Propofol infusion syndrome a serious complication of long term use of Propofol is associated with fatality has been described.

1. Propofol Infusion syndrome
Dr. P K Maharana.
Department of Anesthesiology
KIMS, Bhubaneswar.

2. Definition
Propofol infusion syndrome is a rare but extremely dangerous
condition typically occurring after prolonged infusion of propofol (
more than 24 hours of at rates greater than 4 mg/kg/hr), and is characterized
by sudden onset of refractory bradycardia leading to asystole in the
presence of one or more of the following: high anion gap metabolic
acidosis, rhabdomyolysis, hyperlipidemia, and/or enlarged liver.

3. Incidences
In the early 1980s, propofol was introduced as an anaesthetic induction agent, used extensively
later, both as an induction and maintenance anaesthetic. After approval from the FDA, the
indications for propofol expanded to include long-term sedation in intensive care,currently, 70% of
propofol use is for sedation.
o The first reported death associated with propofol infusion was in Denmark in 1990 , a 3-year-
old girl. This patient developed high anion gap metabolic acidosis (HAGMA), hypotension, and
polyorgan failure .
o In 1992 Parke et al. reported the deaths of five children who had similar presentations to the
Danish case while being on propofol infusion.
o Later, in 1996, the first adult case of lactic acidosis associated with propofol administration was
reported. The patient was a 30-year-old female who was admitted for bronchial asthma
exacerbation and who had developed unexplained lactic acidosis.
o Despite the common use of propofol for sedation of the critically ill, only around 164 cases of
propofol infusion syndrome reported in the literature since 1990.
The term PRIS—propofol infusion syndrome—was originally coined by Bray in 1998 to describe the adverse
effects associated with the use of propofol in the paediatric population, (Bray had reviewed 18 paediatric
cases) .
 However, in a prospective study of critically ill patients, Roberts and colleagues reported an incidence of 1.1%, equating to
three or four patients per year in an ICU admitting 300–400 patients.

4. Aetiology
• The mechanism behind the development of propofol infusion syndrome is yet unclear.
• It has been suggested that propofol infusion syndrome resembles some mitochondrial diseases, such as
medium-chain acyl coenzyme A (CoA) dehydrogenase deficiency, when the defective mitochondria are
placed under significant physiological stress, such as trauma, surgery, or sepsis.
• Cray and colleagues suggested that propofol has a disruptive effect on the respiratory chain, leading to
reduced ATP production, cellular hypoxia, and ultimately metabolic acidosis.
• Wolf and colleagues postulated that propofol causes an ↑increase in malonylcarnitine, inhibitor of CPT I.
(Fatty acids are activated on the outer mitochondrial membrane, but are oxidized within the mitochondrial matrix.
Short- and medium-chain fatty acids can freely diffuse across the mitochondrial membrane; however, longer-chain fatty
acids, such as palmitoyl CoA, require CPT I, which acts as a shuttle system to move them into the matrix.)
Thus, the inhibition of CPT I by malonylcarnitine and propofol itself causes fatty acids to accumulate in the
mitochondria, leading to dysfunction of the respiratory chain, and the cascade of reduced ATP production
occur.
When considering all of these studies, the evidence points to  a defect in the production of ATP as the
probable causative mechanism of propofol infusion syndrome.

5. Enzyme inhibition
 Propofol inhibits  the activity of the enzyme Carnitine palmitoyl
transferase I(CPT I), an outer membrane mitochondrial enzyme .
o Inhibits the enzyme(CPT I) causes  accumulation of fatty acids ,
leading to dysfunction of the respiratory chain, and reduced ATP
production.
o Due to propofol-mediated defects in beta-oxidation of fatty acids, fatty acids tend to accumulate
in various organs (e.g., liver). Thus, patients with propofol infusion syndrome have elevated levels
of free fatty acid, which has actually been shown to promote cardiac arrhythmogenicity and
therefore an adequate carbohydrate intake is highly recommended to suppress lipolysis.
 The Enzyme CPT I, transfers the fatty acyl group to carnitine to form  fatty-acyl-carnitine,
which can then be transported through the inner mitochondrial membrane where its metabolites
participate in the citric acid cycle, ketone body production, and the electron transport chain.

