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Relationship of continuous infusion lorazepam to serum propylene glycol concentration in critically ill adults* Alejandro C. Arroliga, MD; Nadine Shehab, PharmD; Kevin McCarthy, RCPT; Jeffrey P. Gonzales, PharmD, BCPS Objectives: The primary objective was to evaluate the relationship between high-dose lorazepam and serum propylene glycol concentrations. Secondary objectives were a) to document the occurrence of propylene glycol accumulation associated with continuous high-dose lorazepam infusion; b) to assess the relationship between lorazepam dose, serum propylene glycol concentrations, and propylene glycol accumulation; and c) to assess the relationship between the osmol gap and serum propylene glycol concentrations. Design: Prospective, observational study. Setting: Tertiary care, medical intensive care unit. Patients: Nine critically ill adults receiving high-dose lorazepam (>10 mg/hr) infusion. Interventions: Cumulative lorazepam dose (mg/kg) and the rate of infusion (mg·kgⴚ1·hrⴚ1) were monitored from initiation of lorazepam infusion until 24 hrs after discontinuation of the highdose lorazepam infusion. Serum osmolarity was collected at 48 hrs into the high-dose lorazepam infusion and daily thereafter. Serum propylene glycol concentrations were drawn at 48 hrs into the high-dose lorazepam infusion, and the presence of propylene glycol accumulation, as evidenced by a high anion gap (>15 mmol/L) metabolic acidosis with elevated osmol gap (>10 mOsm/ L), was assessed at that time. P ropylene glycol (PG) is used as a solvent for intravenous, oral, and topical pharmaceutical preparations, including intravenous lorazepam. Chronic or large ingestions of PG have been implicated in the development of hyperosmolar metabolic acidosis (1– 8) as well as serious toxicities, including renal dysfunction (4, 9 –12), intravascular hemolysis (13), cardiac arrhythmias (14), seizures (15), and *See also p. 1800. From The Cleveland Clinic Foundation, Department of Pulmonary and Critical Care Medicine (ACA, KM) and Department of Pharmacy (NS, JPG), Cleveland, OH. Address request for reprints to: Jeffrey P. Gonzales, PharmD, BCPS, Cleveland Clinic Foundation, Department of Pharmacy/QQb5, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: [email protected] Copyright © 2004 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000134831.40466.39 Crit Care Med 2004 Vol. 32, No. 8 Measurements and Main Results: The mean cumulative highdose lorazepam received and mean high-dose lorazepam infusion rate were 8.1 mg/kg (range, 5.1–11.7) and 0.16 mg·kgⴚ1·hrⴚ1 (range, 0.11– 0.22), respectively. A significant correlation between high-dose lorazepam infusion rate and serum propylene glycol concentrations was observed (r2 ⴝ .557, p ⴝ .021). Osmol gap was the strongest predictor of serum propylene glycol concentrations (r2 ⴝ .804, p ⴝ .001). Propylene glycol accumulation was observed in six of nine patients at 48 hrs. No significant correlation between duration of lorazepam infusion and serum propylene glycol concentrations was observed (p ⴝ .637). Conclusions: Propylene glycol accumulation, as reflected by a hyperosmolar anion gap metabolic acidosis, was observed in critically ill adults receiving continuous high-dose lorazepam infusion for >48 hrs. Study findings suggest that in critically ill adults with normal renal function, serum propylene glycol concentrations may be predicted by the high-dose lorazepam infusion rate and osmol gap. (Crit Care Med 2004; 32:1709 –1714) KEY WORDS: lorazepam; propylene glycol; toxicity; sedation; adults; osmol gap central nervous system depression (16 – 18). The predominant manifestation of PG accumulation is a high anion gap metabolic acidosis with elevated osmol gap, most commonly reported with lorazepam doses that exceed the upper limit of the recommended lorazepam dosage range (0.1 mg·kg⫺1·hr⫺1) (19). Therefore, patients requiring large doses of lorazepam for sedation may be at risk for PG accumulation. Each vial of lorazepam (2 mg/mL) contains 0.8 mL (830 mg) of PG/mL, and critically ill patients could receive