Inhaled Nitric Oxide Therapy in Adults

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Inhaled Nitric Oxide Therapy in Adults

• Authors Mark J.D. Griffiths, M.R.C.P., Ph.D.,
  and Timothy W. Evans, M.D., Ph.D
• From NEJM 35325 December 22, 2005
• Presenter R5???
• Supervisor Dr. VS ???

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Introduction

• NO and endothelium-derived relaxing factor
  ?modulating vascular tone through stimulated
  formation of cyclic guanosine 3',5'-monophosphate
• NO is formed from semiessential amino acid
  L-arginine by one of three (neural, inducible,
  and endothelial) isoforms of nitric oxide
  synthase
• In 1991, inhaled NO ?selective pulmonary
  vasodilator in patients with pulmonary
  hypertension, as well as in animals with
  pulmonary hypertension induced by drugs or
  hypoxia.

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• NO in ARDS ?? pulmonary vascular resistance
  without affecting BP and ? oxygenation by
  redistributing pulmonary blood flow toward
  ventilated lung units.BUT ?licensed indications
  are restricted to pediatric practice
• This review ? biologic actions of inhaled NO ,
  clinical indications in adults, possible future
  developments

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chemical reactions of inhaled nitric oxide

• Atmospheric concentrations ?between 10 and 500
  parts per billion but may reach 1.5 parts per
  million (ppm) in heavy traffic12 and 1000 ppm in
  tobacco smoke
• NO is potentially cytotoxic, and covalent
  nitration of tyrosine in proteins by reactive
  nitrogen species has been used as a marker of
  oxidative stress

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• NO is rapidly inactivated by hemoglobin in blood
  by haptoglobinhemoglobin complexes in plasma ?
  forms nitrosylhemoglobin in lung ?methemoglobin
  and nitrate on reaction with oxyhemoglobin
  ?reduced to ferrous hemoglobin by NADHcytochrome
  b5 reductase in erythrocytes
• 70 inhaled NO is excreted as nitrate in the
  urine within 48 hours

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• gt100 proteins, including hemoglobin and albumin,
  contain reduced sulfur (thiol) ? react reversibly
  with NO to form S-nitrosothiols ? vasodilators
  that inhibit platelet aggregation, also store
  nitric oxide within the circulation

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physiologic effects of inhaled nitric oxideon
the cardiovascular system
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• Inhaled NO relaxes pulmonary vessels ? ?pulmonary
  vascular resistance, pulmonary arterial pressure,
  and right ventricular afterload
• rapid hemoglobin-mediated inactivation of NO
• biventricular cardiac failure ?inhaled NO ? ?
  pulmonary blood flow ??pulmonary edema

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• positive effect of inhaled NO on gas exchange
  depends on the extent to which pulmonary
  vasoconstriction and ventilationperfusion
  mismatching are contributing to impaired
  oxygenation ? study of mountaineers
• vascular selectivity ?disproportionate arterial,
  as opposed to venous ?dilatation
  ??pulmonary-capillary pressure? may ?risk of
  pulmonary edema ( but NO 40 ppm induced
  venodilatation? ?pulmonary edema)

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• NO decreasing inflammation and helping maintain
  the integrity of the alveolar-capillary membrane
  in animal studies
• inhaled NO has no effect on systemic
  circulation BUT experimental studies have
  demonstrated ?systemic vascular resistance,
  restoration of mesenteric perfusion after
  inhibition of NO synthase

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• rapid withdrawal may induce rebound pulmonary
  hypertension and hypoxemia ??endothelial NO
  synthase activity ?? plasma concentrations of
  endothelin-1.. BUT large clinical studies didnt
  support it

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direct cytotoxicity and effectson inflammation

• protective effects ?specific effects on
  neutrophil function? attenuation of the
  respiratory burst and neutrophil-derived
  oxidative stress, ?neutrophils in the pulmonary
  vasculature and air space in animal models of
  ALI, NO derived from neutrophils acts as an
  autocrine modulating factor in infiltration of
  neutrophils into the lungs during sepsis

