WO2024152075A1

WO2024152075A1 - Hypertension and haemodynamics monitoring system and method

Info

Publication number: WO2024152075A1
Application number: PCT/AU2023/050022
Authority: WO
Inventors: Robert Allan Phillips
Original assignee: Uscom Limited
Priority date: 2023-01-18
Filing date: 2023-01-18
Publication date: 2024-07-25

Abstract

A method of treating hypertension, the method including the step of utilising direct haemodynamic measurements in the calculation of a patient's blood pressure, to determine the levels of hypertension suffered by the patient.

Description

Hypertension and haemodynamics monitoring system and method

FIELD OF THE INVENTION

[0001] The present invention provides for systems and methods for the measurements and treatment of hypertension.

BACKGROUND OF THE INVENTION

[0002] Any discussion of the background art throughout the specification should in no way be considered as an admission that such art is widely known or forms part of common general knowledge in the field.

[0003] Hypertension is defined as an elevated blood pressure (BP) compared to normative data. However, physiologically it is a product of the central haemodynamic variables of stroke volume (SV), cardiac output (CO) and systemic vascular resistance (SVR) (BP = (SV x HR) x SVR).

[0004] Hypertension impacts function of the heart, brain, kidneys and eyes and is particularly associated with stroke and heart failure. Hypertension is the major cause of global human mortality and morbidity with an increasing incidence of >33% in all adults over the age of 35 years.

[0005] International hypertension guidelines uniformly endorse BP led therapeutic targets, and outcomes remain persistently dismal with a mere -25% of hypertension patients achieving therapeutic BP control, confirming a fundamental clinical ineffectiveness.

[0006] As BP is the product of cardiac and vascular function, the rationale of hypertension therapy is the use of diuretics, negative inotropes and vasodilators to directly reduce cardiovascular function, and thereby reduce central haemodynamics and, indirectly, BP.

[0007] Global hypertension guidelines demonstrate a profound bias to BP monitoring and demonstrate an effective neglect of central haemodynamics. This has led to identified flaws in the theory and practice of a BP-led approach to management and treatment of hypertension that may explain current poor clinical outcomes.

[0008] Multiple global clinical guidelines recommend anti -hypertensive therapy to reduce BP, yet effective BP control of people with hypertension remains dismal at -25% while central haemodynamics are ignored. [0009] BP is a cornerstone of hypertension practice, yet it is an insensitive measure of circulation and sheds little light on the critical therapeutic central haemodynamic variables of SV, CO and SVR, and ultimately may limit our understanding of the pathophysiology of hypertension and its management.

[0010] Hypertension is the number one global risk factor for human death accounting for approximately 10.4 million deaths annually. Worldwide about 1.28 billion adults aged 30-79 have hypertension with -46% unaware they have the condition. Approximately 32% of the global adult population have hypertension, of whom only around 50% have been diagnosed, with 38-47% of these having been treated, and a mere 18-26% having their hypertension controlled.

[001 1] In the US, 30-50% of all adults have hypertension with less than 50% of these treated, and -25% treated successfully. The cost of managing hypertension for the US alone in 2018 was $316 billion, while the incidence of hypertension and the associated morbidity and mortality continues to increase globally.

[0012] These dismal global outcomes persist despite 20 years of intense focus on improving the clinical care of hypertensive patients including the publication of multiple global practice guidelines, unprecedented spending, and the marketing of a constellation of evolving pharmacotherapies and monitoring technologies. Worldwide multiple hypertension guidelines steer clinical practice, and therefore an examination of these guidelines may identify practice trends which may improve the diagnosis, management and outcomes of hypertension disease.

SUMMARY OF THE INVENTION

[0013] It is an object of the invention, in its preferred form to provide an improved form of measurement of hypertension characteristics to allow improved guidance of treatment.

[0014] In accordance with a first aspect of the present invention, there is provided a method of treating hypertension, the method including the step of utilising direct haemodynamic measurements in the calculation of a patient’s blood pressure, to determine the levels of hypertension suffered by the patient.

