Propofol Infusion Syndrome Research Articles

Consider Heightened Awareness of Propofol Infusion Syndrome after Extracorporeal Membrane Oxygenation (ECMO) Decannulation

THE PHARMACOKINETICS of sedative drugs can be affected by multiple factors in critically ill patients. Moreover, in patients undergoing extracorporeal membrane oxygenation (ECMO), data regarding appropriate dosing of sedative drugs is limited. ECMO is an invasive management for those who have failed conservative treatment for refractory respiratory or cardiac failure. Currently there are no consensus guidelines regarding sedation strategies for these patients. However, it is understood that lipophilic agents such as propofol can be sequestered in the extracorporeal circuit (ie, tubing and oxygenators), resulting in reduced plasma drug levels and the need for higher doses to achieve the same clinical effect seen in non-ECMO patients. 1 Hammaren E. Rosenberg P. Hynynen M. Coating of extracorporeal circuit with heparin does not prevent sequestration of propofol in vitro. Br J Anaesth. 1999; 82: 38-40 Abstract Full Text PDF PubMed Scopus (25) Google Scholar Further complicating matters, the configuration of ECMO may also affect medication requirements. Patients on venovenous (VV) ECMO appear to need higher doses as compared with patients on venoarterial (VA) ECMO. 2 Shekar K. Roberts J.A. Mullany D.V. Corley A. Fisquet S. Bull T.N. et al. Increased sedation requirements in patients receiving extracorporeal membrane oxygenation for respiratory and cardiorespiratory failure. Anaesth Intens Care. 2012; 40: 648-655 Crossref PubMed Google Scholar Pharmacokinetic data related to ECMO are often derived from in vitro studies, and to the best of the authors’ knowledge there is no strong literature describing this phenomenon that could help guide care for critically ill patients on ECMO. The need for sedation in the critically ill is often unavoidable and frequently necessary to promote comfort, alleviate pain and anxiety, relieve agitation and distress from the acute illness, and facilitate ventilator synchrony. 3 Sessler C.N. Wilhelm W. Analgesia and sedation in the intensive care unit: an overview of the issues. Crit Care (London). 2008; 12: S1 Crossref PubMed Scopus (30) Google Scholar However, excessive use of sedatives can have adverse outcomes. 4 Jackson D.L. Proudfoot C.W. Cann K.F. et al. A systematic review of the impact of sedation practice in the ICU on resource use, costs and patient safety. Crit Care. 2010; 14: R59 Crossref PubMed Scopus (104) Google Scholar Sedation needs in ECMO patients are often safety related, as it reduces the risk of catheter dislodgement or malposition (an important consideration in those centrally cannulated with an open chest), reduces coughing and Valsalva (which may negatively impact venous drainage), and facilitates comfort and ventilator synchrony in those unable to be extubated. The authors describe an interesting case of propofol infusion syndrome developing in a patient who was recently decannulated from VA ECMO.

Kinetic characteristics of propofol-induced inhibition of electron-transfer chain and fatty acid oxidation in human and rodent skeletal and cardiac muscles.

