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Pharmacokinetic Alterations During ECMO

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ClinicalTrials.gov Identifier: NCT01938079
Recruitment Status : Completed
First Posted : September 10, 2013
Results First Posted : September 29, 2016
Last Update Posted : September 29, 2016
Sponsor:
Information provided by (Responsible Party):
Daniel Brodie, Columbia University

Brief 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.

Condition or disease Intervention/treatment Phase
Acute Respiratory Failure Drug: Ketamine Other: Sedative drug regimen Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Pharmacokinetic Alterations During ECMO (Ketamine and Extracorporeal Membrane Oxygenation)
Study Start Date : September 2013
Actual Primary Completion Date : February 2015
Actual Study Completion Date : August 2015


Arm Intervention/treatment
Active Comparator: Sedative without Ketamine
Subjects will receive sedative drug regimen without Ketamine.
Other: Sedative drug regimen
(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.

Experimental: Sedative with Ketamine
Subjects will receive sedative drug regimen with Ketamine.
Drug: Ketamine
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.
Other Name: Ketalar

Other: Sedative drug regimen
(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.




Primary Outcome Measures :
  1. Cumulative Fentanyl Equivalents From ECMO Initiation to Decision to Achieve Wakefulness [ Time Frame: Up to 14 days ]
    Culmulative fentanyl equivalents meaning the combination of sedative drug regimen - measured in mg - from ECMO initiation to decision to achieve wakefulness.



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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Receiving ECMO for acute respiratory failure
  • Requiring deep sedation (RASS -5)

Exclusion Criteria:

  • Allergy to ketamine

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01938079


Locations
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United States, New York
NewYork-Presbyterian Hospital
New York, New York, United States, 10032
Sponsors and Collaborators
Columbia University
Investigators
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Principal Investigator: Daniel Brodie, MD Columbia University

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Responsible Party: Daniel Brodie, Associate Professor of Medicine, Columbia University
ClinicalTrials.gov Identifier: NCT01938079     History of Changes
Other Study ID Numbers: AAAM0950
First Posted: September 10, 2013    Key Record Dates
Results First Posted: September 29, 2016
Last Update Posted: September 29, 2016
Last Verified: August 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Daniel Brodie, Columbia University:
ECMO
Ketamine
Opiates
Lung failure
Extracorporeal membrane oxygenation
Mechanical ventilation
Sedation

Additional relevant MeSH terms:
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Respiratory Insufficiency
Respiratory Distress Syndrome, Adult
Respiration Disorders
Respiratory Tract Diseases
Lung Diseases
Ketamine
Hypnotics and Sedatives
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action