A 45-year-old male with
This is not how you envisioned your shift today. Until you quickly realize that you have an extracorporeal membrane oxygenation (ECMO) team! It’s time to phone a friend. After paging the team, the patient is on ECMO within 60 minutes. Continuous infusions of fentanyl 50 mcg/hour and midazolam 5 mg/hour were initiated in the ED for sedation and analgesia. Two hours later, you’re called back into the room (yes, unfortunately he is not yet in the ICU and is still in the ED. . .) because he has worsening agitation despite increases of both fentanyl (up to 100 mcg/hour) and midazolam (up to 15 mg/hour). What is going on?
The use of ECMO is a
Let’s take a dive into the world of drug dosing on ECMO. Yes, I am a clinical toxicologist. But, no, this patient didn’t overdose on one of his cardiac medications that resulted in the cardiac arrest. This post is not going to be focused on the toxins that cause a patient to require ECMO, but rather focus on what ECMO does to the drugs that are commonly administered during the
ECMO: A Refresher
ECMO was first used in the 1970s in the management of severe acute respiratory distress syndrome (ARDS). Its use became more popular in the mid-2000s when it was effectively used during the H1N1 epidemic with good results.1 This led it to being used more frequently for ARDS and/or refractory shock. Significant improvements in technology and equipment has enabled ECMO to be rapidly available in EDs and ICUs.2 If you haven’t already, you should take a look on the internet at what the first ECMO machine looked like compared to the current ECMO machines. We really are living in the future!
There are two types of ECMO (figures). Veno-venous (VV) ECMO is used for respiratory support while venous-arterial (VA) ECMO is used for both respiratory and cardiac support.2,3
ECMO can alter both the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. PK is best described as the body’s effect on a drug or better yet as @heshiegreshie describes it as the journey that a drug takes through the body from absorption through elimination. It encompasses absorption, distribution, metabolism, and elimination (ADME). PD is most easily described as the drug's effect on the body. Another way to look at it is that it is the relationship between a therapeutic concentration of a drug and its therapeutic effects. A simple way of thinking about PK/PD is how the drug affects the body versus how the body affects the drug.4
Absorption is the process by which a drug is administered and then gets into the body. When a drug is administered, the rate and extent to which it is absorbed
Once a drug reaches the systemic circulation, it is distributed to tissue compartments as well as to the liver and kidney for metabolism and elimination, respectively. Volume of distribution (Vd) represents the dose given and the resulting serum concentration. The easiest way to think of Vd is how much of a given drug is inside versus outside of the plasma compartment.4
If the Vd is
Elimination of a drug includes both metabolism (eg: biotransformation) by the liver and excretion largely by the kidneys but also through the lungs and secretions. The more water soluble a drug is, the more it is excreted by the kidneys.
PK changes caused by ECMO
For the majority of
There are at least 3 ways that ECMO alters the PK of drugs: sequestration by the circuit, altering the volume of distribution, and altering clearance. These changes can result in either increased or decreased serum concentrations, which can result in either toxicity or treatment failure.
Drugs get sequestered in the circuit by sticking to the ECMO tubing. The degree to which this happens is dependent on many different components including the tubing used, the oxygenator used, the type of priming solution used, and specific drug properties such as lipophilicity and protein binding.6,8 Priming the circuit with crystalloid or blood products results in different degrees of drug sequestration as well.9 This results in an increase in the volume of distribution of certain drugs with a decrease in serum concentrations. The circuit can also serve as a drug reservoir and redistribute the drug back into the patient, which can result in prolonged exposure and even toxicity.
From what we know currently, the more lipophilic a drug, the more it is sequestered into the circuit. PVC tubing tends to have the highest amount of sequestration compared to other tubing.
Increased Volume of Distribution
ECMO circuits probably represent another PK compartment as evidenced by drug sequestration. This leads to an increase in the volume of distribution (Vd). Although sequestration has the biggest impact on Vd, the Vd may be altered in other ways. Hemodilution occurs during ECMO and high amounts of volume to maintain circuit flow will increase the volume of distribution of hydrophilic drugs. There are also pH changes in the patient which may result in an increased volume of distribution of some drugs.8
Altered Drug Clearance
ECMO use is associated with increased clearance of some drugs and decreased the clearance of others. Increased drug clearance can occur secondary to increased cardiac output, fluid resuscitation, and inotropic support.6 Decreased drug clearance is attributed to several factors including renal dysfunction, hypoperfusion,
Specific Drug Examples
Let’s focus on some of the more common drugs that you may use in an ECMO patient and what we know about their dosing adjustments.9
The majority of sedatives that we use require increased doses while on the circuit. Doses should be titrated to sedation.5,6,8,9
When choosing analgesics, the most important rule is to dose titrate based on response. Data is quite limited regarding hydromorphone. However, based on its physicochemical properties and log P, it may be an option in patients that don’t tolerate the hemodynamic effects of morphine.5,6,8,9
Antibiotics have a unique advantage in that many can be monitored using therapeutic drug monitoring (TDM). If you can obtain serum concentrations on a drug that you’re administering to a patient on ECMO, you should. That will be your best guide for dose alterations. This holds true for any drug, not just antibiotics (e.g., anticonvulsants).5,6,8,9
Ampicillin is the one beta-lactam that has been shown to be significantly altered on ECMO. Other beta-lactams should be used, if possible.
There is very little data regarding vasopressor dosing. The data that does exist suggests that there are no appreciable dosing adjustments needed for dopamine, epinephrine or norepinephrine.10,11 The log P for norepinephrine and epinephrine are -1.24 and -1.37, respectively, which is suggestive of minimal drug sequestration and gives support to the assumption that dose adjustments are not needed.12,13
Time to come off the circuit. Now what?