[0015] In some embodiments, the direct haemodynamic measurements include at least one of SV, CO and SVR. The haemodynamic measurements can be taken utilising an Ultrasound Cardiac Output Monitor (USCOM 1A) device, from USCOM Uimited. [0016] The inclusion of central haemodynamics targets (SV, CO and SVR) for assessment and guidance of hypertension therapy is physiologically rational and may improve current outcomes.

[0017] The monitoring of central haemodynamics (SV, CO and SVR) is postulated to lead to improved therapeutic care in conditions of hypertension and circulatory dysregulation.

[0018] Monitoring central haemodynamics is a pathophysiologically rational approach to hypertension which may herald a better understanding of the disease and improve clinical outcomes.

[0019] In some embodiments, the haemodynamic measurements are used to identify a preferred anti-hypertensive therapy and monitor the effectiveness of this therapy.

[0020] In accordance with a further aspect of the present invention, there is provided a method of monitoring the levels of hypertension in a patient, the method including the steps of: (a) directly measuring the patient’s haemodynamic blood flow; and (b) utilising the haemodynamic measurement to calculate a level of hypertension suffered by the patient.

[0021] In some embodiments, the step (a) further comprises: determining from the haemodynamic measurement at least one of stroke volume, cardiac output and systemic vascular resistance.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings in which:

[0023] Fig. 1 illustrates a simplified circulatory model demonstrating the normal circulation and the central haemodynamic derangements of prehypertension and hypertension.

[0024] Fig. 2 illustrates different classes of cardiovascular therapy and their direct action on central haemodynamics, and their indirect action modulated by the autonomic nervous system (ANS). SV = stroke volume (mis), HR = heart rate (bpm), SVR = systemic vascular resistance in dyne.s.cm^-5.

[0025] Fig. 3 illustrates a simplified relationship between therapeutic interventions and central haemodynamic responses with directly targeted parameters, and indirect baroreceptor-mediated ANS compensation shown. DETAILED DESCRIPTION

[0026] It has been found that direct measurement of central haemodyanmic parameters provide a much more suitable measurement for monitoring hypertension.

[0027] Poor global outcomes suggest the inclusion of central haemodynamics in everyday practice can improve the understanding of hypertension and facilitate the delivery of precise antihypertensive therapy.

[0028] Hypertension is currently defined and managed to simple BP values, despite BP being the product of cardiac and vascular function as: BP = CO x SVR, where BP = blood pressure (mmHg), CO = cardiac output (1/min), SVR = systemic vascular resistance (dynes. s.cm-5), and CO = SV x HR.

[0029] Therefore, it is axiomatic that hypertension results from elevations of either cardiac function or vascular function, or both. The possible haemodynamic computations associated with hypertension can be simply represented as shown in Fig. 1, ranging from normal, prehypertensive with deranged but compensated central haemodynamics and normotension, and hypertensive with vasogenic, cardiogenic or mixed aetiology.

[0030] Fig. 1 illustrates a simplified circulatory model demonstrating the equations for normal circulation 1 and the central haemodynamic derangements of prehypertension 2 and hypertension 3.

[0031] Consequently, management of hypertension 3 should target the reduction of the appropriate pathological central haemodynamic parameter with the appropriate class of therapy.

[0032] Fig. 2 illustrates different classes of cardiovascular therapy and their direct action on central haemodynamics, and their indirect action modulated by the autonomic nervous system (ANS), whereSV is stroke volume (mis), HR is heartrate (bpm), and SVR represents systemic vascular resistance.

[0033] Significantly no therapy acts directly on blood pressure (BP), a value that is the product of the interplay of cardiac and vascular function and the autonomic nervous system (ANS). In contrast, anti -hypertensive therapy directly targets the reduction of central haemodynamics. While this simple model is complicated by the compensatory regulation of the ANS, quantification of the central haemodynamic variables is an intuitive first step for precise choice of therapy and the monitoring of dose and effectiveness. [0034] Fig. 3 illustrates a simplified relationship 30 between therapeutic interventions and central haemodynamic responses with directly targeted parameters, with the indirect baroreceptor-mediated ANS compensation shown.

