Relationship of continuous infusion lorazepam to 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 relation- Measurements and Main Results: The mean cumulative high- ship between high-dose lorazepam and serum propylene glycol dose lorazepam received and mean high-dose lorazepam in- concentrations. Secondary objectives were a) to document the oc- fusion rate were 8.1 mg/kg (range, 5.1–11.7) and 0.16 currence of propylene glycol accumulation associated with continu- mg·kg؊1·hr؊1 (range, 0.11–0.22), respectively. A significant ous high-dose lorazepam infusion; b) to assess the relationship correlation between high-dose lorazepam infusion rate and ؍ between lorazepam dose, serum propylene glycol concentrations, serum propylene glycol concentrations was observed (r2 was the strongest predictor of .(021. ؍ and propylene glycol accumulation; and c) to assess the relationship .557, p .(001. ؍ p ,804. ؍ between the osmol gap and serum propylene glycol concentrations. serum propylene glycol concentrations (r2 Design: Prospective, observational study. Propylene glycol accumulation was observed in six of nine Setting: Tertiary care, medical intensive care unit. patients at 48 hrs. No significant correlation between duration Patients: Nine critically ill adults receiving high-dose loraz- of lorazepam infusion and serum propylene glycol concentra- .(637. ؍ epam (>10 mg/hr) infusion. tions was observed (p Interventions: Cumulative lorazepam dose (mg/kg) and the Conclusions: Propylene glycol accumulation, as reflected by a -rate of infusion (mg·kg؊1·hr؊1) were monitored from initiation of hyperosmolar , was observed in criti lorazepam infusion until 24 hrs after discontinuation of the high- cally ill adults receiving continuous high-dose lorazepam infusion for dose lorazepam infusion. Serum osmolarity was collected at 48 >48 hrs. Study findings suggest that in critically ill adults with hrs into the high-dose lorazepam infusion and daily thereafter. normal renal function, serum propylene glycol concentrations may be Serum propylene glycol concentrations were drawn at 48 hrs into predicted by the high-dose lorazepam infusion rate and osmol gap. the high-dose lorazepam infusion, and the presence of propylene (Crit Care Med 2004; 32:1709–1714) glycol accumulation, as evidenced by a high anion gap (>15 KEY WORDS: lorazepam; propylene glycol; toxicity; sedation; mmol/L) metabolic acidosis with elevated osmol gap (>10 mOsm/ adults; osmol gap L), was assessed at that time.

ropylene glycol (PG) is used as central nervous system depression (16– case series. Furthermore, interpretation a solvent for intravenous, oral, 18). The predominant manifestation of of the existing literature is limited by a) and topical pharmaceutical PG accumulation is a high anion gap the diversity of patients (age, renal fail- preparations, including intra- metabolic acidosis with elevated osmol ure, and/or liver failure) in whom PG Pvenous lorazepam. Chronic or large in- gap, most commonly reported with loraz- accumulation has been described; b) in- gestions of PG have been implicated in epam doses that exceed the upper limit of consistency in the criteria used to define the development of hyperosmolar meta- the recommended lorazepam dosage PG accumulation; and c) variability in the bolic acidosis (1–8) as well as serious range (0.1 mg·kgϪ1·hrϪ1) (19). Therefore, lorazepam dose received and reported PG toxicities, including renal dysfunction (4, patients requiring large doses of loraz- concentrations. Moreover, PG accumula- 9–12), intravascular hemolysis (13), car- epam for sedation may be at risk for PG tion has been described over a wide range diac arrhythmias (14), seizures (15), and accumulation. Each vial of lorazepam (2 of cumulative lorazepam doses (1124– mg/mL) contains 0.8 mL (830 mg) of 7226 mg), serum PG concentrations PG/mL, and critically ill patients could (12.0–130.8 mg/dL), and infusion periods receive more than the recommended (2–24 days) (1–8, 19). *See also p. 1800. Ϫ1 Ϫ1 From The Cleveland Clinic Foundation, Department daily amount of PG (25 mg·kg ·day ) To help elucidate the occurrence of of Pulmonary and Critical Care Medicine (ACA, KM) and (20). PG accumulation, we undertook a pro- Department of Pharmacy (NS, JPG), Cleveland, OH. Lorazepam is the medication of choice spective, observational study in critically