Propofol Infusion Syndrome Research Articles

Lipid metabolism disturbances and AMPK activation in prolonged propofol-sedated rabbits under mechanical ventilation

To explore the mechanisms underlying the propofol infusion syndrome (PRIS), a potentially fatal complication during prolonged propofol infusion. Male rabbits under mechanical ventilation through endotracheal intubation were divided into 3 groups (n=6 for each) that were sedated with 1% propofol (Group P), isoflurane (Group I) or isoflurane while receiving 10% intralipid (Group II), respectively. Blood biochemical parameters were collected at 0, 6, 12, 18, 24 and 30-36 h after the initiation of treatments. The hearts were removed out immediately after the experiments, and the level of tumor necrosis factor (TNF)-α in the hearts were studied using immunohistochemistry. AMP-activated protein kinase (AMPK) and phospho-AMPK in the hearts were assessed using Western blotting. The mortality rate was 50% in Group P, and 0% in Groups I and II. The serum lipids and liver function indices in Group P were significantly increased, but moderately increased in Group II. Significant decreases in these indices were found in Groups I. All the groups showed dramatically increased release of creatine kinase (CK). Intense positive staining of TNF-α was found in all the heart samples in Group P, but only weak and neglectful staining was found in the hearts from Group II and Group I, respectively. AMPK phosphorylation was significantly increased in the hearts of Group P. Continuous infusion of large dose of propofol in rabbits undergoing prolonged mechanical ventilation causes hyperlipidemia, liver dysfunction, increased CK levels, AMPK activation and myocardial injury. The imbalance between energy demand and utilization may contribute to PRIS.

Behavioral and toxicological effects of propofol

There is increasing concern about abuse of propofol, a widely-used surgical anesthetic and sedative that is currently not a controlled substance. The purpose of this study was to establish a rat model of the psychoactive effect of subanesthetic doses of propofol that could be useful for confirming abuse liability and for studying mechanisms of propofol abuse. Sprague-Dawley rats were trained to discriminate propofol (10 mg/kg, intraperitoneally) from vehicle (2% methylcellulose). Carisoprodol (100 mg/kg), chlordiazepoxide (10 mg/kg), and dizocilpine (0.1 mg/kg) were tested for substitution for the discriminative-stimulus effects of propofol (10 mg/kg), whereas pentylenetetrazol (10 mg/kg) was tested for antagonism of the discriminative-stimulus effects. Propofol (10 mg/kg) was tested for substitution in rats trained to discriminate carisoprodol from vehicle. Carisoprodol produced 59% propofol-appropriate responding, chlordiazepoxide produced 65% propofol-appropriate responding, and dizocilpine produced 34% propofol-appropriate responding. Pentylenetetrazol decreased propofol-appropriate responding to 41%. Propofol produced 52% carisoprodol-appropriate responding. Mortality rate during training of propofol (10 mg/kg) was 38%. Postmortem examination revealed cardiovascular abnormalities similar to those observed in propofol-infusion syndrome in humans. The results demonstrate that propofol can be trained as a discriminative stimulus. Its discriminative-stimulus effects were more similar to compounds promoting γ-aminobutyric acid-A receptor activity than to a compound inhibiting N-methyl-d-aspartate receptor activity. As propofol has discriminative-stimulus effects similar to known drugs of abuse, and occasions a high-mortality rate, its potential for continued abuse is of particular concern.

