The subsequent patient's hospital course was complicated by persistent encephalopathy ascribed to her brainstem astrocytoma, with recurrent airway mucus plugging requiring re-intubation 10 days after extubation. The patient eventually underwent a tracheostomy for difficult ventilator weaning and was transferred to a rehabilitation facility after 3 weeks.
There has been an increasing interest in PG toxicity in recent years,1–3 and multiple adverse reactions have been reported,1,8,18 including hyperosmolality, anion gap metabolic acidosis, lactic acidosis, acute kidney injury, CNS toxicity with seizures, and a sepsis or systemic inflammatory-like syndrome. Although drugs with high PG content, such as benzodiazepines (lorazepam contains as high as 80% v/v of PG), barbiturates, etomidate, phenytoin, and TMP/SMX, are broadly used in the ICU setting, their sometimes life-threatening adverse reactions may be under-recognized. In a prospective observational study, Arroliga and coworkers demonstrated that 6 out of 9 ICU patients being treated with high dose (≥10 mg/h) of intravenous lorazepam developed hyperosmolar high anion gap metabolic acidosis consistent with PG accumulation, the osmolar gap being the strongest predictor of serum PG concentrations.16 Wilson and colleagues also observed that 4 out of 21 patients who had received PG-containing sedative medications (either lorazepam or diazepam) had metabolic abnormalities consistent with PG toxicity.14 These studies suggest that the incidence of PG toxicity is likely much higher than clinically recognized and underscore the need for a better knowledge by clinicians and ICU staff of PG-containing drugs and for a prudent monitoring of patients receiving PG.
Although PG is generally considered safe, the reported cases of mild forms of lactic acidosis following the use of large doses of PG diluted medications led to recommendations to limit PG intakes to 69 g/d or ∼1 g/kg/d,14,18 a dose presumed safe in the absence of risk factors for PG toxicity.1 The precise mechanism by which PG causes toxicity is unclear, as no convincing evidence supports a direct cytotoxicity of either PG or its byproducts. After intravenous administration, PG has a elimination half-life of 2.3 ± 0.7 hours19 and is excreted by two mechanisms: the liver metabolizes approximately half to lactate, acetate, and pyruvate via oxidation by alcohol dehydrogenase and aldehyde dehydrogenase, and the other half is excreted unchanged by the kidneys.3 The renal clearance of PG decreases as the dose administered increases19 (from 390 mL/min/1.73 m2 for a PG dose of 5 g/d to 144 mL/min/1.73 m2 for a dose of 21 g/d); this may explain why patients with chronic kidney diseases or acute renal failure may be predisposed to PG toxicity,1 but our patient's renal function was normal. The present literature suggests a broad spectrum in the severity of clinical manifestations of PG toxicity, ranging from mild metabolic abnormalities14 to life-threatening clinical conditions.7,9,13 Moreover, PG toxicity has been documented over a wide range of serum PG levels (1220 −13,080 17 mg/dL) and significant overlap exists between levels resulting in only mild metabolic abnormalities as compared with critical clinical deterioration. For instance, in the study by Wilson et al, PG plasma levels ranged from 58 to 127 mg/dL for patients presenting only metabolic abnormalities and from 104 to 144 mg/dL in patients with clinical deterioration because of PG toxicity.14 There is no clear correlation between cumulative lorazepam (and therefore PG) dose and serum PG concentration16 and PG pharmacokinetic studies have shown considerable intra- and interpatient variation in serum PG concentrations for a given dosage administered.19,21 A hypothetical critical PG concentration beyond which clinical deterioration may be observed is presently unknown and appears to be patient dependent, suggesting a patient-specific variability in the metabolism, excretion, and thus toxicity of PG.