[0035] In Fig. 3, there is identified the central haemodynamic response to different classes of cardiovascular therapy and demonstrates the potential for inappropriate treatment and iatrogenic complications. Non-physiologic therapies such as a reduction of SV to treat vasogenic hypertension, or vasodilation to decrease SVR for treatment of cardiogenic hypertension may further increase BP and further derange homeostasis and result in clinical deterioration.

[0036] Smith and Madigan’s overview of the pathophysiology of heamodynamics and hypertension (Smith BE, Madigan VM. Understanding the Haemodynamics of Hypertension. Current Hypertension Reports 2018; 20:29. DOI.org/10.1007/sl 1906-018-0832-8) observed that as hypertension is often asymptomatic and therapy ineffective, non-compliance is common. Iatrogenic complications such as postural hypotension, with negative symptoms for patients, further discourage compliance, and contribute to poor therapeutic outcomes.

[0037] Hypertension is a complex circulatory disease influenced by the sympathetic and parasympathetic nervous systems, the renin-angiotensin-aldosterone systems, cardiac natriuretic peptide system and vascular endothelium mediated by the interplay of baroreceptors, chemoreceptors and thermoreceptors to preserve homeostasis. Quantifying the underlying central haemodynamic aetiology of hypertension is essential for the implementation of precision therapy and improved outcomes in this complex disease.

[0038] A basic understanding of the physiology and pathophysiology of hypertension identifies central haemodynamics as the source of the circulatory dysfunction in hypertension and, therefore, the logical target of interventional therapies. This insight provides a clear opportunity to improve the guidelines, clinical practice and most crucially, patient outcomes.

[0039] While the deficiencies of BP-led approaches to hypertension management may be rooted in the non-physiologic focus on pressure-dominated concepts, several other significant aspects of BP monitoring may also contribute.

[0040] Firstly, despite being ubiquitous in clinical practice, automatic office BP (AOBP) monitoring is only modestly accurate. Kallioinen et al. (Kallioinen N, Hill A, Horswill MS, Ward HE, Watson MO. Sources of inaccuracy in the measurement of adult patients’ resting blood pressure in clinical settings: a systematic review. J Hypertens. 2017; 35:421-41. doi: 10.1097/HJH.0000000000001197) identified 29 specific causes of “potential mismeasurement” of BP in adults in clinical settings. The study reported SBP errors ranging from -23.6mmHg to +33mmHg and DBP errors from -14mmHg to +23mmHg across all sources of error, which included eight patient-related causes, two device-related causes, 16 procedure -related causes, and three observer-related causes. The authors concluded that “a single BP value outside the expected range should be interpreted with caution and not taken as a definitive indicator of clinical deterioration.” Importantly the reported errors strongly bias toward the over-measurement of SBP and DBP resulting in the misdiagnosis of subjects as hypertensive, while only 14-17% of errors resulted in undermeasurement.

[0041] It is universally assumed that commercially available AOBP are validated for accuracy, however, many authors have brought this into doubt.

[0042] Validation of brachial AOBP devices is by comparison of measurements from proposed devices with those from reference standards, or by proof of equivalence against existing validated devices. While intra-arterial pressure transducer monitoring of the aortic root is the gold standard comparator, the measurement sites are 25-35cm separate and have discrete pressures and flow waveforms. Additionally, the flow in the ascending aorta is not laminar but helical with velocity and pressure vortices associated with varying arterial morphology and arterial branching, making positioning of the transducer mid-stream in the aortic flow cross-section critical for accurate referencing. Such technical sources of error combine to make invasive validation challenging, potentially contributing to significant variations between invasive aortic and invasive brachial BP measurements, and invasive and non-invasive brachial values. Nakagami et al. (Nakagami A, Okada S, Shoji T, Kabayashi Y. Comparison of invasive and brachial cuff based nininvasive measurements for the assessment of blood pressure amplification. Hypertension Res 2017; 40:237-242. https://doi.org/10.1038/hr.2016.132) found that invasive aortic SBP was 17.7mmHg greater than non-invasive brachial SBP, and invasive brachial measures of SBP were on average 22.2mmHg greater than non-invasive brachial SBP values.

