Printer Friendly

Propofol infusion syndrome: a case of increasing morbidity with traumatic brain injury.

A previously healthy 16-year-old boy with a closed, severe traumatic brain injury was admitted to a surgical and trauma intensive care unit. He was given a continuous infusion of propofol for sedation and to control intracranial pressure. About 3 days after the propofol infusion was started, metabolic acidosis and rhabdomyolysis developed. Acute renal failure ensued as a result of the rhabdomyolysis. Tachycardia with wide QRS complexes developed without hyperkalemia. The patient died of refractory cardiac dysrhythmia and circulatory collapse approximately 36 hours after the first signs of propofol infusion syndrome appeared. Propofol infusion syndrome is a rare but frequently fatal complication in critically ill children who are given prolonged high-dose infusions of the drug. The syndrome is characterized by severe metabolic acidosis', rhabdomyolysis, acute renal failure, refractory myocardial failure, and hyperlipidemia. Despite several publieations on the subject in the past decade, most cases still seem to remain undetectable. (American Journal of Critical Care. 2007;16:82-85)

**********

Propofol infusion syndrome (PRIS) was first reported by Parke et al (1) in 1992 in children receiving propofol. Recently, a similar syndrome has been reported in adults with the use of high doses of propofol for more than 48 hours. (2-11) Patients with acute neurological injury can be at particular risk for development of this syndrome. High doses of catecholamines and/or steroids in addition to propofol are the essential factors for development of PRIS. (2) Anesthetic doses of propofol often are required in these patients because the aim of propofol infusion can be to control intracranial hypertension rather than simply to maintain adequate sedation. (12,13)

Case Report

A 16-year-old boy suffered a traumatic brain injury while riding a bicycle. A computed tomography scan showed a fracture of the left temporal bone and an epidural hematoma in the left temporoparietal area. The patient did not have any other abnormalities. His neurological condition deteriorated with extensor posturing and a fixed, dilated left pupil. He underwent left frontotemporoparietal craniotomy and evacuation of the epidural hematoma. At the end of the surgical procedure, the patient had equal and reactive pupils. He was brought to the surgical intensive care unit (ICU) in stable condition.

Propofol (Diprivan 1%, AstraZeneca Pharmaceuticals, Mississauga, Canada) infusion was started for sedation at 1.66 mg/kg per hour initially. After surgery, the patient remained comatose, and another computed tomography scan revealed evidence of cerebral edema, contusion of the left temporal lobe, and some residual epidural hematoma on the left side. He was managed conservatively with intermittent infusions of mannitol for elevated intracranial pressure (ICP). Right ventriculostomy was performed at the end of the first day, and the protocol for managing severe head trauma was instituted.

The propofol infusion had to be increased up to a rate of 8.33 mg/kg per hour to keep the ICP less than 20 mm Hg. The infusion was between 6.7 and 8.33 mg/kg per hour and was continued for 35 hours in an attempt to decrease the ICP and keep electroencephalographic activity low. Phenylephrine infusion at the rate of 300 [micro]g/min and crystalloids were required to increase the mean arterial pressure and maintain cerebral perfusion pressure at greater than 70 mm Hg. Despite these measures, the patient's ICP varied between 20 and 40 mm Hg and his score on the Glasgow Coma Scale remained 3. His urine became rusty brown 48 hours after the infusion of propofol was started. We decreased his dosage of propofol to 1.66 mg/kg per hour because of signs of acute renal failure (creatinine 141 [micro]mol/L [1.6 mg/dL] and bicarbonate 16 mmol/L). Baseline creatinine and bicarbonate levels were 71 [micro]mol/L (0.8 mg/dL) and 24 mmol/L, respectively.

Because the patient's ICP remained high, he underwent repeat evacuation of the residual epidural hematoma and marsupialization of the left frontotemporal bone flap. The patient had normal ICP and reactive pupils at the end of the procedure. Creatinine level worsened to 194 [micro]mol/L (2.2 mg/dL) during the surgery with metabolic acidosis (pH 7.1), a bicarbonate level of 10 mmol/L, and elevation of creatine phosphokinase level to 75 062 U/L. Aggressive hydration, a bicarbonate infusion, and systemic administration of antibiotics were started. The propofol was replaced by midazolam because it was thought that PRIS was the cause of the acute renal failure. Phenylephrine was discontinued because the patient's systemic blood pressure had stabilized.

