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Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use of iNO in the Institutional Market,  Therapy Demand and Cost of Care vs. Existing Supply Solutions

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Introduction  to Inhaled Nitric Oxide Therapy in Adults

Part 1:             Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market

Part 2:            Clinical Outcomes after Use of iNO in the Institutional Market

Part 3:            Therapy Demand and Cost of Care vs. Existing Supply Solutions

Part 4:            Product Development Concepts for New Medical Devices to Deliver Inhaled Nitric Oxide

Introduction  to Inhaled Nitric Oxide Therapy in Adults: Evidence-based Medicine 

This Introduction section of the article is based on research results and literature survey in:

Mark J.D. Griffiths, M.R.C.P., Ph.D., and Timothy W. Evans, M.D., Ph.D.

Inhaled Nitric Oxide Therapy in Adults, n engl j med 353;25 http://www.nejm.org December 22, 2005

http://www.nejm.org/doi/full/10.1056/NEJMra051884

• On the basis of the evidence, inhaled nitric oxide is not an effective therapeutic intervention in patients with acute lung injury or ARDS, and its routine use to achieve this end is inappropriate. However, inhaled nitric oxide may be useful as a short-term adjunct to cardiorespiratory support in patients with acute hypoxemia, life-threatening pulmonary hypertension, or both.

• Inhaled nitric oxide is a selective pulmonary vasodilator that improves ventilation–perfusion matching at low doses in patients with acute respiratory failure, potentially improving oxygenation and lowering pulmonary vascular resistance.

• Large clinical trials have indicated that physiologic benefits are short-lived in adults with acute lung injury or ARDS, and no associated improvement in mortality rates has been demonstrated. However, clinical trials involving patients with acute lung injury or ARDS have been statistically underpowered to show a decrease in mortality rates and have not considered recent insights into the effect of continuous inhalation on the dose– response relationship of this agent. In patients with acute respiratory failure, the potential toxicity or protective effects of inhaled nitric oxide, particularly any effects on cell survival and inflammation, are poorly understood.

• Ideal Treatment Goals for Inhaled Nitric Oxide

1. Improved oxygenation
2. Decreased pulmonary vascular resistance
3. Decreased pulmonary edema
4. Reduction or prevention of inflammation – rebound phenomena may be avoided by withdrawing inhaled nitric oxide gradually. Despite these concerns, in large clinical studies of patients with ARDS, the abrupt discontinuation of inhaled nitric oxide has not caused a deterioration in oxygenation
5. Cytoprotection
6. Protection against infection

• Administration of Inhaled Nitric Oxide to Adults: Routes and Safety Monitoring

Nitric oxide is most commonly administered to patients receiving mechanical ventilation, although it may also be given through a face mask or nasal cannulae. Limiting the mixing of nitric oxide and high concentrations of inspired oxygen reduces the risk of adverse effects resulting from the formation of nitrogen dioxide. This is minimized further by introducing the mixture of nitric oxide and nitrogen into the inspiratory limb of the ventilator tubing as near to the patient as possible and synchronizing injection of the mixture with inspiration

• Electrochemical analyzers can be used to monitor the concentrations of nitric oxide and nitrogen dioxide in the inspired gas mixture to an accuracy of 1 ppm.

• More sensitive Chemiluminescence monitors can detect nitric oxide and its oxidative derivatives in parts per billion.

• Dose-Response for Respiratory Failure in the Adult Patient – a response is defined as a 20 percent increase in oxygenation. For example, a 10 percentage point improvement in hemoglobin saturation in a patient with hypoxemia who is breathing 100 percent oxygen may be clinically very important.

• Dose-Response for Pulmonary Hypertension in the Adult Patient – a 30 percent decrease in pulmonary vascular resistance during the inhalation of nitric oxide (10 ppm for 10 minutes) has been used to identify an association with vascular responsiveness to agents that can be helpful in the long term. A positive response to nitric oxide was associated with a favorable response to calcium-channel blockers in a small cohort of patients with primary pulmonary hypertension

• Time-dependent variation in the dose–response relationship of inhaled nitric oxide in patients with severe ARDS – Observations imply that the optimal dose of inhaled nitric oxide must be determined by titration against the therapeutic target in each patient at least every two days, and probably more frequently.

