PROPOFOL became available for commercial use in the current lipid emulsion formulation 20 yr ago.1Its superior properties in terms of anesthetic recovery were quickly recognized, and its use became widespread.2The drug has a remarkable safety record in anesthetic practice when used as an intravenous induction agent or for intravenous maintenance of anesthesia. The widespread use of propofol for short-term (< 24 h) sedation in intensive care units (ICUs) has led to an increased interest in long-term use (> 72 h).3The use of propofol in this context, particularly at high doses (e.g. , for cerebral metabolic suppression in brain trauma), has been associated with a range of toxic reactions, including metabolic acidosis, rhabdomyolysis, myocardial failure and death.4–6The role of propofol in these reactions has been debated vigorously in the literature.7–9We present the case of a severe nonfatal metabolic acidosis related to short-term propofol administration during anesthesia in an adult patient.

A 64-yr-old, 71-kg man was scheduled to undergo laparoscopic radical prostatectomy for treatment of prostatic adenocarcinoma. The patient had a history of an uneventful, bilateral, inguinal hernia repair during general anesthesia. He had recently been treated with 40 mg pantoprazole daily for a gastric ulcer and was taking 80 mg gliclazide twice daily for mature-onset diabetes. The patient was in excellent condition before surgery. The usual preoperative test results were strictly normal.

The evening before surgery, the patient received 20 mg hypodermic enoxaparin and 0.5 mg oral alprazolam. On the morning of surgery, he took his 40 mg oral pantoprazole and received an intramuscular injection of 5 mg midazolam.

The patient was anesthetized with a total intravenous technique using 1% propofol (Diprivan-prefilled syringes, sealed until use; produced by AstraZeneca S.p.A., Caponago, Italy, and packaged by AstraZeneca UK Limited, Macclesfield, Cheshire, United Kingdom) and remifentanil, with muscle relaxation being achieved by continuous administration of mivacurium (total amount of propofol: 2500 mg; total amount remifentanil: 6 mg, both infused over approximately 4.5 h).

Surgery went on without any problems, but, after approximately 3 h of anesthesia, the patient suddenly became tachycardic (100–110 beats/min) although his heart rate had been between 45 and 60 beats/min until then. The blood gases, then realized, showed the following: pH, 7.43; partial pressure of oxygen (Po2), 210 mmHg; partial pressure of carbon dioxide (Pco2), 36.9 mmHg; lactate, 1.45 mm; bicarbonate (HCO3), 25.1 mm; base excess, 1.6 mm; glucose, 113 mg/dl; hemoglobin, 13.0 mg/dl.

The surgical procedure continued uneventfully. The patient remained stable hemodynamically, and no arrhythmias were noted. The patient was normothermic (36.5°C), was not bleeding actively, and had a diuresis of approximately 1.5 ml · kg−1· h−1.

The subsequent blood gases, tested 1 h later, showed a moderate metabolic acidosis: pH, 7.28; Po2, 177 mmHg; Pco2, 43.5 mmHg; lactate, 6.99 mm, HCO3, 20.8 mm; base excess, −5.1 mm; glucose, 136 mg/dl; hemoglobin, 12.1 mg/dl.

Acidosis increased in the following hour despite volume administration with crystalloids (1 l normal saline) and colloids (1 l hydroxyethyl starch, 6%). The blood gases were as follows: pH, 7.26; Po2, 155 mmHg; Pco2, 41.9 mmHg; lactate, 8.2 mm; HCO3, 19.1 mm; base excess, −6.9 mm; glucose, 125 mg/dl; hemoglobin, 10.7 mg/dl.

By that time, surgery had ended, and because the source of the acidosis was unclear, transesophageal echocardiography was performed, which showed good left and right contractility, adequate ventricular filling, and an adequate cardiac output of approximately 8.5 l/min. Furthermore, the abdominal cavity was searched for any septic source or hepatic necrosis, without success. It was then decided to transfer the patient, sedated and intubated, to the ICU. The last blood gases showed the following: pH, 7.28; Po2, 162 mmHg; Pco2, 39.6 mmHg; lactate, 8.57 mm; HCO3, 18.9 mm; base excess, −6.7 mm; glucose, 129 mg/dl; hemoglobin, 10.7 mg/dl. The total amount of fluids given during the procedure consisted of 3 l normal saline and 1 l hydroxyethyl starch, 6%.

Because the source of the lactic acidosis was believed to be the propofol infusion, in the ICU, the mode of sedation was changed to intravenous midazolam. Morphine was added to treat postoperative pain. The patient experienced mild pyrexia during the following hour. Blood cultures were taken, and antibiotic therapy was started empirically (2 g intravenous amoxicillin clavulanate every 8 h and 500 mg intravenous amikacin every 8 h).

No alterations in blood parameters were observed except the metabolic acidosis (lactate, 8.9 mm); there were no signs of rhabdomyolysis (creatine kinase, 149 U/l [normal, 0–190 U/l]), no signs of heart ischemia (creatine kinase MB < 15 U/l [normal, 0–24 U/l]; troponin I < 0.4 U/l [normal, 0–0.4 U/l]), no alterations in hepatic enzymology (aspartate aminotransferase, 20 U/l [normal, 0–53 U/l]; alanine aminotransferase, 26 U/l [normal, 0–53 U/l]), no signs of sepsis, and no ketone bodies in the urine.

