Asian Cardiovasc Thorac Ann 2006;14:60-62
© 2006 Asia Publishing EXchange Ltd
A Lethal Complication of Propofol
Hon Chi Suen, MD,
Robert J Haake, MD1,
Victor M Chavez, MD2,
Sultan A Hayat, MD3
Department of Cardiothoracic Surgery
1 Department of Nephrology
2 Department of Pulmonology
3 Department of Cardiology, Memorial Hospital, Belleville, USA
For reprint information contact: Hon Chi Suen, MD Tel: 1 618 233 5722 Fax: 1 618 233 7069 Email: HSUEN{at}earthlink.net, Cardiothoracic Surgery Associates, S.C., 12B Park Place, Swansea, IL 62226, USA
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ABSTRACT
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High-dose propofol infusion for sedation of patients in the intensive care unit can result in rhabdomyolysis, acute renal failure, metabolic acidosis, hyperkalemia, ventricular arrhythmia, hyperthermia, and death. The death of a patient with such complications after lung biopsy is reported. Until a safer dosage range has been determined, propofol infusion at rates higher than 5 mg·kg–1·h–1 should be discouraged for long-term sedation (> 48 h).
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INTRODUCTION
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Propofol is frequently used for the sedation of ventilated patients in the intensive care unit (ICU). Its rapid reversibility accounts for its popularity. However, there are increasing reports of high-dose propofol resulting in rhabdomyolysis, acute renal failure, metabolic acidosis, hyperkalemia, ventricular arrhythmia, hyperthermia, and death.1–10 This complication, recently coined "propofol-infusion syndrome", should be widely disseminated to the medical community to avoid further occurrence.10
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CASE REPORT
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A 31-year-old male heavy smoker presented with an incidental finding of an 8 mm left lower lobe lung nodule that increased to 15 mm in 13 months. He had no known drug allergies. His past medical history included hypertension treated with nifedipine and bupropion. Physical examination was normal. As the pulmonary nodule was non-calcified and had shown progressive enlargement, thoracoscopic wedge resection was performed. The nodule was just underneath the visceral pleura of the left lower lobe, in the major fissure. A frozen section showed atypical alveolar hyperplasia: a premalignant lesion. As the lesion was very close to the resection margin, and that area was close to the pulmonary artery in the fissure, a minithoracotomy was performed to safely obtain optimal resection margins.
The patient was successfully extubated after surgery; however, he developed shortness of breath the next day. Chest radiography showed a new right upper zone infiltrate. He was given a diuretic, and antibiotic treatment was started. However, his breathing continued to deteriorate and chest radiography showed increasing bilateral ground glass opacities. A clinical diagnosis of adult respiratory distress syndrome was made, and the patient was intubated and ventilated. He was transferred to the ICU, and sedated with propofol. Over the next 5 days, the maximum propofol dosages were 7.5, 10, 10, 10, and 13.75 mg·kg–1·h–1. Such high dosages were required to keep the patient calm while being ventilated. It was noticed that his urine was a turbid greenish color but urinalysis showed no hemoglobin and no infection. On postoperative day 6, recovery from respiratory failure was evidenced by decreasing oxygen requirement (FiO2 down to 0.35) and clearing of the bilateral pulmonary infiltrate. Propofol infusion was ceased in anticipation of extubation. Suddenly, severe ST-segment elevation was noticed on the electrocardiogram monitor, and the patient developed ventricular tachycardia and fibrillation. He was resuscitated and cardioverted but he still had an unstable cardiac rhythm in the form of junctional rhythm, widened QRS complex, and bradycardia. Cardiac enzymes showed marked elevation of total creatine kinase (CK) at 62,100 U·L–1 but only minimally elevated CK-MB at 28.2 ng·mL–1. The troponin-T level was normal at < 0.01 ng·mL–1.
