Methods of Reducing the Risk of Mortality Associated With a Medical Treatment

Abstract

Disclosed are methods of treatment that permit a reduction of risk of mortality in infants who are candidates for treatment with inhaled nitric oxide, by identifying a subset of such infants who are at an increased risk of mortality upon treatment with inhaled nitric oxide; also disclosed are related systems for use in administering inhaled nitric oxide and methods of distributing a pharmaceutical product.

What is claimed is: 
     
         1 . A method of treatment comprising
 (a) identifying a plurality of neonates as being candidates for treatment with inhaled nitric oxide;   (b) determining that the race of a first neonate of the plurality is black;   (c) administering inhaled nitric oxide to the first neonate;   (d) determining that the race of a second neonate of the plurality is white;   (e) determining that the gender of the second neonate is male;   (f) determining that the second neonate is of less than 27 weeks gestational age;   (g) determining that the fact that the second neonate is a white male of less than 27 weeks gestational age means the second neonate is at a higher risk of mortality upon administration of inhaled nitric oxide compared to a black male or female neonate of the same gestational age; and   (h) excluding the second neonate from treatment with inhaled nitric oxide, based on the determination of (g).   
     
     
         2 . A method of treatment comprising
 (a) identifying a plurality of neonates as being candidates for treatment with inhaled nitric oxide;   (b) determining that the gender of a first neonate of the plurality is female;   (c) administering inhaled nitric oxide to the first neonate;   (d) determining that the gender of a second neonate of the plurality is male;   (e) determining that the race of the second neonate is white;   (f) determining that the second neonate is of less than 27 weeks gestational age;   (g) determining that the fact that the second neonate is a white male of less than 27 weeks gestational age means the second neonate is at a higher risk of mortality upon administration of inhaled nitric oxide compared to a black male or female neonate of the same gestational age; and   (h) excluding the second neonate from treatment with inhaled nitric oxide, based on the determination of (g).   
     
     
         3 . The method of  claim 1 , wherein the second neonate is treated with ventilatory support, intravenous fluids, surfactant, and/or bicarbonate therapy. 
     
     
         4 . The method of  claim 1 , wherein the second neonate does not have pulmonary hypertension. 
     
     
         5 . The method of  claim 1 , wherein the second neonate is identified as being at risk of developing bronchopulmonary dysplasia (BPD). 
     
     
         6 . The method of  claim 1 , wherein the second neonate is treated with high-frequency oscillatory ventilation. 
     
     
         7 . The method of  claim 1 , wherein the second neonate is not identified as being dependent on right-to-left shunting of blood. 
     
     
         8 . The method of  claim 1 , wherein the second neonate does not have left ventricular dysfunction. 
     
     
         9 . A method of selecting a treatment for a pre-term neonate, the method comprising
 (a) identifying a pre-term neonate of gestational age less than 27 weeks;   (b) treating the pre-term neonate with mechanical ventilation or positive airway pressure support;   (c) determining that the pre-term neonate is at risk for BPD;   (d) determining that the pre-term neonate is a white male;   (e) determining that the fact that the pre-term neonate is a white male means the pre-term neonate is at a higher risk of mortality upon administration of inhaled nitric oxide for prevention of BPD compared to a black pre-term neonate or female pre-term neonate of the same gestational age; and   (f) excluding the white, male, pre-term neonate from treatment with inhaled nitric oxide for prevention of BPD, based on the determination of (e).   
     
     
         10 . The method of  claim 9 , wherein the white, male, pre-term neonate is treated with supplemental oxygen, caffeine, vitamin A, or one or more surfactants. 
     
     
         11 . The method of  claim 9 , wherein the white, male, pre-term neonate is treated with high-frequency oscillatory ventilation instead of inhaled nitric oxide. 
     
     
         12 . A method of selecting a treatment for a pre-term neonate, the method comprising:
 (a) identifying a pre-term neonate of less than 27 weeks gestational age as being in need of inhaled nitric oxide for treatment of a condition involving pulmonary hypertension;   (b) determining that the pre-term neonate is a white male;   (c) determining that the fact that the pre-term neonate is a white male means the pre-term neonate is at a higher risk of mortality upon administration of inhaled nitric oxide compared to a black pre-term neonate or a female pre-term neonate of the same gestational age; and   (d) administering inhaled nitric oxide to the white, male, pre-term neonate for a limited period of time not exceeding four days, for treatment of the condition involving pulmonary hypertension, where the limitation on the length of treatment is due to a concern about the higher risk of mortality in white, male, pre-term neonates of less than 27 weeks gestational age.   
     
     
         13 . The method of  claim 12 , wherein the nitric oxide is administered at 20 ppm. 
     
     
         14 . The method of  claim 12 , wherein the white, male, pre-term neonate is treated with ventilatory support, intravenous fluids, surfactant, and/or bicarbonate therapy, both during the period of inhaled nitric oxide administration and after the administration ceases. 
     
