Patent Publication Number: US-2013239962-A1

Title: Methods Of Administering High Concentrations Of Nitric Oxide

Description:
TECHNICAL FIELD 
     Embodiments of the present invention generally relate to the field of methods and devices for nitric oxide delivery. 
     BACKGROUND 
     Nitric oxide (NO) is a gas that, when inhaled, acts to dilate blood vessels in the lungs and reduces pulmonary hypertension. Because of this, nitric oxide is provided as a therapeutic gas in the inspiratory breathing gases for patients with pulmonary hypertension. 
     Current methods of nitric oxide delivery generally require that low concentrations of nitric oxide be delivered to a patient as high NO delivery concentrations are associated with various toxicities. Therefore, as a result, nitric oxide delivery systems require either the use of cylinders with low NO concentration, or if high concentration cylinders are used, require dilution of the NO prior to administration to the patient. If cylinders with low NO concentration are used, then the cylinders need to have a large volume in order to have a sufficient quantity of NO so that the cylinders do not need to be frequently replaced. Such large cylinders reduce the portability of the nitric oxide delivery system and make it less suitable for home use. 
     Therefore, there is a need to provide alternative methods of nitric oxide delivery that enable portable nitric oxide delivery systems that are convenient for home use. 
     SUMMARY 
     One aspect of the present invention provides a method of delivering nitric oxide to a patient, the method comprising administering a dose of nitric oxide at a delivery concentration of greater than 2000 ppm. According to one or more embodiments of this aspect, the dose of nitric oxide is administered during inspiration. 
     In certain embodiments, the nitric oxide is administered as a “pulse” or “bolus.” Other embodiments provide that the nitric oxide is administered continuously. 
     Some embodiments provide that the nitric oxide is administered every nth breath, wherein n is 1 or greater. According to one or more embodiments, n is 1 such that the dose is administered every breath. In other embodiments, n is greater than 1 such that the dose is intermittent. 
     In one or more embodiments, the delivery concentration is in the range of 2000 ppm to 10,000 ppm. In some embodiments, the delivery concentration is in the range of 2200 ppm to 5000 ppm. 
     According to one or more embodiments, the dose is in the range of 0.001 to 4.5 mg/kg/hr. 
     In one or more embodiments, the nitric oxide is administered in undiluted form such that the delivery concentration is the same as a storage concentration. 
     Another aspect of the present invention relates to a method of administering a therapeutic gas comprising nitric oxide to a patient, the method comprising administering a dose of nitric oxide from a device that comprises a delivery system and a cylinder having a nitric oxide concentration greater than 2000 ppm, wherein the nitric oxide is administered in undiluted form from the cylinder. 
     In one or more embodiments of this aspect, the nitric oxide is administered every nth breath, wherein n is 1 or greater. In some embodiments, n is 1 such that the dose is administered every breath. In other embodiments, n is greater than 1 such that the dose is intermittent. 
     In certain embodiments, the delivery concentration of the dose is in the range of about 2,000 ppm to about 10,000 ppm. In some embodiments, the delivery concentration is in the range of 2200 ppm to 5,000 ppm. In a particular embodiment, the delivery concentration is in the range of 4600 ppm to 5000 ppm. 
     The cylinder that supplies the nitric oxide may be a “mini-cylinder.” In one or more embodiments, the cylinder has a volume in the range of 0.01 to 1 L. According to some embodiments, the cylinder volume is in the range of 0.05 to 0.5 L. 
     According to one or more embodiments of this aspect, the dose is in the range of 0.001 to 4.5 mg/kg/hr. 
     Yet another aspect of the present invention provides a method of treating pulmonary hypertension comprising administering a therapeutic gas comprising a dose of nitric oxide to a patient from a device that comprises a delivery system and a cylinder, wherein the dose has a delivery concentration of greater than 2000 ppm. In one or more embodiments, the nitric oxide is administered every nth breath, wherein n is 1 or greater. 
     In some embodiments of this aspect, the dose is in the range of 0.001 to 4.5 mg/kg/hr. 
     According to one or more embodiments, the nitric oxide is administered in undiluted form such that the delivery concentration is the same as a storage concentration. 
     The foregoing has outlined rather broadly certain features and technical advantages of the present invention. It should be appreciated by those skilled in the art that the specific embodiments disclosed may be readily utilized as a basis for modifying or designing other structures or processes within the scope present invention. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWING 
       So that the manner in which the above recited features of the present invention can be understood in detail, a more particular description of the invention, briefly summarized above, may be had by reference to embodiments, some of which are illustrated in the appended drawing. It is to be noted, however, that the appended drawing illustrates only typical embodiments of this invention and are therefore not to be considered limiting of its scope, for the invention may admit to other equally effective embodiments. 
         FIG. 1  shows a nitric oxide delivery system that can be used in accordance with one or more embodiments of the invention. 
     
