Nitric Oxide Nitric Oxide Ventilation in ARDSVentilation in ARDS

Muhammad Asim RanaMuhammad Asim Rana

►Nitric oxide was formerly known as Nitric oxide was formerly known as endothelium-derived relaxing factor (EDRF).  endothelium-derived relaxing factor (EDRF).  It is one of the nitrogen oxides ("NOx") and It is one of the nitrogen oxides ("NOx") and is synthesized within cells by an enzyme NO is synthesized within cells by an enzyme NO synthase (NOS).  This enzyme catalyses the synthase (NOS).  This enzyme catalyses the oxidation of L-arginine to L-citrulline, oxidation of L-arginine to L-citrulline, producing NO, which diffuses into vascular producing NO, which diffuses into vascular smooth muscle, activating guanylate smooth muscle, activating guanylate cyclase which in turn converts guanosine cyclase which in turn converts guanosine triphosphate into cyclic guanosine triphosphate into cyclic guanosine monophosphate (cGMP), causing vascular monophosphate (cGMP), causing vascular relaxation.relaxation.

NOS is present in two forms:NOS is present in two forms:

►   The constitutive form (eNOS)The constitutive form (eNOS)Present in vascular, neuronal, cardiac tissue, skeletal Present in vascular, neuronal, cardiac tissue, skeletal muscle and platelets, producing small quantities of NO muscle and platelets, producing small quantities of NO continuously.  Here NOS is Ca2+/calmodulin dependant continuously.  Here NOS is Ca2+/calmodulin dependant and is stimulated by cGMP.and is stimulated by cGMP.

►    The inducible form (iNOS)The inducible form (iNOS)

Present in endothelium, myocytes, macrophages and Present in endothelium, myocytes, macrophages and neutrophils, which produces relatively large quatities of NO neutrophils, which produces relatively large quatities of NO after exposure to endotoxins in sepsis.  Following induction after exposure to endotoxins in sepsis.  Following induction high levels of NO produced may form cytotoxic radicals and high levels of NO produced may form cytotoxic radicals and cause capillary leakage.cause capillary leakage.

EffectsEffects

CardiovascularCardiovascular

Nitric oxide is a potent vasodilator.  Nitric oxide is a potent vasodilator.  Shear stresses in vessels increase NO Shear stresses in vessels increase NO production and may account for flow production and may account for flow dependant vasodilatation.  Endothelial dependant vasodilatation.  Endothelial NO inhibits platelet aggregation.  In NO inhibits platelet aggregation.  In septic shock the overproduction of NO septic shock the overproduction of NO results in hypotension and capillary leak.  results in hypotension and capillary leak.  NOS inhibitors have been investigated NOS inhibitors have been investigated experimentally in the treatment of experimentally in the treatment of sepsis.sepsis.

RespiratoryRespiratory

► Important basal vasodilatation in Important basal vasodilatation in pulmonary vessels is provided by pulmonary vessels is provided by endogenous NO and this may be endogenous NO and this may be reversed in hypoxia.  Nitric oxide inhibits reversed in hypoxia.  Nitric oxide inhibits hypoxic pulmonary vasoconstriction and hypoxic pulmonary vasoconstriction and preferentially increases blood flow preferentially increases blood flow through well-ventilated areas of the through well-ventilated areas of the lung, thereby improving ventilation: lung, thereby improving ventilation: perfusion relationships.perfusion relationships.

NeuronalNeuronal

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

GastrointestinalGastrointestinal

►NO is a determinant of gastrointestinal NO is a determinant of gastrointestinal motility and appears to modulate motility and appears to modulate morphine-induced constipation.morphine-induced constipation.

GenitourinaryGenitourinary

►Nitric oxide may play a role in sodium Nitric oxide may play a role in sodium homeostasis in the kidney. homeostasis in the kidney. 

ImmuneImmune

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

HematologicalHematological

Platelet aggregation is inhibited by NO.Platelet aggregation is inhibited by NO.

Basic ConceptBasic Concept

►One hallmark of ARDS is severe One hallmark of ARDS is severe hypoxemia caused by physiologic hypoxemia caused by physiologic shunting and ventilation/perfusion (V/Q) shunting and ventilation/perfusion (V/Q) mismatching. Inhaled vasodilators, mismatching. Inhaled vasodilators, particularly nitric oxide can selectively particularly nitric oxide can selectively dilate vessels that perfuse well ventilated dilate vessels that perfuse well ventilated lung zones, resulting in improved V/Q lung zones, resulting in improved V/Q matching, better oxygenation, and matching, better oxygenation, and amelioration of pulmonary hypertension. amelioration of pulmonary hypertension.