more than the recommended daily amount of PG (25 mg·kg⫺1·day⫺1) (20). Lorazepam is the medication of choice for maintenance sedation in the critically ill population (19). Currently, there is a paucity of data describing lorazepaminduced PG accumulation and/or toxicity in critically ill adults, with the majority of literature consisting of case reports or case series. Furthermore, interpretation of the existing literature is limited by a) the diversity of patients (age, renal failure, and/or liver failure) in whom PG accumulation has been described; b) inconsistency in the criteria used to define PG accumulation; and c) variability in the lorazepam dose received and reported PG concentrations. Moreover, PG accumulation has been described over a wide range of cumulative lorazepam doses (1124 – 7226 mg), serum PG concentrations (12.0 –130.8 mg/dL), and infusion periods (2–24 days) (1– 8, 19). To help elucidate the occurrence of PG accumulation, we undertook a prospective, observational study in critically ill patients receiving high-dose lorazepam (HD-LZ) by continuous infusion. We also wanted to determine whether PG accumulation occurred early in therapy (at 48 hrs) because most of the data describing PG accumulation involve infu1709 sion periods ⬎48 hrs. The primary objective was to evaluate the relationship between continuous infusion of HD-LZ (ⱖ10 mg/hr) and serum PG concentrations early during therapy (at 48 hrs into HD-LZ infusion). Secondary objectives were a) to document the occurrence of PG accumulation associated with continuous HD-LZ infusion; b) to assess the relationship between lorazepam dose, serum PG concentrations, and PG accumulation; and c) to assess the relationship between the osmol gap and serum PG concentrations, all at 48 hrs into HD-LZ infusion. MATERIALS AND METHODS This study was approved by our Institutional Review Board, and written informed consent for participation in the study was obtained. Our medical intensive care unit (MICU) sedation guidelines recommend lorazepam by intermittent bolus or continuous infusion as the benzodiazepine of choice for maintenance sedation, which is consistent with the current Society of Critical Care Medicine Sedation Guidelines (19). Sedation is used only after the provision of adequate analgesia and is titrated and reevaluated daily using the Motor Activity Assessment Scale (21). By clinical observation, in our patient population, a dose of lorazepam of ⱖ10 mg/hr corresponds to a dose of ⱖ0.1 mg·kg⫺1·hr⫺1, which is the upper limit suggested by the Society of Critical Care Medicine Sedation Guidelines (19). MICU patients receiving HD-LZ (ⱖ10 mg/hr) were eligible for enrollment. Patients were excluded if they received other PG-containing medications by continuous or intermittent infusion or if they were undergoing dialysis. Patients were also excluded if they presented with ethanol, methanol, or ethylene glycol intoxication or if they received medications or compounds that would affect the osmol gap. Table 1 lists some parenteral medications containing PG that may be administered to critically ill patients (2, 7, 29). Patient characteristics collected at baseline included patient age, gender, weight, admitting diagnosis, and Acute Physiology and Chronic Health Evaluation II score at admission. Laboratory variables (serum sodium, potassium, chloride, glucose, blood urea nitrogen, creatinine, alkaline phosphatase, bilirubin, alanine aminotransferase, aspartate aminotransferase), as well as arterial blood gases (pH, PaCO2, PaO2, HCO3, oxygen saturation), were monitored daily throughout the study period. Creatinine clearance was calculated using the Cockcroft-Gault equation (22). After enrollment, data were collected from the time the lorazepam infusion was initiated un- 1710 Table 1. Commonly used intravenous drugs containing propylene glycol Drug Amount of Propylene Glycol (% v/v) Lorazepam, 2 mg/mL Phenobarbital, 30–130 mg/mL Diazepam, 5 mg/mL Pentobarbital, 50 mg/mL Phenytoin, 50 mg/mL Trimethoprim-sulfamethoxazole, 16:80 mg/mL Etomidate, 2 mg/mL Nitroglycerin, 5 mg/mL Esmolol, 250 mg/mL 80 67.8–75 40 20–40 