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• endogenously produced NO contributes to control
  and killing of multiple pathogens and malignant
  cells.
• NOderived reactive nitrogen species contribute
  to epithelial damage after a variety of insults
  ?unpredictable and probably depend on the
  relative local concentrations ??oxidative
  products of NO in airway-lining fluid of patients
  with ARDS and MAYBE may be further increased by
  inhalation of NO

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• In rodents, inhalation of nitric oxide (20 ppm)
  did not increase protein nitration unless
  hyperoxia was superimposed
• Endogenous NO inhibits adhesion of platelets to
  endothelial cells and subsequent aggregation ?
  inhalation NO not certain

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• Reactive nitrogen species ?? functions of
  surfactant ?animals receiving inhaled high-dose
  nitric oxide (80 to 100 ppm) had ? capacity to
  lower surface tension. But inhaled NO
  ?surfactant proteins in four-week-old lambs, NOT
  certain in human
• Inhaled NO has a dose-dependent bronchodilator
  effect ?nitric oxidederived S-nitrosothiols

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administration of inhaled nitric oxideto adults

• Limiting mixing of NO with high concentrations of
  inspired oxygen ,and mixture of NO and nitrogen
  into inspiratory limb of ventilator tubing as
  near to patient as possible , synchronizing
  injection of the mixture with inspiration ??risk
  of adverse effects resulting from formation of
  nitrogen dioxide
• a massive overdose of inhaled NO (500 to 1000
  ppm) is rapidly fatal ?lt 40 ppm for up to 6
  months. Safe in animals

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• lt 40 ppm of inhaled NO administered clinically
  should not cause methemoglobinemia ?check
  methemoglobin within 6 hours after initiation of
  NO therapy and after each increase in the dose(
  UK guideline)
• environmental concentrations of NO and NO2 should
  not exceed a time-weighted average of 25 ppm and
  2 ppm, respectively, over an 8 hours
  period----The Control of Substances Hazardous to
  Health Regulations -----( unlikely in a
  well-ventilated room)

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DoseResponse Relationship

• higher doses were required to treat pulmonary
  hypertension than to improve oxygenation
• a minority of patients have no response when a
  response is defined as a 20 percent increase in
  oxygenation ?No radiologic or physiological
  variables predict a response

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• 30 ?pulmonary vascular resistance during
  inhalation of NO (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 (like calcium-channel blockers)

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• Doseresponse relationships ( NO, 0 to 100 ppm)
  were constructed in the two groups on days 0, 2,
  and 4 ? first, the dose response curves for
  changes in oxygenation and mean pulmonary
  pressure were shifted to left only in patients
  who inhaled nitric oxide (10 ppm) continuously.
  Second, supramaximal doses of NO were
  associated with worsening oxygenation-------
  Gerlach H, 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 20031671008-15.

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clinical indications for administeringinhaled
nitric oxide to adults

• failed to determine the therapeutic role of
  inhaled nitric oxide in patients with acute
  respiratory failure
• no decrease in duration of mechanical ventilation
  or the mortality rate----similar at 30 days
  (European multicenter study enroll 600 subjects
  enrolled 268 patients with early ALI)
• ?oxygenation (specifically in the partial
  pressure of arterial oxygen) lasted only for the
  first day of therapy

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• why are the effects of inhaled NO so
  short-lived?------?sensitivity to NO during its
  inhalation may diminish its beneficial effects
  and increase toxicity, constant inhalation may
  lead to equilibration of vasodilator effect
  between ventilated and nonventilated areas
• any continued benefit may depend on use of other
  therapeutic approaches such as maintaining
  alveolar recruitment

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• if clinical benefits are real, why do they not
  translate into improved outcome?-----ARDS is a
  heterogeneous condition with multiple causes
  requiring different interventions that
  independently affect outcome, very large numbers
  of patients would be required for a study to
  demonstrate benefit------many large studies
  evaluating modes of ventilation and prone
  positioning in patients with ARDS have shown no
  correlation between improved oxygenation and the
  outcome----majority die from multiorgan failure

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Targeting Pulmonary Vascular Resistance

