Tox and Hound – A Few Days on the Drug Circuit

by Jeanna Marraffa

A 45-year-old male with history of cardiomyopathy has an out of hospital cardiac arrest. Resuscitative efforts were initiated pre-hospital and return of spontaneous circulation (ROSC) was achieved. However, upon arrival to the emergency department (ED), he was profoundly hypotensive with a blood pressure of 50/palp and a heart rate of 40 beats per minute. Despite IV fluids and the initiation of vasopressors, he deteriorated and had a bradycardic arrest.

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 relatively new-ish territory for many and with anything new, there are numerous questions that we should be asking ourselves. For ECMO, the questions floating in my head revolve around pharmacotherapy. What happens to the drugs that we give? Are they supposed to be dose adjusted? How do I know which drugs to dose adjust? Are there other considerations that I should be thinking about as it relates to their medication regimen? Are we going in blind or is there anything that can help us?

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 care of these patients. And because pediatric patients are not just little adults, this is only focused on adults.

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​

Pharmacokinetics/Pharmacodynamics 101

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

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 into the bloodstream is dependent on each drug and the drug delivery method. Intravenous medications have the quickest onset to get into the bloodstream and then distribute to the target organs. Once a drug is in the bloodstream, it then has to diffuse through multiple membranes before reaching the site of action. Because ECMO has very little effect on this component of PK, I won’t bore you with all of the specifics regarding drug absorption.

Distribution

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 less than 1.0 – 2.0 L/kg, then you can assume that most of the drug is outside of the plasma compartment. As the Vd increases, the less a drug is in the plasma compartment but rather distributed to other organs. The octanol/water coefficient, better known as the log P, is another component of estimating drug distribution into tissues. The greater the log P, the more lipophilic a drug. Drugs with high Vd and extensive protein binding are most affected by ECMO.

Elimination

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 drugs there are limited data. There is however, some guidance on some of the more commonly used ICU drugs, including sedation, analgesia and antibiotics in these patients.^​5–7​ Don’t worry, we will get to the specifics.

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.

Drug Sequestration

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, and hypoxia.

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​

Sedation

The majority of sedatives that we use require increased doses while on the circuit. Doses should be titrated to sedation.^{​5,6,8,9​}

Opioids

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/Antifungals

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.

Vasopressors

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​

Case Resolution

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

Bonus Tox

• 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 few^​14​
• VV-ECMO can be used for pulmonary toxins such as paraquat and phosgene^​15,16​

Robot Piano by Franck V. Telephone by Quino Al Waterfall into Mountain Pond by Jeremy Bishop The Mission Journal by David Iskander

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