In a number of scenarios, it is possible to safely infuse subjects with pharmaceutically active agents or fluids. In other scenarios, for example where a subject is to be infused with an opioid, there remains substantial danger to the subject, unless they are closely monitored, and, even then, in the absence of the safety features provided by the present device, system and method, substantial risk remains. The present invention, therefore, provides a solution to this long-felt need.
Conventional monitoring for respiratory depression in the hospital setting involves monitoring end tidal carbon-dioxide (ETCO2). However, ETCO2 is impractical in many scenarios. For example, it is difficult to measure in ambulatory patients (non-intubated patients). It is also costly, and the relevant equipment is cumbersome. The ability to directly monitor the pharmacodynamic (PD) effects of all of the factors that may contribute to hypopnea and/or apnea is far more valuable, for example, than knowing a single physiologic measurement, such as the ETCO2. Knowing the combined effects of CO2, hypoxemia, opioids, other drugs, and physiologic state of a patient would provide much more valuable information for the patient's safety. Trending of various parameters would also be highly valuable, not only for closed-loop systems, but also for improved monitoring of patients in a hospital setting.
The present inventors have identified a number of existing technologies which may be adapted, as disclosed herein below in the detailed disclosure of the invention, for the particular purposes to be achieved by practice of the present invention. Thus, references to such technologies herein, and the documents in which those technologies are described, are to be considered as having been fully set forth.
For example, pending published US patent application, US2006/0241506 (METHOD AND APPARATUS FOR DIAGNOSING RESPIRATORY DISORDERS AND DETERMINING THE DEGREE OF EXACERBATIONS), hereafter “the '506 publication”, involves the identification of peaks and troughs in plethysmograph signals, preferably acquired from a central site location of a subject, such as the nasal ala(e), identifying midpoints or minima between peaks and troughs, and using an interpolated line to represent venous impedance, permits extracting venous impedance and capacitance to thereby obtain an arterial component signal, thereby facilitating detection of an air obstruction event (such as apnea). As disclosed further herein below, such a system may be integrated into the present system, method, and device for enhanced safety in providing certain types of treatment or therapy in particular contexts. In particular, for example, in providing opioid therapy via a closed loop system, integration of such technology into an infusion device of this invention provides enhanced safety controls.
Likewise, with respect to published US patent application US2010/0192952, herein incorporated by reference, the present invention disclosure provides significant new applications and enhancements to the devices and methods disclosed therein. US2010/0192952 discloses certain pulse oximeter/plethysmography probes designed for securement to the nose, in a stand-alone form or incorporated into a mask of an air pilot or fire-fighter, pulse oximeter/plethysmography probes designed for securement to the pre-auricular portion of the a subject's ear, to the ear canal of a subject's ear, to the post-auricular portion of the subject's ear, or to the cheek of a subject's face. All of these designs are incorporated by reference into this disclosure, with the key modifications of these probes as described herein below, and the key modifications to the methods and systems disclosed herein which facilitate the safe, effective and efficient open- or closed-loop delivery of appropriate medications to the subject, dependent on the analysis of PD and/or PK signals obtained from the subject in either civilian or military contexts. The modifications and enhancement disclosed herein are likewise applicable to the context's disclosed in the US2010/0192952 publication, i.e. to prevent Gravity-induced Loss of Consciousness (GLOC) or Almost Loss of Consciousness (ALOC), as well as, for example, in the context of the fire-fighter. The key enhancements disclosed herein for this purpose include either an integrated or separately housed infusion system as well as enhancements achieved by coupling PPG signal acquisition and processing to nasal pressure signal acquisition and processing. In the contexts of GLOC and ALOC, for example, the present invention provides the option not only of altering the G-force induced loss or almost loss of consciousness, by setting off an alarm or interfacing with an aircraft's onboard computer, but to also, or instead, provide the option pharmacologic intervention, e.g. by detection of GLOC or ALOC and infusing the subject with an appropriate dose, for example, of glucose, epinephrine, oxygen or the like, or combinations thereof, calculated to avert the potentially catastrophic sequelae of a loss of consciousness in these circumstances.
