Nitric Oxide Gas

What is the Nitric Oxide Gas?

In simple terms, Nitric Oxide is a hormone that can be called the vital alarm system in the human body.
At the same time, Nitric Oxide is a gas naturally produced by the human body.
It is chemically defined as a colorless poisonous gas obtained by the oxidation of nitrogen. It easily interacts with the air and turns into NO2. Both NO and NO2 are very strong respiratory stimulants; They can
cause pulmonary edema and chemical pneumonitis. Inhalation of high concentrations of NO causes the formation of methemoglobin.
Once nitric oxide is synthesized, it spreads rapidly to the target tissues and increases the amount of “cyclic guanosine monophosphate” (cGMP) that enables smooth muscle contraction by activating the
guanylate cyclase enzyme inside the cell.
These biochemical events are involved in smooth muscle contraction, vascular tone and regulation of blood flow.
Plays an important role. Nitric oxide also increases the soluble guanylate cyclase activity in platelets, reducing platelet adhesion and aggregation. In addition, it causes the death of microorganisms by
reacting with iron compounds bound to mitochondrial protein, disrupting DNA synthesis, and plays a role in the defense system.

NITRIC OXIDE IN RESPIRATORY SYSTEM

Detection of NO in respiratory air (5-10 ppb in healthy individuals) and NO metabolites in bronchoscopic lavage and induced sputum samples are findings indicating that NO is synthesized in the airways. Potential sources of exhaled nitric oxide are the pulmonary circulation, the lower and upper airways, and the paranasal sinuses. High concentrations of NO are synthesized, especially in the upper respiratory tract and paranasal sinuses. The high diffusion capacity of nitric oxide, its capacity to bind to hemoglobin 3000 times higher than that of oxygen, and the rich vascular structure in the lung make the pulmonary circulation a biological waste depot for NO, and the pulmonary circulation has no role in exhaled NO.

THE ROLE OF NITRIC OXIDE IN LUNG PHYSIOLOGY

Vascular effects

Nitric oxide is a very potent vasodilator. The effects of nitric oxide leading to relaxation in vascular smooth muscles have been clearly demonstrated. As in sepsis, excess NO may cause systemic hypotension, while pulmonary hypertension is detected when NO synthesis is decreased in the opposite case. Exhaled NO (eNO) rates are significantly lower in patients with pulmonary hypertension. Nitric oxide also has an antithrombotic effect. Nitric oxide inhalation has been shown to reduce the in vivo activation of circulating platelets and thrombosis in thromboembolic hypertension. Due to its selective pulmonary vasodilator effect, its use in ARDS will be discussed in the section on the place of NO in treatment.

 ROLE AND IMPORTANCE IN AIRWAY DISEASES

NO measurement in expiratory air

With electrochemical methods, only one unit per million (ppm) Nude measurement can be made. Whereas with the “chemiluminescence” method, a measurement can be made at the rate of one billionth (ppb). This method is based on the principle of collecting the light energy resulting from the reaction of NO with ozone in a tube and proportioning this collected light energy with the Nu level. There are several methods for collecting exhaled gases. These can generally be grouped into two groups as “online” and “offline” methods. In the “offline” method, the exhaled air can be collected in a reservoir and measurements can be made at different times and places. In the “online” method, the patient blows their breath into the device and the measurement is made at that moment. Although eNO levels vary according to the method applied, they are generally in the “offline” method, this is at the level of 5-10 ppb (in healthy individuals). In the “online” method, the Nu levels may vary according to the flow rate.

Asthma

It has been shown in many studies that NOS il enzyme release and related eNO release are increased in the airways of asthmatic patients and this is normalized with steroid treatment. In asthma, Nü is mostly caused by the lower airways and by an increase in NOS il activation. Although nitric oxide measurements are not specific for asthma, increased NU rates may be useful in differentiating asthma from other causes of chronic cough. In the study of Dupont et al., when the threshold value was taken as 15 ppb, the specificity for the diagnosis of asthma was 90% and the positive predictive value was 95%.

