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Posts Tagged ‘ARDS’


Curator: Aviva Lev-Ari, PhD, RN

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

 

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%, 0.001).

Acquisition Cost of Inhaled Nitric Oxide Therapy – Table 6 in the Study

2000–2003 Charge Scale ($) || Current Charge Scale ($)

OHT 9,121 + or – 4,226  ||  7,010 + or – 5,072

OLT 8,040 + or – 3,659a  ||  5,710 + or – 4,132b

Cardiac surgery 9,179  + or – 5,319   ||  7,349 + or – 6,543

VAD 10,726 + or – 4,121   ||  8,722 + or – 4,966

Other surgery 9,324 + or – 4,110 ||  7,056 + or – 4,826

Medical 10,075 + or – 5,215  || 8,867 + or – 7,233

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 RPZimmerman JLTaylor RWStraube RCHauser DLCriner GJDavis K JrHyers TMPapadakos PEffects 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.

Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. Intensive Care Med 1999;25:911-9.

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:

The Pharmacological Treatment of Pulmonary Arterial Hypertension 
Pharmacol. Rev.. 2012;64:583-620,

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Transpulmonary Flux of S-Nitrosothiols and Pulmonary Vasodilation during Nitric Oxide Inhalation: Role of Transport 
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Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis 
Ann Rheum Dis. 2012;71:1019-1026,

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Inhaled Nitric Oxide for Elevated Cavopulmonary Pressure and Hypoxemia After Cavopulmonary Operations 
World Journal for Pediatric and Congenital Heart Surgery. 2012;3:26-31,

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Inhaled Nitric Oxide Improves Outcomes After Successful Cardiopulmonary Resuscitation in Mice 
Circulation. 2011;124:1645-1653,

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Nitrite Potently Inhibits Hypoxic and Inflammatory Pulmonary Arterial Hypertension and Smooth Muscle Proliferation via Xanthine Oxidoreductase-Dependent Nitric Oxide Generation 
Circulation. 2010;121:98-109,

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Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy 
Eur Respir Rev. 2009;18:35-41,

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Intravenous Magnesium Sulphate vs. Inhaled Nitric Oxide for Moderate, Persistent Pulmonary Hypertension of the Newborn. A Multicentre, Retrospective Study 
J Trop Pediatr. 2008;54:196-199,

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RETRACTED: Treating pulmonary hypertension post cardiopulmonary bypass in pigs: milrinone vs. sildenafil analog 
Perfusion. 2008;23:117-125,

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Inhaled Agonists of Soluble Guanylate Cyclase Induce Selective Pulmonary Vasodilation 
Am. J. Respir. Crit. Care Med.. 2007;176:1138-1145,

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Nitric Oxide in the Pulmonary Vasculature 
Arterioscler. Thromb. Vasc. Bio.. 2007;27:1877-1885,

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Soluble Guanylate Cyclase-{alpha}1 Deficiency Selectively Inhibits the Pulmonary Vasodilator Response to Nitric Oxide and Increases the Pulmonary Vascular Remodeling Response to Chronic Hypoxia 
Circulation. 2007;116:936-943,

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Nitric Oxide and Peroxynitrite in Health and Disease 
Physiol. Rev.. 2007;87:315-424,

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Sleeping Beauty-mediated eNOS gene therapy attenuates monocrotaline-induced pulmonary hypertension in rats 
FASEB J.. 2006;20:2594-2596,

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Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury 
Am. J. Physiol. Heart Circ. Physiol.. 2006;291:H379-H384,

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Inhaled nitric oxide does not reduce systemic vascular resistance in mice 
Am. J. Physiol. Heart Circ. Physiol.. 2006;290:H1826-H1829,

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Inhibition of phosphodiesterase 1 augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs with acute pulmonary hypertension 
Am. J. Physiol. Lung Cell. Mol. Physiol.. 2006;290:L723-L729,

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Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension 
Br J Anaesth. 2006;96:317-322,

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Extrapulmonary effects of inhaled nitric oxide: role of reversible s-nitrosylation of erythrocytic hemoglobin. 
Proc Am Thorac Soc. 2006;3:153-160,

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Soluble Guanylate Cyclase Activator Reverses Acute Pulmonary Hypertension and Augments the Pulmonary Vasodilator Response to Inhaled Nitric Oxide in Awake Lambs 
Circulation. 2004;110:2253-2259,

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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