IntroductionPropofol causes a profound inhibition of fatty acid oxidation and reduces spare electron transfer chain capacity in a range of human and rodent cells and tissues–a feature that might be related to the pathogenesis of Propofol Infusion Syndrome. We aimed to explore the mechanism of propofol-induced alteration of bioenergetic pathways by describing its kinetic characteristics.MethodsWe obtained samples of skeletal and cardiac muscle from Wistar rat (n = 3) and human subjects: vastus lateralis from hip surgery patients (n = 11) and myocardium from brain-dead organ donors (n = 10). We assessed mitochondrial functional indices using standard SUIT protocol and high resolution respirometry in fresh tissue homogenates with or without short-term exposure to a range of propofol concentration (2.5–100 μg/ml). After finding concentrations of propofol causing partial inhibition of a particular pathways, we used that concentration to construct kinetic curves by plotting oxygen flux against substrate concentration during its stepwise titration in the presence or absence of propofol. By spectrophotometry we also measured the influence of the same propofol concentrations on the activity of isolated respiratory complexes.ResultsWe found that human muscle and cardiac tissues are more sensitive to propofol-mediated inhibition of bioenergetic pathways than rat’s tissue. In human homogenates, palmitoyl carnitine-driven respiration was inhibited at much lower concentrations of propofol than that required for a reduction of electron transfer chain capacity, suggesting FAO inhibition mechanism different from downstream limitation or carnitine-palmitoyl transferase-1 inhibition. Inhibition of Complex I was characterised by more marked reduction of Vmax, in keeping with non-competitive nature of the inhibition and the pattern was similar to the inhibition of Complex II or electron transfer chain capacity. There was neither inhibition of Complex IV nor increased leak through inner mitochondrial membrane with up to 100 μg/ml of propofol. If measured in isolation by spectrophotometry, propofol 10 μg/ml did not affect the activity of any respiratory complexes.ConclusionIn human skeletal and heart muscle homogenates, propofol in concentrations that are achieved in propofol-anaesthetized patients, causes a direct inhibition of fatty acid oxidation, in addition to inhibiting flux of electrons through inner mitochondrial membrane. The inhibition is more marked in human as compared to rodent tissues.

A Stitch in Time Saved Nine: Early Recognition of Propofol Infusion Syndrome under Anesthesia: A Case Report

AbstractThough propofol infusion syndrome results from a larger dose of infusion over a longer period of time, we observed its development even when it was infused for a shorter period of time. In our patient, it was heralded by progressive acidosis and hyperkalemia. Discontinuation of propofol and simultaneous treatment of hyperkalemia averted any harm to the patient.

Propofol directly induces caspase-1-dependent macrophage pyroptosis through the NLRP3-ASC inflammasome

Propofol infusion syndrome (PRIS) is an uncommon life-threatening complication observed most often in patients receiving high-dose propofol. High-dose propofol treatment with a prolonged duration can damage the immune system. However, the associated molecular mechanisms remain unclear. An increasing number of clinical and experimental observations have demonstrated that tissue-resident macrophages play a critical role in immune regulation during anaesthesia and procedural sedation. Since the inflammatory response is essential for mediating propofol-induced cell death and proinflammatory reactions, we hypothesised that propofol overdose induces macrophage pyroptosis through inflammasomes. Using primary cultured bone marrow-derived macrophages, murine macrophage cell lines (RAW264.7, RAW-asc and J774) and a mouse model, we investigated the role of NLRP3 inflammasome activation and secondary pyroptosis in propofol-induced cell death. We found that high-dose propofol strongly cleaved caspase-1 but not caspase-11 and biosynthesis of downstream interleukin (IL)-1β and IL-18. Inhibition of caspase-1 activity blocks IL-1β production. Moreover, NLRP3 deletion moderately suppressed cleaved caspase-1 as well as the proportion of pyroptosis, while levels of AIM2 were increased, triggering a compensatory pathway to pyroptosis in NLRP3-/- macrophages. Here, we show that propofol-induced mitochondrial reactive oxygen species (ROS) can trigger NLRP3 inflammasome activation. Furthermore, apoptosis-associated speck-like protein (ASC) was found to mediate NLRP3 and AIM2 signalling and contribute to propofol-induced macrophage pyroptosis. In addition, our work shows that propofol-induced apoptotic initiator caspase (caspase-9) subsequently cleaved effector caspases (caspase-3 and 7), indicating that both apoptotic and pyroptotic cellular death pathways are activated after propofol exposure. Our studies suggest, for the first time, that propofol-induced pyroptosis might be restricted to macrophage through an NLRP3/ASC/caspase-1 pathway, which provides potential targets for limiting adverse reactions during propofol application. These findings demonstrate that propofol overdose can trigger cell death through caspase-1 activation and offer new insights into the use of anaesthetic drugs.