     
         15 . The method of  claim 13 , wherein the white, male, pre-term neonate is a candidate for inhaled nitric oxide because of hypoxic respiratory failure or because he is undergoing, or has just undergone, cardiac surgery involving heart/lung bypass. 
     
     
         16 . A method of treatment comprising
 (a) identifying a pre-term neonate of less than 27 weeks gestational age as being in need of inhaled nitric oxide for prevention of BPD;   (b) determining that the pre-term neonate is a white male;   (c) determining that the fact that the pre-term neonate is a white male means the pre-term neonate is at a higher risk of mortality upon administration of inhaled nitric oxide compared to a black pre-term neonate or female pre-term neonate of the same gestational age;   (d) deciding to postpone inhaled nitric oxide treatment until the white, male, pre-term neonate reaches 27 weeks gestational age, due to the determination of (c);   (e) administering a treatment other than inhaled nitric oxide to the white, male pre-term neonate; and   (f) when the white, male, pre-term neonate reaches 27 weeks gestational age, beginning administration of inhaled nitric oxide to the white, male, pre-term neonate.   
     
     
         17 . The method of  claim 16 , wherein the treatment administered prior to beginning inhaled nitric oxide administration comprises caffeine, vitamin A, supplemental oxygen, or one or more surfactants. 
     
     
         18 . The method of  claim 16 , wherein the day that the white, male, pre-term neonate reaches 27 weeks gestational age and the administration of inhaled nitric oxide begins is within 5-14 days after birth. 
     
     
         19 . A method of treatment comprising
 (a) identifying a neonate as being a candidate for treatment with inhaled nitric oxide;   (b) determining that the neonate is a white male of less than 27 weeks gestational age;   (c) providing ventilatory support to the neonate;   (d) determining that the fact that the neonate is a white male of less than 27 weeks gestational age means the neonate is at a higher risk of mortality upon administration of inhaled nitric oxide compared to a black neonate or female neonate of the same gestational age; and   (e) excluding the white, male neonate from treatment with inhaled nitric oxide, based on the determination of (d).   
     
     
         20 . The method of  claim 19 , wherein the white, male neonate is less than 27 weeks gestational age. 
     
     
         21 . The method of  claim 19 , wherein the ventilatory support is high-frequency oscillatory ventilation. 
     
     
         22 . The method of  claim 19 , wherein the white, male neonate is treated with intravenous fluids, surfactant, and/or bicarbonate therapy. 
     
     
         23 . The method of  claim 9 , wherein the white, male neonate or white, male, pre-term neonate is not dependent on right-to-left shunting of blood. 
     
     
         24 . The method of  claim 9 , wherein the white, male neonate or white, male, pre-term neonate does not have left ventricular dysfunction. 
     
     
         25 . A system for use in administering inhaled nitric oxide gas, which system reduces the overall risk of mortality from inhalation of nitric oxide, the system comprising:
 a source of pharmaceutically acceptable nitric oxide gas for inhalation;   a delivery device suitable for delivering nitric oxide gas from the source to a neonatal patient; and   instructions for use in operating the system, the instructions comprising a warning that nitric oxide gas may have an increased risk of mortality in white, male, pre-term infants of less than 27 weeks gestational age, wherein the instructions do not contain a similar warning for pre-term infants of less than 27 weeks gestational age who are not white males, and wherein the instructions reduce the overall risk of mortality from inhalation of nitric oxide compared to a similar system without the instructions.   
     
     
         26 . The system of  claim 25 , wherein the instructions include a description of using the system to deliver 20 ppm inhaled nitric oxide gas to treat a neonatal patient. 
     
     
         27 . The system of  claim 25 , wherein the instructions also include a contraindication for neonates who are dependent on right to left shunting of blood. 
     
     
         28 . The system of  claim 25 , wherein the instructions also include a statement that a patient with pre-existing left ventricular dysfunction, when treated with inhaled nitric oxide, may experience increased pulmonary capillary wedge pressure (PCWP) leading to pulmonary edema. 
     
     
         29 . The system of  claim 25 , wherein the warning is effective in excluding a population of white, male, pre-term infants less than 27 weeks gestational age from treatment with inhaled nitric oxide, thereby reducing the overall risk of mortality resulting from inhaled nitric oxide treatment. 
     
     
         30 . A method of distributing a pharmaceutical product, the method comprising:
 supplying a source of nitric oxide gas to a medical provider responsible for treating a plurality of neonatal patients who are candidates for treatment with inhaled nitric oxide;   informing the medical provider that a recommended dose of inhaled nitric oxide is 20 ppm nitric oxide; and   providing a warning to the medical provider that white, male, pre-term infants of less than 27 weeks gestational age may have an increased risk of death, as compared to non-white pre-term infants and female pre-term infants of the same gestational age, upon treatment with inhaled nitric oxide.   
     
