Patent Application
20210267468
The present invention relates generally to intravenous (IV) therapy, and more specifically, the present invention relates to systems and methods of detecting hypovolemia, hypervolemia and/or IV infiltration and monitoring intravascular placement of an IV catheter using peripheral IV waveform analysis (PIVA) to assess blood volume status of a living subject, and applications of the same.
Hemorrhagic shock remains the leading preventable cause of death in the casualty care setting. Trauma is the leading cause of death in patients less than 40 years of age and poses a significant economic burden worldwide. Survival is contingent upon early recognition of hemorrhage, appropriate triage, and goal-directed transfusion therapy.
Early recognition of hemorrhage and guided fluid administration is critical for providing timely intervention and maintaining end organ viability of human beings and other living animals. For example, Timely damage control surgery (DCS) and restrictive fluid resuscitation (RFR) for wounded soldiers have been shown to significantly improve mortality. While early resuscitation is warranted in patients with hypovolemic shock, over-resuscitation can also have deleterious effects, such as decreased end-organ perfusion, pulmonary edema, and increased mortality. However, there remains a critical technological void for detecting early hemorrhage and resuscitation efficacy, particularly in the clinical setting. Specifically, recognition of subclinical hemorrhage and proper fluid resuscitation has remained elusive, resulting in delayed triage and poor management of the wounded soldier. Often, continuous occult bleeding is not recognized until the onset of hemorrhagic shock and hemodynamic collapse, particularly in a young, healthy soldier with good compensatory mechanisms. Unrecognized hemorrhage leads to delayed triage and DCR, resulting in preventable end-organ damage.
Early recognition of hemorrhage is the mainstay of therapy to prevent end-organ damage and to improve survival. Hypovolemic shock and end organ damage are challenging diagnoses in patients with normal heart rate and blood pressure, particularly in patients with good compensatory mechanisms. Specifically, advanced hemorrhagic shock often precedes significant changes in standard vital sign monitoring, particularly in young healthy individuals. In fact, significant vital sign changes do not occur until the patient has lost 15-30% of blood volume, characteristic for Stage II hemorrhage. Even invasive monitoring modalities such as central venous pressure and pulmonary arterial pressure are poor determinants of volume status. Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects. Furthermore, central monitoring is associated with major vascular complications and central line associated bloodstream infections. More importantly, central venous monitoring offers no survival benefit in critically-ill patients.
Moreover, while seemingly simple, proper intravascular placement of an intravenous (IV) catheter is mandatory for effective IV volume resuscitation and IV pharmacologic administration. Malpositioning or misplacing of IV catheters may occur at any time during hospitalization or when a patient is in a status under the potential need of IV volume resuscitation and/or IV pharmacologic administration. For example, ambulatory patients may inadvertently displace the catheter, often secured with tape; patients in the operating room setting often have their arms tucked in sheets, away from the operative field, precluding inspection of the IV insertion site for signs of infiltration; and pediatric patients often have IV catheters secured with devices to prevent patient tampering, which also obscures the IV insertion site.
Malpositioning of a peripheral IV catheter into the extravascular space precludes the patient from receiving necessary resuscitative therapy. Fluid administration into subcutaneous tissue or fascia may result in compartment syndrome and loss of the extremity. Tissue necrosis and gangrene may result from tissue infiltration of vasoactive medications.
Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.
In one aspect, the present invention relates to an peripheral intravenous (IV) waveform analysis (PIVA) system. In certain embodiments, the PIVA system includes: a peripheral IV device configured to acquire, from a vein of a living subject, peripheral venous signals; and a processing device communicatively connected to the peripheral IV device. The peripheral IV device includes: a peripheral IV catheter, configured to be inserted into the vein of the living subject; and a fluid controlling device in fluid communication with the peripheral IV catheter, configured to control fluid flow from a fluid source to the peripheral IV catheter. The processing device is configured to: receive the peripheral venous signals from the peripheral IV device; perform a spectral analysis on the peripheral venous signals to obtain a peripheral venous pressure frequency spectrum; and perform a statistical analysis on amplitudes of peaks of the peripheral venous pressure frequency spectrum to determine an intravascular volume status of the living subject in real time. The intravascular volume status of the living subject indicates hypovolemia when amplitude decreases greater than a first threshold are detected from the peaks of the peripheral venous pressure frequency spectrum. Further, the processing device is capable of performing the statistical analysis on the amplitudes of the peaks of the peripheral venous pressure frequency spectrum to determine an IV line functionality of the peripheral IV catheter in real time, wherein the IV line functionality of the peripheral IV catheter indicates IV infiltration when amplitude decreases greater than a second threshold are detected from the peaks of the peripheral venous pressure frequency spectrum. When the IV line functionality of the peripheral IV catheter indicates IV infiltration, the processing device is capable of controlling the fluid controlling device to stop the fluid flow from the fluid source to the peripheral IV catheter.
In certain embodiments, the intravascular volume status of the living subject indicates hypervolemia when amplitude increases greater than a third threshold are detected from the peaks of the peripheral venous pressure frequency spectrum.
In certain embodiments, the PIVA system is applied to the living subject during ultrafiltration/dialysis or diuresis of the living subject, wherein the processing device is further configured to generate an alert message when the intravascular volume status of the living subject indicates hypovolemia.
In certain embodiments, the PIVA system is applied to the living subject during resuscitation of the living subject, wherein the intravascular volume status of the living subject indicates a return of euvolemia from a hypovolemic state when the living subject is determined to be in the hypovolemic state at an earlier time period, and amplitude increases greater than a fourth threshold are detected from the peaks of the peripheral venous pressure frequency spectrum; and the intravascular volume status of the living subject indicates over-resuscitation when the living subject is determined to be in an euvolemic state at the earlier time period, and amplitude increases greater than a fifth threshold are detected from the peaks of the peripheral venous pressure frequency spectrum.
In certain embodiments, the processing device is further configured to: detect efficacy of treatment and the return to euvolemia in the living subject based on the intravascular volume status of the living subject.
In certain embodiments, the processing device is a computing device.
In certain embodiments, the processing device is communicatively connected to the peripheral IV device through a wireless connection.
In certain embodiments, the peripheral IV device further includes: a monitoring device connected to the peripheral IV catheter, configured to capture and record the peripheral venous signals from the peripheral IV catheter at a sampling rate.