Propofol improves colonic but impairs hepatic mitochondrial function in tissue homogenates from healthy rats

Evidence suggests that propofol infusion syndrome (PRIS) is caused by an altered mitochondrial function. The aim of this study was to examine the effects of propofol and the vehicle MCT on mitochondrial function in hepatic and colonic tissue.Mitochondrial oxygen consumption was determined in colon and liver homogenates after incubation with buffer (control), propofol (50, 75, 100, 500 μM) or the carrier substances DMSO and MCT. State 2 (substrate-dependent) and state 3 (ADP-dependent respiration) were assessed. RCI (respiratory control index) - an indicator for coupling between electron transport chain system (ETS) and oxidative phosphorylation (OXPHOS) and ADP/O ratio - a parameter for efficacy of OXPHOS were calculated. Data were presented as % of control.In hepatic mitochondria, 500 μM propofol reduced RCI formulation-independently (propofol/MCT 500 μM: complex I: 66.3 ± 8.7%*, complex II: 75.5 ± 9.2%*; propofol/DMSO 500 μM: complex I: 29.1 ± 8.8%*, complex II: 49.3 ± 15.5%*). 75 μM Propofol/MCT reduced ADP/O for complex I (73.5 ± 27.3%*). DMSO did not affect hepatic mitochondria whereas MCT reduced RCI for complex II (87.2 ± 9.8%*) and ADP/O for complex I (93.7 ± 31.7%*). In colon 50 μM Propofol/MCT increased RCI for complex I and II (complex I: 127.2 ± 10.7%*, complex II: 136.8 ± 33.9%*) and 100 μM Propofol/MCT for complex I (131.4 ± 18.7%*). 500 μM Propofol/DMSO increased ADP/O for complex I (139.4 ± 41.4%*). DMSO did not affect RCI but increased ADP/O for both complexes (complex I: 119.9 ± 25.8%*, complex II: 110.2 ± 14.2%*). MCT increased RCI for complex I (123.0 ± 31.6%*).In hepatic mitochondria propofol uncoupled ETS from OXPHOS formulation-independently and propofol/MCT reduced efficacy of OXPHOS. In colonic mitochondria, propofol/MCT strengthened the coupling and propofol/DMSO enhanced the efficacy of OXPHOS.

Propofol Infusion Syndrome: Efficacy of a Prospective Screening Protocol

Propofol infusion syndrome (PIS) is a potentially lethal complication of propofol marked by rhabdomyolysis, metabolic acidosis, and cardiac arrhythmias or collapse. The objective of this study was to determine the effectiveness of a prospective screening protocol to prevent PIS. All trauma patients admitted who received propofol as a continuous infusion were prospectively screened from November 1, 2013 to December 31, 2015. Variables studied included demographics, injury severity, laboratory values, infusion rates, and mortality. Serum creatine phosphokinase (CPK) and lactate were drawn daily. Propofol was stopped for a positive screen defined as an increase in CPK to greater than 5000 IU/L or lactate greater than 4 mmol/L. Positive and negative cohorts were compared. Two hundred and twenty-five patients met the inclusion criteria and 12 patients (5.3%) had propofol stopped because of elevated CPK. No differences were identified in demographics, transfusions, injury severity, hospital length of stay, or propofol dose. The positive screened group had longer intensive care unit length of stay (20 vs 13 days; P = 0.002) and increased vent days (14.5 vs 10 days; P = 0.008). Max serum osmolality (334 vs 305 mosm/kg; P = 0.049) and max serum CPK (6782 vs 1058 IU/L; P < 0.0001) were higher in the positive cohort. No cases of PIS occurred, and mortality (16.7 vs 15.5%; P = 0.999) was not different between the cohorts. The screening protocol was effective in eliminating PIS. Serial CPK evaluations provided an effective screening tool and serum lactate can be dropped from screening.

163 Propofol Infusion Syndrome: A Life Threatening Condition Blunted by Continuous Renal Replacement Therapy

163 Propofol Infusion Syndrome: A Life Threatening Condition Blunted by Continuous Renal Replacement Therapy

Effects of Propofol on Cellular Bioenergetics in Human Skeletal Muscle Cells.