• Other Inhaled Vasodilators – Alternatives and Adjuncts to Inhaled Nitric Oxide

1. Aerosolized sodium nitrite caused potent, selective, nitric oxide–dependent pulmonary vasodilatation through its reaction with deoxyhemoglobin at a low pH, suggesting that nitrite may be a cheap and stable alternative to inhaled nitric oxide
2. Epoprostenol, the most extensively studied alternative to inhaled nitric oxide, is also an endothelium- derived vasodilator with antithrombotic effects. Inhaled epoprostenol has an effect on hemodynamics and oxygenation similar to that of nitric oxide in patients with ARDS, sepsis, or severe heart failure. Nebulized epoprostenol has been studied less frequently than inhaled nitric oxide, but at therapeutic doses (10 to 50 ng per kilogram per minute), the rates of predicted side effects, such as systemic hypotension and bleeding after surgery, have not been clinically important.
3. Iloprost, a long-acting prostacyclin analogue (half-life, 20 to 30 minutes), improves the exercise tolerance of patients with severe pulmonary hypertension when administered by intermittent rather than by continuous nebulization. Inhaled prostaglandin E1 (6 to 15 ng per kilogram of body weight per minute) has effects similar to those of inhaled nitric oxide (2 to 10 ppm) in patients with ARDS

• Agonists to Nitric Oxide – Adjunctive Therapies That Increase the Effectiveness of Inhaled Nitric Oxide

1. Orally administered sildenafil, an inhibitor of phosphodiesterase type 5, is a selective pulmonary vasodilator, partially because phosphodiesterase type 5 is highly expressed in the lung. Sildenafil has augmented pulmonary vasodilatation induced by inhaled nitric oxide,  although a second inhibitor of phosphodiesterase type 5, zaprinast, predictably worsened oxygenation through the attenuation of hypoxic pulmonary vasoconstriction in an ovine model of acute lung injury.  Such agents may therefore be most useful when pulmonary hypertension rather than respiratory failure is the chief concern.

2. Almitrine, an agonist at peripheral arterial chemoreceptors, is a selective pulmonary vasoconstrictor that specifically enhances hypoxic pulmonary vasoconstriction. The addition of almitrine to low-dose inhaled nitric oxide improves oxygenation in patients with ARDS, but concern about the effects of long-term infusion has hampered the wider investigation of this combination. In patients with acute respiratory failure, the effect of nitric oxide depends on the degree of recruitment of injured lung units by — for example — positive end-expiratory pressure, prone positioning, or ventilatory maneuvers designed to inflate collapsed lung, which may explain how the response to nitric oxide varies over short periods. Partial liquid ventilation with perfluorocarbons facilitates the delivery of dissolved gases to alveoli by enhancing recruitment of the injured lung units. Inhaled nitric oxide has enhanced the effects of partial liquid ventilation on gas exchange in animal models, demonstrating the potential benefit of combining therapeutic strategies in patients with ARDS.

For 2005 – 2013 List of References on Inhaled Nitric Oxide Therapy in Adults, see the list of article that has cited  at the bottom of the following seminal paper:

http://circ.ahajournals.org/content/109/25/3106.full

Part 1:

Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market:

SOURCE:

George, Isaac, Xydas, Steve, Topkara, Veli K., Ferdinando, Corrina, Barnwell, Eileen C., Gableman, Larissa, Sladen, Robert N., Naka, Yoshifumi, Oz, Mehmet C.
Clinical Indication for Use and Outcomes After Inhaled Nitric Oxide Therapy
Ann Thorac Surg 2006 82: 2161-2169

Abbreviations and Acronyms

ARDS  adult respiratory distress syndrome

iNO  inhaled nitric oxide

OHT  orthotopic heart transplantation

OLT  orthotopic lung transplantation

PAP  pulmonary artery pressure

PVR  pulmonary vascular resistance

ROC  receiver operating curve

RV  right ventricular

VAD  ventricular assist device

Institutional Guidelines for Inhaled Nitric Oxide Administration – Table 1 in the Study

1. Heart transplantation with evidence of pulmonary hypertension

2. Complicated coronary surgery with evidence of right ventricular failure based on at least one of the following

criteria

• Mean pulmonary artery pressure 25 mm Hg
• Echocardiographic evidence of moderate to severe right
• ventricular dysfunction; severe right atrial or ventricular enlargement
• Cardiac index 2.2 L · min1 · m2

3. Precapillary pulmonary hypertension diagnosis

4. Congenital cardiac disease

5. Acute chest syndrome in sickle cell disease

6. The starting dose for all above indications was 10 to 20 ppm, with an initial trial for 60 minutes before up-titration.

Indication for inhaled nitric oxide (iNO) use – Surgical Patient

1.  orthotopic heart transplantation [OHT] with pulmonary hypertension;

2. precapillary pulmonary hypertension;

3. coronary surgery with right ventricular failure;

4. congenital cardiac disease;

• OLT – orthotopic lung transplantation- patients received iNO for treatment of pulmonary hypertension, 
• OHT – orthotopic heart transplant  –  right ventricular failure was the most common indication for patients undergoing cardiac surgery and ventricular assist device (VAD) implantation.

Indication for inhaled nitric oxide (iNO) use – Medical Patients in ICU

5. hypoxemia                                                                                                                                                                                                    

• Other surgical and medical patients received iNO predominantly for hypoxemia use.

A trend toward a lower average duration of iNO use was seen:

• after OHT (n 67) and OLT (n 45)

versus

• cardiac surgery (n 105),
• VAD (n 66),
• other surgery (n 34), and
• medical patients (n 59; p 0.09).