Halogenated Anesthetics and Intensive Care Unit Sedation: A Note of Caution

We appreciate Dr. Mychaskiw's cautioning words regarding possible negative effects of volatile anesthetics for intensive care unit (ICU) sedation. Perhaps they reflect the apprehension that many anesthetists/intensivists feel regarding the growing body of evidence revealing possible injurious effects of sedatives and anesthetics on the central nervous system. Because these medications are indispensable in modern medicine, we seem to be “damned if we do, damned if we don't.” This may be particularly true in our most vulnerable patients: the very young and very old. We hope to further the discussion with some additional reflections here.The main purpose of our article was to highlight the clinical impact of sedation strategies on patient outcomes.1This specific case using isoflurane illustrates that volatile anesthetics may be a therapeutic option for deep sedation of intubated ICU patients. Although we grant that isoflurane is relatively unproven for this indication, we would tend not to agree with the assertion that “the use of benzodiazepines, narcotics and intravenous hypnotics, like propofol, for ICU sedation is well-established with an acceptable safety profile.” The cited and worrisome recent findings of neurodegenerative and apoptotic effects have been found to apply as well to barbiturates, ketamine, benzodiazepines, and propofol.2–4To our knowledge, only the α-2-agonists have not been found to cause these changes. Dr. Mychaskiw rightly wonders what significance these animal findings bear on clinical medicine, but at least in the pediatric setting Wilder et al. have revealed in a large cohort that relatively modest exposure to general anesthesia before the age of 4 yr was related to increased risk of learning disability later in life.5Unfortunately, at our current level of knowledge there is nothing to say that risk is lessened by using one class of drug over another or that inhaled anesthetics are more harmful than intravenous.In fact, increasing evidence points toward additional clinically relevant problems with commonly used sedative drugs. Benzodiazepines, among the most common drugs in our arsenal, contribute to the development of delirium after ICU sedation.6Delirium is associated with increased hospital length of stay and with increased mortality.7Propofol, common in adult ICUs despite the above mentioned concerns, is not recommended for long-term sedation in children or in higher infusion rates for adults because of the risk of propofol infusion syndrome.8Moreover, long-term use of propofol may contribute to withdrawal.9Several studies of volatile anesthetics for sedation purposes in humans—with clinically relevant endpoints—have shown promising results. Rapid pulmonary excretion and limited metabolism of all the modern agents are intrinsically attractive characteristics. Wake-up times are shorter and more predictable than with intravenous sedatives, as is time to cooperation.10,11There may be beneficial cardiac effects of volatile anesthetic sedation.12The memory panorama from the ICU stay, an important patient-related outcome,13also appears to be favorable compared with that of midazolam.14Simply put, we need more evidence and knowledge about the advantages and risks of the sedative drugs that we use, be they benzodiazepines and propofol or volatile anesthetics. We advocate for additional evaluation of volatile anesthetics as a promising option for long-term sedation in ventilator-dependent ICU patients. In any case, we can not afford to idly administer routine cocktails of sedatives unaware of the risks we may be taking. Every patient deserves a carefully considered sedation strategy.*Karolinska University Hospital, Stockholm, Sweden. peter.sackey@karolinska.se

Treatment strategies for refractory status epilepticus

Status epilepticus is one of the most common emergencies in neurology, and every third patient does not respond to adequate first-line treatment. Refractory status epilepticus may be associated with increased morbidity and mortality, and new treatment options are urgently required. This review critically discusses recently published data regarding the role of 'new' antiepileptic drugs, the efficacy and safety of anesthetic agents, and the overall clinical outcome that is an integral part of treatment decisions. In complex partial status epilepticus, levetiracetam may be administered after failure of first-line and/or second-line agents. Lacosamide may be an interesting new adjunct, but reliable data are pending. In the treatment of refractory generalized convulsive status epilepticus, propofol seems to be as efficient as barbiturates. The latter are associated with prolonged ventilation times due to redistribution kinetics, whereas the former bears the risk of propofol infusion syndrome if administered continuously. Even after prolonged treatment with anesthetics over weeks, survival with satisfactory functional outcome is possible. Unambiguous recommendations regarding treatment strategies for refractory status epilepticus are limited by a lack of reliable data. Therefore, randomized controlled trials or at least prospective observational studies based on strict protocols incorporating long-term outcome data are urgently required.

216 Rare and Fatal Cause of Massive Rhabdomyolysis and Kidney Injury: Propofol Infusion Syndrome

216 Rare and Fatal Cause of Massive Rhabdomyolysis and Kidney Injury: Propofol Infusion Syndrome

Analytic Reviews: Propofol Infusion Syndrome in the ICU

Propofol is an alkylphenol derivative named 2, 6, diisopropylphenol and is a potent intravenous short-acting hypnotic agent. It is commonly used as sedation, as well as an anesthetic agent in both pediatric and adult patient populations. There have been numerous case reports describing a constellation of findings including metabolic derangements and organ system failures known collectively as propofol infusion syndrome (PRIS). Although there is a high mortality associated with PRIS, the precise mechanism of action has yet to be determined. The best preventive measure for this syndrome is awareness and avoidance of clinical scenarios associated with development of PRIS. There is no established treatment for PRIS; care is primarily supportive in nature and may include the full array of advanced cardiopulmonary support, including extracorporeal membrane oxygenation (ECMO). This article reviews the reported cases of PRIS and describes the current understanding of the underlying pathophysiology and treatment options.