Another area of ​​use of nitric oxide measurement in asthma is to detect subclinical forms (PFT is normal, bronchodilator response is negative, but sputum eosinophilic cationic protein is high) and to treat with steroids and to prevent the emergence of clinical disease. The bronchial challenge test to detect airway sensitivity becomes more specific when combined with eNO measurement.

Another use of the No measurement in asthma is to evaluate the response to treatment. Under normal conditions, a single Nude measurement seems more practical instead of invasive methods such as eosinophil count in sputum or investigation of mediator and other inflammation criteria in serum. Moreover, the increase in eNO values ​​is in parallel with the increase in inflammation indicators. In this way, it is an important advantage to prevent unnecessary high-dose steroid use.

 Chronic Obstructive Pulmonary Disease (COPD)

In patients with stable COPD and chronic bronchitis, eNO is found to be normal (29], possibly due to smoking and the down-regulation of high NO in cigarette smoke that reduces the efficacy of eNOS (29). eNO is found to be high in symptomatic COPD patients who are not under.

Cystic Fibrosis (CF)

eNO levels are low in patients with cystic fibrosis. In fact, the low NO despite intense neutrophilic inflammation and increased oxidative stress in CF is probably the primary insufficiency of NOS detected in these patients.

 Bronchiectasis

In patients with bronchiectasis, eNO is found to be high in proportion to the extent of the disease. This is an indicator of active inflammation and returns to normal with steroid treatment, just like in asthma. In some studies, eNO is found to be normal in bronchiectasis and it is shown that the increased secretions trap NO.

Pulmoner Hypertension

Pulmonary hypertension is characterized by abnormal thickening of the pulmonary arteries and increased pulmonary vascular resistance. Nitric oxide is a potent vasodilator and smooth muscle proliferation inhibitor of endothelial origin. Detection of miscarriage in patients with primary pulmonary hypertension suggests that it may have an important role in the pathogenesis of the disease.

THE PLACE OF NITRIC OXIDE IN THE TREATMENT

Pulmoner Hypertension

After the selective pulmonary vasodilator effect was determined, the use of NO in the treatment of pulmonary hypertension came to the fore. The half-life of endogenous NO is only 0.1 to 5 seconds. In contrast, the half-life of inhaled NO before it reaches the gas exchange units and passes through the alveolar wall into the pulmonary capillary blood is 15-30 seconds. It has been determined that pulmonary vasodilation occurs at a dose of approximately 10 ppm. Most of the nitric oxide is inactivated by binding to hemoglobin while still in the pulmonary circulation and thus does not cause systemic hemodynamic changes like sodium nitroprusside and nitroglycerin.

According to data from patients with primary pulmonary hypertension, there is an imbalance between endothelium-derived vasodilator factors [prostacyclin, Nü) and vasoconstrictor mediators (endothelin-1 (ET-1), thromboxane A2 (TXA2)]. One finding supporting this is that the administration of NOS inhibitors It results in pulmonary and systemic hypertension.Systemic symptoms such as hypotension, facial flushing and headache occur with systemic administration of epoprostenol, a prostacyclin analog.However, it is an important advantage that the effects of inhaled nitric oxide are limited in the pulmonary circulation.

Another area of ​​use of nitric oxide in pulmonary hypertension is the planning of treatments to be applied to these patients. In the studies, it was determined that the patients who responded well to inhaled NO benefited from oral vasodilator drugs, and those who did not respond were candidates for transplantation and it was appropriate to be treated with chronic epoprostenol until that day.

ARDS

The most important finding of ARDS is severe hypoxemia resulting from physiological shunt and ventilation/perfusion (V/Q) imbalance. Inhaled vasodilators such as nitric oxide and prostacyclin increase oxygenation by vasodilation, especially in well-ventilated areas, and lead to an improvement in V/Q imbalance. Nitric oxide is consistently used in the treatment of hypoxic respiratory failure at doses of 1.25-40 ppm . However, in case of interruption or abrupt discontinuation of treatment, it causes serious deterioration in oxygenation and a sudden increase in pulmonary artery pressure.

