by Wesley Rogers, FP-C, CCEMT-P

Patient Case

You are part of a flight critical care team responding to an interfacility trauma transfer going from a rural ED to a regional level 1 trauma facility 35 miles away. You arrive to find a 75 year old female, 70kg, who fell down a flight of stairs. She is A&Ox4 with a GCS of 15, and is in full spinal immobilization. She has a pulse rate of 110, blood pressure of 128/88, SPo2 of 94% via NC at 4lpm. Her injuries include an open right tib/fib fracture, several broken ribs, and a grade 3 liver laceration. You note a significant amount of bloody trauma dressings on the bed, on the floor, as well as a blood-soaked dressing to the patient’s right leg. She has a history of alcoholism, liver disease, A-fib and hypertension and takes coumadin and lisinopril. The attending MD states that the patient’s blood pressure has been labile and has received 2 liters of normal saline and 2 units of PRBC’s. The hospital gives you 1 unit of PRBC’s to administer during transport. The head CT was negative. The patient received Fentanyl 100mcg one hour ago and received valium 4mg two minutes prior to your arrival for anxiety. The patient appears in obvious pain and rates it at a 10/10. You and your partner decide to administer 100mcg of fentanyl IV for pain. You finish your assessment and move the patient to your stretcher and proceed to the helipad. Upon placing the patient inside your aircraft, you note the patient is very difficult to arouse before becoming unresponsive with shallow respirations. You and your partner decide to perform RSI, using etomidate 20mg and succinylcholine 150mg. The patient is intubated on the first attempt, but becomes hypotensive with a systolic in the 80’s and a HR of 130. You administer the 1 unit of PRBC along with 250ml of saline to bring the patients’ blood pressure up to 142 systolic. During the transport, you give fentanyl 100mcg and versed 2.5mg for continued sedation, and the patient’s blood pressure again drops to a systolic in the 70’s and again her HR jumps to the 130’s. You deliver the patient to the ER hypotensive and the patient is given several units of whole blood until stabilized.

We are taught to use medications, but often, we come to understand their impact in the general healthy population. There are many factors that influence a medication’s effect on a patient. Absorption, distribution, metabolism, and elimination are all dynamic and subject to change in dying, tenuous patients. In this article, we will talk about a specific factor influencing our medications, plasma proteins, and how we can avoid mistakes related to them.

 

Pharmacokinetics

Many medications we utilize are plasma protein bound. Plasma proteins are large molecules that exist in blood plasma. When a drug is bound to the molecules, it is rendered ineffective as only the unbound portion of the drug is free to distribute throughout the body or is bioavailable for its intended response. Some of the common drug-binding proteins are albumin, glycoprotein, lipoprotein and α, ß‚ and γ globulins. They typically bind in that order, with serum albumin having the most affinity. Drugs can make it all the way through and bind to erythrocytes, but this is typically rare and should not be relied upon. The bound portion of the drug acts as a depot and can slowly release the drug into circulation. Many common prescription drugs have significant binding including Warfarin, Lasix, and some ACE inhibitors (Galvagno, 2003). For example, Warfarin is 97% bound to plasma proteins, which means 3% is unbound and active for therapeutic action. So, if someone currently has a low amount of plasma proteins in their body, this would leave MORE of the medication unbound and active. Hopefully, you are still with me, because we are about to start making some sense out of all this.

Example 1: Versed is 97% protein bound, which leaves 3% unbound. But if someone is low on plasma proteins and say only 94% of the drug is able to bind, then that means 6% of the drug is left unbound.

Example 2:  Fentanyl is 85% protein bound, which leaves 15% unbound. But if someone is low on plasma proteins and only 75% is able to bind, then that means 25% of the drug is left unbound.

Drugs that are highly bound run the risk of having their unbound portion increased substantially. In Example 1 above, the therapeutic effect of versed essentially doubled due to a reduction in available plasma proteins. If this patient in the example was given 2.5mg of versed, it may have the same effect as 5mg. In this example, the reduction of protein binding was minimal, reduced by only 3% yet it doubled the effect of the drug. Yet in Example 2, protein binding is reduced by 10%, yet we only see a 60% increase in the unbound drug.

BOUND (%)
FREE (%)
→ only 10% increase in the free fraction

50

50
45

55

 

BOUND (%)
FREE (%)
100% increase  in the free fraction
95 5
90 10

(Distribution of drugs, 2014)

The next problem to examine is competitive displacement. A drug that is highly bound to plasma proteins will compete and displace another drug that has less affinity for the plasma proteins. So, when you administer two drugs that are extensively bound, a potentiation of the less bound drug will occur. This is seen when combining drugs such as propofol, fentanyl, versed, and valium.