Similarly, the technology described in Diab U.S. Pat. No. 6,157,850 (hereafter the '850 patent) provides, in particular with respect to blood oximetry measurements, methods, systems, algorithms and apparatuses to extract meaningful physiological information. Such a system may be integrated into the present method, device, system, to enhance safety by providing relevant pharmacodynamic (PD), pharmacokinetic (PK), or both PD and PK guided infusion in particular therapeutic contexts.
U.S. Pat. No. 7,569,030 and related Medtronic MiniMed patents (see, e.g. U.S. Pat. No. 6,827,702, and U.S. Pat. No. 6,740,972) describes a system for delivery of insulin for control of physiological glucose concentration. In these patents, however, there is very little disclosure about the “sensing device for sensing a biological state” element even for a closed loop system for delivery of insulin. The only sensing device identified is one for measuring glucose concentration. The main thrust of these patents is a system for setting safety limits for the amount of insulin provided by an infusion pump, and the ability for the user to over-ride certain limits to simulate, for example, the body's “leading insulin secretion reflex”. Other over-rides, to address medications or activity states (sleep, stress, etc), forms a central part of the disclosure. Methods for calculating delivery rates of an infusion formulation of insulin in response to a sensed glucose concentration are disclosed.
The need for dynamic modelling to control opioid administration has been recognized. See, for example, Mitsis et al., J Appl Physiol. 2009 April; 106(4):1038-49, “The effect of remifentanil on respiratory variability, evaluated with dynamic modelling”, (hereafter, “Mitsis et al.) which noted that opioid drugs disrupt signalling in the brain stem respiratory network affecting respiratory rhythm. Mitsis et al., evaluated the influence of a steady-state infusion of a model opioid, remifentanil, on respiratory variability during spontaneous respiration using dynamic linear and nonlinear models to examine the effects of remifentanil on both directions of the ventilatory loop, i.e., on the influence of natural variations in end-tidal carbon dioxide PETCO2 on ventilatory variability, (which was assessed by tidal volume (VT) and breath-to-breath ventilation i.e., the ratio of tidal volume over total breath time VT/Ttot), and vice versa. Breath-by-breath recordings of expired CO2 and respiration were made during a target-controlled infusion of remifentanil for 15 min at estimated effect site (i.e., brain tissue) concentrations of 0, 0.7, 1.1, and 1.5 ng/ml, respectively. They found that Remifentanil caused a profound increase in the duration of expiration. The obtained models revealed a decrease in the strength of the dynamic effect of PETCO2 variability on VT (the “controller” part of the ventilatory loop) and a more pronounced increase in the effect of VT variability on PETCO2 (the “plant” part of the loop). Nonlinear models explained these dynamic interrelationships better than linear models. The described approach allows detailed investigation of drug effects in the resting state at the systems level using noninvasive and minimally perturbing experimental protocols, which can closely represent real-life clinical situations.
By contrast, the present invention involves using physiological signals, software algorithms and infusion devices (e.g. with a subcutaneous catheter, implanted device and, in preferred embodiments, intranasal delivery, e.g. delivery to the mucosa of the nasal septum, particularly at Kiesselbach's plexus [also known as “Little's area”] and/or the nasal mucosa of the turbinates for the safe delivery of drugs which could potentially cause hypopnea, apnea and death if given in excess quantities. Since no single dose is appropriate for all individuals, and due to other medications and/or underlying clinical conditions, dosing without physiologic monitoring as disclosed herein, is unsafe. Furthermore, in the particular context of military operations, the present invention provides a system, method and apparatus, herein referred to by the acronym “WARCARE™”, (Warfighter Autonomous or Remotely Controlled Advanced Resuscitation Ensemble), in which operatives in combat situations are able to receive appropriate pharmacologic intervention at a much earlier stage than has previously been possible. By coupling the PD, PK or PD+PK measurement sensors and signals of the present invention with the processor of this invention, and which then controls delivery of appropriate fluids and/or drugs to the combatant, morbidity and mortality and potentially Post-traumatic Stress Disorder (PTSD) is substantially reduced.
In addition, by incorporating WARCARE into the existing global positioning system, GPS) carried by the warfighter, the present invention will allow the military to locate, triage, monitor, and optimally treat injured warfighters with drugs and/or fluids, either locally (e.g., Level 1 military care) or remotely (e.g., rescue helicopters, and/or Levels 2 through 5 military care, etc.).