I_am_sharing_Propofol_Infusion_Syndrome_with_you.pptx

Adverse effects of propofol

1. Propofol Infusion Syndrome

2. Presented by Dr. Sabrina Shahin Alam DA Student, Session-2021-23 Chittagong Medical College Guided by- Dr. Md. Rezaul Hoque Tipu Assistant Professor Dept of Anesthesiology & ICU Chittagong Medical College

3. AUTHOR Monojit Paul 1 † 1 Anaesthesia Specialist Trainee, University Hospital of North Durham, UK Edited by: Dr. Niraj Niranjan , Consultant, Anaesthesia and Intensive Care, University Hospital of North Durham, UK   † Corresponding author e-mail: [email protected]   Published 27 October 2020

4. KEY POINTS Propofol infusion syndrome is a rare but potentially fatal condition first described in the paediatric population and subsequently reported in adult intensive care, particularly in neurointensive care. Refractory bradycardia , unexplained metabolic acidosis, electrocardiogram changes and rhabdomyolysis are consistent features.

5. CONTINUE There is no diagnostic test; therefore, a low index of suspicion is required for early detection. Pathophysiology is not clearly understood but resembles mitochondrial diseases. The mainstay of management is prevention and early detection. Treatment of established diagnosis is supportive.

6. INTRODUCTION Propofol is a nonbarbiturate intravenous anaesthetic agent that was approved for use in 1989. As with many general anaesthetic agents, it produces its hypnotic effects by potentiating the effects of the inhibitory neurotransmitter gamma- aminobutyric acid (GABA). It is an important drug that is widely used throughout the world. It is currently on the World Health Organisation’s (WHO) ‘Model List of Essential Medicines’, which lists what WHO considers to be the most effective and safe medications needed to meet the needs of a health care system. 1

7. continue Propofol is widely used for the induction and maintenance of general anaesthesia , and it also has many properties that favour its use as a sedative agent in the critically ill. Of note, 70 % of propofol use worldwide is for sedation. These properties include the following: rapid onset and offset of action; sedative, anxiolytic , antiemetic and anticonvulsant properties; and beneficial anti-inflammatory and antioxidant properties.

8. Continue It has an excellent safety profile, but a rare and potentially fatal complication called propofol infusion syndrome (PRIS) is recognized. The first reported case of this syndrome occurred in 1990, in a 3-year-old child in Denmark. Two years later, a case series was published in the British Medical Journal , describing similar presentations in 5 young children. 2 A United States Food and Drug Administration study that year failed to find a link between propofol and further deaths, but propofol’s use for paediatric sedation was abandoned shortly afterward, explaining in part why subsequent literature features mostly adult cases.

9. DEFINITION The term propofol infusion syndrome (PRIS) was first coined by Bray in 1998, in an article that aimed to define some of the common clinical features of the cases in which children had suffered adverse consequences associated with, although not proven to be caused by, high-dose and long-term (48 hours) propofol infusions. 3 Although there has been no universally accepted definition of PRIS, an early definition was as follow: occurrence of acute refractory bradycardia , progressing to asystole , associated with propofol infusion, in the presence of one or more of the following: metabolic acidosis, rhabdomyolysis or myoglobinuria , lipaemic plasma, or enlarged liver or fatty liver. 4

10. continue The description including refractory bradycardia leading to asystole in this phrasing was felt to limit practical value, and so an alternative definition has recently been described, based on primary features (those that can be the sole manifestation of PRIS) and secondary features (those that occur in combination with other features). 5 This latter definition is as follows and these features are detailed in the Table:

11. continue propofol infusion syndrome occurs in critically ill patients receiving propofol infusions, typically either high dose (.5mg/ kg/hr) or of long duration (48 hrs), and is characterised by one or more of the following: otherwise unexplained metabolic acidosis, rhabdomyolysis , or ECG changes with or without acute kidney injury (AKI), hyperkalaemia , lipidaemia , cardiac failure, fever, elevated liver enzymes or raised lactate. 5

12. 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 profofol use is for sedation. 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. In 1992 parke et al. reported the deaths of five children who had similar presentations to the Dasish case while being on propofol infusion. 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.

13. continue 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 propulation , (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.

14. 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 strees , such as trauma, surgery, or sepsis. Cray and colleagues suggested that propofol has a disruptive effcet 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 CPTI. (Fatty acids arte activated on the outer mitochondrial membrane, but are oxidized within the mitochondrial matrix.

15. continue Short-and medium-chain fatty acids can freely diffuse across the mitochondrial membrane; however, longer-chain fatty acids, such as palmitoyl CoA , require CPTI, 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.

16. MECHANISM OF ACTION ENZYME INHIBITION Propofol inhibits- the activity of the enzyme Carnitine pallmitoyl transferase I (CPT I), an outer membrane mitochondrial enzyme. Inhibits the enzyme (CPT I) causes- accumulation of fatty acids, leading to dysfunction of the respiratory chain, and reduced ATP production. Due to propofol – mediated defects in beta-oxidation of fatty acids tend to accumulate in various (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, transfer the fatty acyl group to cornitine to form- fatty- acyl - carnitine , which can then be transported through the inner mitochondrial membrane where its metabolities participate in the citric acid cycle, ketone body production, and the electron trnasport chain.