Most, if not all of the case reports on PG toxicity involved benzodiazepines (mostly lorazepam), which contain the largest amounts of PG among the drugs routinely used in ICU setting. In 2 published cases, patients were receiving TMP/SMX5,7 but the TMP/SMX accounted for only a minor fraction of total PG intake as patients were also receiving large doses of lorazepam. In these cases, the total PG intake was well above the threshold generally considered as safe. For instance, in the case reported by Hayman et al, the patient had received a total of 552 g of PG within 12 days, only 123 g (20%) of which administered with TMP/SMX during the last 6 days.7 The second case involved a PG load of 540 g within 5 days administered with lorazepam infusion in a patient who was also receiving TMP/SMX at unknown dosages.5 Here we report a unique case of severe lactic acidosis developing after only a 3-day course of intravenous TMP/SMX, involving relatively low amounts of PG (162 g within 3 days), well below the levels generally considered as toxic.1 Applying the Naranjo adverse drug reaction probability scale, PG was determined to be the probable cause for her lactic acidosis with a score of 722: we assigned 1 point for previous conclusive reports on this reaction, 2 points for the time between drug administration and the occurrence of lactic acidosis, 1 point for the improvement in lactic acidosis after discontinuation of TMP/SMX, 2 points for the absence of alternative causes, and 1 point for the objective evidence confirming the reaction. Unfortunately our patient's serum osmolality was not measured and we were unable to obtain a serum PG level to add further evidence of PG toxicity.
We believe that this case is clinically relevant and should raise awareness among clinicians, as (1) TMP/SMX is broadly used in critically ill immunocompromised patients and the fact that it contains PG is unrecognized, (2) critically ill patients often have conditions (shock, acute renal failure, and lactic acidosis) that may mimic PG toxicity but also contribute to it, (3) immediate recognition and cessation of TMP/SMX is crucial to prevent the development of life-threatening complications in patients already prone to multiorgan failure. Intravenous TMP/SMX is often used in the setting of immunosuppression, either to treat documented P jirovecii pneumonia or as an empiric treatment in immunocompromised patients presenting with acute respiratory failure and diffuse pulmonary infiltrates concerning for P jirovecii pneumonia. In ICU settings, such patients may be easily exposed to PG toxicity as they are prone to develop acute renal or liver failure, reported as risk factors for PG toxicity.1 On the other hand, patients receiving TMP/SMX often present with signs of sepsis, and any clinical or biological deterioration will easily be attributed to the ongoing sepsis, while potentially severe adverse drug reactions may be overlooked. Despite a severe lactic acidosis, our patient's clinical condition remained stable (except for the acidosis-related tachypnea) as well as her renal function. The normalization of her serum bicarbonates and lactate levels within 24 hours after TMP/SMX cessation is consistent with PG half-life. Without TMP/SMX cessation, the lactic acidosis could have been complicated by progressive multiorgan failure and cardiorespiratory arrest.9 Our patient did not present with acute renal or liver failure, and had no history of chronic kidney, liver disease, or alcohol abuse, described as risks factors for PG toxicity.18 Although TMP/SMX is a known PG-containing drug, PG intake for our patient were below toxic levels and she did not receive other PG-containing drugs except for 2 mg of lorazepam, which only accounted for 0.8 g of PG and likely played a minor role in her lactic acidosis. Our patient had findings on chest imaging concerning for pneumonia; however all of her cultures remained sterile and she never developed hypotension or shock (her mean arterial pressure remained above 65 mm Hg the whole time, as shown in Figure 3), making hypoperfusion and resulting lactic acidosis secondary to sepsis extremely unlikely. Similarly, her severe hypoxemia on presentation (SpO2 79% on room air) is unlikely to account for the delayed lactic acidosis, as it was rapidly corrected with additional oxygen and mechanical ventilation (see Figure 4), and metabolic acidosis developed 48 hours later while her oxygenation had been normal on mechanical ventilation.
To our knowledge, severe lactic acidosis after a 3-day course of TMP/SMX, involving allegedly safe doses of PG, has never been described. Although PG-related toxicity following large doses of lorazepam is now well acknowledged, physicians should bear in mind that TMP/SMX also contains PG, and suspect PG toxicity in patients developing metabolic acidosis while receiving TMP/SMX, even at the recommended dosage and without risk factors for toxicity. Immediate cessation of the drug is crucial to prevent the development of worsening multiorgan failure.
