propylene glycol ( pg ) is a colorless , odorless organic chemical approved by the us food and drug administration for use as a solvent in food , drugs , and cosmetics . it is included in numerous intravenous and oral medications , some of them being broadly used in critically ill patients , like lorazepam or diazepam , barbiturates , etomidate , phenytoin , or trimethoprim / sulfamethoxazole ( tmp / smx ) . although pg is generally considered safe , there is an increasing body of evidence suggesting that large doses or prolonged treatments with intravenous medications containing pg can result in severe toxicity . the reported toxic effects of pg include hyperosmolality and anion gap metabolic acidosis , lactic acidosis , acute kidney injury , cns toxicity with seizures , and cardio - respiratory arrest . the precise mechanism of pg toxicity is presently unknown , however , the accumulation of pg and/or its byproducts may result in hyperosmolality and anion gap metabolic acidosis . furthermore , the findings of swelling and vacuolization of proximal tubular cells in a pg - exposed patient kidney biopsy as well as observed toxicity on cultured human proximal tubular cells suggest a mechanism by which pg - related cellular injury results in acute kidney injury . although the world health organization recommends a maximum consumption of 25  mg / kg / day of pg when used as a food additive , this does not address its use as a drug solvent . among the pg - containing drugs used in icu settings , intravenous lorazepam involves the largest amounts of pg with respect to the administered dosage ; as expected , lorazepam has been associated with most cases of pg toxicity which always involved large doses or prolonged treatments with large amounts of daily or total pg intakes . some authors have suggested risks factors for pg toxicity , including chronic renal or liver disease , alcohol abuse , and have recommended to limit daily intravenous pg intakes to 1  g / kg / d or 69  g / day . although tmp / smx contains pg as well , doses usually administered to treat pneumocystis jirovecii pneumonia ( 1520  mg / kg / d ) involve < 0.5  g / kg / d of pg , well below the reported levels of toxicity . even though 2 case reports of pg toxicity involved tmp / smx as a co - administered drug , both patients were receiving large doses of lorazepam which accounted for most of the pg intakes ( respectively 552  g over 12 days and 540  g over 5 days ) . we present a unique case of severe lactic acidosis after only a 3-day course of intravenous tmp / smx , involving amounts of pg well below the reported toxic levels , in a patient without known risk factor for pg toxicity . a 31-year - old caucasian female ( weight 106 kg ) with a past medical history of hypothyroidism , neurofibromatosis type 1 , and pilocytic astrocytoma ( figure 1 ) recently treated with metronomic temozolomide and steroids , presented with dyspnea at rest , a 2 week duration of nonproductive cough , and a 6 week history of progressive weakness , ataxia , anorexia , weight loss , and throat pain . her vital signs on admission to the emergency department were as follows : temperature 36.5c , heart rate 110/minute , respiratory rate 30/minute , blood pressure 114/83 mm hg , spo2 79% on room air , and then 88% on oxygen 6 l / min nasal cannula . initial assessment , including a chest radiograph and lung computed tomography ( figure 2 ) , revealed patchy bilateral parenchymal opacities with consolidation concerning for multifocal pneumonia , in addition to a small left pleural effusion . laboratory test revealed a white blood cell count of 8.75    10/mm ( normal range 4.010.4    10/mm ) with 92% neutrophils , 5% lymphocytes , 3% monocytes , 0.3% eosinophils , and no basophils or bands . mmol / l ) , potassium 2.8  mmol / l ( 3.55.1  mmol / l ) , chloride 100  mmol / l ( 96107 mmol / l ) , bicarbonate 31  mmol / l ( 2230  mmol / l ) , blood glucose 96  mg / dl ( 74106  mg / dl ) , and baseline blood urea nitrogen ( bun ) and serum creatinine were 7  mg / dl ( 720  mg / dl ) and 1.02  mg / dl ( 0.61.0  mg / dl ) , respectively . the patient 's initial acid base status was normal , with a venous ph of 7.4 . blood , urine , and sputum cultures were obtained , and the patient was treated empirically with intravenous cefepime , vancomycin , and azithromycin . given worsening hypoxia requiring oxygen via high flow nasal cannula ( fio2 65% ) , the patient was admitted to the intensive care unit ( icu ) and intubated shortly after for acute hypoxic respiratory failure requiring mechanical ventilation . brain magnetic resonance imaging with intravenous contrast showing the pilocytic astrocytoma as an enhancing cystic lesion ( 2.5    2.9  cm ) in the region of the hypothalamus and optic chiasm extending into the brain stem . chest computed tomography showing patchy bilateral parenchymal opacities with trace left pleural effusion , consistent with multifocal pneumonia . in the icu , 18  mg / kg / d of intravenous tpm / smx , corresponding to 0.47  g / kg / d of pg , was added for empiric coverage of pneumocystis