Ann Thorac Surg 2006;82:2161-2169
© 2006 The Society of Thoracic Surgeons

Clinical Indication for Use and Outcomes After Inhaled Nitric Oxide Therapy

Isaac George, MDa,*, Steve Xydas, MDa, Veli K. Topkara, MDa, Corrina Ferdinando, MDa, Eileen C. Barnwell, MS, RRTb,Larissa Gablemana, Robert N. Sladen, MDc, Yoshifumi Naka, MD, PhDa, Mehmet C. Oz, MDa

a Department of Surgery, Division of Cardiothoracic Surgery, Columbia University College of Physicians and Surgeons, New York, New York
b Department of Respiratory Therapy, Columbia-Presbyterian Medical Center, New York, New York
c Department of Anesthesia and Critical Care, Columbia-Presbyterian Medical Center, New York, New York 

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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

From Discovery to Innovation

     From Innovation to Therapeutic Targets

From Therapeutic Targets to Clinical Applications

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

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Author: Larry Bernstein, MD

 

Creagh-BrownBC, Griffiths MJD, Evans TW. “Bench-to-bedside review: Inhaled nitric oxide therapy in adults”. Crit Care.  2009;  13(3): 221. Published online 2009 May 29. doi:  10.1186/cc7734. PMCID: PMC2717403.

This article is modified from a review series on Gaseous mediators, edited by Peter Radermacher.  Other articles in the series can be found online athttp://ccforum.com/series/gaseous_mediators

 

Part I.   Basic and downstream effects of inhaled NO

Inhaled nitric oxide (NO), a mediator of vascular tone produces pulmonary vasodilatation with low pulmonary vascular resistance. The route of administration delivers NO selectively improving oxygenation. Developments in our understanding of the cellular and molecular actions of NO may help to explain the results of randomised controlled trials of inhaled NO.

Introduction

Nitric oxide (NO), a determinant of local blood flow is formed by the action of NO synthase (NOS) on L-arginine in the presence of molecular oxygen. Inhaled NO results in preferential pulmonary vasodilatation it lowers pulmonary vascular resistance (PVR), correcting hypoxic pulmonary vasoconstriction (HPV). However, in the therapeutic use of gaseous NO to patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and related conditions, evidence of a benefit is disappointing.

Administration of inhaled nitric oxide to adults

The licensed indication of inhaled NO is restricted to persistent pulmonary hypertension in neonates. Pharma-ceutical NO is costly, and raises concerns over potential adverse effects of NO. Therefore, an advisory board under the auspices of the European Society of Intensive Care Medicine and the European Association of Cardiothoracic Anaesthesiologists published recommendations in 2005 [1]. The sponsor had no authorship or editorial control over the content of the meetings or any subsequent publication.

The NO is administered as a NO/nitrogen mixture to the tubing of ventilated patients, and the NO and NO2 concen-trations are monitored, with methemoglobin levels measured regularly. Even though rapid withdrawal induces rebound pulmonary hypertension, it is avoided by gradual withdrawal [2]. There is variation in vasodilatory response to administered NO between patients [2] and in the same patient, and there is a leftward shift in the dose-response curve with use. Toxicity and loss of the therapeutic effect is a risk of excessive NO administration [3]. A survey of 54 intensive care units in the UK as well as results of a European survey revealed that the most common usage was in treating ARDS, followed by pulmonary hypertension [4], [5]. The only use of therapeutic inhaled NO usage in US adult patients reported from a single medical site (2000 to 2003) reveals that the most common application was in the treatment of RVF in patients after cardiac surgery and then, in surgical and medical patients for refractory hypoxemia[6].

Inhaled nitric oxide in acute lung injury and acute respiratory distress syndrome

ALI and ARDS are characterised by hypoxemia despite high inspired oxygen (PaO2/FiO[arterial partial pressure of oxygen/fraction of inspired oxygen] ratios of less than 300 mm Hg [40 kPa] and less than 200 mm Hg [27 kPa], respectively) in the context of evidence of pulmonary edema, and the absence of left atrial hypertension suggestive of a cardiogenic mechanism [7]. Pathologically, there is alveolar inflammation and injury leading to increased pulmonary capillary permeability and a serous alveolar fluid with inflammatory infiltrate. This is manifest clinically as hypoxemia, inadequate alveolar perfusion, venous-arterial shunting, atelectasis, and reduced compliance.