Echocardiography revealed normal cardiac function, and emergency cardiac catheterization showed insignificant coronary artery disease. As a result of the unstable cardiac rhythm and bradycardia, a temporary transvenous pacing wire was inserted. Inotropics were started for hypotension. Blood tests indicated severe metabolic acidosis and rapidly developing acute renal failure. The serum lactate level was elevated at 2.2 mEq·L–1. The patient was treated with fluid, diuretic, and sodium bicarbonate. He became anuric and developed a high temperature of 41.7°C. Dantrolene was given for fear that he could be suffering from malignant hyperthermia. Unfortunately, he developed cardiovascular collapse despite inotropic support, and died the next day. The serum chemistry immediately prior to death showed potassium 6.9 mmol·L–1, bicarbonate 14 mmol·L–1, creatinine 3.7 mg·dL–1, calcium 1.13 mmol·L–1, serum glutamic pyruvic transaminase 304 U·L–1, serum glutamic oxaloacetic transaminase 1094 U·L–1, phosphorus 7.76 mmol·L–1, total CK 257,500 U·L–1, CK-MB 156.2 ng·mL–1, and troponin-T 0.09 ng·mL–1. Postmortem examination showed a lipemic appearance of the blood, rhabdomyolysis of the diaphragm, quadriceps, and psoas muscles, cardiomegaly, hepatomegaly with steatosis, and splenomegaly.
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DISCUSSION
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Propofol is a very popular sedative for patients in the ICU, due to its rapid onset of action, prompt reversibility upon cessation, and in general, paucity of side effects. The propofol-infusion syndrome was first reported from the United Kingdom among the pediatric population by Parke and colleagues1 in 1992. They described 5 children aged 4 weeks to 6 years who were mechanically ventilated in the ICU for upper respiratory tract infection and sedated with propofol at maximal rates of infusion of 8 to 13.6 mg·kg–1·h–1. Within a few days, they developed metabolic acidosis, lipemic serum, bradycardia, progressive myocardial failure, and died. High fever (up to 41.3°C) was a feature in some patients. Postmortem examination showed severe myocardial myocytolysis in 1, and fatty changes in the livers of 3 patients. It was concluded that propofol should not be used in the pediatric ICU until the appropriate dose range had been determined. Barclay and colleagues2 reported a 20-month-old girl given 5–10 mg·k–1·h–1 propofol who suffered similar complications, except that she survived after hemofiltration was instituted. This patient also had elevation of serum liver enzymes, CK, and myoglobinuria. Bray reported another lethal case in 1995.3 The first case of a similar complication in North America was reported by Strickland and Murray at the Mayo Clinic in 1995, in a 11-year-old girl who was sedated with 9.4 mg·kg–1·h–1 of propofol after craniotomy for removal of an astrocytoma.4 She died 38 hours later after developing acidosis, hyperkalemia, acute renal failure, junctional rhythm and ventricular arrhythmia; myoglobinuria was also documented in this case. Since then, there have been several other reports of this complication among the pediatric population.5–7
Propofol-infusion syndrome was first reported in adults in 2000. An 18-year-old man died after he was sedated with propofol while on a ventilator for multiple injuries from a motor vehicle accident.8 Two other adult asthmatics (aged 42 and 41 years) died from similar complications.9 Between 1996 and 1999, 7 of 67 adult neurosurgical patients died after being sedated with propofol in a neurosurgical ICU.10 The authors found that this complication was related to the dose of infusion and calculated that the odds ratio for the occurrence was 1.93 (95% CI 1.12 to 3.32, p = 0.018) for every 1 mg·kg–1·h–1 increase in mean propofol dose above 5 mg·kg–1·h–1. They suggested that propofol infusion at rates higher than 5 mg·kg–1·h–1 should be discouraged for long-term sedation in the ICU.
The fact that our patient developed propofol-infusion syndrome after the propofol infusion was stopped is not unique. Kelly11 described another patient in an editorial in The Journal of Neurosurgery who developed propofol-infusion syndrome after propofol therapy was stopped. The mechanism of propofol-infusion syndrome is unknown. It has been postulated to be related to malignant hyperthermia as in one patient, the blood pressure, temperature, and cardiac rhythm improved after dantrolene infusion was commenced.5 However, the data presented was not sufficient for a diagnosis of malignant hyperthermia. In addition, propofol has been used without incident for induction and maintenance of anesthesia in individuals known to be susceptible to malignant hyperthermia.12 McKenzie and colleagues13 studied the safety of propofol as an anesthetic agent in patients susceptible to malignant hyperthermia. They found that, in vitro, human malignant hyperthermia-susceptible muscle did not develop contractures with propofol alone. Propofol also had no effect on contracture development in response to halothane and caffeine. In vivo, they also failed to detect a malignant hyperthermia response following induction or maintenance of anesthesia with propofol. Further, Fruen and colleagues14 found that in contrast to malignant hyperthermia-triggering inhalation anesthetics, propofol does not stimulate malignant hyperthermia-susceptible or normal ryanodine receptor channel activity, even at > 100 times the clinical concentration, explaining why propofol does not trigger malignant hyperthermia in susceptible persons. As a result, we do not believe the mechanism of propofol-infusion syndrome was through induction of malignant hyperthermia.