By day 4 of hospitalization, the patient's level of creatine phosphokinase had elevated to 146 266 U/L, the level of aspartate aminotransferase was 3082 U/L, the level of alanine aminotransferase was 1144 U/L, and the level of lactate dehydrogenase was 4687 U/L. The rest of the measurements from the hepatic panel and the levels of lipase and amylase were normal. The level of the MB fraction of creatine phosphokinase was 333.5 U/L and the troponin level was 17.39 ng/mL. Electrocardiography showed left bundle branch block with diffuse changes in the ST segment and the T wave. Metabolic acidosis normalized several hours after discontinuation of the propofol and the start of the bicarbonate infusion. The level of creatine phosphokinase, however, remained high, and anuria developed with a creatinine level of 371 [micro]mol/L (4.2 mg/dL). The electrocardiography showed new onset of diffuse changes in the ST segment and T wave, whereas echocardiography showed normal myocardial function.

On day 5, profound hypotension developed despite aggressive hydration of the patient. Phenylephrine infusion was started; however, hypotension remained refractory to fluid resuscitation and vasopressor therapy. Serum level of bicarbonate was 15.6 mmol/L, potassium level was 4.6 mmol/L, pH was 7.44, and the level of creatine phosphokinase peaked at 251 762 U/L. Wide-complex tachycardia was followed by bradycardia and asystole. The patient was resuscitated according to the Advanced Cardiac Life Support protocol. He died 102 hours after the initial induction of anesthesia.

Discussion

Propofol is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. It is very slightly soluble in water and is therefore marketed as a 1% solution in 10% soybean oil. (14) in addition to the active component, propofol, the formulation also contains glycerol 2.25%, egg lecithin 1.2%, and disodium edetate 0.005%, with sodium hydroxide to adjust pH. (14) Disodium edetate is added to retard the rate of growth of microbial organisms in the event of accidental extrinsic contamination. Bacterial contamination of the drug has been associated with infectious complications. (15)

Propofol was approved by the Food and Drug Administration for sedation of adult patients receiving mechanical ventilation in March 1993; it is a satisfactory and safe agent. (14,16-18) It also is approved for use in inducing and maintaining anesthesia in adults and children more than 3 years old, as well as for sedating adult patients in the ICU. Its rapid onset of action and the short duration of effects are particularly beneficial in patients with head injury who require frequent neurological assessment. (18) The typical dose range for sedation is 0.3 to 4.0 mg/kg per hour, whereas total intravenous anesthesia requires 4 to 12 mg/kg per hour. However, the drug has not been proven safe for sedation in the pediatric ICU' and is not approved for that purpose. (1,14)

Rhabdomyolysis developed on the third day of the patient's propofol infusion, at doses of 6.5 and 8.3 mg/kg per hour, before the second surgery. The muscle destruction occurred despite normal blood pressure, absence of convulsions, and normal serum levels of electrolytes. The patient did not receive depolarizing paralytic agents or antidopaminergic medications. He did not show signs of rigidity, spasm of the masseter muscle, hypertonia, or hyperthermia. Although he had been exposed to isoflurane, an anesthetic agent that predisposes patients to malignant hyperthermia, initial signs of PRIS appeared on the third day following surgery, and the patient did not show all the signs and symptoms of malignant hyperthermia. Severe sepsis can show clinical features similar to those of malignant hyperthermia, but repeat cultures showed no growth, and the patient was receiving systemic antibiotics.

We were impressed by similarities between the signs and symptoms of our patient and those described previously in patients with PRIS. (1-4,6-8) As in previous case reports, echocardiography did not show a structural cardiac lesion, nor did it show poor contractility suggestive of cardiomyopathy. No findings suggestive of an inborn error of metabolism were present. Severe sepsis can show clinical features similar to those we saw, but repeated cultures showed no growth and the patient was receiving systemic antibiotics. Severe acute pancreatitis was ruled out. (19) Elevated levels of alanine aminotransferase and aspartate aminotransferase may suggest hepatic injury, but these elevations along with significantly elevated levels of creatine phosphokinase, lactate dehydrogenase, and a high ratio of aspartate aminotransferase to alanine aminotransferase should indicate the correct diagnosis of rhabdomyolysis. (20)

In a retrospective review, Bray (10) identified the common features of propofol infusion syndrome. The only children who recovered were treated with hemodialysis. Although the mean dose of propofol in these cases was 8.4 mg/kg per hour, doses ranged from 4.5 to 15.2 mg/kg per hour. Similarly, although the mean duration of infusion was 68 hours, the range was 29 to 115 hours.

