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Propofol infusion syndrome

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propofol infusion syndrome
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Propofol infusion syndrome
What is propofol?
Propofol infusion syndrome causes
Risk factors for the development of propofol infusion syndrome
Propofol infusion syndrome prevention
Propofol infusion syndrome symptoms
Propofol infusion syndrome treatment

Propofol infusion syndrome

Propofol infusion syndrome is a rare but extremely dangerous complication of propofol administration, that is defined as acute refractory bradycardia leading to asystole in the presence of one or more of the following: high anion gap metabolic acidosis (base excess of minus 10 mmol/liter), rhabdomyolysis or myoglobinuria, lipemia, or enlarged liver (hepatomegaly) or fatty liver 1. Propofol infusion syndrome usually presents in patients who have been administered propofol for an extended time at high doses. Based on previously published case reports, the odds for developing propofol infusion syndrome increase when propofol is administered for over 48 hours or at a rate of over 4mg/kg/hour (67 mcg/kg/minute) 2. Propofol infusion syndrome was originally coined by Bray in 1998 3 to describe the adverse effects associated with the use of propofol in the pediatric population.

Although first described in the pediatric population 4, propofol infusion syndrome has been increasingly reported in adult intensive care patients, particularly in neurointensive care 5. The safe dose of propofol infusion for sedation in intensive care is considered to be 1–4 mg/kg per hour, but fatal cases of propofol infusion syndrome have been reported after infusion doses as low as 1.9–2.6 mg/kg per hour as well, promoting the idea that genetic factors may have a role to play 6.

Certain risk factors for the development of propofol infusion syndrome are described, such as appropriate propofol doses and durations of administration, carbohydrate depletion, severe illness, and concomitant administration of catecholamines and glucocorticosteroids 2. The pathophysiology of propofol infusion syndrome includes impairment of mitochondrial beta-oxidation of fatty acids, disruption of the electron transport chain, and blockage of beta-adrenoreceptors and cardiac calcium channels 2. Propofol infusion syndrome commonly presents as an otherwise unexplained high anion gap metabolic acidosis, rhabdomyolysis, hyperkalemia, acute kidney injury, elevated liver enzymes, and cardiac dysfunction. Management of overt propofol infusion syndrome requires immediate discontinuation of propofol infusion and supportive management, including hemodialysis, hemodynamic support, and extracorporeal membrane oxygenation in refractory cases 2. However, given the high mortality of propofol infusion syndrome, the best management is prevention. Clinicians should consider alternative sedative regimes to prolonged propofol infusions and remain within recommended maximal dose limits.

Propofol infusion syndrome key points

  • Common presenting features of propofol infusion syndrome are new onset metabolic acidosis, cardiac dysfunction, rhabdomyolysis, renal failure, and hypertriglyceridaemia.
  • Risk factors for developing propofol infusion syndrome include severe head injuries, sepsis, high exogenous or endogenous catecholamine and glucocorticoid levels, low carbohydrate to high lipid intake, or inborn errors of fatty acid oxidation.
  • Propofol infusions for sedation should not exceed 4 mg/kg per hour and routine monitoring of creatine kinase and triglycerides should be performed for the at-risk population 6.

