Abstract:
Inhalant anesthetics are developed with a number of properties including rapid onset and recovery, controllability, and, ideally, a broad safety profile. The efficacy of these agents is measured by their ability to create anesthesia within the framework of the other desirable properties. The instant invention focuses on the dosage level where analgesia occurs but amnesia or lack of consciousness does not. In addition to identifying the dosage level where pain is sharply reduced or eliminated but awareness remains, a delivery system for safe and effective delivery of the agent is described.

Description:
CROSS REFERENCE TO A RELATED APPLICATION  
       [0001]    Applicants hereby claim priority based on U.S. Provisional Patent Application No. 60/330,063, filed Oct. 17, 2001 entitled “Drug Delivery System for Conscious Sedation” which is incorporated herein by reference. 
     
    
     
       FIELD OF THE INVENTION  
         [0002]    This invention relates to the field of analgesia and conscious sedation. More particularly, this invention provides an apparatus and method for the delivery of halogenated ethers for producing analgesia in a patient.  
         DISCUSSION OF RELATED ART  
         [0003]    Since the mid-1800&#39;s conscious sedation/analgesia has been used in hospital and pre-hospital settings to relieve pain. Nitrous oxide (N2O) has been the primary inhalant agent in this regard. Sedative hypnotics such as diazepam and midazolam have been used as alternatives as have any number of barbitutes, opiods and agonist/antagonist agents.  
           [0004]    Dentistry and oral surgery were the first applications of nitrous oxide conscious sedation and gained wide-spread acceptance following successful use on Queen Victoria. Subsequently, the use of conscious sedation spread throughout the hospital, to emergency rooms, in ambulances, and in other doctor offices.  
           [0005]    Conscious sedation is a pain-blocking technique that allows a patient to remain partially alert during an invasive procedure. Analgesia is provided but, unlike anesthesia, the patient maintains awareness and recall. Specifically, the method is unique because patients do not perceive pain, but preserve their protective reflexes, maintain airways independently, and arouse in response to stimuli. Thus the risks of reduced or suppressed respiration associated with anesthesia are mitigated.  
           [0006]    There are many benefits associated with conscious sedation. In particular, conscious sedation reduces anxiety in patients, particularly children. Accordingly, medical procedures are easier for the patient and the health care provider, as conscious sedation reduces patient tension and resistance to treatment. Furthermore, the technique has the potential for expansive applications. Studies have shown success with patient controlled analgesia.  
           [0007]    The inhaled halogenated ethers offer a number of advantages in critical categories versus nitrous oxide conscious sedation or conscious sedation employing the sedative hypnotics. An example of some of the comparison with these agents is shown in Table 1.  
                                     TABLE 1                           Sedative Hypnotics                Halo-                       genated   Nitrous               Features   Ethers   Oxide   IV Diazepam   IV Midazolam               Onset   Rapid   Rapid   Moderate   Moderate       Safety Profile   High   Teratogenic   Moderate   Moderate               &amp; Blood               Disorders       Delivered with   Yes   No   Optional   Optional       High O 2         Concentration       Abuse   No   Recre-   Controlled   Controlled       Potential       ational   Substance   Substance       Ease of Use   Yes   Yes   Reversal Agent   Reversal Agent       &amp; Reversal           Required   Required       Predictable   Yes   Yes   Reasonably   Reasonably       Rapid   Yes   Yes   Long Half-Life   Moderate       Recovery to           Rebound   Half-Life       Street           Possible   Rebound       Ready               Possible                  
 