In certain embodiments, the monitoring device comprises a pressure transducer directly connected to the peripheral IV catheter, wherein the peripheral venous signals are captured and recorded by the pressure transducer.
In certain embodiments, the sampling rate is about 1 kHz.
In certain embodiments, the peripheral IV catheter is a peripherally-inserted central catheter (PICC).
In certain embodiments, the spectral analysis is a spectral fast Fourier transform (FFT) analysis.
In certain embodiments, the statistical analysis includes: obtaining a plurality of baseline peaks {BN_1} on a baseline peripheral venous pressure frequency spectrum, wherein N is a positive integer, and the plurality of baseline peaks {BN_1} respectively corresponds to a plurality of frequencies {F0, F1, . . . , FN}, such that BN-1 is a function of FN-1 satisfying BN-1=BN-1 (FN-1), wherein FN is greater than FN-1; obtaining a plurality of peaks {PN-1} on the aperipheral venous pressure frequency spectrum, wherein the plurality of peaks {PN-1} correspond to the plurality of frequencies {F0, F1, . . . , FN}, such that PN-1 is a function of FN-1 satisfying PN-1=PN-1 (FN-1); and determining the intravascular volume status of the living subject and the IV line functionality in real time by comparing the amplitudes of the peaks {PN-1} to that of the baseline peaks {BN_1} respectively.
In certain embodiments, the plurality of peaks {PN-1} comprises a first peak P0 corresponding to a first frequency F0 and a second peak P1 corresponding to a second frequency F1, wherein the second frequency F1 is greater than the first frequency F0; the first peak P0 corresponding to the first frequency F0 is associated with a respiratory rate of the living subject; and the second peak P1 corresponding to the second frequency F1 is associated with a heart rate of the living subject.
In certain embodiments, the baseline peripheral venous pressure frequency spectrum is obtained by: acquiring, by the peripheral IV device, the peripheral venous signals from the vein of the living subject at an earlier time period; and processing the peripheral venous signals acquired at the earlier time period by the spectral FFT analysis to obtain the baseline peripheral venous pressure frequency spectrum.
In certain embodiments, the PIVA system further includes: a pump connected to the living subject to perform liquid exchange to the living subject; and a pump controlling mechanism communicatively connected to the processing device, configured to control the pump by intermittently pausing the pump or subtract the pump signal when the peripheral IV device acquires the peripheral venous signals, and restarting the pump when the peripheral IV device does not acquire the peripheral venous signals; wherein the processing device is further configured to send a signal to the pump controlling mechanism to notify the pump controlling mechanism to control the pump.
In certain embodiments, the pump is a dialysis pump, a cardiopulmonary bypass pump, an extracorporeal membrane oxygenation (ECMO), or an infusion pump.
Another aspect of the present invention relates to a method for determining an intravascular volume status of a living subject and monitoring an intravenous (IV) line functionality of a peripheral IV device. The peripheral IV device includes: a peripheral IV catheter, configured to be inserted into a vein of the living subject; and a fluid controlling device in fluid communication with the peripheral IV catheter, configured to control fluid flow from a fluid source to the peripheral IV catheter. The method includes: acquiring, from the peripheral IV catheter, peripheral venous signals; performing, by a processing device communicatively connected to the peripheral IV device, a spectral analysis on the acquired peripheral venous signals to obtain a peripheral venous pressure frequency spectrum;
performing, by the processing device, a statistical analysis on amplitudes of peaks of the peripheral venous pressure frequency spectrum to determine the intravascular volume status of the living subject and the IV line functionality of the peripheral IV device in real time; and when the IV line functionality of the peripheral IV device is determined to indicate IV infiltration, controlling, by the processing device, the fluid controlling device to stop the fluid flow from the fluid source to the peripheral IV catheter. The intravascular volume status of the living subject indicates hypovolemia when amplitude decreases greater than a first threshold are detected from the peaks of the peripheral venous pressure frequency spectrum.
In certain embodiments, the intravascular volume status of the living subject indicates hypervolemia when amplitude increases greater than a third threshold are detected from the peaks of the peripheral venous pressure frequency spectrum.
In certain embodiments, the processing device is a computing device.
In certain embodiments, the processing device is communicatively connected to the peripheral IV device through a wireless connection.
In certain embodiments, the peripheral IV catheter is a peripherally-inserted central catheter (PICC).
In certain embodiments, the spectral analysis is a spectral fast Fourier transform (FFT) analysis.
In certain embodiments, the statistical analysis includes: obtaining a plurality of baseline peaks {BN_1} on a baseline peripheral venous pressure frequency spectrum, wherein N is a positive integer, and the plurality of baseline peaks {BN-1} respectively corresponds to a plurality of frequencies {F0, F1, . . . , FN}, such that BN-1 is a function of FN-1 satisfying BN-1=BN-1 (FN-1), wherein FN is greater than FN-1; obtaining a plurality of peaks {PN-1} on the peripheral venous pressure frequency spectrum, wherein the plurality of peaks {PN-1} correspond to the plurality of frequencies {F0, F1, . . . , FN}, such that PN-1 is a function of FN-1 satisfying PN-1=PN-1 (FN-1); and determining the intravascular volume status of the living subject and the IV line functionality in real time by comparing the amplitudes of the peaks {PN-1} to that of the baseline peaks {BN-1} respectively.
In certain embodiments, the plurality of peaks {PN-1} comprises a first peak P0 corresponding to a first frequency F0 and a second peak P1 corresponding to a second frequency F1, wherein the second frequency F1 is greater than the first frequency F0; the first peak P0 corresponding to the first frequency F0 is associated with a respiratory rate of the living subject; and the second peak P1 corresponding to the second frequency F1 is associated with a heart rate of the living subject.
In certain embodiments, the baseline peripheral venous pressure frequency spectrum is obtained by: acquiring the peripheral venous signals from the peripheral IV catheter at an earlier time period; and processing the peripheral venous signals acquired at the earlier time period by the spectral FFT analysis to obtain the baseline peripheral venous pressure frequency spectrum.
A further aspect of the present invention relates to a method for determining hypovolemia, hypervolemia and vascular tone of a living subject based on an intravascular volume status of the living subject using the PIVA system as discussed above.