Table 1. Summary of reported propofol infusion syndrome cases in adults

Authors [ref.]Year and countryAge and genderUnderlying pathologyPropofol dose and durationPropofol infusion syndrome featuresTreatment and outcome
Stelow et al. 72000; USA47-year-old female and 41-year-old maleBronchial asthma exacerbation200–222 mcg/kg/minute and >48 hoursRhabdomyolysis, hyperkalemia, cardiovascular collapse (female). Both patients were also treated with glucocorticosteroids for asthmaRenal replacement therapy, vasopressors. Female patient died, the outcome for a male patient not reported.
Perrier et al. 82000; USA18-year-old maleMultiple trauma (including closed head trauma) after motor vehicle accident≥50 mg//hour and 98 hoursBradycardia, left bundle branch block, lactic acidosis, rhabdomyolysis, and hyperkalemia
and cardiovascular collapse (pulseless electrical activity and asystole)		Inotropes, atropine. The patient died.
Cremer et al. 92001;
Netherlands		7 patients aged
16–55 years (no specific data provided)		Acute traumatic brain injury5.5 mg/kg/hour–7.4 mg/kg/hour;
65–177 hours		Cardiac arrhythmias in all patients, metabolic acidosis in 6 patients hyperkalemia in 6 patients, rhabdomyolysis in 4 patients, and lipemia in 3 patientsPressors and inotropes. All patients died.
Badr et al. 102001;
USA		21-year-old femaleSpontaneous
intracerebral hemorrhage due to arteriovenous malformation		4.5–9 mg/kg/hour;
>48 hours		Metabolic acidosis, cardiovascular collapsePressors, inotropes, intravenous bicarbonate. The patient died.
Friedman et al. 112002;
USA		23-year-old femaleStatus
epilepticus		200 mcg/kg/minute; 106 hoursMetabolic acidosis, hyperkalemia, acute kidney injury, wide complex tachycardia, and cardiovascular collapseThe patient died, no treatment/management was reported.
Ernest and French 122003;
Australia		31-year-old maleClosed head injury4 mg/kg/hour;
157 hours		Metabolic acidosis, acute kidney injury, rhabdomyolysis, and cardiovascular collapseNone reported. The patient died.
Casserly et al.
13		2004;
USA		42-year-old maleCerebral venous thrombosis12 mg/kg/hour;
>96 hours		Metabolic acidosis, rhabdomyolysis, acute kidney injury, and cardiovascular collapsePressors, intravenous bicarbonate. The patient died.
Kumar et al. 142005;
USA		24-year-old female,
27-year-old female and 64-year-old
male		24-year-old female with status epilepticus due to encephalitis,
27-year-old female with seizures due to intracerebral bleeding secondary to arteriovenous malformation and 64-year-old male with status epilepticus		2.6 mg/kg/hour for 64 year old male (non reported for others); 24–86 hoursMetabolic acidosis, hyperkalemia, rhabdomyolysis, acute kidney injury, and cardiovascular collapseInotropes, transvenous pacing, intravenous bicarbonate, intravenous calcium. All patients died.
Machata et al. 152005;
Austria		40-year-old maleMotor vehicle
accident and cervical fracture		Dose not reported; 72 hoursMetabolic acidosis, hyperkalemia, acute kidney injury, and feverContinuous venovenous hemofiltration. The patient died from septic complication.
Eriksen and Povey 162006;
Denmark		20-year-old femalePolytrauma1.4–5.1 mg/kg/hour;
88 hours		Rhabdomyolysis, hyperkalemia, acute kidney injury, and cardiovascular collapsePressors, inotropes, intravenous bicarbonate. The patient died.
Merz et al. 172006;
Switzerland		24-year-old
male		Cervical spine injury and acute respiratory distress syndrome. The patient received high dose methylprednisolone2.6 mg/kg/hour (highest reported range); 86 hoursHyperkalemia, rhabdomyolysis, acute kidney injury, and cardiovascular collapsePressors, inotropes. The patient died.
Corbett et al. 182006;
USA		21-year-old maleTraumatic brain injury31.6–105.5
mcg/kg/minute; 3 days		Metabolic acidosis, rhabdomyolysis, and cardiac dysfunctionSupportive treatment. The patient survived.
Zarovnaya et al. 192007;
USA		31-year-old femaleStatus epilepticus4.2–7.2 mg/kg/hour;
45 hours		Hyperkalemia, rhabdomyolysis, and cardiovascular collapsePressors, inotropes, transvenous pacing, renal replacement therapy. The patient died.
Orsini et al. 202009;
USA		36-year-old femaleHIV, Pneumonia, and sepsis1.5 mg/kg/hour;
7 days		Morbilliform rash, elevated liver enzymes, elevated pancreatic enzymes, elevated triglycerides, and hepatomegaly with hepatic fatty infiltration. The patient was also on glucocorticosteroids and vasopressorsDiscontinuation of propofol infusion. The patient survived.