Propofol may adversely affect the function of mitochondria and the clinical features of propofol infusion syndrome suggest that this may be linked to propofol-related bioenergetic failure. We aimed to assess the effect of therapeutic propofol concentrations on energy metabolism in human skeletal muscle cells. In vitro study on human skeletal muscle cells. University research laboratories. Patients undergoing hip surgery and healthy volunteers. Vastus lateralis biopsies were processed to obtain cultured myotubes, which were exposed to a range of 1-10 μg/mL propofol for 96 hours. Extracellular flux analysis was used to measure global mitochondrial functional indices, glycolysis, fatty acid oxidation, and the functional capacities of individual complexes of electron transfer chain. In addition, we used [1-C]palmitate to measure fatty acid oxidation and spectrophotometry to assess activities of individual electron transfer chain complexes II-IV. Although cell survival and basal oxygen consumption rate were only affected by 10 μg/mL of propofol, concentrations as low as 1 μg/mL reduced spare electron transfer chain capacity. Uncoupling effects of propofol were mild, and not dependent on concentration. There was no inhibition of any respiratory complexes with low dose propofol, but we found a profound inhibition of fatty acid oxidation. Addition of extra fatty acids into the media counteracted the propofol effects on electron transfer chain, suggesting inhibition of fatty acid oxidation as the causative mechanism of reduced spare electron transfer chain capacity. Whether these metabolic in vitro changes are observable in other organs and at the whole-body level remains to be investigated. Concentrations of propofol seen in plasma of sedated patients in ICU cause a significant inhibition of fatty acid oxidation in human skeletal muscle cells and reduce spare capacity of electron transfer chain in mitochondria.

Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner.

The intravenous anesthetic propofol (2,6-diisopropylphenol) has been used for the induction and maintenance of anesthesia and sedation in critical patient care. However, the rare but severe complication propofol infusion syndrome (PRIS) can occur, especially in patients receiving high doses of propofol for prolonged periods. In vivo and in vitro evidence suggests that the propofol toxicity is related to the impaired mitochondrial function. However, underlying molecular mechanisms remain unknown. Therefore, we investigated effects of propofol on cell metabolism and death using a series of established cell lines of various origins, including neurons, myocytes, and trans-mitochondrial cybrids, with defined mitochondrial DNA deficits. We demonstrated that supraclinical concentrations of propofol in not less than 50 μM disturbed the mitochondrial function and induced a metabolic switch, from oxidative phosphorylation to glycolysis, by targeting mitochondrial complexes I, II and III. This disturbance in mitochondrial electron transport caused the generation of reactive oxygen species, resulting in apoptosis. We also found that a predisposition to mitochondrial dysfunction, caused by a genetic mutation or pharmacological suppression of the electron transport chain by biguanides such as metformin and phenformin, promoted propofol-induced caspase activation and cell death induced by clinical relevant concentrations of propofol in not more than 25 μM. With further experiments with appropriate in vivo model, it is possible that the processes to constitute the molecular basis of PRIS are identified.

Effects of L-Carnitine on Propofol-Induced Inhibition of Free Fatty Acid Metabolism in Fasted Rats and &amp;lt;i&amp;gt;in Vitro&amp;lt;/i&amp;gt;

Background: Propofol inhibits fatty acid oxidation and induces mitochondrial deficiency, a possible mechanism involved in propofol infusion syndrome. This study investigated how propofol influences fatty acid, glucose, and amino acid metabolism, as well as whether L-carnitine may improve suppression of free fatty acid metabolism. Methods: Male Sprague-Dawley rats, fasted for 16 hours, were allocated to the following two groups: (Group P; continuous intravenous administration of 10 mg/kg/h propofol; n = 8) and (Group P + C; intravenous administration of 50 mg/kg and then 50 mg/kg/h L-carnitine continuously; n = 8). Concentrations of glucose, free fatty acid (FFA), amino acids, in-sulin, and β-hydroxybutyric acid were measured at the start and then one, two, and three hours after propofol administration. Intrahepatic triglyceride levels were measured at the end of experiments. In vitro experiments comprised measurement of oxygen consumption in human hepatocytes (Hepg2) and investigating dependency on palmitic acid, glucose, and glutamine as fuel during propofol administration, with or without L-carnitine. Results: FFA increased in Group P and gradually decreased in Group P + C. There were significant differences between the two groups (Group P; 331.2 ± 64.5 μM vs. Group P + C; 199 ± 73.6 μM). Glucose decreased in both groups (Group P; 53.8 ±16.6 mg/dL vs. Group P + C; 88 ± 11.3 mg/dL). Amino acid concentrations were higher in Group P + C after experiments; alanine and glutamine increased significantly. β-hydroxybutyric acid increased significantly in Group P + C, and intrahepatic triglyceride decreased in Group P + C. Dependency on fatty acid metabolism significantly decreased with propofol only; addition of L-carnitine prevented these effects. Conclusions: Propofol impaired mitochondrial fatty acid metabolism, which was compensated mainly by a switch to glucose metabolism and partially by amino acid metabolism. Addition of L-carnitine may improve this imbalance of energy metabolism.