Since 1993, when the first investigation on the effects of NO on adult patients with ARDS was published [8], there have been several randomised controlled trials (RCTs) examining the effect in ALI/ARDS  ​(Table 1). The first systematic review and meta-analysis [9] found no beneficial effect on mortality or ventilator-free days. A more recent meta-analysis that considered 12 RCTs with a total of 1,237 patients [10] concluded: [1] no mortality benefit, [2] improved oxygenation at 24 hours (13% improvement in PaO2/FiOratio) at the cost of increased risk of renal dysfunction (relative risk 1.50, 95% confidence interval 1.11 to 2.02). Based on a trend to increased mortality in patients receiving NO, the authors suggested that it not be used in ALI/ARDS.  Why the NO fails to improve patient outcomes requires clarifying the effects of inhaled NO that occur outside the pulmonary vasculature.

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Table 1

Studies of inhaled nitric oxide in adult patients with acute lung injury/acute respiratory distress syndrome

The biological action of inhaled nitric oxide

NO was first identified as an endothelium-derived growth factor (EDGF) and an important determinant of local blood flow [11]. NO reacts very rapidly with free radicals, certain amino acids, and transition metal ions. The action of NOS on the semi-essential amino acid L-arginine in the presence of molecular oxygen and its identity with EDGF was the basis for the Nobel discovery of Furthgott and others [12]. Three isoforms of NO are: neuronal NOS, inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3). Calcium-independent iNOS generates higher concentrations of NO [13] than the other isoforms and its role has been implicated in the pathogenesis septic shock.

Exogenous NO is administered by controlled inhalation or through intravenous administration of NO donors. It was thought to have no remote or non-pulmonary effects. The effect NO has on circulating targets is shown. (Figure 1).

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Figure 1

New paradigm of inhaled nitric oxide (NO) action. Figure 1 illustrates the interactions between inhaled NO and the contents of the pulmonary capillaries. Although NO was considered to be inactivated by hemoglobin (Hb), proteins including Hb and albumin contain reduced sulphur (thiol) groups that react reversibly with NO causing it to lose its vasodilating properties. A stable derivate, in the presence of oxyhemoglobin, is formed by a reaction resulting in nitrosylation of a cysteine residue of the β subunit of Hb.  The binding of NO to the heme iron predominates in the deoxygenated state [14]. If circulating erythrocytes store and release NO peripherally in areas of low oxygen tension, this augments peripheral blood flow and oxygen delivery via decreased systemic vascular resistance [15]. Thus, NO can act as an autocrine or paracrine mediator but when stabilised may exert endocrine influences [16]. In addition to de novo synthesis, supposedly inert anions nitrate (NO3) and nitrite (NO2) can be recycled to form NO, and nitrite might mediate extra-pulmonary effects of inhaled NO [17]. In the hypoxic state, NOS cannot produce NO and deoxy-hemoglobin catalyses NO release from nitrite, potentially providing a hypoxia-specific vasodilatory effect. Given that effects of inhaled NO are mediated in part by S-nitrolysation of circulating proteins, therapies aiming at directly increasing S-nitrosothiols have been developed.

Introduce another effect. When inhaled with high concentrations of oxygen, gaseous NO slowly forms the toxic product NO2, but other potential reactions include nitration (addition of NO2+), nitrosation (addition of NO+), or nitrosylation (addition of NO), and reaction with reactive oxygen species such as superoxide to form reactive nitrogen species (RNS) such as peroxynitrite (ONOO). These reactions of NO, potentially cytotoxic NO2 , and covalent nitration of tyrosine in proteins by RNS lead to measures of oxidative stress.

In a small observational study, inhaled ethyl nitrite safely reduced PVR without systemic side effects in persistent pulmonary hypertension of the newborn [18]. In animal models, pulmonary vasodilatation was maximal in hypoxia and had prolonged duration of action after cessation of administration [19].