6. Other mechanism of actions
In addition, propofol antagonizes β-adrenergic receptor and calcium
channel binding thus further depressing cardiac function.
It also suppresses the activity of sympathetic nerves and the
baroreceptor reflex, thus worsening the cardiac failure in PRIS and
the resistance to inotropes.

7. Stress & Abnormal Metabolism
Under physiological circumstances, glucose is a major source of
energy to the brain, the cardiac, and skeletal muscles.
However, during conditions of stress , there is a shift towards
utilization of free fatty acids as a major source of energy for the vast
majority of biological processes.
This shift in energy metabolism is achieved via the activation of stress
hormones such as epinephrine and cortisol, which modulate the
activity of hormone sensitive lipase in the adipose tissue.

8. Pathophysiology
Due to propofol mediated defects in beta-oxidation of fatty acids, fatty
acids tend to accumulate in various organs.
Thus, patients with PRIS have elevated levels of FFA, which has actually
been shown to promote cardiac arrhythmogenicity.
This energy deprivation and imbalance might explain the observed
myocytolysis of both skeletal and cardiac muscles in patients with PRIS .
 Muscle death leads to  ↑elevations in creatine kinase, myoglobin,
potassium, and lactic acid.
 Rhabdomyolysis is a strong risk factor for acute kidney injury, which, if it
occurs, may worsen metabolic acidosis.
( Inhibition of beta-oxidation fatty acids  free fatty acid accumulation 
decrease production of ATP  energy deprivation muscle necrosis  AKI 
Acidosis  Myocardial dysfunction  Death.)

9. Risk factors
 PRIS is a rare but extremely dangerous complication of propofol administration with a high
mortality.
Certain risk factors for the development of PRIS described are :
o Inappropriate propofol doses and durations of administration,
o Carbohydrate depletion,
o Critical illnesses, sepsis and severe head injury.
o Concomitant administration of catecholamines and
glucocorticosteroids. (High exogenous or endogenous catecholamine and
glucocorticoid levels)

10. Clinical Manifestations
Common presenting features of PRIS are:
oCardiac dysfunction (88%).( widening of the QRS complex; bradycardia;
ventricular tachycardia or fibrillation; asystole).
oNew-onset metabolic acidosis (86%)
oRhabdomyolysis (cardiac and skeletal muscle) (45%),
o Renal failure (37%), AKI,
oHyper triglyceridaemia (15%) &
o Other significant features include hepatomegaly, elevated liver enzymes,
hyperkalemia, and lipaemia.

11. ECG changes in PRIS
Brugada-like ECG changes (Coved type ST
elevations in V1–V3) are characteristic in
PRIS.
Other arrhythmias include :
atrial fibrillation, ventricular or
supraventricular tachycardias,
bundle branch blocks,
bradycardias, and eventually
asystole.

12. Clinical manifestations.(Conti-)
• The metabolic acidosis in PRIS appears to be due to a combination of
renal failure and lactic acidosis. Lactate production is emerging as an
early common feature.
• This lipaemia may be due to increased sympathetic stimulation, high
circulating cortisol and growth hormone levels, and blockade of
mitochondrial fatty acid oxidation impairing lipid metabolism and is
clinically manifested as raised serum triglyceride.
• Rhabodomyolysis of both skeletal and cardiac myocytes and the
release of creatinine kinase (CK) and myoglobin. In most case reports,
the CK at the diagnosis of PRIS is often >10 000 units litre−1.