Short-Term Propofol Infusion and Associated Effects on Serum Lactate in Pediatric Patients.

This study aimed to determine if short-duration procedural sedation in children with propofol is related to an adverse metabolic stress response measured by serum lactate. Propofol infusion syndrome is associated with high-dose and long-duration infusion. It has not been studied with short-duration, outpatient propofol administration. This was a prospective, longitudinal study that included 50 patients between the ages of 2 and 18 years who were undergoing outpatient procedural sedation with propofol at a pediatric sedation unit. Patients received bolus or bolus and continuous infusion doses of propofol. Serum lactate values were obtained before and after the patients' sedated procedures. The average length of procedure was 40.3 minutes, and the mean dose of propofol per patient was 8.2 mg/kg. The highest measured lactate value was 1.8 mmol/L. The average (SD) preprocedure and postprocedure lactate values were 1.0 (0.3) and 0.7 (0.2) mmol/L, respectively, resulting in an overall significant decrease in lactate of -0.3 (0.3) mmol/L (P < 0.001). There was a significant (P = 0.01) positive relationship between age and postprocedure lactate value, when controlling for the length of the procedure in a multivariable regression. No significant association was found between propofol dosage and length of the procedure with lactate values. In this study, we did not find a significant increase in metabolic stress, measured by serum lactate. Using propofol for short-duration procedural sedation may not carry similar risks for propofol infusion syndrome to those for long-duration/high-dose infusion therapy.

Anaesthetic management of patients with myopathies.

: The anaesthetic management of patients with myopathies is challenging. Considering the low incidence and heterogeneity of these disorders, most anaesthetists are unfamiliar with key symptoms, associated co-morbidities and implications for anaesthesia. The pre-anaesthetic assessment aims at the detection of potentially undiagnosed myopathic patients and, in case of known or suspected muscular disease, on the quantification of disease progression. Ancillary testing (e.g. echocardiography, ECG, lung function testing etc.) is frequently indicated, even at a young patient age. One must differentiate between myopathies associated with malignant hyperthermia (MH) and those that are not, as this has significant impact on preoperative preparation of the anaesthesia workstation and pharmacologic management. Only few myopathies are clearly associated with MH. If a regional anaesthetic technique is not possible, total intravenous anaesthesia is considered the safest approach for most patients with myopathies to avoid anaesthesia-associated rhabdomyolysis. However, the use of propofol in patients with mitochondrial myopathies may be problematic, considering the risk for propofol-infusion syndrome. Succinylcholine is contra-indicated in all patients with myopathies. Following an individual risk/benefit evaluation, the use of volatile anaesthetics in several non-MH-linked myopathies (e.g. myotonic syndromes, mitochondrial myopathies) is considered to be well tolerated. Perioperative monitoring should specifically focus on the cardiopulmonary system, the level of muscular paralysis and core temperature. Given the high risk of respiratory compromise and other postoperative complications, patients need to be closely monitored postoperatively.

Propofol versus thiopental sodium for the treatment of refractory status epilepticus.