Address request for reprints to: Jeffrey P. Gonza- for maintenance sedation in the critically ill patients receiving high-dose loraz- les, PharmD, BCPS, Cleveland Clinic Foundation, De- partment of Pharmacy/QQb5, 9500 Euclid Avenue, ill population (19). Currently, there is a epam (HD-LZ) by continuous infusion. Cleveland, OH 44195. E-mail: [email protected] paucity of data describing lorazepam- We also wanted to determine whether PG Copyright © 2004 by the Society of Critical Care induced PG accumulation and/or toxicity accumulation occurred early in therapy Medicine and Lippincott Williams & Wilkins in critically ill adults, with the majority of (at 48 hrs) because most of the data de- DOI: 10.1097/01.CCM.0000134831.40466.39 literature consisting of case reports or scribing PG accumulation involve infu-

Crit Care Med 2004 Vol. 32, No. 8 1709 sion periods Ͼ48 hrs. The primary objec- Table 1. Commonly used intravenous drugs containing propylene glycol tive was to evaluate the relationship between continuous infusion of HD-LZ Amount of Propylene (Ն10 mg/hr) and serum PG concentra- Drug Glycol (% v/v) tions early during therapy (at 48 hrs into Lorazepam, 2 mg/mL 80 HD-LZ infusion). Secondary objectives Phenobarbital, 30–130 mg/mL 67.8–75 were a) to document the occurrence of Diazepam, 5 mg/mL 40 PG accumulation associated with contin- Pentobarbital, 50 mg/mL 20–40 uous HD-LZ infusion; b) to assess the Phenytoin, 50 mg/mL 40 Trimethoprim-sulfamethoxazole, 16:80 mg/mL 40 relationship between lorazepam dose, se- Etomidate, 2 mg/mL 35 rum PG concentrations, and PG accumu- Nitroglycerin, 5 mg/mL 30 lation; and c) to assess the relationship Esmolol, 250 mg/mL 25 between the osmol gap and serum PG concentrations, all at 48 hrs into HD-LZ Data adapted (2, 7, 29). infusion. til the start of HD-LZ. Subsequent data were using the Pearson product moment correla- MATERIALS AND METHODS collected until 24 hrs after discontinuation of tion. Linear regression analysis was used to the HD-LZ infusion. Serum osmolality was examine the relationship between lorazepam This study was approved by our Institu- collected 48 hrs into the HD-LZ infusion and dose, lorazepam infusion rate, osmol gap, and tional Review Board, and written informed daily thereafter. Osmol gap was calculated us- serum PG. consent for participation in the study was ob- ing the following formula: (measured osmola- Ϫ tained. Our medical intensive care unit lity) (calculated osmolarity), where calcu- RESULTS (MICU) sedation guidelines recommend loraz- lated osmolarity ϭ ([2 ϫ sodium] ϩ [/ epam by intermittent bolus or continuous in- 18] ϩ [/2.8]) (23). Anion From January 1, 2003, to May 9, fusion as the benzodiazepine of choice for gap values were corrected for serum albumin, 2003, 70 consecutive intubated patients maintenance sedation, which is consistent based on the principle that for every1gde- were initiated on a lorazepam infusion; with the current Society of Critical Care Med- cline in the serum albumin, a 2.5 mmol/L 19 (27.1%) patients received HD-LZ. icine Sedation Guidelines (19). Sedation is decrease in the anion gap occurs (24). Also, Ten patients were excluded, seven be- used only after the provision of adequate an- serum potassium concentration was not used cause they were undergoing dialysis algesia and is titrated and reevaluated daily to calculate the anion gap. Serum PG concen- and three patients for whom informed using the Motor Activity Assessment Scale trations were drawn 48 hrs into the HD-LZ consent could not be obtained. Nine (21). By clinical observation, in our patient infusion. The presence of PG accumulation, as patients who received HD-LZ for Ն48 population, a dose of lorazepam of Ն10 mg/hr evidenced by a hyperosmolar, high anion gap corresponds to a dose of Ն0.1 mg·kgϪ1·hrϪ1, metabolic acidosis, was also assessed at that consecutive hours were enrolled in the which is the upper limit suggested by the time. Anion gap of Ն15 mmol/L and osmol study. The majority of patients were Society of Critical Care Medicine Sedation gap of Ն10 mOsm/L were considered clinically male (six males), with a mean age of 43 Guidelines (19). MICU patients receiving significant (based on our hospital laboratory’s yrs (range, 20– 62 yrs), mean weight of HD-LZ (Ն10 mg/hr) were eligible for enroll- reference values). All serum PG samples were 95 kg (range, 73–130 kg), mean height ment. Patients were excluded if they received sent to an outside laboratory, and gas chroma- of 65 inches (range, 50–73 inches), and other PG-containing medications by continu- tography was used for quantitative analysis mean Acute Physiology and Chronic ous or intermittent infusion or if they were (National Medical Services, Willow Grove, PA). Health Evaluation II score of 21 (range, undergoing dialysis. Patients were also ex- Lorazepam doses were documented daily 11–37). Acute respiratory failure due to cluded if they presented with , metha- throughout the study period. The cumulative acute respiratory distress syndrome (n ϭ 7) nol, or intoxication or if they dose was defined as the total amount (mg/kg) was the predominant reason for MICU ad- received medications or compounds that of lorazepam received from the point the in- mission. Septic shock (n ϭ 1) and fatty would affect the osmol gap. Table 1 lists some fusion started until the serum PG concentra- liver of pregnancy (n ϭ 1) were the other parenteral medications containing PG that tion was drawn. Cumulative HD-LZ was de- admitting diagnoses. Patient characteris- may be administered to critically ill patients fined as the total amount (mg/kg) of tics are displayed in Table 2. All study pa- (2, 7, 29). lorazepam received from the point the HD-LZ tients had a calculated Patient characteristics collected at baseline infusion started until the serum PG concen- Ն50 mL/min at baseline. Elevated included patient age, gender, weight, admit- tration was drawn. The mean rate of infusion Ͼ Ϫ1 Ϫ1 ( 1.2 mg/dL) was noted in three patients. ting diagnosis, and Acute Physiology and (mg·kg ·hr ) was also calculated for the In all patients, lorazepam was being used Chronic Health Evaluation II score at admis- cumulative lorazepam dose as well as the cu- for sedation, concomitantly with opiates, sion. Laboratory variables (serum sodium, po- mulative HD-LZ period. The cumulative PG during mechanical ventilation. The mean tassium, chloride, glucose, blood urea nitro- dose received was also calculated based on the Ϯ gen, creatinine, , amount of PG (830 mg) found in the 2-mg/mL MICU length of stay was 23.3 15.0 days. bilirubin, alanine aminotransferase, aspartate injectable lorazepam formulation (Ativan, Four of nine patients died in the MICU. aminotransferase), as well as arterial blood Wyeth Laboratories, Philadelphia, PA) (20). The mean cumulative lorazepam dose received was 12.3 mg/kg (range, 7.5– gases (pH, PaCO2,PaO2, HCO3, oxygen satura- Statistical analyses were performed using tion), were monitored daily throughout the Sigma Stat version 2.03 (SPSS, Chicago, IL). 18.5), and the mean rate of infusion was Ϫ1 Ϫ1 study period. Creatinine clearance was calcu- Changes over time, for variables measured at 0.12 mg·kg ·hr (range, 0.06–0.21). lated using the Cockcroft-Gault equation (22). multiple time points, were examined using the The mean cumulative HD-LZ received After enrollment, data were collected from the one-way repeated measures analysis of vari- was 8.1 mg/kg (range, 5.1–11.7), and the time the lorazepam infusion was initiated un- ance. Correlation coefficients were calculated mean rate of infusion during the HD in-

1710 Crit Care Med 2004 Vol. 32, No. 8 fusion period was 0.16 mg·kgϪ1·hrϪ1 Table 2. Baseline patient characteristics (range, 0.11–0.22). The mean duration of lorazepam infusion during the study pe- Baseline CrCl, Bilirubin, riod was 4.9 days (range, 2.1–12.4), and Patient Age, yrs Gender APACHE II mL/min mg/dL all patients received HD-LZ for a mean 1 22 F 37 96 0.4 duration of 3.9 days (range, 2.0–6.8). Se- 2 53 M 27 63 0.8 rum PG concentrations were obtained at 3 62 M 14 88 0.4 a mean of 50.4 Ϯ 3.6 hrs, and the mean 4 51 M 11 56 1.0 serum PG concentration was 199.6 5 54 M 12 100 0.7 6 24 M 28 76 0.2 mg/dL (range, 94–350). The mean cumu- 7 57 F 18 50 1.4 lative PG dose was 1219 mg/kg per day. 8 44 M 26 71 1.5 With regard to lorazepam dose, no sig- 9 20 F 12 76 1.3 nificant correlation between cumulative lorazepam dose (mg/kg) received and se- APACHE, Acute Physiology and Chronic Health Evaluation. rum PG concentrations was found (p ϭ .918). However, a significant correlation was observed between cumulative HD-LZ (mg/kg) and serum PG concentrations (r2 ϭ .481, p ϭ .038) as well as HD-LZ infu- sion rate (mg·kgϪ1·hrϪ1) and serum PG concentrations (r2 ϭ .557, p ϭ .021; Fig. 1). Also, no significant correlation be- tween duration of lorazepam infusion and serum PG concentrations was observed (p ϭ .637). Laboratory findings consistent with PG accumulation (hyperosmolar, high anion gap metabolic acidosis) were ob- served 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 Figure 1. Correlation between high-dose lorazepam (HD-LZ) rate of infusion and serum propylene into HD-LZ was higher compared with 24 glycol (PG) concentrations at 48 hrs. hrs after discontinuation of HD-LZ, 16.8 vs. 15.1, respectively (p ϭ .025). Also, the Table 3. Laboratory variables consistent with propylene glycol (PG) accumulation osmol gap decreased from 72 hrs into HD-LZ compared with 24 hrs after the PG Corrected concentration, Chloride, HCO , Lactate, discontinuation of HD-LZ, 47.7 vs. 40.1, 3 Patient AG Osmol Gap mg/dL pH mmol/L mmol/L mmol/L respectively (p ϭ .025). The mean serum creatinine did not change significantly 1 15.8 44.9 252 7.26 114 21 1.9 from baseline to the end of the HD-LZ 2 19.5 29.7 120 7.43 96 32 NA period (p ϭ .650). The osmol gap strongly 3 21.3 49.6 210 7.35 99 21 4.0 correlated with serum PG concentrations 4 17.8 43.0 120 7.18 108 20 2.3 2 ϭ ϭ 5 13.3 52.1 320 7.43 106 24 NA at 48 hrs (r .804, p .001; Fig. 2). 6 14.5 36.0 140 7.40 115 16 NA 7 16.0 24.3 94 7.21 120 19 NA DISCUSSION 8 12.0 43.4 190 7.29 110 23 2.0 9 21.3 67.1 350 7.20 119 13 NA This is the first prospective study in AG, anion gap; NA, not available. critically ill adults correlating serum PG All data collected 48 hrs into high-dose lorazepam infusion. concentrations with the cumulative amount of HD-LZ (mg/kg) and rate of infusion of HD-LZ (mg·kgϪ1·hrϪ1). A very Patients should be monitored early dur- dose and serum PG concentration at 48 strong and clinically important predictor ing therapy that contains PG to help hrs. A pediatric intensive care unit of serum PG concentrations was the os- avoid complications and toxicities associ- study showed a significant correlation mol gap at 48 hrs into HD-LZ therapy. ated with the compound. (r2 ϭ .65, p Ͻ .005) between cumula- These results show that PG accumulates Interestingly, we did not show a cor- tive lorazepam dose and end-of-therapy as early as 48 hrs into HD-LZ therapy. relation between cumulative lorazepam PG concentrations in 11 patients re-

Crit Care Med 2004 Vol. 32, No. 8 1711 but developed renal toxicity after the ad- dition of trimethoprim-sulfamethox- azole, 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 pop- ulation and have not been validated in critically ill adults (30, 31). As suggested by our linear regression analysis, a theo- retical formula for predicting serum PG concentrations from the osmol gap is (Ϫ82.1 ϩ [osmol gap ϫ 6.5]). This for- mula needs to be validated and perhaps refined using a larger population. How- ever, our preliminary data suggest that osmol gap may be a clinically useful tool to help monitor for PG accumulation Figure 2. Correlation between serum propylene glycol (PG) concentrations and osmol gap at 48 hrs. while patients are receiving HD-LZ. Equations such as these, after validation, ceiving a mean lorazepam dose of 0.2 who described PG-associated toxicity only may help identify as early as 48 hrs those mg·kgϪ1·hrϪ1 (range, 0.1– 0.33) for a after the addition of intravenous tri- patients in whom PG accumulation may mean of 8 days (25). In contrast to our methoprim-sulfamethoxazole to a patient be occurring. study, significant changes in laboratory receiving continuous lorazepam infusion. Limitations of our study include the abnormalities consistent with PG accu- We did not observe renal toxicity dur- criteria that were used to define PG ac- mulation were not observed in the pe- ing our study period; however, there have cumulation. The presence of PG accumu- diatric population. A possible explanation been two recent reports of PG-associated lation was based on laboratory abnormal- may be due to the lower mean PG concen- renal toxicity. In a retrospective chart ities, which did not permit identification tration observed at 48 hrs. Chicella et al. review by Yaucher et al. (29), eight pa- of more serious toxicities that have been (25) showed a mean PG concentration of tients developed an increase in serum reported in the literature. These criteria 