In yet another aspect of the present invention, a PIVA system includes: a peripheral IV device configured to acquire, from a vein of a living subject, peripheral venous signals; and a processing device communicatively connected to the peripheral IV device. The peripheral IV device includes: a peripheral IV catheter, configured to be inserted into the vein of the living subject; and a fluid controlling device in fluid communication with the peripheral IV catheter, configured to control fluid flow from a fluid source to the peripheral IV catheter. The processing device is configured to: receive the peripheral venous signals from the peripheral IV device; perform a spectral analysis on the peripheral venous signals to obtain a peripheral venous pressure frequency spectrum; and perform a statistical analysis on amplitudes of peaks of the peripheral venous pressure frequency spectrum to determine an intravascular volume status of the living subject in real time. The intravascular volume status of the living subject indicates hypovolemia when amplitude decreases greater than a first threshold are detected from the peaks of the peripheral venous pressure frequency spectrum. Further, the processing device is capable of performing the statistical analysis on the amplitudes of the peaks of the peripheral venous pressure frequency spectrum to determine an IV line functionality of the peripheral IV catheter in real time, wherein the IV line functionality of the peripheral IV catheter indicates IV infiltration when amplitude decreases greater than a second threshold are detected from the peaks of the peripheral venous pressure frequency spectrum.
In yet a further aspect of the present invention, a PIVA system includes: a peripheral IV device configured to acquire, from a vein of a living subject, peripheral venous signals; and a processing device communicatively connected to the peripheral IV device. The peripheral IV device includes: a peripheral IV catheter, configured to be inserted into the vein of the living subject; and a fluid controlling device in fluid communication with the peripheral IV catheter, configured to control fluid flow from a fluid source to the peripheral IV catheter. The processing device is configured to: receive the peripheral venous signals from the peripheral IV device; perform a spectral analysis on the peripheral venous signals to obtain a peripheral venous pressure frequency spectrum; and perform at least one of the following statistical analysis on amplitudes of peaks of the peripheral venous pressure frequency spectrum: an analysis to determine whether an intravascular volume status of the living subject in real time indicates hypovolemia when amplitude decreases greater than a first threshold are detected from the peaks of the peripheral venous pressure frequency spectrum; and an analysis to determine whether an IV line functionality of the peripheral IV catheter in real time indicates IV infiltration when amplitude decreases greater than a second threshold are detected from the peaks of the peripheral venous pressure frequency spectrum. In certain embodiments, when the IV line functionality of the peripheral IV catheter indicates IV infiltration, the processing device is capable of controlling the fluid controlling device to stop the fluid flow from the fluid source to the peripheral IV catheter.
In certain embodiments, the first threshold and the second threshold of the amplitudes of peaks of the peripheral venous frequency spectrum are different.
In certain embodiments, the value of the first threshold is greater than the value of the second threshold of the amplitudes of peaks of the peripheral venous frequency spectrum.
In certain embodiments, the system and method as described above may be used for:
In certain embodiments, detection of hypovolemia through the system and method as described above may be performed through the analysis of amplitude increases in the peaks with higher frequencies, such as F2, as well as the amplitude changes in F1.
These and other aspects of the present invention will become apparent from the following description of the preferred embodiments taken in conjunction with the following drawings, although variations and modifications thereof may be affected without departing from the spirit and scope of the novel concepts of the disclosure.
The accompanying drawings illustrate one or more embodiments of the invention and, together with the written description, serve to explain the principles of the invention. Wherever possible, the same reference numbers are used throughout the drawings to refer to the same or like elements of an embodiment.
The invention will now be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Like reference numerals refer to like elements throughout.
The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms may be highlighted, for example using italics and/or quotation marks. The use of highlighting has no influence on the scope and meaning of a term; the scope and meaning of a term are the same, in the same context, whether or not it is highlighted. It will be appreciated that the same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.
It will be understood that when an element is referred to as being “on” another element, it can be directly on the other element or intervening elements may be present there between. In contrast, when an element is referred to as being “directly on” another element, there are no intervening elements present. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items.
It will be understood that, although the terms first, second, third, etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the invention.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising”, or “includes” and/or “including” or “has” and/or “having” when used in this specification specify the presence of stated features, regions, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and/or groups thereof.
Furthermore, relative terms, such as “lower” or “bottom” and “upper” or “top”, may be used herein to describe one element's relationship to another element as illustrated in the Figures. It will be understood that relative terms are intended to encompass different orientations of the device in addition to the orientation depicted in the Figures. For example, if the device in one of the figures is turned over, elements described as being on the “lower” side of other elements would then be oriented on “upper” sides of the other elements. The exemplary term “lower” can, therefore, encompass both an orientation of “lower” and “upper”, depending on the particular orientation of the figure. Similarly, if the device in one of the figures is turned over, elements described as “below” or “beneath” other elements would then be oriented “above” the other elements. The exemplary terms “below” or “beneath” can, therefore, encompass both an orientation of above and below.
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
As used herein, “around”, “about”, “substantially” or “approximately” shall generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the term “around”, “about”, “substantially” or “approximately” can be inferred if not expressly stated.
As used herein, the terms “comprise” or “comprising”, “include” or “including”, “carry” or “carrying”, “has/have” or “having”, “contain” or “containing”, “involve” or “involving” and the like are to be understood to be open-ended, i.e., to mean including but not limited to.
As used herein, the term “hemodynamic” generally refers to blood movement, and “hemodynamic resuscitation” generally refers to increasing blood movement (or blood pressure) in a patient experiencing symptoms of compensated shock (e.g., based on a “hemodynamic score” or “resuscitation score”).
As used herein, the term “peripheral intravenous waveform analysis” or its abbreviation “PIVA” refers to an analysis of the peripheral venous waveforms measured from a vein of a living subject through a standard peripheral intravenous (IV) catheter.
As used herein, the term “hypovolemia” refers to a medical condition of decreased blood volume, and more specifically a decrease in volume of blood plasma. In certain embodiments, hypovolemia stems from loss of blood volume due to hemorrhage, dehydration or intravascular water loss.
As used herein, the term “hypervolemia” refers to a medical condition of fluid overload (i.e., having too much fluid) in the blood. In certain embodiments, hypervolemia stems from compromised regulatory mechanisms for sodium handling, such as congestive heart failure (CHF) or renal failure, or due to iatrogenic fluid administration.
As used herein, the term “infiltration” refers to a medical condition where IV fluid leaks into surrounding tissues. Generally, IV infiltration may be commonly caused by improper placement or displacement of the IV catheter.
The ideal hemodynamic monitoring system for guiding fluid therapy would predict patient volume status accurately with minimal risks. Unfortunately, existing dynamic systems and methods for assessing volume status, such as pulse pressure variation (PPV), stroke volume variation (SVV), and plethysmographic wave respiratory variation, may predict fluid responsiveness, but do not directly measure volume status, and they have not been proven to detect iatrogenic volume overload during resuscitation. These existing non-invasive dynamic monitoring systems, such as SVV and PPV, rely on intrathoracic effects on left ventricular stroke volume during mechanical ventilation. Furthermore, these techniques depend on heart-lung interactions during mechanical ventilation for detection of hypovolemia. This critical limitation renders the techniques ineffective in the spontaneously breathing patient.
In an effort to address the pitfalls associated with the existing central venous monitoring modalities, peripheral venous pressure (PVP) monitoring has been increasingly explored as an alternative for determining intravascular volume status. There is a good correlation between trends in absolute PVP and central venous pressure (CVP) measurements in critically ill patients. However, even trends of CVP, and therefore PVP, are not reliable indicators of volume status, resulting in a need to modify this approach. One such method, cuff-occlusion rate of rise of PVP (CORRP), has been shown to correlate with volume status in critically-ill patients, but is limited by operator-dependent, non-continuous measurements to assess volume status. Another method used peripheral venous waveform spectral analysis for continuous beat-to-beat monitoring of intravascular volume status to quantify changes associated with lower body negative pressure, a simulation of hemorrhage, in spontaneously breathing subjects. However, lower body negative pressure results in vasodilation and may not truly represent the physiological responses to hemorrhage. In other words, there is no existing non-invasive method of accurately assessing patient blood volume status in intrathoracic pressure changes without ventilation-induced or negative pressure. The current gold-standard measurement requires either echocardiography or a pulmonary artery catheter, and both of these measurements have wide variability in their accuracy.
Recently, Sileshi et al. reported that peripheral intravenous waveform analysis (PIVA) can detect early Stage 1 hemorrhage, during perioperative autologous blood donation in patients undergoing cardiac surgery. Moreover, this study demonstrated that PIVA was more sensitive to acute changes in circulating blood volume than standard vital signs and invasive pulmonary arterial monitoring.
Moreover, since not all wounded soldiers require endotracheal intubation and positive pressure ventilation, there is an acute need for accurate and sensitive volume status monitoring in wounded, spontaneously breathing soldiers. There is a need for a point of care monitor that detect small direct changes in volume status and warns of impending hemodynamic collapse in the combat casualty care setting.
On the other hand, patients with different injuries or diseases may require IV volume resuscitation and/or and IV pharmacologic administration.
In certain embodiments, IV tubing may be coupled with pressure sensors to measure the average line pressure of the IV tubing. However, average line pressure is not an efficient parameter for detecting IV infiltration prior to tissue damage.
Accordingly, aspects of the present invention relates to systems and methods of detecting early stage hemorrhage and/or IV infiltration or misplacement on a living subject, or monitoring intravascular placement of an IV catheter, using PIVA to assess blood volume status of the living subject, and applications of the same. The living subject may include human beings and/or other animals
In certain embodiments, the systems and methods may utilize a disposable IV tubing with independent or integrated venous pressure sensors, and durable dongle for wireless connectivity and pump interfacing. In certain embodiments, a proprietary spectral waveform analysis may be performed for confirming IV placement. The systems and methods may implement early stage hemorrhage and/or rapid infiltration detection.
In one aspect, the present invention relates to a PIVA system. In certain embodiments, the PIVA system includes: a peripheral IV device configured to acquire, from a vein of a living subject, peripheral venous signal, and a processing device communicatively connected to the peripheral IV device. The peripheral IV device includes a peripheral IV catheter, configured to be inserted into the vein of the living subject; and a fluid controlling device in fluid communication with the peripheral IV catheter, configured to control fluid flow from a fluid source to the peripheral IV catheter.
In certain embodiments, the processing device is configured to: receive the peripheral venous signals from the peripheral IV device; perform a spectral analysis on the peripheral venous signals to obtain a peripheral venous pressure frequency spectrum; and perform a statistical analysis on amplitudes of peaks of the peripheral venous pressure frequency spectrum to determine an intravascular volume status of the living subject in real time. The intravascular volume status of the living subject indicates hypovolemia when amplitude decreases greater than a first threshold are detected from the peaks of the peripheral venous pressure frequency spectrum. Further, the processing device is capable of performing the statistical analysis on the amplitudes of the peaks of the peripheral venous pressure frequency spectrum to determine an IV line functionality of the peripheral IV catheter in real time, wherein the IV line functionality of the peripheral IV catheter indicates IV infiltration when amplitude decreases greater than a second threshold are detected from the peaks of the peripheral venous pressure frequency spectrum. When the IV line functionality of the peripheral IV catheter indicates IV infiltration, the processing device is capable of controlling the fluid controlling device to stop the fluid flow from the fluid source to the peripheral IV catheter.
In certain embodiments, the processing device is configured to: receive the peripheral venous signals from the peripheral IV device; perform a spectral analysis on the peripheral venous signals to obtain a peripheral venous pressure frequency spectrum; and perform at least one of the following statistical analysis on amplitudes of peaks of the peripheral venous pressure frequency spectrum: an analysis to determine whether an intravascular volume status of the living subject in real time indicates hypovolemia when amplitude decreases greater than a first threshold are detected from the peaks of the peripheral venous pressure frequency spectrum; and an analysis to determine whether an IV line functionality of the peripheral IV catheter in real time indicates IV infiltration when amplitude decreases greater than a second threshold are detected from the peaks of the peripheral venous pressure frequency spectrum.
Another aspect of the present invention relates to a method for determining an intravascular volume status of a living subject and monitoring an intravenous (IV) line functionality of a peripheral IV device. The peripheral IV device includes: a peripheral IV catheter, configured to be inserted into a vein of the living subject; and a fluid controlling device in fluid communication with the peripheral IV catheter, configured to control fluid flow from a fluid source to the peripheral IV catheter. The method includes: acquiring, from the peripheral IV catheter, peripheral venous signals; performing, by a processing device communicatively connected to the peripheral IV device, a spectral analysis on the acquired peripheral venous signals to obtain a peripheral venous pressure frequency spectrum; performing, by the processing device, a statistical analysis on amplitudes of peaks of the peripheral venous pressure frequency spectrum to determine the intravascular volume status of the living subject and the IV line functionality of the peripheral IV device in real time; and when the IV line functionality of the peripheral IV device is determined to indicate IV infiltration, controlling, by the processing device, the fluid controlling device to stop the fluid flow from the fluid source to the peripheral IV catheter. The intravascular volume status of the living subject indicates hypovolemia when amplitude decreases greater than a first threshold are detected from the peaks of the peripheral venous pressure frequency spectrum.
In certain embodiments, the intravascular volume status of the living subject indicates hypervolemia when amplitude increases greater than a third threshold are detected from the peaks of the peripheral venous pressure frequency spectrum.
The peripheral IV device 310 is configured to acquire, from a vein of a living subject 330, peripheral venous signals. In certain embodiments, the living subject 330 may be a human being, or may be other animals. In one embodiment, the living subject 330 may be a human patient, and the patient may be awake and spontaneously breathing/moving, or may be induced with anesthesia such that the patient is not spontaneously moving. In one embodiment, the living subject may be a human patient who is given fluid through the peripheral IV device 310.
The processing device 320 is configured to: receive the peripheral venous signals from the peripheral IV device 310; perform a spectral process and analysis on the peripheral venous signal to obtain a peripheral venous pressure frequency spectrum; and perform a statistical analysis on amplitudes of peaks of the peripheral venous pressure frequency spectrum to determine the blood volume status of the living subject and/or an IV line functionality of the peripheral IV device 310 in real time. In certain embodiments, the processing device 320 may be a computing device, which may be a desktop computer, a laptop computer, a smartphone, a tablet device, or any other computing devices with processors to perform the processing functions. In certain embodiments, the processor may be associated with a circuit board of data acquisition and process. In one embodiment, the processing device 320 may further include a display device (not shown) in communication with the processor for displaying the processed fluid pressures, and the display device may include a graphic interface. In certain embodiments, the spectral analysis may be a spectral fast Fourier transform (FFT) analysis.
In certain embodiments, the PIVA system 300 further includes: a pump (not shown) connected to the living subject to perform liquid exchange to the living subject; and a pump controlling mechanism (not shown) communicatively connected to the processing device, configured to control the pump by intermittently pausing the pump or subtract the pump signal when the peripheral IV device acquires the peripheral venous signals, and restarting the pump when the peripheral IV device does not acquire the peripheral venous signals. In certain embodiments, the pump may be a dialysis pump, a cardiopulmonary bypass pump, an extracorporeal membrane oxygenation (ECMO), or an infusion pump. In this case, the processing device 320 is further configured to send a signal to the pump controlling mechanism to notify the pump controlling mechanism to control the pump.
Specifically, the steps S410 and S420 as shown in
In certain embodiments, the intravascular volume status of the living subject at the second time period indicates hypovolemia when amplitude decreases are detected greater than a first threshold from the baseline peaks {BN-1} to the peaks {PN-1}. In certain embodiments, the intravascular volume status of the living subject at the second time period indicates hypervolemia when amplitude increases greater than a second threshold are detected from the baseline peaks {BN-1} to the peaks {PN-1}. For example, if there is a significant decrease in the F1 amplitude of the second peak of the peripheral venous pressure frequency spectrum that reaches the first threshold, the processing device 320 will determine that hypovolemia (e.g., hemorrhage or intravascular water loss, etc.) has occurred in the living subject. On the other hand, if there is a significant increase in the F1 amplitude of the second peak of the peripheral venous pressure frequency spectrum that reaches the third threshold, the processing device 320 will determine that hypervolemia (e.g., congestive heart failure, renal failure, iatrogenic fluid administration, etc.) has occurred in the living subject. It should be noted that, in addition to the F1 amplitude of the second peak P1, the amplitude of other peaks, such as the first peak P0, the third peak P2, and any subsequent peaks, may also be used to determine hypovolemia or hypervolemia of the living subject.
In certain embodiments, the method is performed to the living subject during resuscitation of the living subject. In one embodiment, the intravascular volume status of the living subject at the second time period indicates a return of euvolemia from a hypovolemic state when the living subject is determined to be in the hypovolemic state at the first time period, and amplitude increases greater than a fourth threshold are detected from the baseline peaks {BN-1} to the peaks {PN-1}. In one embodiment, the intravascular volume status of the living subject at the second time period indicates over-resuscitation when the living subject is determined to be in an euvolemic state at the first time period, and amplitude increases greater than a fifth threshold are detected from the baseline peaks {BN-1} to the peaks {PN-1}.
In certain embodiments, the actual volume calculation may be performed based on a large logic table, with interpolation, that will be generated based on a population study and can be further fit to the specific patient in a chronic-use device. An example of the logic table is provided as follows.
Further, in certain embodiments, a regression model may be provided to calculate the volume status ratio. For example:
Volume Status Ratio=b0+b1·p1+b2·p2++bN·pN
where b0, b1, b2, . . . , bN are linear regression coefficients determined in a multivariate regression model for each independent parameter pi. In certain embodiments, the parameters may include:
1. Amplitudes (or powers) of each harmonic in the frequency domain
2. Noise floor amplitude
3. HR
4. Time domain amplitude of peripheral venous pressure
In certain embodiments, the method may be capable of detecting at least 6% of blood loss of the living subject.
Generally, peripheral venous pressure (PVP) is strongly correlated with central venous pressure (CVP), also known as mean venous pressure (MVP), which is the pressure of blood in the thoracic vena cava, near the right atrium of the heart.
FFT separates the signals into the contributing frequencies. The amplitudes of the contributing frequencies in the signals can then be plotted and evaluated.
In certain embodiments, the steps S410 and S420 as shown in
In certain embodiments, the IV line functionality of the peripheral IV catheter is determined to indicate IV infiltration when amplitude decreases greater than a second threshold are detected from the baseline peaks {BN−1} to the peaks {PN−1}. In certain embodiments, the first threshold (used for determining hypovolemia) and the second threshold (used for determining IV infiltration) of the amplitudes of peaks of the peripheral venous frequency spectrum are different. In one embodiment, the value of the first threshold is greater than the value of the second threshold.
