Metabolic Acidosis Associated with Propofol in the Absence of Other Causative Factors

A 31-yr-old woman (weight, 99.2 kg; height, 162 cm) with chronic atrial fibrillation was scheduled to undergo radiofrequency ablation for pulmonary vein isolation. She had a history of atrial fibrillation since the age of 22 yr and was minimally symptomatic, with no evidence of rate-related ventricular dysfunction or thromboembolic events. Except for occasional gastric reflux, she was otherwise healthy. She had reported “waking up early” during a previous anesthetic. Echocardiography showed normal ventricular function with a left ventricular ejection fraction of 55% and mild atrial enlargement. Medications were limited to 50 mg atenolol daily (stopped 4 days before ablation), 325 mg aspirin daily, and oral contraceptives. Preoperative laboratory results were unremarkable, including 11.5 g/dl hemoglobin, 0.9 mg/dl creatinine, 138 mEq/l Na⁺, and 4.9 mEq/l K⁺.

The initial anesthetic plan was to use propofol as the sole sedative, based on its rapid metabolism and the clinical impression that propofol suppresses arrhythmogenic foci during radiofrequency ablation to a lesser extent than other available anesthetic agents. Monitoring included electrocardiography, pulse oximetry, continuous carbon dioxide monitoring of gas sampled at the nares, a femoral arterial catheter, and a urinary catheter. Because of the potential for respiratory depression with prolonged deep sedation in a nonintubated patient, arterial blood gas analyses were obtained intermittently during the procedure.

Sedation was induced with 25 μg · kg⁻¹· min⁻¹propofol with supplemental oxygen by facemask at 4 l/min. The Diprivan® Injectable Emulsion formulation of propofol (AstraZeneca, Wilmington, DE) was used throughout, containing 10 mg/ml propofol and 0.005% disodium edetate. The exact vial sizes used were not recorded on the written anesthesia record. Based on our practice patterns at that time, the propofol infusion was almost certainly administered directly from a 100-ml infusion vial sterilely spiked with a solution administration set leading to an infusion pump. The source of supplemental boluses was not specified on the written record but would have been either from the 100-ml infusion vial already in use or from a 20-ml glass vial opened separately. Our practice is to discard unused propofol at the end of each case, so that vials would have been opened fresh for this case. The case reported was the first case of the day, and vials would have been open no longer than 1 h before the case. Lot numbers and expiration dates for the vials of propofol used could not be identified on retrospective inspection.

The rate of propofol infusion was quickly increased to assist with patient immobility and ranged from 50 to 125 μg · kg⁻¹· min⁻¹throughout the procedure, together with intermittent boluses. The course of propofol therapy and arterial blood gases during the procedure is shown in figure 1. The average rate at which propofol was administered was 83 μg · kg⁻¹· min⁻¹, over a period of 395 min. An acidosis progressively developed, which was entirely metabolic. Pulse oximetry documented oxygen saturation (Spo²) greater than 95% at all times, and arterial oxygen tension (Pao²) and arterial carbon dioxide tension (Paco²) showed no evidence of hypoxia or respiratory depression on any arterial blood gas. There was no prolonged hypotension, and the average urine output was 250 ml/h throughout the procedure. Blood loss was minimal. The only other drug therapies used while propofol was administered were heparin, cefazolin, and 2 mg midazolam given as 1 mg at 51 min and 2 × 0.5 mg at 180 min after the start of anesthesia. Na⁺and K⁺at 51 and 194 min were 142 and 4.2 mEq/l and 142 and 4.0 mEq/l, respectively.

At 395 min, the pH was 7.30, and base excess was −8. Because of patient restlessness and movement despite heavy sedation, intermittent airway obstruction requiring manual positioning to correct, and concern about an evolving metabolic acidosis with high-dose propofol, the patient was intubated and mechanically ventilated. The propofol infusion was discontinued, and no further propofol boluses were given. Total intravenous fluid to this point was between 2 and 3 l saline, 0.9%. A fentanyl infusion at 17–34 ng · kg⁻¹· min⁻¹with 75% N²O was begun and continued for the rest of the procedure. Sodium bicarbonate 15 mEq was given at 475 min, but the largest change in pH and base excess toward normal occurred between discontinuation of propofol at 395 min and the blood gas sampled at 433 min. By 560 min, the metabolic acidosis had partially resolved. At the end of the procedure at 720 min, the trachea was extubated without complications. Total intravenous fluid during the procedure was 5.85 l saline, 0.9%. No further arterial blood gas analyses were obtained on the day of the procedure. After the procedure, the patient had normal physical examination results and no complaints. Laboratory values obtained 2–4 days after the procedure were unremarkable: Na⁺, 137–139 mEq/l; K⁺, 3.5–3.9 mEq/l; Cl⁻103–106 mEq/l; venous HCO³⁻25–26 mEq/l; anion gap, 8.

