JP2008534071A - System and method for discrimination between vascular conditions using dynamic vascular assessment and for investigation of intracranial pressure - Google Patents

Abstract

The present invention assesses blood flow in single or multiple blood vessels and segments, assesses vascular health, conducts clinical experiments, screens for therapeutic intervention to obtain effects, assesses risk factors, The present invention relates to a system and method for evaluating internal pressure and analyzing results according to a defined method. The present invention can directly monitor treatments, materials and devices to blood vessels, particularly cerebral blood vessels. Relevant blood flow parameters include mean flow velocity, systolic acceleration, and pulsatile index. These parameters and other measurements and analyzes provide details on individual and multiple vascular health, and extensive analysis provides an individual's overall vascular health. The present invention can track the effects of disease onset, progression and treatment of individuals experiencing elevated intracranial pressure, i.e., identifying vulnerabilities under the vasculature associated with symptomatic or dementia and presenting symptoms, Helps to normal pressure.

Description

<Cross-reference to related applications>
This application claims priority from US Provisional Application No. 60/664295 filed on March 23, 2005, and this application is co-pending by the same applicant filed on May 21, 2003. This is a continuation-in-part of US Patent Application No. 10/442194. This U.S. Patent Application No. 10/442194 is a U.S. Provisional Patent Application Nos. 60/236661, 60/236662, 60/236663, 60/236875, all filed September 29, 2000, and 60/236876 and the United States filed on October 1, 2001 claiming the priority of US Provisional Applications 60/263165 and 60/263221 both filed January 23, 2001 This is a continuation-in-part of patent application No. 09/966367 (current US Pat. No. 6,665,122). The above application is expressly incorporated herein by reference in its entirety.
This application is a continuation-in-part application claiming priority from co-pending US patent application Ser. No. 10/442194, filed May 21, 2003, and co-pending US patent application Ser. No. 10/442194. Is a continuation-in-part of US patent application Ser. No. 09/966367, filed Oct. 1, 2001. This application also claims priority from US Provisional Application No. 60/664295, filed Mar. 23, 2005. The above application is expressly incorporated herein by reference in its entirety.

<Background of the invention>
TECHNICAL FIELD The present invention relates to a system and method for assessing vascular health, and a system and method for assessing the effects of substances including treatments, risk factors, and therapeutic agents on blood vessels, particularly cerebral blood vessels. In general, they are all achieved by measuring various parameters of blood flow in one or more blood vessels and analyzing the results in the established problem. Furthermore, the present invention relates to integrating, analyzing and using measurements of various parameters of blood flow in one or more blood vessels to establish clinical trial protocols and to monitor clinical trials. Furthermore, the present invention relates to an automatic decision support system for interpreting the values of various parameters of blood flow in one or more blood vessels in the assessment of individual vessel health.

  The proper functioning of the vascular system is essential for the health and fitness of the body. The vascular system carries essential nutrients and blood gases to all living tissues and removes waste products for excretion. The blood vessels are divided into various sites depending on the supplied organ system. If the blood vessels supplying specific organs or groups of organs are damaged, the organs and tissues supplied by those blood vessels will be adversely affected and will not function fully.

  Blood vessels, particularly various types of arteries, are active in not only propagating fluid to various locations, but also responding to pressure changes during the cardiac cycle. With each contraction of the heart's left ventricle during systole, blood is pumped into the aorta and travels throughout the body. Many arteries contain elastic membranes in their walls that help the blood vessels expand during systole. These elastic membranes also function to smooth the pulsating blood flow throughout the vascular system. Such arterial vessel walls often rebound the next passage of the systolic pressure waveform.

  In autoregulation, cerebral blood vessels maintain constant cerebral blood flow by contracting or expanding beyond a range of mean arterial pressures so that constant oxygen delivery to the brain is maintained. Vascular dysfunction occurs when the pressure drops too low and the velocity begins to drop. If blood pressure becomes too high and the blood vessels cannot contract any more to restrict flow, breakthrough, hyperemia breakthrough, and loss of self-regulation occur. Both of these conditions are pathological conditions and have been described in the literature in terms of mean arterial pressure and cerebral blood flow velocity. However, there are outliers that could not be explained based on the model. The model failure is that it depends on systemic blood pressure. The pressure of blood in the brain itself is not directly measured. The resultant pressure curve has an S-shaped curve.

  The force applied to the blood from each heartbeat is to propel it. In physics, force is not equal to the product of mass and acceleration. However, when blood is examined for changes in heart rate intervals, each heart rate provides approximately the same amount of blood, unless there is massive blood loss or a very irregular heart rhythm. Thus, as a first approximation, the force of flow on the blood, especially at that moment, is directly proportional to its acceleration.

  A diseased blood vessel loses elasticity. The elasticity or expansion and contraction of blood vessels is extremely important for maintaining pulsatile flow. It is not passive relaxation when muscles are stretched. As a blood bolus passes by each heartbeat, it stretches the vessel wall, but the blood vessels then contract and give a forward kick, thereby covering such a large surface area by a relatively small organ called the heart There is a chemical reaction that takes place inside the muscle itself that generates a micro-contracture and increases contraction. This creates ripples of waves that begin in the large blood vessels of the aorta and enter through other blood vessels. When blood vessels are affected, they lose the ability to maintain this type of pulsatile flow.

Furthermore, if the blood vessel is compromised by various factors such as stenosis or stenosis of the vessel lumen, blood flow becomes abnormal. If the stenosis of the blood vessel is extensive, turbulence may occur at the location of the stenosis, resulting in damage to the blood vessel. In addition, blood does not flow sufficiently past the stenosis, thereby damaging the tissue distal to the stenosis. Although such vascular damage can occur throughout the body, coronary arteries and cerebral vascular beds are vital for the survival and health of the body. It will reduce cardiovascular function and reduce blood flow to the myocardium, causing a heart attack.
The development of such symptoms will result in a significant decrease in cardiac function and death.

  Cerebral vascular abnormalities may interfere with adequate blood flow to the nervous tissue, leading to transient cerebral ischemic attacks (TIAs), migraine headaches and strokes. The blood vessels that supply the brain are led from the internal carotid artery and the vertebral artery. These blood vessels and their branches are anastomosed via a large arterial ring, also known as the Willis artery ring. From this annulus, the anterior cerebral artery, middle cerebral artery and posterior cerebral artery are generated. Other arteries, such as the anterior and posterior arterial arteries, provide collateral flow routes through large arterial rings. The vertebral arteries connect to form the basilar artery, which itself supplies the branches of the artery to the cerebellum, brainstem and other brain regions. Blockage of blood flow inside any of the anterior cerebral artery, posterior cerebral artery, middle cerebral artery, or other arteries distal to the large arterial ring is at risk to the nerve tissue supplied by that artery Causes (deteriorated) blood flow. If the glucose and oxygen that are in the blood and provided to neurons by the glial cells are not at a normal, constant level, nerve tissue cannot survive, so obstruction of blood flow in any of these vessels Cause death of nerve tissue that is supplied by its blood vessels.

  Stroke results from blockage of blood flow in the blood vessels of the cerebrum due to constriction of blood vessels due to embolism or stenosis. Strokes can also be caused by tearing of the vessel wall in many situations. Thus, an obstruction will result in an ischemic stroke that deprives oxygen tissue and glucose from nerve tissue more distal to the obstruction. A tear or rupture of a blood vessel will result in bleeding into the brain, also known as a hemorrhagic stroke. Intracerebral hemorrhage has a detrimental effect on surrounding tissues due to increased intracranial pressure (increased intracranial pressure) and direct exposure of neurons to blood

  Regardless of the cause, stroke is the leading cause of illness and death. Stroke is the leading cause of death for women, killing more women than breast cancer. Currently, more than 3/4 of 1 million people in the United States experience stroke each year, and more than 25 percent of those people die. Nearly one third of people who have their first stroke will die in the next year. In addition, about one third of all survivors of the first stroke will experience additional strokes within the next three years.

  In addition to its final form, stroke is a major cause of disability in the adult population. Such disorders can cause permanent dysfunction and decline in function in any part of the body. Paralysis of various muscle groups innervated by neurons affected by stroke can lead to wheelchair containment and muscle spasm and stiffness. Stroke leaves many patients without the ability to communicate either by oral or written means. In many cases, stroke patients may not be able to think clearly and clearly, may be difficult to say the correct names of things, interact with others, and generally function in society. is there.

  In addition, stroke also results in tremendous expenditures in society and places a great economic burden on affected people and their families. In the US economy alone, the total annual cost is estimated to be over $ 30 billion per year, and about $ 35,000 for the treatment of strokes with average first aid. Artificial age increases will dramatically increase the incidence of stroke. In fact, the risk of stroke will always double in the next decade. As the average life expectancy of a population has increased dramatically over the past 100 years, the number of people over 50 has risen sharply. Stroke potential is indeed very high in the population of people who live to an unexpected age. Thus, the economic and emotional impact of cerebral vascular damage is expected to increase dramatically over the next decades.

  Despite the great risk of stroke, there is currently no convenient and accurate way to access vascular health. Many methods rely on invasive procedures such as arteriography to determine if vascular stenosis has occurred. These invasive techniques are often not ordered until symptoms appear in the patient. For example, an arteriogram of the carotid artery will be ordered following a physical examination according to the appearance of clinical symptoms. Arterography cannot be performed without risk, as contrast agents are introduced into the vascular system that may cause allergic reactions. Arteriography also uses a catheter that can remove intraluminal plaques that can damage vessel walls and cause embolic stroke at downstream sites.

  Many methods and devices available for cerebral vascular imaging cannot provide a dynamic assessment of vascular health. Instead, these imaging techniques and devices simply provide a snapshot or still image of the vessel at a particular time. Since cerebral angiography is the “most standard test” for analyzing blood flow to the brain, it is maintained as usual. However, this invasive analysis method simply provides the shape of the blood vessel in diagnostic imaging. Obtaining the same type of flow criteria obtained from the present invention from angiography would require a great deal of labor and multiple dangerous measures.

  Instruments have been developed to obtain non-invasive measurements of anterior arterial and venous blood flow rates using the Doppler principle. In accordance with known Doppler phenomena, these instruments provide observers moving relative to the wave source with waves from a wave source having a frequency different from that of the wave at the wave source. When the wave source is approaching the observer, higher frequency waves are received by the observer. Conversely, if the wave source is far from the observer, a lower frequency wave is received. The difference between the emitted frequency and the received frequency is known as the Doppler shift. This Doppler technology will be achieved through the use of ultrasonic energy.

The operation of such an instrument according to the Doppler principle will be illustrated with respect to FIGS. In FIG. 1, the ultrasonic probe 40 plays a role as a stationary wave source, and emits pulse ultrasonic waves at a frequency of 2 MHz, for example. This ultrasonic wave is transmitted to the blood vessel 42 through the skull 41 and the brain parenchyma. For illustration, blood cell 43 approaches the probe and acts as a moving observer. As illustrated in FIG. 2, blood cells reflect ultrasonic pulses and can be considered as moving wave sources. The probe receives this reflected ultrasonic wave and acts as a stationary observer. The frequency f ₁ of the ultrasonic wave received by the probe is higher than the frequency f ₀ emitted first. Thereafter, the Doppler shift of the received wave can be calculated. 3 and 4 show the effect on the pulse of ultrasound as blood flows in a direction away from the probe. In this case, the reception frequency (f ₂ ) reflected by the blood cells is lower than the emitted frequency f ₀ . Again, the Doppler shift can be calculated.

ここで、
Ｆ_ｄ＝周波数のドップラーシフト
Ｆ_ｔ＝送信器の周波数
Ｖ＝血流速度
θ＝プローブと動脈との間の入射角
Ｖ_０＝生体組織内での超音波の速度
である。 The Doppler effect can be used to determine the blood flow velocity of the cerebral artery. The Doppler equation used for this is as follows.

here,
F _d = Doppler shift in frequency F _t = Transmitter frequency V = Blood flow velocity θ = Angle of incidence V ₀ between probe and artery = Velocity of ultrasound in living tissue.

Typically, F _t is a constant, for example 2, 4 or 8 MHz, and V ₀ is approximately 1540 meter seconds (m / s) in living soft tissue. Assuming that the angle of incidence between the probe and the artery is zero, the value of cos θ is equal to one. The effect of the angle θ is significant only for incident angles exceeding 30 °.

  In a typical instrument, ultrasonic energy is provided in bursts at a pulse repetition rate or frequency. The probe receives echoes from each burst and converts acoustic energy into an electrical signal. In order to obtain signal data corresponding to reflections occurring at a specific depth (range) in the head, the electronic gate opens and receives a signal of reflection at a selected time after the excitation pulse, which is selected Corresponds to the expected time of arrival of an echo from a depth location. Range resolution is generally limited by the bandwidth and burst length of the various parts of the instrument. Bandwidth can be reduced at the expense of increased sample volume length by filtering the received signal.

  Other body movements, such as vascular wall contraction, can also scatter ultrasound, which will be detected as “noise” in the Doppler signal. In order to reduce this noise interference, a high-pass filter is used to reduce low frequency and high amplitude signals. The high pass filter can typically be adjusted to have a higher passband than a selectable cutoff frequency, for example, between about 0 and about 488 Hz.

  Many healthcare professionals rarely have such flow diagnostic capabilities at their disposal. For example, a health care worker may be located in a remote area such as a rural area, on the ocean, or in a battlefield situation. These medical personnel need access to analytical capabilities in order to analyze blood flow data generated at remote locations.

  Health professionals facing these geographical obstacles are limited in their ability to provide the high quality medical services needed for their patients, especially in an emergency. In addition, both physicians and individuals who are concerned about their own health are often limited in their ability to consult with specialists in specific medical specialties. Therefore, there is a need for a system that facilitates access to physicians at various locations to high-performance medical diagnosis and prognostic capabilities related to vascular health. Such access will facilitate the delivery of higher quality healthcare to people throughout the country, especially those remote from major medical centers.

  A central receiving facility that receives the data, analyzes it, generates a value indicative of vascular health, and transmits this information to another location, such as an outgoing data transfer station or directly to the health care professional's office, There is also a need for a system that can transmit patient vascular data. The system should provide access to high-performance computing capabilities that improve the accuracy of medical personnel's diagnostic and prognostic capabilities regarding vascular health. This system must be able to receive large amounts of patient data and process the data quickly in order to obtain disease diagnosis and prognosis. Such a system may be used for diagnosis and prognosis of diseases or conditions associated with vascular health.

  There is a further need for a system that facilitates the ability of medical personnel to conveniently and quickly transmit vascular flow data parameters obtained from patients to a location where consistent and reproducible analysis can be performed. The analysis results can then be sent to medical personnel to facilitate accurate diagnosis or prognosis of the patient, recommend treatment options, and explain the impact of the patient and those treatment options.

  There is also a need for a system that allows health professionals to measure the incidence and type of vascular disease and recommend interventions that prevent, minimize, stabilize, or recover from the disease.

  A system that allows healthcare professionals to predict vascular response to a proposed therapeutic intervention and to modify the proposed therapeutic intervention if adverse or adverse vascular responses are expected There is also a need. Physicians often prescribe therapeutic drugs to patients with conditions related to the circulatory system that affect vascular health. For example, hypertensive patients may be prescribed beta receptor blockers in order to lower blood pressure and thereby reduce the likelihood of a heart attack. Patients often accept one or more therapeutic agents for their condition. The potential interaction of therapeutic agents with various biological targets such as blood vessels is often poorly understood. Therefore, there is a need for a non-invasive method that can be used to evaluate the effects on blood vessels by substances such as therapeutic agents or by combinations of therapeutic agents. A clear understanding of the effects of one or more substances on the blood vessels in the blood vessels would prevent the formulation of substances with undesirable and potentially fatal effects such as stroke, vasospasm and heart attacks. Therefore, what is needed is a system and method that can be used for repeated assessments within the patient population under clinical trials without the deleterious effects of potential vascular effects of the substance or combination of substances. is there. Such clinical studies will also reveal the dosing of individual substances and combinations of substances at specific dosages that provide desirable and unexpected effects on the blood vessels.

  Further, there is a need for systems and methods that can provide an assessment of an individual's vascular health. There is also a need for systems and methods that are routinely used to assess vascular health, such as during routine physical examinations. The system and method are preferably non-invasive and provide information regarding vascular compliance and elasticity. There is also a need for systems and methods that can be used to quickly assess an individual's vascular health. Such systems and methods should be enabled for routine health check-ups, particularly in emergency rooms, intensive care units, or neurology clinics. There is also a need for systems and methods that can be applied within each person's long-term method so that an individual's vascular health can be assessed over time. Thus, the problem or disease process will be detected before the appearance of a serious cerebrovascular attack or stroke.

  Furthermore, there is a need for a system and method for assessing treatment, risk factors, the effects of substances on blood vessels, particularly cerebral blood vessels, so that their potential to produce vascular responses can be determined. By determining the treatment, risk factors and the effect of the substance on the blood vessels, the physician will be able to encourage the patient to avoid the treatment, risk factors and / or substance. Alternatively, the desired effect on the blood vessel by treatment, therapeutic intervention and / or substance will result in treatment, therapeutic intervention and / or administration of the substance to obtain the desired effect.

  Furthermore, in the treatment of vascular disorders, measures are taken, treatments are performed, and the identification of those treatments that are most effective in the treatment of vascular disorders can be determined and used to restore vascular health. There is also a need for a system and method for assessing the efficacy of a treatment that includes administering a pharmaceutical substance.

  Due to federal regulatory requirements, treatments involving drugs and other therapies intended for the treatment of individuals must be tested by people. These tests, called clinical trials, provide a variety of information about the efficacy of the treatment, such as whether it is safe and effective, how much it works optimally, and what side effects it brings. This information guides healthcare professionals and consumers who use drugs appropriately if they can be bought without a prescription. In comparative clinical trials, the results observed in patients being treated are compared with those of similar patients receiving different treatments, such as placebo or no treatment at all. A comparative clinical trial has determined that the new treatment will provide "substantial evidence of efficacy as well as a relative safety confirmation regarding the risk-to-effect ratio for the disease being treated" FDA) is the only legal basis.

  It is important to test test drugs, treatments and measures on those people whose purpose is to help the treatment. It is also important to plan clinical studies that ask and answer the exact questions about the treatment being studied. Before clinical trials begin, researchers analyze the main physical and chemical properties of the treatment in the laboratory and study its pharmacological and toxic effects in laboratory animals. If results from laboratory studies and animal studies are promising, treatment sponsors can apply to the FDA and begin testing in people. Once the FDA has reviewed the sponsor's plan, a local institutional review board--typically a committee of scientists, ethicists, and non-scientists who monitor clinical studies at medical centers -But if the protocol for the clinical trial is approved, the investigator will treat a small number of healthy volunteers or patients. These Phase 1 studies assess the most common and serious adverse effects and test the doses that patients can safely take without frequent side effects. The first clinical study also shows what happens to the drug in the human body, such as how the drug changes, how much drug is absorbed into the bloodstream and various organs, and how long the drug is in the body. Begin to clarify what remains in the body, how the body removes the drug, and how the drug affects the body.

  If phase 1 studies do not reveal significant problems, such as unacceptable toxicity, then a clinical study will be conducted in which the patient is treated for a medical condition for which the treatment is intended. . The investigator will then evaluate whether the treatment has a favorable effect on the condition. The clinical research process simply requires recruiting a group of one or more patients to participate in a clinical trial, administering treatment to those who agree to participate, and determining whether the treatment will help them. To do.

Usually, treatments do not miraculously recover from fatal illnesses. For the most part, they reduce the risk of death but do not eliminate it completely. This is typically accomplished by relieving one or more symptoms of illness such as nasal congestion, pain or anxiety. Treatment may also change clinical measurements in a way that the doctor considers valuable, such as lowering blood pressure or lowering cholesterol. The effects of such treatments can be difficult to detect and evaluate. This is mainly because the disease does not follow a predictable pathway. For example, many acute illnesses or medical conditions such as viral diseases such as influenza, minor injuries and insomnia cure spontaneously without treatment. Some chronic symptoms, such as arthritis, multiple sclerosis or asthma, often change without a clear reason, usually for example, once it gets better, then gets worse and then gets better again Follow the treatment unit you want.
Heart attacks and strokes have a wide range of variable mortality rates that depend on treatment, age, and other risk factors that create “expected” deaths for individual patients that are difficult to predict.

  An additional difficulty in measuring the effectiveness of treatments in clinical trials is that in some cases, disease measurements are subjective and depend on interpretation by a physician or patient. In those situations, it is difficult to tell if the treatment has a positive effect, no effect, or even a bad effect. The way to answer important questions about treatments under study is to have them undergo comparative clinical trials.

  In a comparative clinical trial, one group of patients will receive treatment during the trial. The patients in the group to be compared, the control group, receive either no treatment, placebo (inactive material component that looks like a study drug), or treatment known to be effective. Test groups and control groups are typically studied simultaneously. Usually, the same group of patients is divided into two subgroups, each subgroup receiving a different treatment.

  In some special cases, the study uses “historical controls”, in which patients treated in the trial are compared with similar patients treated with control treatment at different times and locations. The Often, the patient is examined at some point after treatment of the trial, and the investigator compares the patient's status both before and after treatment. Again, the comparison is historical and is based on an estimate of what would have happened without treatment. Historical control planning is particularly useful when the disease being treated is high and has a predictable mortality or morbidity. It is important that the treatment group and the control group be as similar as possible in characteristics that can affect the outcome of the treatment. For example, in a particular group, all patients must have the disease that the treatment is intended for treatment or have the same stage of the disease. The treatment group and the control group are also similar in other characteristics that may affect study results at similar ages, weights and general health conditions, and other treatments that are accepted at the same time. Must-have.