17. OTHER MECHANISM OF ACTIONS In addition, propofol antagonizes B-adrenergic receptor and calcium channel binding thus further depressing cardiac function. It also suppresses the activity of sympathetic nerves and the baroeceptor reflex, thus worsening the cardiac failure in PRIS and the resistance to inotropes .

18. 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 shift towards utilization of free fattty acids as a major source of energy for the vast majority of biological processes. This shift in energy metabolism is achieved fia the activation of stress hormones such as epinephrine and cortisol , which modulate the activity of hormone sensitive lipase in the adipose tissue.

19. Clinical manifestations Common presenting features of PRIS are: Cardiac dysfunction (88%). (widening of the QRS complex; bradycardia ; ventricular tachycardia or fibrillation; asystole . New-onset metabolic acidosis (86%) Rhabdomyolysis (cardiac and skeletal muscle) (45%), Renal failure (37%), AKI, Hyper triglyceridaemia (15%) & Other significant features include hepatomegaly , elevated liver enzymes, hyperkalemia and lipaemia .

20. 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 . ECG charcteristies in Brugada Syndrome a. Broad P weve with some PQ prolongation b. J point elevation c. Coved type ST segment elevation d. Inverted T weve

21. 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 myoctes and the release of creatinine kinase (CK) and myoglobin . In most case reports, the CK at the diagnosis of PRIS is often > 10000 units litre-1.

22. Continue 20 Primary Features ECG changes New-onset severe metabolic acidosis Rhabdomyolysis Secondary Features Lipidaemia Hyperkalaemia Acute kidney injury Fever Cardiac dysfunction Deranged liver enzymes Raised serum lactate Table. Clinical Features of PRIS as per Hemphill’s Classification 5

23. RISK FACTORS Cumulative Dose There is plenty of evidence to suggest a linear relationship between the cumulative dose of propofol and quantity and severity of features. Although the definition given above referenced high doses (.5 mg/kg/h) or long duration of administration (.48 hours), there have been many cases reported at lower cumulative doses. Obesity Pharmacokinetic studies suggest that dosing for propofol should be based on a patient’s lean body weight rather than actual body weight. (Target controlled infusion models are not formally validated in the obese and use different weight values in their calculations). Although there has been no clear relationship between obesity and the development of PRIS, the dose for sedation should be calculated based on lean body weight. Cases have been reported in which administration of propofol based upon actual body weight has been associated with PRIS and may have been exacerbated by the ‘relative overdose’ of propofol .

24. continue Catecholamines There is a link between the use of vasopressors and the development of PRIS. 7 It is thought that propofol clearance is increased by the raised levels of endogenous catecholamines seen in the brain-injured patient or the patient with a hyperdynamic circulation in the context of sepsis or a systemic inflammatory response syndrome. This is also thought to occur with administration of higher doses of inotropic or vasopressor infusions. The increased clearance may reduce the therapeutic effect of propofol , leading to the need to increase the administered dose of propofol . Whether this is a causal effect is not clear; acidosis due to PRIS may impair vasomotor tone, leading to an increased vasopressor requirement.  

25. continue Critical Illness The neuroendocrine stress response to critical illness causes a surge in catecholamines and glucocorticoids , which are implicated as risk factors for PRIS. These hormones modulate the activity of lipase enzymes, promoting breakdown of triglycerides into glycerol and free fatty acids (FFAs). Furthermore, in critical illness, there is a shift from carbohydrate to lipid- based substrates for energy production, which also increases FFAs. This is of importance as FFAs are a key substrate for the part of the pathophysiological mechanism of PRIS (see below).

26. continue Steroids Steroids are known to contribute to the development of a critical illness myopathy , possibly by triggering enzymes that cause direct muscle damage. The rhabdomyolysis seen in PRIS may occur as a result of a similar mechanism, and there is certainly a link between steroid therapy and the development of PRIS. Lipid Overload It is possible for patients to develop a relative lipid overload associated with parenteral nutrition, propofol infusions or both. 4 This leads to an accumulation of unused FFAs. There should be an adequate source of carbohydrate to balance this out and suppress excessive lipolysis , perhaps in the form of a dextrose infusion. This may be one of the reasons that children, with their relatively limited glycogen stores, exhibit an increased susceptibility to PRIS.

27. PATHOPHYSIOLOGY The exact mechanism underlying PRIS is not fully understood. We know that propofol uncouples oxidative phosphorylation and energy production in mitochondria as well as inhibits electron transfer in the myocyte electron transport chain, leading to a disturbance in ATP production, cellular hypoxia and acidosis. Most of the existing evidence points to this as the most likely pathway for the aetiology of PRIS. FFAs, which are an essential fuel for these myocytes during ‘stress’, cannot be used when oxidative phosphorylation is uncoupled. They can build up and act as a proarrhythmogenic substance, contributing to cardiac dysfunction in PRIS. 8

28. continue Propofol also antagonises beta-adrenergic receptors and calcium channel binding, further depressing cardiac function and causing a degree of resistance to inotropic agents. It has also been suggested that the pathophysiology resembles certain mitochondrial diseases, such as medium-chain acyl coenzyme dehydrogenase deficiency, suggesting that a genetic predisposition to PRIS may exist. Ultimately, the uncoupling effect on the respiratory chain and the resultant imbalance between energy demand and utilisation causes the accumulation of lactate and myocyte necrosis. This leads to metabolic acidosis, cardiac dysfunction and rhabdomyolysis .

