) and occlusions of arteries in the vertebrobasilary territory may have influenced our results and may represent a major limitation for the use of POCUS with this purpose. We could not demonstrate objective differences in DUS parameters between M1 and carotid-T occlusions, but our study population size is too small to allow conclusions in this respect. Another potential limitation of POCUS for identification of LVO is its feasibility in the hyperacute setting in the emergency department or in the ambulance, which we did not analyze in our study. Patients with LVO received DUS significantly earlier after symptom begin than patients with no LVO, which is explained by the study design. This may induce bias and influence the pattern of blood flow seen in DUS, even though raters were unaware of the time point at which DUS was performed. However, no patient with no LVO developed new neurological symptoms between CTA and DUS (<24 hours in all patients), therefore the likelihood of a new nondiagnosed LVO in these group of patients is very low. DUS pitfalls which could explain false positive and false negative results must also be recognized, and it may be difficult for observers to discern them in the hyperacute phase of ischemic stroke.^{Reference Alexandrov15} High cardiovascular flow states and severe aortic stenosis may cause Doppler waveforms that resemble CCA flow profile compatible with LVO. On the contrary, more distal occlusions may not cause a significant change in Doppler waveforms, and occlusions which last for several hours may allow compensation and ongoing collateralization, which could cause partial normalization of Doppler waveforms. Other possible pitfalls that could influence CCA flow profiles include heart arrhythmia and significant intracranial and extracranial atherosclerotic vessel changes with increased arterial stiffness.

Nevertheless, these results are a basis for future research, and larger studies both in the emergency department and the prehospital setting are needed to confirm the results found in the current study. Follow-up studies with larger patient populations, which standardize the time interval between symptom onset and performance of POCUS, and which examine both cervical and intracranial arteries are needed to explore the questions raised by the current study. Despite the lack of benefit of “mothership” when compared to “drip-and-ship” in the RACECAT trial, the authors suggest that the employment of a “mothership” strategy using more accurate and novel technological triage tools warrants additional investigation.^{Reference de la Ossa, Abilleira and Jovin7}

In conclusion, DUS of the CCA in the acute stroke setting is feasible and may serve as a complementary tool for the detection of LVO in the prehospital setting.