OTHER LUNG DISEASES

Other areas where nitric oxide therapy has been shown to be beneficial are intractable pulmonary hypertension caused by patent ductus arteriosus and right-to-left shunt associated with patent ductus ova/eye, pulmonary hypertension after repair of congenital heart disease, and pulmonary hypertension that subsides after lung transplantation.

In conclusion, the measurement of NO or NO metabolites in respiratory air or respiratory materials by various methods reflects the state of the airways in a very easy and non-invasive method. It is a method that can be preferred especially in children and elderly patients due to its non-invasiveness and easy application. In recent years, there has been an increasing number of studies on NO using eNO all over the world and in our country.

• IN HEART AND LUNG TRANSPLANTATION

As it is known, nitric oxide has a very important place in heart and lung transplantation. If the patient has been diagnosed with pulmonary hypertension, nitric oxide should definitely be started to provide vasodilation preoperatively. Because the newly transplanted donor will be tired anyway, the pulmonary defense encountered at the pump outlet causes right failure, and the patient has to stay in the pump for a long time and even cannot get out of the pump. It is of vital importance in such cases.

BENEFIT

1- The patient and the donor will not be lost.

2- Since the intensive care period will be reduced to a minimum, a great profit will be obtained from medicine, manpower and other intensive care expenses.

3- The price paid by the state to the hospital will not be wasted because the patient is alive.

• IN RIGHT FAILURE

Especially in artificial heart implantation, the most feared case is right failure. Nitric oxide is the biggest weapon in right failures that may occur during artificial heart implantation. It is seen that pulmonary pressure decreases and saturation increases a few minutes after the use of nitric oxide in right failure. Therefore, since the right failure due to pulmonary hypertension is eliminated, it is very fast to remove the patient from the heart-lung pump, and accordingly, the necessity of installing a second pump with a value of tens of thousands of € for the right ventricle is eliminated.

BENEFIT

• The state will not have to pay extra, as the obligation to install a second pump on the patient is eliminated.
• The duration of intensive care will be shortened, therefore, extra medication and expenses will be avoided.
• Risk of the pump installed for the left ventricle will also be avoided.

• NOTE: IN EUROPE AND AMERICA, IT IS MANDATORY TO HAVE A NITRIC OXIDE SYSTEM IN TRANSPLANTATION, ARTIFICIAL HEART INSTALLED CENTERS AND ALL CENTERS WHO OPEN HEART OPERATION IS PERFORMED. IT IS THE CHEAPEST AND THE MOST EFFECTIVE WEAPON IN THE TREATMENT OF PATIENTS DIAGNOSED OR ENCOUNTERED WITH PULMONARY HYPERTENSION.
• IN PEDIATRIC AND CONGENITAL CHILDREN’S SURGERY

Pulmonary hypertension is one of the most common problems in children due to postcapillary indications. Pulmonary hypertension due to VSD or ASD is much more aggressive, so nitric oxide is the biggest weapon in the pre-operative pump output and postoperative period. When the vasodilative effect of nitric oxide is activated, it is seen that the pulmonary pressure drops in a short time and the saturation increases rapidly. The duration of intensive care is shortened significantly and the child is connected to life again. For these reasons, nitric oxide is also of vital importance in this field of surgery.

BENEFIT

• New lives saved
• Due to the nature of children, the intensive care process is long and arduous. This process is shortened with nitric oxide, and difficulties and expenses are minimized.

 IN THE DIAGNOSIS OF PULMONARY HYPERTENSION DUE TO VALVE DISEASES IN HEART SURGERY

The diagnosis of pulmonary hypertension due to valve diseases is easily resolved with nitric oxide. In such indications, after valve repair or replacement, the problem is experienced at the pump outlet, while nitric oxide helps again. Nitric oxide contributes greatly to the comfortable and short duration of the intensive care process.