  The primary technique used in controlled clinical trials is called “randomization”. Rather than intentionally selecting one or the other group, patients are randomly assigned to either a treatment group or a control group. An important assumption, albeit severely flawed, is that if the study population is large enough and the criteria for participation are carefully defined, randomization will yield similar treatment and control groups in key features. Randomization also eliminates the possibility of "selection bias", i.e. the tendency to choose healthier patients for new treatment or placebo because assignment to one group or another is not under investigator control . In a double-blind study, no patient, investigator, or data analyst knows which patient has taken the study drug.

  Unfortunately, a careful definition of selection criteria that fit for participation in clinical trials has not previously been available. Vascular health, particularly cerebral vascular health, was a difficult, if not impossible, criterion to assess who could participate in clinical trials. Thus, there remains a technical need for the ability to conduct truly random clinical trials by selecting clinical trial participants with matched vascular and cerebral vascular characteristics.

  Furthermore, an important aspect of clinical trials is to assess the risk of adverse effects of the treatments performed. This makes it unwieldy as a bad effect that only appears on their own long after a short run of a clinical trial has been run on that therapeutic unit. Unfortunately, vascular effects, particularly cerebral vascular effects, are difficult, if not impossible, to evaluate during clinical trials. Thus, there remains a technical need for the ability to accurately assess the adverse effects caused by treatments on vascular and cerebral vascular health features.

  In the treatment of vascular disorders, it is possible to determine the identification of harmful treatments by assessing the efficacy of the treatment, including taking action, carrying out therapy, and administering medicinal substances or combinations thereof, and prescribing There is also a need for systems and methods that prevent this from happening.

  In addition, assess the impact of treatment, including taking action, performing therapy, and administering a drug substance or combination of medical substances to elucidate the impact of treatment that is effective on vascular health in vascular health There is also a need for systems and methods that enable it.

<Outline of the invention>
The present invention provides a means to solve the above-mentioned drawbacks by providing a system and method for assessing an individual's vascular health. This system and method is inexpensive, rapid, non-invasive, and provides excellent data on vascular dynamic functions. Thus, the systems and methods include, but are not limited to, periodic physical examinations, intensive care units, emergency rooms, field such as emergency scenes on the battlefield or highway or suburbs, and neurological clinics. It can be used in a variety of situations. By using this system and method, doctors can assess individuals by detecting deviations from vascular health by assessing specific parameters of vascular function as well as their current vascular health status. Can do.

  In addition to use in routine health checks, the systems and methods of the present invention may be used to evaluate persons with risk factors for cerebral vascular dysfunction. Such risk factors include, but are not limited to, a history of stroke, genetic predisposition to stroke, smoking, alcohol consumption, caffeine consumption, obesity, hypertension, aneurysm, transient cerebral ischemia Includes seizures (TIAs) closed head trauma, history of migraine, previous intracranial trauma, increased intracranial pressure, and history of drug abuse.

  The system and method of the present invention provides a system and method for evaluating people with high risk factors, as well as a mechanism for selecting a group of patients for clinical trials and monitoring the patient population in a particular clinical group I will provide a. For example, the patient population of people at high risk for stroke is systematically evaluated over time to determine whether ongoing vascular changes indicate early cerebral vascular events such as stroke. May be. In this way, it may be possible to predict the occurrence of the first stroke and thereby prevent the stroke. In another embodiment, the present invention provides a mechanism for monitoring a person who has experienced a stroke.

  In yet another embodiment of the invention, an individual's vascular responsiveness to various substances is assessed, including but not limited to drugs, nutrients, alcohol, nicotine, caffeine, hormones, cytokinins and other substances. . Through the use of this system and method, research studies may be conducted using animals or humans to assess the effects of various substances on the vascular system. Collect and evaluate valuable information about the potential vascular effects of a substance before it is medically prescribed by performing the low-cost and efficient non-invasive test of the present invention Can do. Furthermore, the effects of individual substance dosages on blood vessels, and the effects of different dosages of substances on blood vessels may be evaluated in selected clinical populations using the systems and methods of the present invention. Good. Accordingly, the present invention provides a system and method for assessing the potential vascular effects of a substance or combination of substances by performing non-invasive clinical research studies in selected dosages and selected patient populations. I will provide a.

  In another embodiment, the present invention may be applied to a particular population of people with a particular disease to determine whether the use of the material creates an undesirable effect in that population. For example, the population of people with diabetes may react differently to certain substances such as drugs than the population of people without diabetes. Furthermore, the population of people with hypertension may respond differently to certain substances such as catecholamine agonists or ephedrine-containing natural extracts than those of people who do not have hypertension. The use of the present invention allows the vascular response whether in any individual or in any population it is the population of individuals with a particular disease, medical condition or prior exposures to various treatments. Allows sex assessment.

  The present invention provides a method for assessing the vascular health of a human or animal. In one embodiment, the evaluation method includes obtaining information regarding the flow velocity in the blood vessel, calculating an average blood flow velocity value for the blood vessel, and calculating a systolic acceleration for the blood vessel. And inserting an average blood flow velocity value and systolic acceleration into a schema for further analysis of the calculated values. Such a schema can consist of multiple arrangements of their values, including but not limited to diagrams, graphs, nomograms, spreadsheets, and databases, thereby enabling mathematical calculations, comparisons, and Allows operations involving calculated values such as the order to be performed. Ru

  In some embodiments, the evaluation method may further include calculating a pulsatility index. With the calculated pulsatile index, the evaluation method can plot the values of pulsatile index, systolic acceleration, and average blood flow velocity for the blood vessel in three-dimensional space, where The sex index plot, systolic acceleration, and average blood flow velocity values in three-dimensional space produce a first characteristic value for the blood vessel. The blood vessel is then automatically adjusted by comparing the first characteristic value for the blood vessel with other first characteristic values obtained from measurements of blood flow velocity collected from similar blood vessels from other people or animals. It may be determined whether it is in mode.

  The evaluation method further includes collecting information relating to the additional change amount, converting the information into a value, and determining the value as a value of a pulsatile index, a systolic acceleration, and an average blood flow velocity. Plotting together in an n-dimensional space may include generating a second characteristic value for the blood vessel. The blood vessel is then automatically adjusted by comparing the second characteristic value for the blood vessel with another second characteristic value obtained from measurement of blood flow velocity collected from similar blood vessels from other people or animals. It may be determined whether it is in mode.

  The blood vessel of the above evaluation method may be an intracranial blood vessel. Further, the blood vessel may be an artery. The artery may be a blood vessel that feeds the central nervous system. In addition, the artery is a group consisting of the common carotid artery, internal carotid artery, external carotid artery, middle cerebral artery, anterior cerebral artery, posterior cerebral artery, anterior communicating artery, posterior communicating artery, spinal artery, skull base, ophthalmic artery, and branches thereof. You can choose from.

  Information regarding blood flow velocity collected by the above-described evaluation method can be collected using ultrasonic energy. In this manner, blood flow velocity information can be collected using a Doppler probe.

  The influence of a substance on a blood vessel can be determined by applying the above-described evaluation method before and after the substance is administered. This substance may be a drug. This drug may be a drug that acts on blood vessels. The substance may be suspected of having vascular activity.

  The assessment methods described above may be used when a person or animal is suspected or has a vascular disease or condition affecting vascular function. A person or animal can be analyzed at a time when there is no health abnormality and at a time when there is a health abnormality.

  The present invention further provides a method for assessing the vascular effects of treatment in a human or animal. The method includes collecting a first set of information regarding blood flow velocity within the blood vessel, administering a drug, collecting a second set of information regarding blood flow velocity within the blood vessel, and for the blood vessel. Calculate the average blood velocity value, calculate the systolic acceleration for the blood vessel, and insert the average blood velocity value and the systolic acceleration into the schema for analysis of the calculated value A process of performing;

  The step of administering the treatment in the method for evaluating the effect on blood vessels can be selected from the group consisting of administering a drug, taking a measure, and performing a treatment. When administration includes administration of a drug, the drug may include a statin. The administered statin can include atorvastatin calcium.

  The step of collecting the first set of information and the step of collecting the second set of information in the above-described blood vessel evaluation method can be performed using ultrasonic energy. More specifically, the collection step can be performed using a Doppler probe.

  The present invention further provides a method for assessing the vascular effects of treatment in a human or animal. The treatment can include taking action, performing therapy, and administering a drug. The method includes collecting a first set of information regarding blood flow velocity in the blood vessel, obtaining a first average blood flow velocity value prior to administration of the treatment, and prior to administration of the treatment. Obtaining a first systolic acceleration; administering a treatment; collecting a second set of information relating to blood flow velocity in the blood vessel; and second average blood flow velocity following administration of the treatment. Obtaining a second systolic acceleration after administration of the treatment, comparing the first average blood flow velocity value and the second average blood flow velocity value, And comparing the first systolic acceleration and the second systolic acceleration to determine if the treatment has an effect on the blood vessel.

  The method for assessing the vascular effect of the treatment described above comprises calculating a first pulsatility index from a first set of information, and a second pulsatility index from a second set of information. Plotting a first pulsatile index, a first average blood flow velocity value, and a first systolic acceleration to generate a first characteristic value for the blood vessel; Plotting a second pulsatile index, a second average blood flow velocity value, and a second systolic acceleration to generate a second characteristic value for the blood vessel; and the first characteristic Comparing the value and the second characteristic value to determine if the drug has an effect on the blood vessel.

The step of administering the treatment in the above-described method for evaluating effects on blood vessels can be selected from the group consisting of administering a drug, taking a measure, and performing a treatment.
When administration includes administration of a drug, the drug may include a statin. The administered statin can include atorvastatin calcium.

  The step of collecting the first set of information and the step of collecting the second set of information in the above-described blood vessel evaluation method can be performed using ultrasonic energy. More specifically, the collection step can be performed using a Doppler probe.

  When a person or animal has a risk factor for stroke, a method for assessing the vascular effects of the treatment described above may be used. The person or animal may receive at least one medication before collecting the first set of information.

  The methods for assessing vascular effects of the above-described treatments may be used to determine whether a person or animal receiving a drug has an undesirable vascular effect.

  When a person or animal has a vascular disease or condition that affects the function of blood vessels, a method for evaluating the effects of the aforementioned drugs on blood vessels can be used.

  In another embodiment of the invention, a method is provided for assessing the vascular effects of treatment in a human or animal. A method for accessing effects on blood vessels assigns individual persons or animals to various groups for each person or animal by performing a step of obtaining a first set of information about blood flow velocity within the blood vessel. Obtaining a first average blood flow velocity value prior to administration of the drug; obtaining a first systolic acceleration prior to administration of the treatment; administering the treatment; Obtaining a second set of information relating to blood flow velocity within, obtaining a second average blood flow velocity value following administration of the treatment, and second systolic acceleration after administration of the treatment. Comparing the first average blood flow velocity value with the second average blood flow velocity value, comparing the first systolic acceleration and the second systolic acceleration. Determining whether the treatment has vascular effects, and before and after administration of the treatment, And a step for statistical analysis of over data, the.

    In the method of assessing vascular effects by assigning individual persons or animals to various groups as described above, administering treatment includes administering a drug, taking action, and performing therapy. Can be selected from the group consisting of When administration of a drug is selected, the drug may include a statin. The statin can be atorvastatin calcium.

  In the method of assessing the vascular effects of treatment by assigning individual people or animals to the various groups described above, the data collection step can be performed using ultrasound energy. Furthermore, the data collection process can be performed using a Doppler probe.

  The method of assessing the vascular effects of treatment by assigning individual persons or animals to the various groups described above further comprises statistically analyzing the data within each group before or after administration of the treatment. Can do.

  In one embodiment, the present invention further comprises a screening method for adverse effects of treatment. The screening method includes applying a treatment to a large number of people, monitoring the blood flow of those cerebral blood vessels after applying the treatment, and cerebral blood vessels occurring in those people after applying the treatment. Identifying a negative effect on blood flow of the blood;

  The cerebral vascular health data obtained by the screening method of the present invention can include both an average blood velocity value for an individual's intracranial blood vessel and a systolic acceleration for the individual's intracranial vessel. The intracranial blood vessel may be an artery. The artery may be selected from the group consisting of the common carotid artery, internal carotid artery, external carotid artery, middle cerebral artery, anterior cerebral artery, posterior cerebral artery, anterior traffic artery, posterior traffic artery, vertebral artery, skull base, and branches thereof. it can. Moreover, the obtained data may include a pulsatility index.

  Screening methods make it possible to obtain quantitative data on the blood flow of many people's cerebral blood vessels. The obtained quantitative data may be collected using ultrasonic energy. In addition, data on cerebral blood vessel health can be collected using a Doppler probe.

  The applied screening method treatment can include at least one treatment selected from the group consisting of performing therapy, taking action, and administering a drug.

  When the selected treatment is administration of a drug, the drug or substance can be a vasoactive drug or a drug that is believed to have vascular activity.

  The screening methods for adverse effects of treatment on blood vessels described above may be applied before and after administration of treatment.

  The above-described screening methods for adverse effects on blood vessels may be applied to those who are suspected of having or actually have a vascular disease or condition affecting vascular function.

  The present invention involves the measurement of blood vessel function parameters. Specifically, the present invention uses, but is not limited to, energy including any form of acoustic energy and electromagnetic energy to determine the rate of cell movement through blood vessels. While not wishing to be bound by the following statement, red blood cells are believed to account for the majority of cells detected by this technique. In a preferred embodiment, ultrasonic energy is utilized.

  According to the present invention, the sample volume of red blood cells is measured using acoustic energy. Since not all blood cells in the sample volume are moving at the same speed, the Doppler shift frequency range or spectrum is reflected back to the probe. Thus, the signal from the probe is converted to digital by an analog-to-digital converter, and the spectral content of the sampled Doppler signal can be calculated by a computer or a digital signal processor using a fast Fourier transform. Good. This processing method produces a blood flow velocity profile that varies over the heartbeat. The process causes the heartbeat interval flow pattern, or sonograph, to be repeated on the video display. The instrument can be configured to analyze a plurality of isolated frequency ranges within the spectrum of the Doppler signal. Color coding may be used to indicate signal strength at different points on the spectral line. The strength of the signal will particularly represent the percentage of blood cells that flow within that velocity range. Information displayed on the video screen can be used by trained observers to determine blood flow characteristics at specific locations in the brain of the person being examined, and can also be used to occlude Alternatively, abnormalities in the blood flow that introduce transient distortions in the displayed information, such as the presence of a restriction or the passage of an embolus through an artery, can be detected. The instrument may also include a processing option that provides an envelope curve displayed on the video screen as a white frequency outline of a maximum frequency follower or blood flow spectrum.

  In another preferred embodiment, coherent light in the form of a laser may be used. In yet another embodiment, infrared or ultraviolet light may be used.

  In one preferred embodiment, the systems and methods of the present invention allow determination of vascular health based on an analysis of two blood flow parameters, average blood flow velocity and systolic acceleration.

Early studies analyzed how blood flow velocity was related to blood flow to the brain. Flow is a concept different from speed. Flow is the amount per unit time delivered to a part of the brain. This is partially dependent on speed. Thus, early work demonstrates a one-to-one relationship between flow and velocity. Thus, average blood flow velocity is a very good indicator of cerebral blood flow.
Thus, conventionally, this theory has relied on determining blood flow to the brain. There is a second calculated number called the pulsatile index, which is the resistance downstream of the blood flow, and others have also measured it. Still, any combination of flow parameters needs to be considered to assess vascular health or autoregulation.

  In a further preferred embodiment of the present invention, a transcranial Doppler is used to obtain the above speed measurement results. Application of selected forms of energy to cells within the blood vessel allows calculation of the flow rate of the cells within the blood vessel. Data analysis may be performed by measuring specific parameters included in the flow of cells through the blood vessel.

ここで、
Ｖ_ｓ＝最大収縮期の速度
Ｖ_ｄ＝拡張末期の速度
である。 One parameter relevant to the present invention is the average blood flow velocity (V _m ). The value of this parameter is given by

here,
V _s = Maximum systolic velocity V _d = End diastolic velocity.

ここで、
Ｖ_ｍ＝平均の血流速度
Ｖ_ｓ＝最大収縮期の速度
Ｖ_ｄ＝拡張末期の速度
である。 The second parameter relevant to the present invention is the pulsatility index (P _i ). The value of this parameter is given by

here,
V _m = average blood flow velocity V _s = maximum systolic velocity V _d = end diastolic velocity.

ここで
ｔ_ｓ＝Ｖ_ｓのときの時間
ｔ_ｄ＝Ｖ_ｄのときの時間
Ｖ_ｓ＝最大収縮期の速度
Ｖ_ｄ＝拡張末期の速度 Another parameter relevant to the present invention is the systolic acceleration. This variable measures the blood flow velocity at the end of the diastole, measures the blood flow velocity at the peak of the systole, and then compares the difference between these measurements at the end of the diastole and the maximum systolic velocity. Determined by dividing by the length of time between hours. This is the index of acceleration during systole. The value of this parameter is given by

Where t _s = V _s time t _d = V _d time V _s = maximum systolic velocity V _d = end diastolic velocity

  In one preferred embodiment of the invention, the unique signature of each vessel is defined by a plot of systolic acceleration against average blood flow velocity. With the average blood flow velocity plotted on the Y-axis and the systolic acceleration plotted on the X-axis, blood vessels can be represented as points on this graph.

  The present invention reveals that the vessels are in a normal auto-regulation state when their vessel state values are within the range of the auto-adjustment region of the graph described above. The points on the graph represent the state of the blood vessel. It is also determined that a significant problem has occurred or will be in progress when the value corresponding to an individual blood vessel is within the range of other regions of the graph outside the zone of self-adjustment. Thus, the present invention not only determines the location of individual vessels on such a graph, but also takes into account distance and / or orientation deviations from what is considered to be within the normal range of such vessels. To provide insight into vascular health.

  In another preferred embodiment of the invention, another unique signature of each vessel is defined by plotting systolic acceleration against average blood flow velocity and pulsatile index. With the average blood flow velocity plotted on the Y-axis, the pulsatile index plotted on the Z-axis, and the systolic acceleration plotted on the X-axis, the blood vessel becomes a point in this three-dimensional space. Can be represented.

  The present invention further reveals that the blood vessels are in a normal autoregulatory state when their values are within a certain area of this three-dimensional space. A three-dimensional plot provides a unique shape that represents a collection of points, each point representing the center of mass from an individual specific blood vessel. When the value corresponding to an individual blood vessel is within the range of other regions of the three-dimensional space outside the auto-adjustment zone, it is determined that a serious problem has occurred or will be ongoing. Thus, the present invention not only determines the location of individual vessels on such a graph, but also takes into account distance and / or orientation deviations from what is considered to be within the normal range of such vessels. To provide insight into vascular health.

  By the present invention, it has been defined that each cerebral blood vessel has a unique state and a signature represented in a three-dimensional graph. A unique state and sign corresponding to a single blood vessel in an individual can be represented as a point in the vascular situation diagram, and a unique state and sign corresponding to the same blood vessel type in the population is a mathematical center of mass. Can be expressed as a set of points expressed as. This value corresponding to the center of mass is obtained through the analysis described above. The present invention reveals that an individual's blood vessels, particularly an individual's cerebral blood vessels, display clustering of points in a three-dimensional space that defines the shape.

Of course, in addition to systolic acceleration, average blood flow velocity, and pulsatile index, other variables may be used to provide additional information about a particular vessel. When additional variables are used, the data may be plotted in a dimension space of 4 dimensions or more. Analysis of a specific centroid value of a person's blood vessel assesses the meaning of the difference between normal and abnormal blood vessels by distance from the mean value of the center of mass of blood vessels of the same name obtained from other people Provide the basis for the anomaly and enable the prediction of anomalies. Therefore, the present invention is not limited to a three-dimensional space. In addition, an individual's blood vessels may be represented in n-dimensional space, where each dimension may be an appropriate clinical parameter. For example, additional dimensions or variables include, but are not limited to, age, medical history or previous stroke history, risk factors such as obesity, smoking, alcohol consumption, caffeine consumption, hypertension, closed head History of head injury, migraine, vasculitis, TIAs, previous intracranial trauma, increased intracranial pressure, history of drug abuse, medication of steroids including estrogen and / or progesterone, lipid deposition, hyperlipidemia, With parathyroid disease, abnormal electrolyte levels, adrenal cortex disease, atherosclerosis, arteriosclerosis, calcification, diabetes, kidney disease, prior medication of vascular effective treatments, post-sympathetic fiber ending Prior medication of a therapeutic agent effective in the release or reuptake of norepinephrine, prior medication of a therapeutic agent effective in the release or reuptake of acetylcholine at the parasympathetic ganglion fiber ending, Nerves, shock, electrolyte levels, _pH, pO 2, pCO _2, or any combination thereof, may be included.

  The present invention allows analysis of all blood vessels of an individual. These analytical techniques provide an index of vascular health of an individual, especially an individual's vascular compliance. In a preferred embodiment, the present invention allows analysis of the ability of a blood vessel to self-regulate. Such a vessel may be analyzed if the device used to analyze the blood flow can locate it. Both arteries and veins can be analyzed with the system and method of the present invention. Regarding arteries, both cerebral blood vessels and non-cerebral blood vessels can be analyzed. For example, the common carotid artery, internal carotid artery, external carotid artery and other extracranial arteries can be evaluated. It may be done. In addition, analysis of an individual's cerebral blood vessels, including the blood vessels contributing to the aortic rings and their first branches, can be performed with the systems and methods of the present invention. The present invention further includes, for example, a group in a specific age group or a specific age, a group considered healthy, a group classified into a clinically confirmed group such as a diabetic patient, and a common group such as obesity. Analysis of individual cerebral blood vessels from different groups of people, such as groups of people who share risk factors, groups of people exposed to similar substances such as nicotine, or pharmaceuticals such as beta blockers Enable.

