DOSIMETRIC THERAPEUTIC GAS DELIVERY METHOD WITH FEED BACK CONTROL FOR RAPID DOSIMETRY ADJUSTMENT AND OPTIMIZATION

Abstract

The disclosure describes a technique for monitoring patient utilization of inhaled Nitric Oxide as well as waste exhaust of Nitric Oxide in gases exhaled from patient lungs. By monitoring the real dose provided to a patient, actual compliance with therapeutic target doses may be monitored to improve patient safety and therapeutic benefit from inhaled Nitric Oxide. Simultaneously, unnecessary waste of inhaled Nitric Oxide may be avoided thereby increasing the cost effectiveness of Nitric Oxide therapy. The minimization of Nitric Oxide waste has the further benefit of reducing environmental Nitrogen Dioxide levels in e.g. a NICU environment thereby mitigating medical personnel's Nitrogen Dioxide exposure.

Description

TECHNICAL FIELD

The field relates to the control of medical gas dosimetry and monitoring of excess medical gas waste.

BACKGROUND ART

Current standard Nitric Oxide (“NO”) delivery devices control the concentration of NO delivered into a conduit carrying gas to the patient for inhalation (e.g. the inspiratory limb of a ventilator breathing circuit or other breathing-gas administration system). Monitoring of delivered time-averaged NO concentrations is also performed on inspired gases. Accordingly, such systems do not differentiate between a) NO that is efficiently transported to gas-exchange regions of the lung and absorbed into the capillary blood and b) NO which is ultimately exhaled and wasted. As a result, NO uptake may be significantly different from patient to patient, even when inhaled NO concentrations are equivalent. This complicates optimization of dosing and weaning, as well as strategies to avoid adverse effects, all of which are areas of ongoing work (see, e.g., Gentile, Respiratory Care. 2011; 56: 1341-1359). Further, comparisons between different devices for administering NO is made difficult, and innovations that would potentially reduce the consumption of NO required for treatment, as well as ambient exposure of healthcare workers to NO and nitrogen dioxide, have not been commercialized.

Numerous publications and patents exist pertaining to delivery of inhaled NO. These are summarized, for example, in U.S. Pat. No. 6,581,599 issued to Stenzler, and can be broadly sorted into the following categories:

Continuous Delivery

NO contained in a gas cylinder, typically at concentrations between 100 and 1000 ppmv in nitrogen, is delivered through a pressure regulator and control valve at a constant flow rate into the inspiratory limb of a breathing circuit. Such systems are simple, and if the flow of air and/or oxygen in the breathing circuit is also constant, they deliver a fixed concentration of NO to the patient (in the range of 1-100 ppm, and more typically 1-40 ppm). However, it is well-known (see, e.g., Imanaka et al, Anesthesiology. 1997; 86: 676-688) that when used with the majority of ventilators, for which flow in the inspiratory limb is zero or at least reduced during exhalation, continuous NO delivery results in large variation, in the form of sharp spikes or boluses, in inhaled NO concentrations. This unintentional variation is generally considered unfavorably, and certainly leads to inaccuracies when inhaled NO concentrations are monitored with conventional, slow time-response electrochemical sensors.

Intermittent/Sequential Delivery

This technique evolved from continuous delivery to address the inaccuracies described above. Delivery of NO into the breathing circuit is sequenced to correspond with patient inspiration, and switched off during exhalation. However, when on, the delivery of NO is done at a constant flow rate. As a result, when the inspiratory flow rate is constant (i.e. a square wave pattern, as typically occurs for volume control ventilation), the inhaled NO concentration is constant, but when the inspiratory flow rate varies (as occurs for pressure control ventilation, or during spontaneous breaths), the inhaled NO concentration varies (see, e.g., Imanaka et al, Anesthesiology. 1997; 86: 676-688, or Mourgeon et al, Intensive Care Med. 1997; 23: 849-858). As for continuous delivery, intra-breath variation in inhaled NO concentration goes unnoticed when monitored with conventional, slow time-response sensors, and in such circumstances causes measurement inaccuracies in the monitored concentration.

Proportional Delivery

Devices that deliver NO at flow rates that vary in proportion to the flow in the inspiratory limb of the breathing circuit are the current standard for NO administration systems. Inspiratory flow patterns are obtained directly from the ventilator, or through flow sensors inserted into the inspiratory limb, and the delivered flow rate of NO is adjusted proportionally so as to maintain a constant, or near-constant, inhaled NO concentration. Such systems have been described in numerous past publications, for example in Hiesmayr et al, Brit. J. Anaesthesia; 1998; 81: 544-552, and in Kirmse et al, Chest; 1998; 113: 1650-1657, and in several patents, for example in U.S. Pat. No. 5,558,083 issued to Bathe et al.

Pulsed/Bolus/Spiked Delivery

This category is made up of a family of techniques in which the inhaled NO concentration is deliberately varied over a single inhalation, and is most pertinent to the present invention. Generally, the intention is to target delivery of NO to preferred lung regions (e.g. the alveolar spaces) and limit delivery to non-preferred regions (e.g. the conducting airways). Examples may be found in publications by Katayama et al, Circulation. 1998; 98: 2129-2432, by Heinonen et al, Intensive Care Med. 2000; 26: 1116-1123, and in U.S. Pat. Nos. 5,839,433 6,581,599 and 6,694,969 issued to Higenbottam, Stenzler, and Heinonen, respectively. These techniques offer significant potential for improved dosing of NO; however, the traditional dose-metric of inhaled NO concentration is ill-suited to such approaches.

In an animal model, Heinonen et al evaluated a pulsed delivery technique by measuring changes in pulmonary arterial pressure with increasing NO dose, defined in terms of nanomoles NO delivered per minute. However, in this case the NO delivery represented the inhaled NO, and did not differentiate between NO absorbed into the capillary blood and NO that was exhaled. These authors do go on to write an equation for the NO uptake into the blood as:

NO_uptake=(∫F_INO·{dot over (V)}_I·dt−∫F_ENO·{dot over (V)}_Edt)·RR  (1)

where F_INO and F_ENO represent the inhaled and exhaled NO concentrations, respectively, V′_I and V′_E represent the inspiratory and expiratory flow rates, respectively, and RR represents the respiratory rate.

The method for determining NO uptake outlined in equation 1 suffers several drawbacks. First, it requires that NO concentrations and flow rates be known a priori or measured in both the inspiratory and expiratory flow. Second, it does not account for NO that reacts with O₂ and is subsequently exhaled as NO₂. In the accounting described by equation (1), such NO would be erroneously included as uptake. Third, as defined by Heinonen et al, V′_E is the flow rate, and F_ENO the NO concentration, of gas exhaled by the patient. This makes monitoring F_ENO difficult when using a ventilator with expiratory bypass flow, as in such cases the expiratory branch of the breathing circuit may contain both gas exhaled by the patient and gas passing directly from the inspiratory branch.

The problem addressed by the invention therefore is the administration of nitric oxide (NO) to a patient with the desired dosage of NO specified as the rate of uptake of NO into the capillary blood, expressed in units of mass, volume, or moles per unit time. Additionally, the solution preferably includes a way to monitor the uptake of NO in such a manner as to distinguish NO that is taken up into the blood from that which is exhaled and wasted. Accordingly, the medical practitioner administering NO may adjust dosing parameters so as to achieve a desired, known rate of uptake regardless of patient specific variation in, e.g., breathing pattern, minute volume, anatomical dead space and/or alveolar dead space.

The present invention therefore refines and improves NO dosing by controlling and monitoring the mass, volume, or molar uptake of NO, as well as monitoring NO wastage. This will allow users to better compare alternative NO delivery methods, and to titrate dosing to individual patients.

SUMMARY OF INVENTION

The invention may be understood in relation to the following embodiments listed as numbered sentences with internal cross referencing:

• • 1] A method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation, the method comprising:
    • a) Delivering an oxygen containing gas to a patient interface for inhalation,
    • b) Injecting a Nitric Oxide containing gas into the oxygen containing gas prior to the patient interface,
    • c) Providing an exhaust line configured to receive an exhaled gas from a patient and to transport the exhaled gas to an exhaust vent,
    • d) Taking a sample of an exhaust line gas comprising any exhaled gas through an exhaust sampling line in fluid communication with the exhaust line prior to the exhaust vent,
    • e) Directing the sample of the exhaust line gas comprising any exhaled gas to a chemiluminescent NO detection sensor in fluid communication with the exhaust sampling line,
    • f) Measuring an amount of NOx in the sample of the exhaust line gas comprising any exhaled gas,
    • g) Calculating a Nitric Oxide dose provided to a patient,
    • h) Calculating an amount of NOx in the sample of the exhaust line gas comprising any exhaled gas,
    • i) Based on the values calculated in step g) and step h), calculating an amount of Nitric Oxide absorbed by a patient,
    • j) Comparing the amount of Nitric Oxide absorbed by the patient with a pre-defined amount, or amount range, corresponding to one or more of:
      • A) a therapeutically effective dose of Nitric Oxide,
      • B) a therapeutically ineffective dose of Nitric Oxide, and
      • C) An overdose of Nitric Oxide,
    • k) Providing in a visually perceptible format one or both of:
      • A) the amount of Nitric Oxide absorbed by a patient and
      • B) an indication of whether or not said amount is within or outside the pre-defined amount(s) of step j).
  • 2] The method of claim 1, further comprising the step of providing a result of step j) to a Nitric Oxide delivery apparatus configured to perform step b) and adjusting the an amount of Nitric Oxide injected by the Nitric Oxide delivery apparatus in a subsequent step b) based on the result of step j).
  • 3] The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation sentence 1 or 2, further comprising the step of forming a bypass flow of oxygen containing gas into the exhaust line during a patient exhalation.
  • 4] The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation sentence 1, 2, or 3, further comprising a step of directing the sample to a NO₂ converter and converting NO₂ molecules in the sample to Nitric Oxide molecules on a one-to-one basis prior to directing the sample to the chemiluminescent NOx detection sensor.
  • 5] The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation sentence 1, 2, 3, or 4, further comprising a step of directing the sample to an electrochemical cell in fluid communication with the exhaust sampling line and measuring an amount of a NO₂ in the sample.
  • 6] The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation sentence 1, 2, 3, 4, or 5, wherein steps h) and i) based on the following calculations:

${\stackrel{\stackrel{\_}{.}}{m}}_{\mathrm{NO},\mathrm{waste}}=\frac{{\int }_t^{t^{\prime }}\left(C_{\mathrm{NO}}+C_{{\mathrm{NO}}_2}\right)·{\rho }_{\mathrm{NO}}·Q_Et}{T}$ $\mathrm{and}$ ${\mathrm{Uptake}}_{\mathrm{NO}}={\stackrel{\stackrel{\_}{.}}{m}}_{\mathrm{NO},\mathrm{del}}-{\stackrel{\stackrel{\_}{.}}{m}}_{\mathrm{NO},\mathrm{waste}}.$

• • 7] The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation sentence 1, 2, 3, 4, 5, or 6, further comprising providing a positive expiratory pressure system comprising an exhalation valve and an exhalation pressure sensor in the exhaust line.
  • 8] The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation of sentence 3, 4, 5, 6, or 7, wherein the a NO₂ converter comprises one or more of a thermal converter, a catalytic converter, and a reducing converter.
  • 9] The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation of sentence 1, 2, 3, 4, 5, 6, 7, or 8, further comprising a step of measuring a flow rate of the exhaust line gas comprising any exhaled gas.
  • 10] The method of sentence 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein the visually perceptible format is a video display or a paper chart.
  • 11] A method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation, the method comprising:
    • a) Providing a ventilation apparatus configured to deliver an oxygen containing gas to a patient interface for inhalation, the ventilation apparatus comprising,
      • A) A source of medical air,
      • B) A source of medical oxygen
      • C) An oxygen containing gas injection device in fluid communication with the source of medical air via a medical air supply line and the source of medical oxygen via a medical oxygen supply line,
      • D) One or more medical air pressure regulators in fluid communication with the medical air supply line and configured to control the pressure of the medical air in the medical air supply line,
      • E) One or more medical oxygen pressure regulators in fluid communication with the medical oxygen supply line and configured to control the pressure of the medical oxygen in the medical oxygen supply line,
      • F) A medical oxygen working pressure sensor configured to measure the pressure of a medical oxygen dose emitted from the oxygen containing gas injection device,
      • G) A medical air working pressure sensor configured to measure the pressure of a medical air dose emitted from the oxygen containing gas injection device,
      • H) An medical oxygen flow sensor configured to measure a flow rate of the medical oxygen dose emitted from the oxygen containing gas injection device,
      • I) An medical air flow sensor configured to measure a flow rate of the medical air dose emitted from the oxygen containing gas injection device,
      • J) An inspiratory gas tube in fluid communication with the oxygen containing gas injection device and configured to receive an injection of oxygen containing gas from the oxygen containing gas injection device,
      • K) A patient circuit pressure sensor configured to measure a gas pressure in the inspiratory gas tube,
    • b) Providing a Nitric Oxide delivery apparatus configured to inject a Nitric Oxide containing gas into the oxygen containing gas prior to the patient interface, wherein the Nitric Oxide delivery apparatus comprises
      • A) A Nitric Oxide dose control system configured to inject a controlled amount of Nitric Oxide into the oxygen containing gas,
    • c) Providing an exhaust line configured to receive an exhaled gas from a patient, a bypass flow of oxygen containing gas, or both, and to transport the exhaled gas to an exhaust vent,
    • d) Providing a positive expiratory pressure system comprising an exhalation valve and an exhalation pressure sensor in the exhaust line,
    • e) Providing an exhaust sampling line in fluid communication with the exhaust line prior to the exhaust vent and configured to receive a portion of a gas in the exhaust line comprising any exhaled gas,
    • f) Providing a NO₂ converter in fluid communication with the exhaust sample line and configured to receive at least part of the portion of the gas in the exhaust line comprising any exhaled gas,
    • g) Providing a chemiluminescent NO detection sensor in fluid communication with the NO₂ converter and configured to receive at least part of the portion of the gas in the exhaust line comprising any exhaled gas from the NO₂ converter and further configured to measure the amount of NOx in the at least part of the portion of the gas in the exhaust line comprising any exhaled gas,
    • h) Providing an exhaust line flow sensor configured to measure a flow rate of the gas in the exhaust line,
    • i) Providing a patient interface in fluid communication with the inspiratory gas tube and the exhaust line,
    • j) Providing a computer specifically programmed or a microprocessor specifically configured to execute the following functions:
      • A) Calculate a Nitric Oxide dose provided to a patient by the Nitric Oxide delivery apparatus,
      • B) Calculate an amount of NOx in the gas in the exhaust line comprising any exhaled gas based on the formula:

${\stackrel{\stackrel{\_}{.}}{m}}_{\mathrm{NO},\mathrm{waste}}=\frac{{\int }_t^{t^{\prime }}\left(C_{\mathrm{NO}}+C_{{\mathrm{NO}}_2}\right)·{\rho }_{\mathrm{NO}}·Q_Et}{T},$