Ramaiah et al. 212011; USA42-year-old morbidly obese femaleElective
parathyroidectomy		4 mg/kg/hour; 65 hoursRhabdomyolysis, acute kidney injury, metabolic acidosis (also the patient developed septic shock secondary to ventilator associated pneumonia and urinary tract infection)Vasopressors, renal replacement therapy. The patient survived her illness, but later died (65 days later, from tracheostomy occlusion in prone position due to fall).
Lee et al. 222011;
Korea		29-year-old femaleDilation and curettage for intrauterine fetal death100 mg bolus doseHyperkalemia, metabolic acidosis, and cardiovascular arrestCalcium gluconate, furosemide, inotropes. The authors deemed other potential causes like anaphylaxis, primary respiratory failure and amniotic fluid embolism to be unlikely in her case. The patient died.
Faulkner et al. 232011;
USA		23-year-old maleTraumatic brain injury and status epilepticus4.8 mg/kg/hour;
5 days		Type I pattern of Brugada pattern on electrocardiography (ECG), rhabdomyolysis, hyperkalemia, hypertriglyceridemia, and metabolic acidosisIntravenous hydration, plasma exchange. ECG findings resolved 48 hours after discontinuation of propofol. The patient survived.
Annecke et al. 242012;
Germany		36-year-old femaleSevere head trauma2.8 mg/kg/hour;
5 days		Rhabdomyolysis, Brugada syndrome pattern on ECG,
hyperkalemia, metabolic acidosis, and cardiovascular collapse		Vasopressors, inotropes, hemofiltration, transvenous pacing. The patient died.
Mijzen et al. 252012;
Netherlands		23-year-old maleOpen skull fracture4.7–5.8 mg/kg/hour;
6 days		ECG changes (biphasic T waves, Brugada syndrome type 1 like pattern, S T segment depression, wide QRS complexes), hyperkalemia, metabolic acidosis, and cardiovascular collapseCalcium gluconate, insulin and dextrose, hemodialysis. The patient died.
Vanlander et al. 262012;
Belgium		40-year-old maleHead trauma, underlying blindness2.67–5.35 mg/kg/hour;
88 hours		Metabolic acidosis, rhabdomyolysis, Brugada syndrome type 1 like pattern. The patient was also on vasopressorCarnithine, thiamine, vitamin B 12, renal replacement therapy. The patient died. Genetic testing demonstrated the presence of Leber hereditary optic neuropathy.
Deters et al. 272013;
USA		35-year-old maleStatus epilepticus150 mcg/kg/minute; 3 daysRhabdomyolysis (day 3), metabolic acidosis, hyperkalemia, acute kidney injury, elevated liver enzymes, and Brugada syndrome like pattern (type 1)Hemodialysis. The patient survived.
Agrawal et al. 282013;
India		53-year-old femalePolytrauma (subarachnoid hemorrhage, hepatic and pelvic bleeding, femoral neck fracture, and pelvic fractures)20–65 mcg/kg/min;
5 days		Metabolic acidosis, hyperkalemia, and cardiovascular collapseVasopressors. The patient died.
Pothineni et al. 292015;
USA		25-year-old maleHead trauma and subdural hematoma75–100 mcg/kg/minute; 3 daysHyperkalemia, metabolic acidosis, rhabdomyolysis, acute kidney injury, elevated liver enzymes, and cardiovascular collapseAmiodarone, lidocaine, continuous renal replacement therapy. The patient died.
Savard et al. 302013;
Canada		23-year-old femaleStatus epilepticus10.7 mg/kg/hour;
69 hours		Metabolic acidosis and rhabdomyolysis. The patient was found to be positive for mutated polymerase gamma 1 mutationHemofiltration. The patient survived P RIS, but the care was later withdrawn (day 75) due to refractory status epilepticus and poor prognosis.
Mayette et al. 312013;
USA		20-year-old femaleStatus epilepticus9 mg/kg/hour;
2 days		Shock, elevated liver enzymes, rhabdomyolysis, hyperkalemia, acute kidney injury, wide QRS, and ventricular tachycardiaIntravenous hydration, pressors, renal replacement therapy, extracorporeal membrane oxygenation. The patient survived.
Linko et al. 322014;
Finland		19-year-old femaleBurnUp to 6.95 mg/kg/hour;
11 days		Rhabdomyolysis, acute kidney injury, right-sided cardiac failure, and Brugada
syndrome type 1 like pattern		Intravenous bicarbonate, continuous venovenous hemofiltration. The patient survived.
Bowdle et al. 332014;
USA		39 year
old female		Vestibular schwannomaUp to 160 mcg/kg/minute;Hypertriglyceridemia
(intraoperatively), elevated liver enzymes		The patient survived.
Diaz et al. 342014;
USA		38-year-old maleAbdominal gunshot woundUp to 125 mcg/kg/minute; 5 daysMetabolic acidosis, rhabdomyolysis, hyperkalemia, acute kidney injury, hypertriglyceridemia, and elevated liver enzymesPressors, hemodialysis. The patient died.
[Source 2 ]