Propofol treatment in adult refractory status epilepticus. Mortality risk and outcome

To retrospectively study effect and safety of propofol treatment in adult refractory generalised tonic clonic status epilepticus. Therapy refractory status epilepticus (RSE) is defined as a status that does not respond to 1st or 2nd line of treatment. Different anaesthetics are used to treat RSE, but no definite recommendations or priority has been scientifically established. Propofol has been the preferred agent for treating RSE at our intensive care unit since 2001. We present treatment mode, effect and outcome in 18 patients with 27 consecutive cases of RSE treated 2001-2010. Fifteen patients had 1 episode, and 3 patients had 2, 3 and 7 episodes, respectively. Mortality risk for each case of RSE was estimated using the Simplified Acute Physiology (SAPS) II score. Probable trigger factors were identified for 22 of the 27 RSE episodes. In 16/27 episodes seizures lasted more than 2h before anaesthesia was induced. A mean total dose of 7885.1mg was given for a mean duration of 34.4h. Break through seizures occurred in 8 of the patients and in 2 episodes of RSE in one patient, i.e. 9/27 episodes of RSE. Propofol was changed to another anaesthetic agent in 2 episodes. Complications occurred in 17 of the RSE episodes, the most frequent was pneumonia (9/27). One patient had complications that could be related to a propofol infusion syndrome (PRIS). In 8 of 18 patients and 14/27 RSE episodes no sequelae occurred. Seven episodes were associated with mild and 4 with severe sequelae and 2 of the patients died. We found a trend only for SAPS II score being higher in patients with more severe sequelae. Our data support propofol as an effective anaesthetic for treating RSE. Close clinical observation for possible PRIS is warranted if propofol is given for more than 48h.

Neurologic Complications of Anesthesia

Neurologic complications after anesthesia are relatively uncommon but occasionally severe. Intraoperative intracranial hypertension in patients with brain masses, delayed arousal, and postoperative delirium and cognitive dysfunction are among the main complications of general anesthesia. Neuropathy and transient gluteal and leg pain are the most frequent complications of regional blockade. Seizures are infrequent with both anesthesia modalities. Patients with primary neurologic disorders, such as neurodegenerative or neuromuscular conditions, can be at risk for specific complications, and the anesthesia plan must be cautiously adjusted in these patients. In the neurointensive care unit, the complications from large doses of anesthetic agents used for suppression of seizures or control of intracranial pressure are different from those seen perioperatively. Propofol infusion syndrome can be life-threatening when administered for those indications.

Propofol infusion syndrome in a super morbidly obese patient (BMI = 75)

Propofol infusion syndrome (PRIS) is a rare but often fatal complication as a result of large doses of propofol infusion (4–5 mg/kg/hr) for a prolonged period (>48 h). It has been reported in both children and adults. Besides large doses of propofol infusion, the risk factors include young age, acute neurological injury, low carbohydrate and high fat intake, exogenous administration of corticosteroid and catecholamine, critical illness, and inborn errors of mitochondrial fatty acid oxidation. PRIS manifestation include presence of metabolic acidosis with a base deficit of more than 10 mmol/l at least on one occasion, rhabdomyolysis or myoglobinuria, acute renal failure, sudden onset of bradycardia resistant to treatment, myocardial failure, and lipemic plasma. The pathophysiology of PRIS may be either direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism mediated by propofol. We report a case of supermorbidly obese patient who received propofol infusion by total body weight instead of actual body weight and developed PRIS.

Accidental five fold overdose of propofol for induction in a 38-days-old infant undergoing emergency bilateral inguinal hernia repair

The induction dose of propofol is higher in younger children (2.9 mg/kg for infants younger than 2 years) than in older children (2.2 mg/kg for children 6-12 years of age). A modest reduction in systolic blood pressure often accompanies bolus administration. The major concern with propofol is the potential for propofol infusion syndrome (lactic acidosis, rhabdomyolysis, cardiac and renal failure), which is generally associated with high-dose infusion for an extended period. We report a 38-days-old male infant underwent emergency bilateral inguinal hernia repair who accidentally received a five-fold dose of propofol for induction of general anesthesia.

Propofol Infusion Syndrome with Severe and Dynamic Brugada Electrocardiogram but Benign Clinical Outcome

Propofol Infusion Syndrome with Severe and Dynamic Brugada Electrocardiogram but Benign Clinical Outcome

Lactate-to-Pyruvate Ratio as a Marker of Propofol Infusion Syndrome After Subarachnoid Hemorrhage