13. Prevention
• In 2006 the FDA updated the labelling information and limited the maximum
dose of propofol recommended for sedation to 4 mg/kg per hour.
• At the same time European regulatory authorities suggested that patients be
monitored for metabolic acidosis, hyperkalaemia, rhabdomyolysis or an elevated
creatine kinase level, and or signs of heart failure.
• New onset and otherwise unexplained high anion gap metabolic acidosis, cardiac
dysfunction (Brady or tachyarrhythmias, Brugada syndrome-like patterns on ECG,
and cardiogenic shock and asystole), elevated liver and pancreatic enzymes,
hypertriglyceridemia, rhabdomyolysis, hyperkalemia, and acute kidney injury
should warrant strong consideration of propofol infusion syndrome
• If any of these conditions developed, they recommended a dosage reduction or
discontinuation of propofol .
• Considering the high mortality of propofol infusion syndrome, the best
management is prevention.

14. Monitoring
Normally in addition to routine monitoring of different vital parameters the
followings should also be assessed.
 Arterial blood gases,
 Serum lactate, and
 Serum triglyceride
 Creatine kinase
 should be monitored frequently, especially if propofol sedation is required
for more than 48 hours.
After 48 hour of propofol infusion, increasing levels of creatine kinase in
the absence of other muscular pathologies triggers the suspicion of
propofol infusion syndrome and propofol is immediately stopped.

15. Management
The management of propofol infusion syndrome requires a high index of
suspension in the at-risk population and rapid recognition of the clinical signs.
Management of overt PRIS includes:
(I ) Immediate discontinuation of propofol infusion and Glucose infusion should
be started immediately and need to support other complications.
(ii) Hemodynamic support,
(iii) Hemodialysis, and
(iv) Extracorporeal membrane oxygenation in refractory cases.
 However, we must emphasize that, given the high mortality of PRIS, the best
management is prevention.
 Clinicians should consider alternative sedation agents in patients who are
receiving prolonged or high-dose propofol infusions, acute kidney injury should
warrant strong consideration of PRIS.

16. Management. ( Conti-)
• Brady arrhythmias were managed with transvenous pacing in the reported cases.
(Electrical pacing (either via temporary wire or transcutaneously) has been met with limited success for the
bradycardia).
• Cardiogenic shock should be managed with the support of vasopressors and inotropes, such as norepinephrine and
dobutamine, for example, and mechanical devices in refractory cases.
• Management of metabolic acidosis in the reported cases includes administration of sodium bicarbonate and renal
replacement therapy. However, the role of sodium bicarbonate in the management of lactic acidosis is quite
controversial and not universally accepted .
• Euvolemia should be maintained in patients with traumatic brain injuries, which is a common comorbid condition
in patients who have developed propofol infusion syndrome .
• Calcium administration (either chloride or gluconate), insulin with or without dextrose, beta-2 agonist
administration, sodium bicarbonate, and potassium binding resin can also be considered in the management of
hyperkalemia .
• Renal replacement therapy: Hyperkalemia, acute renal failure, acidosis favors renal replacement therapy.
• ECMO: In refractory cases of propofol infusion syndrome, extracorporeal membrane oxygenation should be
strongly considered.

17. Conclusion
• It is evident that the use of propofol for long-term sedation is associated with a number
of cases of propofol infusion syndrome in both adults and children around the world.
• Propofol infusion syndrome presents in a number of ways from cardiovascular collapse to
a metabolic response, and is a disease of multiple organ systems.
• It is demonstrated that there is an associations between the cumulative dose of propofol
and predicated mortality, and the number of clinical features and organ systems involved
in adults.
• As there is no diagnostic test, a high degree of clinical suspicion is required in all patients
receiving high-dose short-term infusions and patients receiving long-duration infusions
with a variable dose range.
• At present, treatment is mainly supportive, and we recommend that clinicians keep an
open mind and consider propofol infusion syndrome in cases of unexplained metabolic
acidosis, ECG changes, and rhabdomyolysis.
• Recommend that early consideration of continuous renal replacement therapy in the
management of propofol infusion syndrome..