 REFERENCE  HOSPITALS

EGE UNIVERSITY HOSPITAL  –  IZMIR

KOŞUYOLU CARDIOVASCULAR TRAINING AND RESEARCH HOSPITAL – ISTANBUL

SİYAMİ ERSEK HEART – VASCULAR TRAINING AND RESEARCH HOSPITAL – ISTANBUL

SUREYYAPAŞA CHEST DISEASES HOSPITAL – ISTANBUL

MEMORIYAL HOSPITAL – ISTANBUL (LUNG TRANSPLANTATION   PROF.DR MÜNCİ  KALAYCIOĞLU)

IN VASODILATATION TEST

The vasodilation test is a test performed by cardiologists to establish the diagnosis of Eisenmenger. When this test is performed with nitric oxide, the cost of the test is reduced by 90%, results are obtained in a short time, unnecessary sending of patients to surgery is prevented, and accordingly unnecessary surgical expenses can be avoided.

Note: Nitric oxide is taken as reference in clinical studies on vasodilation test.

REFERENCE  HOSPITALS

 MARMARA UNIVERSITY OF MEDICINE CARDIOLOGY DEPARTMENT –ISTANBUL

EGE UNIVERSITY CARDIOLOGY DEPARTMENT – IZMIR

GAZI UNIVERSITY CARDIOLOGY DEPARTMENT ­ – ANKARA

IN THE NEWBORN DEPARTMENT

Respiratory failure is the most common reason for infants to be admitted to the intensive care unit. In the literature, this rate is reported to be between 30-50%. The majority of infants hospitalized due to respiratory failure are premature infants. However, 30% of term babies also have respiratory distress.

Important and vital differences between the antenatal circulatory system (prenatal) and postnatal circulatory system (postnatal) play a role in respiratory distress being such a frequent and important health problem in both premature and term babies. Factors affecting this process, which is known as the transition period and ensures the normal continuation of postnatal circulation, cause hypoxic respiratory failure (HSY) and/or pulmonary hypertension (PPHT).

In the etiology of HSY syndrome or PPHT,

Anatomical Reasons

Pulmonary hypoplasia

Pulmonary vascular anomalies (often with cardiovascular malformation)

Perinatal reasons

Perinatal asphyxia

Meconium aspiration and other aspiration syndromes

Diseases that cause pulmonary reactivity, such as shock or sepsis

Absence of a risk factor for idiopathic pulmonary hypovascularity and PPHT

PPHT associated with pulmonary parenchymal diseases

Congenital heart diseases with increased pulmonary blood flow (1/3 of cases with uncorrected congenital heart disease die from pulmonary vascular disease)

Post-cardiac surgery (PPHT develops in 2% of cases who underwent serious cardiac surgery in the neonatal period)

Factors affecting alveolar or vascular development

Congenital diaphragmatic hernia

Congenital cystic adenomatoid malformation

Scimitar syndrome

Potter’s syndrome

severe bronchopulmonary dysplasia

Alveolar capillary dysplasia

Drug-associated PPHT

Exposure to intrauterine anti-inflammatory or antidepressant medication that inhibits serotonin reabsorption

Among the treatments used in HSY or PPHT treatment, oxygen and magnesium sulfate treatments have been proven to be beneficial, while hyperventilation, alkalization, sedation, and Tolazoline use have been shown to be useless or even harmful. Today, however, inhaled nitric oxide (iNO) therapy is accepted as a more successful, life-saving and ECMO-reducing treatment compared to all conventional treatments in the treatment of HSY and PPHT in babies older than 35 weeks of gestation.

Who can be treated with iNO?

It is recommended to be used in preterm babies whose gestational week is term or close to term. Studies on its use in preterm infants are continuing, and studies with high evidence on the effects of early and low-dose use on the development of BPD are continuing..