What is propofol?

Propofol is an intravenous sedative-hypnotic drug that is used for procedural sedation, during monitored anesthesia care, as an induction agent for general anesthesia and for sedation in the intensive care unit 35. Propofol may be administered as a bolus or an infusion or some combination of the two. Propofol is prepared in a lipid emulsion which gives it the characteristic milky white appearance and allows for rapid distribution into the tissues including across the blood-brain barrier 36. The formula contains soybean oil, glycerol, egg lecithin and a small amount of the preservative EDTA. Strict aseptic technique must be used when drawing up propofol as the emulsion can support microbial growth 37.

Propofol is commonly used for sedation in the ICU because it has a short duration of action and rapid clearance. Propofol has dose-dependent effects leading to changes in blood pressure and heart rate at higher doses. Initial administration can cause pain at the injection site. Though propofol has a generally favorable profile as a sedative, administering toxic doses can have deleterious effects on a patient’s overall condition. Propofol infusion syndrome is the manifestation of propofol toxicity 38.

Clinical uses of propofol:

  • Induction of general anesthesia in patients ≥ three years old; though it may be used as an induction agent if a child less than three years of age has IV access.
  • Maintenance of anesthesia in patients > 2 months old
  • Sedation during monitored anesthesia care for patients undergoing procedures
  • Sedation in intubated, mechanically-ventilated ICU patients

Off-Label uses of propofol:

  • Status Epilepticus, refractory (children and adults)
  • Treatment of refractory postoperative nausea and vomiting

Propofol use was approved by the food and drug administration (FDA) in November 1989 2. Propofol administration has many important advantages, such as a rapid onset of action—within seconds after administration—and a short duration of action—up to 15 minutes 39. Propofol possesses sedative, anxiolytic, and anticonvulsant properties 39. Furthermore, propofol may have beneficial anti-inflammatory and antioxidative effects as well as neuroprotective properties including reduction of intracranial pressure 39. Common side effects to anticipate after administration of propofol include a decrease in heart rate and in blood pressure 40.

Like most general anesthetic agents, the mechanism of action for propofol is poorly understood but thought to be related to the effects on GABA (gamma-Aminobutyric acid, or γ-aminobutyric acid) mediated chloride channels in the brain 35, block N-methyl-D-aspartate receptors, and diminish calcium influx via slow calcium ion channels 39. Propofol may work by decreasing dissociation from GABA receptors in the brain and potentiating the inhibitory effects of the neurotransmitter. This, in turn, keeps the channel activated for a longer duration resulting in an increase in chloride conductance across the neuron causing a hyper-polarization of the cell membrane making it harder for a successful action potential to fire 41.

Nevertheless, it has become obvious that propofol is not without risks. The first reported death associated with propofol infusion was of a 3-year-old girl in Denmark in 1990 42. This patient developed high anion gap metabolic acidosis, hypotension, and polyorgan failure 42. In 1992 Parke et al. 43 reported the deaths of five children who had similar presentations to the Danish case while being on propofol infusion. The term “propofol infusion syndrome” first appeared in pediatric literature and was proposed by Bray who had reviewed 18 pediatric cases 3. The clinical spectrum of propofol infusion syndrome consists of bradycardia, cardiovascular collapse, high anion gap metabolic acidosis, rhabdomyolysis, hepatomegaly, and lipemia 3.

Later, in 1996, the first adult case of lactic acidosis associated with propofol administration was reported 44. The patient was a 30-year-old female who was admitted for bronchial asthma exacerbation and who had developed unexplained lactic acidosis 44. Propofol infusion was stopped, and the lactic acidosis resolved with a favorable outcome 44. Unfortunately, in 1998 a first adolescent mortality associated with propofol use was reported in a 17-year-old male with refractory status epilepticus 45.

Propofol infusion syndrome causes

The mechanism behind the development of propofol infusion syndrome remains unclear 46. Propofol infusion syndrome is thought to be secondary to an imbalance between energy demand and utilization caused by impairment of mitochondrial oxidative phosphorylation and free fatty acid utilization, ultimately leading to lactic acidosis and myocyte necrosis 6. In addition, propofol antagonizes β-adrenergic receptor and calcium channel binding thus further depressing cardiac function 6.