           [0008]    The combination of these features makes the halogenated ethers attractive candidates for conscious sedation. However, there is also a need for a safe, accurate and cost effective delivery system.  
           [0009]    The use of nitrous oxide based conscious sedation has declined in recent years principally reflecting the issues with the safety profile of the gas including those items listed above, but also because of its interference with methionine synthesis in prolonged exposure. These factors are particularly relevant to female health care professionals of childbearing age who face increased risk of spontaneous abortion due to nitrous oxide&#39;s teratogenetic profile.  
           [0010]    N 2 O is relatively impotent. As discussed in the description of the invention below, this impotence requires that limits are placed on the inspired percentage of N 2 O to insure patients receive sufficient oxygen. The concentration of oxygen in the atmosphere approximates 21%. As a result, most international regulatory agencies, including the United States Food and Drug Administration (“FDA”) established oxygen delivery guidelines to avoid hypoxia. The most common ratio is 70% N 2 O/30% oxygen, although some delivery systems maintain 50% oxygen. At a 70% mixture of N 2 O, conscious sedation occurs in most patients. The 70% N 2 O/30% oxygen mixture, on a sustained basis at the delivery level has a Minimum Alveolar Content (“MAC”) of 0.636 MAC.  
           [0011]    Six inhaled ethers are in use today: halothane, methoxyflurane, enflurane, isoflurane, sevoflurane and desflurane. (Terrell, then of Airco, Inc., synthesized enflurane, isoflurane and desflurane.) These compounds were developed focusing on being non-flammable, non-addictive, potent, having rapid induction properties and cardiovascular stability. Traditionally these products have been packaged in 100 ml and 250 ml brown glass bottles and vaporized using an agent specific, temperature compensated system.  
           [0012]    These drugs were developed for anesthesia. None of the inhaled ethers was developed as an inhalant analgesic. This reflected industry perceptions that either there was no need for an inhalant analgesic or there was the absence of cost-effective specialized equipment to administer these agents as analgesics. The equipment developed for anesthesia use in hospital settings was both sophisticated and expensive, frequently costing over $100,000. The combination of these factors virtually eliminated the ability to use these drugs as conscious sedation agents, particularly in the pre-hospital setting.  
         SUMMARY OF THE INVENTION  
         [0013]    Inhalant anesthetics are developed with a number of properties including rapid onset and recovery, controllability, and, ideally, a broad safety profile. The efficacy of these agents is measured by their ability to create anesthesia (analgesia, amnesia, and loss of consciousness) within the framework of the other desirable properties. The instant invention focuses on the dosage level where analgesia occurs but amnesia or lack of consciousness does not. In addition to identifying the dosage level where pain is sharply reduced or eliminated but awareness remains, a delivery system for safe and effective delivery of the agent is described. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0014]    [0014]FIG. 1 is a block diagram showing an embodiment of the invention.  
         [0015]    [0015]FIG. 2 is a diagrammatic perspective view of another embodiment of the invention.  
         [0016]    [0016]FIG. 3 is a diagrammatic perspective view similar to FIG. 2 but rotated about 180°. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0017]    Modern inhalation agents are halogenated ethers. They are generally characterized by a specific gravity between 1.0 and 2.0, low molecular weights (165.0-200.0), a low boiling point (22° C. to 104° C.), and significant potency—0.16%-7.8% of an agent on oxygen will put 99% of adults into anesthesia. These particular variables are important in the characterization of this invention as the drugs are converted from liquid to gas and delivered with a carrier gas—usually oxygen but sometimes a combination of oxygen and another gas or gases including oxygen, nitrous oxide and/or air.  
         [0018]    However, the agents vary in many important respects. Some agents including methoxyflurane, halothane and sevoflurane are known to react to metals. To some extent these same agents decompose in the presence of “soda lime” (calcium hydroxide) and/or UV light. To a greater or lesser extent, all halogenated agents are solvents. A delivery system for conscious sedation must be compatible with the agent in use.  
       EXAMPLE I  
       [0019]    The potency of anesthetic agents is measured by the minimum alveolar concentration of an anesthetic producing immobility in 50% of patients, defined as 39 year old males, undergoing surgical incision (“MAC”). The MAC of potent inhaled agents varies significantly. The MAC of nitrous oxide, the leading inhalant conscious sedation drug, can only be determined under unusual conditions of temperature and pressure, such as a hyper baric chamber, when additional dosages can be provided without creating hypoxia. Research suggests the MAC of nitrous oxide to be 110%. Thus, to create anesthesia, most patients would suffocate. Conversely, the MAC of methoxyflurane, an early-halogenated ether is only 0.16%. In present inhalant conscious sedation systems, nitrous oxide is delivered in conjunction with a minimum of 30% oxygen to insure the patient maintains a sufficient level of oxygen. In the United States, the Food and Drug Administration (“FDA”) has set 70% nitrous oxide as the limit for delivery in a conscious sedation unit. For this description a MAC equivalent of 70% nitrous oxide will be used for comparison with other inhalants, as shown in Table 2.  
                               TABLE 2                               Implied   MAC           Drug   MAC*   CS Level   Equivalent   Inhaled Oxygen                   Nitrous Oxide   110.00%   70.00%   .636   30.00%       Existing       Inhalation       Drugs       Methoxyflurane    0.16%    0.11%       99.89%       Halothane    0.75%    0.48%       99.52%       Isoflurane    1.15%    0.73%       99.27%       Enflurane    1.68%    1.07%       98.93%       Sevoflurane    2.00%    1.27%       98.73%       Desflurane    6.00%    3.82%       96.18%                          
 
         [0020]    For patients who would benefit from higher levels of oxygen delivery including, but not limited to, those with Coronary Artery Disease (CAD), replacement of nitrous oxide with an inhalant analgesia could provide improvement in myocardial oxygenation.  
       EXAMPLE II  
       [0021]    To deliver a concentration of the relevant agent that creates analgesia but not loss of awareness (either amnesia or loss of consciousness) requires a finely calibrated instrument through which the agent can flow with very minimal risk of overdose or delivery of hypoxic mixture (FIG. 1.) To be practical in the outpatient setting the device must be cost-effective, preferably costing less than anesthesia machines which presently cost $100,000 or more. Compared to the sedative hypnotics, barbitutes, opoids and agonist/antagonists that can also be used of sedation, the invention offers more rapid onset and recovery and less risk of abuse potential. The invention therefore comprises an oxygen delivery mechanism, either an O 2  cylinder(s) and/or manifold system to oxygen storage (“O 2  source”)  16  and a reservoir for the analgesia agent  12 , for example but not limited to an agent compatible cylinder; a heating element  14  attached to the analgesia reservoir  12 , for example but not limited to a heating plate, linked to an ambient temperature sensor to allow compensation for environmental temperature and pressure. Heating of the analgesia reservoir  12  by the heating element  14  allows control of the pressure of the agent in the reservoir such that the flow of the agent can be properly regulated despite changing ambient temperatures. The reservoir system comprises a mated index system  10  to insure that only the agent specified can be filled into the reservoir and, once filled, can only be mated to a delivery system specific to that agent. Oxygen from the O 2  source  16  flows through a delivery manifold system  22  including a sensitive pressure regulator  18  to a flow meter  20 , either analog or electronic, where it is mixed in strict proportions with the agent from the reservoir  12  and will accurately meter the dosage of the agent to +/−0.1% of gas flow or less. While the agent could be routed to the flow meter  20  directly, it may be also be arranged to flow through the delivery manifold  22  to regulate flow and insure that safety devices including but not limited to an automatic agent shutoff system if oxygen flow is shutoff or determined to be insufficient. An oxygen flush system  24  allows the practitioner to rapidly fill a patient&#39;s lungs and force exhalation of the residual agent. The system is arranged so that when the O 2  flush  24  is triggered the flow of analgesic is automatically ceased because the O 2  flush  24  is linked to the analgesia reservoir  12  by a three-way valve  25  such that when the O 2  flush  24  is on the analgesic  12  is off, and vice versa. The mixing head and/or flow meter system allows the user to regulate gas flow and agent concentration up to the conscious sedation limits established by the appropriate regulatory authority, and is sufficiently accurate in calibration to allow agent flow to approach the desired CS levels. In addition, the controlled heating element  14  and the flow meter  20  can be operated in a co-operative relationship to regulate the flow of the analgesic agent.  
         [0022]    As shown in FIGS. 2 and 3, an embodiment of the invention is a stand alone doctor&#39;s office unit. FIG. 2 shows a heater  14 ; mixer head  28 ; an oxygen pressure control  42 ; a vapor pressure control  44 ; an oxygen flush control  46 ; a nasal cannula out port  48 ; an inhaler out port  50 ; an oxygen pressure gauge  52 ; a vapor pressure gauge  54 ; an optional monitor  56 ; a flow rate control  58 ; an anesthetic concentration control  60 ; a select nasal/off/inhaler switch  62 ; and an on/off control  64 .  
         [0023]    [0023]FIG. 3 shows an oxygen source  10 ; an anesthetic source  12 ; a heater  14 ; a mixer head  28 ; electric receptacles  30 ; an optional air cylinder  32 ; and a power cord  40 . These features may be coupled with others including but not limited to the ability to modify the unit to be portable for emergency or military use; the ability to modify the unit for patient controlled analgesia (“PCA”); attaching a scavenging system for recovering exhaled agent and removing it from the environment; incorporating or allowing the unit to be compatible with physiologic monitoring including but not limited to oximetry, EKG, blood pressure, carbon dioxide monitoring and depth of consciousness monitors; the ability in one or more configurations to make the device compatible with diagnostic imaging devices including but not limited to nuclear magnetic resonance devices (MRI&#39;s) to allow analgesic delivery to patients requiring sedation or pain relief during MRI imaging.  
         [0024]    Clinical utilization of conscious sedation system is possible in a wide ranging number of procedures including but not limited to dental and oral surgery procedures, burn debridment, pain relief in emergency and trauma situations, administration in the intensive care, cardiac care or critical care units, in examination or work on the extremities including podiatric procedures, labor and delivery, to reduce anxiety in individuals with fear of needle insertion, and where prolonged immobilization would be difficult without the delivery of a sedation agent.  
         [0025]    Additionally, the invention has the following attributes. The invention increases oxygenation of blood, an important feature for individuals with poor myocardial or cerebral oxygenation. The invention increases occupational safety when analgesics described herein are substituted for nitrous oxide, an important feature for women of child-bearing age. The invention can reduce claustrophobia-associated anxiety and relieve pain in patients facing prolonged periods of inactivity, such as during nuclear magnetic resonance imaging (MRI) when used with an MR-safe (1.5 tesla) version of the delivery system. Similarly, the invention may be used for sedation in Intensive Care Units (ICU), Critical Care Units (CCU), or during cardiac catheterization, implantable defibrillator or pacemaker adjustments, and in general pain relief. The device may be provided in alternative configurations, such as with a stand or method for holding patient monitors, including integration of the monitors with the system. Additionally, the device may be provided with a regulator system that senses the depth of a patient&#39;s inhalation to allow safe patient controlled analgesia administration.  
         [0026]    Although embodiments of the invention have been described herein, the invention is not limited to such embodiments. The claims that follow are directed to the invention, and are intended to describe the invention, but their literal language is not intended to limit the scope of the invention.