Question 29

With respect to propofol infusion syndrome in the ICU:    
a) Outline the pathophysiology.    (2 marks)
b) List six risk factors for this syndrome.    (3 marks)
c) Outline the clinical features, including relevant investigations.    (5 marks)

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College Answer

Syllabus topic/section:

2.1.21 Applied Pharmacology in Intensive Care.

Aim:
To explore the complications of a ubiquitous sedative agent in the ICU routine practice.

Discussion:

Despite some individual high marks achieved, many candidates demonstrated limited knowledge of this important drug and its potential adverse effects. A list of 6 risk factors would have included but not limited to, dosage, catecholamines, disease severity, and many others.

The syllabus has outlined that questions on the mechanism of action, pharmacokinetics, and pharmacodynamics will no longer be examined in the second part examination.

Pathophysiology is examinable in the second part examination. This knowledge is considered essential for the safe practice and management of common or severe adverse effects such as propofol infusion syndrome.
In part C, some candidates listed the investigations required but did not outline the investigations with the associated abnormalities. More time should be spent on acquiring in-depth, precise, and comprehensive knowledge about PRIS.
 

Discussion

This is very similar to Question 20 from the first paper of 2010, except management was not the focus this time, and pathophysiology was.

Pathophysiology

  • 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.

Risk factors

  • 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, including relevant investigations.

  • 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
  •     Hyperlipidaemia
  •     Fatty liver and hepatomegaly
  •     Coagulpathy
  •     Raised plasma malonylcarnitine and C5-acylcarnitine

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).