    
    
     DETAILED DESCRIPTION 
     Nitric oxide (NO) is typically supplied from cylinders that contain up to about 1000 ppm NO in a carrier gas, such as nitrogen. Embodiments of the present invention use NO in a carrier gas, the NO having a concentration of 2000 ppm or more (e.g., up to 5,000 or even 30,000 ppm), where a volume of gas from the source is controlled to deliver dosing of the NO using either a constant concentration, pulsed or other method of NO delivery to patients and measured in ppm, mL/breath, mg/breath, mg/kg/hour or any other manner of dosing measurement. The carrier gas may be nitrogen. Embodiments of the present invention also include continuous NO delivery. 
     In addition, it has been surprisingly found that nasal tolerability of NO was independent of concentration of NO being delivered, but was dependent on dose. Prior to the current application, high concentrations of nitric oxide were considered toxic, especially concentrations above 1000 ppm. The Occupational Safety and Health Administration (OSHA) has recognized the potential toxicity of nitric oxide and has established a Permissible Exposure Limit (PEL) of 25 ppm. However, unexpectedly this invention describes a method of safely administering nitric oxide at concentrations above 2000 ppm. 
     Before describing several exemplary embodiments of the invention, it is to be understood that the invention is not limited to the details of construction or process steps set forth in the following description. The invention is capable of other embodiments and of being practiced or being carried out in various ways. 
     As used herein, “cylinder concentration” refers to the concentration of nitric oxide in the therapeutic gas source, which is typically a gas storage cylinder. Cylinder concentrations are typically expressed in parts per million (ppm), with the remainder of the gas in the cylinder comprising a carrier gas such as nitrogen. 
     “Delivery concentration” refers to the concentration of nitric oxide in the delivery tube immediately prior to the delivery point to the patient, i.e. entering the breathing mask, exiting the nasal cannula, etc. Delivery concentration does not necessarily refer to the alveolar (i.e. lung) concentration, as the delivery concentration may be diluted in the patient&#39;s trachea or lungs. “Alveolar concentration” refers to the concentration of nitric oxide in the alveoli or lungs. 
     According to certain embodiments, the therapeutic gas comprising nitric oxide may undergo dilution in the patient delivery tube due to the presence of other gases entering through the patient end of the patient delivery tube. 
     In some embodiments, a “cylinder exit concentration” is defined as the concentration of nitric oxide in the therapeutic gas immediately after exiting the gas storage cylinder and entering the patient delivery tube, but prior to any dilution in the patient delivery tube. In other embodiments, a “valve exit concentration” is defined as the concentration of nitric oxide in the therapeutic gas immediately after exiting the control valve, but prior to any dilution in the patient delivery tube. 
     One aspect of the current invention relates to a method of delivering nitric oxide to a patient comprising administering a dose of nitric oxide having a delivery concentration of greater than 2000 ppm. In certain embodiments, the delivery concentration is in the range of 2000 ppm to 30,000 ppm. According to one or more embodiments, the delivery concentration is in the range of 2000 ppm to 5000 ppm. In other embodiments, the delivery concentration is greater than 2200 ppm. Some embodiments provide that the delivery concentration is in the range of 2200 ppm to 10,000 ppm. In certain embodiments, the delivery concentration is in the range of 2200 ppm to 5000 ppm. In a particular embodiment, the delivery concentration is in the range of 2200 ppm to 2600 ppm. In another embodiment, the delivery concentration is in the range of 4000 ppm to 6000 ppm. According to another embodiment, the delivery concentration is in the range of 4600 ppm to 5000 ppm. In some embodiments, the delivery concentration is about 2440 ppm or about 4880 ppm. 
     According to one or more embodiments, the cylinder exit concentration is greater than 2000 ppm. In certain embodiments, the cylinder exit concentration is in the range of 2000 ppm to 30,000 ppm. According to one or more embodiments, the cylinder exit concentration is in the range of 2000 ppm to 5000 ppm. In other embodiments, the cylinder exit concentration is greater than 2200 ppm. Some embodiments provide that the cylinder exit concentration is in the range of 2200 ppm to 10,000 ppm. In certain embodiments, the cylinder exit concentration is in the range of 2200 ppm to 5000 ppm. In a particular embodiment, the cylinder exit concentration is in the range of 2200 ppm to 2600 ppm. In another embodiment, the cylinder exit concentration is in the range of 4000 ppm to 6000 ppm. According to another embodiment, the cylinder exit concentration is in the range of 4600 ppm to 5000 ppm. In some embodiments, the cylinder exit concentration is about 2440 ppm or about 4880 ppm. 