[0043] These disagreements between invasive and cuff based brachial measurements, and between invasive central BP measurements and brachial AOBP measurements undermines the reliability of the technologies on which reliance is placed. The recent introduction of brachial AOBPs that measure central BP and waveforms is targeted at reducing this source of error and improving their clinical reliability. [0044] A further challenge in determining the accuracy of BP measurement is that circulatory physiology and its component measures, BP, SV, CO and SVR are dynamic variables with significantly wide normal ranges and standard deviations. These fluxes may reflect normal physiology, such as in respiration, excitement and exercise, or pathophysiologic changes. As SBP and DBP are measured non-contemporaneously during cuff deflation, the accuracy of BP measurements may be influenced by the stage of the respiratory cycle at which the measurements are taken. Inspiration increases the SBP, DBP, PP and the SV, while they fall during expiration at a rate correlating with the depth of respiration and intra-thoracic pressure changes. As the resting adult respiratory cycle is 4-8 seconds and a normal cuff inflation and deflation cycle of an AOBP is in the order of 5-10 seconds, the SBP and DBP measurements will almost certainly be acquired from separate phases of the cardiac cycle, including from the apex and nadir of respiration ensuring maximum inaccuracy. This adds a further ±6% physiologic variability to BP measures even assuming pressures are measured precisely.

[0045] These multiple errors of AOBP measures vary within and across subjects, operators and devices, and result in summed errors in clinical measurement of at least ±15mmHg. This scale of mismeasurement may result in significant misclassification of hypertensive status, and an insensitivity for monitoring the effectiveness of therapy, thus seriously limiting the implementation of current BP-led hypertension guidelines.

[0046] So not only is BP a physiologically inappropriate target for monitoring circulatory dysregulation and guiding its treatment, but its clinical resolution is inadequate for the implementation of precision therapeutics, both of which may conspire to impair outcomes from current hypertension management and explain inadequacies of current outcomes.

[0047] The potential to adopt central haemodynamic-led approaches to improve management of hypertension depends on the availability of a non-invasive technology with clinical resolution at least as accurate as that of AOBPs. Continuous wave Doppler (CW) is well validated with a sensitivity of ±3% in string phantoms. An anthropometrically calibrated CW (USCOM, Uscom Ltd, Australia) has been validated from 0.121/min to 18.71/min across multiple clinical applications, is non-invasive, simple to use and interpret, with an examination time of less than five minutes, and can effectively guide therapy in free breathing subjects and those in sinus rhythm and with atrial fibrillation. The technology generates multiple parameters of cardiovascular performance beat to beat, including SV, CO and SVR, and can display values from each stroke, or as an average output value from a 10- second window, thus negating the effects of respiratory variation and increasing the reliability of measurements and its sensitivity to change. [0048] Kusomoto estimated a single measure to measure sensitivity of CW of 11% (Kusumoto F, Venet T, Schiller NB, Sebastian A, Foster E. Measurement of Aortic Blood Flow by Doppler Echocardiography: Temporal, Technician and Reader Vaariability in Normal Subjects and the Application of Generalizability Theory in Clinical Research. J Am Soc Echocardiogr 1995;8:647- 53. doi: 10.1016/s0894-7317(05)80378-5), and using generalizability theory predicted the sensitivity from 10 averaged SV measures repeated as being approximately 3.5%. In vivo sensitivity of ±5% was reported in sheep studies against surgically implanted ultrasonic flow probes over a six-fold range of cardiac outputs varied using inotropes and vasoactive therapies. These high sensitivities to therapeutic change, which are much greater than AOBP measurements, are essential to the early detection and management of early central haemodynamic changes in occult hypertension, prehypertension and hypertension.