Primary Surgical Procedure –  Table 4. in the Study – All Patients in the Study

Abbreviations and Acronyms

BiVAD biventricular assist device;

CABG coronary artery bypass grafting;

LVAD left ventricular assist device;

MVR mitral valve replacement or repair;

OHT orthotopic heart transplantation;

OLT orthotopic lung transplanatation;

RVAD right ventricular assist device;

Txp transplant;

VAD ventricular assist device.

AVR aortic valve replacement;

OHT = 67 OLT = 45 Cardiac Surgery = 105  VAD = 66  Other Surgery = 34  Medical (No Surgery) = 59

N (%)

OHT – Heart Txp – 67 (100)

OLT – Lung Txp – 45 (100)

Cardiac Surgery = 105

• AVR, 10 (9.5) 59 (100)
• AVR/MVR, 10 (9.5)
• CABG, 23 (21.9)
• CABG/Valve, 23 (21.9)
• MVR, 22 (20.9)
• Other cardiac, 11 (10.5)
• Other valve, 3 (2.9)

VAD = 66

• LVAD, 54 (81.8)
• BiVAD, 12 (18.2)
• RVAD, 0

Other surgery = 34

• Other surgery 21 (61.8)
• Thoracic surgery, 8 (23.5)
• Other Txp. 5 (14.7)

Medical =59 in ICU

• No Surgery, 59 (100)

Part 2:

Clinical Outcomes after Use of iNO in the Institutional Market

Use of iNO for pulmonary hypertension in patients undergoing

• OHT and orthotopic lung transplantation was associated with a significantly lower overall mortality rate compared with its use after cardiac surgery or for hypoxemia in medical patients.
• Inhaled nitric oxide does not appear to be cost effective when treating hypoxemia in medical patients with high-risk scores and irreversible disease.

In conclusion,

• the present study reports comprehensive long-term survival data from a critically ill adult population receiving iNO therapy.
• Inhaled nitric oxide treatment is a valuable pharmacologic adjunct in OHT and OLT for short-term hemodynamic improvements, and long-term data from the present study suggest a translation into long-term survival benefits.
• Mortality outcomes after iNO are directly related to the clinical indication for use, and prolonged therapy for patients with irreversible systemic disease processes, such as hypoxemia or respiratory failure in medical patients, is not warranted.
• Poor outcomes and high cost for medical patients with respiratory failure and hypoxemia in this study require further investigation to determine the appropriate duration of iNO use based on clinical response and appropriate endpoints of treatment.
• A prospective clinical study controlling for severity of illness and addressing clinical efficacy in both surgical and medical populations is needed to definitively answer these questions, and may help reduce the burden of intensive care expenses.

Comment

Inhaled nitric oxide therapy has been shown to lead to reductions in PAP and PVR and improvement in oxygenation in several populations, including neonates and adult patients with ARDS and RV dysfunction, and after OHT or OLT [3, 6, 9, 10, 14]. These effects may improve short-term outcomes, but a study of long-term outcomes, costs, and clinical use of iNO use in other populations has not been conducted to date. This study is the first to describe outcomes and cost of iNO therapy in an unselected population of critically ill adult patients in a tertiary care center. These study results demonstrate that (1) outcomes after iNO vary substantially based on clinical indication of use, (2) iNO may benefit transplant patients more than other patients, and (3) iNO does not appear to alter the natural history or long-term clinical course of hypoxemic respiratory failure. This study also identifies the medical patient population with respiratory failure as one with substantial morbidity whose high mortality after iNO precludes prolonged therapy.

In the present study, OHT and OLT patients had a 1-year survival rate four times greater than medical patients not undergoing surgery, as well as higher survival rates compared with patients undergoing other types of surgery. The large differences in mortality after iNO therapy may be attributed to differences in the underlying etiology of the cardiac or respiratory failure (pulmonary hypertension versus hypoxemia) and the reversibility of pulmonary hypertension versus respira- tory failure.

In OHT, acutely elevated PAP, which accounts for 19% of early deaths after heart transplantation [24], may be secondary to both increases in flow (increased backward transmission of elevated left ventricular pressure) and increases in resistance in the pulmonary bed. With iNO use, PVR and PAP are reduced [25], decreasing RV afterload, ameliorating the wean from cardiopulmonary bypass, and preventing RV failure without affecting systemic vascular resistance. By providing temporary support, iNO therapy after transplant allows for the stabilization of hemodynamics until PVR returns to normal levels, which is attained in 80% of patients 1 year after OHT [26], reinforcing its reversible nature after cardiac transplantation. Short-term use of iNO after OHT has been demonstrated to improve RV function, PVR, and mean PAP after 12 to 76 hours of iNO use in 16 OHT patients, although there were no statistically significant differences in survival [9]. In 23 OLT patients, iNO therapy has been shown to reduce reimplantation edema, increase PaO2/FIO2, decrease the need for mechanical ventilation, and reduce the 2-month mortality rate [10].

