Cerebral Venous Return and high altitude cerebral edema (HACE): hypothesis and study protocol

Francesco Prada,1 Davide Santuari,2 Federico Legnani,1 Massimiliano Del Bene,1 Luca Mattei,1,3 Luca Lodigiani,4 Luigi Caputi,5 Carlo Boffano,6 Davide Vailati7

1Department of Neurosurgery, Fondazione IRCCS “Istituto Neurologico C. Besta”, Milan; 2Department of Vascular Surgery, A.O. S. Carlo Borromeo, Milan; 3Università degli Studi di Milano, Milan; 4Esaote s.p.a, Genoa; 5Department of Neurology, Fondazione IRCCS “Istituto Neurologico C. Besta”, Milan; 6Radiology Unit, Fondazione IRCCS “Istituto Neurologico C. Besta”, Milan; 7Intensive Care Unit, Fondazione IRCCS “Istituto Neurologico C. Besta”, Milan, Italy


Background

Neurological deficits represent the epiphenomenon related to acute mountain sickness (AMS),10,11,17 that probably recognize a multifactorial origin. One of the possible causes is an abnormal venous drainage of the cephalic district,11,12,13,14,15 which might lead to intracranial fluid accumulation and extravasation within the interstitial and intra-cellullar spaces, determining cerebral parenchyma edema and development of neurological dysfunction such as gait ataxia, nausea and vomiting, dizziness, impaired consciousness and diencephalic dysfunction.9,18
The blood leaves the brain using the propulsion of the residual return of arterial blood pressure (vis a tergo), supplemented by anterograde postural and respiratory mechanisms (face to face). The latter consists in an increased centripetal venous flow during inhalation, thanks to an increased negative thoracic pressure which determines the intake of blood to the right atrium.16 The supine position favours the cerebral venous flow through the internal jugular veins (IJV). On the contrary in orthostatic position blood outflow is redirected through the vertebral (VV) and the azygos veins (AZY). This posterior venous system becomes the main cephalic outflow route.1,2 The extra-cranial (EC) cerebro-spinal venous system (ECCSV) form a complex valves deficient vascular anastomotic system with the exception of IJV, which has proximal valve systems approximately in 85% of the population.3 Its physiological function is fundamental for the maintenance of normal brain function.4
The combination of morphological and hemodynamic parameters of the Echo-Color-Doppler (ECD) high resolution represents an ideal direct and real-time method for the study of hemodynamics of cerebral venous outflow. Indeed ECD has recently shown different posture related patterns of extracranial outflow vicariate in IJV and VV.5,6 Furthermore Doppler study for chronic cerebrospinal venous insufficiency (CCSVI) has been shown in patients with MS the existence of different hemodynamic patterns of intra- and extra-cranial venous reflux and loss of postural regulation of cerebral venous outflow.7,8
The cerebral venous outflow has never been thoroughly studied in a direct, dynamic and continuous manner under physiological conditions nor in conditions of prolonged physical effort and/or at high altitude.9,10 ECD with IJV’s and VV’s assessment seems to be an ideal method to test cerebral venous outflow in those conditions.

Aims of the study

The main aim of the study is to evalute and describe ECCSV hemodynamic patterns in a homogenous population of healthy subjects at different altitude and their correlation with eventual development of neurological symptoms due to AMS.

Methods

Study design and patient population

Descriptive prospective study.
20 healthy volunteer subjects, age > 18 years or older.

Procedure

The subjects will undergo different clinical and laboratory testing at sea level (Milano city circa 120 a.s.l.) and at high altitutude (p.es. Capanna Regina Margherita 4559 a.s.l.).
Sea level evaluation:
- Neurological evaluation
- Blood Test
- Trans-cranial Doppler (TCD) sonography: measurements of the mean diameter of the Middle Cerebral Artery (MCA) and flow velocity assessment. Phased array multifrequency probe.
- Extra-cranial Doppler (ECD) sonography: the transducer used at the cervical level it is set at high frequency (7-11 Mhz or more), according to the different depth of the veins in respect to the body surface where the transducer is placed. The subject should be investigated in both supine and sitting position (0°and 90°), but it has further been proposed to assess venous flow from the brain with the body positioned at 0°, +15°, +30°, +45°, +90° in both the IJVs and VVs. The extracranial Doppler venous examination pathways is performed either on the IJVs and VVs by using both the transversal and/or the longitudinal cervical access. The operator uses minimal pressure over the skin in order to prevent compressing the vein and thereby affecting the measurement. We will assess the following parameters: flow direction, flow velocity, competence of the IJV valve, cross sectional area in relation to change in posture, duplex derived flow-metry and anomalous morphology.
- Hypoxic pre-test with 10% O2 mask, followed by TCD and ECD investigation protocol as described above.

High altitude evaluation

The same investigations (apart from the hypoxic pre-test) will be perfomed at high altitude (p.es. Capanna Regina Margherita 4559 a.s.l.)
- TCD and ECD will be perfomed the evening of the arrival at high altitude and between 10 am. and 13 am. the next day before returning down.
- volunteers will also be evaluated for the assessment of acute mountain sickness with AMS Questionnaire based on the Lake Louise Score.

Expected results and impact

We expect to be able to evaluate cerebral venous outflow with ECD and obtain IJV and VV measurements in all subjects, both at sea level and at high altitude. All data will be correlated to clinical and test evaluation.
Assessing the role of ECD in the evaluation of different cephalic venous drainage pattern and/or changes and correlating it with clinical and intrumental findings will lead us to define a new tool to evaluate those patient at risk of developing AMS, identifying those patients harbouring venous pattern related to AMS.
ECD can be a fast, safe, dynamic, feasible and repeatable, relatively economic, precise and accurate tool that might be used both by physicians in a clinical setting as a screening for patients before going at high altitude and to assess pre-clincal symptoms of AMS on-field, with the eventual help of tele-medicine.

References

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