(a)        List the risk factors for and the clinical and laboratory findings of propofol infusion syndrome.

(b)        Outline your management of a patient with suspected propofol infusion      syndrome.

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College Answer

(a)        List the risk factors for and the clinical and laboratory findings of propofol infusion syndrome.

Risk Factors 
Large doses (> 4mg/kg/hr for > 48 hours in adults): typically, but not always, large dose, long time
Younger age
Acute neurological injury
Low carbohydrate intake
Catecholamine and/or corticosteroid infusion

Clinical and laboratory findings Unexplained lactic acidosis Increasing inotrope support
(Lipaemic serum, propofol levels / chromatography (if available??))
Brugada-like ECG abnormalities (Coved-type = convex-curved ST elevation in V1-
3) 
(Green urine)
Cardiovascular collapse, reflected in PICCO / PAC / ECHO Rhabdomyolysis, high CK, hyperkalaemia
Arrhythmia / heart block
Renal failure

(b)        Outline your management of a patient with suspected propofol infusion      syndrome.

Management: 
High index of suspicion
Discontinue immediately
Monitor for early warning signs: lactate, CK, Urine myoglobin, ECG Standard cardio-respiratory support
Consider pacing (bradycardia often resistant to high dose CA and pacing)

Adequate carbohydrate intake (6-8mg/kg/min)
Carnitine supplementation: theoretical benefit
Haemodialysis and haemoperfusion, used, unproven benefit
ECMO: 2 case reports, readily reversible pathology

Discussion

Propofol infusion syndrome is discussed elsewhere.

It is well covered in an article by Prof Kam.

Pathophysiology of propofol infusion syndrome

  • This tends to happen after about 48 hours of infusion, at over 4mg/kg/hr.
  • The mechanism is likely the inhibition by propofol of coenzyme Q and Cytochrome C.
  • This results in a failure of the electron transport chain, and thus the failure of ATP production.
  • In the event of such a breakdown of oxidative phosphorylation the metabolism becomes increasingly anaerobic, with massive amounts of lactate being produced. Furthermore, fatty acid metabolism is impaired- the conversion of FFAs to acetyl-CoA is blocked, and thus no ATP is produced by lipolysis.
  • On top of that, unused free fatty acids leak into the bloodstream, contributing to the acidosis directly.

a) Risk factors for propofol infusion syndrome

  • Propofol infusion dose of >4mg/kg/hr for over 48 hrs
  • Traumatic brain injury
  • Catecholamine infusion
  • Corticosteroid infusion
  • Carnitine deficiency
  • Low carbohydrate intake: because energy demand is met by lipolysis if carbohydate intake is low, thus leading to the accumulation of free fatty acids.
  • Children more susceptible than adults - probably because their glycogen store is lower, and they depend on fat metabolism.
  • Congenital weirdness: Medium-chain acyl CoA dehydrogenase (MCAD) deficiency

   Clinical features and laboratory findings in propofol infusion syndrome

  •     Acute bradycardia leading to asystole.
    • A prelude to the bradycardia is a sudden onset RBBB with ST elevation in V1-V3; Kam’s article has the picture of this ECG. 
  •     Arrhythmias    
  •     Heart failure, cardiogenic shock
  •     Metabolic acidosis (HAGMA) with raised lactate (and also due to fatty acids)
  •     Rhabdomyolysis, raised CK and myoglobin
  •     Hyperlipidaemia
  •     Fatty liver and hepatomegaly
  •     Coagulpathy
  •     Raised plasma malonylcarnitine and C5-acylcarnitine

Management of propofol infusion syndrome

Enhanced elimination

  • Stop the propofol infusion!
  • "decontamination" might be impossible, but haemodalysis should be commenced to wash out propofol and its toxic metabolites
  • Plasma exchange may be required (Da Silva et al, 2010)

Specific antidote

  • Carnitine  has been mentioned as one of the potential antidotes to propofol infusion syndrome (Uezono et al, 2005). The authors observed a patient who developed a propofol-infusion-like syndrome in response to intravenous lipid emulsion, while in the context of an acquired carnitine deficiency. This led to the hypothesis that "acute fat burden in the setting of inadequate delivery of carbohydrate and acquired carnitine deficiency may impair fatty acid oxidation, leading to the conditions similar to those seen in mitochondrial beta-oxidation defects."

Supportive care

  • Pacing and atropine may be useless (the bradycardia is refractory)
  • Vasopressors and inotropes are aso usually ineffective
  • ECMO is the only answer if circulatory collapse with bradycardia has developed
  • Nutrition with a satisfactory amount of carbohydrate  to reduce the use of fat for metabolism. The college answer quotes a dose rate (6-8mg/kg/min) but it is unclear where the got this value from.

References

Kam, P. C. A., and D. Cardone. "Propofol infusion syndrome." Anaesthesia62.7 (2007): 690-701.

Marinella, Mark A. "Lactic acidosis associated with propofol." CHEST Journal109.1 (1996): 292-292.

Vasile, Beatrice, et al. "The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome." Intensive care medicine 29.9 (2003): 1417-1425.

Schenkman KA, Yan S. Propofol impairment of mitochondrial respiration in isolated perfused guinea pig hearts determined by reflectance spectroscopy. Critical Care Medicine 2000; 28: 172–7.

Fodale, Vincenzo, and Enza La Monaca. "Propofol Infusion Syndrome." Drug Safety 31.4 (2008): 293-303.

Da-Silva, Shonola S., et al. "Partial-exchange blood transfusion: an effective method for preventing mortality in a child with propofol infusion syndrome." Pediatrics 125.6 (2010): e1493-e1499.

Uezono, Shoichi, et al. "Acquired carnitine deficiency: a clinical model for propofol infusion syndrome?." The Journal of the American Society of Anesthesiologists 103.4 (2005): 909-909.

Mirrakhimov, Aibek E., et al. "Propofol Infusion Syndrome in Adults: A Clinical Update." Critical care research and practice 2015 (2015).