Under physiological circumstances, glucose is a major source of energy to the brain, the cardiac system, and skeletal muscles 47. However, during stress conditions, there is a shift towards utilization of free fatty acids as a major source of energy for the vast majority of biological tissues. 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. Hormone sensitive lipase in turn promotes the degradation of triglycerides into glycerol and free fatty acids. Both of these triglyceride constituents are taken by the liver cells: glycerol may be used as a source for glucose synthesis de novo, and free fatty acids are used in the mitochondrial beta-oxidation. This change in energy sources is quite important and aims to provide more glucose to the central nervous system and to the red blood cells. Beta-oxidation of fatty acids produces biochemical intermediates, which are used in the citric acid (also known as Krebs) cycle, which provide electrons to the electron transport chain and are used in the synthesis of ketone bodies, which can also be utilized as an energy source 47.

Because propofol is a hydrophobic substance, lipid emulsion is used as its solvent. A rabbit model showed both lipid solvent and propofol itself contribute to the development of hyperlipidemia and hypertriglyceridemia, which are commonly seen as features of propofol infusion syndrome 48. However, the pathogenesis of propofol infusion syndrome is a very complex process and is not just a result of solvent lipid emulsion. Current understanding of propofol infusion syndrome includes the fact that it involves an intricate interplay between propofol-mediated biochemical changes that underlie the host state (e.g., sepsis, shock, cranial trauma, etc.) and the concomitant use of other pharmacological agents.

Propofol inhibits the activity of the carnitine palmitoyl transferase 1, an outer membrane mitochondrial enzyme 49. This enzyme transfers the fatty acyl group to carnitine to form fatty-acyl carnitine 47. Fatty acyl carnitine 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 47. Analyses of propofol infusion syndrome cases have shown accumulation of acylcarnitine in reported patients 50. 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 51 and therefore an adequate carbohydrate intake is highly recommended to suppress lipolysis 52. A simple glucose infusion is usually sufficient to reduce endogenous lipolysis. Children are more prone to the development of propofol infusion syndrome due to low glycogen storage and high dependence on fat metabolism 52. Lipid overload associated with propofol or parenteral nutrition infusions may also contribute to increased plasma fatty acids.

Furthermore, propofol is known to directly affect the mitochondrial electron transport chain. Animal studies have demonstrated that propofol uncouples oxidative phosphorylation 53, inactivates cytochrome c, and cytochrome a/a3 54 as well as decreasing electron complex chain complex 2, complex 3, and coenzyme Q activity 55.. Clinical data have shown a decrease in cytochrome c oxidase activity 56 and electron transport chain complex 4 activity 57.

Other factors that may contribute to the development of propofol infusion syndrome include decreased carbohydrate stores, advanced stress, and/or catecholamine administration and use of glucocorticoids. Again, we point out that propofol infusion syndrome was first recognized in the pediatric population 3. Carbohydrate depletion will lead to a reduction in citric acid levels, which slows lipid metabolism 47. Animal models show that propofol inhibits beta-adrenergic receptors 58 thereby explaining why patients on propofol may require higher doses of exogenous catecholamine. On the other hand, an increase in catecholamines leads to greater clearance of propofol 59, which may, potentially, lead to the need of a higher propofol dose. Administration of glucocorticoids may potentiate protein degradation in both skeletal and cardiac muscle cells, which may contribute to cellular death 60. Moreover, glucocorticosteroids and catecholamines are stress hormones that enhance lipolysis 47.

Furthermore, as was described above, propofol has calcium channel blocking properties on the heart, which lead to decreased cardiac performance 61 and promote inflammation in the cardiac muscle 62. It is also possible that some patients who develop propofol infusion syndrome have a subclinical mitochondrial disorder 30.

Thus, patients with propofol infusion syndrome have decreased energy availability at a time of increased demand (underlying critical illness, shock, etc.). This energy deprivation and imbalance might explain the observed myocytolysis of both skeletal and cardiac muscles in patients with propofol infusion syndrome 26. 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. As was described above, propofol has numerous pathways to negatively affect the heart 51. Furthermore, metabolic acidosis by itself creates an arrhythmogenic environment 63. On the other hand, heart dysfunction may further worsen kidney function and metabolic acidosis due to cardiogenic shock. It is also important to note that features of the primary illness (sepsis, other forms of shock, status epilepticus, etc.) may overlap with propofol infusion syndrome and explain the features of propofol infusion syndrome in some of the cases 64.