Propofol infusion syndrome (PRIS) is a rare but frequently fatal condition. It is characterized by cardiovascular collapse and metabolic derangement due to propofol exposure. The pathophysiology of PRIS is poorly understood, and its study has previously been limited to animal models and clinical observations. We present the first in vivo brain biochemical data in a patient with PRIS. We report the case of a 37-year-old woman with PRIS following aneurysmal subarachnoid hemorrhage who was monitored by cerebral microdialysis (CMD). A CMD catheter was inserted into the brain and provided near real-time monitoring of brain energy-related metabolites, including lactate and pyruvate, during the time period surrounding the diagnosis of PRIS. We recorded propofol exposure, clinical manifestations, and relevant laboratory measurements. CMD revealed a temporal association between propofol exposure and the cerebral lactate-to-pyruvate ratio (LPR). The LPR increased linearly after propofol was restarted following an off period, and the LPR decreased linearly after propofol was discontinued. Serum lactate correlated with clinical worsening after the onset of PRIS, whereas cerebral LPR correlated with propofol exposure. Cerebral LPR may be a sensitive marker of PRIS. Increases in LPR following propofol exposure should alert clinicians to the possibility of PRIS and might prompt early discontinuation of propofol thereby avoiding fatal complications.

Reversible Lactic Acidosis and Electrocardiographic Changes in a Neurosurgical Patient During Propofol Anesthesia

Reversible Lactic Acidosis and Electrocardiographic Changes in a Neurosurgical Patient During Propofol Anesthesia

Propofol as a bridge to extubation for high-risk children with congenital cardiac disease

Children with congenital cardiac defects may have associated chromosomal anomalies, airway compromise, and/or pulmonary hypertension, which can pose challenges to adequate sedation, weaning from mechanical ventilation, and successful extubation. Propofol, with its unique properties, may be used as a bridge to extubation in certain cardiac populations. We retrospectively reviewed 0-17-year-old patients admitted to the Cardiac Intensive Care Unit between January, 2007 and September, 2008, who required mechanical ventilation and received a continuous infusion of propofol as a bridge to extubation. Medical charts were reviewed for demographics, associated comorbidities, as well as additional sedation medications and haemodynamic trends including vital signs and vasopressor support during the peri-infusion period. Successful extubation was defined as no re-intubation required for respiratory failure within 48 hours. Outcomes measured were successful extubation, evidence for propofol infusion syndrome, haemodynamic stability, and fluid and inotropic requirements. We included 11 patients for a total of 12 episodes. Propofol dose ranged from 0.4 to 5.6 milligram per kilogram per hour with an average infusion duration of 7 hours. All patients were successfully extubated, and none demonstrated worsening metabolic acidosis suggestive of the propofol infusion syndrome. All patients remained haemodynamically stable during the infusion with average heart rates and blood pressures remaining within age-appropriate ranges. One patient received additional fluid but no increase in vasopressors was needed. This study suggests that propofol infusions may allow for successful extubation in a certain population of children with congenital cardiac disease. Further studies are required to confirm whether propofol is an efficient and safe alternative in this setting.

Fulminant Hepatic Failure Complicated by Propofol Infusion Syndrome

Fulminant Hepatic Failure Complicated by Propofol Infusion Syndrome

A Randomized Trial for the Treatment of Refractory Status Epilepticus

Refractory status epilepticus (RSE) has a mortality of 16-39%; coma induction is advocated for its management, but no comparative study has been performed. We aimed to assess the effectiveness (RSE control, adverse events) of the first course of propofol versus barbiturates in the treatment of RSE. In this randomized, single blind, multi-center trial studying adults with RSE not due to cerebral anoxia, medications were titrated toward EEG burst-suppression for 36-48 h and then progressively weaned. The primary endpoint was the proportion of patients with RSE controlled after a first course of study medication; secondary endpoints included tolerability measures. The trial was terminated after 3 years, with only 24 patients recruited of the 150 needed; 14 subjects received propofol, 9 barbiturates. The primary endpoint was reached in 43% in the propofol versus 22% in the barbiturates arm (P = 0.40). Mortality (43 vs. 34%; P = 1.00) and return to baseline clinical conditions at 3 months (36 vs. 44%; P = 1.00) were similar. While infections and arterial hypotension did not differ between groups, barbiturate use was associated with a significantly longer mechanical ventilation (P = 0.03). A non-fatal propofol infusion syndrome was detected in one patient, while one subject died of bowel ischemia after barbiturates. Although undersampled, this trial shows significantly longer mechanical ventilation with barbiturates and the occurrence of severe treatment-related complications in both arms. We describe practical issues necessary for the success of future studies needed to improve the current unsatisfactory state of evidence.