  The present invention relates to various connection mechanisms, such as access to the Internet, that provide an accurate prediction of future occurrence of vascular disease, vascular disease diagnosis, vascular disease severity determination and / or prognosis of vascular disease. Includes a system with capabilities. The present invention provides one or more highly sophisticated trained to diagnose, predict, determine the severity of vascular disease, predict future occurrence, and provide a more accurate diagnosis and prognosis. Provide a database using a computer.

  The system of the present invention receives patient blood vessel data from other locations via a receiver or data receiving means, and the data is sent to one computer or to a specific blood vessel or a number of normal and / or diseased conditions. By sending through multiple computers containing blood vessel data about the blood vessel, comparing the patient's blood vessel data with a database to generate one or more results, and sending one or more results to another location Can be operated. Another location may be a remote computer or other data receiving means.

  In one embodiment of an automated decision support system for interpreting the values of various parameters of blood flow in one or more blood vessels in an assessment of an individual's vascular health according to the present invention, at least three different modules Are provided, each interactive with the other. These modules include a module for accessing data, a module for interfacing with a user, and a module for processing patient data, ie an inference module.

  The data access module provides a method for accessing and storing transcranial Doppler and clinical data entered by the user and inference from the inference engine. This data may be accumulated by any method known to those skilled in the art including, but not limited to, saving on a network server or saving to a file on a personal computer. Data access modules include, but are not limited to, commands that initialize the module, those that retrieve patient data, commands that save patient data and / or graphs, commands that delete patient data and / or graphs, It can respond to various commands, such as a command to search a list and a command to query a database.

  The user interface module is not limited to processing user input and sending it to the data access module, running commands for the inference module, querying patient data for the data access module, Various functions can be performed, such as inquiring about inference results from the inference module. The user interface module may further be designed to display patient data for at least one patient received from the data access module and concept instances received from the reasoning module. The user interface module may be designed to display patient clinical and demographic data, raw transcranial Doppler velocimetry data, and analysis of the patient's hemodynamic status. Analysis of the patient's hemodynamic status includes, but is not limited to, an assessment of the condition of each artery, the detected global conditions, and the risk of the patient's stroke. The user interface preferably provides the user with the ability to drill down from an assessment of the patient's risk of stroke to determine how to reach a conclusion.

  The inference interface module includes, but is not limited to, accepting commands and processing patient data to infer a concept, a specific concept instance or a given concept instance in a concept graph Perform various functions, including searching for instances and saving concept graphs or loading old concept graphs. The inference interface further analyzes at least two separate modules--input data including but not limited to user input, stored concepts and / or data, clinical data, and transcranial Doppler data. Can be divided into an analysis module for and an interface module for hiding the details of the interaction of the analysis module with other modules. The interface module allows other modules to access data and conceptual graphs present in the analysis module without being exposed to the analysis interface. Preferably, the file created by the reasoning module is stored by the data access module.

  In accordance with the present invention, patient data includes all data derived from transcranial Doppler interpretation and all clinical data. Preferably, patient data is accessed and stored as a single block of data for each patient referenced by a unique patient ID.

  In one embodiment of the invention, transcranial Doppler data and clinical data are entered by a user at a user interface. Once input is complete, the user can save the data to a file for later access, or analyze the data immediately before saving it. In one case, patient data is retrieved from the data access module by the reasoning module. Both modules retrieve patient data based on patient ID. Preferably, the user can search a list of all patients stored in the file so that he can select specific patient data to analyze and observe, edit or analyze it. Preferably, but not required, the set of parameters sent to the data access module includes a user ID.

  The analysis module can provide one or more classes of service. For example, the module includes a method for instructing the analysis module to include module initialization, start, run and stop commands. Another service classification provided by the module may include a method for setting and / or retrieving values of conceptual attributes.

  As defined by the modules described above, the present invention provides an automated decision support system for interpreting the values of various parameters of blood flow in one or more blood vessels in an assessment of an individual's vascular health. Sequence can be provided. These sequences include, but are not limited to, storing patient data, analyzing patient data, loading the analysis into an analysis page, and retrieving evidence from a conceptual graph.

  By means of the modules described above, the present invention provides a software design for an automated decision support system to interpret the values of various parameters of blood flow in one or more blood vessels in assessing an individual's vascular health. be able to.

  In conjunction with the use of the modules described above, the present invention is for useable prototypes of an automated decision support system for interpreting the values of various parameters of blood flow in one or more blood vessels in assessing an individual's vascular health. An example of use can be provided. These use cases, ie user interface commands, include but are not limited to entering new patient data, loading existing patient data, observing clinical data, observing transcranial Doppler velocity measurements Analyzing patient data, observing the analysis, and collecting evidence hidden in the analysis.

  In a preferred embodiment of the present invention, processing of patient data information obtained by ultrasound measurements of cerebral vascular health from various blood flow parameters is performed at one location while the patient's data at another location. A process is provided that allows for questions about vascular health, whereby the assessment of vascular health is performed remotely. This process is preferably managed in a step-by-step manner with a decision matrix developed to obtain an appropriate data set given the particular situation of the patient at that time. Thus, the process can be managed remotely and the data can be processed remotely.

  For example, a technician or doctor will assist the patient by applying an appropriate device to the patient's head to obtain the necessary transcranial Doppler data, or place the probe in the appropriate window on the skull. You will get Doppler data. Vascular health data will then be collected and sent to another device that performs an assessment of vascular health. The data is then processed to generate an interpretation as well as potential suggestions for additional measurements. The evaluation process itself could be tested one at a time in batch mode, or could be done continuously on an online system. The interpretation and potential suggestions can then be relayed to another location, which includes several options including the location of the patient, the location of the health care professional, or the location where the diagnosis is communicated. Can do.

  In performing the analysis, an analyst, such as a computer or assessor, will perform the analysis and preferably make a comparison with a reference population. The reference population can be a group of patients evaluated that day, or it can be an appropriate population in several other ways. In any case, it is important to consider the reference population and set new data for the reference population, since the predicted value is influenced by the basic prevalence of the person, especially in the reference group.

  Of course, the transmission of vascular health information from the measuring device to the vascular health assessor and the transmission of the vascular health interpretation to the connection location can be done by modem, cable modem, DSL, Tl or wireless transmission. This can be achieved by various communication links including. The transmission can be batch or continuous.

  Of course, in the client-server information embodiment, some evaluation functions may exist on the client side, while others may exist on the server side, and the ratio is optimal. Depending on the bandwidth, computer speed and memory. Other considerations include remote communication of data, either stepwise or in batch mode, through a computational device attached to the ultrasound probe.

  The present invention further includes a system coupled with access to the Internet and other connectivity mechanisms, which may include vascular disease, vascular disease diagnosis, vascular disease severity determination, and / or prognostic future of vascular disease. Provide a fairly accurate prediction of the occurrence of the disease, so that the present invention diagnoses, predicts, determines the severity of vascular disease, predicts future occurrence, and provides a more accurate diagnosis and prognosis It further provides a database using one or more trained very sophisticated computers. The present invention also provides a sensitive tool for assessing subtle differences in blood flow characteristics following exposure to a drug-like substance in a clinical environment.

  The present invention may be combined with a file system such as an electronic file system to be stored in a patient file as a result of analysis of individual patient blood vessel data files, blood flow characteristics of the blood vessels. In this way, a healthcare professional or patient can access information in the patient file at high speed. Intervention strategies or therapeutics are effective if changes in vascular health since the last visit to a healthcare professional can be readily determined, indicating if the progression of vascular disease has changed, and if recommended . The present invention also provides additional recommended after receiving information from a computerized database regarding vascular disease, disease diagnosis, determination of severity of vascular disease and / or prediction of future occurrence of vascular disease prognosis. Provides the ability of a physician to promptly advise a patient regarding diagnostic tests and available treatment options.

  Accordingly, it is an object of the present invention to provide a new method for assessing vascular health.

  A further object of the invention is to provide a method for repeated assessment of cerebral vascular health.

  Yet another object of the present invention is to assess the vascular health of individuals at risk for disease.

  Yet another object of the present invention is to provide a method for monitoring patients who have experienced vascular problems such as stroke.

  Another object of the present invention is to provide a method for assessing the vascular response to a procedure that includes taking action, performing therapy, and administering a substance.

  A particular object of the present invention is to assess vascular responses to substances for individuals at risk for cerebral vascular pathology.

  Yet another object of the present invention is to assess the vascular response to a procedure, including taking action, performing therapy, and administering a substance that may be used in the method of therapy.

  Another object of the present invention is the following stroke, closed head trauma, contra coup injury, blunt trauma, transient cerebral ischemic attack, migraine, intracranial hemorrhage, arteritis, hydrocephalus, loss of consciousness, sympathy Nervectomy, orthostatic hypotension, carotid sinus irritability, decreased blood volume, decreased cardiac output, arrhythmia, anxiety attack, hysterical syncope, hypoxia, sleep apnea, increased intracranial pressure , Anemia, changes in blood gas levels, hypoglycemia, partial or complete carotid occlusion, atherosclerotic thrombosis, embolic infarction, carotid endarterectomy, oral contraceptives, hormone replacement therapy, drug treatment Treatment with blood anticoagulants, including coumadin, warfarin, and antiplatelet drugs, treatment with excitatory amino acid antagonists, brain edema, arterial amyloidosis, aneurysm, ruptured aortic aneurysm, arteriovenous Malformation, or It is to provide an assessment of the ongoing health of the patient's blood vessel in the other conditions that affect the brain blood vessels. In addition, changes in blood flow in the blood vessels following aneurysm rupture can also be monitored.

  Another object of the present invention is to evaluate drugs or other substances suspected of having vascular activity.

  Yet another object of the present invention is to evaluate drugs for suspicious vascular activity in individuals who are known to be at risk for vascular disease.

  Another object of the present invention is to evaluate substances such as drugs suspected of having vascular activity in a person's next stroke.

  Yet another object of the present invention is to provide a non-invasive method for assessing substances such as drugs suspected of having vascular activity in individuals who do not have obvious vascular problems. Is,

  Another object of the present invention is to provide a non-invasive method for assessing various dosages of substances such as drugs suspected of having vascular activity in an individual.

  Yet another object of the present invention is to provide a non-invasive method for evaluating various combinations of substances such as drugs suspected of having vascular activity in an individual.

  Yet another object of the present invention is to provide a non-invasive method for evaluating various combinations of selected dosages of substances, such as drugs suspected of having vascular activity, in an individual. That is.

  Yet another object of the present invention is to assess the health of a particular blood vessel or vascular bed blood vessel after a vascular injury at another site of the cerebral blood vessel. In this way, the ability of other blood vessels to properly and automatically adjust to distribute the collateral blood flow can be evaluated.

  An advantage of the present invention is that it is not invasive.

  A further advantage of the present invention is that it is quick and inexpensive.

  Another advantage of the present invention is that each cerebral vascular feature is characterized by a vascular injury or damage, or exposure to a drug, over a long period of time, particularly to monitor an individual's vascular health during routine health checks. That may be established as a baseline.

  Yet another advantage of the present invention is that analysis of an individual's blood vessels and their deviations from the normal values of other people's corresponding blood vessels may indicate a particular medical condition. The treatment of those medical conditions may then be evaluated with the present invention to determine if the treatment was effective for the particular blood vessel being evaluated.

  Accordingly, it is an object of the present invention to provide a system for the efficient distribution of information regarding an individual's vascular health.

  Yet another object of the present invention is to provide a system that can be utilized by medical personnel to provide future development of vascular disease, diagnosis of vascular disease, determination of severity of vascular disease, and / or prognosis of vascular disease. Providing a more accurate and more accurate prediction.

  It is an object of the present invention to provide a system that can be used by medical personnel to provide a more accurate and more accurate prediction of vascular disease diagnosis and prognosis, and is not limited to it. Provide relevant treatment options for such diseases including.

  A further object of the present invention is to receive blood vessel blood flow data from an input device, interpret existing blood vessel blood data in the same blood vessel or normal or diseased blood vessel, and benefit blood vessel health. Providing a database that uses a computer to generate values that provide information and optionally communicate information to another location.

  Yet another object of the present invention is to provide a system for delivering complete patient reports to healthcare professionals in short time intervals.

  Another object of the present invention relates to vascular health by receiving vascular blood flow data from an input device, interpreting vascular blood flow data taking into account existing data of the same or normal or diseased blood vessels. The value of the treatment point linked via a connection means to a local or remote computer that contains a database using a computer that can generate useful information and optionally communicate information elsewhere Provides analytical ability. Such output values may be distributed to a variety of locations, including treatment points within the office of the healthcare professional that delivered the results from the blood flow measurement device at the treatment points. The present invention provides accurate, effective and complete information for use by healthcare professionals to improve the delivery of quality patient health care at an affordable cost.

  These and other objects, features, and advantages of the present invention will become apparent after reviewing the following detailed description of the disclosed embodiments.

<Detailed Description of the Invention>
This application is the entirety of co-pending U.S. patent applications 09/966366, 09/966368, 09/966360 and 09/966359 filed October 1, 2001. Is explicitly incorporated herein by reference.

  The present invention provides a novel system and method for assessing vascular health. This invention can be used to assess an individual's risk of cerebral vascular disease. The present invention can also be used to assess an individual's vascular health after a vascular disorder or stroke. The present invention can also be used to evaluate the effects of individual substances or substance combinations on cerebral blood vessels.

  As mentioned above, the present invention includes the measurement of parameters of blood vessel functions. Specifically, the present invention uses energy, including but not limited to acoustic energy or any form of electromagnetic energy, to determine the rate of cell movement through the blood vessel. In a preferred embodiment, ultrasonic energy is utilized.

<Explanation of blood flow data collection and analysis>
In accordance with the system and method of the present invention, a non-invasive instrument is utilized to obtain blood flow velocity measurements of intracranial arteries and veins using the Doppler principle. Since body motion such as vessel wall contraction is detected as “noise” in the scattered ultrasound of the Doppler signal, a high pass filter is used to reduce these low frequency, high amplitude signals. Typically, this high pass filter can be adjusted to have a passband higher than a selectable cutoff frequency between 0 and for example 488 Hz.

Since not all blood cells in the sample volume are moving at the same speed, the Doppler shift frequency range or spectrum is reflected back to the probe.
Thus, the signal from the probe is converted to digital by an analog-to-digital converter, and the spectral content of the sampled Doppler signal can be calculated by a computer or a digital signal processor using a fast Fourier transform. Good. This processing method produces a blood flow velocity profile that varies over the heartbeat. The process causes the heartbeat interval flow pattern, or sonograph, to be repeated on the video display. The instrument can be configured to analyze a plurality of isolated frequency ranges within the spectrum of the Doppler signal. Color coding may be used to indicate signal strength at different points on the spectral line. The strength of the signal will particularly represent the percentage of blood cells that flow within that velocity range. Information displayed on the video screen can be used by trained observers to determine blood flow characteristics at specific locations in the brain of the person being examined, and can also be used to occlude Or abnormalities in the blood flow that introduce transient distortions in the displayed information, such as the possibility of a restriction or the passage of an embolus through an artery, can be detected. The instrument can also include a processing option that provides an envelope displayed on the video screen as a white outline of the maximum frequency follower or blood flow spectrum.

  5A-5D show the Doppler waveform definitions provided by the system according to the invention. FIG. 5A is a graph that provides the results of a transcranial Doppler ultrasound analysis where velocity is shown on the Y-axis and time is provided on the X-axis. The maximum systolic velocity is shown in the figure.

  FIG. 5B is a graph that provides the results of a transcranial Doppler ultrasound analysis where velocity is shown on the Y-axis and time is provided on the X-axis. The end-diastolic velocity is shown in the figure.

  FIG. 5C is a graph that provides the results of a transcranial Doppler ultrasound analysis where velocity is shown on the Y-axis and time is provided on the X-axis. The average blood flow velocity is shown in the figure.

  FIG. 5D is a graph that provides the results of a transcranial Doppler ultrasound analysis where velocity is shown on the Y-axis and time is provided on the X-axis. The systolic rise time or acceleration is shown in the figure.

  The present invention provides a plot of the systolic acceleration and average blood flow velocity on a two-dimensional graph. Referring to the self-adjusting model, one new thing is seen that the self-adjusting curve more accurately describes the vascular health of the system. The addition of 3D, or pulsatility index, provides a 3D plot that gives a more accurate view of how blood is flowing in a particular subsection of a blood vessel. Thus, the present invention combines different blood flow parameters to give a nomogram or graph that shows how blood is flowing in the brain itself.

  The present invention makes it possible to determine vascular health or disease status by examining vascular blood flow parameters and comparing them to normal values for cerebral vascular investigations. It is also possible to conduct clinical trials because this relatively quick and non-invasive technique can interrogate the entire population, thereby gaining insights into the population as well as individual patients . In addition, it monitors the group's rheological dynamics over time and, according to clinical measurements, the untreated group becomes more ill or the treated group stabilizes, improves or the occurrence of illness Whether the rate drops can be determined. Thus, the present invention provides a very sensitive cerebral blood flow interrogation device to determine whether it is safe or effective to use a drug in a patient.

  By using an ultrasonic probe, the blood velocity can be determined. The relationship between the blood velocities at two distant points within the point will provide the blood flow parameters of the present invention. By analyzing the relationship of the three parameters in individual segments while relating to the normal population, the disease state of a particular segment of the blood vessel can be determined. Furthermore, by evaluating all segments of blood vessels throughout the brain, it is possible to determine the interconnection and abnormal blood flow conditions in all parts of the brain. Risk at many parts of the brain increases the patient's risk of stroke. Thus, the present invention makes it possible to measure the amount of risk of a patient's stroke.

  According to the present invention, various transcranial Doppler ultrasonographic measurement values of many patients are collected in the database of the present invention. In addition, the database may provide a range of transcranial Doppler ultrasonography measurement results for various cerebral arteries. FIG. 6 provides a nomogram with a mean blood velocity value on the Y-axis and a systolic acceleration value on the X-axis for transcranial Doppler ultrasound analysis of many individuals' ophthalmic arteries. Of course, the majority of data points are gathered on the lower left side of the nomogram. These represent values corresponding to vascular health. An abnormal point found in the upper left part of the nomogram corresponds to a state of vascular injury, in particular vasodilation. Abnormal points found in the lower right of the nomogram also correspond to the state of vascular injury, however, here these points correspond to stenosis. These observations are provided in FIG.

  In another preferred embodiment, the system and method of the present invention determines an vascular health based analysis based on three blood flow parameters: average blood flow velocity, systolic acceleration, and pulsatile index. Enable. For example, FIG. 8 shows that for the transcranial Doppler ultrasound analysis of many individuals' cerebral arteries, the mean blood flow velocity value is on the Y axis, the systolic acceleration value is on the X axis, and the beat A nomogram in which the value of the mobility index is on the Z axis is provided. Of course, the majority of data points are gathered in the center of mass located in the first octant (x> 0, y> 0 and z> 0) close to the origin of the nomogram. If plotted as a logarithm of values, these show a normal distribution. The logarithmic range of these values represents a value corresponding to the vascular health of the reference population. Thus, the present invention allows interpretation of any or all reference populations based on data collected from the reference population. The data set is an ideal reference set, as the reference population can be determined in any way, eg, by these patients showing a specific set of signs or desired features.

  An abnormal point found distal to the origin in the nomogram and having a large mean blood flow velocity (y value) corresponds to a vascular disorder, in particular a state of vasodilation. Furthermore, abnormal points found distal to the origin in the nomogram and having a large systolic acceleration (x value) correspond to the state of vascular injury, however, where these points correspond to stenosis.

  These measurements, collected from a significant number of people to date, show that the observed values for the normal population are for three blood flow parameters: average blood flow velocity, systolic acceleration, and pulsatile index. Demonstrate statistically normal distribution values. When examined by standard multivariate statistical methods such as significance tests, multivariate distances, and cluster analysis, the observations for all three parameters are completely statistically normally distributed.

  A preferred embodiment aspect of the present invention is the collection of data by transcranial Doppler ultrasonography. As previously described, instruments for performing transcranial Doppler ultrasonography are typically 2 MHz pulsed Doppler and spectrum analyzers, where the examiner examines the intracranial blood vessels without image assistance. Such a technique is called freehand, blind, or non-image transcranial Doppler ultrasonography. In recent years, dual ultrasound systems incorporating B-mode imaging and color and power Doppler have been used to conduct transcranial Doppler studies. However, despite the advances in dual ultrasound technology, the technology can be made freehand as it is comparable in accuracy, less expensive and more portable when compared to dual ultrasound. Transcranial Doppler ultrasonography is commonly performed.

  Although freehand transcranial Doppler ultrasonography is characterized as operator dependent, the technique is objective and reproducible. The operator considers the relevant anatomy, natural cranial window, and recognized examination techniques when performing transcranial Doppler ultrasonography. Specifically, an understanding of extracranial arterial circulation contributing to intracranial blood flow, intracranial arterial circulation, carotid artery, vertebral artery, basilar artery and their common anatomical changes is essential It is a condition.

  In addition, when performing an examination, the examiner must also identify the blood vessel. Such identification often presupposes the acoustic window being utilized, the depth of the sample volume, the direction of blood flow relative to the transducer, the relative velocity, and the spatial relationship.