In certain embodiments, the PIVA system 300 may be implemented by an instrumented IV catheter interfaced with a smart phone device for early hemorrhage detection and guided fluid therapy to improve survival in the casualty care setting. The device uses: (1) A ruggedized miniature pressure transducer integrated into an IV catheter, (2) real-time algorithm for early hemorrhage detection and guided goal-directed fluid resuscitation (3) wireless immediate data transfer for remote or centralized monitoring and intervention. In certain embodiments, the device may involve a portable, lightweight (<50 grams) sensor that attaches directly to a standard peripheral IV catheter interfaced to a Bluetooth radio for transmission to a Smartphone device. The form factor of the device will be comparable to a USB stick. The cost of the device may be USD <$25 making it feasible to integrate the device into every IV catheter used in casualty care and trauma settings. Further, the device may utilize immediate data transfer and storage to a secure database and mobile application for remote Damage Control Resuscitation and emergency telemedicine. In addition to immediate graphic display for field medics, the smart IV will have Bluetooth technology allowing data transfer to a Smart phone mobile application. Bidirectional data transfer and feedback from remote clinical practitioners provides emergency telemedicine assistance to field medics in the battlefield. Further, physiologically data can be uploaded to a server, providing an electronic medical record for all care providers throughout the resuscitation period. Such device may be potentially relevant in military use, as the military needs a robust point-of-care method for early hemorrhage detection in the wounded soldier. This device will be rugged, wireless, lightweight and portable with minimal, self-contained energy requirements, conducive to austere environments.
As described above, the PIVA system 300 includes the processing device 320, which serves as a controller device that is configured to receive the peripheral venous signals from the monitoring device of the peripheral IV device 310. The processing device 320 may then perform the Fourier transform on the peripheral venous signals of the time domain data to process the signal to obtain a spectrum. Once the fourier spectrum is generated, the second peak at the frequency F1 that correspond to the heart rate or another hemodynamic parameter's amplitude or power is measured and each resonant frequency of that hemodynamic parameter's amplitude or power is also measured. The amplitudes and/or powers are input into the algorithm that weights each resonant frequency and outputs a measurement of a hemodynamic parameter. Additional inputs may also be required, including but not limited to the following: age, weight, gender, and height, these variables may be input into the algorithm to determine a more accurate depiction of the patient's hemodynamic state. Based on the Fourier transform of the piezoelectric signal the processor is used to generate a resuscitation score based on the hemodynamic parameter.
The invention relates to methods for peripheral venous pressure analysis algorithm that uses spectral analysis to estimate intravascular volume status and/or IV infiltration, and its applications. In certain aspects, the invention recites, among other things:
In the following examples, the inventors have utilized the PIVA systems and corresponding methods in different models, including a porcine hemorrhage-resuscitation model, a controlled human hemorrhagic model, a human being model (n=6) for linear SSE analysis and a porcine model (n=8) for spectral analysis, to analyze and study dynamic volume changes and shifts in the peripheral venous waveforms. Some of the tests in the examples are performed in standardized settings in order to test the hypothesis that PIVA is more sensitive and specific than standard and invasive monitors for detecting and quantitating acute hemorrhage, as well as resuscitation to euvolemia and iatrogenic fluid overload.
Further, the accuracy and linearity of the PIVA estimation of blood volume has been evaluated as compared to absolute volume removal and administration. Some other tests in the examples are performed in standardized settings in order to test the hypothesis that the systems and methods are is more sensitive and specific than standard and invasive line pressure sensing of IV filtration.
In this example, a test has been performed using PIVA in a porcine hemorrhage-resuscitation model to study dynamic volume shifts in a standardized setting. Under an approved Institutional Animal Care and Use Committee protocol, 8 adult Yorkshire pigs, each weighing 45+/−0.8 kg, were monitored non-invasively with a noninvasive blood pressure cuff, 5-lead electrocardiogram, and pulse oximeter (SurgiVet, Norwell, Boston, Mass.). Each animal was induced with general anesthesia Telazol 2 mg, Ketamine 50 mg, and Xylazine 2 mg given via an ear vein. After intubation with a cuffed 5.0 ID endotracheal tube the pigs were ventilated with a volume controlled ventilator (Hallowell EMC, MA, USA) with a volume-controlled mode of 8 mL/kg tidal volume with a positive end-expiratory pressure of 5 cm H2O, I:E ratio 1:2, and a FiO2 1.0. Respiratory rate (16-22 breaths/minute) was titrated to maintain an end-tidal CO2 of 35-40 mmHg.
Anesthesia was maintained with 1% isoflurane (Primal Healthcare, Boston, Mass.). Surgical exposure of the femoral artery and vein was obtained. A 6 Fr catheter (Mila International, Erlanger, Ky.) was inserted directly into the femoral vein and sutured in place. A 20 g angiocatheter (Mila International, Erlanger, Ky.) was placed in the femoral artery for continuous blood pressure measurements. A 20 g peripheral IV (Smiths Medical, Dublin, Ohio) was inserted into the front extremity of each animal. Details of the test are provided as follows:
After induction of anesthesia, a 20 gauge peripheral intravenous (IV) catheter was inserted into an upper extremity vein and directly connected to a pressure transducer (ADInstruments, Colorado Springs, Colo.) via standard high-pressure tubing. The IV catheter was dedicated to obtaining venous waveforms and was not used for infusion of fluids or drug delivery during the test. Peripheral venous waveform tracings were recorded continuously throughout the procedure and analyzed on LabChart (ADInstruments, Colorado Springs, Colo.). Peripheral intravenous waveform data was captured at 1 kHz to allow adequate sampling to perform spectral analysis of the waveform data.
After induction of anesthesia, baseline measurements of the peripheral venous signal were obtained. Standard IV tubing was attached proximally to the femoral venous line and distally to a sterile collection bag, producing a closed system. Intravenous Heparin 10 units/kg was administered immediately prior to hemorrhage. Venous blood was removed via gravity in a stepwise fashion of 50 mL per minute over a 10-minute period. Vital signs including heart rate, arterial blood pressure, and peripheral venous waveforms were continuously recorded throughout the procedure. The procedure was terminated at 400 mL blood removal or mean arterial pressure (MAP)<40 mmHg.