Emergence delirium after propofol anaesthesia

Dear Editor: Propofol is a commonly used anaesthetic agent. Recent findings suggest that low-dose propofol sedation reduces the risk of delirium in the elderly [1]. In children, emergence agitation was reported [2], even with convulsions, ataxia and hallucinations [3]. In addition to the rare complication of a propofol infusion syndrome, sexual hallucinations [4, 5], epileptic seizures and seizure-like phenomena [6, 7] were reported. We report a severe delirious and aggressive state during emergence after propofol anaesthesia. A 20-year-old female patient (175 cm, 75 kg) was passed to a gastroenterological service for nausea and vomiting. She had been suffering from Crohn’s disease, continuously treated with prednisolone 5 mg and azathioprine 150 mg for 3 years, adalimumab (TNF-α antagonist) for 3 months and pantoprazole and tropisetron for 2 weeks. The past medical history was negative for drug abuse, alcohol or nicotine abuse, metabolic diseases, allergic reactions or treatment with psychiatric drugs. EEG was normal and there was no history of epilepsy or neurological disorder in the patient or among her relatives. Cranial and abdominal MRI were regular. She had already undergone two gastroscopies under propofol anaesthesia without adverse effects. Anaesthesia was prepared with propofol (1%, 100 mg bolus, 180 mg continuously over 15 min). Sedation was delayed with minimal restlessness. Continuous monitoring showed no relevant hypotonia or hypoxia. During waking, restlessness increased, but the patient was not responsive, and her eyes were closed. She did not recognise her mother, who was present during the gastroscopy, and refused body contact by beating, scratching, biting and crying not to touch her. Here agitation increased and bed rails had to be attached. The patient received prednisolone 125 mg for a coughing fit and midazolam 2 mg for sedation, but without improvement. An epileptic seizure was deemed unlikely due to the intentioned and coordinated movement pattern and the lack of response to midazolam. Finally, after 25 min she received haloperidol 5 mg, which caused a decline of the agitation and aggression within a few minutes, followed by 1 h of sleep. After waking, she was fully orientated and reported dreamless sleep for the period of anaesthesia and complete amnesia regarding the delirious state. Muscle or bone pain or muscle rigidity did not appear. The patient was observed on the normal ward until the following day. Reports of severe or prolonged agitation are sparse [8]; other findings represent the adverse effects of sexual hallucinations or seizure-like phenomena (SLP). The latter is characterised by uncoordinated and tonic–clonic muscle movements [6, 7], opisthotonus and athetoid neck and limb movements [9]. Signs of SLP or grand mal epilepsy did not occur in our patient; rather, she showed intentional, coordinated movements, a purposeful defence reaction and anxiety, whilst being unresponsive. Complete amnesia and a dreamless sleep suggest the absence of sexual hallucinations [4, 5], despite there probably being delusions and anxiety. The sudden decline of all symptoms after haloperidol medication supports the diagnosis of delirium. It has to be discussed whether the new medication was responsible for the incident. Adalimumab may cause mood U. Palm (*) :M. Lieb Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University, Nussbaumstrasse 7, 80336 Munich, Germany e-mail: ulrich.palm@med.uni-muenchen.de

Propofol overdose in a preterm baby: may propofol infusion syndrome arise in two hours?

Propofol overdose in a preterm baby: may propofol infusion syndrome arise in two hours?

Propofol Infusion Syndrome

A review of the history, incidence, presentation, pathophysiology, and treatment of propofol infusion syndrome.

Multiple organ failure after an overdose of less than 0.4 mg/kg of colchicine: role of coingestants and drugs during intensive care management

Introduction. Although the ingestion of a dose of colchicine lower than 0.5 mg/kg is usually complicated by a mortality rate less than 5%, severe complications may be associated with drug–drug interactions in case of overdose combining other drugs. Case report. A 33-year-old previously healthy woman was admitted after a drug overdose combining colchicine, atorvastatin, ibuprofen, diclofenac, and furosemide. The amount of colchicine ingested was exactly 20 mg, corresponding to 0.33 mg/kg. Despite this relatively low dose, she presented the clinical course that is usually seen with much larger colchicine ingestions. She developed acute renal and liver failure, acute lung injury, pancytopenia with sepsis, rhabdomyolysis, hypertriglyceridemia, and ultimately died on Day 14 from hyperammonemic encephalopathy, refractory hypoxemia, and cardiac arrhythmias. Discussion. Serious drug–drug interactions may have complicated colchicine poisoning. In particular, atorvastatin, an inhibitor of P-glycoprotein and cytochrome P450 3A4, was likely responsible for an increased severity of rhabdomyolysis. In addition, propofol used for sedation during mechanical ventilation may have induced symptoms consistent with “propofol infusion syndrome,” with further muscular injury and hypertriglyceridemia. The mechanism of death was unusual and similar to Reye's syndrome.