  The inspector can pass sufficient ultrasound energy into and out of the skull, either through the bone being thin enough or having a natural opening through the bone, and performing a transcranial Doppler test It must be recognized that there are three acoustic windows or sites on the skull when possible, i.e. where the signal-to-noise ratio is appropriate at the "window". However, an improved phased array detector can provide a sufficiently improved signal to noise ratio that does not require a “window”. The three acoustic windows are located in the transtemporal window located above the zygomatic arch above the temporal bone, and the transducer is positioned directly on the closed eyelid, slightly straight in the longitudinal direction A transorbital window when tilted to the side and a transforamenal window located in the upper midline of the back of the neck approximately 1 inch below the palpable bottom of the skull. It will be appreciated that other windows can be used for other approaches using sound or other electromotive forces for detection of cell movement within the vessel. Of course, many textbooks provide them with sufficient guidance so that inspectors can perform optimal transcranial Doppler ultrasonography. One such textbook is L. Nonoshita-Karr and KA Fujioka, “Transcranial Doppler Sonography Freehand Examination Techniques”, J. Vase. Tech. 24 , 9 (2000), which is incorporated herein by reference.

  In another preferred embodiment of the invention, the alignment of the ultrasound beam is controlled quickly and automatically in two dimensions. A device that quickly scans the azimuth angle while making changes that slightly increase the elevation angle has been used for 3-dimensional image construction, but lacks speed in controlling the elevation angle. In a similar area of laser scanning, it is common to steer rays in two dimensions using a pair of right-angled mirrors driven by the action of a galvanometer. However, the double mirror approach does not work as well with ultrasound. The size and handling difficulty of a pair of galvanometer driven mirrors are particularly disadvantageous in medical applications in confined spaces such as transesophageal and transrectal probes. Another design constraint is that the ultrasonic diagnostic wavelength is much larger than the wavelength of the light when needed, as the attenuation of the ultrasonic wave increases rapidly with decreasing wavelength. As a rule of thumb, even with the large wavelengths required to image through highly attenuated tissue, the wavelength of the ultrasound cannot be much less than 1% of the maximum depth to be imaged. At relatively large wavelengths, the diffractive effect makes it impossible to produce a very thin collimated beam that can be steered by a small mirror, such as with a laser.

  For sharp focusing of ultrasound, a relatively large aperture is required to avoid angular dispersion due to diffraction. A well-focused near-field ultrasound beam has a converging cone shape, and a diverging cone through a short focal neck representing a small depth of near-optimal focus in the target area. Connected. Resolution approaching the actual minimum spot diameter, which is only two wavelengths below the focal point, requires an included cone angle on the order of 60 °. If the originating end of a cylindrical beam is reduced while maintaining a fixed depth of focus, and the focus neck is thickened by diffraction, a comparison is made at the expense of resolution at the optimum depth. Increases the range of depth that provides a good focus. To achieve fine focus with a double mirror device, the mirror must be relatively large, increasing the difficulty of achieving a fast angular response.

  A typical electromechanical ultrasound image scanner achieves the desired azimuth angle scan by sacrificing multiple transducers on the rotating head or the possibility of precise angle servo control in non-scan mode. Use an ultrasonic mirror that oscillates and rotates with a resonant approach to the angle.

  In radar, a phased array allows two-dimensional rapid scanning and abrupt alignment changes from a fixed transmit / receive surface. An equivalent approach is applicable to medical ultrasound. As the use of one-dimensional ultrasonic phased arrays has been expanded, limited control of alignment within two dimensions has begun to appear. In one preferred embodiment, to build a three-dimensional digital image, a stepper motor is used to rotate the scan plane of the one-dimensional phased array through small incremental steps. This approach requires that the target and the ultrasound scanner be mechanically stable so that the slow scan frame is an accurate registration. A phased array with a double set of electrodes capable of steering the beam by either of two selected scan planes can be used. For example, a system using a one-dimensional ultrasound array can achieve controllable alignment and depth of focus in a plane, and can be used with a range-gated pulse Doppler to characterize blood flow velocity profiles on arterial sections. Put it on. The device also measures the angular relationship by comparing the Doppler velocities at different axial positions along the artery so that the relationship between Doppler frequency shift and blood flow velocity can be accurately determined. Useful.

  In many new ultrasound applications, visual image scans are used to identify structures and analyze them in preparation for analysis in small areas related to measurement of long-term blood flow velocity profiles beyond arterial dimensions. It serves as an auxiliary in determining the position of the blood flow, characterizes volumetric flow, and detects blood flow disturbances caused by stenotic lesions. Vibration tracking and diameter pulsation tracking in a system for determining blood pressure, intraocular pressure and mechanical tissue properties by using a defocused beam of fixed alignment or an electromechanically aligned beam with respect to two axes For this purpose, it is possible to track the position of the organ surface that changes specularly with time by using ultrasonic waves. One preferred embodiment includes an unfocused biaxial ultrasound aiming device, which is an ultrasonic transducer disk and a biaxial gimbal bearing stacked on a short magnet cylinder. A pair of transducer-magnet pairs mounted on the gimbal bearing, which includes a pin on the ring and magnet and a fitted bearing cup, and a flexible wire is gimbaled in a stationary housing The (gimbaled) part is connected. A toroidal ferromagnetic core divided into four, surrounding the gimbal with four windings on its four quadrants quadrants at 90 °. Opposing windings are interconnected to provide two electrical circuits that generate two perpendicular magnetic fields intersecting a pair of gimbaled transducer magnets. The gimbaled portion tilts in response to the two applied magnetic fields and directs the ultrasound beam.

  In this aiming device, the axially polarized central magnet is inherently unstable in its central alignment and is attracted to the point where it intersects the toroid. In order to stabilize the alignment, recovery of the twisting of the connecting wire must overcome the magnetic instability. The direction of alignment is determined in an open loop by a balance of mechanical and magnetic forces without direct detection for servo control. In a non-compensated open loop control situation, if the net alignment recovery is weak, sedation is slow, and if recovery is strong, the stable force required to maintain off-center alignment is excessive. Become. A specific design, ie, a corrected open loop controller of operation that takes into account the known dynamic properties of inertia, angular spring rate, damping, and strength of electromagnetic coupling, can facilitate response. Since LaPlace pole-zero analysis is commonly used to design the transfer function of a controller, the term “pole-zero compensation” is often applied to this type of controller. The To facilitate the response, the transfer function of the controller cancels the low frequency zero of the electrical machine to the pole and cancels the low frequency pole to zero, and as far as the left side of the origin is concerned, it is practically a bandwidth constraint. In general, the pole moved inside is exchanged for a new pole.

  Something that is very necessary and unavailable to existing designs is fast mechanical alignment capability, along with alignment detection and error feedback for rapid and fast sedation changes in alignment. The ability to scan quickly for image presentation and continuous software control in the area of alignment tracking and analysis of echo characteristics and their movement or velocity, especially in extended monitoring of unanesthetized subjects There is a need for coupling with the ability to do a well-tuned two-dimensional beam alignment, and the alignment can be dynamically maintained on the tissue structure subject to extended monitoring.

  In the combined scan and fixed beam alignment monitoring area, a phased array device can be used that easily switches between B-mode image scanning and Doppler tracking at a specific alignment in the image plane. Such devices with phased array speeds repeat scan sweeps and short-time Doppler data collected with fixed alignment in time-sharing mode to achieve both image and Doppler data relatively continuously. it can. Manual control requires two axes, but electronic alignment control is limited to one axis. A dual beam ultrasound device can also be used, using a single beam for tracking data from a fixed target and continuing the scan so that the operator maintains alignment on the desired target. Use another ray to help. Again, the other axis of alignment is controlled manually.

  In many applications, it is advantageous to achieve a sufficiently small device so that it is affixed directly to the subject's body and put on body movement rather than taking measurements in a clinical setting. The advantages of the present invention in these and other needs will be appreciated in the following specification and claims.

<Description of data telemetry>
The present invention combines several unique technologies to provide an integrated system that assists physicians in improved, efficient and timely medical control, management and delivery for patients. The key components of this total system include, but are not limited to: (1) a processor, including but not limited to a desktop personal computer, laptop computer or multi-user server system; and (2) a monitor, printer, liquid crystal display, And other output devices known to those skilled in the art, including an output device for displaying information from the processor, and optionally (3) an analytical analyzer for evaluating the clinical profile of the patient. Such an analyzer can be used to analyze blood flow characteristics of a blood vessel or vessels.

  All patient data may be placed in a format such as a digital format or other format that can be read and communicated by a computer and sent to another location. In one embodiment, the computer-based database may be located in a healthcare professional's office, perhaps a doctor's office. In another embodiment, the computer-based database is in a centralized hospital facility, in an emergency room / service, in a clinical chemistry laboratory, or exclusively in a computer-only database storage and maintenance facility. It may be located inside. In yet another embodiment, the computer database may be located in a home computer. In further embodiments, the computer-based database may be portable for use on the battlefield, in rural areas, and in case of incidents.

  Another configuration in the system of the present invention includes a transmitting device such as a modem or other communication device known to those skilled in the art. Such devices include, but are not limited to, satellites, radios, telephones, cables, infrared devices, and other mechanisms known to those skilled in the art for information transmission. The sending device modem sends the information to a database using a central computer. In the preferred embodiment, the modem is used for computer access to the Internet. Such reporting means are essential for transmitting patient information from the assessment of blood vessel blood flow parameters from a point of care, such as a healthcare professional's office, to another containment facility in a computerized database. . Computerized database storage facilities can be located locally, in the same office, in the same building, across towns, or in remote locations such as another city, another state, another country, or It will be understood that it may be located on a ship, airplane or satellite.

Computer-based systems may be configured using data communication technology and distributed networks, which enable the delivery of data in an efficient and timely manner virtually anywhere in the world. This system according to the present invention can transfer clinical vascular blood flow data from a remote source to a central server via one or more networks. The central server hosts a computer-based database and related configuration hosts. Thus, the central server uses the expert system to generate information related to diagnosis, prognosis, decision support, analysis and interpretation of clinical data, and receives laboratory and clinical blood vessels. Can be analyzed. The obtained information may then be delivered from a central server to one or more remote client stations via one or more networks. The entire process of transferring data from a remote source to the central server, analyzing the data at the central server to generate information, and transferring the information to the remote client site is thus done online or in real time. May be.

  In an automated decision support system for interpreting the values of various parameters of blood flow in one or more blood vessels in an assessment of individual vascular health, the data collected in each blood vessel is individually for each patient. Is analyzed, and is also analyzed as a whole covering the patient. In other words, all of the blood vessels and their respective parameters, i.e. their respective health conditions, are compared with each other and an overall system analysis is made. Data points in the n-dimensional state described for vascular health are tracked over time to determine the starting point and velocity. The speed in this case will be in the direction of change, as well as the rate of change in n-dimensional space. In more traditional terms, if non-compliance is detected in a blood vessel as a dimension in n-dimensional space, after treatment, a numerical value representing non-compliance, ie the degree of non-compliance, is in a certain direction- For example, it appears to move in the direction of compliance—because it follows a procedure aimed at making the vessel more compliant. The significance of the change will be assessed by looking at the speed of health movement in dimensional space throughout the individual's cerebral blood vessels.

  The movement from baseline of any one vascular point may be difficult to assess due to statistical significance. However, there are suitable statistical tools to analyze all health shifts of blood vessel points simultaneously. An example would be the Wilcox Test, which allows comparison of groups of non-parametric values and checks if the variables are statistically different from each other. Other tests may be given an appropriate data set. Basically, however, the process is to measure the amount of health of each individual blood vessel in n-dimensional space, and to determine the significance and direction of change, if direction and degree of change. If they are significant when considered together, it may be concluded that the treatment is effective. In the case of an individual, it is possible to confirm that the observed effect is actually due to the medicine by observing that the treatment is stopped and the effect is reversed.

  Compared to treatment groups and control groups in clinical trials, the process may be similar to that performed in individuals. There is a problem of evaluating whether or not the number of specific features regarding the state of vascular health can be interpreted as significant for each dimension in the dimensional space. A discussion of statistical analysis used here can be found in Jerrold H. Zar, “Biostatistical Analysis,” Prentice Hall Inc., New Jersey, pages 153-161, and is referenced in the book. Incorporate in the description.

  One way to train the system of the present invention is for the software to measure the amount of logical basis used by the skilled person. In such a system, the expert and system will reflect each other during this process. In this process, the expert is very clear, specific and quantitative with respect to data analysis. In their turn, the software keeps a detailed bookkeeping of the analysis process. Thus, each of the software system and the skilled person begins to diversify their role in this knowledge development. The purpose of the software is to capture expert analysis.

  The expert system of the present invention provides features of various functions of an automatic decision support system for interpreting various parameter values of blood flow in one or more blood vessels in the assessment of individual vascular health. These features can be derived into various functions, for example, transcranial Doppler readings at the left anterior carotid or basilar artery test points, blood flow parameters for various arteries, patient data summary, patient Outline of clinical trials, presence of vasodilators and / or vasoconstrictors in patients, pattern of stenosis or pattern showing arterial stenosis at a specific examination point, pattern showing vasodilation or vasodilation, non-compliance pattern Or a pattern indicating loss of arterial compliance, such as an example of arteriosclerosis, a pattern indicating normal or normal radius blood vessels, widespread vasoconstriction or reversible vascular stenosis, widespread vasodilation or Pseudo-normalized pattern of dilation of all cranial blood vessels, stenosis or dilation at arterial examination points Quasi-standardized pattern of loss of compliance in arteries, stenosis of blood vessels due to occlusion, dilation of arteries to compensate for loss of blood flow elsewhere, permanent dilation of arteries, non-compliance or blood vessels Such as a loss of flexibility in the wall, collateral blood flow through the artery due to reversal of blood flow, and / or patient risk assessment for any type of stroke.

  Parameters for determining various functions include, but are not limited to, identification of the person who received the Doppler reading, reading date, patient identification, patient gender, patient race, patient birth date, identification Drug use, Doppler value, Doppler time, acceleration, blood flow direction, reading depth, average and / or standard deviation of blood flow velocity in blood vessels, average of systolic acceleration in blood vessels And / or standard deviation, vascular pulsatile index. These parameters can be static values that are entered or maintained in the database or calculated. Other calculated parameters may include a belief calculation of whether there is a vasodilator or vasoconstrictor in the patient, which may be in blood vessels such as caffeine and / or methylxanthine. It may be based on the presence of an acting substance. Examples of other calculated parameters may include belief in the severity of arterial stenosis at a particular examination point, which may be characterized as none, minimal, gentle, or severe. Another calculated parameter example of the present invention may include belief in dilation of the blood vessel, which may be characterized as none, hyperemic, normal, or abnormal. Another calculated parameter example of the present invention may include a belief in loss of arterial compliance, which may be characterized as none, normal, or abnormal. Another example of a calculated parameter of the present invention may include normal radius vessel belief, which may be characterized as none, hyperemic, normal, or abnormal. Another example of a calculated parameter of the present invention may include a high beating index blood vessel belief, ie, a belief that one blood vessel has a higher beating index than the other, which is correct or It may be characterized as an error. As can be seen from the above examples, various beliefs will be calculated by the expert system of the present invention based on the functions studied.

  The automated decision support system according to the present invention provides domain ontology for interpreting the values of various parameters of blood flow in one or more blood vessels in assessing an individual's vascular health. These parameters may be determined by a transcranial Doppler velocimetry technique, which is a non-invasive technique for measuring blood flow in the brain. With this technique, the ultrasound beam from the transducer is guided through one of three natural acoustic windows in the skull and the waveform of the arterial blood flow is measured using Doppler sonography. Generate. Data collected to determine blood flow includes pulse period, blood flow velocity, end-diastolic velocity, maximum systolic velocity, average blood flow velocity, total volume of cerebral blood flow, blood flow acceleration, arteries Values such as mean blood pressure, pulsatile index, or impedance of blood flow through the blood vessel. From this data, arterial conditions can be derived, including stenosis, vasoconstriction, irreversible stenosis, vasodilation, compensated vasodilatation, hyperemia vasodilation, vascular failure, compliance, breakthrough and pseudo-standardization Is included.

In order to best analyze the patient's risk of stroke, additional patient data is utilized by the automated decision support system according to the present invention. This data may include personal data such as date of birth, race, gender, physical activity level, and address. The data may further include clinical data such as visit identification, height, weight, visit date, age, blood pressure, pulse rate, respiratory rate, and the like. Data further antinuclear antibody panel, vitamin B deficiency, C-reactive protein value, calcium values, cholesterol, entidal CO _2, fibromogin, the amount of folic acid, the blood glucose level, hematocrit, H- pylorus antibody, Hemocysteine value, Data collected from blood tests such as excess carbon dioxide, magnesium, methyl maloric acid, platelet count, potassium, erythrocyte sedimentation rate (so-called ESR), serum osmolality, sodium concentration, zinc concentration May be included. The data also include alcohol consumption, autoimmune disease, caffeine consumption, carbohydrate intake, carotid artery disease, coronary artery disease, diabetes, drug abuse, syncope, glaucoma, head trauma, hypertension, lupus, drugs, It may include patient history data, including smoking, stroke, family stroke history, surgery history, etc.

  The automated decision support system according to the present invention relates to analyzing a patient's risk of stroke, including but not limited to gastritis, increased intracranial pressure, sleep disorders, small vascular diseases, and vasculitis. Consider further the medical condition. In a preferred embodiment, the invention includes a decision support system and a method for screening people who can participate in drug testing. A general reference book detailing the principles and terminology known to those skilled in the art of decision support systems can be found in (1) Schank, RC and Abelson, R. Scripts, Plans, Goals and Understanding Goals and Understanding ”, Hillsdale, New Jersey, Lawrence Erlbaum Associates (1977), (2) Schank, RC and Riesbeck, CK“ Inside Computer Understanding ”Hillsdale, New Jersey, Lawrence Erlbaum Associates (1981), (3) Sacerdoti, ED, "A Structure for Plans and Behaviors", New York, Elsevier (1978) (4) Rinnooy Kan, AHG, "Machine Scheduling Problems ) "The Hague, Martinus Nijhoff (1976), (5) Charaiak, E., Riesbeck, CK., And McDermott, D. Programming (Artificial Intelligence Programming) "Hillsdale, New Jersey, and includes the Lawrence Erlbaum Associates (1980).

  Several terms used in disclosing the present invention are generally described by the following definitions accepted by those skilled in the art.

  A Concept Graph is a knowledge representation of the dependencies between observable data values and high-level calculations and assertions made on the data. The concept graph can be implemented as a non-periodic graph with direction of concept nodes, which are a specific type of extended transition network (ATN).

  A decision support system is a computer program that supports solving problems using a knowledge base. Most expert systems use an inference engine to derive new facts and beliefs that use the knowledge base.

  An inference engine is a computer program that infers new facts and ideas from known facts or ideas using a knowledge base and a set of logical operations.

  A Knowledge Base is a collection of knowledge (eg, objectives, concepts, relationships, facts, rules, etc.) expressed so that it can be used by an inference engine. For example, the knowledge base may include rules and facts or assertions as in conventional expert systems.

  One preferred embodiment of the decision support system of the present invention includes the ability to assess the hemodynamic status of a subject's cerebrovasculature through the use of transcranial Doppler measurements. Referring to FIG. 10, the embodiment consists of three software modules: a data access 1010 module, an inference 1020 module, and a graphical user interface (GUI) module 1030. The inference 1020 module includes a domain knowledge base 2362 and consists of two submodules: a situation assessment module including a PreAct DSA 1022 submodule provided by Applied System Intelligence, and an inference interface 1024 submodule. . Cognitive engines other than DSA may be used. The sub-module of the inference interface 1024 serves to hide details of interaction with the DSA 1022 sub-module from other objects. In this embodiment, these modules are run sequentially as part of the same process, with one instance of each module.

  The data access 1010 module provides access and storage methods for TCD measurements / data, clinical data, and inference from the inference 1020 module. In the preferred laptop configuration, this collection of data is stored in a file.

  The GUI 1030 module processes user input and sends it to the data access 1010 module, executes commands for the inference 1020 module, queries the data access 1010 module for patient data, and queries the inference 1020 module for inference results. The GUI 1030 module also displays patient data received from the data access 1010 module and a concept instance associated with the concept graph instance received from the inference 1020 module.

  The Preact DSA 1022 submodule accepts leaf level concepts representing patient data and processes them for inferred concepts such as disease. The concept graph being processed may query all instances of a particular concept pattern or evidence that supports a particular instance. The graph being processed may be saved for future queries, and the saved conceptual graph may be reloaded for queries. The DSA 1022 submodule also has access to the underlying knowledge base 2362. The inference interface 1024 sub-module accepts the command, processes patient data for the inferred concept, searches the active concept graph for evidence that demonstrates a particular concept instance or a given concept instance, and Save the ongoing conceptual graph or load the saved conceptual graph. The inference interface 1024 submodule converts these commands into a command language understood by the DSA 1022 submodule.

  This preferred embodiment uses the data structure found in Table 1.

  Patient data consists of data derived from TCD measurement results and clinical data. This data is used to fill in the leaf level concept in the concept graph. Patient data is queried by a unique patient ID and accessed and stored as a single block of data for each patient.

  TCD measurement results and data may be entered in a streaming manner via a network or direct connection or as a file. Clinical data may be entered as a file or manually via the GUI 1030 module. After the data entry is complete, the user may choose to save the data or file for later access or to analyze the data. In either case, the reasoning 1020 module retrieves patient data via the data access 1010 module. For this purpose, the GUI 1030 module stores data in a file. Both modules retrieve patient data by patient ID. Further, the interface allows the GUI 1030 module to search all patient lists stored in the file so that the user can select patient data for viewing, editing, or analysis. In the preferred embodiment, the set of parameters passed through the functions of the data access 1010 module includes a user ID.

  The inference data includes concept instances within a specific patient concept graph. The DSA 1022 submodule has its own access mechanism for loading a concept graph from a text file and saving the concept graph in the text file. The data access 1010 submodule is responsible for storing the files created by the inference 1020 module. Table 2 identifies the commands used in the data access 1010 module.