29. Monitoring Normally in addition to routine monitoring of different vital parameters the following 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.

30. PREVENTION It is known that the risk of PRIS rises with dosage of propofol , in terms of both the infusion rate and the duration of the infusion. The existing literature recommends infusion rates less than 5 mg/kg/h, although most manufacturers actually recommend a lower maximum infusion rate of 4 mg/kg/h. 9

31. continue Although it makes sense to follow this recommendation, it is worth noting that cases of PRIS have been described after only a few hours of propofol or at infusion rates much lower than these. 10 The coadministration of other agents, such as opioids or the use of additional/alternative agents if sedation requirements are high is another way to control the dose of administered propofol . If high doses are needed, close monitoring of pH, lactate and creatinine kinase (CK) is imperative.

32. continue Propofol should be avoided in patients with proven or suspected mitochondrial diseases because of the resemblance in pathophysiology of the two. Given the role of FFAs in PRIS, it is also prudent to ensure a continuous carbohydrate supply to patients receiving a propofol infusion for sedation.

33. MANAGEMENT The lack of a clear definition and the inevitable presence of confounding organ dysfunction in critically ill patients means that there are no established guidelines for treatment of PRIS. The condition is difficult to treat, and awareness of its existence and the risk factors for its development, along with a high index of suspicion for signs in at-risk patients, is critical. Some institutions monitor CK levels daily after 48 hours of a propofol infusion. 8 Once diagnosed, the following are priorities: stopping further administration of propofol and commencing alternative sedation, supportive therapy to treat the complications of PRIS and elimination of propofol from the body.

34. continue Cardiovascular support in the form of inotropic agents and/or vasopressors may be needed. Arrhythmias are treated in line with standard treatment algorithms. Catecholamine-resistant cardiac shock has been reported, possibly as a consequence of the calcium channel–blocking effect of propofol . The use of extracorporeal membrane support has been reported in such cases, whereas electrical pacing has been of limited use, possibly because of the direct nature of myocyte damage.

35. Continue Metabolic acidosis should be addressed as it may propagate arrhythmias or reduce their effective treatment as well as potentially decrease the effects of vasoactive agents. This is done by ensuring an adequate minute ventilation, adequate intravascular volume and the early consideration of continuous haemofiltration .

36. continue Haemofiltration also has a role in the elimination of propofol from the body. Propofol is metabolised in the liver to water-soluble phenol derivatives, which are then excreted in the urine. Hemofiltration cannot eliminate the highly lipophilic propofol , but it can eliminate the water-soluble metabolites as well as help manage acidosis and hyperkalaemia , which may be caused by cardiac dysfunction or rhabdomyolysis .

37. continue There is limited evidence to suggest a role for bicarbonate other than as a temporising measure for hyperkalaemia in the presence of metabolic acidosis. Adequate fluid therapy is needed to treat myoglobinuria .

38. TAKE HOME MASSAGE 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 collaspse 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.

39. continue 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.

40. REFERENCES World Health Organisation . The selection and use of essential medicines: twentieth report of the WHO Expert Committee 2015 (including 19th WHO Model List of Essential Medicines and 5th WHO Model List of Essential Medicines for Children). https://apps.who.int/iris/ bitstream /handle/10665/189763/ 9789241209946_eng.pdf?sequence¼1. Accessed December 3, 2019. Parke TJ, Stevens JE, Rice ASC, et al. Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. Br Med J . 1992;305:613-616. Bray RJ. Propofol infusion syndrome in children. Paediatr Anaesth . 1998;8:491-499. Fudickar A, Bein B. Propofol infusion syndrome: update of clinical manifestation and pathophysiology . Minerva Anesth . 2009;75:339-344. Hemphill S, McMenamin L, Bellamy MC, et al. Propofol infusion syndrome: a structured literature review and analysis of published case reports. Br J Anaesth . 2019;122(4):448-459. Roberts R, Barletta J, Fong J, et al. Incidence of propofol -related infusion syndrome in critically ill adults: a prospective, multicenter study. Crit Care . 2009;13(5):R169. Smith H, Sinson G, Varelas P. Vasopressors and propofol infusion syndrome in severe head trauma. Neurocrit Care . 2009;10:166-172. Loh NW, Nair P. Propofol infusion syndrome. Cont Educ Anaesth Crit Care Pain . 2013;13(6):200-202. Medicines and Healthcare Products Regulatory Agency. Summary of product characteristics for propofol . http://www. mhra.gov.uk/ spc-pil /?subsName¼PROPOFOL&pageID¼SecondLevel. Accessed December 18, 2019. Fodale V, La Monaca E. Propofol infusion syndrome: an overview of a perplexing disease. Drug Saf . 2008;31:293-303.