We report the development of significant, reversible, metabolic acidosis without ventilatory depression or hypoxia in a healthy patient receiving high-dose propofol and no other drugs likely to cause metabolic acidosis. The mechanism for this mild probable propofol infusion syndrome remains unclear. There was no evidence of renal failure causing decreased excretion of endogenous acids or increased loss of bicarbonate. Moreover, venous bicarbonate, creatinine, and anion gap values obtained after the procedure were normal, showing the absence of underlying chronic renal disease.

Increased lactic acid production caused by low cardiac output or a regional steal syndrome must be considered because propofol is both a cardiac depressant and vasoactive,14and cardiac failure has been reported with the propofol infusion syndrome.1,2However, cardiac failure with propofol is usually a late, fatal development after metabolic acidosis, rather than an early cause of metabolic acidosis. This patient’s hemodynamics, urine output, and stable renal status argue against cardiovascular failure as the proximate cause of her metabolic acidosis.

Another potential cause of this patient’s metabolic acidosis is impaired hepatic lactate metabolism. In several cases of propofol infusion syndrome, the development of a fatty or enlarged liver has been reported, and a case of isolated severe hepatotoxicity associated with propofol has also been reported.15The patient reported here did not have liver function laboratory tests, but she had no clinical evidence of hepatic disease before or after the procedure.

There is both in vitro  16and clinical7evidence that high doses of propofol can inhibit mitochondrial respiration, which could cause metabolic acidosis. The glucuronide and sulfate products of phase II propofol metabolism are unlikely to be toxic, but the intermediate dihydroxylated products are poorly characterized and potentially interconvertible to toxic quinones. Propofol quinone has been synthesized, and preliminary evidence has been presented of its mitochondrial toxicity.17Both a direct and a metabolite mitochondrial toxicity of propofol would be consistent with the idiosyncratic appearance of the propofol infusion syndrome, requiring both a sustained, high-dose infusion and as yet undetermined genetic variants of propofol clearance and metabolism.

Sepsis can lead to metabolic acidosis and could occur with contaminated propofol because its lipid emulsion is a good culture medium.18Here, the lack of fever and sustained hypotension and the uneventful postoperative recovery argue against sepsis in this patient. No exogenous acid load was administered to this patient; she received only the Diprivan® formulation of propofol (pH 7.5–8.0), rather than a generic formulation (pH 4.5–6.4; Baxter Healthcare Corporation, New Providence, NJ).

Rapid administration of large volumes of 0.9% intravenous saline can cause dilutional acidosis.19,20Unfortunately, the concentration of serum chloride, which would have clarified the contribution of saline administration to this patient’s acidosis, was not determined during the acidosis. However, comparison to published studies of dilutional acidosis suggests that 0.9% saline is unlikely to account for all of this patient’s acidosis. In adult gynecologic surgery patients receiving 6 l saline, 0.9%, over 2 h, base excess decreased to −6.7 mm by 2 h.20Such dilutional changes require rapid administration of volumes beyond the ability of native homeostatic mechanisms to compensate.19At the time of intubation, our patient had received at most 3 l saline, 0.9%, over 6.5 h, with a base excess of −8. Hence, compared with that study,20our patient had a more negative base excess despite receiving half the saline volume over more than triple the time period, with more time for urinary response to a putative dilutional acidosis. Furthermore, her acidosis improved after the propofol was stopped, although she received a similar volume (at least 2.85 l) of 0.9% saline over the final 5.5 h of the anesthetic.

In conclusion, the case reported here is significant because it is the first documented example of propofol potentially causing metabolic acidosis in the absence of any other drug likely to cause acidosis and without any other reasonable causative factors. It suggests that propofol infusion syndrome is in fact due to propofol or a propofol metabolite, is reversible in its early stages, and is consistent with previous cautions to avoid high-dose, prolonged infusions of propofol.1,2It also illustrates the utility of monitoring arterial blood gases in cases where the advantages of propofol infusion greater than 75 μg · kg⁻¹· min⁻¹for more than a few hours seem to outweigh its risks.