     In one or more embodiments, the dose of nitric oxide has a valve exit concentration of greater than 2000 ppm. In certain embodiments, the valve exit concentration is in the range of 2000 ppm to 30,000 ppm. According to one or more embodiments, the valve exit concentration is in the range of 2000 ppm to 5000 ppm. In other embodiments, the valve exit concentration is greater than 2200 ppm. Some embodiments provide that the valve exit concentration is in the range of 2200 ppm to 10,000 ppm. In certain embodiments, the valve exit concentration is in the range of 2200 ppm to 5000 ppm. In a particular embodiment, the valve exit concentration is in the range of 2200 ppm to 2600 ppm. In another embodiment, the valve exit concentration is in the range of 4000 ppm to 6000 ppm. According to another embodiment, the valve exit concentration is in the range of 4600 ppm to 5000 ppm. In some embodiments, the valve exit concentration is about 2440 ppm or about 4880 ppm. 
     The amount of nitric oxide that is delivered to the patient will depend on many factors. For example, patients that are receiving nitric oxide treatment for various conditions may be prescribed different doses of nitric oxide. Doses that have been reported for use in treating pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), chronic thromboembolic pulmonary hypertension (CTE), idiopathic pulmonary fibrosis (IPF) or pulmonary hypertension (PH), or using nitric oxide as an antimicrobial agent, may be in the range of 0.001 to 4.5 mg/kg/hr. Therefore, in certain embodiments, the dose of nitric oxide is in the range of 0.001 to 4.5 mg/kg/hr. In other embodiments, the dose of nitric oxide is in the range of 0.001 to 0.5 mg/kg/hr. 
     Also, the dose of nitric oxide may depend on the ideal body weight of the patient. The ideal body weight is related to the lung size of the patient, and will typically be based on the patient&#39;s height and gender. As a result, patients with differing lung sizes may be administered different amounts of nitric oxide (in mg/kg/hr or mg/kg/breath). 
     According to one or more embodiments, the nitric oxide is only delivered during a portion of the patient&#39;s breathing cycle. In such embodiments, the nitric oxide is delivered as a pulse instead of a continuous flow of nitric oxide-containing gas. A “pulse,” also known as a “bolus” or “plug” or “spike,” refers to a single abrupt pulsation or emission of gas. This pulse may be administered during various parts of the patient&#39;s breathing cycle. In certain embodiments, the pulse is administered during the first half of inspiration. 
     In other embodiments, the nitric oxide is delivered continuously to the patient. 
       FIG. 1  shows an exemplary nitric oxide delivery system  100  for carrying out certain embodiments of the nitric oxide administration method. Gas storage cylinder  103  contains a therapeutic gas comprising nitric oxide, with a cylinder concentration greater than 2000 ppm. Gas storage cylinder  103  is in fluid communication with patient delivery tube  113 , which carries the therapeutic gas from gas storage cylinder  103  to patient breathing mask  111 . Control valve  105  regulates the flow of therapeutic gas through patient delivery tube  113 . Central processing unit (CPU)  107  is in communication with control valve  105 , and CPU  107  sends and receives signals from the control valve  105  to open and close the control valve  105 . To deliver a pulse of therapeutic gas, CPU  107  opens control valve  105  to allow therapeutic gas to flow through patient delivery tube  113  to patient breathing mask  111 . Control valve  105  is only open for a certain period of time, and the length of the time period will determine the volume of the pulse of therapeutic gas. For example, when control valve  105  is open for a longer period of time, the amount of therapeutic gas in the pulse increases. In certain embodiments, the pulse size may vary from one pulse to the next so that the total amount of therapeutic gas administered over a given time interval is constant, even though a patient&#39;s breathing rate may change during this interval. 
     The pulse of gas comprising nitric oxide may be administered every breath, or it may be administered intermittently. Thus, according to one or more embodiments, the nitric oxide is administered every nth breath, wherein n is 1 or greater. In some embodiments, n is 1, so the pulse is administered to the patient every breath. According to other embodiments, n is greater than 1, thus providing intermittent administration of the dose. For example, when n is 2, the dose is administered every other breath. When the administration is intermittent, n does not need to be a whole number, thus allowing for many possible dosing schedules. For example, when n is 1.5, the dose will be administered 2 out of every 3 breaths. 
     The CPU  107  may be in communication with a user input device  115 . This user input device  115  can receive desired settings from the user, such as the patient&#39;s prescription in mg/kg/hr or mg/kg/breath, patient&#39;s age, height, sex, weight, etc. 
     The CPU  107  may also be in communication with a flow sensor (not shown), which would measure the flow of therapeutic gas through control valve  105 . The CPU  107  can be coupled to a memory  117  and may be one or more of readily available memory such as random access memory (RAM), read only memory (ROM), flash memory, compact disc, floppy disk, hard disk, or any other form of local or remote digital storage. Support circuits (not shown) can be coupled to the CPU  107  to support the CPU  107  in a conventional manner. These circuits include cache, power supplies, clock circuits, input/output circuitry, subsystems, and the like. 
     The memory  117  may store a set of machine-executable instructions for calculating the desired volume of the gas pulse and the pulsing schedule to achieve a particular patient prescription. For example, if the patient&#39;s breathing rate and the cylinder concentration are known, then the CPU  107  can calculate how much volume of therapeutic gas needs to be administered each breath or set of breaths to provide the desired dosage of nitric oxide. The memory  117  may also record the time that the control valve  105  is open during each pulse, so that future calculations can take into account how much nitric oxide has previously been administered. 
     When the gas pulse is delivered only during a portion of the patient&#39;s breathing cycle, the system further comprises a patient trigger sensor (not shown). The patient trigger sensor can be any suitable pressure sensor. When the patient breathes in during inspiration, it creates a small subatmospheric pressure in the patient delivery tube  113 . The patient trigger sensor detects this pressure drop and provides a signal to the CPU  107  that the patient is beginning inspiration. The CPU  107  can then send a signal to the control valve  105  so that the control valve  105  may be opened to deliver the pulse of therapeutic gas. 
     Similarly, when the patient breathes out, there is a positive pressure in the patient delivery tube  113  and the patient trigger sensor can detect the positive pressure and provide a signal to the CPU  107  indicating the beginning of expiration. As a result, when a patient trigger sensor is used, it is possible for the system to determine the inspiratory and expiratory times in addition to the respiratory rate of the patient. 
     As the pulse of therapeutic gas contains a high concentration of nitric oxide, the pulse may have a relatively small volume of therapeutic gas and still have the same amount of nitric oxide as a higher volume pulse with a lower concentration of nitric oxide. Therefore, in certain embodiments, the dose of nitric oxide is a small-volume pulse. 
     According to one or more embodiments, the pulse volume is in the range of 0.001-20 mL. The pulse volume may be as high as 80 ml. 
     Certain embodiments provide that the nitric oxide is undiluted before administering to the patient. As shown in  FIG. 1 , the therapeutic gas can be delivered to patient breathing mask  111  without dilution prior to delivery. Thus, the delivery concentration measured at point  109  is the same as or similar or substantially similar to the cylinder concentration in gas storage cylinder  103 . Reference to the delivery concentration and the cylinder concentration being the same concentration means that no inert gas is used to dilute the storage concentration, and the delivery concentration is the same order of magnitude as the storage concentration. 
     Administering high nitric oxide concentrations allows for the use of smaller gas storage cylinders  103  as the nitric oxide source. For example, a cylinder with about 4880 ppm of nitric oxide and having a volume of about 0.16 L would generally only need to be changed every 24-96 hours for a 70 kg patient with a prescription of 0.029-0.114 mg/kg/hr. In contrast, the same patient would need to change a 0.16 L cylinder with a concentration of about 800 pm every 4 to 16 hours. 
     Thus, another aspect of the current invention pertains to administering a dose of nitric oxide from a portable device that comprises a delivery system and a mini-cylinder. As used herein, a “mini-cylinder” is a gas storage cylinder that has a smaller volume and/or lighter weight than a typical cylinder used for delivering nitric oxide. In certain embodiments, a mini-cylinder is a storage cylinder having a volume of less than 2 L or less than 1 L. In other embodiments, a mini-cylinder has a volume less than 0.5 L. According to other embodiments, a mini-cylinder has a volume less than 0.2 L 
     According to one or more embodiments, the mini-cylinder has a volume in the range of 0.01 to 1 L. In certain embodiments, the mini-cylinder has a volume in the range of 0.05 to 0.5 L. In other embodiments, the mini-cylinder has a volume in the range of 0.1 to 0.3 L. In a particular embodiment, the mini-cylinder has a volume in the range of 0.15 to 0.2 L. 
     In one or more embodiments, the concentration of nitric oxide in the mini-cylinder is greater than 2000 ppm. In certain embodiments, the mini-cylinder concentration is in the range of 2000 ppm to 10,000 ppm. According to one or more embodiments, the mini-cylinder concentration is in the range of 2000 ppm to 5,000 ppm. In other embodiments, the mini-cylinder concentration is greater than 2200 ppm. Some embodiments provide that the mini-cylinder concentration is in the range of 2200 ppm to 10,000 ppm. Other embodiments provide that the mini-cylinder concentration is in the range of 2000 ppm to 5,000 ppm. In a particular embodiment, the mini-cylinder concentration is in the range of 2200 ppm to 2600 ppm. In another embodiment, the mini-cylinder concentration is in the range of 4000 ppm to 6000 ppm. In a specific embodiment, mini-cylinder concentration is in the range of 4600 ppm to 5000 ppm. 
     A portable device with a mini-cylinder may also be used to provide a pulse of therapeutic gas. Thus, according to one or more embodiments, a portable device administers nitric oxide every nth breath, wherein n is 1 or greater. In some embodiments, n is 1, so the pulse is administered to the patient every breath. According to other embodiments, n is greater than 1, thus providing intermittent administration of the dose. 
     Another aspect of the current invention provides a method of treating pulmonary hypertension comprising administering a therapeutic gas comprising a dose of nitric oxide having a delivery concentration greater than 2000 ppm. The therapeutic gas may be administered to the patient from a portable device comprising a delivery system and a mini-cylinder. As with the methods of delivering nitric oxide described above, the delivery concentration, cylinder exit concentration, valve exit concentration, or cylinder concentration of the therapeutic gas used for treating pulmonary hypertension may be within any of the specified ranges. 
     For treating pulmonary hypertension, the nitric oxide can be administered every nth breath, wherein n is 1 or greater. In certain embodiments, n is 1. In other embodiments, n is greater than 1, thus providing intermittent dosing. Some conditions are treated more effectively with pulsed administration versus continuous administration of therapeutic gas. For example, chronic obstructive pulmonary disease (COPD) is more effectively treated with pulsed administration, and continuous delivery of nitric oxide can actually worsen the symptoms of COPD. 
     The dose of nitric oxide for treating pulmonary hypertension can be in the range of 0.001 to 4.5 mg/kg/hr. As mentioned above, doses that have been reported for use in treating pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), chronic thromboembolic pulmonary hypertension (CTE), idiopathic pulmonary fibrosis (IPF) or pulmonary hypertension (PH), or using nitric oxide as an antimicrobial agent, may be in the range of 0.001 to 4.5 mg/kg/hr. Therefore, in certain embodiments, the dose of nitric oxide is in the range of 0.001 to 4.5 mg/kg/hr. In other embodiments, the dose of nitric oxide is in the range of 0.001 to 0.5 mg/kg/hr. In certain embodiments, the mini-cylinder used to treat pulmonary hypertension has a volume of less than 1 L. In other embodiments, the mini-cylinder has a volume less than 0.5 L. According to other embodiments, the mini-cylinder has a volume less than 0.2 L 
     According to one or more embodiments, the mini-cylinder has a volume in the range of 0.01 to 1 L. In certain embodiments, the mini-cylinder has a volume in the range of 0.05 to 0.5 L. In other embodiments, the mini-cylinder has a volume in the range of 0.1 to 0.3 L. In a particular embodiment, the mini-cylinder has a volume in the range of 0.15 to 0.2 L. 
     In one or more embodiments of the method for treating pulmonary hypertension, the therapeutic gas is not diluted prior to administering to the patient. In such embodiments, the delivery concentration is the same as or similar to the cylinder concentration. 
     EXAMPLES 
     Example 1 
     Nasal Tolerability of Nitric Oxide Dosing 
     A multiple-dose, single-blind, placebo-controlled, tolerance study of pulsed volumes of nitric oxide was completed using healthy subjects. An objective of the study was to determine safe dosing limits of inhaled nitric oxide delivered via a pulse system at cylinder concentrations of 100, 400, and 800 ppm and gas volumes ranging from 4 to 60 mL/breath. Yet another objective of the study was to determine the safety profile, including adverse events (AEs), vital signs and laboratory parameters. 
     Methodology: 
     Six subjects were assigned to each cohort (5 NO, 1 placebo) in a randomized, single-blind fashion. All subjects received 72 hours of continuous inhalation. A total of 22 cohorts were evaluated, with NO doses ranging from 125 to 1500 nmol/breath at delivery concentrations of 100, 400, or 800 ppm and varying volumes (4 to 60 mL per breath) in a matrix design, as shown in Table 1. Vital signs and safety laboratory were evaluated. Blood samples for determination of methemoglobin (MetHb) in venous blood, were collected for 72 hours at selected time points. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Group Assignment Matrix 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Cylinder 
                   