Histopathological results in propofol infusion syndrome show that the basic mechanism is the destruction and breakdown of skeletal and cardiac myocytes 52. In animal and human models, propofol uncouples intracellular oxidative phosphorylation and energy production in the mitochondria and inhibits electron flow through the electron transport chain in myocytes. This unfortunately leads to an imbalance between energy demand and utilization, thus compromising cardiac and peripheral muscle cell function.

Muscle biopsies and fat metabolism analysis of patients with propofol infusion syndrome resemble those found in mitochondrial cytopathies and acquired acyl-carnitine metabolism deficiencies. A hereditary mitochondrial fatty acid metabolism impairment resembling medium-chain acyl-CoA dehydrogenase deficiency has been postulated as being responsible for the susceptibility to propofol infusion syndrome, but research into this has been inconclusive 65. Propofol increases the activity of malonyl CoA, which in turn inhibits camitine palmitoyl transferase 1, responsible for the transport of long-chain free fatty acids into the mitochondria. Another mechanism by which propofol exerts its effects is by uncoupling β-oxidation and the respiratory electron transport chain at complex 1, meaning that neither medium- nor short chain free fatty acids, which freely cross the mitochondria membranes, can be utilized 52. Free fatty acids are an essential fuel for myocardial and skeletal muscle under fasting or ‘stress’ conditions. Under such conditions, oxidation of fatty acids in the mitochondria is the principal process for producing electrons, which are transferred to the respiratory chain. Any prolonged impairment of free fatty acid utilization leads to muscle necrosis 66.

Increased endogenous catecholamine levels caused by intracerebral lesions and hyperdynamic circulations caused by systemic inflammatory response syndrome decrease propofol plasma levels by increased hepatic and extrahepatic clearance. This may lead to insufficient sedation and increased propofol infusion rates. Propofol inhibits cardiac β-adrenoceptor binding and cardiac calcium channel function. It also suppresses the activity of sympathetic nerves and the baroreceptor reflex, thus worsening the cardiac failure in propofol infusion syndrome and the resistance to inotropes 67.

Risk factors for the development of propofol infusion syndrome

When assessing the potential risk factors for the development of propofol infusion syndrome among adults, one must keep in mind that some of the data that apply actually came from pediatric research studies. For example, the notion that low carbohydrate stores play a role in the pathogenesis of propofol infusion syndrome came from a pediatric study 68. Thus, the possibilities of generalizing the findings and applying them to the adult population are unclear.

Nevertheless, certain risk factors or risk markers for the development of propofol infusion syndrome merit discussion. First of all, based on its name, propofol infusion syndrome cannot develop without current or recent propofol administration. As was discussed above, propofol is a popular choice for sedation in the ICU setting. However, propofol infusion syndrome occurs predominantly in patients receiving high doses for a prolonged period (see Table 1 above). As was shown by Cremer et al. 9, the odds for propofol infusion syndrome increase significantly with higher propofol doses. Thus, based on the data from case reports and case series, administering propofol for more than 48 hours is not recommended, nor is it to administer a dose of more than 4 mg/kg/hour or 67 mcg/kg/minute.

Other potential risk factors for the development of propofol infusion syndrome are critical illness (sepsis, head trauma, status epilepticus, etc.), use of vasopressors and glucocorticosteroids, carbohydrate depletion (liver disease, starvation, or malnutrition), carnitine deficiency, and subclinical mitochondrial disease 69. It is not clear whether these factors represent only a marker of a severe illness or if they play a direct role in the development of propofol infusion syndrome. Furthermore, subclinical mitochondrial disease is a risk marker for propofol infusion syndrome that was only reported in pediatric literature. However, supplementary carbohydrate administration at 6–8 mg/kg/minute might, possibly, mitigate the risk of propofol infusion syndrome 60.