This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 6, 2015).Failure to respond to antiepileptic drugs in patients with uncontrolled seizure activity such as refractory status epilepticus (RSE) has led to the use of anaesthetic drugs. Coma is induced with anaesthetic drugs to achieve complete control of seizure activity. Thiopental sodium and propofol are popularly used for this purpose. Both agents have been found to be effective. However, there is a substantial lack of evidence as to which of the two drugs is better in terms of clinical outcomes. To compare the efficacy, adverse effects, and short- and long-term outcomes of refractory status epilepticus (RSE) treated with one of the two anaesthetic agents, thiopental sodium or propofol. We searched the Cochrane Epilepsy Group Specialized Register (16 August 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 16 August 2016), MEDLINE (Ovid, 1946 to 16 August 2016), ClinicalTrials.gov (16 August 2016), and the South Asian Database of Controlled Clinical Trials (16 August 2016). Previously we searched IndMED, but this was not accessible at the time of the latest update. All randomised controlled trials (RCTs) or quasi-RCTs (regardless of blinding) assessing the control of RSE using either thiopental sodium or propofol in patients of any age and gender. Two review authors screened the search results and reviewed the abstracts of relevant and eligible trials before retrieving the full-text publications. One study with a total of 24 participants was available for review. This study was a small, single-blind, multicentre trial studying adults with RSE receiving either propofol or thiopental sodium for the control of seizure activity. This study was terminated early due to recruitment problems. For our primary outcome of total control of seizures after the first course of study drug, there were 6/14 patients versus 2/7 patients in the propofol and thiopental sodium groups, respectively (risk ratio (RR) 1.50, 95% confidence interval (CI) 0.40 to 5.61, low quality evidence). Mortality was seen in 3/14 patients versus 1/7 patients in the propofol and thiopental sodium groups, respectively (RR 1.50, 95% CI 0.19 to 11.93, low quality evidence). Our third primary outcome of length of ICU stay was not reported. For our secondary outcomes of adverse events, infection was seen in 7/14 patients versus 5/7 patients in the propofol and thiopental sodium groups, respectively (RR 0.70; 95% CI 0.35 to 1.41). Hypotension during administration of study drugs and requiring use of vasopressors was seen in 7/14 patients versus 4/7 patients in the propofol and thiopental sodium groups, respectively (RR 0.87; 95% CI 0.38 to 2.00). The other severe complication noted was non-fatal propofol infusion syndrome in one patient. Patients receiving thiopental sodium required more days of mechanical ventilation when compared with patients receiving propofol: (median (range) 17 days (5 to 70 days) with thiopental sodium versus four days (2 to 28 days) with propofol). At three months there was no evidence of a difference between the drugs with respect to outcome measures such as control of seizure activity and functional outcome. Since the last version of this review we have found no new studies.There is a lack of robust, randomised, controlled evidence to clarify the efficacy of propofol and thiopental sodium compared to each other in the treatment of RSE. There is a need for large RCTs for this serious condition.

Paediatric total intravenous anaesthesia

### Key points Total i.v. anaesthesia (TIVA) has been used in adult practice since 1982 with target-controlled infusion (TCI) regimes available since 1989. Conversely, the use of TIVA in paediatric practice is far less routine with a survey finding only 10% of paediatric anaesthetists using it weekly or more.1 It has previously been the subject of a special edition of the journal Pediatric Anaesthesia 2 and the use for paediatric anaesthesia care is an increasing component at international meetings: educational sessions at the European Society for Paediatric Anaesthesia (2013), ASA (2014), and the Society for Intravenous Anaesthesia meeting in November 2015. Despite a number of obstacles (including interindividual pharmacokinetic and pharmacodynamic variability and safety concerns regarding propofol infusion syndrome—PrIS), there are notable benefits to TIVA and particular areas where it is indicated for anaesthetic or surgical reasons, where it may surpass volatile anaesthesia.3 It is a mandatory technique when inhalation agents are contraindicated. ### Advantages and disadvantages For physiological and clinical3 reasons (Table 2), TIVA has increasingly established a significant role in surgery in or around the airway (e.g. ENT) by obtunding airway reflexes (Table 2). The changes in airway reactivity facilitate extubation and result in a minimal incidence of laryngospasm and stridor …

Propofol Is Mitochondrion-Toxic and May Unmask a Mitochondrial Disorder.

There are indications that preexisting mitochondrial disorders or beta-oxidation defects predispose for propofol infusion syndrome. This review aimed at investigating if propofol infusion syndrome occurs exclusively in patients with mitochondrial disorder and if propofol can unmask a mitochondrial disorder. Propofol infusion syndrome has been reported in genetically confirmed mitochondrial disorder patients. In addition, muscle biopsy of patients with propofol infusion syndrome revealed complex IV or complex II deficiency. In animal studies propofol disrupted the electron flow along the respiratory chain and decreased complex I, complex II, and complex III of the respiratory chain. In addition, propofol disrupted the permeability transition pore and reduced the mitochondrial membrane potential. In conclusion, propofol is mitochondrion-toxic and mitochondrial disorder patients should not receive propofol in high dosages over a prolonged period of time. Short-term application of propofol should be safe even in mitochondrial disorder patients. Not only does propofol infusion syndrome occur in mitochondrial disorder patients, but mitochondrial disorder patients are likely at higher risk to develop propofol infusion syndrome. Patients who develop propofol infusion syndrome should be screened for mitochondrial disorder. Propofol infusion syndrome is preventable if risk factors are thoroughly assessed, and if long-term propofol is avoided in patients at risk for propofol infusion syndrome.

In vivo study of hepatic oxidative stress and mitochondrial function in rabbits with severe hypotension after propofol prolonged infusion.

In humans, prolonged sedations with propofol or using high doses have been associated with propofol infusion syndrome. The main objective of this study was to evaluate the effects of prolonged high-dose administration of a specific propofol emulsion (Propofol Lipuro) and an improved lipid formulation (SMOFlipid) in liver mitochondrial bioenergetics and oxidative stress of rabbits, comparatively to a saline control. Twenty-one male New Zealand white rabbits were randomly allocated in three groups that were continuously treated for 20 h. Each group of seven animals received separately: NaCl 0.9 % (saline), SMOFlipid (lipid-based emulsion without propofol) and Lipuro 2 % (propofol lipid emulsion). An intravenous propofol bolus of 20 mg kg−1 was given to the propofol Lipuro group to allow blind orotracheal intubation and mechanical ventilation. Anesthesia was maintained using infusion rates of: 20, 30, 40, 50 and 60 mg kg−1 h−1, according to the clinical scale of anesthetic depth and the index of consciousness values. The SMOFlipid and saline groups received the same infusion rate as the propofol Lipuro group, which were infused during 20 consecutive hours. At the end, the animals were euthanized, livers collected and mitochondria isolated by standard differential centrifugation. Mitochondrial respiration, membrane potential, swelling and oxidative stress were evaluated. Data were processed using one-way ANOVA (p < 0.05). The animals revealed a significant decrease in cardiovascular parameters showing bradycardia and severe hypotension. No statistical differences were observed when using pyruvate as substrate, however, when using succinate as respiratory substrate, significant decrease in ADP-stimulated respiration rate was observed for SMOFlipid group (p = 0.002). Lipid peroxides (p < 0.01) and protein carbonyls (p = 0.01) showed a statistically significant difference between propofol Lipuro and the SMOFlipid groups. These results suggest that lipid-based emulsions can be involved in the regulation of different pathways that ultimately lead to a decrease of state 3 mitochondrial respiration rate. The infusion of propofol Lipuro during prolonged periods, in addition to marked hypotension and hypoperfusion, also showed to have higher anti-oxidant activity and lower impairment of the mitochondrial function comparatively to the improved lipid formulation, SMOFlipid, using the rabbit as animal model.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-2970-2) contains supplementary material, which is available to authorized users.

Propofol Use in Israeli PICUs.