  The GUI 1030 module accepts input from the user, converts the user input into data and commands for other modules, and displays the returned value on the screen or printout. The GUI 1030 module provides display of patient clinical and demographic data, raw TCD data and measurement results, and analysis of the patient's hemodynamic status. Analysis of the patient's hemodynamic status includes an assessment of the status of each artery for which TCD measurements are available, the wide range of conditions found, and the risk of the patient's stroke. The GUI 1030 also allows the user to drill down from the risk of the patient's stroke to determining how the conclusion has been reached.

  The inference interface 1024 submodule allows other modules to access the concepts stored in the DSA 1022 submodule without being partially exposed to the DSA 1022 interface. The inference interface 1024 submodule commands include the commands in Table 3.

  The DSA 1022 submodule includes a method for instructing the submodule, including initialization, start, execute, and stop commands. The DSA 1022 submodule also includes services for setting and retrieving concept attribute values.

  The DSA1022 submodule data request is responded with one of three values: "1" means the data was found correctly, "0" means the data was not found, but no critical error occurred "-1" means critical error, see exception log file. In addition to requesting specific attribute values in known concept instances, the present invention can request both a concept index and a deep copy of a specific concept instance. The system also allows user requests to list all child concept instances of a particular concept instance, user requests to clear all concept instances from a concept graph (the pattern will remain loaded), specific To a user request to save a conceptual graph to a file name (in the preferred embodiment, this file will be saved as an XML file) and to a user request to load a saved conceptual graph from a specific file name Also respond.

  In a broad sense, this preferred embodiment allows the user to enter new patient data through GUI 1030 and save the data, load existing patient data from a database, raw data (eg, clinical data or TCD data). Viewing patient data, analyzing patient data for inferences about the patient's hemodynamic status, viewing the results of the analysis, and viewing the evidence used to reach a particular reasoning.

  Upon initialization, the main program instantiates and initializes modules and submodules in the order of data access 1010, inference interface 1024 (which will initialize DSA 1022), and GUI 1030. After initialization is complete, control is passed to GUI 1030. Control is maintained in GUI 1030 until the user signs out, and upon signing out, the main program shuts down the modules in the reverse order of initialization. The inference interface 1024 module shuts down the DSA 1022.

  Certain operations of the GUI 1030 module can include being initialized by one or more external commands. In addition, the operation of the GUI 1030 accepts user commands and signs in to the system, changes the group of patients currently being processed (depending on the user's authority to access new group data), Create new groups, sign out of the system, create new patient records, process patient data for inference, edit new or existing patient data, save patient data Display a list of subjects in a particular group (including an indication of whether hemodynamic analysis has been performed on the patient data), display patient data for existing patients, patient comprehensive To display the risk of major strokes, the concept used as evidence, and evidence for a more detailed display Display a description of the patient's stroke risk, including the ability to lower, and data available, including blood flow characteristics at each test point, extensive blood flow characteristics, and blood flow direction Displaying the status of arterial blood flow in all arteries of a patient / subject.

  Certain operations of the Data Access 1010 module serve as an interface to an existing relational database management system, initialize, shut down, generate new patient records, retrieve specific patient data blocks, retrieve patient data Accepting commands for updating, deleting records, searching concept graphs, updating concept graphs, and deleting concept graphs, and accepting queries of all patient lists in the database .

Specific operations of the inference interface 1024 submodule include initialization by one or more external commands, processing of patient data, saving of analysis results of patient data being processed, loading of saved analysis results, and suspension of processing Accepting commands for
And accepting a specific concept pattern instance in the concept graph, a specific concept instance, and a query for further explanation of the concept instance.

  Specific operations of the DSA 1022 submodule store initialization based on one or more external commands and knowledge base algorithms used to store concept patterns and infer concepts from provided leaf level data Use of a knowledge base for the reasoning, and the basis for inference is TCD data and clinical data. The algorithm infers concepts in several intermediate steps, and each step is represented in a concept graph so that one skilled in the problem area can follow a series of inferences. Conditions represented in the conceptual graph include, but are not limited to, vasodilation, hyperemic vasodilation, pathological vasodilation, non-compliance, and irreversible stenosis. The concept graph provides a path to follow a series of backward inferences from the conclusion. The algorithm uses a plurality of inference techniques, such as Bayesian reasoning, to search for support data in related concepts. Further operations of the DSA1022 sub-module allow loading the knowledge base, accepting patient data processed through transactions, saving the concept derived from the inference, and loading the saved concept And querying for a specific concept pattern instance, a specific concept instance, and a further description of the concept instance in the concept graph being processed. This query accepts a command to delete and accordingly deletes all concept instances from the graph being processed, keeps the concept pattern loaded, and deallocates all allocated memory. Accepting a terminating kill command and writing a non-fatal error to the log file.

  In another preferred embodiment, the present invention is a networked based system and method for analyzing a subject's hemodynamic status based on TCD measurement results. When using this embodiment, the user submits data to a centralized system for analysis similar to the analysis described in the previous embodiment.

  Referring to FIG. 23, a block diagram illustrating the context and relationships between modules for a preferred application service provider (ASP) embodiment is shown. Modules run in separate processing spaces. In the case of the Internet using connection protocols known to those skilled in the computer arts, the user interface (one or more instances of the web browser 2310) and the system interface 2320 are connected via a network. The system interface 2320 manager provides an adaptive layer between the web server and the remainder of the system. Account manager 2340 maintains authentication and accounting materials for each user count. The inference manager 2350 manages data analysis requests and existing analysis inquiries. It also maintains connections to one or more instances of inference module 2360. Inference module 2360 includes a DSA component, similar to the previously described embodiments. The DSA component uses the knowledge base of the present invention to analyze TCD data and provide access to results. Inference module 2360 provides translation to and from the interface language used by the DSA component. Monitor 2370 monitors the performance of the invention functioning within acceptable parameters.

  The present invention is accessed over the Internet through a website using a standard browser 2310. 24-27 illustrate the data available through a typical page displayed in the browser in response to appropriate user action. The system is entered through a login page, an example of which is illustrated in FIG. In this embodiment, the same login page is used by both users and administrators. Based on the account identification, the present invention will display either an administrator start page or a user start page. The administrator start page provides the administrator with access to the administrator functions described below. The user start page illustrated in FIG. 25 lists their patients relevant to the user. From this point on, the user may add new patient data, edit existing patient data, or delete patient data.

  The patient data page illustrated in FIG. 26 displays patient clinical data and allows the user to edit this data. The patient data page also provides access to the patient's TCD data tab. The patient's TCD data tab provides access to TCD measurement results. The user may add new TCD measurement results, view and edit existing measurement results, or delete measurement results. This page also provides access to the patient hemodynamic analysis tab illustrated in FIG. The hemodynamic analysis tab displays the results of analysis of the patient's TCD data. If analysis has not been performed for a set of TCD readings, the user may request that such analysis be performed from this page.

  Knowledge base 2362 maintains knowledge for TCD analysis. The analysis techniques of the present invention may be modified by changing these knowledge base 2362 files. The patient database 2382 stores data about patients that are relevant to the analysis of his TCD data. Each patient is assigned a unique ID by the user of the system. The information contained in the patient database 2382 includes those shown in Table 4.

  Patient analysis database 2384 stores inference 1020 module analysis for a set of TCD data. The analysis is stored as a file in a format that can be read into the inference 1020 module, eg, an Extensible Markup Language (XML) file. Information included in the registration of the patient analysis database 2384 includes the information in Table 5.

  The authentication database 2342 stores IDs and passwords of authenticated users and administrators. The information included in the registration of the authentication database 2342 includes the information in Table 6.

  Transaction log 2344 records user and administrator activity in the system, and the information contained in transaction log 2344 includes the types found in Table 7.

  The system database 2390 stores data used to set up application processing. The example includes parameters for the IPC connection and for the data file location specified in the above description.

  In this and other preferred embodiments, the knowledge structure is defined and developed over the life cycle of the invention. The knowledge structure identifies broad functionality and envisions the behavior of the present invention. The preferred embodiment of the present invention uses a concept graph (CNG) for knowledge representation. The CNG shown in FIGS. 11 to 22 includes input data to the system and a state inferred from the input data. The arrows in the concept graph indicate the direction of inference. Inference eventually becomes a top-level risk concept for stroke.

  The system allows authenticated users to log in using existing accounts, create new patient records, edit existing patient records, and analyze previously entered sets of patient TCD readings. Requesting, getting the user to request a list of all patients who have entered data with the presence of the indicated analysis, displaying previously entered data and possibly analyzing the data A variety of functionality is provided including requesting, deleting patient data entered by the user, deleting a set of TCD readings, and logging off.

  The system logs into authorized system administrators, creates new accounts, lists all existing accounts, deletes existing accounts, downloads transaction data, monitors 2370 Provides various functionalities, including changing the email address to which notifications are sent to and logging off.

  Upon initialization, the main program creates and initializes module instances in the order of monitoring 2370, system interface 2320, account manager 2340, data manager 2380, and inference manager 2350. These modules are executed in a processing space separated from the main program. When shutting down, the main program shuts down the modules in the order of a theoretical 1020 module, a data manager 2380, an account manager 2340, a system interface 2320, and a monitor 2370.

  System interface 2320 is initialized by an external command. It converts data submitted to Hypertext Markup Language (HTML) into commands for other system modules and, conversely, reformats data from other system modules into HTML pages for presentation to the user. To do. The system interface 2320 module maintains a list of users currently logged into the system and automatically logs off the user after some time without any activity. The system interface 2320 accepts a shutdown command and accepts a request for system data from another module.

  Data manager 2380 can be initialized by an external command and maintains the data in persistent storage. The data manager 2380, for example, retrieves patient IDs entered by a particular user, creates new patient records, retrieves patient data, modifies patient data, stores analysis of specific TCDV readings, specific Various commands can be accepted and responded, such as searching for TCDV reading analysis, deleting patient records, and shutting down.

  The account manager 2340 can be initialized by an external command and can accept transactions recorded in the transaction log 2344. The account manager 2340 creates a new account, deletes an existing account, authenticates the account ID and password (if the account ID and password are valid, the account manager can be either a regular user or an administrator. 2340 can indicate a response), accept the command and respond, such as downloading the transaction log 2344, downloading the authentication database 2342, and shutting down.

  The inference manager 2350 can be initialized by an external command. Upon initialization, the inference manager 2350 initializes one instance of the inference 1020 module. The inference manager 2350 maintains connections to all existing instances of the inference 1020 module. The inference 1020 module is executed in a processing space separated from the inference manager 2350. The inference manager 2350 initializes additional instances of the inference 1020 module, or deletes inference 1020 module instances as necessary to optimize system load.

  The inference manager 2350 can accept and respond to various commands, such as analyzing patient data, for example. Patient data is considered accessible through the data manager. Inference manager 2350 retrieves data from the data manager, loads it into a particular inference 1020 module, and issues commands to the inference 1020 module to analyze the data. Inference manager 2350 may further accept and respond to various other commands, such as querying patient analysis for a particular concept instance, for example. In this instance, the inference manager 2350 loads the analysis into the inference 1020 module and sends a query to the inference 1020 module if necessary. The inference manager 2350 can further accept and respond to various other commands, for example, query patient analysis for all instances of a particular concept pattern. In this instance, the inference manager 2350 loads the analysis into the inference 1020 module and sends a query to the inference 1020 module if necessary. The inference manager 2350 can further accept and respond to various other commands, for example, query patient analysis for further explanation of the concept instance. If necessary, inference manager 2350 loads the analysis into inference 1020 module and sends a query to inference 1020 module. The inference manager 2350 can further accept and respond to various other commands, such as shutting down. When shutting down, the inference manager 2350 preferably shuts down all instances of the inference 1020 module.

  The inference 1020 module is initialized by an external command. No other commands are processed until the module is initialized. The PreAct DSA 1022 module from Applied System Intelligence, an inference 1020 module, stores data and analyzes it using conceptual graphs. The inference 1020 module uses a knowledge base unrelated to the preact library to store concept patterns and necessary algorithms. These knowledge bases 2362s are loaded after the modules are initialized. The algorithm uses various inference techniques, such as Bayesian inference, to propagate belief values through the graph. Sample concept graphs can be found in FIGS. Inference module 2360 includes an access mechanism to input patient data into the conceptual graph.

  The reasoning module 2360 clears the conceptual graph being processed, analyzes the patient data (preferably the module sends a notification when the analysis is complete), and saves the analysis of the patient data being processed (preferably Can accept and respond to various commands, such as loading and stopping the saved patient analysis).

  The inference 1020 module may accept and respond to one or more queries for all instances of a particular concept pattern in a concept graph, for a particular concept instance, and for further explanation of the concept instance. it can. The inference 1020 module can also write non-fatal errors to the log file.

  Since the monitor 2370 is initialized by an external command that sets all the necessary parameters, it sends a notification to the specified set of email addresses when available disk space falls below a pre-set level, so the system load Selected to send a notification to a specified set of email addresses when the pre-set level is exceeded, and to accept and respond to a command to change the set of email addresses to which the notification was sent Includes ready-made modules.

  An exemplary network architecture of an exemplary system according to the present invention is described below. A typical system includes one or more client stations, a central server, and a communication link. One or more client stations function as remote access points to the central server. The client station may be located in a laboratory, a doctor's office, and / or other suitable site. The client station may be configured to send and / or receive information to or from a central server in either interactive or batch mode.

  A client station may include any type of computer-like device capable of transmitting and / or receiving data. For example, the client station may include a desktop computer, a laptop computer, a mobile terminal, and the like. The client station may also include laboratory equipment that has the functionality to collect raw data (such as patient vascular data) and transfer the raw data via a communication link to a central server. In addition, the client station can receive data from a blood flow analysis device or a laboratory device such as a device that holds data transmitted from the blood flow analysis device and then passes the data to a central server via a communication link. A device for receiving raw data may be included. These and other embodiments of client station configurations will be apparent to those skilled in the art.

  The first client station may be configured to send raw data to the central server via the communication link, and the second client station may process data (results) from the central server via the communication link. May be configured to receive. The client station may implement various user interfaces, printing and / or other data management tasks and may have the ability to store data at least temporarily.

  The communication link may include a dedicated communication link such as a leased line or modem dial-up connection. Alternatively, the communication link may include a network such as, for example, a computer network, a telecommunications network, a cable network, a satellite network, etc., or a combination thereof. Thus, a communication link may include a distributed network and / or one or more interconnected networks. In an exemplary embodiment, the communication link may include the Internet. As should be apparent to those skilled in the art, the communication link may be fixed round and / or wireless. Communication over the communication link between the client station and the central server may also be performed using known methods for data transmission such as e-mail, facsimile, FTP, HTTP and other data transmission protocols.

  The central server includes a computer database for blood vessel information. The central server implements analytical and interpretive algorithms. However, it will be apparent to those skilled in the art that the communication station and the computing station may be implemented on a single computer. A typical central server configuration will be described in more detail below.

  A system according to an exemplary embodiment of the present invention may scan in interactive mode or batch mode. In interactive operating mode, data samples are processed interactively one by one. For example, in interactive processing mode, a user connects to a central server through a client station. Thereafter, the data samples to be processed are sent from the client station to the central server. The processing data (result file) may be returned from the central server to the client station where it may be printed and / or archived. After the results file is received at the client station, subsequent data samples may be sent from the client station to the central server.

  A typical system configured for interactive processing mode will now be described. The client station may be configured to execute a communication browser program module and to execute one or more print and / or archive program modules. As is known in the art, a convenient and effective communication link that facilitates interactive operation is the Internet. Communication browsers are also known as world wide web browsers or internet browsers.

  The central server components may be distributed among two stations, a communication station and a computing station. Configured for interactive processing mode, the communication station may include a communication server, such as a standard http server, to interact with a communication browser running on the client station. Communication between the communication server and the contact browser may occur using an html page or using a computer graphics interface (CGI) program transferred using TCP / IP as a means.

<Substance>
In one preferred embodiment of the invention, the vascular reactivity to the substance is assessed. Substances include, but are not limited to, alcohol, nicotine, food, plant extracts, dietary supplements, and drugs. Many drugs are known to have effects on the vascular system. A list of drugs that are known to have an impact on the vasculature, including but not limited to the following, is a beta adrenergic receptor antagonist, calcium channel antagonist, angiotensin I that converts enzyme inhibitors, alpha adrenergic receptor antagonist Medicine, cholesterol antagonist, angiotensin II 1 antagonist, HMGCoA reductase inhibitor, thrombin inhibitor, adrenergic receptor antagonist, endothelin A receptor antagonist, NMDA antagonist, platelet aggregation antagonist, NMDA antagonist, platelet aggregation Antagonist, sodium channel antagonist, 5-hydroxytrypltamine Ia agonist, AMPA receptor antagonist, GPIIb IIIa receptor antagonist, lipase clearing factor stimulator, potassium channel agonist, potassium channel antagonist, 5-alpha reductase Inhibitor, acetylcholine agonist, Paminergic agonist, endopeptidase inhibitor, estrogen antagonist, GABA receptor agonist, glutamate antagonist, peroxisome proliferator-activated receptor agonist, plasminogen activator stimulator, platelet derived growth Factor receptor kinase inhibitor, prostacyclin agonist, sodium / hydrogen exchange inhibitor, vasopressin 1 antagonist, 15-lipoxygenase inhibitor, acetyl CoA transferase inhibitor, adenosine Al receptor agonist, aldose reductase inhibitor, Aldosterone antagonist, Angiogenesis stimulant, Apoptosis antagonist, Atrial peptide antagonist, Beta tubulin antagonist, Osteogenesis stimulator Caspase inhibitor, CC chemokine receptor 2 antagonist, CD18 antagonist, Cholesterol ester transfer protein antagonist Drugs, complement Inhibitor, cyclooxygenase inhibitor, diuretic, DNA topoisomerase ATP hydrolysis inhibitor, elastase inhibitor, endothelial growth factor agonist, enkephalinase inhibitor, stimulating amino acid antagonist, factor Xa inhibitor, fibrinogen antagonist, Free radical scavenger, glycosylation antagonist, growth factor agonist, guanylate cyclase stimulant, imidazoline I1 receptor agonist, immunostimulant, immunosuppressant, interleukin 1 beta converting enzyme inhibitor, interleukin 8 antagonist Drugs, LDL receptor function stimulants, MCP-I antagonists, melanocortin MC-4 antagonists, inorganic corticoid antagonists, nerve growth factor agonists, neuropeptide Y antagonists, oxygen absorbers, phosphodiesterase inhibitors, potassium retention Diuretic, proline hydroxylase Contains noxious agents, prostaglandin El agonists, purine receptor P2T antagonists, reducing agents, thromboxane A2 antagonists, thyroid hormone functional agonists, transcription factor inhibitors, vasopressin 2 antagonists, and especially vitronectin antagonists It is out.

  In addition, other drugs are suspected of having vascular activity. These agents include, but are not limited to, danaparoid sodium, nitrate scavenger, clomethiazole, remacemide, TP10, cerivastatin, nimodipine, nitrendipine, BMS-204352, BIII-890, dipyridamole + ASA, fradafiban, irampanel hydrochloride, lefradafiban, aptiganel, sipatrigine, NRT, cromfiban, eptifibatide, nematode anticoagulant protein NAPc2, UK-279276, Flocor, DMP-647, ASA, GPI-6150, dermatan sulfate, NOS inhibitor, ancrod, PARP inhibitor, tinzaparin sodium, NOX-100, LDP-01, argatroban, fosphenytoin, tirilazad mesylate, dexanabinol, CPC-211, CPC-111, bosentan, clopidogrel hydrogensulfate, nadroparin, ticlopidine, NS-1209, ADNF III, vinconate ONO-2506, including cilostazol, SUN-N4057, SR-67029i, nicardipine, the YM-337 and YM-872.

  The present invention may be utilized for the following dosing by an acceptable dosing method for assessing the effects on blood vessels. It will be appreciated that the present invention may be practiced with a variety of blood vessels including, but not limited to, limb blood vessels, coronary blood vessels, and extracranial and intracranial cerebral blood vessels. In a preferred embodiment, extracranial and intracranial cerebral blood vessels are examined in the present invention.

  Measurements may be taken before drug administration and after a specific time from drug administration to determine the effect of the drug on vascular reactivity. In this way, each individual subject and individual vessel functions as its own control to assess the effect of the drug on a particular vessel.

  All cerebral blood vessels may be analyzed to determine if the drug has different effects on different cerebral blood vessels. Analyzing a large number of people will provide valuable data on the vascular effects of a particular drug. And (a) a person who has no known medical condition, (b) a person who has no known medical condition in a specific age group, (c) a person who has a known medical condition in a specific disease group, (d) A person with a known medical condition within a specific disease group of a specific age group or at a specific stage of progression of a specific disease, and (e) a specific disease currently being mediated by a specific treatment You can also select people from different groups, such as group members.

  Through application of the present invention from a desired group to an individual, effects on various disease processes, or effects of prior or simultaneous administration of other drugs, and blood vessels of test drugs to different people at different ages and conditions Valuable information about the effects on

  Of course, the preferred embodiment of the present invention collects data on the cerebral vascular health of many people who serve as patients in clinical trials, and allows patients with similar cerebral vascular health to gather. Grouping into at least two groups, applying treatment to at least two groups of patients, monitoring each of at least two groups of patients for outcome of therapy, and to each of at least two groups of patients Allows analysis of treatment efficacy, including determining treatment efficacy based on the outcome of treatment. In a preferred embodiment of the present invention, the cerebral vascular health data includes an average blood velocity value of at least three cerebral blood vessels of the individual and an acceleration value of the at least three cerebral blood vessels of the individual. In another preferred embodiment of the invention, the cerebral vascular health data further includes a pulsatile index calculation.

