Nitric Oxide Ventilation in ARDS

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Nitric Oxide Ventilation in ARDS

• Muhammad Asim Rana

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• Nitric oxide was formerly known as
  endothelium-derived relaxing factor (EDRF).  It
  is one of the nitrogen oxides ("NOx") and is
  synthesized within cells by an enzyme NO synthase
  (NOS).  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.

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NOS is present in two forms

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

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Effects
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Cardiovascular

• Nitric oxide is a potent vasodilator.  Shear
  stresses in vessels increase NO production and
  may account for flow dependant vasodilatation. 
  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.

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Respiratory

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

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Neuronal

• Nitric oxide appears to have a physiological role
  as a neurotransmitter within the autonomic and
  central nervous system.  Proposed roles 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.

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Gastrointestinal

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

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Genitourinary

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

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Immune

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

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Hematological

• Platelet aggregation is inhibited by NO.

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Basic Concept

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

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MECHANISM OF ACTION 

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

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Inhaled vasodilators

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

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

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• Inhaled Nitric oxide (NO) has been well-studied
  in patients with acute lung injury and ARDS.
• Inhaled NO has beneficial physiological effects,
  but there is little evidence that patient outcome
  improves. This is illustrated by the following
  clinical trials

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

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

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• It has also been hypothesized that NO may have
  benefits unrelated to improved V/Q matching,
  including
• 1.antiinflammatory properties,
• 2.antiplatelet activity, and
• 3.effects which diminish vascular permeability

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Dosing

• Inhaled NO is typically administered at a dose
  between 1.25 and 40 parts per million (ppm).
• It has been used continuously for days to weeks,
  with interruptions or attempts to discontinue
  therapy resulting in worsened oxygenation and
  increased pulmonary artery pressure.
• However, there is evidence that patients treated
  with continuous inhaled NO might become
  sensitized, such that lower doses improve
  oxygenation and continued higher doses have
  little or no effect.

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Metabolism

• Nitric oxide combines with hemoglobin that is 60
  to 100 oxygenated. Nitric oxide combines with
  oxyhemoglobin to produce methemoglobin and
  nitrate. Within the pulmonary system, nitric
  oxide can combine with oxygen and water to
  produce nitrogen dioxide and nitrite
  respectively, which interact with oxyhemoglobin
  to then produce methemoglobin and nitrate. At 80
  ppm the methemoglobin percent is 5 after 8
  hours of administration. Methemoglobin levels gt7
  were attained only in patients receiving 80 ppm.

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PHARMACODYNAMICS / KINETICS

• Absorption Systemic after inhalation
• Excretion Urine (as nitrate)
• Clearance Nitrate At a rate approaching the
  glomerular filtration rate.

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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.

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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.

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Monitoring

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

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Potential harms

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

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

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• Inhaled NO is associated with renal dysfunction.
• Inhaled NO has immunosuppressant properties that,
  in theory, could increase the risk of nosocomial
  infection.
• NO can cause DNA strand breaks and base
  alterations, which are potentially mutagenic.

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SUMMARY

• Management of acute respiratory distress syndrome
  (ARDS) is supportive, aimed at improving gas
  exchange and preventing complications while the
  underlying disease that precipitated ARDS is
  treated.
• Potential ARDS-specific therapies like inhaled NO
  have been studied however, they have not been
  shown to improve clinical outcome and, thus,
  cannot be recommended for routine care.

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Predictors when to use Inhaled NO

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

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• One retrospective study found that patients with
  septic shock responded to inhaled NO less
  frequently than patients without sepsis or septic
  shock.
• A different study reported that a high baseline
  pulmonary vascular resistance and responsiveness
  to positive end-expiratory pressure (PEEP)
  predicted a positive response.

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

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Acknowledgements

• Dr. Mostafa Adel
• Dr. Omar Alsayed
• Dr. Ahmed fouad
• Dr. Ahmed Hossam

• Dr. Ahmed Rajab
• Dr. Sameer Ibrahim
• Dr. Bashir Ahmed
• Dr. Sayed Afzal

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Thank You