The observed improvement in pulmonary hypertension also predicts significant outcome benefits, as OHT patients with reversible preoperative PVR have a much lower mortality than do those with a fixed elevated PVR [27, 28]. Survival at 4 years after iNO therapy was 68% in the transplant cohort in the present study, comparing favorably to reported 5-year survival rates of 71% for OHT [29] and 63% for OLT [30]. This study confirms prior studies that have shown acute benefits with iNO therapy after transplantation and shows that long-term survival in OHT and OLT after iNO therapy is comparable to that of patients not requiring iNO. In addition, although mortality in the VAD group was not appreciably different than that in the cardiac surgery group, a likely benefit of iNO in these patients was the avoidance of right ventricular assist device placement, as evidenced by the low rate of left ventricular assist device patients requiring a right ventricular assist device (5 of 66, 7.6%).

Furthermore, iNO therapy has not been shown to lead to long-term benefits in the treatment of severe respiratory failure, which was present in 80% of the medical cohort in this study, or hypoxemia, which was the primary indication in 85% of the medical patients. No benefit beyond 1 day of therapy was seen in indices of lung function in a randomized controlled clinical trial of 30 medical patients with severe respiratory failure and ARDS, yielding a 30-day mortality rate of 60% in iNOtreated patients and 53% in nontreated patients (p _ 0.71) [31]. More importantly, nonresponders had a 30-day mortality rate of 80%, whereas responders had a 50% mortality rate. The lack of short-term mortality benefit was confirmed by Michael and colleagues [32] in a randomized controlled trial of iNO in ARDS patients that showed transient improvements after 1 hour but no sustained improvements after 72 hours in PaO2, FIO2, and PaO2/FIO2. These two studies highlight important findings that iNO initially improves indices of lung function but does not produce lasting effects on oxygenation.

The inability to produce sustained effects on hypoxia and respiratory failure may explain the striking 1-year survival of only 17.3% and 4-year survival of 0% in our medical cohort, rates higher than the 90-day mortality rates of 40% to 50% that have been previously reported [33, 34]. Medical patients with severe cardiac or respiratory failure requiring iNO therapy represent a critically ill, challenging population with numerous comorbidities.

Judicious use of iNO is warranted for such patients if the immediate mortality risk is estimated to be high. The risk-scoring model reported here allows stratification of patients based on clinical history and provides prognostic information on mortality outcomes. The model predicted a mortality of 76.5% versus 37.2% (p _ 0.001) for a risk score greater than 1, with a sensitivity of 60%, specificity of 79%, and area under ROC of 0.731.

For cases in which the benefit is likely to be limited with a risk score greater than 1 (namely, respiratory failure in any non-OHT patient), efforts should be made to determine whether a patient responds to iNO therapy before prolonged administration is undertaken. As expected, hours of iNO use were highest in the medical group at 133 hours, and lowest after OHT and OLT at 71 and 57 hours, respectively. However, longer average duration of use did not produce higher iNO costs using the 2000 to 2003 charging practice, as many patients in all subgroups reached the maximal monthly charge after the first 4 days of therapy. This cap on iNO charges served to equalize costs in surgical and nonsurgical groups, and healthcare providers may continue iNO use in nonresponders as salvage therapy, given that it may not increase iNO-associated charges. However, the cost difference was more pronounced for OLT patients compared with medical and VAD patients using the current hourly charging practice, which was intended to reduce the overall cost of iNO therapy through more precise hourly billing. These findings confirm that prolonged iNO use is associated with higher cost and provides a financial rationale for limiting therapy for patients without expected survival benefit.

The study limitations include those inherent to an observational study. The lack of a randomized design and a control cohort not receiving iNO therapy precludes any definitive conclusions regarding the long-term clinical efficacy or cost effectiveness of iNO use, as long-term hemodynamics were unable to be measured and costeffectiveness measurements were not calculated. The transient but clinically important appearance of RV dysfunction in the operating room may only be apparent on hemodynamic analysis rather than on echocardiography, and RV dysfunction may be underreported using our echocardiographic definition. The poor survival rates observed in the medical cohort may be attributed to late initiation of iNO therapy in this group; it cannot, therefore, be excluded that earlier iNO administration may have led to higher survival rates. Finally, the absence of indirect hospital costs is a major limiting factor in the description of iNO costs, which may be significant.

Ann Thorac Surg 2006;82:2161-2169

Part 3:

Therapy Demand and Cost of Care vs. Existing Supply Solutions

Acquisition Cost of Inhaled Nitric Oxide Therapy

Charges for each iNO therapy encounter were calculated based on the charging practice of INO Therapeutics (AGA Healthcare, Clinton, New Jersey) between 2000 and 2003, and recalculated using the current 2005 charging practice. For the years 2000 to 2003, the charge to hospitals was $3,000 per 24 hours of therapy, up to a maximum charge of $12,000 per month, independent of  total hourly usage. Using the current 2005 charging practice, the charge for iNO was changed to an hourly rate of $125, with a maximum charge of $12,000 per month, independent of hourly usage. Indirect costs associated with iNO administration, including those for respiratory personnel, intensive care unit care, and daily monitoring were not included in this analysis.

