NITRIC OXIDE: THE SAVIOUR.

Nitric oxide (NO) is one of the nitrogen oxides and is synthesized within cells by an enzyme NO synthase. It  was formerly known as endothelium-derived relaxing factor (EDRF).  Being one of the fundamental mediators in physiological processes, this enzyme catalyses the oxidation of L-arginine to L-citrulline, producing NO, which diffuses into vascular smooth muscle, activating guanylate cyclase  which in turn converts guanosine triphosphate into cyclic guanosine monophosphate (cGMP),causing vascular relaxation.
                                 Nitric oxide synthetase is present in two forms a)The constitutive form (eNOS), which is present in vascular, neuronal, cardiac tissue, skeletal muscle and platelets, producing small quantities of NO continuously. Here NOS is Ca2+/calmodulin dependant and is stimulated by cGMP.and b)the inducible form (iNOS),present in endo thelium, myocytes, macrophages and neutrophils, which produces relatively large quatities of NO after exposure to endotoxins in sepsis.

Biological effects of Nitric oxide ;
• Vascular endothelium: producing vascular relaxation.
• Platelets: involved in aggregation and adhesion of platelets
• Brain tissue: acts as a neurotransmitter.
• Macrophages: involved in the response to infection.


Proposed mechanisms of action:

• Increases intracellular cyclic gmp
• Protein kinase activation
• Inhibition of inositol triphosphate
• Inhibition phosphodiesterase through cyclic amp
• Decrease in intracellular calcium
• Inhibition of calcium influx

Systemic effects  and application 

• Septic shock

Nitric oxide is a potent vasodilator.  A flow dependant vasodilatation is caused due to increase in NO production as a result of shear stress and inflammation. Endothelial NO inhibits platelet aggregation. In septic shock the overproduction of NO results in hypotension and capillary leak. NOS inhibitors have been investigated experimentally in the treatment of sepsis.

• Neuronal

Nitric oxide appears to have a physiological role as a neurotransmitter within the autonomic and central nervous system which include modulation of the state of arousal, pain perception, apoptosis and long term neuronal depression and excitation whereby neurones may “remember” previous signals. Peripheral neurones containing NO control regional blood flow in the corpus cavernosum.

• Genitourinary

Nitric oxide is thought  to play a role in sodium homeostasis in the kidney. It is the physiological mediator of penile erection.

• Immune

Macrophages and neutrophils synthesize NO which can be toxic to certain pathogens and may be important in host defence mechanisms.

• Haematological

Platelet aggregation is inhibited by NO

• Respiratory :      explained below
• Cardiovascular:  explained below

Indications and uses:

1)Respiratory:
When given as inhalation, nitric oxide reaches the ventilated areas of the lung, where it produces elective vasodilatation and thereby reduces ventilation perfusion mismatch. Systemic vasodilatation and hypotension will not occur as it is immediately converted to met hemoglobin while entering systemic blood vessels.reduces pulmonary artery pressure.helpful in ARDs as it improves oxygenation and fio2 /peep can be reduced which are beneficial.nitric oxide is administered as inhaled form. 1-40 ppm conc can be  achieved by inhalation from cylinders attached to ventilator. the dis advantage is dependancy or tolerance whereby the effects are decreased on long term use.beneficial effects are observed in COPD patients  also due to direct bronchodilatation and improving lung function folowing cor pulmonale.HME humidifier is advised as excessive water content can cause formation of nitric acid.

2) Cardiovascular:
Decreases pulmonary vascular pressure and resistance  leading to a reduced rt ventricular afterload hence prevents rt ventricular failure. so useful in post cardiac surgery patients. following cardiac transplantation  the function of heart will be good whereas the lungs remain vasoconstricted with high pulm artery pressure.nitric oxide can  help better vejection of RV by selective pulmonary vasodilatation. Also useful for the treatment of pulmonary embolism as pulm hypertension is prevented.

3)Other uses:    Congenital diaphragmatic hernia,congenital heart dosease and idiopathic pulmonary hypertension inpediatric patients

Storage
NO is stored in aluminium or stainless steel cylinders which are typically 40 litres. These contain 100/1000/2000 p.p.m. nitric oxide in nitrogen. Pure NO is corrosive and toxic.

Dosage:
Start 1ppm for about 10 mts and monitor Pao2/Fio2 ratio, then every 10 minutes according to response,  maximum being 30 ppm

Administration
The drug is injected via the patient limb of the inspiratory circuit of a ventilator. The delivery system is designed to minimise the oxidation of nitric oxide to nitrogen dioxide.

Metabolism
Inhaled NO readily reacts with oxidised haemoglobin to yield methaemoglobin. NO has a half-life of less than 5 seconds.

Monitoring
Chemiluminescence and electrochemical analysers should be used and are accurate to 1 ppm.

Toxicity
Exposure to 500-2000 ppm of NO results in methaemoglobinaemia (by combining with Hb and forming nitrosylHb and then to metHb) and pulmonary oedema. Methaemoglobinaemia is only rarely significant and is more common in paediatric patients or those with methaemoglobinaemia reductase deficiency. Contamination by nitrogen dioxide(2NO+O2>2NO2) can similarly lead to pneumonitis and pulmonary oedema by epithelial and endothelial damage, decreased alveolar permeability and diffusion capacity Environmental levels should not exceed 25 ppm for 8 hours.Direct toxic effects of nitric oxide  causing inflammatory effects on resp tract also described.

Ref:  Anaesthesia UK online, BJA 1996, Anaesthesiology 1993,  NEJM 1993