During the subsequent hours, the clinical condition of the patient improved, and the acidosis resolved completely without any other particular treatment than a change in the mode of sedation and discontinuation of the propofol infusion. The patient was then allowed to wake up, and the trachea was extubated approximately 6 h after admission to the ICU. He made a complete recovery. The results of the blood cultures taken during the ICU admission were negative.

Since 1990, multiple reports in the pediatric literature have raised questions as to whether propofol, given as a long-term infusion, has been responsible for the death of certain pediatric patients.4–6In 1992, five cases of metabolic acidosis, bradyarrhythmia, and fatal myocardial failure were reported in children receiving intensive care treatment for upper respiratory tract infections necessitating positive-pressure ventilation.4The patients were aged 4 weeks to 6 yr and had received average propofol infusion rates of 7.5–10 mg · kg−1· h−1for 66–115 h. The total dose of propofol administered over a prolonged period was well outside of past experience with propofol in the anesthetic setting, and the role of propofol in causing death versus  the usually ascribed sepsis or viral myocarditis in sick patients was intensely debated.4,7,8 

Other correspondence has attempted to discount the reports of adverse effects of propofol.9One study demonstrated that propofol in lower dosages (not exceeding 67 μg · kg−1· min−1) could safely be used for sedation of critically ill children.10 

Nevertheless, there seem to be a lethal “syndrome” associated with prolonged (> 24–48 h), high-dose (> 150 μg · kg−1· min−1) propofol infusion in children. This propofol infusion syndrome  is defined as sudden, or relative sudden, onset of marked bradycardia, resistant to treatment, with progression to asystole plus one of the following: (1) the presence of lipemia, (2) a clinically enlarged liver secondary to fatty infiltration, (3) the presence of severe metabolic acidosis, or (4) the presence of muscle involvement with evidence of rhabdomyolysis or myoglobinuria.11 

However, until recently, there have been few reports of propofol infusion syndrome in adults. In 1996, Marinella12reported the case of a 30-yr-old woman with asthma exacerbation complicated by acute respiratory failure necessitating mechanical ventilation and sedation that was achieved by intravenous infusion of propofol. After only 2 h of infusion, the patient showed a worsening anion gap, metabolic acidosis, and increased serum lactate. Propofol was discontinued because it was believed that it might have caused metabolic acidosis. Serial measurements showed that pH, HCO3−, and anion gap values subsequently normalized, and the patient was extubated without any problems.

In 2000, Perrier et al.  13reported what was believed to be the first case of death related to propofol infusion in an adult. An 18-yr-old man involved in an automobile accident required sedation with propofol. Based on his weight, he received propofol infusion at a rate of 5.8 mg · kg−1· h−1for the first 39 h and 7.6 mg · kg−1· h−1for the remaining 59 h of his ICU stay. On posttrauma day 3, the patient’s creatine kinase was increased. On posttrauma day 5, he had atrial fibrillation with rapid ventricular response. Soon after, a left bundle branch block with bradycardia developed. Clinical status was complicated by progressive metabolic acidosis, lipemia, and an increased serum potassium concentration. Myocardial failure ensued, and the patient died secondary to pulseless electrical activity and asystole.

Another report described a dose-dependent association between long-term propofol infusion and cardiac failure in critically ill adults.14 

In 2001, Badr et al.  15reported a case of metabolic acidosis associated with the use of a new formulation of propofol. The generic propofol used in this case was different in formulation (pH and preservative) than the Diprivan brand we used in our case.

During a recent pediatric case in the ICU setting,16important metabolic analysis were performed. The hypothesis to explain this propofol infusion syndrome is consistent with an impairment in free fatty acids oxidation, namely reduced mitochondrial entry of long-chain acylcarnitine esters due to inhibition by propofol of the transport protein carnitine palmityl transferase I, and failure of the respiratory chain at complex II, resulting in an imbalance between energy demand and supply, which may lead to lactic acidosis and ultimately to cardiac and peripheral muscle necrosis.

The so-called propofol infusion syndrome mimics the mitochondrial myopathies, in which there are specific defects in the mitochondrial respiratory chain associated with specific mitochondrial DNA abnormalities, resulting in a abnormal lipid metabolism in cardiac and skeletal muscle. These individuals, who are probably genetically susceptible, remain well until stressed by infection or starvation, although subclinical biochemical abnormalities of mitochondrial transport can be demonstrated. During the management of their critical disease, diversion of metabolism to fat substrates may cause “propofol infusion syndrome.” Because adults have larger carbohydrate stores and require lower doses of propofol for sedation, this may account for the relative rarity of this syndrome in adults. It is unclear whether the dose or duration of propofol infusion alters this effect.

No metabolic analyses were performed in the current patient to try to explain the propofol-related metabolic acidosis.

To our knowledge, this is the first case report of severe nonfatal metabolic acidosis probably due to propofol administration in a previously healthy and non–intensive care patient anesthetized with relative low doses of propofol for a short period of time in the perioperative period.

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