40 40 35 30 25 Data adapted (2, 7, 29). til the start of HD-LZ. Subsequent data were collected until 24 hrs after discontinuation of the HD-LZ infusion. Serum osmolality was collected 48 hrs into the HD-LZ infusion and daily thereafter. Osmol gap was calculated using the following formula: (measured osmolality) ⫺ (calculated osmolarity), where calculated osmolarity ⫽ ([2 ⫻ sodium] ⫹ [glucose/ 18] ⫹ [blood urea nitrogen/2.8]) (23). Anion gap values were corrected for serum albumin, based on the principle that for every 1 g decline in the serum albumin, a 2.5 mmol/L decrease in the anion gap occurs (24). Also, serum potassium concentration was not used to calculate the anion gap. Serum PG concentrations were drawn 48 hrs into the HD-LZ infusion. The presence of PG accumulation, as evidenced by a hyperosmolar, high anion gap metabolic acidosis, was also assessed at that time. Anion gap of ⱖ15 mmol/L and osmol gap of ⱖ10 mOsm/L were considered clinically significant (based on our hospital laboratory’s reference values). All serum PG samples were sent to an outside laboratory, and gas chromatography was used for quantitative analysis (National Medical Services, Willow Grove, PA). Lorazepam doses were documented daily throughout the study period. The cumulative dose was defined as the total amount (mg/kg) of lorazepam received from the point the infusion started until the serum PG concentration was drawn. Cumulative HD-LZ was defined as the total amount (mg/kg) of lorazepam received from the point the HD-LZ infusion started until the serum PG concentration was drawn. The mean rate of infusion (mg·kg⫺1·hr⫺1) was also calculated for the cumulative lorazepam dose as well as the cumulative HD-LZ period. The cumulative PG dose received was also calculated based on the amount of PG (830 mg) found in the 2-mg/mL injectable lorazepam formulation (Ativan, Wyeth Laboratories, Philadelphia, PA) (20). Statistical analyses were performed using Sigma Stat version 2.03 (SPSS, Chicago, IL). Changes over time, for variables measured at multiple time points, were examined using the one-way repeated measures analysis of variance. Correlation coefficients were calculated using the Pearson product moment correlation. Linear regression analysis was used to examine the relationship between lorazepam dose, lorazepam infusion rate, osmol gap, and serum PG. RESULTS From January 1, 2003, to May 9, 2003, 70 consecutive intubated patients were initiated on a lorazepam infusion; 19 (27.1%) patients received HD-LZ. Ten patients were excluded, seven because they were undergoing dialysis and three patients for whom informed consent could not be obtained. Nine patients who received HD-LZ for ⱖ48 consecutive hours were enrolled in the study. The majority of patients were male (six males), with a mean age of 43 yrs (range, 20 – 62 yrs), mean weight of 95 kg (range, 73–130 kg), mean height of 65 inches (range, 50 –73 inches), and mean Acute Physiology and Chronic Health Evaluation II score of 21 (range, 11–37). Acute respiratory failure due to acute respiratory distress syndrome (n ⫽ 7) was the predominant reason for MICU admission. Septic shock (n ⫽ 1) and fatty liver of pregnancy (n ⫽ 1) were the other admitting diagnoses. Patient characteristics are displayed in Table 2. All study patients had a calculated creatinine clearance ⱖ50 mL/min at baseline. Elevated bilirubin (⬎1.2 mg/dL) was noted in three patients. In all patients, lorazepam was being used for sedation, concomitantly with opiates, during mechanical ventilation. The mean MICU length of stay was 23.3 ⫾ 15.0 days. Four of nine patients died in the MICU. The mean cumulative lorazepam dose received was 12.3 mg/kg (range, 7.5– 18.5), and the mean rate of infusion was 0.12 mg·kg⫺1·hr⫺1 (range, 0.06 – 0.21). The mean cumulative HD-LZ received was 8.1 mg/kg (range, 5.1–11.7), and the mean rate of infusion during the HD inCrit Care Med 2004 Vol. 32, No. 8 fusion period was 0.16 mg·kg⫺1·hr⫺1 (range, 0.11– 0.22). The mean duration of lorazepam infusion during the study period was 4.9 days (range, 2.1–12.4), and all patients received HD-LZ for a mean duration of 