References

  1. Germann P, Braschi A, Della Rocca G, Dinh-Xuan AT, et al. Inhaled nitric oxide therapy in adults: European expert recommendations.  Intensive Care Med. 2005;31:1029–1041. [PubMed]
  2. Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med. 2005;353:2683–2695. [PubMed]
  3. Gerlach H, Keh D, Semmerow A, Busch T, et al. Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study. Am J Respir Crit Care Med. 2003;167:1008–1015. [PubMed]
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  8. Rossaint R, Falke KJ, López F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med.1993;328:399–405. [PubMed]
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  12. Nitric Oxide: The Nobel Prize in Physiology or Medicine 1998 Robert F. Furchgott, Louis J. Ignarro, Ferid Murad. Leaders in Pharmacutical Intelligence.  A blog specializing in Pharmaceutical Intelligence and Analytics
  13. McCarthy HO, Coulter JA, Robson T, Hirst DG. Gene therapy via inducible nitric oxide synthase: a tool for the treatment of a diverse range of pathological conditions. J Pharm Pharmacol. 2008;60:999–1017. [PubMed]
  14. Coggins MP, Bloch KD. Nitric oxide in the pulmonary vasculature.   Arterioscler Thromb Vasc Biol. 2007;27:1877–1885. [PubMed]
  15. McMahon TJ, Doctor A. Extrapulmonary effects of inhaled nitric oxide: role of reversible S-nitrosylation of erythrocytic hemoglobin. Proc Am Thorac Soc. 2006;3:153–160. [PMC free article] [PubMed]
  16. Cokic VP, Schechter AN. Effects of nitric oxide on red blood cell development and phenotype. Curr Top Dev Biol. 2008;82:169–215. [PubMed]
  17. Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 2008; 7:156–167. [PubMed]
  18. Moya MP, Gow AJ, Califf RM, Goldberg RN, Stamler JS. Inhaled ethyl nitrite gas for persistent pulmonary hypertension of the newborn. Lancet  2002; 360:141–143. [PubMed]

Creagh-BrownBC, Griffiths MJD, Evans TW. “Bench-to-bedside review: Inhaled nitric oxide therapy in adults”. Crit Care.  2009;  13(3): 221. Published online 2009 May 29. doi:  10.1186/cc7734. PMCID: PMC2717403.

This article is modified from a review series on Gaseous mediators, edited by Peter Radermacher.

Other articles in the series can be found online athttp://ccforum.com/series/gaseous_mediators

Part II. Application of inhaled NO and circulatory effects

Cardiovascular effects

NO activates soluble guanylyl cyclase by binding to its heme group to form cyclic guanosine 3’5′-monophosphate (cGMP)   activating a protein kinase. Consequently, myosin sensitivity to calcium-induced contraction is reduced lowering the intracellular calcium concentration as a result of activating calcium-sensitive potassium channels and inhibiting release of calcium. The smooth muscle cell (SMC) relaxation with decrease in pulmonary vascular resistance (PVR) and decreased RV after load could improve cardiac output. However, left ventricular impairment associated with decrease in PVR allows increased RV output to a greater extent than the left ventricle can accommodate and the increase in left atrial pressure reinforces pulmonary edema.

Inhaled NO augments the normal physiological mechanism of hypoxic pulmonary ventilation (HPV) and improves systemic oxygenation ​(Figure 2). The effects of inhaled NO on systemic oxygenation are limited. Experiments show that intravenously administered vasodilators counteract HPV [3]. However, the non-pulmonary effects of inhaled NO include increased renal and hepatic blood flow and oxygenation [14].

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Figure 2

Hypoxic pulmonary vasoconstriction (HPV).       (a) Normal ventilation-perfusion (VQ) matching. (b) HPV results in VQ matching despite variations in ventilation and gas exchange between lung units. (c) Inhaled nitric oxide (NO) augmenting VQ matching by vasodilating.

Non-cardiovascular effects relevant to lung injury

Neutrophils are important cellular mediators of ALI. Limiting neutrophil production of oxidative species and proteolysis reduces lung injury. In neonates, prolonged administration of NO diminished neutrophil-mediated oxidative stress [19]. Neutrophil deformability and CD18 expression were reduced in animal models [20] accomp-anied by decreases in adhesion and migration [21]. These changes limit damage to the alveolar-capillary membrane and the accumulation of protein-rich fluid within the alveoli. Platelet activation and aggregation, intra-alveolar thrombi, contribute to ALI. Inhaled NO attenuates the procoagulant activity in animal models of ALI [22] and a similar effect is seen in patients with ALI [23], but also in healthy volunteers [23,24]. In patients with ALI, decreased surfactant activity in the alveoli and noncompliance, as we recall is hyaline membrane disease accompanied by impaired pulmonary function [25].  The deleterious effects of the NO damages the alveolar wall with loss of surfactant by reactions with RNS [26]. Finally, prolonged exposure to NO in experimental models impairs cellular respiration [27].

The failure of inhaled NO to improve outcome in ALI/ARDS is therefore potentially due to several factors. First, patients with ALI/ARDS die of multi-organ failure, as the actions of NO are not expected to improve the outcome of multi-organ failure, which is a cytokine driven process leading to circulatory collapse. Indeed, the expected beneficial effect of inhaled NO is abrogated by detrimental downstream systemic effects discussed. Second, ALI/ARDS is a heterogeneous condition with diverse causes. Finally, using inhaled NO without frequent dose titration risks unwanted systemic effects without the expected benefits.