51.9 mg/dL at 48 hrs, compared with our creatinine while receiving continuous in- for PG accumulation were chosen be- mean PG concentration of 199 mg/dL at 48 fusion of lorazepam. The mean cumula- cause, in combination, they correlate hrs. A direct comparison between the two tive dose of lorazepam in this study was strongly with organic acidosis and the studies is limited by obvious differences in 4305 mg and the median lorazepam in- hyperosmolar state previously described study populations and the choice of labora- fusion duration was 8 days. The mean PG with PG accumulation. In our popula- tory markers used to document the pres- obtained at the peak serum creatinine tion, six of nine patients demonstrated ence of PG accumulation. was 1103 ␮g/mL (110 mg/dL). Similar to PG accumulation based on our definition. Our correlation with HD-LZ and lack our findings, the authors found a corre- However, all patients had an osmol gap of correlation with cumulative lorazepam lation between the osmol gap and PG Ͼ20, which may alone be an indication of may be partially explained by the metab- concentration (r ϭ .80). However, we did PG accumulation and suggests that anion olism of PG. PG displays nonlinear phar- not observe an increase in the serum gap may be a poor indication of PG accu- macokinetics with capacity-limited me- creatinine in our population; this may be mulation. Another limitation is that only tabolism in healthy volunteers (26, 27). due to the time interval that we studied one serum PG concentration was ob- Approximately 12–45% of PG is excreted (48 hrs of HD-LZ). In the report by tained, which did not allow us to assess unchanged in the , and the remain- Yaucher et al., the median time to serum the change in serum PG concentrations der is metabolized by the liver to pyruvic creatinine increase was 9 days. At the alongside the change in lorazepam dose acid and . For ICU sedation, time of peak serum creatinine, lorazepam over the study period. Last, only patients HD-LZ may overwhelm hepatic metabo- dose was Ͼ10 mg/hr in five of eight pa- on HD-LZ were studied, because we be- lism and/or renal elimination if renal in- tients. lieved that this was the patient popula- sufficiency exists, thus increasing the risk Hayman et al. (28) reported a case of tion at greatest risk for PG accumulation, of PG accumulation. The time frame that acute tubular necrosis secondary to the due to the potential amount of PG admin- we studied may also explain why we only administration of two medications that istered. Patients who are receiving loraz- observed a correlation between HD-LZ contain propylene glycol, lorazepam and epam at Ͻ10 mg/hr may still be a risk for and PG concentration. The infusion of trimethoprim-sulfamethoxazole. Acute PG accumulation, and this population HD-LZ may administer a PG load faster tubular necrosis was identified after 9 needs to be studied. than the patients can metabolize and/or days of continuous infusion of lorazepam Although we found a significant cor- eliminate the compound, subsequently and 3 days of intravenous trimethoprim- relation between HD-LZ and serum PG leading to accumulation. This concept sulfamethoxazole. The patient received concentrations, to more accurately was demonstrated by Hayman et al. (28), an average lorazepam dose of 7.5 mg/hr identify the lorazepam dosing threshold

1712 Crit Care Med 2004 Vol. 32, No. 8 elevated osmol gap, was observed in crit- 9. Laine GA, Hossain SM, Solis RT, et al: Poly- ically ill adults receiving continuous ethylene glycol nephrotoxicity secondary to ropylene glycol HD-LZ (Ն10 mg/hr) infusion for Ն48 prolonged high-dose intravenous lorazepam. Ann Pharmacother 1995; 29:1110–1114 accumulation, as hrs. Study findings suggest, in critically ill adults, that serum PG concentrations 10. Yorgin PD, Theodorou AA, Al-Uzri A, et al: Propylene glycol-induced proximal renal tu- reflected by a hyper- may be predicted by the rate of HD-LZ Ϫ1 Ϫ1 bular cell injury. Am J Kidney Dis 1997; P infusion (mg·kg ·hr ) and the osmol 30:134–139 osmolar anion gap metabolic gap. Furthermore, serum PG concentra- 11. Levy ML, Aranda M, Zelman V, et al: Pro- tions may be increased as early as 48 hrs pylene glycol toxicity following continuous acidosis, was observed in crit- after the initiation of HD-LZ. 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