Thus based on the factors above, clinicians must keep a high index of suspicion for the development of propofol infusion syndrome. The duration of propofol administration should not exceed 48 hours, and the dose should not be higher than 4 mg/kg/hour nor greater than 67 mcg/kg/minute. Schroeppel et al. 70 demonstrated that daily serum creatine kinase (CK) measurements to detect increased levels while on propofol may detect a high risk group for the development of propofol infusion syndrome. In particular, they used a cut-off of less than 5,000 U/L to represent a low-risk population for the development of propofol infusion syndrome. Indeed, this study has shown that the incidence of propofol infusion syndrome was only 0.19% in patients deemed to be low risk for propofol infusion syndrome. Nevertheless, future studies are needed to replicate this approach and potentially find new biomarkers for an early detection of propofol infusion syndrome risk.

In conclusion, clinicians must be aware of the potential for propofol infusion syndrome in patients receiving propofol and restrict the duration and the dose of propofol to the limits described above. It is unclear whether carbohydrate supplementation, avoidance of vasopressors (particularly catecholamines), and glucocorticosteroids (whenever possible) will translate into a reduced risk of propofol infusion syndrome. However, whenever feasible, avoiding these medications (glucocorticosteroids and catecholamines) is advised for patients receiving propofol.

Propofol infusion syndrome prevention

Propofol should be used with caution for long-term sedation in critically ill patients. Cremer and colleagues 71 showed a proportional risk of propofol infusion syndrome (odds ratio of 1.93) for every milligram per kilogram per hour increase in the mean propofol dose above 4 mg/kg/hour. It is recommended that for long-term sedation, propofol dose should not exceed 4 mg/kg/hour 6. Arterial blood gases, serum lactate, and creatine kinase should be monitored frequently, especially if propofol sedation is required for more than 48 hours. However, Fodale and La Monaca 66 have reviewed rare reports of the development of propofol infusion syndrome after 3–5 hours of high-dose propofol anesthesia and also cases where propofol infusion rates as low as 1.4 mg/kg/hour were used.

Low carbohydrate supply can be a risk factor for propofol infusion syndrome due to the increased lipolysis in periods of starvation brought on by high energy demands 52. Providing adequate carbohydrate intake with glucose infusions and minimizing lipid loads (e.g. from lipid-based parenteral nutrition) might prevent propofol infusion syndrome 67

Risk factors for developing propofol infusion syndrome include severe head injuries, sepsis, high exogenous or endogenous catecholamine and glucocorticoid levels, low carbohydrate to high lipid intake, and inborn errors of fatty acid oxidation. A high index of clinical suspicion and routine monitoring of creatine kinase and triglyceride in high-risk groups helps to prevent most cases of propofol infusion syndrome from progressing.

Propofol infusion syndrome symptoms

It has been established that the common presenting features of propofol infusion syndrome are new-onset metabolic acidosis (86%) and cardiac dysfunction (88%). Other features include rhabdomyolysis (cardiac and skeletal muscle) (45%), renal failure (37%), and hypertriglyceridaemia (15%) 72. Other significant features include hepatomegaly, hyperkalemia, and lipemia. It is prudent to emphasize that propofol infusion syndrome lacks specific signs and symptoms (other than propofol administration) and its presentation overlap greatly with other conditions leading to critical illness (various forms of shock, renal disease due to other causes, etc.)  2. Therefore, clinicians should keep a broad differential in mind while managing a patient with possible propofol infusion syndrome.

As was discussed above, the pathogenesis of propofol infusion syndrome involves the interaction between enhanced lipolysis, impaired fatty acid oxidation, mitochondrial dysfunction, underlying critical illness, and concurrent medication use (like catecholamines and glucocorticosteroids).

Common organ systems affected by propofol infusion syndrome include the cardiovascular, the hepatic, the skeletal muscular, the renal, and the metabolic. Cardiovascular manifestations of propofol infusion syndrome include widening of QRS complex, Brugada syndrome-like patterns (particularly type 1), ventricular tachyarrhythmias, cardiogenic shock, and asystole 2. Skeletal muscle manifestations include myopathy and overt rhabdomyolysis. Skeletal muscle injury may be complicated by hyperkalemia and acute kidney injury. Metabolic manifestations of propofol infusion syndrome also include high anion gap metabolic acidosis (due to elevation in lactic acid). However, other causes of elevated lactic acid, such as other forms of shock (septic, cardiogenic, etc.), tissue ischemia (bowel, limb), and certain medications (epinephrine, beta 2 agonists, etc.) may account for elevated lactic acid 73. Metabolic acidosis can further worsen hyperkalemia due to increased transcellular shift 74. Hepatic manifestations include liver enzymes elevation, hepatomegaly, and steatosis. Hypertriglyceridemia is an expected side effect of propofol administration, and it is unclear whether this alone represents a true feature of propofol infusion syndrome.

