Propofol infusion syndrome


Propofol infusion syndrome or propofol related infusion syndrome (PRIS) can be  defined as the occurrence of acute bradycardia resistant to treatment and progressing to asystole associated with propofol infusion.

Bradycardia has to be combined with lipemic plasma, fatty liver enlargement, metabolic acidosis with negative base excess >10 mmol . l/1, rhabdomyolysis or myoglobinuria.

PRIS usually leads to fatal cardiac and renal failure. Symptoms and signs are lactacidosis, arrhythmia, hypotension, renal, cardiac and circulatory failure, oliguria, rhabdomyolysis, elevated serum creatine kinase, serum urea and serum potassium, lipemic plasma, liver enlargement.

ketonuria, increased liver enzymes and green or red coloured urine.

Risk factors identified from case reports are airway infection, severe head injury, high dose longterm propofol sedation for more than 48 hours  at more than 5 mg/kg/h , increased catecholamine and glucocorticoid serum levels and low energy supply.

OVERVIEW

  • Propofol-related Infusion Syndrome is a life-threatening condition characterised by acute refractory bradycardia progressing to asystole and one or more of:

(1) metabolic acidosis
(2) rhabdomyolysis
(3) hyperlipidaemia
(4) enlarged or fatty liver

MECHANISM

Poorly understood — even the central role of propofol has been questioned “AstraZeneca recently emphasized in a review the role of the most important risk factors for the development of PRIS, focussing on poor oxygen delivery, sepsis, serious cerebral injury and high propofol dosage. In addition to this, lipemia, likely due to a failure of hepatic lipid regulation, possibly related to poor oxygenation or low glucose plasma levels, could lead to sequestration of propofol into the lipid phase, thus leading to lowered free propofol levels and apparent insensitivity to propofol. The manufacturer recommends good hemodynamic and oxygen delivery management, adequate glucose control, adherence torecom- mended propofol dosing regimes to prevent and treat the “so-called propofol infusion syndrome”

  • ? direct mitochondrial respiratory chain inhibition
  • ? impaired mitochondrial fatty acid metabolism

“Cytolysis of skeletal and cardiac muscle cells. Clinical and experimental findings show that propofol uncou- ples the respiratory chain in heart and muscle cells. Free fatty acids have been identified as a proarrhythmogenic risk factor. Muscle biopsies and fat metabolism analyses of patients with PRIS resemble these found in mitochondrial cytopathias and acquired acylcarnitine metabolism deficiencies by inhibition of beta oxidation” 

CLINICAL FEATURES

  • high dose, long duration proprofol infusion (maximum dose should be 28mL/hr (70kg adult, 1% propofol at maximum of 4mg/kg/hr)
  • on propofol!
  • increasing inotrope support
  • green urine (some sources say no correlation with PRIS)
  • cardiovascular collapse (reflected in PICCO, PAC, ECHO)

RISK FACTORS

  • >4mg/kg/hr for 48 hours (large dose, long time); but can occur at lower doses
  • younger age
  • acute neurological injury
  • low carbohydrate intake
  • catecholamine infusion
  • corticosteroids infusion

INVESTIGATIONS

Bedside

  • ECG: Brugada like pattern (coved type = convex-curved ST elevation in V1-V3), RBBB, arrhythmia, heart block
  • blood gas: unexplained lactic acidosis; hyperkalaemia (if rhabdomyolysis or renal failure)

Laboratory

  • lipids (lipaemic serum)
  • UEC (renal failure)
  • CK (rhabdomyolysis)
  • propofol levels or chromatography (if available)

MANAGEMENT

  • high index of suspicion
  • monitor for early warning signs (lactate, CK, urinary myoglobin, ECG)
  • discontinue propofol immediately
  • supportive care and monitoring
  • consider pacing
  • adequate carbohydrate intake (6-8mg/kg/min)
  • carnitine supplementation (theoretical benefit)
  • haemodialysis and haemoperfusion (used with success in case reports)
  • ECMO (at least 2 cases reported, reasonable strategy given readily reversible pathology)

PROPHYLAXIS

The occurrence of PRIS has lead to restrictions to the use of propofol. Propofol is not approved for sedation in pediatric ICU patients. Nevertheless, offlabel use at high doses is still often clinical practice, due to pharmacodynamic properties and high dose requirements of propofol in children. Monitoring of pH, serum lactate and creatinine kinase was recommended when high doses or long infusion periods cannot be avoided. The Drug Commission of the German Medical Association (Arzneimittelkommission der deutschen Ärzteschaft) recommended to avoid propofol in children younger than 16 years for intensive care sedation. A dose limit of 4 mg/kg/h  is recommended for sedation of adult patients and a period of seven days should not be exceeded. Acidbase metabolism and creatinine kinase should be monitored frequently. Propofol should not be used as the only sedative but in combination with others to avoid dose escalation.

In total intravenous anesthesia (TIVA)  propofol is regarded as a safe procedure with few side effects in paediatric anesthesia and is considered as a standard procedure. Although PRIS was reported in patients with epilepsy, propofol is still recommended in patients with epileptic seizures due to lack of epileptic potential and postoperative agitation and delirium as compared to sevoflurane.

Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

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