Pharmacokinetic Alterations During ECMO
Condition: Acute Respiratory Failure
MeSH terms: Respiratory Insufficiency
Study type: Interventional

Summary: 
      In a healthy patient, the lungs provide oxygen to the blood and remove carbon dioxide.
      However, in patients with severe lung failure, blood may not adequately be delivered to the
      lungs, or the lungs may not adequately supply blood with oxygen. In this case, patients may
      require assistance from a machine to help provide this oxygen. Extracorporeal membrane
      oxygenation (ECMO) is a device that acts as an artificial lung, allowing the patient to
      recover from their illness. Patients receiving support from ECMO are often put in a medically
      induced coma while their lungs heal. Certain drugs may stick to the internal surfaces of the
      machine; therefore leading to decreased concentrations. Patients receiving ECMO often require
      high doses of both pain medications and sedatives in order to provide comfort. Low doses of a
      drug, ketamine, may help to provide additive effects to pain relief and allow lower doses of
      other pain medications. The hypothesis is that patients treated with continuous intravenous
      ketamine, will have lower requirements of other pain medications while receiving ECMO for
      acute respiratory failure while achieving the desired level of sedation.
    

Detailed description: 
      The administration of analgesia and sedation is common practice for patients receiving
      mechanical ventilation with extracorporeal membrane oxygenation (ECMO). Maintaining patient
      comfort and safety, while not oversedating and thereby risking prolonged mechanical
      ventilation and delirium, is an ongoing balancing act which presents a daily challenge for
      Intensive Care Unit (ICU) clinicians. Medication selection should be based on the patient's
      needs with titration to a predetermined goal in accordance with published guidelines.

      However, there are major pharmacokinetic changes that occur with the use of ECMO, including
      sequestration of medications within the circuit, increased volume of distribution, and in
      some cases decreased clearance. As a result patient's receiving ECMO often require very high
      doses of both analgesics and sedatives in order to provide comfort and ventilator synchrony.
      In patients not receiving ECMO, excess sedative exposure, especially with benzodiazepines,
      leads to increased mechanical ventilation time, prolonged ICU stay, short and long term
      neurocognitive impairments, and increased mortality. No studies address these outcomes in
      patients receiving ECMO.

      Ketamine, a non-barbiturate phencyclidine derivative, provides analgesia with relative
      hemodynamic stability and maintained airway reflexes. However, its popularity waned because
      of an undesirable side effect profile: Hallucinations, delirium, lacrimation, tachycardia,
      and potential for an increase in intracranial pressure (ICP) and coronary ischemia. Recent
      research, however, suggests that low doses of ketamine infusions in combination with opiates
      may not be associated with adverse sequelae and may improve outcomes in the critically ill
      population. To date, there are no studies that have compared clinical outcomes in ICU
      patients sedated with ketamine as compared with other sedative agents.

      Supplemental sedation with intravenous ketamine infusion may decrease opioid and sedative
      requirements for patients receiving mechanical ventilation and ECMO. The benefits of
      decreased opioid and sedative requirements may translate to fewer gastrointestinal side
      effects, decreased withdrawal syndromes, and a reduced rate of delirium.

      Deep levels of sedation are often required at the commencement of ECMO for acute respiratory
      failure, which correlates to a Richmond Agitation Sedation Score (RASS) of -5. Supplemental
      low doses of ketamine infusions may help the prescriber achieve this goal without having to
      use very high doses of fentanyl or hydromorphone and midazolam.
    

Intervention name(s): Ketamine; Sedative drug regimen
Intervention type(s): Drug; Other
Intervention description(s): Ketamine will be initiated as a one-time 40 mg bolus of ketamine followed by a continuous intravenous infusion of 5 micrograms/kg/min at the start of ECMO.; (Standard of Care) Fentanyl or hydromorphone and midazolam infusions will be administered to all patients and titrated at the discretion of the attending physician to maintain the desired level of sedation.
Other intervention name(s): Ketalar
Intervention MeSH terms: Ketamine; Hypnotics and Sedatives
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: ECMO; Ketamine; Opiates; Lung failure; Extracorporeal membrane oxygenation; Mechanical ventilation; Sedation