3.9 days (range, 2.0 – 6.8). Serum PG concentrations were obtained at a mean of 50.4 ⫾ 3.6 hrs, and the mean serum PG concentration was 199.6 mg/dL (range, 94 –350). The mean cumulative PG dose was 1219 mg/kg per day. With regard to lorazepam dose, no significant correlation between cumulative lorazepam dose (mg/kg) received and serum PG concentrations was found (p ⫽ .918). However, a significant correlation was observed between cumulative HD-LZ (mg/kg) and serum PG concentrations (r2 ⫽ .481, p ⫽ .038) as well as HD-LZ infusion rate (mg·kg⫺1·hr⫺1) and serum PG concentrations (r2 ⫽ .557, p ⫽ .021; Fig. 1). Also, no significant correlation between duration of lorazepam infusion and serum PG concentrations was observed (p ⫽ .637). Laboratory findings consistent with PG accumulation (hyperosmolar, high anion gap metabolic acidosis) were observed in six of nine (66.7%) patients. Two of these patients had evidence of elevated bilirubin at baseline. However, all patients had an elevated osmol gap at 48 hrs, and the mean osmol gap was 48.0 (range, 24.3– 67.1; Table 3). There were significant laboratory changes over time in the osmol gap and corrected anion gap. The corrected anion gap at 48 hrs into HD-LZ was higher compared with 24 hrs after discontinuation of HD-LZ, 16.8 vs. 15.1, respectively (p ⫽ .025). Also, the osmol gap decreased from 72 hrs into HD-LZ compared with 24 hrs after the discontinuation of HD-LZ, 47.7 vs. 40.1, respectively (p ⫽ .025). The mean serum creatinine did not change significantly from baseline to the end of the HD-LZ period (p ⫽ .650). The osmol gap strongly correlated with serum PG concentrations at 48 hrs (r2 ⫽ .804, p ⫽ .001; Fig. 2). DISCUSSION This is the first prospective study in critically ill adults correlating serum PG concentrations with the cumulative amount of HD-LZ (mg/kg) and rate of infusion of HD-LZ (mg·kg⫺1·hr⫺1). A very strong and clinically important predictor of serum PG concentrations was the osmol gap at 48 hrs into HD-LZ therapy. These results show that PG accumulates as early as 48 hrs into HD-LZ therapy. Crit Care Med 2004 Vol. 32, No. 8 Table 2. Baseline patient characteristics Patient Age, yrs Gender APACHE II Baseline CrCl, mL/min Bilirubin, mg/dL 1 2 3 4 5 6 7 8 9 22 53 62 51 54 24 57 44 20 F M M M M M F M F 37 27 14 11 12 28 18 26 12 96 63 88 56 100 76 50 71 76 0.4 0.8 0.4 1.0 0.7 0.2 1.4 1.5 1.3 APACHE, Acute Physiology and Chronic Health Evaluation. Figure 1. Correlation between high-dose lorazepam (HD-LZ) rate of infusion and serum propylene glycol (PG) concentrations at 48 hrs. Table 3. Laboratory variables consistent with propylene glycol (PG) accumulation Patient Corrected AG 1 2 3 4 5 6 7 8 9 15.8 19.5 21.3 17.8 13.3 14.5 16.0 12.0 21.3 Osmol Gap PG concentration, mg/dL pH Chloride, mmol/L HCO3, mmol/L Lactate, mmol/L 44.9 29.7 49.6 43.0 52.1 36.0 24.3 43.4 67.1 252 120 210 120 320 140 94 190 350 7.26 7.43 7.35 7.18 7.43 7.40 7.21 7.29 7.20 114 96 99 108 106 115 120 110 119 21 32 21 20 24 16 19 23 13 1.9 NA 4.0 2.3 NA NA NA 2.0 NA AG, anion gap; NA, not available. All data collected 48 hrs into high-dose lorazepam infusion. Patients should be monitored early during therapy that contains PG to help avoid complications and toxicities associated with the compound. Interestingly, we did not show a correlation between cumulative lorazepam dose and serum PG concentration at 48 hrs. A pediatric intensive care unit study showed a significant correlation (r2 ⫽ .65, p ⬍ .005) between cumulative lorazepam dose and end-of-therapy PG concentrations in 11 patients re1711 Figure 2. Correlation between serum propylene glycol (PG) concentrations and osmol gap at 48 hrs. ceiving a mean lorazepam dose of 0.2 mg·kg⫺1·hr⫺1 (range, 0.1– 0.33) for a mean of 8 days (25). In contrast to our study, significant changes in laboratory abnormalities consistent with PG accumulation were not observed in the pediatric population. A possible explanation may be due to the lower mean PG concentration observed at 48 hrs. Chicella et al. (25) showed a mean PG concentration of 51.9 mg/dL at 48 hrs, compared with our mean PG concentration of 199 mg/dL