Inspired (by) Nitric in ARDS

Rationale and Background

• Main mechanism driving hypoxia in ARDS is shunt

              o This may be further exacerbated by pharmacological blunting of our physiological
                  protective mechanisms (hypoxic pulmonary vasoconstriction) by use of deep sedation
                   in these patients
              o Hypoxia due to significant shunt responds very poorly to increases in FiO2 -with a
                  potential paradoxical fall in PaO2
              o Pulmonary vasodilators such as iNO improve V/Q matching and thereby reduce shunt
                  and improve oxygenation irrespective of FiO2
              o If hypoxia is considered to be the main driver behind MOF and death in ARDS then
                  improving oxygenation should lead to improved morbidity and mortality. On the
                  other-hand effects of iNO are short-lived and do not treat underlying pathology, -so
                  on its own as a treatment, other than buying time (short-lived: tachyphylaxis) it may
                  not improve outcomes

• Other strategies for improving oxygenation in ARDS include increasing mean airway pressure;

           whilst this may recruit alveoli and improve gas exchange it potentially may increase RV
           afterload (which we know already to be acutely elevated as part of ARDS pathophysiology)
               o This is individual, as the effect of increased intrathoracic pressure on RV afterload may
                   be offset/balanced by the beneficial effect on the RV of improved oxygenation / CO2
                   clearance
               o iNO shown to be effective in treatment of pulmonary hypertension and reducing RV
                   afterload (especially in neonates)

Advantages and Disadvantages

• Advantages;

                o Good physiological rationale; improves oxygenation and RV afterload -both of which
                    are a problem in ARDS and which may contribute to M&M and reduced ventilatorfree
                    days
                o Cheap, readily accessible in most ICUs, minimal additional training required to use

• Disadvantages;

                o Practical: Requires scavenging / adequate air changes, monitoring for potential toxic
                    NO2 levels, dedicated inserts increase dead space of circuit
                o Physiological: May cause systemic hypotension, associated AKI, pulmonary oedema (if
                    LV dysfunction), platelet inhibition may increase bleeding, methaemoglobinaemia, if
                    complications cannot rapidly wean/discontinue (rebound PHtn and hypoxia), increase
                    ICP
                o Other: not all patients are responsive, dose-response unclear, tachyphylaxis occurs
                    (short-term treatment)

Evidence

• A number of small RCTs exist – randomising patients with varying severity of ARDS into iNO

          versus placebo / no treatment. A variety of dose ranges and protocols were used to include
          identification of responders and use of differing dosing regimens (low dose to high dose tried)

• Cochrane review 2016 (adults and children with ARDS)

                o 14 trials (1275 participants)
                o No effect on 28d mortality or ventilator free days
                o Improved P/F (and/or oxygenation index) at 24h
                o Increase in renal failure in iNO group
                 o Cannot recommend as a treatment in this group

Summary (my practice)

• I do not use iNO routinely in my management of severe ARDS
• I do use it for short periods (<48h) in those with severe refractory hypoxaemia (SaO2/SpO2

          <85%) refractory to conventional ventilation strategies, as a bridge to another intervention
          with a better evidence-base of benefit e.g. proning, ECMO

• I individually weigh-up potential risks of benefit-harm, start low (5ppm) and slowly increase

           up to a maximum of 20ppm – if unresponsive at 20ppm I do not expect to see a benefit
           increasing beyond this and am likely to experience marked worsening in systemic
           hypotension etc., I am vigilant for other anticipated complications

• I ensure adequate monitoring and scavenging systems are in place and staff are familiar with

           its use

• If non-responsive or marked complications, I wean and discontinue this therapy early

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