Early management of critically ill children may not include sufficient energy intake to meet the increase in metabolic demands. Moreover, glycogen reserves are limited. Early use of secondary energy sources (fats) becomes imperative, and such use requires fully competent fatty-acid oxidation in the mitochondria. Most of the energy of fatty acids is extracted through oxidation to produce the reduced forms of high-energy electron carriers nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide ([FADH.sub.2]). From there, the energy is transferred to the electron transport system associated with the mitochondrial inner membrane. Although several studies have suggested that propofol has a direct effect on oxidative phosphorylation, (2,21,22) it remains unclear whether propofol exerts this effect by uncoupling the mitochondrial electron flow (20) or by a protonophoric effect, increasing the proton influx across the inner mitochondrial membrane. (22)

Because beta oxidation of fatty acids occurs in the mitochondrial matrix, long-chain fatty acids must be actively transported into the mitochondria. Propofol inhibits the transport protein for long-chain fatty acids. (8) The resultant lack of substrates and the buildup of intermediaries in the metabolism of long-chain, medium-chain, and short-chain fatty acids might account for the clinical features. The diversion of metabolism to fat substrates might cause PRIS in children because of the susceptibility of mitochondrial respiratory function to blockade by propofol. This effect of propofol is dependent on dose and duration. Adults have larger carbohydrate stores and require lower doses of propofol for sedation than do children, which might account for the rarity of this syndrome in adults. (8)

As previously noted, (2) many patients with PRIS received catecholamines, (4,7-9) which increase cardiac output and concurrently reduce mean arterial concentration of propofol by increasing first-pass dilution and clearance of the drug. (23) This reduced concentration of propofol is associated with decreased propofol anesthetic properties and reversal of anesthesia. Propofol antagonism of [beta]-adrenergic receptors may depress cardiac function and increase catecholamine requirements. (24) The negative inotropic effect of propofol creates a vicious cycle in which propofol and catecholamines drive each other in a progressive myocardial impairment. In addition, cardiac failure and metabolic acidosis can be aggravated or precipitated by the frequent use of vasopressors needed to maintain an acceptable cerebral perfusion pressure.

Stress-related hormones such as epinephrine and glucagon stimulate activity of lipase, which releases fatty acids from triglycerides. We speculate that exogenous administration of high doses of catecholamines might cause huge release of fatty acids, which travel to muscles, where they are oxidized to provide energy through the mitochondrial beta-oxidation pathway. Therefore, catecholamines are apt to aggravate propofol inhibition of fatty acid metabolism and cause prompt and irreversible muscle damage with concurrent and lethal damage of cardiac muscle.

The potential genetic factors that may account for PRIS seem similar to those associated with mitochondrial myopathies. Susceptible patients generally remain well until they are in a stressful situation, which is exacerbated by administration of exogenous catecholamines. Their catabolic demands are colossally increased while beta oxidation of fatty acids and oxidative phosphorylation are compromised by the presence of propofol in the mitochondria. It is unknown whether all patients receiving long-term infusions of propofol have measurable subclinical chemical abnormalities. (25)

FINANCIAL DISCLOSURES

None reported.

Ilya Sabsovich, MD, MSc, Zia Rehman, MD, Jose Yunen, MD, and George Coritsidis, MD. From Surgical and Trauma Intensive Care Unit, Elmhurst Hospital Center, and Department of Surgery, Mount Sinai School of Medicine, New York, NY

Corresponding author; Jose Yunen, MD, Montefiore Medical Center/Albert Einstein School of Medicine, 111 East 210th St, Bronx, NY 10467-2490 (e-mail: jyunen@montefiore.org).

To purchase reprints, contact The InnoVision Group, 101 Columbia, Aliso Viejo, CA 92656 Phone, (800) 809-2273 or (949) 362-2050 (ext 532); fax, (949) 362-2049; e-mail, reprints@aacn.org.

REFERENCES

(1.) Parke TJ, Stevens JE, Rice AS, et al. Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. BMJ. 1992;305:613-616.

(2.) Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med. 2003;29:1417-1425.

(3.) Marinella MA. Lactic acidosis associated with propofol [letter]. Chest. 1996;109:292.

(4.) Perrier ND, Baerga-Varela Y, Murray MJ. Death related to propofol use in an adult patient. Crit Care Med. 2000;28:3071-3074.

(5.) Freidman JA, Manno E, Fulgham JR. Propofol. J Neurosurg. 2002;96:1161-1162.

(6.) Cray SH, Robinson BH, Cox PN. Lactic acidosis and bradyarrhythmia in a child sedated with propofol. Crit Care Meal 1998;26:2087-2092.

(7.) Hanna JP, Ramundo ML. Rhabdomyolysis and hypoxia associated with prolonged propofol infusion in children. Neurology. 1998;50:301-303.

(8.) Stelow EB, Johari VP, Smith SA, Crosson JT, Apple FS. Propofol-associated rhabdomyolysis with cardiac involvement in adults: chemical and anatomic findings. Clin Chem. 2000;46:577-581.