• • • k) Delivering a Nitric Oxide containing gas to an Oxygen containing gas,
    • l) Delivering the Oxygen containing gas and the Nitric Oxide containing gas to a patient interface,
    • m) Delivering an exhaled gas, a bypass flow of oxygen containing gas, or both, to the exhaust line,
    • n) Taking a sample of a gas in the exhaust line comprising any exhaled gas,
    • o) Measuring a concentration of one or more of Nitric Oxide, NO₂, or NOx in the gas in the exhaust line comprising any exhaled gas,
    • p) Calculating an amount of NOx in the sample of the exhaust line gas comprising any exhaled gas,
    • q) Based on the values calculated in step o) and step p), calculating an amount of Nitric Oxide absorbed by a patient based on the formula:

Uptake_NO={dot over ( m_NO,del−{dot over ( m_NO,waste,

• • • r) Comparing the amount of Nitric Oxide absorbed by the patient with a pre-defined amount, or amount range, corresponding to one or more of:
      • A) a therapeutically effective dose,
      • B) a therapeutically ineffective dose, and
      • C) An overdose,
    • s) Providing in a visually perceptible format one or both of:
      • A) the amount of Nitric Oxide absorbed by a patient and
      • B) an indication of whether or not said amount is within or outside the pre-defined amount(s) of step j).
  • 12] The method of sentence 11, further comprising the step of providing a result of step q) to the Nitric Oxide delivery apparatus and then adjusting an amount of Nitric Oxide injected by the Nitric Oxide delivery apparatus in a subsequent step k) based on the result of step q).

DISCLOSURE OF INVENTION

An example general concept configuration is displayed schematically in FIG. 1. A cylinder (1) or other gas source supplies NO-containing gas (typically with NO concentration between 100 and 1000 ppm in nitrogen) through a pressure regulator (2) to the NO supply line (3) of the apparatus (15). The NO supply line carries the NO-containing gas to the administration block (4), which is controlled by the administration CPU (5). The administration CPU receives the desired NO dose from a user interface (6), and receives information (13) sent from a ventilator or other breathing gas delivery device, and/or from a flow sensor positioned in a conduit supplying breathing gas to a patient, describing, for example, the flow rate of breathing gas delivered to the patient, the volume of gas delivered to the patient per breath, and/or the timing of cycling between inspiration and expiration. Based on this information and the desired NO dose, the administration CPU controls the timing and positions of a system of one or more valves and/or switches contained in the administration block so as to administer a flow of NO-containing gas through an administration line (7) to a patient breathing circuit or other conduit carrying breathing gas to the patient (9). The flow of NO-containing gas may be constant, intermittent, pulsed, or otherwise varied according to the NO dosing strategy. External to the administration block, a flow sensor (8) is positioned in the administration line to measure the variation in the rate of flow of NO-containing gas with time. This information is sent to a monitoring CPU (10), which also receives the concentration of NO in the NO-containing gas from the user interface.

Optionally, the concentration of oxygen is also sent to the monitoring CPU (10). From this information the monitoring CPU (10) calculates the delivered flux of NO in terms of mass, volume, or moles NO per unit time. Using the concentration of oxygen, the monitoring CPU (10) may also be programmed to calculate an estimated amount of NO₂ production.

Concurrently, a continuous sample of exhaled gas (12) is drawn into the apparatus (15) to a gas analysis block (11). Gas is sampled from a position in the expiratory portion of the breathing circuit through which passes gas exhaled by the patient as well as any gas from the inspiratory portion of the circuit that bypasses the patient. The gas analysis block contains sensors to measure the concentrations of NO and NO₂, or the total NO_x concentration, in the sampled gas. This information is sent to the monitoring CPU (10). Additionally, the monitoring CPU receives information (14) sent from a ventilator or other breathing gas delivery device, or from a flow sensor positioned at or near the location of gas sampling, which describes the flow rate of gas through the expiratory portion of the breathing circuit. From this information, the monitoring CPU calculates the waste flux of NO in terms of mass, volume, or moles NO per unit time.

Finally, the monitoring CPU (10) calculates the NO uptake in terms of mass, volume, or moles NO per unit time by subtracting the waste flux of NO from the delivered flux of NO. The delivered flux of NO, the waste flux of NO, and the NO uptake are sent from the monitoring CPU to the user interface, where they may be displayed.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 schematically outlines an example configuration of apparatus for dosimetric administration and monitoring of NO.

FIG. 2 is a more detailed schematic of a delivery system incorporating a preferred embodiment of the invention.