Estimated Cost of iNO Therapy

The cost for iNO therapy is summarized in Table 6 using the 2000 to 2003 charging practice and current 2005 charging practice, demonstrating a higher cost of therapy in VAD and medical patients. Under the current 2005 pricing, a significantly lower proportion of OHT and OLT patients reached the maximal charge versus medical patients (23% versus 51%, p 0.001).

a p 0.05 versus VAD. b p 0.05 versus VAD, medical.

OHT orthotopic heart transplantation; OLT orthotopic lung transplantation; VAD ventricular assist device.

Ann Thorac Surg 2006;82:2161-2169

Present Market Demand for inhaled Nitric Oxide Gas

Clinical Policy Bulletin: Nitric Oxide, Inhalational (INO) Number: 0518

Aetna Policy

• Aetna considers inhaled nitric oxide (INO) therapy medically necessary as a component of the treatment of hypoxic respiratory

failure in term and near-term (born at 34 or more weeks of gestation) neonates when both of the following criteria are met:

Neonates do not have congenital diaphragmatic hernia; and  When conventional therapies such as administration of high concentrations of oxygen, hyperventilation, high-frequency ventilation, the induction of alkalosis, neuromuscular blockade, and sedation have failed or are expected to fail.

Note: Use of INO therapy for more than 4 days is subject to medical necessity review.

• Aetna considers the diagnostic use of INO medically necessary as a method of assessing pulmonary vaso-reactivity in persons

with pulmonary hypertension.

• Aetna considers INO therapy experimental and investigational for all other indications because of insufficient evidence in the

peer-reviewed literature, including any of the following:

• Acute bronchiolitis; or
• Acute hypoxemic respiratory failure in children (other than those who meet the medical necessity criteria above) and in adults; or
• Adult respiratory distress syndrome or acute lung injury; or
• Post-operative management of pulmonary hypertension in infants and children with congenital heart disease; or
• Premature neonates (less than 34 weeks of gestation); or
• Prevention of ischemia-reperfusion injury/acute rejection following lung transplantation; or
• Treatment of persons with congenital diaphragmatic hernia; or
• Treatment of vaso-occlusive crises or acute chest syndrome in persons with sickle cell disease (sickle cell vasculopathy).

Part 4:

Product Development Concepts

A. Institutional Applications – Adult Patient Market

Dr. Pearlman’s Flywheel Concept, presents a solution in this Space, with potential NEW product design for POC for the Institutional Market and the HomeCare Market

Protected: Flywheel iNO, Three Novel Adult Patient Inhaled Nitric Oxide Product Concepts by Justin D. Pearlman MD ME PhD FACC

INDICATIONS for Flywheel

a.                  Hypoxic respiratory failure (HRF)

Aa.1      Neonatal market – Solution in Existence, [NOT COVERED BY LPBI]

Aa.2     Adult market hypoxic respiratory failure (HRF) associated with pulmonary hypertension or from other etiologies

b.                  Pulmonary Arterial Hypertension (PAH)

Ab.1    Neonatal market [NOT COVERED BY LPBI]

Ab.2   Adult market

c.                  Diagnostic Use of inhaled Nitric Oxide

Ac.1 Pulmonary Vasoreactivity Testing in the Cardiac Catheterization Laboratory

Ac2 Treatment of Perioperative Pulmonary Hypertension With Inhaled NO for  Congenital Heart Disease

Ac3 Cardiac Transplantation

Ac4 Insertion of Left Ventricular Assist Device

Ac5 Inhaled NO to Treat Ischemia-Reperfusion Injury

Ac6 Inhaled NO and Acute Respiratory Distress Syndrome

Ac7 Lung Transplantation

Ac8 Sickle Cell Disease

Ac9 Airway chronic inflammation: Nebulized epoprostenol, Iloprost, a long acting prostacyclin analogue, inhaled prostaglandin E1, Adjuctive therapy with inhaled Nitric Oxide

B. Home Care Applications –

Applications for the HomeCare Segment, as the POC is the Home – Types of Products:

For the Institutional Market:

A1. PiNO
A2. SiNO

For the HomeCare Market

Bx. HiNO –   Dr. Pearlman’s solution

B1. HiNO –    LPBI’s PORTABLE inspiratory pulsing device with option to turn off pulsing feature

B2. HiNO –   LPBI’s Home Care Facial Inhaling Device

a.                 COPD

b                  Unstable Angina

Present Market Supply for inhaled Nitric Oxide gas

The market supply of inhaled Nitric Oxide gas experience the structure of a Monopoly. No competition, one product type very expensive in use by Institutions, i.e., Hospitals, only AND Pediatric population, primarily

The Massachusetts General Hospital owns patents covering the use of nitric oxide inhalation, which it has licensed to INO Therapeutics, a division of AGA Linde, and Dr Zapol receives a portion of the royalties.