1. Zar T, Graeber C, Perazella MA. Recognition, treatment, and prevention of propylene glycol toxicity. Semin Dial
2. Liamis G, Milionis HJ, Elisaf M. Pharmacologically-induced metabolic acidosis: a review. Drug Saf
3. Barnes BJ, Gerst C, Smith JR, et al. Osmol gap as a surrogate marker for serum propylene glycol concentrations in patients receiving lorazepam for sedation. Pharmacotherapy
4. Neale BW, Mesler EL, Young M, et al. Propylene glycol-induced lactic acidosis in a patient with normal renal function: a proposed mechanism and monitoring recommendations. Ann Pharmacother
5. Arbour R, Esparis B. Osmolar gap metabolic acidosis in a 60-year-old man treated for hypoxemic respiratory failure. Chest
6. Kelner MJ, Bailey DN. Propylene glycol as a cause of lactic acidosis. J Anal Toxicol
7. Hayman M, Seidl EC, Ali M, et al. Acute tubular necrosis associated with propylene glycol from concomitant administration of intravenous lorazepam and trimethoprim-sulfamethoxazole. Pharmacotherapy
8. MacDonald MG, Getson PR, Glasgow AM, et al. Propylene glycol: increased incidence of seizures in low birth weight infants. Pediatrics
9. Fligner CL, Jack R, Twiggs GA, et al. Hyperosmolality induced by propylene glycol. A complication of silver sulfadiazine therapy. JAMA
10. Yorgin PD, Theodorou AA, Al-Uzri A, et al. Propylene glycol-induced proximal renal tubular cell injury. Am J Kidney Dis
11. Morshed KM, Jain SK, McMartin KE. Propylene glycol-mediated cell injury in a primary culture of human proximal tubule cells. Toxicol Sci
12. Additives F-WECoF. Toxicological evaluation of certain food additives with a review of general principles and of specifications. Seventeenth report of the joint FAO-WHO Expert Committee on Food Additives. World Health Organ Tech Rep Ser
13. Parker MG, Fraser GL, Watson DM, et al. Removal of propylene glycol and correction of increased osmolar gap by hemodialysis in a patient on high dose lorazepam infusion therapy. Intensive Care Med
14. Wilson KC, Reardon C, Theodore AC, et al. Propylene glycol toxicity: a severe iatrogenic illness in ICU patients receiving IV benzodiazepines: a case series and prospective, observational pilot study. Chest
15. Nelsen JL, Haas CE, Habtemariam B, et al. A prospective evaluation of propylene glycol clearance and accumulation during continuous-infusion lorazepam in critically ill patients. J Intensive Care Med
16. Arroliga AC, Shehab N, McCarthy K, et al. Relationship of continuous infusion lorazepam to serum propylene glycol concentration in critically ill adults. Crit Care Med
17. Al-Khafaji AH, Dewhirst WE, Manning HL. Propylene glycol toxicity associated with lorazepam infusion in a patient receiving continuous veno-venous hemofiltration with dialysis. Anesth Analg
2002; 94:1583–1585.table of contents.
18. Lim TY, Poole RL, Pageler NM. Propylene glycol toxicity in children. J Pediatr Pharmacol Ther
19. Speth PA, Vree TB, Neilen NF, et al. Propylene glycol pharmacokinetics and effects after intravenous infusion in humans. Ther Drug Monit
20. Cawley MJ. Short-term lorazepam infusion and concern for propylene glycol toxicity: case report and review. Pharmacotherapy
21. Yu DK, Elmquist WF, Sawchuk RJ. Pharmacokinetics of propylene glycol in humans during multiple dosing regimens. J Pharm Sci
Copyright © 2016 The Authors. Published by Wolters Kluwer Health, Inc. Health, Inc. All rights reserved.
22. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther