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A possible treatment for propofol-induced neuroexcitation or propofol frenzy

Barsoum, Sylviana; Kim, Adeline; Tse, James

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European Journal of Anaesthesiology: August 2019 - Volume 36 - Issue 8 - p 618-620
doi: 10.1097/EJA.0000000000000963
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A 20-year-old obese man (American Society of Anesthesiologists Physical Status Class II, 111 kg, 183 cm, BMI 33.1 kg m−2) presented for elective open reduction and internal fixation of a left distal tibia fracture under femoral and sciatic nerve blocks. He was surgically naive. He was not on any medication and denied recreational drug use. Baseline measurements were blood pressure (BP) 145/80 mmHg, heart rate (HR) 74 bpm, respiratory rate 16 min−1, oxygen saturation (SpO2) 100%.

Between 8 : 33 and 8 : 53 a.m., he received midazolam 2 mg and fentanyl 100 μg premedication. Under ultrasound guidance, 20 and 25 ml of 0.5% ropivacaine were used for single shot femoral and sciatic nerve blocks, respectively. He watched TV in the holding area until 9 : 30 a.m. when he received an additional 2 mg of midazolam and was transported to the operating room.

He was awake and alert and moved himself with slight assistance to the operating room table. Vital signs were BP 121/69 mmHg, HR 84 bpm, respiratory rate 16 min−1, room air SpO2 100%. After 100 mg of intravenous lidocaine, propofol infusion (Diprivan; Fresenius-Kabi, Lake Zurich, Illinois, USA) was started at 6 mg kg−1 h−1 for the first 25 min and was titrated down to 4.8 mg kg−1 h−1 for the last 10 min (total dose of 366 mg). He was deeply sedated and tolerated the procedure well with stable vital signs throughout.

Emergence appeared to be delayed. He was not arousable to sound or touch at the conclusion of surgery. Soon after, he became agitated and was thrashing bilateral upper and lower extremities. This was associated with head turning to right greater than left, not following commands, increased muscle rigidity and pupillary dilation. The periods of agitation were impressive: requiring several people to keep him from hurting himself. These periods of agitation alternated with periods of apparent unconsciousness. This continued for over 1 h in the operating room. It was an exact replica of the patients in videos by Carvalho et al.1

In Post-Anesthesia Care Unit, these periods of severe agitation alternating with unconscious calmness continued. His BP ranged from 140/70 to 190/80 mmHg, HR from 70 to 90 bpm, respiratory rate from 12 to 25 min−1, SpO2 was 100%. Flumazenil 0.2 mg and narcan 0.08 mg were given with no change.

Several possibilities were considered on the basis of the clinical picture such as local anaesthetic systemic toxicity (LAST), new-onset seizures, illicit drug use and propofol neuroexcitation. However, the signs and symptoms did not fit LAST with regard to dose, timing (significant delay of 2 h since last local anaesthetic injection), lack of progression to cardiovascular collapse, and finally, venous plasma ropivacaine concentration was 0.57 μg ml−1 (below the threshold for central nervous system symptoms).2,3 New-onset seizures were excluded by neurology. MRI and electroencephalography were unremarkable. Urine toxicology screen detected opiates and benzodiazepines.

It was surmised that this was propofol neuroexcitation or ‘propofol frenzy’.1 Recalling the ability of intravenous lipid emulsion (ILE) to bind lipophilic molecules,4–6 a trial to reverse this frenzy was attempted. One hundred millilitre of 20% Intralipid was given over 1 min followed by continuous infusion of approximately 18 ml min−1 over the next 15 to 20 min. He woke up almost immediately. It was like turning on a light switch! He had no recall of the events.

Possible propofol neuroexcitation was discussed with the patient and his mother. The patient was discharged home on postoperative day 2. Informed consent for publication was obtained.

Although rare, reports of propofol neuroexcitation have been reported almost since its introduction. Abnormal movements range from increased extensor muscle tone, to rhythmic involuntary movements, to opisthotonus,7 to outright seizures.1,7–9 These movements alternate with periods of unresponsiveness and can be associated with an altered mental status.1,7–9 They can last hours to days8,9 and can recur periodically.1 These movements have been noted to occur anytime during propofol sedation and anaesthesia (induction, maintenance, emergence) and may be delayed.7 It is also known to take its course.9

Various hypotheses exist in the literature regarding the pathophysiology of propofol neuroexcitation. There is no complete understanding and no clear treatment plan. Numerous case reports, reviews and retrospective studies have reported previously attempted yet unsuccessful treatments consisting of supportive measures, sedatives, anticholinergics and even anticonvulsants.1,8 Alas, definitive treatment is elusive.

Propofol is a highly soluble lipid with an octanol/water partition coefficient of 6761 : 1 ( It is therefore formulated in an oil in water emulsion. Propofol emulsion is very similar in composition to intralipid, minus the active drug, 2,6-diisopropylphenol (Table 1;,018449s039lbl.pdf). A bolus of propofol achieves a rapid equilibrium between plasma and brain concentrations. The decrease in plasma concentration is due equally to metabolism and distribution. However, distribution declines with time, as body tissue stores become saturated. Propofol enhances gamma-Aminobutyric acid-induced inhibitory neurotransmission. It may also antagonise subcortical glycine receptors.10

Table 1
Table 1:
Composition of propofol and intralipid

ILE is the recommended therapy in LAST. It has also been used successfully in other lipophilic drug toxicities.4–6 Propofol's lipophilicity (log P of 3.79) is similar to that of other drugs whose overdoses were successfully rescued by ILE.6 Although propofol neuroexcitation is not an overdose or toxicity, we theorised that the ILE would temporarily sequester the propofol away from the sensitive brain, allowing accelerated distribution to other tissues. This is consistent with one of the latest mechanisms of action of lipid resuscitation therapy delineated in a recent review by Fettiplace and Weinberg.5

Propofol is administered to millions of people worldwide, yet, neuroexcitation remains a very rare event. It can be quite impressive to watch and quite frustrating to treat. Multiple case reports in the literature describe varying, yet unsuccessful attempts at treatment. Although case reports have their limitations, ILE administration in this patient was associated with an immediate return to normal function and responsiveness. In the absence of more specific or targeted treatment regimens and minimal side effects of ILE, we used the dosing regimen for ILE in cases of LAST. This may be the first successful treatment of propofol neuroexcitation with ILE. Further clinical and pharmacokinetic studies are needed to prove ILE as an effective treatment for propofol neuroexcitation.

Acknowledgements relating to this article

Assistance with the letter: none.

Financial support and sponsorship: none.

Conflicts of interest: none.


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