In a 10-month-old boy who recovered from propofol-infusion syndrome after continuous venovenous hemofiltration was instituted, blood toxicology studies revealed a substance that probably represented a metabolite of propofol, but could not be identified formally.6 The authors also found reduced cytochrome C oxidase activity in the muscle homogenate but not in the cultured fibroblasts harvested from that patient. They postulated that a metabolite of propofol had caused the reduced cytochrome C oxidase activity in the muscle, contributing to the development of propofol-infusion syndrome. More research is needed to elucidate the mechanism behind propofol-infusion syndrome. Two recently published review articles on propofol-infusion syndrome support the notion that the complications seen in our patients were due to high dose propofol over a prolonged period of time.15,16
In summary, high-dose propofol infusion (> 5 mg·kg–1·h–1) for long-term sedation (> 48 h) can result in a propofol-infusion syndrome which consists of rhabdomyolysis, acute renal failure, hyperkalemia, metabolic acidosis, arrhythmia, abnormal liver function, severe myocardial failure, hyperthermia and death. Hemofiltration may be able to reverse this highly lethal complication and should be instituted as soon as this syndrome is diagnosed. The exact mechanism of action is unknown, but it could be related to a metabolite of propofol reducing cytochrome C oxidase activity in the muscle. Until a safer dosage range has been ascertained, propofol infusion at rates higher than 5 mg·kg–1·h–1 should be discouraged for long-term sedation (> 48 h) in the ICU.
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REFERENCES
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- Parke TJ, Stevens JE, Rice AS, Greenaway CL, Bray RJ, Smith PJ, et al. Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. BMJ 1992;305:613–6.[Abstract/Free Full Text]
- Barclay K, Williams AJ, Major E. Propofol infusion in children. BMJ 1992;305:953–4.[Free Full Text]
- Bray RJ. Fatal myocardial failure associated with a propofol infusion in a child. Anaesthesia 1995;50:94.[Medline]
- Strickland RA, Murray MJ. Fatal metabolic acidosis in a pediatric patient receiving an infusion of propofol in the intensive care unit: Is there a relationship? Crit Care Med 1995;23:405–9.[Medline]
- Plotz FB, Waalkens HJ, Verkade HJ, Strengers JL, Knoester H, Mandema JM. Fatal side-effects of continuous propofol infusion in children may be related to malignant hyperthermia. Anaesth Intensive Care 1996;24:724.[Medline]
- Cray SH, Robinson BH, Cox PN. Lactic acidemia and bradyarrhythmia in a child sedated with propofol. Crit Care Med 1998;26:2087–92.[Medline]
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- Kelly DF. Propofol-infusion syndrome. J Neurosurg 2001;95:925–6.[Medline]
- Mathews EL, Dhamee MS. Propofol in patients susceptible to malignant hyperthermia: a case report and review of the literature. J Clin Anesth 1992;4:331–2.[Medline]
- McKenzie AJ, Couchman KG, Pollock N. Propofol is a "safe" anesthetic agent in malignant hyperthermia susceptible patients. Anaesth Intensive Care 1992;20:165–8.[Medline]
- Fruen BR, Mickelson JR, Roghair TJ, Litterer LA, Louis CF. Effects of propofol on Ca2+ regulation by malignant hyperthermia-susceptible muscle membranes. Anesthesiology 1995;82:1274–82.[Medline]
- Okamoto MP, Kawaguchi DL, Amin AN. Evaluation of propofol infusion syndrome in pediatric intensive care. Am J Health Syst Pharm 2003;60:2007–14.[Free Full Text]
- Kang TM. Propofol infusion syndrome in critically ill patients. Ann Pharmacother 2002;36:1453–6.[Abstract]
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ABSTRACT
INTRODUCTION