Dr Roberts is a member of the Scientific Advisory Board of INOTherapeutics, a company that sells inhaled nitric oxide gas. Dr Roberts is not compensated for this activity by the company.

http://inomax.com/

Clinical Trials – Newborns, full-term and nearly full-term infants

Hypoxic Respiratory Failure (HRF)

Clinical trials have shown that INOMAX is effective and well tolerated in the treatment of HRF associated with pulmonary hypertension.3 Its safety has been demonstrated in clinical trials and through post-marketing experience.

NINOS
Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. 1997;336:597-604. Detailed description.

CINRGI
Clark RH, Kuesser RJ, Walker MW, et al. Clinical Inhaled Nitric Oxide Research Group (CINRGI). Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med. 2000;342:469-474. Detailed description.

I-NO/PPHN 
Davidson D, Barefield ES, Kattwinkel J, et al. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. Pediatrics. 1998;101:325-334.

Wessel DL, Adatia I, Van Marter LJ, Thompson JE, Kane JW, Stark AR, Kourebanas S. Improved oxygenation in a randomized trial of inhaled nitric oxide for persistent pulmonary hypertension of the newborn. J Pediatr. 1997;100:E7. [PubMed]

Neonatal Inhaled Nitric Oxide Group. Inhaled nitric oxide in full term and nearly full term infants with hypoxic respiratory failure. N Engl J Med. 1997;336:597–604. [PubMed]

Roberts JD, Fineman JR, Morin FC, Shaul PW, Rimer S, Schreiber MD, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Group. N Engl J Med. 1997;336:605–610. [PubMed]

Wessel DL, Adatia I, Giglia TM, Thompson JE, Kulik TJ. Use of inhaled nitric oxide and acetylcholine in the evaluation of pulmonary hypertension and endothelial function after cardiopulmonary bypass. Circulation. 1993;88:2128–2138. [PubMed]

Petros AJ, Turner SC, Nunn AJ. Cost implications of using inhaled nitric oxide compared with epoprostenol for pulmonary hypertension. J Pharm Technol. 1995;11:163–166. [PubMed]

Industry LEADER for the Neonatal Market : INOMAX®

http://inomax.com/about-inomax/

Nitric oxide delivery systems designed for critical care

With the INOMAX® delivery systems, you can be confident that you have continual innovative devices.

Dedication to developing next-generation technologies.

Continuous innovation supports evolving information and technology needs

Compatible with 60 ventilation systems, including HFOV and noninvasive modalities

Allow for operator-determined concentrations of nitric oxide (NO) in the breathing unit

Provide for a concentration that is constant throughout the respiratory cycle

Monitor for NO, oxygen (FiO2), and nitrogen dioxide (NO2)

Prevent generation of excessive inhaled NO2

INOMAX® demostrates safety and efficacy in the treatment of hypoxic respiratory failure (HRF)

Clinical trials have shown that INOMAX is effective and well tolerated in the treatment of HRF associated with pulmonary hypertension.3 Its safety has been demonstrated in clinical trials and through post-marketing experience.

INOMAX has a well-established safety profile

More than 530,000 patients treated worldwide*2

Meet all FDA-required specifications

In the US in 2013 – Inhaled Nitric Oxide is NOT a FDA approved Drug  Therapy for the Adult Patient. 

CLINICAL TRIALS on the Use of Inhaled Nitric Oxide by Adult Patients, include:

Inhaled Nitric Oxide for Acute Respiratory Distress Syndrome and Acute Lung Injury in Adults and Children: A Systematic Review with Meta-Analysis and Trial Sequential Analysis

1. Arash Afshari, MD*†,
2. Jesper Brok, MD, PhD‡§,
3. Ann M. Møller, MD, MSDC†‖ and
4. Jørn Wetterslev, MD, PhD§

Published online before print March 3, 2011, doi:10.1213/​ANE.0b013e31820bd185A & A June 2011 vol. 112 no. 6 1411-1421

http://www.anesthesia-analgesia.org/content/112/6/1411.short

CONCLUSION: iNO cannot be recommended for patients with acute hypoxemic respiratory failure. iNO results in a transient improvement in oxygenation but does not reduce mortality and may be harmful.