jirovecii pneumonia , given the patient 's immunocompromised state . after intubation and mechanical ventilation , the patient 's hypoxia quickly improved and the fio2 was weaned down to 40% within 24  hours with spo2 99% . the patient was successfully extubated after 36  hours of mechanical ventilation . her vital signs after extubation were unremarkable with normal heart rate and blood pressure , respiratory rate at 18/minute , and spo2 97% on oxygen 2 twenty - four hours after extubation , the patient developed progressively worsening tachypnea ( respiratory rate 32/minute ) without worsening hypoxemia ( spo2 97% on oxygen 2 l with nasal cannula ) or change in her chest x - ray . this prompted an arterial blood gas analysis which revealed a severe metabolic acidosis with ph 7.2 , pco2 19 mm hg , po2 107 mm hg on 2 l oxygen , bicarbonate 8 mmol / l , an anion gap of 25  meq / l , and a lactate of 12.1 blood , urine , and sputum cultures remained negative and the patient 's vital signs ( temperature , heart rate , and blood pressure ) remained normal . as tmp / smx was suspected as the cause of her lactic acidosis and the p jirovecii , direct fluorescent - antibody test returned negative , tmp / smx was discontinued . the other medications received between admission and the occurrence of lactic acidosis included cefepime , vancomycin , azithromycin , enoxaparin , fentanyl , propofol , dexmedetomidine , hydrocortisone , levothyroxine , pantoprazole , and lorazepam ( 1  mg twice ) , among them only lorazepam included pg ( 0.8  g for 2  mg of lorazepam ) . within 24  hours of stopping the tmp / smx and without any additional intervention , the lactate decreased from 12.1 to 2.9  mmol / l and serum bicarbonate increased to 23  mmol / l . figures 3 and 4 display the course of relevant vital signs ( mean arterial pressure and spo2 ) and biological data ( serum bicarbonates , creatinine , and lactic acid ) during the initial 6-day course . in total , the patient received 54  g ( 0.5  g / kg ) of pg daily for 3 days while being treated with tmp / smx and an additional 0.8  g with lorazepam . no other cause for the patient 's lactic acidosis was identified , and her acid  base status remained normal for the rest of her hospital admission . course of mean arterial pressure ( map , diamond markers with straight line on the left y - axis ) and spo2 ( x markers with dotted line on the right y - axis ) over the first 6 days of admission . tmp / smx was started on admission ( day 0 ) and stopped at day 4 . scales are different for the sake of legibility . except for initial hypoxemia ( spo2 79% on room air on admission ) and a brief ( 1 hour ) episode of desaturation at day 2 ( spo2 8687% on o2 2 liters ) , map and spo2 remained above 65  mmhg and 90% respectively . course of serum bicarbonates ( diamonds ) and lactates ( circles ) on the left y - axis and creatinine ( x markers ) on the right y - axis over the first 6 days of admission . tmp / smx was started on admission ( day 0 ) and stopped at day 4 . scales are different for the sake of legibility . while serum bicarbonates was normal on admission , a severe metabolic acidosis developed at day 3 , concomitant with an increased lactates . after tmp / smx cessation , serum bicarbonates and lactates levels normalized within 24 hours . 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 , and multiple adverse reactions have been reported , 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 . 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 . 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 , a dose presumed safe in the absence of risk factors for pg toxicity . 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  hours 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 . the renal clearance of pg decreases as the dose administered increases ( from 390  ml / min/1.73 m for a pg dose of 5  g / d to 144  ml / min/1.73 m 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 , 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 abnormalities to life - threatening clinical conditions . moreover , pg toxicity has been documented over a wide range of serum pg levels ( 12 13,080   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 . there is no clear correlation between cumulative lorazepam ( and therefore pg ) dose and serum pg concentration and pg pharmacokinetic studies have shown considerable intra- and interpatient variation in serum pg concentrations for a given dosage administered . 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 / smx 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 . 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 . 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 . applying the naranjo adverse drug reaction probability scale , pg was determined to be the probable cause for her lactic acidosis with a score of 7 : 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 . 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 , 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 . 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 .