Other clinical uses of inhaled nitric oxide

Pulmonary hypertension and acute right ventricular failure

RVF may develop when there is abnormally elevated PVR and/or impaired RV perfusion.  ​Table 2 lists common causes of acute RVF. The RV responds poorly to inotropic agents but is exquisitely sensitive to after load reduction.

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Table 2

Reducing PVR will have beneficial effects on cardiac output and therefore oxygen delivery. In the context of high RV afterload with low systemic pressures or when there is a limitation of flow within the right coronary artery [28], RV failure triggers a backward failure of venous return, as diagrammatically represented in  ​Figure 3.

From:

Published online 2009 May 29. doi: 10.1186/cc7734

Figure 3

Pathophysiology of right ventricular failure. CO, cardiac output; LV, left ventricle; PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; RV, right ventricle.

Inhaled NO is used when RV failure complicates cardiac surgery, as cardiopulmonary bypass per se causes diminished endogenous NO production [29]. There is marked variation in response to inhaled NO between patients [30] and in the same patient over time. After prolonged use, there is a leftward shift in the dose-response curve.  The risk of excessive NO administration is associated with toxicity and loss of the therapeutic effect without regular titration against a therapeutic goal [31].  Further, cardiac transplantation may be complicated by pulmonary hypertension and RVF that are improved with NO [32]. Early ischemia-reperfusion injury after lung transplantation manifests clinically as pulmonary edema and is a cause of significant morbidity and mortality [33,34]. Although NO has been administered in this circumstance [35], it hasn’t prevented ischemia-reperfusion injury in clinical lung transplantation [36]. Inhaled NO has been used successfully in patients with cardiogenic shock and RVF associated with acute myocardial infarction [37,38,46], and in patients with acute RVF following acute pulmonary venous thrombo-emboli [39, 47].  An explanation is needed in view of the downstream effects of systemic vasoconstriction and MOF previously identified. No systematic evaluation of inhaled NO and its effect on clinical outcome has been conducted in these conditions.

Acute chest crises of sickle cell disease

Acute chest crises are the second most common cause of hospital admission in patients with sickle cell disease (SCD) and are responsible for 25% of all related deaths [40]. Acute chest crises are manifest by fever, respiratory symptoms or chest pain, and new pulmonary infiltrate on chest  x-ray. The major contributory factors are related to vaso-occlusion. Hemolysis of sickled erythrocytes releasing Hb into the circulation generates reactive oxygen species and reacts with NO [41]. In SCD, the free Hb depletes NO. In addition arginase 1 is released, depleting the arginine needed for NO production, [42]. While secondary PVH is common in adults with SCD the physiological rationale for the use of inhaled NO needs to be considered, except for the complication just referred to. Thus far, iNO has failed to demonstrate either persistent improvements in physiology or beneficial effects on any accepted measure of outcome in clinical trials (other than its licensed indication in neonates). Therefore, inhaled NO is usually reserved for refractory hypoxemia.

Potential problems in designing and conducting RCTs in the efficacy of inhaled NO are numerous. Blinded trials will be difficult to conduct as the effects of inhaled NO are immediately apparent. Recruitment is limited as there is little time for consent/assent or randomization. Finally, industry funding might cast doubt on the independence of the trial results.

Inhaled NO is an unproved tool in the intensivist’s armamentarium of rescue therapies for refractory hypoxemia even though it has an established role in managing complications of cardiac surgery and in heart/lung transplantation. The current place for inhaled NO in the management of ALI/ARDS, acute sickle chest crisis, acute RV failure, and acute pulmonary embolism is a rescue therapy.

Abbreviations

ALI: acute lung injury; ARDS: acute respiratory distress syndrome; Hb: haemoglobin; HPV: hypoxic pulmonary vasoconstriction; iNO: inhaled nitric oxide; iNOS: inducible nitric oxide synthase; NO: nitric oxide; NO2: nitrogen dioxide; NOS: nitric oxide synthase; PaO2/FiO2: arterial partial pressure of oxygen/fraction of inspired oxygen; PVR: pulmonary vascular resistance; RCT: randomised controlled trial; RNS: reactive nitrogen species; RV: right ventricle; RVF: right ventricular failure; SCD: sickle cell disease; SMC: smooth muscle cell.

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