Immediately following the hemorrhage protocol, the entire autologous blood was returned to the pig at a continuous rate of 50 mL/min over 10 minutes through the femoral venous catheter. Vital signs were continuously recorded throughout this process. Following return of the autologous blood, each pig was considered to be in an euvolemic state.
Following volume resuscitation to a euvolemic state, warm (40° C.) 500 mL Plasmalyte (Baxter International, Deerfield, Ill.) balanced crystalloid solution was administered through the femoral venous catheter over a 10-minute period. Continuous hemodynamic monitoring was performed as previously described.
The spectral fast Fourier transform (FFT) analysis of peripheral venous pressure was performed using an 8K sampling window with no window overlap. Data was recorded at a sampling rate of 1 kHz necessitating 8 seconds of continuous time-domain signal to perform the 8K-FFT spectral analysis. Following Fourier transformation, the amplitude of each frequency peak was calculated in LabChart. The peak amplitude associated with the heart rate was used to acquire F1 (the fundamental frequency) amplitude of the signal. Data was captured in triplicate for each point used in analysis.
All 8 pigs successfully underwent hemorrhage, resuscitation, and volume overload without complications. Conversion of the time domain signal into the frequency domain was performed to determine the amplitude of each of the fundamental frequency recorded during the experiment.
Taken together, these results show that changes in F1 amplitude is a more sensitive measure for hemorrhage and transfusion of blood than HR, MAP, or SI.
Taken together, these results show that changes in F1 amplitude is a more sensitive measure for hypervolemia than HR, MAP, or SI.
Further, HR, MAP, SI and F1 amplitude were measured during hemorrhage and fluid administration to the porcine volume status model.
The test results are in agreement with findings of Sileshi, et al. which demonstrated hemorrhage detection after approximately ˜6% estimated blood loss in a cardiac surgery population. The ROCs illustrate that PIVA had a significantly greater sensitivity and specificity for detecting hemorrhage compared to HR, MAP, and SI, as shown in
Further, the significant changes in the F1 amplitude has been demonstrated not only during hemorrhage, but also a return of the F1 amplitude to baseline with transfusion of a matched quantity of autologous blood during resuscitation, as shown in
In addition, the test simulated iatroagenic volume overload with balanced crystalloid, an inadvertent, yet common event during acute resuscitation. PIVA detected iatrogenic volume overload following only 200 mL (5.9% estimated total blood volume) of crystalloid administration beyond the euvolemic state, as shown in
In this example, a test has been performed using PIVA in a controlled human hemorrhagic model to analyze dynamic changes in the peripheral venous waveforms to assess volume status. The test was approved by the Vanderbilt University Institutional Review Board (IRB), and informed written consent was obtained preoperatively in select patients scheduled for elective cardiac surgery. Any patient undergoing elective cardiac surgery met the inclusion criteria. Patients with a history of moderate or severe right ventricular dysfunction, severe anemia (hemoglobin <8 g/dl) or patients who presented with arrhythmias or hemodynamic instability were excluded. A total of 12 patients were studied.
All patients were induced with an opiate and propofol and received non-depolarizing neuromuscular blockade so that there was no evidence of spontaneous respirations. All patients were intubated with an endotracheal tube and received mechanical ventilation with tidal volumes of 7 to 9 mL/kg, positive end-expiratory pressure of 4 mmHg, and a fraction of inspired oxygen of 1.0. Patients were maintained with 0.8 to 1 MAC of isoflurane. In five patients, mechanical ventilation was halted for brief intervals (<10 seconds) for reasons unrelated to this protocol, such as surgeon's request. This opportunity was used to evaluate the effects of mechanical ventilation on the peripheral venous signal. Comparisons have been conducted between the peripheral venous waveform tracings during breath holding and immediately after mechanical ventilation resumed. The ventilator circuit remained connected to the endotracheal tube throughout this period.
All patients were monitored with standard non-invasive monitors including 5-lead electrocardiogram, non-invasive blood pressure cuff, and pulse oximetry. Prior to induction of anesthesia, a 20 g arterial catheter (Arrow International, Reading, Pa.) was inserted into the radial artery. Following induction of anesthesia, all patients received a right 9 Fr central catheter (Cook Critical Care, Bloomington, Ind.), and a pulmonary artery catheter (Edwards Lifesciences, Irvine, Calif.). To minimize complications, the pulmonary artery catheter was not placed in the wedge position. The pulmonary artery diastolic pressure was used as a surrogate for pulmonary artery occlusion pressure. All pressure transducers were placed at the level of the right atrium and zeroed to atmospheric pressure.
After induction of anesthesia, an 18 or 16 gauge peripheral intravenous catheter (IV) was inserted into an upper extremity vein and directly connected to a pressure transducer (ADInstruments, Colorado Springs, Colo.) via standard high-pressure tubing. The IV catheter was dedicated to obtaining venous waveforms and was not used for infusion of fluids or drug delivery during the study. Peripheral venous waveform tracings were recorded continuously throughout the procedure and analyzed on LabChart (ADInstruments, Colorado Springs, Colo.). Peripheral intravenous waveform data was captured at 1 kHz for adequate sampling to perform spectral analysis on the data.
Following induction of anesthesia and central line placement, the hemorrhage protocol was initiated. Standard IV tubing was attached proximally to the central venous catheter and distally to a citrate bag, producing a closed system. Venous blood was removed from the central venous catheter via gravity over a 10-minute period. Up to 500 ml or 10% of blood volume was removed from each patient. All were successfully completed within 10 minutes without protocol interruption. Vital signs including heart rate, arterial blood pressure, central venous pressure, pulmonary artery pressure, and PVA were continuously recorded throughout the procedure.
The spectral FFT analysis of peripheral venous pressure was performed using an 8K sampling window with no window overlap. Since data was recorded at a sampling rate of 1 kHz, 8 seconds of continuous time-domain signal was required to perform the 8K-FFT spectral analysis. Once the data is transformed into the frequency domain the amplitude of each frequency is calculated in LabChart. The lowest frequency peak is associated with the patient's respiratory rate (F0) followed by the patient's heart rate (F1). Data was captured in triplicate for each point used in analysis. Peripheral waveform is sensitive to patient movement and electrocautery signal. To minimize signal noise, data was captured during periods of minimal patient movement and no electrocautery use.
Data for physiologic measurements and their associated blood loss was analyzed using a one-way ANOVA analysis with a post-test of Tukey's multiple comparison with paired analysis. Data was also entered as baseline measurements and blood loss of 500 mL in patients into MedCalc to determine a pairwise comparison of ROC curves. Area under the curve, standard error, and a 95% confidence interval for each data set was acquired. ROC curves were plotted on the same graph to easily identify differences between the sensitivity and specificity of physiologic parameters. To determine the effect of positive pressure ventilation, F0 and F1 values were compared using a paired student's t-test with values of P<0.05 being considered statistically significant. Statistical analysis was performed using GraphPad Prism and MedCalc.
In order to demonstrate independence of F1 signal from effects of positive pressure ventilation, the F1 and F0 amplitudes are recorded with and without mechanical ventilation.
Based on the test results, PIVA is able to detect as little as 6% blood volume loss, and the signal was independent of mechanical ventilation. This amount of blood loss is well within the definition of Stage I or subclinical hemorrhage. In contrast, heart rate, MAP, CVP, and dPAP were poor predictors of early stage hemorrhage, a finding that is consistent with previously published studies.
As shown in the previous examples, the inventors have found that venous waveform analysis overcomes many critical barriers associated with arterial-based monitoring. The inventors discovered and confirmed with tests that PIVA obtained via a pressure transducer in a standard intravenous catheter detects hemorrhage in humans and porcine models.
The inventors have conducted additional tests on PIVA detections of blood loss in pigs: In the test, the PIVA device is applied to intubated and sedated pigs (n=4). All pigs were monitored in real time with intra-arterial blood pressure, heart rate, pulse oximeter, and a 5-lead electrocardiogram. The PIVA device was interfaced with LabChart (ADInstruments, Colorado Springs, Colo., USA) software for continuous, real-time data collection. Up to 15% of blood volume was incrementally removed during a 20-minute period.
Fluid overload is responsible for increased mortality in injured patients. However, standard vital sign monitoring fails to detect thresholds for euvolemia and hypervolemia, contributing to unnecessary and potentially harmful over-resuscitation. We studied a porcine animal resuscitation model to determine intravascular volume status during fluid administration. Animals were considered euvolemic upon presentation based on weight and hemodynamic stability. After completion of the hemorrhagic stage, pigs (n=8) underwent fluid resuscitation. Autologous blood was re-administered followed by an additional 10 mL/kg of balanced crystalloid solution over 20 minutes.
In this example, IV infiltration tests have been performed in a human being model (n=6) for linear SSE analysis and a porcine model (n=8) for spectral analysis, to analyze and study the sensitivity and specificity of shifts in the peripheral venous waveforms. The tests in the examples are performed in standardized settings in order to test the hypothesis that the systems and methods are is more sensitive and specific than standard and invasive line pressure sensing of IV infiltration.
In certain embodiment, the data undergoes the Fourier transform and a physiologic signal associated with the same frequency (e.g. heart rate) is used to determine proper line placement.
In summary, the ability of PIVA to detect subclinical hemorrhage and/or IV infiltration and goal-directed fluid therapy offers significant advantages over standard and possibly dynamic monitoring modalities. Further, PIVA is minimally invasive, requires minimal training, and it averts infectious and major vascular complications associated with central venous and pulmonary artery catheters. The PIVA signal is independent of effects of mechanical ventilation and may be useful in in patients receiving lung protective ventilator strategies and possibly in spontaneously breathing individuals. PIVA has the potential to provide a low-cost, minimally invasive method for detecting and quantitating subclinical hemorrhage. As shown in the examples, PIVA is more sensitive than standard and invasive monitoring for detecting subclinical hemorrhage, and may provide a powerful alternative to central venous catheterization. Further, the method is independent of effects of mechanical ventilation, a potential advancement for monitoring spontaneously breathing patients.
The foregoing description of the exemplary embodiments of the invention has been presented only for the purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to explain the principles of the invention and their practical application so as to enable others skilled in the art to utilize the invention and various embodiments and with various modifications as are suited to the particular use contemplated. Alternative embodiments will become apparent to those skilled in the art to which the present invention pertains without departing from its spirit and scope. Accordingly, the scope of the present invention is defined by the appended claims rather than the foregoing description and the exemplary embodiments described therein.
This application is a continuation application of, and claims benefit of U.S. patent application Ser. No. 16/740,888, filed Jan. 13, 2020, now pending, which itself is a continuation application of U.S. patent application Ser. No. 15/547,935, filed Aug. 1, 2017, now issued as U.S. Pat. No. 10,531,799, which is a national stage entry of PCT Application Serial No. PCT/US2016/016420, filed Feb. 3, 2016, which claims priority to and the benefit of U.S. Provisional Patent Application Ser. No. 62/111,337, filed Feb. 3, 2015 and is a continuation-in-part of U.S. patent application Ser. No. 14/853,504, filed Sep. 14, 2015, which claims priority to and the benefit of U.S. Provisional Patent Application Ser. No. 62/049,829, filed Sep. 12, 2014. All the above disclosures are incorporated herein in their entireties by reference. This application is also a continuation-in-part of U.S. patent application Ser. No. 14/853,504, filed Sep. 14, 2015, which itself claims priority to and the benefit of U.S. Provisional Patent Application Ser. No. 62/049,829, filed Sep. 12, 2014. All the above disclosures are incorporated herein in their entireties by reference. Some references, which may include patents, patent applications and various publications, are cited and discussed in the description of this invention. The citation and/or discussion of such references is provided merely to clarify the description of the present invention and is not an admission that any such reference is “prior art” to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entireties and to the same extent as if each reference was individually incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| 62111337 | Feb 2015 | US | |
| 62049829 | Sep 2014 | US | |
| 62049829 | Sep 2014 | US |
| Number | Date | Country | |
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| Parent | 16740888 | Jan 2020 | US |
| Child | 17315651 | US | |
| Parent | 15547935 | Aug 2017 | US |
| Child | 16740888 | US |
| Number | Date | Country | |
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| Parent | 14853504 | Sep 2015 | US |
| Child | 15547935 | US | |
| Parent | 14853504 | Sep 2015 | US |
| Child | 14853504 | US |