MECHANISM OF ACTION MECHANISM OF ACTION 

► Nitric oxide relaxes vascular smooth muscle Nitric oxide relaxes vascular smooth muscle by binding to the heme moiety of cytosolic by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which cyclic guanosine 3',5'-monophosphate, which leads to vasodilation. When inhaled, leads to vasodilation. When inhaled, pulmonary vasodilation occurs and an pulmonary vasodilation occurs and an increase in the partial pressure of arterial increase in the partial pressure of arterial oxygen results. Dilation of pulmonary vessels oxygen results. Dilation of pulmonary vessels in well ventilated lung areas redistributes in well ventilated lung areas redistributes blood flow away from lung areas where blood flow away from lung areas where ventilation/perfusion ratios are poor.ventilation/perfusion ratios are poor.

Inhaled vasodilators Inhaled vasodilators

► Inhaled vasodilators Inhaled vasodilators (green circles) (green circles) preferentially dilate the preferentially dilate the pulmonary vessels that pulmonary vessels that perfuse functioning perfuse functioning alveoli (white circles), alveoli (white circles), recruiting blood flow recruiting blood flow away from poorly away from poorly ventilated units (black ventilated units (black circles). The net effect is circles). The net effect is improved improved ventilation/perfusion ventilation/perfusion matching. matching.

► In addition, inhaled vasodilators have In addition, inhaled vasodilators have few systemic effects and rarely cause few systemic effects and rarely cause hypotension because they act locally hypotension because they act locally and have short half-lives.and have short half-lives.

► Inhaled Nitric oxide (NO) has been Inhaled Nitric oxide (NO) has been well-studied in patients with acute well-studied in patients with acute lung injury and ARDS. lung injury and ARDS.

► Inhaled NO has beneficial physiological Inhaled NO has beneficial physiological effects, but there is little evidence that effects, but there is little evidence that patient outcome improves. This is patient outcome improves. This is illustrated by the following clinical illustrated by the following clinical trials: trials:

► A well-designed multicenter trial randomly A well-designed multicenter trial randomly assigned 385 patients with moderate to severe assigned 385 patients with moderate to severe acute lung injury (P/F ratio ≤ 250 mmHg) to acute lung injury (P/F ratio ≤ 250 mmHg) to either placebo or inhaled NO at 5 ppm. The either placebo or inhaled NO at 5 ppm. The acute lung injury was not caused by sepsis, and acute lung injury was not caused by sepsis, and significant nonpulmonary organ dysfunction significant nonpulmonary organ dysfunction was absent. Inhaled NO induced short-term was absent. Inhaled NO induced short-term improvement of oxygenation; however, there improvement of oxygenation; however, there was no improvement in the duration of was no improvement in the duration of mechanical ventilation, 28-day mortality, or mechanical ventilation, 28-day mortality, or one-year survival.one-year survival.

► Another multicenter double-blind trial Another multicenter double-blind trial randomly assigned 177 with ARDS to receive randomly assigned 177 with ARDS to receive increasing concentrations of inhaled NO or increasing concentrations of inhaled NO or placebo. Inhaled NO improved oxygenation placebo. Inhaled NO improved oxygenation modestly, but was not sustained. There was modestly, but was not sustained. There was no difference in 28-day mortality, although no difference in 28-day mortality, although this was not a primary end point. The modest this was not a primary end point. The modest improvement of oxygenation detected in this improvement of oxygenation detected in this trial caused some to argue that further trial caused some to argue that further investigation of inhaled NO for ARDS is not investigation of inhaled NO for ARDS is not warranted, although this view is not universal.warranted, although this view is not universal.

► It has also been hypothesized that NO may have It has also been hypothesized that NO may have benefits unrelated to improved V/Q matching, including benefits unrelated to improved V/Q matching, including

1.antiinflammatory properties, 1.antiinflammatory properties,

2.antiplatelet activity, and 2.antiplatelet activity, and

3.effects which diminish vascular permeability 3.effects which diminish vascular permeability

Dosing Dosing

► Inhaled NO is typically administered at a dose Inhaled NO is typically administered at a dose between 1.25 and 40 parts per million (ppm). between 1.25 and 40 parts per million (ppm).

► It has been used continuously for days to It has been used continuously for days to weeks, with interruptions or attempts to weeks, with interruptions or attempts to discontinue therapy resulting in worsened discontinue therapy resulting in worsened oxygenation and increased pulmonary artery oxygenation and increased pulmonary artery pressure. pressure.

►However, there is evidence that patients However, there is evidence that patients treated with continuous inhaled NO might treated with continuous inhaled NO might become sensitized, such that lower doses become sensitized, such that lower doses improve oxygenation and continued higher improve oxygenation and continued higher doses have little or no effect. doses have little or no effect.