On the other hand, propofol infusion syndrome must be considered if suggestive clinical features (e.g., high anion gap metabolic acidosis or cardiac arrhythmias) develop in patients receiving high dose (>4 mg/kg/hour or >67 mcg/kg/minute) and/or prolonged infusions of propofol (≥48 hours). Clinicians may consider screening patients for propofol infusion syndrome with creatine kinase measurements that have been shown to detect patients at high risk for the development of propofol infusion syndrome 70.

Propofol infusion syndrome treatment

The management of propofol infusion syndrome requires a high index of suspension in the at-risk population and rapid recognition of the clinical signs. Monitor creatine kinase (CK) and triglyceride levels daily, 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 and alternative drugs (midazolam and alfentanil) are used for sedation 6. Of a particular note, 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 2. The notion that prevention of a disease is always better than the treatment of an established disease is very true for propofol infusion syndrome, given the high associated mortality rate. Therefore, clinicians should aim to limit the duration of propofol use (not more than 48 hours) and dosage (not more than 4 mg/kg/hour or 67 mcg/kg/minute). Substitution with a different sedative agent should be considered once the patient reaches the aforementioned limits.

Propofol infusion syndrome is difficult to treat once it occurs. As was described above and presented in Table 1, all of current knowledge on the management of propofol infusion syndrome is based on case reports and case series. Unfortunately, most patients with reported propofol infusion syndrome have died 2. Of note, there is no specific antidote or treatment targeted against propofol infusion syndrome. The management approach in described cases is purely supportive and targeted to the features of propofol infusion syndrome 2.

First line therapy of suspected propofol infusion syndrome is to immediately discontinue the administration of propofol and alternative sedative agents commenced. 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 75. Hyperkalemia and rhabdomyolysis are strong indications to consider renal replacement therapy for patients with metabolic acidosis due to propofol infusion syndrome. Also, patients with hyperkalemia and rhabdomyolysis should receive vigorous fluid administration 76. However, euvolemia should be maintained in patients with traumatic brain injuries, which is a common comorbid condition in patients who have developed propofol infusion syndrome 77. 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 78.

Cardiac dysfunction and arrhythmias represent a major cause of mortality in patients with propofol infusion syndrome. Bradyarrhythmias 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 67. Extracorporeal membrane oxygenation has been reported as successful in the cardiovascular support of propofol infusion syndrome. Aggressively managing the hyperkalemia is important, given the fact that it can detrimentally affect cardiac function. Appearance of Brugada-like patterns on the ECG should be considered as anonymous sign, which may represent an increased risk of ventricular tachyarrhythmias. Cardiac arrest should be managed according to the American Heart Association Advanced Cardiovascular Life Support guidelines 79. 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 80. Many published papers have reported a cathecholamine-resistant shock with escalating doses of inotropes. Futhermore, propofol pharmacology includes the blockage of cardiac calcium channels and beta blocking properties, thus making the use of catecholamine mimetic potentially less efficacious 58. Based on theoretical data that the inhibition of phosphodiesterase via medications such as milrinone, the administration of glucagon, and calcium may bypass the effect of propofol on these receptors, some advocate the use of the aforementioned agents for augmenting cardiovascular support 58. In refractory cases of propofol infusion syndrome, extracorporeal membrane oxygenation should be strongly considered 31. It is important to mention that managing other aspects of regular intensive unit care is important—such as the prevention of ventilator-associated pneumonia and other infections, deep venous thrombosis prophylaxis, stress ulcer prophylaxis, decubitus ulcer prophylaxis, and skin care as well as nutritional support. Of particular importance, carbohydrate administration may prevent or mitigate the risk of the development of propofol infusion syndrome 69. It is unclear whether carnitine supplementation will result in decreased risk of propofol infusion syndrome.

In conclusion, the best management of propofol infusion syndrome lies in its prevention. Complications of propofol infusion syndrome such as hyperkalemia, acute renal failure, cardiovascular collapse, and malignant arrhythmias should be aggressively treated.

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