MODE(S) FOR CARRYING OUT THE INVENTION

In a preferred embodiment of the invention, a breathing gas mixture consisting of air and/or oxygen is delivered to a patient through a breathing circuit consisting of at least an inspiratory branch, an expiratory branch, and a Y-piece or other adapter which connects these two branches to the patient interface. NO is administered as a short-duration pulse or bolus timed to start with the onset of patient inhalation. NO-containing gas is injected into the breathing gas at a location close to the patient, for example between the Y-piece and the patient interface. The delivered flux of NO may be expressed in terms of mass, volume, or moles NO per unit time—if, for example, the delivered flux is expressed in terms of mass, the following calculation is made:

$\begin{array}{cc}{m}_{\mathrm{NO},\mathrm{del}}={\int }_t^{t^{\prime }}C_{\mathrm{NO}}·{\rho }_{\mathrm{NO}}·Q_{\mathrm{NO}/N_2}t& \left(2\right)\end{array}$

where, m_NO,del is the delivered mass of NO, C_NO is the concentration of NO in the supplied NO-containing gas (typically between 100 and 1000 ppmv in nitrogen, and preferably 800 ppmv), ρ_NO is the density of NO (at 1 atmosphere and at the temperature of the supplied NO-containing gas, which may be assumed, e.g., as 20 degrees C., or may be measured at flow sensor (8)) and Q_NO/N2 is the administered volumetric flow rate of the NO-containing gas. Time t corresponds to the start of an inhalation, and time t′ corresponds to the start of the next inhalation, after one full breathing cycle is completed. The delivered flux is then expressed as:

$\begin{array}{cc}{\stackrel{\stackrel{\_}{.}}{m}}_{\mathrm{NO},\mathrm{del}}=\frac{m_{\mathrm{NO},\mathrm{del}}}{T}& \left(3\right)\end{array}$

where T is the time period of the breath cycle (inhalation and exhalation).

The delivered flux may be thus calculated and displayed on a breath-by-breath basis, or alternatively, values determined for several breaths in sequence may be averaged, and the average flux used in subsequent calculations and/or displayed.

Concurrently, a continuous sample of gas is drawn (typically at a sampling flow rate of between 100 and 500 ml/min) from the expiratory branch of the breathing circuit. The total NO_x concentration in the sampled gas is analyzed by chemiluminescence detection, that is, NO molecules in the sample gas are made to react with ozone whereby they are oxidized to NO₂ in an excited state, and a portion of the excited NO₂ molecules decay by emitting photons in the near-infrared portion of the electromagnetic spectrum. The amount of energy or light emitted in these photons may be measured and is correlated to the concentration of NO in the sample gas. As only NO can be determined in such manner, in order to measure the total NO_x (NO+NO₂) concentration in the sample gas, the sample gas is first passed through a NO₂ converter (for example a thermal converter, a catalytic converter, or a reducing converter) that converts NO₂ molecules to NO molecules on a one-to-one basis prior to the chemiluminescence analysis. The waste flux of NO is then calculated as:

$\begin{array}{cc}{\stackrel{\stackrel{\_}{.}}{m}}_{\mathrm{NO},\mathrm{waste}}=\frac{{\int }_t^{t^{\prime }}C_{{\mathrm{NO}}_x}·{\rho }_{\mathrm{NO}}·Q_Et}{T}& \left(4\right)\end{array}$

where C_NOx is the total NOx concentration in the sampled gas, ρ_NO is the density of NO (at 1 atmosphere and at the temperature of gas in the expiratory branch of the breathing circuit, which may be assumed, e.g., as 36.6 degrees C., but is preferably measured, or acquired from the ventilator or breathing gas delivery device), and Q_E is the total volumetric gas flow rate through the expiratory branch of the breathing circuit.

The waste flux may be thus calculated and displayed on a breath-by-breath basis, or alternatively, values determined for several breaths in sequence may be averaged, and the average flux used in subsequent calculations and/or displayed.

The monitored NO uptake is then calculated as:

Uptake_NO={dot over ( m_NO,del−{dot over ( m_NO,waste  (5)

The monitored NO uptake may be calculated and displayed on a breath-by-breath basis, or alternatively, values determined for several breaths in sequence may be averaged, and the average flux used in subsequent calculations and/or displayed.

Normally, the user interface will simultaneously display the target NO uptake (input by the user), the delivered flux, the waste flux, and the monitored NO uptake. Alarms may be activated when for example the waste flux becomes non-negligible or exceeds a threshold value based on the delivered flux and monitored NO uptake to alert the user that NO dosing is being performed inefficiently, that uptake has dropped below a therapeutic level, etc.

FIG. 2 shows a more detailed schematic of an example of the preferred embodiment. The numbered Figure elements are:

• • 1—source of gas mixture containing therapeutic gas and carrier (e.g. 800-2000 ppm NO in balance N₂; but also could be CO, H₂ or H₂S in balance nitrogen, balance medical air, or balance inert noble gas such as helium or argon)
  • 2—therapeutic gas supply regulator (delivery pressure, e.g., 3-6 bar)
  • 3—therapeutic gas supply line
  • 4—one or more control valves or switches used to supply therapeutic gas at a desired rate
  • 5—therapeutic gas dosing CPU(s); may also include monitoring CPU(s) 10
  • 6—GUI
  • 7—therapeutic gas administration line
  • 8—therapeutic gas line flow sensor
  • 9—external therapeutic gas administration line connecting to breathing circuit distal to Y-piece
  • 10—optional separate monitoring CPU (may be combined with administration CPU(s) 5)
  • 11—therapeutic gas analysis block
  • 12—sample line from expiratory flow
  • 16—source of medical air
  • 17—source of medical oxygen
  • 18—medical air supply line
  • 19—medical oxygen supply line
  • 20—pressure sensor for medical air supply pressure
  • 21—pressure sensor for medical air working pressure
  • 22—pressure sensor for medical oxygen supply pressure
  • 23—pressure sensor for medical oxygen working pressure
  • 24—medical air flow sensor
  • 25—medical oxygen flow sensor
  • 26—medical air control valve
  • 27—medical oxygen control valve
  • 28—mixed breathing gas flow sensor
  • 29—oxygen sensor
  • 30—low pressure sensor to measure pressure delivered to patient from ventilator (in cm H₂O)
  • 31—inspiratory limb of breathing circuit
  • 32—Y-piece
  • 33—patient interface (endotracheal tube; facemask; hood; nasal mask/cushion/pillow/cannula)
  • 34—expiratory limb of breathing circuit
  • 35—low pressure sensor to measure positive expiratory pressures (in cm H₂O) (optional)
  • 36—expiratory control valve
  • 37—expiratory flow sensor
  • 38—exhaust of breathing gases to atmosphere
  • 39—exhaust of sample line gases to atmosphere
  • 40—pressure sensor for therapeutic gas supply pressure
  • 41—one or more pressure sensors for therapeutic gas working pressures on one or more dosing lines
  • 42—Reference for the entire System
  • 43—medical air supply regulator (with delivery pressure, e.g., 3-6 bar)
  • 44—medical oxygen supply regulator (with delivery pressure, e.g., 3-6 bar)
  • 45—medical air regulator (to more precisely control working pressure)
  • 46—medical oxygen regulator (to more precisely control working pressure)
  • 47—one or more therapeutic gas regulators to fix working pressure on one or more dosing lines
  • 48—ventilation CPU

DEFINITIONS AND/OR EXAMPLES

• • Ventilation apparatus—ventilation apparatuses are established and widespread medical technology designed to support or substitute for a patient's physiological breathing. An overview of ventilation apparatuses encompassed within this definition is EDUARDO MIRELES-CABODEVILA, ENRIQUE DIAZ-GUZMAN, GUSTAVO A. HERESI, and ROBERT L. CHATBURN, Alternative modes of mechanical ventilation: A review for the hospitalist, Cleveland Clinic Journal of Medicine 2009; 76(7):417-430; doi:10.3949/ccjm.76a.08043.
  • Oxygen containing gas—An oxygen containing gas is any gas or gas mixture comprising or consisting of oxygen and medically suitable for administration to a patient. This includes medical oxygen meeting all applicable U.S. Food & Drug Administration requirements. See, e.g., CPG Sec. 435.100 Compressed Medical Gases—Warning Letters for Specific Violations Covering Liquid and Gaseous Oxygen, FDA, issued Nov. 5, 1987, revised Aug. 31, 1992; FDA, COMPRESSED MEDICAL GASES GUIDELINE (REVISED) FEBRUARY 1989. The oxygen concentration in a gas mixture may be for example anywhere from 21-100% and generally is adjusted based on blood oxygen saturation levels of a patient.
  • Positive expiratory pressure system—Positive expiratory pressure is also referred to as Positive end-expiratory pressure (PEEP). A positive expiratory pressure means a lung gas pressure above atmospheric pressure. A Positive expiratory pressure system is a device configured to ensure PEEP by artificially pressurizing the lungs. This is referred to as applied or extrinsic PEEP support. Generally a positive expiratory pressure system in the context of this invention is a subcomponent of a ventilation apparatus. Positive expiratory pressure systems within the scope of this term are described in “Mechanical Ventilation”, by Ryland P Byrd Jr, MD and Thomas M Roy, MD, accessed on <emedicine.medscape.com/article/304068-overview#aw2aab6b5>, last updated: Apr. 26, 2012.
  • Medical oxygen—This includes medical oxygen meeting all applicable U.S. Food & Drug Administration requirements. See, e.g., CPG Sec. 435.100 Compressed Medical Gases—Warning Letters for Specific Violations Covering Liquid and Gaseous Oxygen, FDA, issued Nov. 5, 1987, revised Aug. 31, 1992; FDA, COMPRESSED MEDICAL GASES GUIDELINE (REVISED) FEBRUARY 1989.
  • Medical air—means air that complies with one or more of the following standards:
    • U.S. Food & Drug Administration requirements in CPG Sec. 435.100 Compressed Medical Gases—Warning Letters for Specific Violations Covering Liquid and Gaseous Oxygen, FDA, issued Nov. 5, 1987, revised Aug. 31, 1992; FDA, COMPRESSED MEDICAL GASES GUIDELINE (REVISED) FEBRUARY 1989;
    • Medical air criteria defined in the current U.S. Pharmacopeia;
    • The definition of Medical Air Quality from National Fire Protection Association 99, Standard for Health Care Facilities, 2005 edition, section 5.1.3.5.1.
  • Patient interface for inhalation—This is defined as any device adapted to deliver a medical gas for inhalation by a patient. There are many types of patient interfaces for inhalation including intubation tubes used in many mechanical ventilation situations, nasal cannula, and medical face masks. The choice of patient interface for inhalation depends on several factors such as the therapeutic purpose of the medical gas and the form of medical gas delivery. In the context of ventilation apparatus delivery of oxygen containing gases comprising Nitric Oxide, the most common choices are intubation tubes and nasal cannula.
  • Nitric Oxide delivery apparatus—These are medical devices designed to provide medically relevant doses of Nitric Oxide. Such devices may operate in a stand alone fashion or in conjunction with a ventilation apparatus. Nitric Oxide delivery apparatuses include but are not limited to those meeting the criteria defined by
    • the U.S. Food and Drug Administration's Guidance Document for Premarket Notification Submissions for Nitric Oxide Delivery Apparatus, Nitric Oxide Analyzer and Nitrogen Dioxide Analyzer, issued Jan. 24, 2000; or
    • European Committee for Standardization—CEN/TS 14507-1:2003 Inhalational nitric oxide systems—Part 1: Delivery systems 93/42/EEC (No).
  • Nitric Oxide containing gas—means a gas comprising Nitric Oxide that is medically suitable for inhalation by a patient. Medical suitability includes but is not limited to a gas comprising Nitric Oxide that is a bioequivalent of the Nitric Oxide gas drug submitted under NDA 20845 and approved under U.S. Food and Drug Administration. Nitric Oxide containing gases include but are not limited to concentrated Nitric Oxide source gases and dilutions thereof. Concentrated Nitric Oxide containing gases are most commonly Nitric Oxide at a concentration of 100 ppm to 5000 ppm in a balance of U.S.P. Nitrogen gas. The FDA approved Nitric Oxide containing gases are 100 ppm and 800 ppm Nitric Oxide in a balance of U.S.P. Nitrogen gas.
  • NOx—means Nitric Oxide (NO) and Nitrogen Dioxide (NO₂).
  • Chemiluminescent NO detection sensor—Chemiluminescent NOx detection sensors are devices configured to use ozone-chemiluminescence technology to quantify Nitric Oxide in a gas sample based on the chemical reaction:

NO+O₃==>NO₂+O₂+hv

• • Nitrogen Dioxide must be first converted to Nitric Oxide to measure NOx. Examples of commercially available Chemiluminescent NO detection sensors include the Sievers Nitric Oxide Analyzer (NOA 280i).
  • NO₂ converter—Is a device adapted to quantitatively convert NO₂ to Nitric Oxide. NO₂ converters may be, for example, a thermal converter (>650 degrees C./stainless steel; 450 degrees C./Molybdenum), a catalytic converter (generally an Ag catalyst), or a reducing converter (reducing agents used include ascorbic acid).
  • Computer specifically programmed—means a general purpose programmable computer with specific software written to a component thereof such as a RAM component. Specific software is software designed to execute particular functions such as operating a robotic arm to carry out a manufacturing step or performing specific calculations or data transformations.
  • Microprocessor specifically configured—means an integrated circuit that is structurally designed to execute particular functions such as operating a robotic arm to carry out a manufacturing step or performing specific calculations or data transformations.

While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as fall within the spirit and broad scope of the appended claims. The present invention may suitably comprise, consist or consist essentially of the elements disclosed and may be practiced in the absence of an element not disclosed. Furthermore, if there is language referring to order, such as first and second, it should be understood in an exemplary sense and not in a limiting sense. For example, it can be recognized by those skilled in the art that certain steps can be combined into a single step.

The singular forms “a”, “an” and “the” include plural referents, unless the context clearly dictates otherwise.

“Comprising” in a claim is an open transitional term which means the subsequently identified claim elements are a nonexclusive listing (i.e., anything else may be additionally included and remain within the scope of “comprising”). “Comprising” as used herein may be replaced by the more limited transitional terms “consisting essentially of” and “consisting of” unless otherwise indicated herein.

“Providing” in a claim is defined to mean furnishing, supplying, making available, or preparing something. The step may be performed by any actor in the absence of express language in the claim to the contrary.

Optional or optionally means that the subsequently described event or circumstances may or may not occur. The description includes instances where the event or circumstance occurs and instances where it does not occur.

Ranges may be expressed herein as from about one particular value, and/or to about another particular value. When such a range is expressed, it is to be understood that another embodiment is from the one particular value and/or to the other particular value, along with all combinations within said range.

All references identified herein are each hereby incorporated by reference into this application in their entireties, as well as for the specific information for which each is cited.

Claims

1. A method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation, the method comprising: a) delivering an oxygen containing gas to a patient interface for inhalation,b) injecting a Nitric Oxide containing gas into the oxygen containing gas prior to the patient interface,c) providing an exhaust line configured to receive an exhaled gas from a patient and to transport the exhaled gas to an exhaust vent,d) taking a sample of an exhaust line gas comprising any exhaled gas through an exhaust sampling line in fluid communication with the exhaust line prior to the exhaust vent,e) directing the sample of the exhaust line gas comprising any exhaled gas to a chemiluminescent NO detection sensor in fluid communication with the exhaust sampling line,f) measuring an amount of NOx in the sample of the exhaust line gas comprising any exhaled gas,g) calculating a Nitric Oxide dose provided to a patient,h) calculating an amount of NOx in the sample of the exhaust line gas comprising any exhaled gas,i) based on the values calculated in step g) and step h), calculating an amount of Nitric Oxide absorbed by a patient,j) comparing the amount of Nitric Oxide absorbed by the patient with a pre-defined amount, or amount range, corresponding to one or more of: A) a therapeutically effective dose of Nitric Oxide,B) a therapeutically ineffective dose of Nitric Oxide, andC) an overdose of Nitric Oxide,k) providing in a visually perceptible format one or both of: A) the amount of Nitric Oxide absorbed by a patient andB) an indication of whether or not said amount is within or outside the pre-defined amount(s) of step j).

2. The method of claim 1, further comprising the step of providing a result of step j) to a Nitric Oxide delivery apparatus configured to perform step b) and adjusting the an amount of Nitric Oxide injected by the Nitric Oxide delivery apparatus in a subsequent step b) based on the result of step j).

3. The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation claim 1, further comprising the step of forming a bypass flow of oxygen containing gas into the exhaust line during a patient exhalation.

4. The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation claim 1, further comprising a step of directing the sample to a NO2 converter and converting NO2 molecules in the sample to Nitric Oxide molecules on a one-to-one basis prior to directing the sample to the chemiluminescent NOx detection sensor.

5. The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation claim 1, further comprising a step of directing the sample to an electrochemical cell in fluid communication with the exhaust sampling line and measuring an amount of a NO2 in the sample.

6. The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation claim 1, wherein steps h) and i) based on the following calculations:

7. The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation claim 1, further comprising providing a positive expiratory pressure system comprising an exhalation valve and an exhalation pressure sensor in the exhaust line.

8. The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation claim 3, wherein the a NO2 converter comprises one or more of a thermal converter, a catalytic converter, and a reducing converter.

9. The method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation claim 1, further comprising a step of measuring a flow rate of the exhaust line gas comprising any exhaled gas.

10. The method of claim 1, wherein the visually perceptible format is a video display or a paper chart.

11. A method for delivering precise dosing of a Nitric Oxide containing gas to a patient for inhalation, the method comprising: a) providing a ventilation apparatus configured to deliver an oxygen containing gas to a patient interface for inhalation, the ventilation apparatus comprising, A) a source of medical air,B) a source of medical oxygenC) an oxygen containing gas injection device in fluid communication with the source of medical air via a medical air supply line and the source of medical oxygen via a medical oxygen supply line,D) one or more medical air pressure regulators in fluid communication with the medical air supply line and configured to control the pressure of the medical air in the medical air supply line,E) one or more medical oxygen pressure regulators in fluid communication with the medical oxygen supply line and configured to control the pressure of the medical oxygen in the medical oxygen supply line,F) a medical oxygen working pressure sensor configured to measure the pressure of a medical oxygen dose emitted from the oxygen containing gas injection device,G) a medical air working pressure sensor configured to measure the pressure of a medical air dose emitted from the oxygen containing gas injection device,H) an medical oxygen flow sensor configured to measure a flow rate of the medical oxygen dose emitted from the oxygen containing gas injection device,I) an medical air flow sensor configured to measure a flow rate of the medical air dose emitted from the oxygen containing gas injection device,J) an inspiratory gas tube in fluid communication with the oxygen containing gas injection device and configured to receive an injection of oxygen containing gas from the oxygen containing gas injection device,K) a patient circuit pressure sensor configured to measure a gas pressure in the inspiratory gas tube,b) providing a Nitric Oxide delivery apparatus configured to inject a Nitric Oxide containing gas into the oxygen containing gas prior to the patient interface, wherein the Nitric Oxide delivery apparatus comprises A) a Nitric Oxide dose control system configured to inject a controlled amount of Nitric Oxide into the oxygen containing gas,c) providing an exhaust line configured to receive an exhaled gas from a patient, a bypass flow of oxygen containing gas, or both, and to transport the exhaled gas to an exhaust vent,d) providing a positive expiratory pressure system comprising an exhalation valve and an exhalation pressure sensor in the exhaust line,e) providing an exhaust sampling line in fluid communication with the exhaust line prior to the exhaust vent and configured to receive a portion of a gas in the exhaust line comprising any exhaled gas,f) providing a NO2 converter in fluid communication with the exhaust sample line and configured to receive at least part of the portion of the gas in the exhaust line comprising any exhaled gas,g) providing a chemiluminescent NO detection sensor in fluid communication with the NO2 converter and configured to receive at least part of the portion of the gas in the exhaust line comprising any exhaled gas from the NO2 converter and further configured to measure the amount of NOx in the at least part of the portion of the gas in the exhaust line comprising any exhaled gas,h) providing an exhaust line flow sensor configured to measure a flow rate of the gas in the exhaust line,i) providing a patient interface in fluid communication with the inspiratory gas tube and the exhaust line,j) providing a computer specifically programmed or a microprocessor specifically configured to execute the following functions: A) calculate a Nitric Oxide dose provided to a patient by the Nitric Oxide delivery apparatus,B) calculate an amount of NOx in the gas in the exhaust line comprising any exhaled gas based on the formula:

12. The method of claim 11, further comprising the step of providing a result of step q) to the Nitric Oxide delivery apparatus and then adjusting an amount of Nitric Oxide injected by the Nitric Oxide delivery apparatus in a subsequent step k) based on the result of step q).