1) CASE REPORT : Grand mal seizures were reported in an 11-year-old boy after 13 months of treatment with medication dissolved in propylene glycol and ethanol (total amount 4 to 8 mL/day) (Arulanatham & Genel, 1978).

1) Low birth weight infants who received 3 g/day of propylene glycol from intravenous multivitamin solutions had a significantly higher incidence of seizures than infants receiving 300 mg/day (MacDonald et al, 1987). Infants receiving the larger dose also had higher BUN and serum osmolality, but the bilirubin, creatinine, and SGPT were the same as in the low dose group.

1) In a retrospective chart review of 128 patients that had received a continuous infusion of lorazepam (range: 2 to 28 mg/hr), 8 patients developed elevated creatinine concentrations during the continuous infusion of lorazepam. The mean cumulative dose of lorazepam was 4305 mg (range: 1200 to 10920 mg), and the mean propylene glycol concentration at the time of peak serum creatinine was 1103 mcg/mL (range: 186 to 3450 mcg/mL). Serum creatinine increased at a median of 9 days (range: 3 to 60 days), with most patients having a decrease in creatinine within 3 days of drug cessation. A weak-to-moderate correlation (r = 0.53) was observed between the degree of serum creatinine concentration rise and propylene glycol concentration. However, the degree of serum creatinine concentration rise correlated positively with both cumulative lorazepam dose and duration of therapy (r = 0.43 and 0.60, respectively). Although the exact mechanism that produces an alteration in serum creatinine concentration is unknown, it may result from proximal renal tubular cell injury. The authors also suggest that clinical markers useful in determining propylene glycol toxicity in patients receiving prolonged lorazepam therapy were serum osmolality and osmol gap (Yaucher et al, 2003).

1) Lactic acidosis occurred in a patient with underlying uremic renal disease receiving medication dissolved in propylene glycol (Cate & Hedrick, 1980).
2) After the acute ingestion of ethanol and automotive antifreeze containing propylene glycol (PG). Serum levels of PG and lactate were as follows (Brooks et al, 2001):
3) D-LACTIC ACID ACIDOSIS: Twelve hours after a 72-year-old man ingested a large amount of propylene glycol he became comatose and was admitted to the intensive care unit. Laboratory findings included an anion gap (27 mEq/L) metabolic acidosis (arterial pH, 7.16) with an increased osmolal gap. Biochemical analysis indicated that very high amounts of D-lactic acid (up to 110 mmol/L) produced metabolic acidosis. Hemodialysis was initiated and resulted in a decline of the acidosis and D-lactic acid levels. He regained consciousness 10 hours after initiation of the hemodialysis, but required dialysis for an additional 16 days to normalize his renal function (Jorens et al, 2004).

1) NITROGLYCERIN: Lactic acidosis was associated with administration of 31 to 414 g/day of propylene glycol to patients with renal dysfunction receiving intravenous nitroglycerin (Demey et al, 1986). Most cases of elevated lactate could be explained by underlying conditions of hemodynamic instability and tissue hypoxia, but one case was unexplained (Demey et al, 1988).
2) PARENTERAL MEDICATIONS: Serum and CSF lactate concentrations correlated with propylene glycol concentrations in 5 patients with normal renal function receiving parenteral medications containing propylene glycol. The serum PG level ranged from 6 to 711 mg/L. A patient with a PG level of 304 mg/L 5 hours after receiving Dilantin(R) and Valium(R) (total PG dose 512 mg/kg/day) had an anion gap of 21 and serum lactate of 15.5 mEq/L (Kelner & Bailey, 1985).
3) LORAZEPAM: In 6 critically ill adults, who received high-dose lorazepam (greater than or equal to 10 mg/hour) for 48 hours or more, PG accumulation, as evidenced by a high anion gap metabolic acidosis with elevated osmol gap, was observed. In these patients, there was a significant correlation between infusion rate and PG concentrations. The osmol gap was the strongest predictor of serum PG concentrations (Arroliga et al, 2004).
4) CASE REPORT: A 57-year-old woman with end-stage renal disease and medical history of hypertension, seizure disorder, multiple strokes, diastolic heart failure, and chronic hepatitis C, developed generalized tonic clonic seizures after undergoing right cranioplasty surgery. Despite treatment with phenytoin, levetiracetam, IV lacosamide, and propofol, she continued to experience seizures. She received phenobarbital infusion to induce barbiturate coma and continued to undergo regular dialysis 3 times weekly, but developed severe hypotension on day 8, requiring vasopressors. Laboratory analysis revealed a high anion gap metabolic acidosis (anion gap of 22) due to lactic acidosis (12 g/dL; reference range: 0.6 to 2.4 g/dL), and serum albumin of 3.5 g/dL (range 3.5 to 5 g/dL). After further investigation, it was determined that the cause of high lactic acid was propylene glycol in the phenobarbital product. Following the discontinuation of phenobarbital, the patient underwent continuous renal replacement therapy (CRRT), resulting in the resolution of lactic acidosis and normalization of anion gap. After developing seizures again, she received lower doses of phenobarbital, in addition to IV phenytoin and valproic acid, but she developed severe high anion gap lactic acidosis (lactic acid 15 g/dL; range, 0.6 to 2.4 g/dL) and hypotension 4 days later. Following the discontinuation of phenobarbital and valproic acid and supportive care, including CRRT, her condition improved the next day and she became hemodynamically stable with the resolution of lactic acidosis. Overall, she received about 3900 mg of IV phenobarbital and 8900 mg of IV phenytoin over 7 days (Pillai et al, 2014).