  Another preferred embodiment of the invention provides a method of screening for adverse effects of treatment, which method applies the treatment to many people, and monitors the blood flow of the person's cerebral blood vessels after the treatment is applied. And identifying adverse effects on cerebral blood flow that occur in the person after application of the treatment. In a preferred embodiment, quantitative data regarding cerebral blood flow in many people is obtained. In yet another preferred embodiment of the present invention, the cerebral vascular health data includes an average blood flow velocity value of at least three cerebral blood vessels of the individual and a systolic acceleration value of at least three cerebral vessels of the individual. Including. In yet another preferred embodiment, the data regarding cerebral vascular health further includes calculating a pulsatile index.

  Of course, the present invention contemplates the formation of corresponding groups with a full range of vascular problems, such as, for example, plaque and general vasculitis. The present invention also provides for the formation of response groups with specific blood circulation problems, such as, for example, stenosis in specific blood vessels, inappropriate number of microvessels in the back of the brain, migraine, and apnea. provide.

  The traditional approach to clinical trials is that participants with less or less fit participation in whether both groups have essentially the same severity and the same incidence for the condition being examined Person cannot be identified. Thus, traditional approaches to clinical trials (1) deal with less specific conditions, such as the overall risk of stroke, for example, rather than the exact severity of the condition and the incidence being examined. (2) including persons who have not shown illness / decline; and (3) persons who are likely to suffer from sudden sudden disabilities. Despite numerous attempts to conduct major clinical trials for stroke prevention, this problem has remained unresolved in the absence of a history of stroke or acute heart event.

<Example 1: Effect of propranolol on vascular reaction>
Propranolol, also known as Inderal, is routinely prescribed for people with hypertension, one of the major risk factors for stroke. To evaluate the effect of propranolol on vascular response, transcranial Doppler analysis was performed on cerebral blood vessels of a 46 year old hypertensive male. Thereafter, about 40 mg of propranolol was orally administered. Another transcranial Doppler analysis was performed approximately 2 hours after administration of propranolol. Specific vascular changes were compared to pre-dose readings. Analysis of pre- and post-administration vascular dynamics provides an indication of the effects of the beta-adrenergic inhibitor propranolol in the blood flow dynamics of specific cerebral vessels.

<Example 2: Effect of Plavix on vascular reaction>
Plavix is one of a class of drugs known as blood anticoagulants or antiplatelet agents. Plavix is often prescribed for upcoming strokes to minimize platelet aggregation and thrombus formation. However, one of the main risks of Plavix is intracranial hemorrhage. Thus, using Plavix to prevent or minimize the possibility of stroke due to infarction will increase the likelihood of cerebral hemorrhage. Therefore, proper selection of patients suitable for Plavix is important for maintaining vascular health.

  A 63-year-old man with a history of hypertension experienced an initial stroke in the left middle cerebral artery, resulting in a deficit in the right hand, right leg and some motorized language. These are symptoms presented in neurological clinics. In addition to analysis of the common carotid artery and internal carotid artery, a transcranial Doppler analysis of all cerebral vessels is performed. The analysis reveals a change in vascular flow in the internal carotid artery just distal to the common carotid artery bifurcation. A region of stenosis is observed. In addition, additional flow abnormalities are detected in the left middle cerebral artery, consistent with the presentation of motor paralysis on the right side of the patient. Transcranial Doppler analysis revealed superior collateral blood flow to the contralateral hemisphere and the absence of defects in the left anterior and left posterior cerebral arteries.

  The physician will consider taking Plavix at the same time as the calcium channel inhibitor. Transcranial Doppler analysis was performed monthly. By analyzing changes in a person's cerebral blood vessels in response to administration of a Plavix +/− calcium channel inhibitor, the doctor observes that there is no effect on the cerebral blood vessels. The doctor will then administer higher doses. Again, transcranial Doppler analysis is performed on all cerebral vessels. The doctor observes a significant change in the vascular dynamics of the blood vessel being studied, due to a decrease in the pulsatile index and an autoregulation curve shifted to the left from normal. Based on these results, the physician determined the appropriate dosage of vasoactive agent for the patient.

  Thereafter, patients are monitored on a monthly basis after the first dose of Prabix to determine if vascular changes that require treatment changes have occurred.

<Example 3: Evaluation of cerebral blood vessel status under battlefield conditions>
A 21-year-old paratrooper jumps from the plane and arrives at the battlefield below. While parachuting down to the ground, his parachute gets tangled in a large tree branch. A soldier hears a shot near his place and cuts one of the lines connecting the parachute to his harness in an attempt to release himself. He falls to the ground, but his head hits a large branch of the tree during the fall. A military doctor discovers that a soldier has lost consciousness. After determining that there is no cervical fracture, the doctor moves the soldier to the field hospital. Transcranial Doppler is performed by a doctor trained in the technique. Data is acquired and sent to battlefield command center hospital by uplink satellite communication. The military's advance data is collected during regular health checks when entering the army. New transcranial Doppler data is compared to previous data. The results show dramatic changes in the autoregulation of the left anterior cerebral artery. This is caused by vasospasm due to subarachnoid hemorrhage due to a blunt force trauma to the fronto-parietal suture. There are also subdural hematomas. The surgeon doubts this possibility in light of the obvious contusion in the suture area. The results of the comparative analysis of cerebral blood vessels are then communicated to a military physician performing emergency craniotomy in the left frontal-parietal suture region. Transcranial Doppler analysis is performed immediately after surgery, 12 hours, and 24 hours after releasing and fixing the pressure on the patient's brain. The result is that the flow dynamics of the left anterior cerebral artery change, and this blood vessel index moves from the lower right quadrant in the plot of blood flow velocity against systolic acceleration to the direction of normal autoregulation. It is shown that.

  Another scenario is the development of convulsions or post-traumatic hyperemia that clinically worsened at 24 ° C. Transcranial Doppler analysis was performed at a field hospital. An exacerbation of vasospasm was discovered and treatment changed accordingly.

<Example 4: Application of transcranial Doppler analysis in emergency room>
A 23 year old patient is brought into the emergency room with extreme excitement and madness. The medical staff suddenly loses consciousness while trying to obtain a blood work-up and waiting for the analysis results. A rapid drop in blood pressure is observed. Transcranial Doppler analysis is performed on the patient's cerebral blood vessels. The result shows that the normal regulation curve of the left middle cerebral artery is shifted to the lower left. Electrocardiagraphic analysis reveals atrial fibrillation. Blood chemistry reveals that the patient took a large amount of cocaine with amphetamine. The results of transcranial Doppler analysis are consistent with the induction of cerebral vascular dysfunction following a heart attack due to extreme vascular compression of the coronary vasculature.

<Example 5: A female case study showing gait instability>
A 62-year-old woman appeared at a neurology clinic complaining of slight instability while walking. Transcranial Doppler analysis was performed and various cerebral blood vessels were analyzed. Of the two-dimensional nomograms of transcranial Doppler ultrasound data, a schematic diagram of the first nomogram is provided in FIG. 9a, in which the mean blood flow velocity is on the Y axis and the systolic acceleration is X Shown on the axis. Shortly thereafter, the patient's symptoms worsened, but no definitive analysis has yet been established. A second transcranial Doppler analysis was performed and transcranial Doppler ultrasonography data was shown in the second nomogram provided in FIG. 9b. The results were compared to the first test and showed a clear rightward shift in the plot of blood flow velocity against systolic acceleration.

The patient was then ill and hospitalized, but analysis has not yet been established. The technician performed another transcranial Doppler test, and transcranial Doppler ultrasonography data was shown in the third nomogram provided in FIG. 9c. Many of the vessel points were observed to shift dramatically to the right. The cisternogram revealed hydrocephalus and therefore a shunt was inserted. Neurologists say that increased intracranial pressure has a detrimental effect on cerebral blood vessels,
It was concluded that they were moved from the normal self-adjusting zone. Following surgery, a fourth transcranial Doppler analysis was performed and transcranial Doppler ultrasonography data was shown in the fourth nomogram provided in FIG. 9d. The result showed a clear return to baseline, i.e. the analyzed vessel-specific data points shifted to the left towards their previous position during the second test.

  This example shows that the results of a non-invasive and highly accurate test by transcranial Doppler analysis provide valuable information to the neurologist and selects the appropriate procedure, thereby enabling an obstructive stroke And demonstrated that an excessive increase in intracranial pressure, possibly resulting in death, can be prevented. These results also provided an indication of the development of life-threatening changes that occurred between Test 2 and Test 3.

<Example 6: Use of transcranial Doppler to analyze blunt trauma for athletes>
A 17-year-old high school student receives a hard blow on the forehead when he and his opponent jump together and head on the ball during a soccer game. Students lose consciousness, but are revived with care. After the match, he complains of visual changes. He is taken to the emergency room and a transcranial Doppler analysis is performed. The results of the analysis are compared to the transcranial Doppler analysis performed at the beginning of the soccer season. Transcranial Doppler analysis shows small changes in blood flow dynamics of the left posterior cerebral artery, showing increased blood flow often observed in patients with hyperemia or cerebral contusion. After 24 hours, the patient's mental condition worsened and a CT scan reveals only subarachnoid hemorrhage. Repeated transcranial Doppler analysis shows vasospasm of the same artery. In this case, an interventional neuroradiologist is called to perform angiogenesis. According to the procedure, transcranial Doppler analysis is performed periodically over 6 weeks. The results are compared to a normal reading transcranial Doppler profile when taken into the emergency room and obtained at the beginning of the soccer season. The result shows that it gradually returns to the normal flow pattern of left hind cerebral motion.

<Example 7: Use of transcranial Doppler to analyze blunt trauma for effects of drugs on blood vessels>
Pharmaceutical companies are developing new substances that are suspected of having hypertensive activity by inducing partial vasodilation. The company selects a normal blood pressure patient population, a mild hypertensive population, and a severe hypertensive population. The sub-population is configured based on age (40s, 50s, and 60s) and gender.

  All patients' cerebral blood vessels are analyzed using the transcranial Doppler analysis described in the present invention 2 hours before and 2 hours after oral administration of 25 mg of test substance. Blood pressure was monitored for 2 hours at 30 minute intervals before and after oral administration of the new substance. The results show that no discernable effects have been demonstrated in normal blood pressure and mild hypertension groups, and no significant antihypertensive effects in patients with severe hypertension have been demonstrated in all age groups tested. It was. Analysis of the data obtained with transcranial Doppler revealed that blood flow velocity was reduced in the blood vessels of the aortic ring.

  Significant changes are found in data sets from female test groups in the 50s and 60s. Further questions to those people revealed the use of anti-menopausal hormone replacement therapy with the combination of estrogen and progesterone. The removal of data contributed by these individuals dramatically reduced the variance among these test groups. Pharmaceutical companies have begun exposure to exposure to hormone replacement therapy or oral contraceptives in normotensive, mild, and severely hypertensive women in premenopausal and postmenopausal groups, starting with a new study Within the subdivision of the history, the potential interaction of estrogen, progesterone, or a combination of estrogen and progesterone test substances is examined.

  The invention as described above is applicable to both systems and methods for evaluating and treating hydrocephalus. Specifically, the invention provides a system and method for identifying critical variables affecting the intracranial lumen, including increased intracranial pressure (increased intracranial pressure, ICP), and hydrocephalus from a normal population. It can be used to identify a patient suffering from one of several forms.

  Hydrocephalus is a symptom characterized by an increase in intracranial pressure that results in a decrease in blood flow within the skull. Increasing intracranial pressure places additional external forces on the blood vessels, compressing small blood vessels such as the capillaries of the distal capillaries and / or blood vessels that supply blood to the arterial wall (vaso-vasorum). The reduced flow of blood vessels to the blood vessels reduces the ability of the arterial wall smooth muscle to relax, thereby reducing conductance vessel compliance. The combination of reduced compliance and increased impedance limits vessel movement. Specifically, this flow restriction affects deeper brain structures that are supplied by deeply invading arteries such as periventricular spaces. This reduced flow characteristically leads to edema formation in ventricular horns, which are thought to be ischemic events at bifurcation points

  Little is known about the causes of hydrocephalus in most cases. For example, it has been observed to affect patients in various conditions, including meningitis and intracranial hemorrhage (eg, subarachnoid hemorrhage) and speculated that it may be promoted by certain metabolic abnormalities or common inflammatory conditions Is done. It will also particularly affect older people who do not show pre-existing symptoms. The symptom of hydrocephalus often seen in older people is known as normal pressure hydrocephalus (NPH).

  NPH is a neurological disorder. Since the exact cause is unknown, there are several competing theories about the cause. In the main hypothetical theory, NPH results from an increase in intracranial pressure on brain tissue due to inadequate or inefficient reabsorption or clearance of accumulated cerebrospinal fluid. Spinal fluid is produced at a rate of 0.5 liters per day and must be reabsorbed. If the skull is a finite space, there must be an equilibrium between the inflow and outflow of liquid into that space, otherwise the inner pressure will increase. Modern research has shown that the generation and reabsorption of spinal fluid is an active process as opposed to a passive one. Therefore, deterioration and weakness are likely to occur due to various causes that can cause the accumulation of excess liquid and the resulting increase in intracranial pressure. In the second theory, the increase in intracranial pressure associated with NPH is caused by a disease of the brain's small blood vessels that causes cortical atrophy (ie, the reduced flow into the small blood vessels causes relative expansion of the ventricles). Claim). It is also possible that NPH is due to a combination of these theories--when a patient lies on his back at night, the simultaneous vascular changes due to temporary spinal fluid accumulation occur outside the skull. Associated with reduced venous flow, it results in an increase in blood volume within the cranial vascular space, causing a relative increase in pressure. The data derived from the invention definitively conveys the fact that NPH is the resulting fluid accumulation that in turn causes vascular injury. Furthermore, the invention has given the possibility of specific characterization (ie monitoring and diagnosis) of vascular disorders through the pathogenesis, treatment and additional care of NPH.

  There is considerable confusion in modern medicine about identifying the root cause of two suspicious NPHs. Traditional imaging studies only show an increase in the space occupied by cerebrospinal fluid. However, these studies cannot comment directly on the liquid behavior. That is, an MRI or CAT scan can only show simultaneous liquid swelling associated with brain atrophy. However, these “causes” alone are generally interpreted as a change with age rather than a cause that can be treated with another condition (ie, NPH).

  Further complicating the accurate diagnosis of NPH is the “classic three signs” of incontinence, dementia, and gait instability, although other signs are often present or more likely It is characterized. These signs are often mistakenly attributed to other causes. As a result, NPH is frequently misdiagnosed because historically a highly suspicious index of the treating physician is required. Once suspected, NPH is difficult to evaluate critically and accurately diagnose. As usual, confirmation of the diagnosis of NPH requires an invasive procedure known as the cisternogram, which includes the injection of radioactive tracer material into the subdural space (ie, the cerebrospinal fluid space), To measure half the clearance of the radionuclide tracer, a nuclear detector is used to capture tracer uptake at specific points within the skull at intervals of 24, 48 and 72 hours after the first injection. Monitor. Other methods of diagnosing hydrocephalus and NPH include repeated lumbar puncture tests, withdrawing 20-40 cc of spinal fluid to see if the patient gets clinical improvement. The most significant improvements are gait and mental status. Continuous monitoring of spinal fluid pressure can also be performed via an indwelling catheter. However, this methodology is only performed in institutions that have dedicated clinical care units dedicated to this task. In addition, this method carries a very high risk of infection (ie meningitis).

  Although cisternograms or other clinical studies can indicate NPH pathology, they do not adequately rule out other causes of the observed signs, so alone, typically determine patients with NPH Cannot be diagnosed automatically. The only definitive diagnostic procedure requires a large invasive neurosurgical procedure. However, usually the presence of symptoms alone is not a valid reason for performing such a procedure. Therefore, it was well known that it was difficult to accurately and quickly evaluate and diagnose NPH.

  Finally, significant damage to the central nervous system has already occurred by the time the three classic signs appear in the patient enough to provoke the suspicion of the treating physician. If the central nervous system has little ability to repair damage, especially in the elderly, patients should be prophylactically monitored before signs become apparent, and once symptoms appear It is highly desirable to be able to use the system for both quickly and accurately diagnosing.

  The use of the dynamic vascular analysis (DVA) (also called DCA or dynamic cerebral vascular analysis) methodology described above is unique before and after surgical reduction for the diagnosis and assessment of hydrocephalus, including NPH. Has been applied. It has been used to follow the natural course and progression of NPH pathogenesis. It also includes various intracranial pressure data such as natural course NPH data, supine data, Trendelenberg (approximately 15 degrees head-down tilt) to generate a reference database useful for future diagnosis. Has been used. Finally, the invention provides a reliable, non-invasive, portable and cheap method for diagnosing and monitoring hydrocephalus and in particular NPH.

  In accordance with embodiments of the present invention, as illustrated in FIGS. 1-4, the DVA / hydrocephalus protocol is a fixed TCD probe / device so that the artery being examined can be continuously monitored. Includes interrogation by. Alternatively, other forms of emissive and reflective wave technology can be used, such as laser technology. Monitoring is performed on patients at Trendelenberg positions at various angles (optimally between 15 and 20 degrees), followed by data collection at 30, 60, 90 and 120 second intervals. Following analysis at the Trendelenberg position, the patient is placed in a supine position. Again, data is collected at 30, 60, 90 and 120 second intervals. Under standard patient conditions, there will be no statistically significant change in the vascular flow dynamics being investigated. Patients who have experienced a wide range of intracranial changes (i.e., increased intracranial pressure) are partially affected by vascular stiffness, increased acceleration, and slight impedance increases, but with little change in velocity. Characterized, dramatic changes between elevated states and shifts in flow dynamics will be revealed.

  While in the Trendelenberg position, a relationship between the middle cerebral artery and the ophthalmic artery is observed from the patient. In patients who experienced elevated intracranial pressure associated with hydrocephalus, there would be an impedance index reversal relative to normal baseline conditions. It is also useful to diagnose an increase in intracranial pressure as well before evaluating the subject at the Trendelenberg position.

  It is also possible to apply the protocol after the patient has undergone an intracranial shunt operation.

  One common drawback of most diagnostic systems is the lack of sensitivity and selectivity associated with the diagnosis that distinguishes the various symptoms explained by many physiological phenomena (ie, increased intracranial pressure and / or changes in flow). Is related to This invention has made it possible to observe anomalous flow characteristics, particularly evident in the Trendelenberg test, for patients suffering from hydrocephalus. An important feature of the test is the ability to detect and observe homogeneous and widespread increases in both pulsatile index and flow acceleration, which allows for homogeneous and heterogeneous effects from a wide range of intracranial events. Enables distinction between them. For example, if the TCD data is correlated (ie, a heterogeneous event), a wide range of events may typically be widespread inflammation that is sparsely distributed, or homogeneous to all blood vessels that do not necessarily exclude a particular region It may be a metabolic disorder that affects it. These metabolic abnormalities may include, for example, Fabry disease or diabetes.

  One example of the application of the present invention included an elderly patient representing a natural course study originally documented for the progression of increasing intracranial pressure. In other words, it represented the first progressive study on the pathogenesis of NPH. Figures 28A-28D illustrate this progressive study. It was observed that long-term NPH pathogenesis was characterized not only by an increase in pulsatile index but also by a wide range of blood flow accelerations in cerebral blood vessels. There was also an observed inversion in the impedance index of the relationship from the middle cerebral artery to the ophthalmic artery. Typically, in the standard state, the ophthalmic artery is considered a terminal artery and has a higher impedance value (or pulsatile index) than the middle cerebral artery, which is considered a conductance artery. If impedance reversal occurs, the impedance is greater in the conductance vessel than in the terminal artery. Furthermore, when impedance reversal occurs, it is present on both skulls. Therefore, the reversal is likely the result of an increase in intracranial pressure. FIG. 29 demonstrates that a conventional blood flow test would not have detected a change in intracranial pressure that occurred in a subject that could be observed using dynamic blood vessel assessment based on transcranial.

  As an extension of the above study, Table 8 shows the two series of mean blood flow velocity and contraction suffering from increased intracranial pressure obtained by TCD when the subject is moved from a supine position to a tilted position with the head down. Includes period acceleration and pulsatility index data. Figures 30-32 show this same data after exposure to DVA analysis.

As described above, when calculated, TCD data was analyzed by dynamic vessel analysis (DVA). The DVA for each subject is: a) TCD values (peak systolic velocity (PSV) and end diastolic velocity (EDV) and peak systolic time (PST) for each of the 19 vascular segments established in the cerebral blood vessels. ), End diastolic time (EDT), mean flow velocity (MFV), systolic acceleration (SA), pulsatile index (PI) natural logarithm of SA (LnSA)), b) from mean A comparison of TCD values against a reference database for quantifying the degree of variance of c, and c) a series of indices derived from TCD values representing blood vessel status / motion / health of each of the 19 blood vessel segments Rations). The derived index is
1. Acceleration / average flow velocity index (VAI) (systolic acceleration value divided by average flow velocity value and / or inverse thereof)
2. 2. Velocity / impedance index (VPI) (average flow velocity value divided by the pulsatility index value and / or its reciprocal); Acceleration impedance index (API) (systolic acceleration value divided by pulsatile index value and / or its reciprocal).

  The 19 intracranial blood vessel segments considered are illustrated in FIGS. The vascular segments illustrated in FIGS. 33 and 34 are the left and right vertebral arteries (VA), basilar artery (BA), posterior cerebral artery / PCAt (heading) (P1), posterior cerebral artery / PCAa (away) (P2), internal carotid artery / ICAt (heading), middle cerebral artery (M1), anterior cerebral artery (Al), anterior traffic artery (ACOM) (C1), carotid artery siphon (heading) (C4), carotid artery siphon (leaving) (C2) and ocular artery (OA).