• ?expression of endothelial NO synthase in
  pulmonary arteries of patients with chronic
  primary and secondary pulmonary hypertension?
  possible therapeutic role for nitric oxide
  ?Inhaled NO improves hemodynamic variables and
  exercise tolerance in patients with chronic
  pulmonary hypertension of various causes

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• inhaled NO alleviates pulmonary HTN in severe
  COPD but exacerbates hypoxemia at rest-----BUT
  pulsed therapy (O2 with inhaled NO as a bolus
  after the start of inspiration) markedly ?
  pulmonary arterial pressure and ? cardiac output
  without impairing oxygenation (Vonbank K,et al.
  Controlled prospective randomised trial on the
  effects on pulmonary haemodynamics of the
  ambulatory long term use of nitric oxide and
  oxygen in patients with severe COPD. Thorax
  200358289-93)
• During exercise, inhaled NO alleviates pulmonary
  HTN without inducing hypoxemia

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Lung Transplantation

• ischemia and reperfusion and oxidative stress is
  an important cause of morbidity and mortality
  after lung transplantation---also ?Endogenous NO
  activity-----randomized, placebo-controlled trial
  of 84 transplant recipients, starting 10 minutes
  after reperfusion and continuing for a minimum of
  6 hours, demonstrated no benefit in terms of
  oxygenation, the time to extubation, or the
  30-day mortality rate.

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Sickle Cell Disease

• results in widespread chronic inflammation and
  recurrent ischemiareperfusion injury in organs
  such as the lungs and is caused by microvascular
  occlusion by stiff erythrocytes containing
  polymerized deoxyhemoglobin S-----high-dose
  inhaled NO (80 ppm for 1.5 hours) ??scavenging
  potential of hemoglobin within the circulation
  (because of the weak interaction of nitric oxide
  with methemoglobin)

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alternatives and adjuncts to inhalednitric oxide

• aerosolized sodium nitrite
• Epoprostenol, the most extensively studied
  alternative to inhaled NO, also an endothelium-
  derived vasodilator with antithrombotic
  effects---longer half-life (three to six
  minutes), causing recirculation ---- greater
  pulmonary and systemic hypotensive effect, but
  causes less improvement in oxygenation
• Inhaled NO and nebulized prostacyclin have been
  observed to have additive effects

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• Nebulized epoprostenol (10 to 50 ng per kilogram
  per minute) , Iloprost, a long-acting
  prostacyclin analogue (half-life, 20 to 30
  minutes) , Inhaled prostaglandin E1 (6 to 15 ng
  per kilogram of body weight per minute)

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Adjunctive Therapies That Increase the
Effectivenessof Inhaled Nitric Oxide

• sildenafil, an inhibitor of phosphodiesterase
  type 5, is a selective pulmonary vasodilator,
  partially because phosphodiesterase type 5 is
  highly expressed in the lung ---- augmented
  pulmonary vasodilatation induced by NO inhalation
• But zaprinast, predictably worsened oxygenation
  through the attenuation of hypoxic pulmonary
  vasoconstriction in an ovine model of acute lung
  injury---most useful when pulmonary HTN rather
  than respiratory failure

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• Almitrine, an agonist at peripheral arterial
  chemoreceptors, is a selective pulmonary
  vasoconstrictor that specifically enhances
  hypoxic pulmonary vasoconstriction
• PEEP , prone positioning, or ventilatory
  maneuvers designed to inflate collapsed lung
• Partial liquid ventilation with perfluorocarbons
  facilitates delivery of dissolved gases to
  alveoli by enhancing recruitment of injured lung
  units

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conclusionsand future directions

• 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-------statistically underpowered to
  show a decrease in mortality rates and have not
  considered recent insights into effect of
  continuous inhalation on dose response
  relationship of this agent

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• On basis of evidence, inhaled NO is not an
  effective therapeutic intervention in patients
  with acute lung injury or ARDS, and its routine
  use to achieve this end is inappropriate-----may
  be useful as a short-term adjunct therapy

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Thank you for your attention!!!
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