Before Displacement
After Displacement
 % increase in unbound fraction
Drug A
  % bound 95 90
  % unbound 5 10 +100
Drug B
  % bound 50 45
  % unbound 50 55 +10

(Shargel, 2005)

If a patient was to have a decrease in their amount of plasma proteins and are given medications that compete for the remaining plasma proteins (such as the patient above), the effect of either medication can be unpredictable.

 

Who to Worry About

Some patient populations should raise our suspicions of plasma protein deficits and trigger a cautious medication strategy. Elderly, cancer, and liver failure patients produce less serum albumin. Renal failure patients have difficulty synthesizing both albumin and glycoprotein (Distribution of drugs, 2014), making these patient populations good candidates for a reduced dosage of medications. You may have noticed that the patient in the case above was both elderly and suffered from alcohol-induced liver disease.

Some of the most difficult patients to predict medication response is in are hemorrhagic patients (Trauma, GI bleeds) – this group is where I hope to enlighten you. As patients bleed out, they lose their plasma proteins. These patients are able to maintain a normal blood pressure, despite losing a significant amount of blood, potentially tricking you into thinking they will be able to handle analgesia or a typical RSI dose of a medication. Because these proteins are found in blood plasma, crystalloids and PRBC’s do not replace them. A patient in hemorrhagic shock who has been resuscitated with normal saline and PRBC’s will still experience a profound effect from the medications administered. The patient above, who already had a decrease in plasma proteins before the trauma, had normotension with a shock index of 0.85 from being resuscitated with normal saline and PRBC’s. You still must augment medication dosing despite fluid resuscitation of the hemorrhagic patient (Steven L. Shafer, 2004).

 

The Medications to Worry about

Propofol is 95-99% bound (Wishart DS, 2017). It is 50% bound to erythrocytes in hemoglobin, and 48-49% bound to serum albumin (Jean Xavier Mazoit, 1999). Because of this, propofol can be very tricky to use in some of our critical care patients. If they were to be just a little low on either hemoglobin or serum albumin, then the effects can be increased unpredictably.

Versed is 97% bound. And, like the rest of our medications on this list, it primarily binds to serum albumin and glycoprotein (Wishart DS, 2017).

Valium is 98-99% bound. Fentanyl is 80-85% bound. Etomidate is 76% bound (Wishart DS, 2017).

Ativan is 91% bound (Wishart DS, 2017), which is one of the reasons why it is the benzo of choice for alcoholics.

Ketamine comes in the lowest at 53% (Wishart DS, 2017), although some reports show it to be lower around 40%. Because of this, ketamine can be thought to be safe to administer with other drugs such as fentanyl and propofol.

 

Now that you know this information, you can use it to your advantage. Even if it is providing poor sedation in the transport environment, consider continuing a propofol infusion. You can give smaller doses of fentanyl because the propofol is monopolizing all the plasma proteins. If a third medication must be added, consider reducing the dose by more than half. If you are choosing to RSI a patient in shock, even if you resuscitate first, you still must temper medication dosages.

 

Key Points
  • Propofol and versed are some of the most highly bound medications with significant hemodynamic effects.
  • Mixing medications, especially when one is highly protein bound, can be volatile and should be used with caution.
  • Liver failure and hemorrhagic patients are some of the most at risk for negative effects.
  • Crystalloids and packed red blood cells DO NOT replace plasma proteins.
  • Despite what the patient’s blood pressure is, a hemorrhagic patient that has been resuscitated still requires careful medication dosing.

References:

Distribution of drugs. (2014). Retrieved from file:///C:/Users/wesle/Downloads/Distribution_of_drugs_-_2014%20(4).pdf

Galvagno, S. M. (2003). Emergency Pathophysiology: Clinical Applications for Prehospital Care. jackson, WY.

Heflin, C. (2018). Despicable me- Minion. Flicker. pinterest. Retrieved May 2018, from https://www.pinterest.com/pin/485896247267379845

Jean Xavier Mazoit, K. S. (1999). Binding of propofol to blood components: implications for pharmacokinetics and for pharmacodynamics. doi: 10.1046/j.1365-2125.1999.00860.x

Shargel, L. (2005). Applied Biopharmaceutics & Pharmacokinetics. New York: Mcgraw-Hill.

Steven L. Shafer, M. (2004, November 9). Shock Values. The journal of american society of Anesthesiologists, 101, 567-568. Retrieved from http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1942673

Wishart DS, F. Y. (2017, Nov 8th). DrugBank 5.0: a major update to the DrugBank database for 2018. doi: 10.1093/nar/gkx1037.

 

 

 

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