Once the ECMO circuit is off, there is a rapid change in the volume of distribution of drugs, so you should be prepared to rapidly change doses. For sedatives and opioids, a general rule of thumb is to rapidly decrease the dose by 50%. For antibiotics, the dose should be changed to the ‘regular’ dosed based on the specific antibiotic and end organ function of the patient.5
A very resourceful ED physician thought that there may be dosing adjustments needed due to the patient being on the ECMO. The patient’s regimen was changed to morphine via continuous infusion, along with lorazepam. Sedation was achieved and he went to the ICU. He did well on the circuit over the next 3 days and eventually on day 4 was able to come off the circuit. He had a complete neurologic recovery.
Take Home Points
- The effects of ECMO on most drug pharmacokinetics remains largely unknown
- Doses for sedation and analgesia likely need to be increased
- If you need an opiate/opioid, choose morphine
- Avoid ampicillin
- If you can get drug levels, get them! And then dose adjust accordingly
- More research is needed to better tailor a particular patient’s pharmacotherapy while on ECMO
- You know I have to throw in some acute toxicology here . . . VA-ECMO may be a very helpful intervention for cardiotoxic drugs including tricyclic antidepressants, verapamil, diltiazem, metoprolol, flecainide, and bupropion, just to name a few14
- VV-ECMO can be used for pulmonary toxins such as paraquat and phosgene15,16
- 1.Australia and, Davies A, Jones D, et al. Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome. JAMA. 2009;302(17):1888-1895. https://www.ncbi.nlm.nih.gov/pubmed/19822628.
- 2.de L, Sikma M, Meulenbelt J. Extracorporeal membrane oxygenation in the treatment of poisoned patients. Clin Toxicol (Phila). 2013;51(5):385-393. https://www.ncbi.nlm.nih.gov/pubmed/23697460.
- 3.Bellezzo J, Shinar Z, Davis D, et al. Emergency physician-initiated extracorporeal cardiopulmonary resuscitation. Resuscitation. 2012;83(8):966-970. https://www.ncbi.nlm.nih.gov/pubmed/22306260.
- 4.Howland M. Pharmacokinetic and Toxicokinetic Principles. In: Nelson L, Howland M, Lewin N, Smith S, Goldfrank L, Hoffman R, eds. Goldfrank’s Toxicologic Emergencies. 11th ed. New York, NY: McGraw Hill Education; 2018:140-154.
- 5.Dzierba A, Abrams D, Brodie D. Medicating patients during extracorporeal membrane oxygenation: the evidence is building. Crit Care. 2017;21(1):66. https://www.ncbi.nlm.nih.gov/pubmed/28320466.
- 6.Cheng V, Abdul-Aziz M, Roberts J, Shekar K. Optimising drug dosing in patients receiving extracorporeal membrane oxygenation. J Thorac Dis. 2018;10(Suppl 5):S629-S641. https://www.ncbi.nlm.nih.gov/pubmed/29732181.
- 7.Cheng V, Abdul-Aziz M, Roberts J, Shekar K. Overcoming barriers to optimal drug dosing during ECMO in critically ill adult patients. Expert Opin Drug Metab Toxicol. 2019;15(2):103-112. https://www.ncbi.nlm.nih.gov/pubmed/30582435.
- 8.Shekar K, Fraser J, Smith M, Roberts J. Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care. 2012;27(6):741.e9-18. https://www.ncbi.nlm.nih.gov/pubmed/22520488.
- 9.Ha M, Sieg A. Evaluation of Altered Drug Pharmacokinetics in Critically Ill Adults Receiving Extracorporeal Membrane Oxygenation. Pharmacotherapy. 2017;37(2):221-235. https://www.ncbi.nlm.nih.gov/pubmed/27931091.
- 10.Watt K, Li J, Benjamin D, Cohen-Wolkowiez M. Pediatric cardiovascular drug dosing in critically ill children and extracorporeal membrane oxygenation. J Cardiovasc Pharmacol. 2011;58(2):126-132. https://www.ncbi.nlm.nih.gov/pubmed/21346597.
- 11.Yeo H, Jeon D, Kim Y, Cho W, Kim D. Veno-veno-arterial extracorporeal membrane oxygenation treatment in patients with severe acute respiratory distress syndrome and septic shock. Crit Care. 2016;20:28. https://www.ncbi.nlm.nih.gov/pubmed/26861504.
- 12.Epinephrine. PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/5816. Accessed June 8, 2019.
- 13.Norepinephrine. PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/439260. Accessed June 8, 2019.
- 14.Johnson N, Gaieski D, Allen S, Perrone J, DeRoos F. A review of emergency cardiopulmonary bypass for severe poisoning by cardiotoxic drugs. J Med Toxicol. 2013;9(1):54-60. https://www.ncbi.nlm.nih.gov/pubmed/23238774.
- 15.Bertram A, Haenel S, Hadem J, et al. Tissue concentration of paraquat on day 32 after intoxication and failed bridge to transplantation by extracorporeal membrane oxygenation therapy. BMC Pharmacol Toxicol. 2013;14:45. https://www.ncbi.nlm.nih.gov/pubmed/24010554.
- 16.He Z, Yang X, Yang C. [Extracorporeal membrane oxygenation for acute respiratory distress syndrome caused by acute phosgene poisoning: a report of 4 cases]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2019;31(2):232-235. https://www.ncbi.nlm.nih.gov/pubmed/30827316.