In Israel, the recommendation for the use of propofol is age limited. Furthermore, procedural sedations involving propofol must be performed only by anesthesiologists. Propofol is frequently used in the PICUs in Israel. Questionnaire survey. PICUs in Israel. None. None. Physicians from 13 PICUs (86.6%) responded to the questionnaire. Propofol was used for induction, procedural sedation, and ongoing ICU sedation in 100%, 70%, and 12% of cases, respectively. Eighty-eight percent of the participants limited the duration of propofol infusion to 24 hours at a dose of less than or equal to 4 mg/kg/1 hr, but 40% administered propofol as needed without specifying an upper dose limit. Twenty-five percent encountered adverse effects such as apnea, desaturation, and bradycardia, but only two of the participants suspected propofol infusion syndrome, each in one patient. All the participants agreed to expand the indications for propofol use in the pediatric age group. Ketamine was the drug mostly used instead of propofol (50%), followed by fentanyl (30%), midazolam (30%), and remifentanil (5%). Apart from anesthesiologists, PICU physicians support the use of propofol by physicians who have the technical skills for rapid-sequence intubation and advanced airway management. Off-label use of propofol is an accepted practice in Israeli PICUs. Propofol has a unique profile that makes it an attractive sedative agent in many clinical settings. PICU physicians may want to prescribe it, at least for short periods and at low doses.

Propofol Infusion Syndrome in Refractory Status Epilepticus: A Case Report and Topical Review.

Propofol infusion syndrome (PRIS) is a fatal complication when doses of propofol administration exceed 4 mg/kg/h for more than 48 hours. Propofol overdosage is not uncommon in patients with refractory status epilepticus (RSE). We describe a case of refractory status epilepticus complicated by propofol infusion syndrome and collect from 5 databases all reports of refractory status epilepticus cases that were treated by propofol and developed the syndrome and outline whether refractory status epilepticus treatment with propofol is standardized according to international recommendations, compare it with alternative medications, and discuss how this syndrome can be treated and prevented. A total of 21 patients who developed this syndrome reported arrhythmia in all cases (100%), rhabdomyolysis in 9 cases (42%), lactic acidosis in 13 cases (62%), renal failure in 8 cases (38%), lipemia in 7 cases (33%), and elevated hepatic enzymes in 6 cases (28%). 13 patients died (66%). Propofol is still given in a dosage higher than what is internationally recommended, and new treatment modalities such as renal replacement therapy, blood exchange, and extracorporeal membrane oxygenation seem to be promising. In conclusion, propofol should be carefully titrated, the maximal infusion rate needs to be reassessed, and combination of different sedative agents may be considered.

大血管手術後にプロポフォール注入症候群による横紋筋融解を発症したと考えられる一症例

大血管手術後にプロポフォール注入症候群による横紋筋融解を発症したと考えられる一症例

Propofol infusion syndrome: a structured review of experimental studies and 153 published case reports.

IntroductionPropofol infusion syndrome (PRIS) is a rare, but potentially lethal adverse effect of a commonly used drug. We aimed to review and correlate experimental and clinical data about this syndrome.MethodsWe searched for all case reports published between 1990 and 2014 and for all experimental studies on PRIS pathophysiology. We analysed the relationship between signs of PRIS and the rate and duration of propofol infusion causing PRIS. By multivariate logistic regression we looked at the risk factors for mortality.ResultsKnowledge about PRIS keeps evolving. Compared to earlier case reports in the literature, recently published cases describe older patients developing PRIS at lower doses of propofol, in whom arrhythmia, hypertriglyceridaemia and fever are less frequently seen, with survival more likely. We found that propofol infusion rate and duration, the presence of traumatic brain injury and fever are factors independently associated with mortality in reported cases of PRIS (area under receiver operator curve = 0.85). Similar patterns of exposure to propofol (in terms of time and concentration) are reported in clinical cases and experimental models of PRIS. Cardiac failure and metabolic acidosis occur early in a dose-dependent manner, while arrhythmia, other electrocardiographic changes and rhabdomyolysis appear more frequently after prolonged propofol infusions, irrespective of dose.ConclusionPRIS can develop with propofol infusion <4 mg/kg per hour and its diagnosis may be challenging as some of its typical features (hypertriglyceridaemia, fever, hepatomegaly, heart failure) are often (>95 %) missing and others (arrhythmia, electrocardiographic changes) occur late.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1112-5) contains supplementary material, which is available to authorized users.