  The data revealed that patients with hydrocephalus had higher values than normal PSV values in the M1 and C1 segments. These patients also showed an increase in PI in the M1, A1, C1, and C2 segments, just as SA in the M1, A1, and C4 segments showed an increase. LnSA also increased in the M1, A1 and C4 segments. Conversely, the acceleration impedance ratio was reduced in the M1, A1, and C1 segments. The speed-impedance ratio also decreased in the A1 segment. The present invention further revealed that increased PI is a prediction of hydrocephalus in the A1 and C1 segments. Increased SA in the C4 segment is also an indicator of hydrocephalus. Finally, a collective increase in SA, PI and LnSA in the M1 segment was also predicted. It was concluded based on this data that observation of changes in blood flow in the C1 segment provides the most effective indicator and predictive material for hydrocephalus. Blood flow data derived from the M1 and C1 segments is also well suited for the prediction and monitoring of hydrocephalus.

  The present invention is particularly suitable for use in the assessment and assessment of hydrocephalus and NPH. Methods to do so are for patients suspected of being at risk of experiencing an elevated intracranial pressure associated with hydrocephalus and NPH, either in supine or Trendelenburg positions, or both, It includes measuring by TCD at one or more points in the cerebral blood vessel and performing DCA analysis.

  The present invention has further applications than direct detection and monitoring of hydrocephalus patients. For example, there are currently programmable shunt systems. A shunt is a tube placed in the fluid cavity of the brain that drains into the abdominal cavity and usually passes through a pressure control valve. After reaching a pre-set intracranial pressure level, the valve activates the shunt and drains. Continuous drainage is undesirable because it creates the risk of excessive drainage and the formation of the cause of subdural hematoma. A programmable shunt system has been developed, whereby the shunt is initially set at a high opening pressure and gradually adjusted by clinical effects. The difficulty of such a process is that it usually takes 2-3 weeks to observe the appropriate clinical effect to change the pressure setting of the shunt system. The present invention allows observations about any dynamic changes in vascular performance long before the patient has clinical changes. Indeed, the present invention allows for almost immediate changes in blood vessel performance. Thus, it is possible to adjust these types of shunt systems very quickly and accurately. For example, a monitoring physician can utilize the present invention as an indicator of when to lower the valve opening pressure level without attempting to reduce the patient's risk progression for subdural hematoma. It also waits for observation of clinical effects and eliminates the need to follow the traditional process of adjusting pressure levels after a few weeks, so doctors can cerebrum over a period of 2-3 days rather than months. Normalization of perfusion can be optimized.

  The device also has practical value to manufacturers and distributors of shunts and related devices. The present invention offers the potential for manufacturers and sellers of such devices as it allows for better product development and sales activities, which in turn facilitates the expansion of the product market. For example, a nursing facility may be given the invention as part of a contract to purchase a shunt exclusively from a particular manufacturer or distributor.

  It is also envisioned that the present invention will be used as a screening device in hospitals, nursing homes, and other nursing facilities. Specifically, by enabling not only the staff needed to transplant the shunt into the skull, but especially the administrator and the treating physician to request a prediction for the shunt in the skull, It will help make management easier. The present invention also facilitates more effective monitoring and tracking of patients with known intracranial conditions that are more susceptible to increased intracranial pressure. These patients may include, for example, patients who have experienced or tend to experience cerebral hemorrhage or who are in an abnormal mental state suspected of having increased intracranial pressure. In addition, because the present invention has a tendency to be operated both monitor and / or remotely, it can be operated from a central location in a nursing facility (eg, a nurse station), and thus many at the same time by one person. Allows monitoring of patients.

  The present invention is suitable for the development and optimization of NPH drugs, treatments and therapies. That is, the invention can be readily used to evaluate the impact of various hydrocephalus therapies by monitoring both pre- and post-treatment of the patient. In addition, the treatment data can be further combined with long-term patient data to specifically adjust the patient's treatment plan.

  Finally, it will be appreciated by those skilled in the art that the present invention relating to methods of diagnosis and treatment of hydrocephalus further relates to local methods in an automated manner, via telecommunications lines or in simple local bed tests. Can be applied remotely or remotely. Like any diagnostic test, the present invention contemplates, in at least one embodiment, a fully automatic, remotely controlled diagnostic system for detecting and monitoring elevated intracranial pressure.

  It has also been discovered in comparative studies that the present invention is applicable to both systems and methods for assessing and treating dementia. In particular, in a study of 56 patients diagnosed with dementia of the patient Alzheimer's disease type and a 39-year-old matched control, the present invention shows a critical impact on intracranial blood flow that gradually leads to dementia. It was observed that variables could be identified.

  Participants were classified into either patient groups or control groups based on several factors. Patients in the patient group had an existing diagnosis of dementia and had sub-average performance in the Mini Mental Status Test (MMSE). The control group was selected from friends and family members of patients with dementia based on being not diagnosed with dementia, no previous history of cognitive damage and being above average in MMSE.

  Other forms of radiating and reflecting wave technology such as laser technology could be used instead, but the study was evaluated using TCD. TCD measurements were taken in a small 10 'x 10' faintly lit room and asked to sit in a reclining style chair used in conventional TCD methods. TCD measurements were obtained non-invasively and provided blood flow velocity data for the main arteries supplying blood to the brain. Waveforms were obtained from several skull windows. The transtemporal window was used on both sides to see segments of the middle cerebral artery, anterior cerebral artery, internal carotid artery and posterior cerebral artery. Both transophthalmic windows were used to view segments of the ophthalmic artery as well as the internal carotid artery. The transoccipital window was used to observe not only the depth of the basilar artery but also the left and right vertebral arteries. A sweep rate of 4 seconds per screen was used to generate 3-7 quality waveforms per page based on the participant's heart rate. Saves display when technician identifies at least one waveform that was able to measure clear diastolic trough and systolic peaks on one waveform during several consecutive waves It was done. The blood vessels were insonated with a well established depth corresponding to 19 established blood vessel segments.

  Analysis of the TCD data included software assisted time and speed determination. Specifically, the TCD engineer placed the computer cursor on the end-diastolic trough just prior to the upslope and the second cursor on the next peak systole. Each x-axis value and y-axis value at each cursor position produced time and speed. From this data, values for peak systolic velocity, peak systolic time, end diastolic velocity, and end diastolic time were determined. Using this data, the average flow velocity, systolic acceleration and pulsatile index values for each subject were calculated using a conventional TCD scheme.

Once calculated, TCD data was analyzed by dynamic vessel analysis (DVA) as described above. The DVA for each subject is: a) from a single waveform, simultaneous consideration of TCD values (MFV, SA and PI) for 19 vascular segments established in the cerebral blood vessels, b) of the variance from the mean Comparison of TCD values collected from a single wave against a reference database to quantify the degree, and c) representation of vessel status / performance / health for each of the 19 vessel segments illustrated in FIGS. A series of indexes (assignment of blood flow velocity) derived from TCD values to be included. The derived index is: Acceleration / average flow velocity index (systolic acceleration value divided by average flow velocity value and / or inverse thereof)
2. 2. velocity / impedance index (average flow velocity value divided by the pulsatility index value and / or its reciprocal), and Acceleration impedance index (systolic acceleration value divided by pulsatile index value and / or reciprocal thereof).

  The data show that patients with dementia have a decrease in mean flow velocity and a corresponding increase in pulsatile index within the vascular segment of M1, A1, C1, C2, C4, VA, BA, P1, and P2. Clarified that he had. Except for a decrease in basilar artery, it was observed that the acceleration of the onset of systole was unchanged in the patient group compared to the control group.

  The blood flow rate ratio was also found to be important for the evaluation of patients with dementia. First, the acceleration / velocity ratio, an indicator of kinetic energy transfer to the advancing blood flow, increased in the M1, A1, C1, C2, C4, VA, BA, P1, and P2 vessel segments. Conversely, the acceleration impedance ratio showing the result of the downstream impedance force in the force ahead of the blood flow, as well as the effect of the downstream impedance force on the forward mean flow velocity and the velocity indicating the surrogate marker for relative blood flow The impedance ratio was reduced in vascular segments of M1, A1, C1, C2, C4, VA, BA, P1 and P2 of patients with dementia.

  In subjects with dementia, a decrease in mean cerebral blood flow velocity in many vascular segments in the holocephalic (relative to the control group) demonstrates a decrease in cerebral perfusion in dementia Consistent with traditional cerebral blood flow studies (ie, changes in average cerebral blood flow velocity are associated with decreased cerebral blood flow). The discovery that the systolic rise acceleration is otherwise unchanged in patients with dementia when associated with the widespread reduction in blood flow velocity associated with this condition otherwise. If reduced blood flow to the cerebrum is a side effect of widespread low blood flow, the cerebral blood vessels should expand to compensate for the reduced flow force to the point of self-regulation . In this “traditional” scenario, the systolic acceleration must show a continuous decline. However, the present invention has demonstrated the opposite effect in patients suffering from dementia (i.e., a decrease in mean flow velocity did not correspond to a change in start-up acceleration during systole). In other words, the invention makes static forward forces on blood have a less direct effect on blood advancement over time, especially in patients affected by dementia. It was used to specifically quantify and verify that. The present invention shows this effect on the blood flow as an acceleration-velocity ratio that reflects the amount of kinetic energy required for forward blood movement. The present invention has demonstrated that the acceleration-velocity ratio is increased in all blood vessels other than the ophthalmic artery in patients with dementia. This finding is supported by the observed increase in pulsatile index in the M1, A1, C1, C2, C4, VA, BA, P1, and P2 vascular segments.

  In short, the assumption that dementia is an apoptotic process following the deposition of harmful substances is inconsistent with the data developed by the present invention. If dementia is the result of a decline or loss of brain tissue, the amount of work required to advance the blood (ie kinetic energy) should be reduced. Thus, the present invention has definitively demonstrated that dementia is at least largely a direct function of blood flow dynamics, as opposed to the consequences of brain degradation problems. Thus, the present invention provides a reliable and efficient for the diagnosis and evaluation of patients suffering from dementia, as well as monitoring and optimizing treatment and feeding aimed at combating the onset and progression of the condition. Provide a means.

  In addition, the above-described invention also seeks to maintain normal physiological performance, for example, vasospasm (or other similar and more rapid onset of structural vascular changes due to pathogenesis), vascular stenosis conditions In order to adapt to such changes, characterized by a narrowing of the blood vessels due to a period of onset that is slower than the time possible for the blood vessels, any of which leads to hyperemia (or other physiological changes) It is applicable to both systems and methods for identification and evaluation in the treatment of various vascular conditions, including: In particular, the present invention is a method of distinguishing between various vascular conditions and conditions, particularly for use in TCD technology, particularly for vasospasm (ie structural conditions) and hyperemic conditions (ie physiological conditions). Provide a method that facilitates characterizing transitions between Such ability to distinguish between vascular conditions (which may otherwise be indistinguishable until after a vascular event) is particularly applicable to subarachnoid hemorrhage from, for example, a ruptured aortic aneurysm.

  Vascular disease processes can affect the tone of the blood vessels or form points of obstruction along the blood vessels (eg inflammation around the blood related to bleeding, inflammation in blood vessels or atherosclerosis) There is sex. Today, various methods exist for the assessment of static vascular function (more commonly referred to as endothelial function). These tests generally measure the response to physiological stimuli such as breathing or hyperventilation. However, arterial occlusion is usually assessed functionally from changes induced by average flow velocity (eg, by transcranial Doppler (“TCD”) ultrasound) or by angiography of arterial segments. It is evaluated structurally (showing only the cross-sectional silhouette of a narrowed vessel).

  Stenosis is defined as the narrowing of blood vessels caused by inflammation, external compression, or arteriosclerosis within a segment of an artery. In this regard, structural vascular changes (eg, narrowing due to vasospasm, inflammation, calcification, or hemorrhage) are physiological (or functional) such as hyperemia or pressure / flow changes in the associated vascular segment. Result in change. These physiological changes due to structural changes are manifested in turn in clinical symptoms, features or signs (eg dementia, unstable gait, etc.). Thus, in this respect there is a structural functional relationship between the anatomical changes within a particular vessel segment and the function of the blood flow characteristics from those results, in this respect any stenosis (ie, narrow May also result in functionally apparent relative hyperemia and vasospasm as a coordinating physical (extreme) hyperemia. For example, vasospasm is manifested by hyperphysiological stenosis hyperemia (ie, a hyperphysiological change defined as a change beyond that expected from physiological compensation by a process beyond that segment) and stenosis Bring. Such is unique to diseases starting from the segment being measured rather than crossing the segment around the segment. When there is atherosclerotic stenosis following an inflammatory change at a particular point or vascular segment, usually elsewhere in the vasculature (ie both near or distal to that point) and other It should always be taken into account that there are similar changes that produce stenotic segments. The most common form of stenosis is stenosis due to atherosclerosis. In addition, there may be compensatory changes that occur in adjacent or distal segments of the vasculature.

  The most common form of stenosis is stenosis due to atherosclerosis. In coronary arteries and elsewhere, stenosis is evaluated by various methods. In coronary arteries, for example, stenosis is measured primarily by angiography. However, as noted above, angiography provides only a narrowed vessel cross-sectional silhouette. As such, angiographic analysis is (in some cases) inaccurate due to asymmetric narrowing within the arteries (i.e., when there is a change in the visible flesh, no stenosis exists or is measured physiologically) It may be much smaller, or it may seem either).

  Stenosis events and conditions that result in significant flow changes due to structural changes (ie, narrowing), including those that require therapeutic intervention, are changes within the vessel segment (as measured by the DVA index). As well as a compensatory change in the physiological state of adjacent segments. In other words, the (narrowed) segment of the stenosis manifests a physiological state characterized by more reliable information that can be gathered by examination of the DVA index and adjacent segment physiological states (in the same vessel) . The set of segments that simultaneously prove the significance of narrowing is the stenosis segment considered together with adjacent segments: (1) the segment before the stenosis, (2) the stenosis segment and (3) the segment after the stenosis May be defined by If critical stenosis is addressed, the physiological state of these three segments is to preserve distal perfusion impedance mismatch ("PIMM"), flow volume and pressure in the area after stenosis. There will be a breakthrough of hyperemia at the site of stenosis and an adjacent PIMM in the area after stenosis.

  PIMM is defined as the instability of a force vector such that the impedance vector contributes more to the balance than the forward force vector. The end result of this condition is a forward flow drop. There may be two reasons for the occurrence of a PIMM. The first possible reason is the “proximal” PIMM that was caused by a decrease in the nearby perfusion pressure as a result of significant stenosis. The second cause is “distal” PIMMs due to increased impedance vectors that cause instability. Distal PIMMs also occur when there is significant small vessel disease. The combination of both types of PIMM significantly inhibits the forward movement of blood and if it is present in the area after stenosis, it will show a flow of compensation from other blood vessels.

  Traditionally, neurology critical care defines two different types of cerebral vascular events. The first event is ischemic flow or low flow. The second event is a vascular rupture (most commonly an aneurysm resulting from an excessively enlarged blood vessel). When a patient suffers or bleeds from an aneurysm, it typically occurs in the subarachnoid space (ie, subarachnoid hemorrhage). The initial response to subarachnoid hemorrhage is damage to the nervous system with loss of consciousness.

  However, patients who survive the first event also frequently have a secondary response to bleeding. In particular, it is well documented that the patient is congested in the recovery of the initial phase. Hyperemia is defined as a pathological increase in blood flow that exceeds the amount required for metabolism in the tissue served by the vessel.

  Another secondary response that often occurs 5-10 days after the first event is the development of vasospasm. Vasospasm is the prevention and treatment of vasospasm (more importantly, defined as the pathological contraction of muscles into the blood vessel that resulted in significant stenosis leading to a second ischemic stroke or low blood flow stroke. (The prevention of clinical and pathological conditions associated with vasospasm) mainly includes the treatment of hypertension and polycythemia. Thus, patients who have experienced subarachnoid hemorrhage frequently receive a regimen that includes mendicants of hemodilution, hypertension, and pre-emptive treatment ("HHH treatment") of circulating blood volume. These therapies strive to increase blood vessel volume by infusion of fluids and by artificially raising the patient's blood pressure with drugs. However, it can cause a state of cerebral hyperemia while raising the patient's blood pressure and / or increasing blood volume. Thus, treatment of one condition (vasospasm) may unintentionally cause the other (hyperemia). Therefore, physiological hyperemia resulting from HHH treatment and / or blood flow reduction due to stenosis of the vessel (ie, physiological state or condition) and minimal convulsions (ie, physiological conditions or conditions) following advanced vasospasm It is important to be able to identify (state).

  As can be seen from the above discussion, it becomes very important to be able to identify naturally occurring hyperemia, treatment-induced hyperemia, and whether the hyperemia is actually vasospasm. However, it is actually difficult to achieve such a distinction by conventional methods. For example, current treatment modalities for assessing vasospasm include transporting the patient to an angiography suite and performing angiogenesis on the convulsive lesion. Similarly, premature treatment of overt vasospasm conditions (ie with HHH treatment) may actually increase the risk of congestive swelling from the patient's first vascular event or cerebral edema. Therefore, it is critical to determine whether and when a patient is transitioning from a hyperemic state to an early stage of vasospasm. Conversely, starting HHH treatment too late after the onset of vasospasm is of little value because it does not provide a difference in clinical outcome. In this regard, the unnecessary initiation of HHH treatment too late after the onset of vasospasm has been associated with certain age (ie middle-aged and elderly) patients who are actively treated for hypertension and / or polycythemia. Given the well-known incidence of congestive heart failure in between, it may be detrimental to the patient's health.

  Thus, the timing and use of hypertension and / or polycythemia treatment after subarachnoid hemorrhage is highly dependent on being able to better define when a patient transitions from hyperemia to vasospasm. Currently, such a determination is made by comparing the peak systolic velocity ratio of the intracranial blood vessels to the extracranial carotid artery (derived from TCD ultrasound, among other methods). This comparison is called the Lindegaard ratio. However, this analysis is not accurate. Some studies have shown that the Lindegaard ratio only predicts at most 50% the identification of the transition from hyperemia to vasospasm.

  Other methods have been investigated but have not entered widespread use for assessing and distinguishing vascular conditions. Such methods include measuring blood pressure waves with a catheter that is pulled through a narrow point inside a bent artery. Similarly, some effort has been directed to using intravascular ultrasound (“IVUS”) to guide the assessment of blood vessels. However, these studies do not use synthesized ultrasound images and / or vasodilators to calculate an anomaly defined ratio called coronary flow volume reserve or arterial flow accumulation ( For example, it is almost completely focused on its use in assessing the physiological response to ejaculation of adenosine).

  As explained below, DVA quantifies the transition from hyperemic to vasospasm, which can be changed dynamically on a daily or instantaneous basis in a neurocritical care unit It can be used to identify automatically. However, it should be further understood that the physiological key features described herein may be extended and / or applied to distinguish other forms of vascular stenosis.

  DVA includes analysis of transcranial Doppler data (TCD). As applied to the assessment and differentiation of vascular conditions and conditions, DVA is collected (by software) as a function of TCD and / or time and velocity, and intravascular ultrasound (“IVUS”) data (population "Ultrasound data"). Among the factors that can be measured and taken into account when assessing and distinguishing vascular conditions and conditions are: (a) ultrasound data values (peak contractions) for each of the 19 vascular segments established in the cerebral vasculature. Diastolic velocity (PSV), end diastolic velocity (EDV), peak systolic time (PST), end diastolic time (EDT), mean flow velocity (MFV), systolic acceleration (SA), pulsatile Simultaneous consideration of index (PI) SA natural logarithm (LnSA)), (b) comparison of ultrasound data values against a reference database to quantify the degree of variance from the mean, and (c) 19 vessels A series of indices (blood flow velocity ratio) derived from ultrasound data values representing the status / performance / health of each vessel in the segment.

  As discussed above, the considered 19 vascular segments within the skull are illustrated in FIGS. The vascular segments illustrated in FIGS. 33 and 34 are the left and right vertebral arteries (VA), basilar artery (BA), posterior cerebral artery / PCAt (heading) (P1), posterior cerebral artery / PCAa (away) (P2), internal carotid artery / ICAt (heading), middle cerebral artery (M1), anterior cerebral artery (Al), anterior traffic artery (ACOM) (C1), carotid artery siphon (heading) (C4), carotid artery siphon (leaving) (C2) and ocular artery (OA).

The derived indexes include the following:
1. Dynamic compliance index (DCI) (also called dynamic work index (DWI), or acceleration / mean flow velocity index (VAI)) = (natural logarithm of systolic acceleration value divided by average flow velocity value and / or Or the inverse of it). Thus, DCI describes the motion efficiency of a segment that advances blood in terms of flow force to an average flow velocity.
2. Dynamic flow index (DFI, or velocity / impedance index (VPI)) = (average flow velocity value divided by pulsatile index value and / or inverse thereof). Thus, DFI relates the average flow velocity to impedance (pulsatile index) and explains how the capacitance volume affects flow through the conductance vessel.
3. Dynamic pressure index (DPI, or acceleration / impedance index (API)) = (natural logarithm of systolic acceleration value divided by pulsatile index value and / or inverse thereof). Thus, DPI relates the flow force to the impedance and describes the effect of capacitance vessel volume on the flow force.

Pathologically compromised blood vessels (due to stenosis or atherosclerotic disease) are present before the stenosis segment immediately before the stenosis point, after the stenosis segment, and after the stenosis immediately after the stenosis point Defined by three physiological segments.
Physiological conditions within these three segments are perfusion impedance mismatch (PIMM) in the segment prior to stenosis, hyperemia breakthrough at the site of stenosis (for flow volume and pressure conservation), and stenosis. Contains adjacent PIMMs in later segments.

  As noted above, PIMM is defined as the instability of a force vector such that the impedance vector contributes to overwhelm the forward force vector so that there is a net reduction in forward flow. Within the segment prior to stenosis, PIMM results from a decrease in proximal perfusion pressure due to effects downstream of the stenosis. Within the segment after stenosis, the PIMM is due to an increase in the impedance vector, possibly indicating a flow of compensation from other vessels. The segment of stenosis is defined as the segment of the relative hyperemia. In particular, the segment of the stenosis shows an increase in anterior flow due to a narrowed artery that cannot expand (or “stretch”) due to the reduced elasticity of the artery. In this way, there is a dramatic increase in speed through the segment, maintaining the flow.

  FIG. 35 outlines the flow effects in the region proximate the stenotic vessel segment. In FIG. 35, within the segment before stenosis (labeled “PIMM (distal)”) and the segment after stenosis (labeled “PIMM (proximal)”), Although DCI (also called DWI) is increasing, it is observed that both DFI and DPI are decreasing. At the same time, within the stenotic segment, it increases with DFI and DPI, but decreases with DCI (also called DWI).

  DVA has been used to determine that DCI (also called DWI) is a marker of elastic properties that determines the compliance of a given vascular segment. In particular, the transition from a hyperemic state (which is due to HHH treatment, but also occurs after initial stenosis) to vasospasm is quantifiable to define the DVA (ie, the point at which the vessel transitions from hyperemic to vasospasm) It has been observed in advance that it can be characterized as a function of DCI (also called DWI) measured by FIG. 36 illustrates a plot of DCI (also called DWI) against time. In FIG. 36, it has been observed that there is a threshold DCI (also called DWI) value over time, below which patients who have experienced vascular events have become hypervascular from engorged. Transition (pathological changes in the DCI (also called DWI) index indicating the transition from hyperemia to vasospasm can be defined as compliance separation or elastic separation). In this regard, as the patient begins to transition from hyperemia to vasospasm (based on analysis of the patient's blood flow vector), a timely and advantageous notification to initiate various appropriate intravenous injections and other treatments Can be provided to the management team. These therapies may involve the use of certain agents that expand within the blood vessels simultaneously with angiogenesis and / or other pharmaceutical treatments.

  In one embodiment of the invention, measured changes in DVA of DCI (also referred to as DWI) are used to evaluate and segment different vascular conditions in a patient in a neurocritical care unit. Can be used.

  In another embodiment of the invention, measured changes in DCI (also referred to as DWI) DVA are used in clinical trials to better define the scope and timing of treatments with pharmaceuticals and devices As well as quantitative conditions and endpoints that define the state of hyperemia, vasospasm, and transition points between those states can be further developed. For example, when subarachnoid hemorrhages occur in the basilar blood vessels, they essentially use up any nitrous oxide and / or expansion capacity, thus leading to severe tightening or convulsions of the blood vessels. Under such circumstances, treatment with a stent may be appropriate. FIG. 37 illustrates a plot of DFI against patient DCI (also referred to as DWI) over time following a vascular event and transition between hyperemia and vasospasm. In FIG. 37, on the first day following a vascular event, it is observed that the affected blood vessel has a very low DCI (also called DWI), which is very “hard or flexible” Suggests "no blood vessels". As a result, there is a corresponding high forward flow velocity (about 15 standard deviations from normal). This state corresponds to vasospasm. After a few days, the blood vessels begin to “loose” and the flow velocity is reduced. In this way, the blood vessels begin to transition to a hyperemic state. After a few days, the vessel segment continues to experience shrinking flow. This data suggests that changes in DCI (also called DWI) reflect the amount of elastic properties of a particular vessel and thus show a transition between hyperemia and vasospasm. . In particular, when the DCI (also called DWI) value falls below a certain value, it appears to indicate an absolute loss of elastic properties and a significant stiffening of that segment of the vessel.

  In another embodiment of the invention, changes measured in DVA of DCI (also referred to as DWI) monitor the continuous metrics of clinical trial participants that can be easily correlated to specific treatment and / or safety procedures. Can be used to Similarly, direct quantitative metrics direct monitoring can be used with surrogate markers to align the bisection endpoints. In this way, continuous metrics such as DVA can predict bisection results with sufficient reliability that clinical trials can be performed quickly and with improved efficiency.

  According to another embodiment of the invention, the measured change in DCI (also referred to as DWI) DVA allows for stent insertion (or step-by-step) stent expansion (by step). Can be used to manage the incidence of induced hyperemia that occurs after the procedure of stenting). Pathological hyperemia refers to an increase in flow breakthrough following any revascularization (ie, stent insertion) procedure. Downstream blood vessels may be weakened or deflated (eg reduced elasticity) by requiring minimal properties during the time flow is reduced (which may be many years) It is particularly sensitive to such effects.

  According to another embodiment of the invention, the state of the blood vessel can be represented by a computer-embedded algorithm that can access the server and / or communicate with a communication network such as the Internet. Such an algorithm can also be applied to a computerized platform coupled to a detection system capable of generating and / or receiving flow data, including, for example, TCD ultrasound and / or other Doppler ultrasound devices. Can be implemented.

  According to another embodiment of the invention, conventional freehand Doppler techniques are used in conjunction with the present invention to determine arterial segments (eg, to ascertain the depth of measurement and to determine the location in three-dimensional space. Manual adjustment of the reflected sound gating).

  According to another embodiment of the invention, a robotic or self-oriented TCD device may be used. In particular, robotic TCD devices that use computer-guided probes tuned by robotic control can be used to continuously maintain locks at specific target positions to be measured. An example of such a probe is a mechanical robot that can be strapped to the patient's head and used in a neurocritical care unit that allows continuous monitoring of TCD data signals indicative of vasospasm development. Includes probes.

Instead, use different robotic probes to sample different depths along a single artery or scan a region to obtain data from several different arteries during analysis Can do. The collected data can then be processed using DVA to provide continuous visual and audible readouts regarding the patient's developed vascular condition.

  According to another embodiment of the invention, changes measured in DVA of DCI (also referred to as DWI) can be measured using a thin wire intravascular ultrasound (IVUS) procedure. it can. For example, a thin wire IVUS device can be pulled across a region of a stented blood vessel, thereby passing the region before, after, and after the stenosis. As illustrated in FIG. 38, when the data is evaluated according to such a procedure, three separate vectors representing the net effect on the flow can be observed. This type of data is also particularly important, especially as part of diversion procedures and research. The drainage procedure and study involves shunting the occluded blood vessel (insertion of a tube, such as a ventriculostomy procedure or other similar procedure, to relieve pressure in the skull) Whether monitoring a second ancillary blood vessel that shares a common blood supply and increasing flow in the occluded blood vessel (eg, due to stent insertion) impacts flow in the unoccluded blood vessel Need to be determined.

<Example 8: DVA analysis of vasospasm>
DVA was used to obtain data from 14 subjects who had subarachnoid hemorrhage with vasospasm. Although not necessary at the time of their first TCD analysis, all subjects received HHH treatment at different times. Some of the subjects were not receiving HHH treatment when they had a TCD test. Others were receiving 3H treatment, and some of the subjects had multiple TCD tests after they became convulsive and after the convulsion resolved. Thus, DVA analysis is the first hemorrhage without 3H, cerebral hemorrhage with 3H, cerebral hemorrhage with vasospasm, and then after resolution of vasospasm (ie, before convulsions, before hyperemia, before convulsions) After, and after convulsion and convulsions) at multiple critical states along the path of the disease (ie care pathway).

The results of DVA analysis in these subjects were as follows.
1. First, it was observed that patients who had developed hyperemia experienced an increase in DFI and DPI with a slight decrease in DCI (also called DWI). This data distinguishes these patients from those who had not received 3H treatment.
2. Second, especially if DVA can reliably identify their controls and score their DFI and DPI scores in vasospasm in those who have not and / or just received 3H treatment Observe that DFI reached approximately 8 standard deviations above normal, and DCI (also called DWI) was approximately 2 standard deviations below standard It was done. Such high DFI and low DCI (also called DWI) scoring profiles represent a second superphysiological hemodynamic change indicative of substantial vascular stenosis.

  As mentioned above, the DVA process takes measurements in three parameter nomograms based on each segment. These measurements can be made reliably on any segment of the body and any arterial and venous segment of the body or heart. In vasospasm, it means the state of the first blood vessel (this is a single point state in the blood vessel where it is being measured but has upstream and / or downstream flow effects. ). As a first condition, vasospasm is an intrinsic disease process of a single or several vascular segments, but it is a segmental disease. In the case of vasospasm, you have a disease in the arterial system in the brain. Generate incidental uncompensated hemodynamic changes (i.e., surrounding segments with or without ensemble compensation for the segment level legion within the first vessel). However, if the threshold criteria described above are met, it is not necessary to measure surrounding segments to characterize vasospasm. That is, vasospasm is characterized by a DVA having a flow index of about 8 standard deviations or more with a compliance index of about 2 or less.

  The situation for vasospasm can be contrasted with a second vascular condition, which is a disease with a systematic flow effect and an ensemble pattern to identify the disease. (Such as dementia) characterized by observing the relationship between specific blood vessels and segments that correlate such information to develop ensemble patters and can only be measured .

  Various preferred embodiments of the invention have been described in accomplishing the various objects of the invention. It should be appreciated that these embodiments are merely illustrative of the principles of the invention. Numerous modifications and adaptations of the present invention will be readily apparent to those skilled in the art without departing from the spirit and scope of the present invention.

FIG. 1 is an explanatory diagram showing a method in which an ultrasonic pulse is applied to a human head in order to obtain information about a blood flow velocity flowing through an intracranial blood vessel. FIG. 2 is an explanatory diagram showing a method in which an ultrasonic pulse is applied to a human head in order to obtain information about a blood flow velocity flowing through an intracranial blood vessel. FIG. 3 is an explanatory diagram showing a method in which an ultrasonic pulse is applied to a human head in order to obtain information about a blood flow velocity flowing through an intracranial blood vessel. FIG. 4 is an explanatory diagram showing a method in which an ultrasonic pulse is applied to a human head in order to obtain information about a blood flow velocity flowing through an intracranial blood vessel. FIG. 5A provides a schematic diagram of a transcranial Doppler ultrasound analysis where velocity is shown on the Y-axis and time is provided on the X-axis. FIG. 5B provides a schematic diagram of a transcranial Doppler ultrasound analysis with velocity shown on the Y axis and time provided on the X axis. FIG. 5C provides a schematic diagram of a transcranial Doppler ultrasound analysis where velocity is shown on the Y-axis and time is provided on the X-axis. FIG. 5D provides a schematic diagram of a transcranial Doppler ultrasound analysis with velocity shown on the Y axis and time provided on the X axis. Figure 2 is a schematic diagram of a two-dimensional nomogram in which the mean blood flow velocity is shown on the Y axis and the systolic acceleration is provided on the X axis. FIG. 7 shows the nomogram of FIG. 6 in addition to the area of the nomogram showing the deviation from the normal automatic adjustment state. FIG. 8 shows a schematic diagram of a three-dimensional nomogram. FIG. 9A shows a schematic diagram of a two-dimensional nomogram in which the average blood flow velocity of a patient who feels a little unstable is shown on the Y-axis and the systolic acceleration is provided on the X-axis. FIG. 9A shows a schematic diagram of a two-dimensional nomogram in which the average blood flow velocity of a patient who feels a little unstable is shown on the Y-axis and the systolic acceleration is provided on the X-axis. FIG. 9B shows a schematic diagram of a two-dimensional nomogram in which the average blood flow velocity of a patient who feels a little unstable is shown on the Y-axis and the systolic acceleration is provided on the X-axis. FIG. 9C shows a schematic diagram of a two-dimensional nomogram in which the average blood flow velocity for a patient who feels a little unstable is shown on the Y-axis and the systolic acceleration is provided on the X-axis. FIG. 9D shows a schematic diagram of a two-dimensional nomogram in which the average blood flow velocity of a patient who feels a little unstable is shown on the Y-axis and the systolic acceleration is provided on the X-axis. FIG. 10 is a block diagram of an exemplary system architecture in a preferred embodiment of the present invention. FIG. 11 is a conceptual graph of the concept of the left extracranial frontal artery in a preferred embodiment of the present invention. FIG. 12 is a conceptual graph of the concept of the frontal artery in the left cranium in a preferred embodiment of the present invention. FIG. 13 is a conceptual graph of the concept of the frontal artery in the right skull in the preferred embodiment of the present invention. FIG. 14 is a conceptual graph of the right extracranial frontal artery concept in a preferred embodiment of the present invention. FIG. 15 is a conceptual graph of the occipital artery concept in a preferred embodiment of the present invention. FIG. 16 is a conceptual graph of the concept of collateral blood flow in a preferred embodiment of the present invention. FIG. 17 is a conceptual graph of a parameter concept in a preferred embodiment of the present invention. FIG. 18 is a conceptual graph of the concept of stroke candidates in a preferred embodiment of the present invention. FIG. 19 is a conceptual graph of the concept of small vascular disease in a preferred embodiment of the present invention. FIG. 20 is a conceptual graph of a data concept in a preferred embodiment of the present invention. FIG. 21 is a conceptual graph of an arterial condition concept in a preferred embodiment of the present invention. FIG. 22 is a conceptual graph of an arterial condition concept in a preferred embodiment of the present invention. FIG. 23 is a block diagram for the application service provider architecture in the preferred embodiment of the present invention. FIG. 24 is an illustration of a logon page in the preferred embodiment of the present invention. FIG. 25 is an illustration of a user activation window in a preferred embodiment of the present invention. FIG. 26 is an illustration of a window of transcranial Doppler data in a preferred embodiment of the present invention. FIG. 27 is an illustration of a hemodynamic analysis window in a preferred embodiment of the present invention. FIG. 28A illustrates the status of the subject's extensive blood vessels based on data from many blood vessels in early onset symptoms associated with increased intracranial pressure. FIG. 28B illustrates a shift in vascular status in an individual's blood vessels due to progressive deterioration of the subject's symptoms. FIG. 28C illustrates a dramatic globalized shift in vascular status in an individual's blood vessels after the subject's symptoms have increased to the point requiring hospitalization. FIG. 28D illustrates recovery of vascular status close to normal after treatment to reduce intracranial pressure. FIG. 29 demonstrates that a conventional blood flow test will not detect changes in intracranial pressure occurring within a subject that are observable using transcranial-based dynamic vascular assessment. is doing. FIG. 30 is a schematic of correlated MFV and SA data from the two series of subjects shown in Table 8. FIG. 31 is a bar graph of PI data for the two series of Trendelenberg of interest from Table 8. FIG. 32 is a schematic diagram of correlated PI and SA data from the two series of subjects shown in Table 8. FIG. 33 illustrates 19 intracranial blood vessel segments that can be used for evaluation according to the present invention. FIG. 34 illustrates 19 intracranial blood vessel segments that can be used for evaluation according to the present invention. FIG. 35 illustrates the influence on the blood flow at the blood vessel site adjacent to the stenosis site and the change in the blood flow behavior associated therewith. FIG. 36 illustrates a plot of DCI (also referred to as DWI) versus time and a decrease in the threshold of DCI (also referred to as DWI) indicating the onset of vasospasm. FIG. 37 illustrates a plot of DFI vs. DCI (also referred to as DWI) over time after a vascular event and transition between hyperemia and vasospasm. FIG. 38 illustrates the effect measured by IVUS on blood flow in a blood vessel site adjacent to a blood vessel stenosis site and the resulting change in blood flow behavior.

Claims (29)

A method for assessing vasospasm status in a human or animal comprising:
Obtaining a first set of intracranial blood flow data;
Generating at least two blood flow factor values from the first set of intracranial blood flow data;
Correlating the at least two blood flow factor values;
Evaluating the vasospasm state based on at least the correlated blood flow factor value.   The at least two blood flow factor values are: mean flow velocity value, systolic acceleration value, pulsatile index value, natural logarithm of systolic acceleration value, peak systolic velocity value, end diastolic velocity value, peak systolic phase. Time value, end diastolic time value, acceleration / average flow velocity index value, velocity / impedance index value, acceleration / impedance index value, natural logarithm of systolic acceleration divided by average flow velocity value, average flow velocity value Reciprocal of natural logarithm of systolic acceleration value divided by, average flow velocity value divided by pulsatile index value, reciprocal of average flow velocity value divided by pulsatile index value, contraction divided by pulsatile index value 2. The method according to claim 1, comprising at least one of a natural logarithm of the systolic acceleration value and an inverse of the natural logarithm of the systolic acceleration value divided by the pulsatile index value. Evaluation method of vasospasm state of the mounting.   The vasospasm state evaluation method according to claim 1, further comprising the step of correlating at least three blood flow factor values.   The method of evaluating a vasospasm state according to claim 1, wherein the step of obtaining intracranial blood flow data includes the use of radiated and reflected wave techniques.   The vasospasm state evaluation method according to claim 4, wherein the radiated and reflected wave technique includes an ultrasonic technique.   6. The method for evaluating a vasospasm state according to claim 5, wherein the ultrasonic technique includes a Doppler technique.   5. The method for evaluating a vasospasm state according to claim 4, wherein the radiation wave reflected technique includes a laser technique.   The method for evaluating a vasospasm state according to claim 1, further comprising the step of generating a reference data set of correlated blood flow factor values.   The method of evaluating a vasospasm state according to claim 1, further comprising the step of supplementing a set of reference data of correlated blood flow factor values with additional correlated blood flow factor values and data.   The method of evaluating a vasospasm state according to claim 1, further comprising the step of comparing the correlated blood flow factor value with a reference data set of correlated blood flow factor values.   2. The blood vessel of claim 1, further comprising diagnosing a subject suffering from or suspected of suffering from a condition characterized by increased intracranial pressure based on at least the step of evaluating intracranial pressure. Evaluation method of convulsions.   12. The method for evaluating a vasospasm state according to claim 11, wherein the diagnosing step includes diagnosing that the subject is suffering from at least one hyperemia state.   The vasospasm state evaluation method according to claim 12, wherein the at least one hyperemia state is subarachnoid hemorrhage.   12. The method for evaluating a vasospasm state according to claim 11, wherein the diagnosing step includes diagnosing that the subject is suffering from at least one hyperemia state.   The method for evaluating a vasospasm state according to claim 1, wherein the method includes a part of a treatment plan for a subject suffering from or suspected of suffering from a condition characterized by increased intracranial pressure.   16. The method of claim 15, wherein the method comprises monitoring the effect of a treatment plan on a subject suffering from or suspected of suffering from a condition characterized by increased intracranial pressure. Evaluation methods.   16. The method for evaluating a vasospasm state according to claim 15, wherein the state characterized by increased intracranial pressure includes at least one hyperemia state.   16. The method for evaluating a vasospasm state according to claim 15, wherein the state characterized by increased intracranial pressure includes subarachnoid hemorrhage.   The method for evaluating a vasospasm state according to claim 18, wherein the treatment plan includes at least use of a shunt.   20. The method for evaluating a vasospasm state according to claim 19, wherein the shunt is a programmable shunt.   The method according to claim 1, wherein the method is used as part of the development and improvement of shunt technology.   The assessment of vasospasm status according to claim 1, further comprising a step of programming or reprogramming a shunt based on at least the step of assessing intracranial pressure based on at least the correlated blood flow factor value. Method.   The method for evaluating a vasospasm state according to claim 1, further comprising the step of inserting a blood flow factor value into the schema. A method for assessing a vasospasm condition caused by subarachnoid hemorrhage in a human or animal comprising:
Obtaining a first set of intracranial blood flow data;
Generating at least two blood flow factor values from the first set of intracranial blood flow data;
Correlating the at least two blood flow factor values with each other;
And a method of evaluating a vasospasm state caused by subarachnoid hemorrhage based on at least the correlated blood flow factor value, and a method for evaluating a vasospasm state caused by subarachnoid hemorrhage.   The at least two blood flow factor values are: mean flow velocity value, systolic acceleration value, pulsatile index value, natural logarithm of systolic acceleration value, maximum systolic velocity value, end diastolic velocity value, maximum systolic phase. Time value, end diastolic time value, acceleration / average flow velocity index value, velocity / impedance index value, acceleration / impedance index value, natural logarithm of systolic acceleration divided by average flow velocity value, average flow velocity value Reciprocal of natural logarithm of systolic acceleration value divided by, average flow velocity value divided by pulsatile index value, reciprocal of average flow velocity value divided by pulsatile index value, contraction divided by pulsatile index value 25. The method according to claim 24, comprising at least one of a natural logarithm of the systolic acceleration value and a reciprocal of the natural logarithm of the systolic acceleration value divided by the pulsatile index value. Evaluation method of vasospasm state due to subarachnoid hemorrhage.   The step of assessing vasospasm status based at least on the correlated blood flow factor values includes determining whether the subject's DFI value is approximately 8 standard deviations above the normal DFI value, and the subject's DCI value is greater than the normal DCI value. 2. The method for evaluating a vasospasm state according to claim 1, comprising determining whether or not about two standard deviations are lower.   The step of assessing a vasospasm condition resulting from subarachnoid hemorrhage based at least on the correlated blood flow factor values includes determining whether the subject's DFI value is approximately 8 standard deviations higher than the normal DFI value, and the subject's DCI 25. The method for evaluating a vasospasm state according to claim 24, comprising determining whether the value is approximately 2 standard deviations below a normal DCI value.   The step of assessing vasospasm based on at least the correlated blood flow factor value includes determining whether at least one of the subject's DFI and DPI values is increased and the subject's DCI value is decreased. The method for evaluating a vasospasm state according to claim 1.   The step of assessing vasospasm based on at least the correlated blood flow factor value includes determining whether at least one of the subject's DFI and DPI values is increased and the subject's DCI value is decreased. The method for evaluating a vasospasm state according to claim 24.

Images