1) CASE REPORT: A 62-year-old alcoholic man with community acquired pneumonia and acute respiratory failure was mechanically ventilated and received continuous high-dose lorazepam (10 mg/h) sedation for 4 days, and developed high anion gap (26 mEq/L) metabolic acidosis along with high plasma osmolal gap. The patient had a markedly elevated D-lactic acidosis of 11.8 mmol/L and a high propylene glycol concentration (382 mg/dL). Following drug cessation and an extended course of hemodialysis (approximately 8 h), the patient was stable with rapid correction of acid-base status (Tsao et al, 2008)

1) CASE SERIES: In a study of 44 patients receiving diazepam, 23% developed venous complications by the third day and 39% by the tenth day (Hegarty & Dundee, 1977).
2) CASE SERIES: In a study comparing the venous sequelae of diazepam in various solvents, the incidence was 48% with propylene glycol, 9% with Cremophor, and 6% with soybean oil (Schou Olesen & Huttel, 1980).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

1) There is no minimum dose (de Caen et al, 2015).
2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).

1) Serum levels of 930 milligrams/deciliter were associated with hyperosmolality following administration of 3 grams/day in a premature infant (Glasgow et al, 1983).
2) A serum level of 771 milligrams/deciliter was demonstrated in an 8-month-old infant with mild lactic acidosis due to topical administration of propylene glycol (Fligner et al, 1985).

1) Lactic acidosis, coma, and hyperosmolality were reported in an elderly patient with a propylene glycol serum level of 910 milligrams/deciliter (Demey et al, 1984).
2) Through least-squares regression analysis of data from 5 patients receiving propylene-glycol containing intravenous solutions in whom serial PG and lactate levels were obtained, serum PG concentrations greater than 177 milligrams/liter were required to increase the serum lactate level by 6 milliequivalents/liter and result in an elevated anion gap (Kelner & Bailey, 1985).
3) Following 3 days of lorazepam infusions containing propylene glycol (PG), a 34-year-old woman was reported to have PG serum levels on day 3 of 12 milligrams/deciliter. Calculated doses of PG on days 1 through 3 were reported as 26,975, 129,895 and 126,575 milligrams, respectively. The patient developed anion gap metabolic acidosis with hyperlactacidemia, hyperosmolality, and increased osmolal gap, all of which improved on cessation of the lorazepam infusion (Cawley, 2001).
4) A 60-year-old male developed PG serum level of 78 milligrams/deciliter following 5 days of lorazepam infusions, with a calculated PG load of 540 grams. The patient developed an osmolar gap metabolic (lactic) acidosis which returned to normal within 72 hours after stopping the lorazepam infusion (Arbour & Esparis, 2000).
5) In 6 critically ill adults who received high-dose lorazepam (greater than or equal to 10 mg/hour) for 48 hours or more, PG accumulation, as evidenced by a high anion gap metabolic acidosis with elevated osmol gap, was observed. In these patients, the osmol gap was the strongest predictor of serum PG concentrations (Arroliga et al, 2004).
6) A 46-year-old male was reported to have a serum PG level of 1300 milligrams/deciliter after receiving approximately 3000 milligrams intravenous diazepam over 24 hours. The patient developed osmolar gap lactic metabolic acidosis which improved following hemodialysis (Wilson et al, 2000).
7) Serum PG levels were compared to total osmol gap in a patient receiving high-dose infusions of lorazepam and nitroglycerin (Velendzas & McKay, 1999):
8) Patients have been conscious with serum levels of 760 mg/dL (HSDB, 2003)