Awake, Paralyzed and Transported- A Pharmacological Failure when Transporting an ECMO Patient

A Patient’s Worst Nightmare

You and your partner walk to the Intensive Care Unit to check on a patient that you recently transported. The patient is a 22-year-old male who, following the onset of fungal sepsis, developed intractable vasoplegia and acute respiratory distress syndrome requiring a 10 day run of Venoarterial Extracorporal Membrane Oxygenation (ECMO).  He was initially treated and cannulated to ECMO on hospital day one.  On the second day of hospitalization, he was flown to the receiving hospital for tertiary care and the potential need for continuous dialysis (that was not available at the referring hospital).  The ECMO course was relatively uncomplicated and the patient is being prepared for transport back to the referral hospital for rehabilitation services.

Upon entering the ICU room, the patient is awake and alert, on 2 liters nasal cannula and surrounded by his family.  As the flight team introduces themselves to the patient, he becomes acutely anxious and states,” I remember your voices and all of the sounds from the helicopter flight…I remember hurting and not being able to tell anyone how terrified I was during the time they were moving me here.” When the crew returned to the flight office (and after a psychological consult was ordered on the patient for potential Post Traumatic Stress Disorder (PTSD) interventions) the flight record was reviewed.

Upon Review of the Case…

During the transport the patient received the following sedation medications-

Fentanyl- 175 mcg/hour by continuous infusion

• Per the referring hospital formulary:
  • Recommendation for Fentanyl is 12.5-25 mcg/hr titrated every 15 minutes based on Richmond Agitation Sedation (RASS) Score.
  • Maximum Dose 200 mcg/hr

Dexmedetomidine-1.2 mcg/kg/hour

• Per the referring hospital formulary:
  • Dexmedetomidine- 0.02 mcg/kg/hr titrated in increments of 0.1-0.2 mcg/kg/hr every 20 minutes until goal RASS is achieved.
  • Maximum Dose 1.5 mcg/kg/hr

Vecuronium Infusion-Titrated for a ¼ response using the train of four (TOF) monitor.

PRN Medications-Versed 2 mg IV PRN every 1 hour as needed for elevated RASS Score.

• 1 mg of Versed was administered x2 during the two hour transport when an elevated heart rate and blood pressure were noted.

Clinical Question

How could a paralyzed and sedated patient recall the events of the transport?

Review of Literature

There is a large volume of recently published literature addressing the pharmacodynamics of medications when they are administered to patients receiving Extracorporeal Membrane Oxygenation.

Key Discussion (“Bullet”) Points of the cited articles.

1. The sum of a multitude of pathophysiologic factors (see Dzierba et al., below) can result in significant and uncertain alterations in how medications will behave in the body and in the ECMO circuit.
2. Absorption of lipophilic medications in the medical grade PVC tubing of an ECMO circuit has been proven and confirmed. The circuit itself can increase the volume of distribution through either hemodilution or sequestration of drugs, causing them to not get to the patient or having their desired effect.
3. Three ex vivo studies using adult ECMO circuits composed of PVC tubing and a hollow polymethylpentene fiber membrane oxygenator (common in modern ECMO circuits) showed the loss of common narcotic analgesics and benzodiazepines previously predicted by precedent studies. This included:
   1. An approximately 93% loss of Dexmedtomidine concentrations at 24 hours.
   2. A circuit loss of up to 70% of Fentanyl and 50% of Midazolam.
   3. A 10% or less detection of fentanyl and midazolam in the ECMO circuit at 24 hours.
   4. Morphine on the other hand was substantially detected in the ECMO circuit at 24 hours.
   5. Patients receiving morphine for analgesia required substantially less analgesia and had lower rates of withdrawal.  
4. Common for all critically ill patients on high doses of sedation and analgesia is the potential to develop drug tolerance. Additionally, organ maturation and improvement in organ function as patient clinical status improves is also possible, requiring the caregiver to have a lower threshold for adjusting the patient’s pain management plan.

Take Home Points

Without question, there are potentially significant physiological and psychological impacts of being “awake” while being transported with potential painful procedures in place or under the effect of chemical paralysis.  Morphine seems to clearly be the best approach to analgesia in the ECMO patient, especially as the trajectory of care in critical care is now focusing on the “analgesia first” model.

Ketamine is noted in several articles as potential bridge to both sedation and analgesia. However, there is no research currently on the use of Ketamine in ECMO patients. More research is needed to see if the desired effects of ketamine are universal given the unique physiological differences experienced during ECMO.

Obviously, this is never something that we as critical care transport providers do on purpose for ANY patient. We have been educated since the first day of our intensive care training that NO patient gets neuromuscular blocking agents without adequate and appropriate sedation and analgesia. It is therefore imperative that we better understand the pharmacokinetics, pharmacodynamics and physiology of this unique patient population and learn from this terrible experience.

Discussions beyond the scope of this article.

• The use of a validated sedation score or monitoring device in chemically paralyzed patients in ICU and Critical Care Transport Settings
• Antibiotic/Antifungal dosage requirements for ECMO patients
• Post Traumatic Distress Disorder in patients and families experiencing critical illness

References

Dzierba et al., Medicating patients during extracorporeal membrane oxygenation: the evidence is building, Critical Care (2017) 21:66. DOI 10.1186/s13054-017-1644-y

Ha ands Steig, Evaluation of Altered Drug Pharmacokinetics in Critically Ill Adults Receiving Extracorporeal Membrane Oxygenation, Pharmacotherapy 2017;37(2):221–235) doi: 10.1002/phar.1882

Ill Adults Receiving Extracorporeal Membrane Oxygenation, Pharmacotherapy 2017;37(2):221–235) doi: 10.1002/phar.1882

Himebauch, a. et al, Pharmocotherapy in pediatric extracorporeal membrane oxygenation, an overview, Expert Opinion on Drug Metabolism and Toxicology, 2:10, 1133-1142, DOl: 10.1080/17425255.2016.1201066

Hodgson CL, Fan E. A step up for extracorporeal membrane oxygenation: active rehabilitation. Respir Care. 2013;58(8):1388–1389.

Shekar K, Roberts JA, McDonald CI, et al. Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation. Crit Care. 2012;16:R194.

Wagner D, Pasko D, Phillips K, et al. In vitro clearance of dexmedetomidine in extracorporeal membrane oxygenation. Perfusion. 2013;28:40–6.