MetabolismMetabolism

►Nitric oxide combines with hemoglobin that is Nitric oxide combines with hemoglobin that is 60% to 100% oxygenated. Nitric oxide 60% to 100% oxygenated. Nitric oxide combines with oxyhemoglobin to produce combines with oxyhemoglobin to produce methemoglobin and nitrate. Within the methemoglobin and nitrate. Within the pulmonary system, nitric oxide can combine pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen with oxygen and water to produce nitrogen dioxide and nitrite respectively, which interact dioxide and nitrite respectively, which interact with oxyhemoglobin to then produce with oxyhemoglobin to then produce methemoglobin and nitrate. At 80 ppm the methemoglobin and nitrate. At 80 ppm the methemoglobin percent is ~5% after 8 hours of methemoglobin percent is ~5% after 8 hours of administration. Methemoglobin levels >7% were administration. Methemoglobin levels >7% were attained only in patients receiving 80 ppm.attained only in patients receiving 80 ppm.

PHARMACODYNAMICS / PHARMACODYNAMICS / KINETICSKINETICS

►Absorption: Systemic after inhalationAbsorption: Systemic after inhalation►Excretion: Urine (as nitrate)Excretion: Urine (as nitrate)►Clearance: Nitrate: At a rate Clearance: Nitrate: At a rate

approaching the glomerular filtration approaching the glomerular filtration rate.rate.

StorageStorage

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

Administration Administration

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

Monitoring Monitoring

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

Potential harms Potential harms

► Inhaled NO may produce toxic Inhaled NO may produce toxic radicals. However, it is unknown radicals. However, it is unknown whether the toxic radicals are more whether the toxic radicals are more harmful than ongoing exposure to high harmful than ongoing exposure to high fractions of inspired oxygen.fractions of inspired oxygen.

►Methemoglobin and NO2 Methemoglobin and NO2 concentrations may increase when concentrations may increase when high doses of NO are given(500-2000 high doses of NO are given(500-2000 ppm of NO), and the concentration of ppm of NO), and the concentration of both should be monitored frequently.both should be monitored frequently.

► Inhaled NO is associated with renal Inhaled NO is associated with renal dysfunction. dysfunction.

► Inhaled NO has immunosuppressant Inhaled NO has immunosuppressant properties that, in theory, could properties that, in theory, could increase the risk of nosocomial increase the risk of nosocomial infection.infection.

►NO can cause DNA strand breaks and NO can cause DNA strand breaks and base alterations, which are potentially base alterations, which are potentially mutagenic.mutagenic.

SUMMARYSUMMARY

►Management of acute respiratory distress Management of acute respiratory distress syndrome (ARDS) is supportive, aimed at syndrome (ARDS) is supportive, aimed at improving gas exchange and preventing improving gas exchange and preventing complications while the underlying disease complications while the underlying disease that precipitated ARDS is treated. that precipitated ARDS is treated.

► Potential ARDS-specific therapies like Potential ARDS-specific therapies like inhaled NO have been studied; however, inhaled NO have been studied; however, they have not been shown to improve they have not been shown to improve clinical outcome and, thus, cannot be clinical outcome and, thus, cannot be recommended for routine care. recommended for routine care.

Predictors when to use Inhaled Predictors when to use Inhaled NO NO

► Inhaled NO does not improve Inhaled NO does not improve oxygenation in all patients and the oxygenation in all patients and the factors that determine responsiveness factors that determine responsiveness are uncertain. are uncertain.

►One retrospective study found that One retrospective study found that patients with septic shock responded patients with septic shock responded to inhaled NO less frequently than to inhaled NO less frequently than patients without sepsis or septic patients without sepsis or septic shock.shock.

►A different study reported that a high A different study reported that a high baseline pulmonary vascular baseline pulmonary vascular resistance and responsiveness to resistance and responsiveness to positive end-expiratory pressure positive end-expiratory pressure (PEEP) predicted a positive response.(PEEP) predicted a positive response.

►So the decision lies with treating So the decision lies with treating Intensivist about starting a patient on Intensivist about starting a patient on inhaled NO keeping in view the inhaled NO keeping in view the potential benefits and harms of such potential benefits and harms of such therapy.therapy.

AcknowledgementsAcknowledgements

►Dr. Mostafa AdelDr. Mostafa Adel►Dr. Omar Alsayed Dr. Omar Alsayed ►Dr. Ahmed fouadDr. Ahmed fouad►Dr. Ahmed HossamDr. Ahmed Hossam

►Dr. Ahmed RajabDr. Ahmed Rajab►Dr. Sameer IbrahimDr. Sameer Ibrahim►Dr. Bashir AhmedDr. Bashir Ahmed►Dr. Sayed AfzalDr. Sayed Afzal

Thank YouThank You