                 Delivery 
                 Number of 
               
               
                 Dose 
                   
                 Dose (nmol 
                 Concentration 
                 Volume (mL 
                 System 
                 Subjects 
               
               
                 Level a   
                 Cohort 
                 per breath) 
                 (ppm) 
                 per breath) 
                 (High/Low) b   
                 (NO/Placebo) a   
               
               
                   
               
            
           
           
               
            
               
                 LOW-DOSE ANALYSIS GROUP 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 1 
                 1 
                 125 
                 100 
                 30 
                 High 
                 5/1 
               
               
                   
                 2 
                 125 
                 400 
                 8 
                 Low 
                 5/1 
               
               
                   
                 3 
                 125 
                 800 
                 4 
                 Low 
                 5/1 
               
               
                 2 
                 4 
                 250 
                 100 
                 60 
                 High 
                 5/1 
               
               
                   
                 5 
                 250 
                 400 
                 15 
                 High 
                 5/1 
               
               
                 3 
                 6 
                 340 
                 400 
                 20 
                 High 
                 5/1 
               
               
                   
                 7 
                 340 
                 800 
                 10 
                 Low 
                 5/1 
               
               
                 4 
                 8 
                 420 
                 400 
                 25 
                 High 
                 5/1 
               
               
                 5 
                 9 
                 500 
                 400 
                 30 
                 High 
                 5/1 
               
               
                   
                 10 
                 500 
                 800 
                 15 
                 High 
                 5/1 
               
            
           
           
               
            
               
                 MID-DOSE ANALYSIS GROUP 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 6 
                 11 
                 585 
                 400 
                 35 
                 High 
                 5/1 
               
               
                 7 
                 12 
                 670 
                 400 
                 40 
                 High 
                 5/1 
               
               
                   
                 13 
                 670 
                 800 
                 20 
                 High 
                 5/1 
               
               
                 8 
                 14 
                 750 
                 400 
                 45 
                 High 
                 5/1 
               
               
                 9 
                 15 
                 840 
                 400 
                 50 
                 High 
                 5/1 
               
               
                   
                 16 
                 840 
                 800 
                 25 
                 High 
                 5/1 
               
               
                 10 
                 17 
                 920 
                 400 
                 55 
                 High 
                 5/1 
               
               
                 11 
                 18 
                 1000 
                 400 
                 60 
                 High 
                 5/1 
               
               
                   
                 19 
                 1000 
                 800 
                 30 
                 High 
                 5/1 
               
            
           
           
               
            
               
                 HIGH-DOSE ANALYSIS GROUP 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 12 
                 20 
                 1160 
                 800 
                 35 
                 High 
                 5/1 
               
               
                 13 
                 21 
                 1340 
                 800 
                 40 
                 High 
                  5/0 c   
               
               
                 14 
                 22 
                 1500 
                 800 
                 45 
                 High 
                 5/1 
               
               
                   
               
               
                   a For analysis purposes, placebo-treated subjects from all cohorts were combined into a single dose level [15th] and 1 dose analysis group. 
               
               
                   b Low-dose system delivered volumes ranging from 3 mL through 10 mL per pulse; High-dose system delivered volumes ranging from 15 mL through 60 mL. 
               
               
                   c One subject in cohort 21 did not receive placebo due to a limitation in supplies. 
               
            
           
         
       
     
     Number of Subjects: 
     A total of 132 subjects were enrolled, 131 received treatment (110 NO, 21 placebo) and 129 completed the 72-hour treatment period. 
     Safety: 
     Primary safety evaluations included: (1) qualitative assessment of local nasal tolerability via a scoring system (0 to 3); and (2) formation of MetHb (compared with a standard of 7%) following varying concentrations and volumes of pulsed doses of NO. Safety evaluations included assessments of adverse events (AEs), medical history, physical examinations, vital signs, electrocardiograms (ECGs) and laboratory assessments at baseline and during the study period. 
     Statistical Methods: 
     All evaluations were performed on the ‘Safety’ population, defined as all subjects who were enrolled and treated with any amount of study drug. Descriptive statistics included mean, standard deviation (SD), range, median, CV %, geometric mean and geometric CV %. 
     For analysis purposes, cohorts that received the same dose of NO but different cylinder concentrations and volumes were pooled, thereby creating 15 dose levels (n=14 active NO and 1 placebo, from all dose groups combined). These 15 dose levels were grouped into 4 dose analysis groups: placebo, low-dose NO (1-500 nmol/breath), mid-dose NO (501-1000 nmol/breath), and high-dose NO (1001-1500 nmol/breath). 
     Adverse Events: 
     The overall incidence of AEs was only dose related. Table 2 below shows that the most frequently occurring AEs, including headache, back pain, and nausea. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Most Frequently Occurring Adverse Events  
               
               
                 (% of subjects at each dose level) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 NO 1 - 500 
                 NO 501 - 1000 
                 NO 1001-1500 
               
               
                   
                 Placebo 
                 nmol/breath 
                 nmol/breath 
                 nmol/breath 
               
               
                 Preferred Term 
                 (N = 21) 
                 (N = 50) 
                 (N = 45) 
                 (N = 15) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Total % with  
                 28.6 
                 28.0 
                 33.3 
                 53.3 
               
               
                 any AE 
                   
                   
                   
                   
               
               
                 Headache 
                 4.8 
                 8.0 
                 4.4 
                 20.0 
               
               
                 Back pain 
                 0.0 
                 6.0 
                 4.4 
                 0.0 
               
               
                 Nausea 
                 0.0 
                 2.0 
                 4.4 
                 6.7 
               
               
                   
               
               
                 One subject (6.7%) in the high-dose NO group withdrew due to chest discomfort, decreased O 2  saturation, and dyspnea. 
               
            
           
         
       
     
     Nasal Tolerability: 
     Analysis for nasal tolerability at 72 hours by individual NO dose group, pulse volume of carrier airflow, and NO cylinder concentration demonstrates that the nasal tolerability was related to the dose levels used in the trial as there was no correlation with either pulse volume or cylinder concentration. A multivariate analysis, with tolerability score as the response variable and with dose level, cylinder concentration and pulse volume as the covariates, demonstrated that the NO dose level was the only significant covariate (p=0.006). The cylinder concentration (p=0.525) and the pulse volume (p=0.077) were not significant. Therefore, the nasal tolerability after 72 hours of pulsed dosing of NO is related to the NO dose and not to either the pulsed volume of carrier airflow or the NO cylinder concentration. Tables 3, 4 and 5 show the local tolerability analysis based on dose level, cylinder concentration, and pulse volume, respectively. 
     Furthermore, at clinical doses less than 420 nmol/breath (about 0.4 mg/kg/hr in an average 70 kg adult with a respiratory rate of 12 breaths/min), there was no evidence of nasal irritation with 48 hours of continuous administration of NO and at 72 hours the nasal tolerability is no different than for placebo (3/18 placebo subjects with nasal redness vs. 2/18 NO subjects with nasal redness). 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Local Tolerability Analysis at 72 Hours by Dose Group 
               
            
           
           
               
               
               
            
               
                 Dose Group 
                   
                   
               
               
                 (nmol/breath) 
                 Mean Score 
                 P-value 1   
               
               
                   
               
            
           
           
               
               
               
            
               
                 Placebo 
                 0.14 
                 0.006 
               
               
                 125 
                 0.07 
                   
               
               
                 250 
                 0.00 
                   
               
               
                 340 
                 0.10 
                   
               
               
                 420 
                 0.00 
                   
               
               
                 500 
                 0.10 
                   
               
               
                 585 
                 0.40 
                   
               
               
                 670 
                 0.00 
                   
               
               
                 750 
                 0.00 
                   
               
               
                 840 
                 0.60 
                   
               
               
                 920 
                 0.00 
                   
               
               
                 1000 
                 0.33 
                   
               
               
                 1160 
                 0.40 
                   
               
               
                 1340 
                 0.20 
                   
               
               
                 1500 
                 0.75 
               
               
                   
               
               
                   1 Obtained from a multivariate analysis with tolerability score as the response variable and dose, cylinder concentration, and pulse volume as the covariates. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Local Tolerability Analysis at 72 Hours by Cylinder Concentration 
               
            
           
           
               
               
               
            
               
                 Cylinder 
                   
                   
               
               
                 Concentration 
                   
                   
               
               
                 (ppm) 
                 Mean Score 
                 P-value 1   
               
               
                   
               
            
           
           
               
               
               
            
               
                 0 
                 0.14 
                 0.525 
               
               
                 100 
                 0.10 
                   
               
               
                 400 
                 0.09 
                   
               
               
                 800 
                 0.33 
               
               
                   
               
               
                   1 Obtained from a multivariate analysis with tolerability score as the response variable and dose, cylinder concentration, and pulse volume as the covariates. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Local Tolerability Analysis at 72 Hours by Pulse Volume 
               
            
           
           
               
               
               
            
               
                 Pulse Volume 
                   
                   
               
               
                 (mL/pulse) 
                 Mean Score 
                 P-value 1   
               
               
                   
               
            
           
           
               
               
               
            
               
                 0 
                 0.14 
                 0.077 
               
               
                 4 
                 0.00 
                   
               
               
                 8 
                 0.00 
                   
               
               
                 10 
                 0.20 
                   
               
               
                 15 
                 0.10 
                   
               
               
                 20 
                 0.00 
                   
               
               
                 25 
                 0.60 
                   
               
               
                 30 
                 0.07 
                   
               
               
                 35 
                 0.40 
                   
               
               
                 40 
                 0.10 
                   
               
               
                 45 
                 0.33 
                   
               
               
                 50 
                 0.00 
                   
               
               
                 55 
                 0.00 
                   
               
               
                 60 
                 0.30 
               
               
                   
               
               
                   1 Obtained from a multivariate analysis with tolerability score as the response variable and dose, cylinder concentration, and pulse volume as the covariates. 
               
            
           
         
       
     
     Example 2 
     Administration of High Doses of Nitric Oxide 
     In this prophetic example, patients are administered a dose of nitric oxide during inspiration, the dose comprising a delivery concentration of greater than 2000 ppm. Some patients are administered a dose of nitric oxide in the range of 2200 to 2600 ppm, such as about 2440 ppm nitric oxide. Other patients are administered a dose of nitric oxide in the range of 4400 to 5000 ppm nitric oxide, such as about 4880 ppm nitric oxide. Other patients may be administered doses above 5000 ppm, including up to about 10,000 ppm nitric oxide. 
     The patients are administered a pulse of therapeutic gas comprising nitric oxide every nth breath, with n being greater than or equal to 1. For one group of patients, n is equal to one such that the pulse of therapeutic gas is administered every breath. For another group of patients, n is greater than 1 such that the pulse of therapeutic gas is administered intermittently. Reference throughout this specification to “one embodiment,” “certain embodiments,” “one or more embodiments” or “an embodiment” means that a particular feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrases such as “in one or more embodiments,” “in certain embodiments,” “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily referring to the same embodiment of the invention. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. 
     Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It will be apparent to those skilled in the art that various modifications and variations can be made to the method and apparatus of the present invention without departing from the spirit and scope of the invention. Thus, it is intended that the present invention include modifications and variations that are within the scope of the appended claims and their equivalents.