(9.) Cremer OL, Moons KG, Bouman EA, Kruijswijk JE, de Smet AM, Kalkman CJ. Long term propofol infusion and cardiac failure in adult headinjured patients. Lancet. 2001;357:117-118.

(10.) Bray RJ. Propofol infusion syndrome in children. Paediatr Anaesth. 1998;8:491-499.

(11).Eriksen J, Povey HM. A case of suspected non-ncurosurgical adult fatal propofol infusion syndrome. Aeta Anaesthesiol Scand. 2006;50:117-119.

(12.) Oertel M, Kelly DF, Lee JH, et al. Efficacy of hyperventilation blood pressure elevation and metabolic suppression therapy in controlling intracranial pressure after head injury. J Neurosurg. 2002;97:1045-1053.

(13.) Matta B, Menon D. Severe head injury in the United Kingdom and Ireland: a survey of practice and implications for management. Crit Care Med. 1996;24:1743-1748.

(14.) Diprivan (propofol) product monograph. Mississauga, Canada: Zeneca Pharma Inc.

(15.) Bennett SN, McNeil MM, Bland LA, ct al. Postoperative infections traced to contamination of an intravenous anesthetic, propofol. N Engl J Med. 1995;333:147-154.

(16.) Grounds RM, Lalor JM, Lumley J, Royston D, Morgan M. Propofol infusion for sedation in the intensive care unit: preliminary report. BMJ. 1987;294:397-400.

(17.) Aitkenhead AR, Pepperman ML, Willats SM, et al. Comparison of propofol and midazolam for sedation in critically ill patients. Lancet. 1989;2(8665):704-709.

(18.) McKeage K, Perry CM. Propofol: a review of its use in intensive care sedation of adults. CNS Drugs. 2003;17:235-272.

(19.) Leisure GS, O'Flaherty J, Green L, Jones DR. Propofol and postoperative pancreatitis. Anesthesiology. 1996;84:224-227.

(20.) Nathwani RA, Pals S, Reynolds TB, Kaplowitz N. Serum alanine aminotransferase in skeletal muscle diseases. Hepatology. 2005;41:380-382.

(21.) Branca D, Roberti MS, Vincenti E, Scutari G. Uncoupling effect of the general anesthetic 2,6-diisopropylphenol in isolated rat liver mitochondria. Arch Biochem Biopto's. 1991;290:517-521.

(22.) Schenkman KA, Yan SY. Propofol impairment of mitochondrial respiration in isolated perfused guinea pig hearts determined by reflectance spectrometry. Crit Care Med. 2000;28:172-177.

(23.) Myburgh JA, Upton RA, Grant C, Martinez A. Epinephrine, norepinephrine and dopamine infusions decrease propofol concentrations during continuous propofol infusion in an ovine model. Intensive Care Med. 2001:27:276-282.

(24.) Zhou W, Fontenot HJ, Wang SN, Kennedy RH. Propofol-induced alterations in myocardial beta-adrenoceptor binding and responsiveness. Anesth Analg. 1999;89:604-608.

(25.) Haase R, Sauer H, Eichler G. Lactic acidosis following short-term propofol infusion may be an early warning of propofol infusion syndrome. J Neurosurg Anesthesiol. 2005;17:122-123.
COPYRIGHT 2007 American Association of Critical-Care Nurses
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2007, Gale Group. All rights reserved. Gale Group is a Thomson Corporation Company.

Article Details
Printer friendly Cite/link Email Feedback
Author:Coritsidis, George
Publication:American Journal of Critical Care
Date:Jan 1, 2007
Words:2760
Previous Article:Psychosocial issues for patients with ventricular assist devices: a qualitative pilot study.
Next Article:Healing environments and the limits of empirical evidence.
Topics:


Related Articles
Promoting self-direction: consumer involvement in regional RSA brain injury centers.
A model systems approach to the rehabilitation of people with traumatic brain injury.
Mild traumatic brain injury: when symptoms linger.
Proving cognitive and behavioral brain injuries.
Refuting common defenses in traumatic brain injury cases.
Rehabilitation Considerations Following Mild Traumatic Brain Injury.
Kluver-Bucy syndrome after minor brain injury. (Editorials).
High-tech proof in brain injury cases: new developments in biomechanical animation and brain imaging can help jurors 'see' the damage caused by head...
TBI: vets, VA face new war's hallmark injury.
A clinical report of adverse health effects due to bed sharing in two children with spinal cord injury and traumatic brain injury.

Terms of use | Copyright © 2017 Farlex, Inc. | Feedback | For webmasters