     
         31 . The method of  claim 30 , wherein the warning is effective in reducing the use of inhaled nitric oxide in white, male, pre-term infants of less than 27 weeks gestational age who are at risk of developing BPD. 
     
     
         32 . The method of  claim 30 , further comprising manufacturing the source of nitric oxide gas by a process comprising diluting nitric oxide gas with nitrogen gas to produce a gaseous mixture of nitric oxide and nitrogen in a cylinder. 
     
     
         33 . A method of distributing a pharmaceutical product, the method comprising:
 supplying a source of nitric oxide gas to a medical provider responsible for treating a plurality of infants who have pulmonary hypertension or who are at risk of BPD;   informing the medical provider that a recommended dose of inhaled nitric oxide gas is 20 ppm nitric oxide;   providing a warning to the medical provider that inhaled nitric oxide should not be administered to white, male, pre-term infants less than 27 weeks gestational age who are at risk of BPD.   
     
     
         34 . The method of  claim 33 , wherein the warning is effective in excluding from treatment with inhaled nitric oxide a population of white, male, pre-term infants less than 27 weeks gestational age who are at risk of BPD, thereby reducing the overall risk of mortality resulting from inhaled nitric oxide treatment. 
     
     
         35 . The method of  claim 33 , further comprising manufacturing the source of nitric oxide gas by a process comprising diluting nitric oxide gas with nitrogen gas to produce a gaseous mixture of nitric oxide and nitrogen in a cylinder. 
     
     
         36 . The method of  claim 30 , wherein the source of nitric oxide gas comprises a container containing compressed nitric oxide or nitrogen dioxide, and the method further comprises generating the nitric oxide or nitrogen dioxide and introducing it into the container in compressed form, prior to supplying it to the medical provider. 
     
     
         37 . The method of  claim 30 , wherein the source of nitric oxide gas comprises a container of N 2 O 4 , and the method further comprises generating the N 2 O 4 . 
     
     
         38 . The method of  claim 30 , wherein supplying the source of nitric oxide gas to the medical provider comprises manufacturing the source of nitric oxide gas at a manufacturing location and transporting the source from the manufacturing location to a site where the medical provider administers inhaled nitric oxide treatment to patients. 
     
     
         39 . The method of  claim 30 , wherein supplying the source of nitric oxide gas to the medical provider comprises transporting the source from a manufacturing, distribution or storage site to a site where the medical provider administers inhaled nitric oxide treatment to patients. 
     
     
         40 . A method of treatment comprising
 (a) identifying a plurality of neonates as being candidates for treatment with inhaled nitric oxide;   (b) determining that the race of a first neonate of the plurality is non-white;   (c) administering inhaled nitric oxide to the first neonate;   (d) determining that the race of a second neonate of the plurality is white;   (e) determining that the gender of the second neonate is male;   (f) determining that the second neonate is of less than 27 weeks gestational age;   (g) determining that the fact that the second neonate is a white male of less than 27 weeks gestational age means the second neonate is at a higher risk of mortality upon administration of inhaled nitric oxide compared to a non-white, male neonate or a female neonate of the same gestational age; and   (h) excluding the second neonate from treatment with inhaled nitric oxide, based on the determination of (g).   
     
     
         41 . A system for use in administering inhaled nitric oxide gas, which system reduces the overall risk of mortality from inhalation of nitric oxide, the system comprising:
 a source of pharmaceutically acceptable nitric oxide gas for inhalation;   a delivery device suitable for delivering nitric oxide gas from the source to a neonatal patient; and   instructions for use in operating the system, the instructions comprising a warning that nitric oxide gas may have an increased risk of mortality in white, male, pre-term infants of less than 27 weeks gestational age who are at risk of developing BPD and who do not have pulmonary hypertension, wherein the instructions do not contain a similar warning regarding an increased risk of mortality for pre-term infants of less than 27 weeks gestational age who are not white males, and wherein the instructions reduce the overall risk of mortality from inhalation of nitric oxide compared to a similar system without the instructions.   
     
     
         42 . A system for use in administering inhaled nitric oxide gas, which system reduces the overall risk of mortality from inhalation of nitric oxide, the system comprising:
 a source of pharmaceutically acceptable nitric oxide gas for inhalation;   a delivery device suitable for delivering nitric oxide gas from the source to a neonatal patient; and   instructions for use in operating the system, the instructions communicating that, in a subset of white, male, pre-term infants less than 27 weeks gestational age, without pulmonary hypertension and at risk of developing BPD, there was seen in one study an imbalance in deaths in the INOmax treated group as compared to placebo at doses of 20 ppm for 3 days reduced to 10 ppm for 10 days and 5 ppm for remainder of 24 days;   wherein the instructions reduce the overall risk of mortality from inhalation of nitric oxide compared to a similar system without the instructions, by reducing use of inhaled nitric oxide in white, male, pre-term infants less than 27 weeks gestational age.