Field of invention

The method, which is a subject of the present invention, is applicable to all areas of medicine where blood oxidation levels must be monitored and more specifically - in maternal fetal medicine.

Prior Art

Doppler velocimetry has been widely used throughout the years as a most valuable tool in the follow-up and prognosis of various pregnancy complications, such as fetal growth restriction, fetal anaemia, as well as twin-to-twin transfusion syndrome in multiple pregnancies (1).

The concept of intra-uterine growth restriction first emerged in 1960, as Battaglia and Lubchenco began to adjust newborn birth weight according to the corresponding gestational age (2).

Since then, numerous Doppler indices have been introduced to quantitatively describe fetal blood flow. Currently, the Pulsatility index seems to be the most widely used tool for that purpose. It was originally defined in 1969 by Gosling and King [3] and later simplified to today’s well-known formulation (Fig. 1)

In current clinical practice, the measurement of middle cerebral artery’s pulsatility index is a commonly used modality to assess fetal well-being, especially in late FGR. In 1986, it has been shown [5] that lower impedance to flow in the middle cerebral artery (detectable by a decrease in the pulsatility index) is uniformly associated with a redistribution of cardiac output flow towards the central nervous system, to address oxygen deficiency (brain-sparing effect). Cerebral vasodilation and thus lowered cerebral vascular resistance lead to increased end-diastolic flow velocity in the cerebral arteries [6]. Almost 40 years after the original concept introduction, the measurement of middle cerebral artery’s pulsatility index continues to serve as a gold standard for the assessment of fetal brain-sparing.

Limitations of the current clinical practice

However, a large number of authors have proposed that the calculation of cerebroplacental ratio is of additional value to diagnose brain-sparing [7, 8, 9].

Data from a recent meta-analysis underlines that this ratio between middle cerebral artery and umbilical artery pulsatility indexes, delivers higher sensitivity than middle cerebral artery alone to predict adverse perinatal and neonatal outcomes [10]. Namely, the middle cerebral artery Doppler is found to be significantly inferior to umbilical artery Doppler in predicting low Apgar score (p=0.017) and emergency delivery for fetal distress (p=0.034), and significantly inferior to cerebroplacental ratio in predicting composite adverse outcome (p<0.001) and emergency delivery for fetal distress (p=0.013).

Due to the aforementioned observations, clinical implementation of fetal brain Doppler assessment is currently narrowed to monitoring late fetal growth restriction (>32 weeks of gestation), where cerebroplacental ratio and middle cerebral artery Doppler may be of specific clinical value [11,12,13].

In a comparison between normal and abnormal middle cerebral artery Doppler waveforms (Error! Reference source not found.), it is clearly seen that most of the changes appear in the diastolic part of the heart cycle. Therefore, the pulsatility index which contains elements both from systole (peak systolic velocity - S, Error!

Reference source not found.) and from diastole (end diastolic velocity - D, Error! Reference source not found.), may not be the most effective tool to quantify brain sparing. We hypothesize that another measurement modality, which focuses predominantly on the diastole, needs to be introduced. Subject-matter of the invention

An easy to identify notching, appearing on the declining part of Doppler waveforms could be a more accurate tool for the interpretation of brain vessels vasodilatation.

The so called “dicrotic notch” is a small and brief increase in arterial blood pressure that appears when the aortic valve closes. This landmark has been widely referred to in the descriptive analysis of the arterial waveform (especially of aortic and radial arteries) and is commonly used as an equivalent of end-systolic left ventricular pressure [14,15,16,17],

The dicrotic notch is universally associated with aortic valve closure [18], and possibly with changes in the peripheral vascular resistance [19], although to date, no physical mechanism for the existence of the dicrotic notch has been demonstrated convincingly.

In middle cerebral artery Doppler velocimetry, it can be used as a marker of the end of systole and beginning of diastole. Visual dicrotic notch representation, as it appears on Pulse wave Doppler, is shown on figure 3.

With the dicrotic notch serving as a readily recognizable marker to indicate the beginning of diastole, it is necessary to appoint a suitable measurement tool to quantify the brain-sparing effect.

This can be achieved by a method (subject of the claimed invention) for evaluation of the blood flow, characterized by measurement of areas under the curve of Pulse wave waveforms (or other Doppler modalities) of blood vessels (arteries or veins).

In one embodiment of the method, the systolic area in Pulse wave waveforms (or other Doppler modalities) is being measured, defined by the presence of dicrotic notch in Doppler velocimetry of blood vessels (arteries or veins).

In another embodiment the method, subject of measurement is the diastolic area in Pulse wave waveforms (or other Doppler modalities), defined by the presence of dicrotic notch in Doppler velocimetry of blood vessels (arteries or veins).

Brief description of the drawings Figure 1 represents the common use of the Doppler measurement of the blood velocity;

Figure 1. Shown in the image on the left is a PI of 1.74 at 34 weeks of gestation (normal finding).

Figure 2. The DN can be used as a demarcation tool to define systole and diastole

Figure 3. the DDA shape is defined by DN - dicrotic notch, D - end diastolic velocity and At - (t2 - tl).

Embodiment of the invention

Method (subject of the claimed invention) for evaluation of the blood flow, characterized by measurement of areas under the curve of Pulse wave waveforms (or other Doppler modalities) of blood vessels (arteries or veins).

In one embodiment of the method, the systolic area in Pulse wave waveforms (or other Doppler modalities) is being measured, defined by the presence of dicrotic notch in Doppler velocimetry of blood vessels (arteries or veins).

In another embodiment the method, subject of measurement is the sdiastolic area in Pulse wave waveforms (or other Doppler modalities), defined by the presence of dicrotic notch in Doppler velocimetry of blood vessels (arteries or veins).

It is hypothesized that in order to calculate the amount of vasodilatation more precisely (compared to pulsatility index), the area of the highlighted trapezoid shape (which we refer to as “diastolic deceleration area”) can be used (Error! Reference source not found.).

The diastolic deceleration area can be quantified with the following trapezoid area formula:

A = V2 (a + b) h where A is area; “a ” and “b ” are the bases of the trapezoid; “h ” is height.

This formula needs to be customized, using the variables from Error! Reference source not found.:

DDA = / ₂ (DN + D) At where DDA is diastolic deceleration area; DN is dicrotic notch (measured as velocity — m/s); D is end diastolic velocity (measured as velocity - m/s); At = t2 - tl (measured as DT- deceleration time).

Use of the invention

As demonstrated in Figure 3, the introduction of dicrotic notching to Doppler indices allows for a clear distinction between systole and diastole. This, in turn, is an important prerequisite for the implementation of new measurement modalities, not only applicable to the diastole, but to systole as well.

This new approach has several important implications:

- it delivers unprecedented precision in the evaluation of vasodilatation and therefore - fetal brain sparing effect;

- area under the Doppler curve quantification provides means for earlier diagnosis of fetal hypoxemia/hypoxia and anaemia, growth restriction, as well as broader spectrum of diagnostic possibilities in twin-to-twin transfusion syndrome and other conditions;

- calculation of systolic and diastolic areas in Pulse wave Doppler is applicable in all areas of human and veterinary medicine.

References: Mone F., McAuliffe FM, Ong S. The clinical application of Doppler ultrasound in obstetrics. The Obstetrician and Gynaecologist 2015;17:13-19. F.C. Battaglia et al. A practical classification of newborn infants by weight and gestational age. J Pediatr. 1967. Gosling RG, King DH, Newman DL and Woodcock JP. Transcutaneous measurement of arterial blood velocity ultrasound. Ultrasonics for Industry Conference Papers (Guildford: IPC) 1969; 16-32. Lees, C. C., Stampalija, T., Baschat, A. et al. ISUOG Practice Guidelines: diagnosis and management of small-for-gestational-age fetus and fetal growth restriction. Ultrasound in Obstetrics and Gynecology (Vol. 56, Issue 2, pp. 298-312) 2020. https://doi.org/10.1002/uog.22134 Wladimiroff JW, Tonge HM, Stewart PA. Doppler ultrasound assessment of cerebral blood flow in the human fetus. Br J Obstet Gynaecol 1986; 93: 471—475 Cohen E, Baerts W, van Bel F. Brain-Sparing in Intrauterine Growth Restriction: Considerations for the Neonatologist. Neonatology 2015;108:269-276. doi: 10.1159/000438451 Baschat AA, Gembruch U. The cerebroplacental Doppler ratio revisited. Ultrasound Obstet Gynecol. 2003 Feb;21(2): 124-7. doi: 10.1002/uog.20. PMID: 12601831. DeVore GR. The importance of the cerebroplacental ratio in the evaluation of fetal well-being in SGA and AGA fetuses. Am J Obstet Gynecol. 2015 Jul;213(l):5-15. doi: 10.1016/j.ajog.2015.05.024. PMID: 26113227. C. C., Stampalija, T., Baschat, A., da Silva Costa, F., Ferrazzi, E., Figueras, F., Hecher,

K., Poon, L. C., Salomon, L. J., Unterscheider, J. (2020). ISUOG Practice Guidelines: diagnosis and management of small-for-gestational-age fetus and fetal growth restriction. In Ultrasound in Obstetrics and Gynecology (Vol. 56, Issue 2, pp. 298-312). John Wiley and Sons Ltd. https://doi.org/ 10.1002/uog.22134 Vollgraff Heidweiller-Schreurs, C. A., de Boer, M. A., Heymans, M. W., Schoonmade,

L. J., Bossuyt, P. M. M., Mol, B. W. J., de Groot, C. J. M. Bax, C. J. (2018). Prognostic accuracy of cerebroplacental ratio and middle cerebral artery Doppler for adverse perinatal outcome: systematic review and meta-analysis. In Ultrasound in Obstetrics and Gynecology (Vol. 51, Issue 3, pp. 313-322). John Wiley and Sons Ltd. https://doi.org/10.1002/uog.18809 11. Dunn L, Sherrell H, Kumar S. Review: Systematic review of the utility of the fetal CPR measured at term for the prediction of adverse perinatal outcome. Placenta. 2017; 54: 68-75.

12. Meher S, Hernandez- Andrade E, Basheer SN, Lees C. Impact of cerebral redistribution

5 on neurodevelopmental outcome in small-for-gestational-age or growth-restricted babies: a systematic review. Ultrasound Obstet Gynecol 2015; 46: 398-404.

13. Gordijn SJ, Beune IM, Thilaganathan B, Papageorghiou A, Baschat AA, Baker PN, Silver RM, Wynia K, Ganzevoort W. Consensus definition for placental fetal growth restriction: a Delphi procedure. Ultrasound Obstet Gynecol 2016; 48(3): 833-9.

1014. G. Dahlgren, F. Veintemilla, G. Settergren, J. Liska, Left ventricular end- systolicpressure estimated from measurements in a peripheral artery, J. Cardiothorac.Vasc. Anesth. 5 (6) (1991) 551-553.

15. H.L. Falsetti, R.E. Mates, R.J. Carroll, R.L. Gupta, A.C. Bell, Analysis and correction of pressure wave distortion influid-filled catheter systems, Circulation 49(1) (1974)

15 165-172.

16. A.C. Guyton, J.E. Hall, Textbook of Medical Physiology, 11th edition, Elsevier Inc, Philadelphia , PA (2006), p. pl 09.

17. J.L. Hebert, Y. Lecarpentier, K. Zamani, C. Coirault, G. Daccache, D. Chemla,N. Wuilliez, L. Larsonneur, Relation between aortic dicrotic notch pressure andmean

20 aortic pressure in adults, Am. J. Cardiol. 76 (4) (1995) 301-306.

18. Politi, M. T., Ghigo, A., Fernandez, J. M., Khelifa, I., Gaudric, J., Fullana, J. M., Lagree, P. Y. (2016). The dicrotic notch analyzed by a numerical model. Computers in Biology and Medicine, 54—64. https://doi.org/ 10.1016/j .compbiomed.2016.03.005

19. Gamrah, M. A., Xu, J., el Sawy, A., Aguib, H., Yacoub, M., Parker, K. H. (2020).

25 Mechanics of the dicrotic notch: An acceleration hypothesis. Proceedings of the Institution of Mechanical Engineers, Part H: Journal of Engineering in Medicine, 1253— 1259. https://doi.org/10.! 177/0954411920921628