at 48 hrs. A direct comparison between the two studies is limited by obvious differences in study populations and the choice of laboratory markers used to document the presence of PG accumulation. Our correlation with HD-LZ and lack of correlation with cumulative lorazepam may be partially explained by the metabolism of PG. PG displays nonlinear pharmacokinetics with capacity-limited metabolism in healthy volunteers (26, 27). Approximately 12– 45% of PG is excreted unchanged in the urine, and the remainder is metabolized by the liver to pyruvic acid and lactic acid. For ICU sedation, HD-LZ may overwhelm hepatic metabolism and/or renal elimination if renal insufficiency exists, thus increasing the risk of PG accumulation. The time frame that we studied may also explain why we only observed a correlation between HD-LZ and PG concentration. The infusion of HD-LZ may administer a PG load faster than the patients can metabolize and/or eliminate the compound, subsequently leading to accumulation. This concept was demonstrated by Hayman et al. (28), 1712 who described PG-associated toxicity only after the addition of intravenous trimethoprim-sulfamethoxazole to a patient receiving continuous lorazepam infusion. We did not observe renal toxicity during our study period; however, there have been two recent reports of PG-associated renal toxicity. In a retrospective chart review by Yaucher et al. (29), eight patients developed an increase in serum creatinine while receiving continuous infusion of lorazepam. The mean cumulative dose of lorazepam in this study was 4305 mg and the median lorazepam infusion duration was 8 days. The mean PG obtained at the peak serum creatinine was 1103 g/mL (110 mg/dL). Similar to our findings, the authors found a correlation between the osmol gap and PG concentration (r ⫽ .80). However, we did not observe an increase in the serum creatinine in our population; this may be due to the time interval that we studied (48 hrs of HD-LZ). In the report by Yaucher et al., the median time to serum creatinine increase was 9 days. At the time of peak serum creatinine, lorazepam dose was ⬎10 mg/hr in five of eight patients. Hayman et al. (28) reported a case of acute tubular necrosis secondary to the administration of two medications that contain propylene glycol, lorazepam and trimethoprim-sulfamethoxazole. Acute tubular necrosis was identified after 9 days of continuous infusion of lorazepam and 3 days of intravenous trimethoprimsulfamethoxazole. The patient received an average lorazepam dose of 7.5 mg/hr but developed renal toxicity after the addition of trimethoprim-sulfamethoxazole, which separately added 123 g of propylene glycol. Since serum PG concentrations are not readily available at most institutions, theoretical formulas for predicting serum PG concentrations from osmol gaps have been suggested. Most of these proposed formulas are based on the pediatric population and have not been validated in critically ill adults (30, 31). As suggested by our linear regression analysis, a theoretical formula for predicting serum PG concentrations from the osmol gap is (⫺82.1 ⫹ [osmol gap ⫻ 6.5]). This formula needs to be validated and perhaps refined using a larger population. However, our preliminary data suggest that osmol gap may be a clinically useful tool to help monitor for PG accumulation while patients are receiving HD-LZ. Equations such as these, after validation, may help identify as early as 48 hrs those patients in whom PG accumulation may be occurring. Limitations of our study include the criteria that were used to define PG accumulation. The presence of PG accumulation was based on laboratory abnormalities, which did not permit identification of more serious toxicities that have been reported in the literature. These criteria for PG accumulation were chosen because, in combination, they correlate strongly with organic acidosis and the hyperosmolar state previously described with PG accumulation. In our population, six of nine patients demonstrated PG accumulation based on our definition. However, all patients had an osmol gap ⬎20, which may alone be