Oxygenation index (OI) is a parameter that shows the severity of hypoxemia. 50% of infants with an OI level of 25 and above require ECMO therapy or die. Therefore, iNO should be used in suitable cases with severe hypoxemia and OI value of 25 and above.

 Recommended doses of Ino

The recommended starting dose is 20 ppm and can be increased up to 40 or 80 ppm. However, it has been reported that high doses do not improve oxygenation in cases unresponsive to 20 ppm.

Expected time to iNO response and total treatment time

The onset of a positive response in newborn babies is quite rapid. An increase in PaO2 and a decrease in OI are expected 30-60 minutes after treatment. The duration of treatment is considered to be until the oxygen desaturation is corrected or a maximum of 14 days. In the rare case of iNO addiction, this period varies according to the response obtained from alternative treatments. However, alveolar-capillary dysplasia should be considered in cases lasting longer than 5 days and with insufficient vasodilator response. In PPHT cases accompanying parenchymal lung disease, the preferred ventilator treatment mode may change the response, and it has been reported that the use of HFOV increases the iNO response.

Discontinuation of iNO therapy

Different cutting protocols are used in different centers. After a positive response to treatment, the dose of iNO should be reduced within the first four hours at the latest. During this period, the amount of FiO2 should be reduced gradually before reducing the dose of iNO. When the FiO2 level falls below 0.6, the dose of iNO should be reduced without waiting for four hours. If the patient’s condition is stable and the OI level does not increase, the dose of iNO should be reduced every four hours and discontinued. When applying the cutting protocol, every reduction between 20 ppm and 5 ppm should be reduced by 5 ppm, then 1 ppm. After the treatment is stopped, the patient should be observed closely for one hour, and if hemodynamic deterioration or an increase in oxygen demand is observed, the treatment should be started again..

  BENEFIT

• While the results are obtained in 6 -7 days in oxygen and magnesium sulfate treatments, this process takes only a few hours in nitric oxide, and accordingly the duration of intensive care is dramatically reduced, and the brain and other damages that may occur in the child depending on the length of the process in conventional treatment are prevented.

 REFERENCE HOSPITAL

 ZEKAİ TAHİR BURAK TRAINING AND RESEARCH HOSPITAL – ANKARA

ÇERRAHPAŞA UNIVERSITY NEWBORN DEPARTMENT – İSTANBUL

ŞİŞLİ  ETFAL  RESEARCH AND TRAINING HOSPITAL – İSTANBUL

INDICATIONS FOR INHALED NITRIC OXIDE THERAPY

1. Newborn respiratory failure (persistent neonatal pulmonary hypertension, meconium aspiration, pneumonia, respiratory distress syndrome)
2. After congenital heart surgery performed in patients with pulmonary hypertension or at risk of pulmonary hypertensive crisis
3. Adult Respiratory Distress Syndrome
4. After pulmonary thromboendarterectomy in cases of chronic pulmonary thromboembolism
5. Lung Transplantation
6. Heart transplantation cases with pulmonary hypertension at risk of right heart failure
7. Prevention of right heart failure and treatment of pulmonary hypertension in patients with heart failure in whom a left ventricular assist device is inserted.
8. Valve patients with severe pulmonary hypertension and risk of right heart failure

NITRIC OXIDE SET CONNECTION DIAGRAM

The nitric oxide set is of two types, pediatric and adult.
Connecting is the same. The nitric oxide set is inserted into the inspiration line from the ventilator.
It is connected from the closest point to the patient (proximal) as shown in the diagram.
must be connected. A hose emerges from each end of the nitric oxide line.
of these, the hose coming out of the connection point to the inspiration line is nitric oxide
It should be connected to the output part (output) of the regulator connected on the tube.
if the hose (the part close to the patient) is the water behind the nitric oxide monitor
It should be plugged into the hopper input (input). Thus, the Nitric Oxide line is included in the system.
has been done.

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