Michael JR, Barton RG, Saffle JR, Mone M, Markewitz BA. Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS Am J Resp Crit Care Med 1998;157:1361-1362. [Free Full Text]

Abstract  A randomized, controlled clinical trial was performed with patients with acute respiratory distress syndrome (ARDS) to compare the effect of conventional therapy or inhaled nitric oxide (iNO) on oxygenation. Patients were randomized to either conventional therapy or conventional therapy plus iNO for 72 h. We tested the following hypotheses: (1) that iNO would improve oxygenation during the 72 h after randomization, as compared with conventional therapy; and (2) that iNO would increase the likelihood that patients would improve to the extent that the FI(O2) could be decreased by > or = 0.15 within 72 h after randomization. There were two major findings. First, That iNO as compared with conventional therapy increased Pa(O2)/FI(O2) at 1 h, 12 h, and possibly 24 h. Beyond 24 h, the two groups had an equivalent improvement in Pa(O2)/FI(O2). Second, that patients treated with iNO therapy were no more likely to improve so that they could be managed with a persistent decrease in FI(O2) > or = 0.15 during the 72 h following randomization (11 of 20 patients with iNO versus 9 of 20 patients with conventional therapy, p = 0.55). In patients with severe ARDS, our results indicate that iNO does not lead to a sustained improvement in oxygenation as compared with conventional therapy.

Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis K Jr, Hyers TM, Papadakos P. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group.

Conclusions: From this placebo-controlled study, inhaled NO appears to be well tolerated in the population of ARDS patients studied. With mechanical ventilation held constant, inhaled NO is associated with a significant improvement in oxygenation compared with placebo over the first 4 hrs of treatment. An improvement in oxygenation index was observed over the first 4 days. Larger phase III studies are needed to ascertain if these acute physiologic improvements can lead to altered clinical outcome.

Conclusions: Inhaled nitric oxide at a dose of 5 ppm in patients with acute lung injury not due to sepsis and without evidence of nonpulmonary organ system dysfunction results in short-term oxygenation improvements but has no substantial impact on the duration of ventilatory support or mortality.

Conclusions: Improvement of oxygenation by INO did not increase the frequency of reversal of ALI. Use of inhaled NO in early ALI did not alter mortality although it did reduce the frequency of severe respiratory failure in patients developing severe hypoxaemia.

Inhaled Nitric Oxide as Drug Therapy continue to be a very HOT research subject as 2004 article was cited by the following studies, 2004-2013:

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REFERENCES for the Introduction, Part 1,2,3,4