an indication of PG accumulation and suggests that anion gap may be a poor indication of PG accumulation. Another limitation is that only one serum PG concentration was obtained, which did not allow us to assess the change in serum PG concentrations alongside the change in lorazepam dose over the study period. Last, only patients on HD-LZ were studied, because we believed that this was the patient population at greatest risk for PG accumulation, due to the potential amount of PG administered. Patients who are receiving lorazepam at ⬍10 mg/hr may still be a risk for PG accumulation, and this population needs to be studied. Although we found a significant correlation between HD-LZ and serum PG concentrations, to more accurately identify the lorazepam dosing threshold Crit Care Med 2004 Vol. 32, No. 8 P ropylene glycol accumulation, as reflected by a hyper- osmolar anion gap metabolic acidosis, was observed in critically ill adults receiving continuous high-dose lorazepam infusion for ⱖ48 hrs. elevated osmol gap, was observed in critically ill adults receiving continuous HD-LZ (ⱖ10 mg/hr) infusion for ⱖ48 hrs. Study findings suggest, in critically ill adults, that serum PG concentrations may be predicted by the rate of HD-LZ infusion (mg·kg⫺1·hr⫺1) and the osmol gap. Furthermore, serum PG concentrations may be increased as early as 48 hrs after the initiation of HD-LZ. Clinically, these results may be applied to assess patients for PG accumulation and/or toxicity when serum PG concentrations are not readily available and to establish a lorazepam dosing threshold for PG accumulation and PG toxicity. ACKNOWLEDGMENTS for PG toxicity, future studies are needed to evaluate lorazepam at wider dosage ranges with serial serum PG concentrations. PG pharmacokinetic studies are limited mainly to noncritically ill patients; however, these studies demonstrate considerable intra- and interpatient variation in serum PG concentrations occurring over a narrow dosage range (26, 27). The critically ill population may display an even wider intra- and interpatient variation in serum PG concentrations than noncritically ill patients. This stresses the importance of further studies involving PG accumulation and toxicity in critically ill adults. Also, the relationship between PG concentration and actual toxicity is unknown, which suggests that PG concentrations are a surrogate end point of unclear significance at this time. Based on these findings, we recommend that patients should be monitored for PG accumulation and PG toxicity if they are receiving HD-LZ for ⱖ48 hrs. We recommended calculating an osmol gap to determine whether PG is accumulating. Monitoring an osmol gap in patients who are at risk of PG accumulation may be helpful to avoid complications and toxicities associated with elevated PG concentrations. Other causes of increased osmol gap should be evaluated. Patients with renal and hepatic dysfunction may need to be monitored more closely for PG accumulation. If PG accumulation does occur, it may be important to use another sedative to help avoid PG toxicities. CONCLUSIONS PG accumulation, as evidenced by a high anion gap metabolic acidosis with Crit Care Med 2004 Vol. 32, No. 8 We thank all of the medical intensive care nurses, respiratory therapists, dietitians, and physicians for their cooperation in this study and for their daily contributions to the multidisciplinary team and patient care. REFERENCES 1. D’Ambrosio JA, Borchardt-Phelps P, Nolen JG, et al: Propylene glycol induced lactic acidosis secondary to a continuous infusion of lorazepam. Abstr. Pharmacotherapy 1993; 13:274 2. Seay RE, Graves PG, Wilkin MK: Possible toxicity from propylene glycol in lorazepam infusion. Ann Pharmacother 1997; 31: 647– 648 3. Arbour R, Esparis B: Osmolar gap metabolic acidosis in a 60-year-old man treated for hypoxemic respiratory failure. Chest 2000; 118: 545–546 4. Reynolds HN, Teiken P, Regan ME, et al: Hyperlactatemia, increased osmolar gap, and renal dysfunction during continuous lorazepam infusion. Crit Care Med 2000; 28: 1631–1634 5. 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