Remifentanil-Induced Respiratory Failure in PACU after a Brainstem Tumor Debulking: Acute Diagnostic Dilemma-Juniper Publishers
Juniper Publishers-Journal of Anesthesia
Abstract
A 66 year old man developed sudden apnea and 
unresponsiveness after a large cerebellopontine angle tumor debulking. 
Based on the findings of a focused neurologic exam, the patient was 
emergently mask ventilated with subsequent return of spontaneous 
ventilation minutes later and recovery without further complications. 
Remifentanil bolus from residual infusion in an IV line was suspected 
due to rapid return to baseline and acute neurologic findings. We review
 remifentanil and highlight a challenging diagnostic dilemma in an 
acutely apneic patient after major neurosurgery.
  Keywords:      Remifentanil; Neuroanesthesia; Post-op respiratory failure; Neurologic Emergencies Key Messages
a. A focused neurologic exam can affect emergent management.
b. A high index of suspicion and staff education are 
necessary for those involved in the care of patients receiving 
remifentanil. 
Introduction
Remifentanil is a potent, ultra short-acting μ-opioid
 receptor agonist with a rapid onset of action in 30-60 seconds, peak 
analgesic and respiratory effects within 2.5 minutes (min), and rapid 
clearance (T1/2 = 3 min) [1].
 It is commonly used as part of a balanced anesthetic in many anesthesia
 practices as well as in the intensive care unit. Its use is 
particularly prominent in neuroanesthesia, where precise hemodynamic 
control is as important as a crisp, quick emergence of anesthesia to 
facilitate neurologic evaluation. Respiratory depression is a common 
severe adverse effect of opioids that may be most prevalent with 
remifentanil [2].
Case History
A 66 year old man with a large acoustic neuroma presented for cerebellopontine (CP) angle tumor resection (Figure 1).
 Neuromonitoring of cranial nerves IX, X, XI, XII, somatosensory evoked 
potentials and motor evoked potentials was used during the case, while 
the patient received an intravenous anesthetic consisting of propofol 
100mcg/kg/min and remifentanil at 0.3mcg/kg/min. Neuromuscular blockade 
was not used for the case. The surgery progressed without complication, 
and thepatient was stable throughout. The case lasted 7.5 hours, and 
propofol and remifentanil were discontinued 60min and 15min prior to 
conclusion of case, respectively. The patient was able to spontaneously 
ventilate, protrude tongue, and demonstrate intact cranial nerves IX and
 X with gag reflex prior to extubation.

In the PACU, the patient was awake and following 
commands. Shortly after administration of flush through a secondary 
peripheral IV, the patient acutely closed his eyes, becoming 
unresponsive and apneic. Rapid physical exam to check for increased 
intracranial pressure given the setting of recent intracranial surgery 
demonstrated the patient's pupils were actually pinpoint. The patient 
was then mask-ventilated until spontaneous ventilation returned several 
minutes later. Pinpoint pupils and rapid recovery makes a remifentanil 
bolus from residual infusion in the second IV line the most likely 
etiology. Patient recovered without further difficulty and was 
discharged home 3 days later.
Discussion
Remifentanil review

Remifentanil is a potent selective μ-opioid agonist. 
Its major distinction from other fentanyl analogues is its rapid onset 
and short duration of action with a terminal elimination half-life of 
3-10 min, usually negating the need for Naloxone reversal [3].
 The rapid onset of action is directly related to the rapid blood brain 
equilibration time of 1-2 minutes, while the short duration of action is
 a result of its unique structure of ester linkages making it 
susceptible to hydrolysis by blood and non-specific esterases (Figure 2).
 This rapid extra-hepatic metabolism makes its pharmacokinetics 
reproducible and dependable. Time to spontaneous movement, following 
commands, and extubation are all shorter than when compared with other 
opioids such as fentanyl and morphine. These pharmacokinetic and 
pharmacodynamic characteristics make remifentanil a nearly ideal 
analgesic in the operating room. However, due to its short duration of 
action, patients receiving remifentanil frequently require rescue 
analgesia in the postoperative period for pain management [4].
Remifentanil is rapidly metabolized regardless of the
 duration of infusion and is used commonly in clinical situations 
requiring a rapid offset with the benefit of minimal side effects such 
as respiratory depression [5].
 While the risk for respiratory depression still exists, the ability to 
rapidly titrate the drug based on response allows for an overall lower 
rate when compared to most other opioids. In neuroanesthetic cases, it 
is commonly used in conjunction with propofolas part of a total 
intravenous anesthetic. It is easily titratable, facilitates stable 
hemodynamics, and minimally affects neuro-monitoring. Perhaps most 
importantly, this total intravenous anesthesia combination can allow for
 rapid emergence and the ability to perform post-operative examination 
for neurological status shortly after conclusion of the case [2].
Clinical experience
Rapid bolus of remifentanil can result in potentially
 life threatening respiratory depression, hemodynamic changes, or muscle
 rigidity. Respiratory depression has been documented in case reports 
after bolus in laboring patients with patient controlled analgesia [6] as well as in non-obstetric patients receiving remifentanil [7].
 This appears to be even more pronounced and observed at lower doses in 
patients greater than 60 years old. Even infusions as low as 
0.05mcg/kg/min have been reported to cause changes in ventilatory drive 
in healthy volunteers. Muscle rigidity, likewise, is a concerning 
complication of opioids that can lead to decreased ventilation and 
compliance resulting in hypoxia and hypercapnia. It is suggested that 
difficult ventilation may be primarily due to vocal cord closure. 
Remifentanil, however, primarily affects respiratory drive by activating
 opioid receptors on the respiratory neurons in the brainstem. By 
depressing the respiratory drive, the arterial carbon dioxide not only 
increases but increases in oxygen consumption and intracranial pressure 
are to be expected [8]. Muscle rigidity however can be prevented with pretreatment or concurrent administration of neuromuscular blockade [9].
Apnea

Our case brings up the challenge and importance of 
differentiating causes of sudden apnea and mental status change in the 
immediate post-operative period. The differential for postoperative 
respiratory failure is large and includes pharmacologic, hemodynamic and
 mechanical causes (Table 1).
 In addition to those listed, the patient's comorbidities may be one of 
the most fundamental things to consider. In the setting of recent 
intracranial surgery, both opioid overdose and intracranial pathology 
and dysfunction such as increasing intracranial pressure and seizures 
are important considerations. Cerebellopontine angle procedures are 
technically challenging and carry significant risk for postoperative 
bleeding, increasing intracranial pressure, venous insufficiency and 
cranial nerve palsy. Physical exam, including neurological exam, may be 
the most useful and potentially life-saving in this case.
Prevention
Prevention is a keystone of patient care, and the use
 of more dilute concentrations of remifentanil and initiating rapid 
resuscitation with possible muscle relaxation have been identified as 
ways to decrease the chance of similar events from occurring (Table 2).
 Remifentanil is a very useful opioid in a variety of settings for 
controlling autonomic responses during procedures and allowing for rapid
 recovery [2,5].
 However, its dangers as a bolus should be known to healthcare providers
 and ancillary staff so appropriate identification and supportive care 
can be initiated as soon as a problem is identified.

Acknowledgement
Special thanks to Damian Pickering for assistance with
manuscript preparation.
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