http://circ.ahajournals.org/content/109/25/3106.full

http://www.nejm.org/doi/full/10.1056/NEJMra051884

1. Steudel W, Hurford WE, Zapol WM. Inhaled nitric oxide: basic biology and clinical applications Anesthesiology 1999;91:1090-1121.[Medline]
2. Gianetti J, Bevilacqua S, De Caterina R. Inhaled nitric oxide: more than a selective pulmonary vasodilator Eur J Clin Invest 2002;32:628-635.[Medline]
3. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn Lancet 1992;340:818-820.[Medline]
4. Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn Lancet 1992;340:819-820.[Medline]
5. Ashutosh K, Phadke K, Jackson JF, Steele D. Use of NO inhalation in chronic obstructive pulmonary disease Thorax 2000;55:109-113.[Abstract/Free Full Text]
6. Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome N Engl J Med 2004;328:399-405.
7. Gladwin MT, Schecter AN, Shelhamer JH, Pannell LK, Conway DA. Inhaled NO augments NO transport on sickle cell hemoglobin without affecting oxygen affinity J Clin Invest 1999;104:847-848.[Medline]
8. Stobierska-Dzierzek B, Awad H, Michler RE. The evolving management of acute right-sided heart failure in cardiac transplant recipients J Am Coll Card 2001;38:923-931.[Medline]
9. Ardehali A, Hughes K, Sadeghi A, Esmailian F, Marelli D, Moriguchi J. Inhaled NO for pulmonary hypertension after heart transplantation Transplantation 2001;72:638-641.[Medline]
10. Thabut G, Brugiere O, Leseche G, Stern JB, Fradj K. Preventive effect of inhaled NO and pentoxyfylline on ischemia-reperfusion injury after lung transplantation Transplantation 2001;71:1295-1300.[Medline]
11. Sitbon O, Brunet B, Denjan A, et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension Am J Respir Crit Care Med 1995;151:384-389.[Abstract/Free Full Text]
12. Semigran MJ, Cockrill BA, Kacmarek R, et al. Hemodynamic effects of inhaled nitric oxide in heart failure J Am Coll Cardiol 1994;24:982-988.[Medline]
13. Girard C, Lehot J, Pannetier J, Filley S, Ffrench P, Estenove S. Inhaled nitric oxide after mitral valve replacement in patients with chronic pulmonary artery hypertension Anesthesiology 1992;77:880-883.[Medline]
14. Bhorade S, Christenson J, O’Connor M, Lavoie A, Pohman A, Hall JB. Response to inhaled nitric oxide in patients with acute right heart syndrome Am J Respir Crit Care Med 1999;159:571-579.[Abstract/Free Full Text]
15. Radermacher P, Santak B, Wust HJ, Tarnon J, Falke KJ. Prostacyclin and right ventricular function in patients with pulmonary hypertension associated with ARDS Intens Care Med 1990;16:227-232.[Medline]
16. Neonatal Inhaled Nitric Oxide Study Group Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure N Engl J Med 1997;336:597-604.[Medline]
17. Roberts JD, Fineman JR, Morin FC, et al. Inhaled nitric oxide and persistent pulmonary hypertension in the newborn N Engl J Med 1997;336:605-610.[Medline]
18. Lonnquist PA. Efficacy and economy of inhaled nitric oxide in neonates accepted for extra-corporeal membrane oxygenation Acta Physiol Scand 1999;167:175-179.[Medline]
19. Baigorri F, Joseph D, Artigas A, Blanch L. Inhaled NO does not improve cardiac or pulmonary function in patients with an exacerbation of chronic obstructive pulmonary disease Crit Care Med 1999;27:2153-2158.[Medline]
20. Kaisers U, Busch T, Deja M, Donaubauer B, Falke K. Selective pulmonary vasodilatation in acute respiratory distress syndrome Crit Care Med 2003;31(Suppl):337-342.[Medline]
21. Abman AH, Griebel JL, Parker DK, et al. Acute effects of inhaled nitric oxide in children with severe hypoxemic respiratory failure J Pediatr 1994;124:881-888.[Medline]
22. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome Crit Care Med 1998;26:15-23.[Medline]
23. Jacobs PD, Finer NN, Robertson CMT, Etches P, Hall E, Saunders LD. A cost-effectiveness analysis of the application of nitric oxide versus oxygen gas for near-term newborns with respiratory failure: results from a Canadian randomized clinical trial Crit Care Med 2000;28:872-878.[Medline]
24. Hosenpud JD, Bennett LE, Keck BM, Boucek MM, Novick RJ. The Registry of the International Society for Heart and Lung Transplantation: seventeeth official report–2000 J Heart Lung Transplant 2000;19:909-931.[Medline]
25. Doyle AR, Dhir AK, Moors AH, Latimer RD. Treatment of perioperative low cardiac output syndrome Ann Thorac Surg 1995;59(Suppl 2):3-11.
26. Bhatia SJ, Kirshenbaum JM, Shemin RJ, et al. Time course of resolution of pulmonary hypertension and right ventricular remodeling after orthotopic cardiac transplantation Circulation 1987;76:819-826.[Abstract/Free Full Text]
27. Chen JM, Levin HR, Micheler RE, et al. Reevaluating the significance of pulmonary hypertension before cardiac transplantation: determination of optimal thresholds and quantification of the effect of reversibility on perioperative mortality J Thorac Cardiovasc Surg 1997;114:627-634.[Abstract/Free Full Text]
28. Tenderich G, Koerner MM, Stuettgen B, et al. Does preexisting elevated pulmonary vascular resistance (transpulmonary gradient >15 mmHg or >5 Wood) predict early and long-term results after othotopic heart transplantation? Transplant Proc 1998;30:1130-1131.[Medline]
29. Bennett LE, Keck BM, Hertz MI, Trulock EP, Taylor DO. Worldwide thoracic organ transplantation: a report from the UNO/ISHLT international registry for thoracic organ transplantation Clin Transplant 2001;15:25-40.
30. Harringer W, Wiebe K, Struber M, et al. Lung transplantation—10 year experience Eur J CardioThorac Surg 1999;16:546-554.[Abstract/Free Full Text]
31. Troncy E, Collet JP, Shapiro S, et al. Should we treat acute respiratory distress syndrome with inhaled nitric oxide? Lancet 1997;350:111-118.[Medline]
32. Michael JR, Barton RG, Saffle JR, Mone M, Markewitz BA. Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS Am J Resp Crit Care Med 1998;157:1361-1362.[Free Full Text]
33. Luhr OR, Antonsen K, Karlsson M, et al. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland Am J Resp Crit Care Med 1999;159:1849-1861.[Abstract/Free Full Text]
34. Krafft P, Fridrich P, Pernerstorfer T, et al. The acute respiratory distress syndrome: definitions, severity, and clinical outcome Intens Care Med 1996;22:519-529.[Medline]

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RESOURCES on this Open Access Online Scientific Journal

1. electronic Book on Nitric Oxide by Nitric Oxide Team @ Leaders in Pharmaceutical Business Intelligence (LPBI), Amazon-Kindle, 2013

Perspectives on Nitric Oxide in Disease Mechanisms

 The Nitric Oxide Discovery, Function, and Targeted Therapy  Opportunities

Aviral Vatsa, PhD, Editor

Larry H Bernstein, MD, Editor

2. The rationale and use of inhaled NO in Pulmonary Artery Hypertension and Right Sided Heart Failure Larry H. Bernstein 8/20/2012

3. Inhaled Nitric Oxide in Adults: Clinical Trials and Meta Analysis Studies – Recent Findings Aviva Lev-Ari, PhD, RN, 6/2/2013