[0049] A pilot validation of central haemodynamics -led diagnosis and management of hypertension is in the field of hypertensive disease in pregnancy (HDP), a common and dangerous complication of pregnancies worldwide. Despite widespread publicity and public health spending, HDP remains the second most common cause of maternal and foetal morbidity and mortality worldwide. (Anthropometrically calibrated CW monitoring of central haemodynamics has recently been adopted in HDP to better understand the normal evolution of the maternal circulation and its pathophysiology Kager CCM, Dekker GA, Stam MC. Measurement of cardiac output in normal pregnancy by a non-invasive two-dimensional independent Doppler device. ANZ J Obs Gyn 2009 DOI: 10.1 l l l/j, 1479-828X.2009.00948.x). While the aetiology of HDP is unique, the circulatory dysregulation and therapeutic approach are analogous to non-matemal hypertension. Eighty five percent of normal haemodynamic adaptation in pregnancy occurs before the 16th gestational week, while early dysregulation of maternal SV, CO and SVR leading to HDP can be detected at 5-11 weeks gestational age. However, BP changes of hypertension are not detected until 20-25 weeks, thus providing a therapeutic window for early and physiologically precise therapy during the period of ANS compensated normotension. Importantly the concept of cardiogenic and vasogenic aetiology has been established allowing for a simplified approach to treatment using vasodilators, negative inotropes and diuretics implemented before the decompensated phase of frank hypertension is established by the re-set of baroreceptor set-points. Precision management according to objective measures of SV, CO and SVR is consistent with circulatory physiology and pathophysiology and is improving the understanding of HDP, with an SVR value greater than 1069 dynes. s.cm-5 significantly associated with increased maternal -foetal complications.

[0050] Anthropometrically calibrated CW has also established a utility in adult and paediatric critical care for the guidance of fluid, inotropes and vasoactive agents in sepsis, where BP can be either pathologically high or low, and labile, and where circulatory performance is characterised by shifting intravascular volumes, and intermittent vasoplegia and cardioplegia.

[0051] The Framingham Heart Study has provided a cornerstone of our understanding of hypertension with 74 years of study of a database of -15,000 participants covering three generations resulting in 10 and 30-year risk prediction algorithms for heart disease, including hypertension (Andersson C, Johnson AD, Benjamin EJ, Levy D, Vasan RS. 70-year legacy of the Framingham Heart Study. Nat Rev Cardiol 2019;16:687-698. https://doi.org/10.1038/s41569-019-0202-5). However, this monumental study is referenced substantially from BP measurements, thus embedding in the data all the limitations addressed in the preceding above discussion. While the Framingham data has provided unequalled epidemiological evidence, the benefit with regard to therapeutic precision is less established, a limitation perhaps partly explained by its dependence on BP measurements. The predominance of BP data in this foundation study has also ensured that the evidence bar for the adoption of new technologies is exceptionally high. This limits the adoption of complimentary technologies which may expand our understanding and management of hypertension, and ensures the persistence of the “treatment of all with the therapy to benefit the majority” strategy; a strategy that may partially explain the substantial “BP treated but uncontrolled” cohort in hypertension outcomes data.

[0052] The clinical adoption of central haemodynamic-led hypertension management will require the establishment of bespoke hypertensive clinics, with specialised clinicians and technicians accompanying expanded data monitoring, and thus additional cost. However the potential savings from even a small improvement in cost-effectiveness of care, particularly in early detection and treatment of prehypertension, will be offset by the savings from public health budgets and may be rewarded by improved clinical outcomes.

[0053] The poor outcomes of hypertension management in the prior art can be attributed to multiple causes including pressure-led management, inaccuracy of BP technologies, the complexity of the underlying pathophysiology, and inadequacy of examination and monitoring techniques. Global hypertension practice guidelines, founded on BP-led monitoring, are widely adopted, yet substantially ineffective, while central haemodynamics which are core to the aetiology and therapy of hypertension remain neglected. In the absence of significant changes it is difficult to envisage improvements in clinical outcomes, while adoption of flow-led practices is physiologically rational and may improve our understanding of hypertension and facilitate the delivery of earlier and more precise anti -hypertensive therapy and improved outcomes. Interpretation

[0054] Reference throughout this specification to “one embodiment”, “some embodiments” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment”, “in some embodiments” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments.

[0055] As used herein, unless otherwise specified the use of the ordinal adjectives "first", "second", "third", etc., to describe a common object, merely indicate that different instances of like objects are being referred to, and are not intended to imply that the objects so described must be in a given sequence, either temporally, spatially, in ranking, or in any other manner.

[0056] In the claims below and the description herein, any one of the terms comprising, comprised of or which comprises is an open term that means including at least the elements/features that follow, but not excluding others. Thus, the term comprising, when used in the claims, should not be interpreted as being limitative to the means or elements or steps listed thereafter. For example, the scope of the expression a device comprising A and B should not be limited to devices consisting only of elements A and B. Any one of the terms including or which includes or that includes as used herein is also an open term that also means including at least the elements/features that follow the term, but not excluding others. Thus, including is synonymous with and means comprising.

[0057] As used herein, the term “exemplary” is used in the sense of providing examples, as opposed to indicating quality. That is, an “exemplary embodiment” is an embodiment provided as an example, as opposed to necessarily being an embodiment of exemplary quality.

[0058] It should be appreciated that in the above description of exemplary embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects. This method of disclosure, however, is not to be interpreted as reflecting an intention that the claimed invention requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed embodiment. Thus, the claims following the Detailed Description are hereby expressly incorporated into this Detailed Description, with each claim standing on its own as a separate embodiment of this invention.

[0059] Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those skilled in the art. For example, in the following claims, any of the claimed embodiments can be used in any combination.

[0060] Furthermore, some of the embodiments are described herein as a method or combination of elements of a method that can be implemented by a processor of a computer system or by other means of carrying out the function. Thus, a processor with the necessary instructions for carrying out such a method or element of a method forms a means for carrying out the method or element of a method. Furthermore, an element described herein of an apparatus embodiment is an example of a means for carrying out the function performed by the element for the purpose of carrying out the invention.

[0061] In the description provided herein, numerous specific details are set forth. However, it is understood that embodiments of the invention may be practiced without these specific details. In other instances, well-known methods, structures and techniques have not been shown in detail in order not to obscure an understanding of this description.

[0062] Similarly, it is to be noticed that the term coupled, when used in the claims, should not be interpreted as being limited to direct connections only. The terms "coupled" and "connected," along with their derivatives, may be used. It should be understood that these terms are not intended as synonyms for each other. Thus, the scope of the expression a device A coupled to a device B should not be limited to devices or systems wherein an output of device A is directly connected to an input of device B. It means that there exists a path between an output of A and an input of B which may be a path including other devices or means. "Coupled" may mean that two or more elements are either in direct physical or electrical contact, or that two or more elements are not in direct contact with each other but yet still co-operate or interact with each other.

[0063] Thus, while there has been described what are believed to be the preferred embodiments of the invention, those skilled in the art will recognize that other and further modifications may be made thereto without departing from the spirit of the invention, and it is intended to claim all such changes and modifications as falling within the scope of the invention. For example, any formulas given above are merely representative of procedures that may be used. Functionality may be added or deleted from the block diagrams and operations may be interchanged among functional blocks. Steps may be added or deleted to methods described within the scope of the present invention.

Claims

CLAIMS:

1. A method of treating hypertension, the method including the step of utilising direct haemodynamic measurements in the calculation of a patient’s blood pressure, to determine the levels of hypertension suffered by the patient.

2. A method as claimed in claim 1 where the direct haemodynamic measurements include at least one of stroke volume, cardiac output and systemic vascular resistance.

3. A method as claimed in any previous claim wherein the haemodynamic measurements are taken utilising an ultrasound cardiac output monitoring device.

4. A method as claimed where the haemodynamic measurements are used to identify a preferred anti-hypertensive therapy and monitor the effectiveness of this therapy.

5. A method of monitoring the levels of hypertension in a patient, the method including the steps of:

(a) directly measuring the patient’s haemodynamic blood flow; and

(b) utilising the haemodynamic measurement to calculate a level of hypertension suffered by the patient.

6. A method as claimed in claim 5 wherein said step (a) further comprises: determining from the haemodynamic measurement at least one of stroke volume, cardiac output and systemic vascular resistance.