Safety of Rapid Intravenous Loading of Valproate

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1 Epilepsia, 48(3): , 2007 Blackwell Publishing, Inc. C 2007 International League Against Epilepsy Safety of Rapid Intravenous Loading of Valproate Nita A. Limdi, Robert K. Knowlton, Stacey S. Cofield, Lawrence W. Ver Hoef, Alfred L. Paige, Sandeep Dutta, and Edward Faught Department of Neurology, University of Alabama at Birmingham Epilepsy Center; Department of Biostatistics, University of Alabama at Birmingham; and Abbott Laboratories, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A. Summary: Background: The introduction of IV valproic acid (VPA) has facilitated its use in situations where oral administration is not feasible. The present study was designed to evaluate the safety of administration of undiluted VPA (20 or 30 mg/kg/min) administered intravenously at rates of 6 or 10 mg/kg/min. Methods: Forty patients received a VPA loading dose (20 or 30 mg/kg) at 6 or 10 mg/kg/min. Heart rate (HR), mean arterial pressure (MAP), oxygen saturation, respiratory rate, and three lead ECG measurements were taken at baseline. Following dose administration the measurements were repeated at 2.5-min intervals for the first 20 min, then at 30, 45, 60 min, and 4 h. Local tolerance was defined as absence of irritation or phlebitis at the site of injection. Systemic tolerability was defined as absence of significant changes in vital signs and level of consciousness (LOC). Changes in vital signs and local intolerance scores were compared across time using repeated measures analysis of variance. Results: Rapid administration was well tolerated with no significant changes in HR (p = 0.9) or MAP (p = 0.7). Complaints of local irritation were transient, lasting less than 3 min in all patients with no indication of redness, irritation, or phlebitis. No patient exhibited a decline in the LOC. Conclusions: Rapid administration of undiluted valproate is safe and well tolerated at infusion rate up to 10 mg/kg/min and doses of up to 30 mg/kg. The lack of serious cardiovascular, neurological, hepatic, or local adverse effects supports the use of VPA in emergent situations. Key Words: Safety Intravenous Valproate Loading doses Pharmacokinetics. Valproic acid (VPA) is widely used in the treatment of epilepsy, migraines, and psychiatric disorders and has an increasing role in the management of behavioral problems in elderly patients (Davis et al., 1994; Perucca, 2002). In 1996 the US Food and Drug Administration approved the intravenous (IV) formulation of VPA for use when clinical factors make oral VPA administration difficult or impossible. Original labeling indicates that VPA should be administered over a period of 60 min at rates up to 20 mg/min and recommends that doses exceeding 250 mg should be given in divided doses. Although earlier studies established the safety of IV administration of VPA (Devinsky et al., 1995; Ramsay, 1997; Wheless and Venkataraman, 1998), slow infusion rates limited its use in emergent situations such as seizure clusters, status epilepticus (SE), or rapid introduction of a new agent if seizures are uncontrolled on baseline medications. In the past few years, several studies have demonstrated the safety of rapid administration (up to 6 mg/kg/min) Accepted November 6, Address correspondence and reprint requests to Nita A. Limdi at Department of Neurology, University of Alabama at Birmingham, th Avenue South, CIRC-312, Birmingham, AL , U.S.A. nlimdi@uab.edu doi /j x of VPA loading doses (up to 45 mg/kg) (Venkataraman and Wheless, 1999; Wheless et al., 2004). One recent study established the safety of rapid (1.5 mg/kg/min or 3.0 mg/kg/min) administration of VPA doses of up to 15 mg/kg with a minimal dilution of 1:5 (Ramsay et al., 2003). The present study was designed to evaluate the safety of administration of undiluted VPA (20 or 30 mg/kg/min) administered intravenously at rates of 6 or 10 mg/kg/min. METHODS Study design and subject selection This was an open-label, prospective, trial of rapid IV loading of VPA sodium in patients with epilepsy admitted to the epilepsy monitoring unit. Patients over 19 years of age, who were either taking VPA to control seizures or had an epilepsy indication for its use, were eligible to participate in the study. Patients with known allergy to VPA, liver disease, SE, or concurrent high-dose lamotrigine therapy (>200 mg/day) were excluded. The absence of liver disease was confirmed by assessment of admission laboratory values and medical history. All subjects provided informed consent before entering the study. The study protocol necessitated a 24-h observation period after 478

2 RAPID INTRAVENOUS LOADING OF VALPROATE 479 administration of VPA loading dose. The study was approved by the Institutional Review Board at the University of Alabama at Birmingham (UAB). Dose administration VPA sodium injection (Depacon, Abbott Laboratories) was supplied in 5-ml single-use vials. Each milliliter contained VPA sodium equivalent to 100 mg of valproic acid. All doses were decided by the treating physician. Twenty patients received a VPA loading dose of 20 mg/kg and another 20 patients received a dose of 30 mg/kg. Within each dose group, the patients were equally divided into two cohorts of 10 to receive VPA infusion at the rates of 6 mg/kg/min or 10 mg/kg/min. A rate of 6 mg/kg/min translates an administration time of 3.3 min for a 20 mg/kg dose and 5 min for a 30 mg/kg dose. A rate of 10 mg/kg/min translates an administration time of 2 min for a 20 mg/kg dose and 3 min for a 30 mg/kg dose. All doses were administered undiluted through peripheral access by manual injection using a stopwatch to monitor administration rate. The patency of IV access was confirmed with a saline flush before and after dose administration. Maintenance dosing was initiated using oral formulations of VPA as directed by the treating physician. Monitoring systemic and local tolerability Cardiovascular parameters and signs of local irritation were monitored closely. Systemic tolerability was defined as the absence of significant changes in vital signs and level of consciousness (LOC). Changes were considered significant if they required medical attention and or medical intervention. The LOC tool of the NIH Stroke Scale criteria was used to assess the effect of rapid infusion on LOC. Heart rate (HR), mean arterial pressure (MAP), oxygen saturation, respiratory rate, and three-lead ECG measurements were taken at baseline. Following dose administration these measurements were repeated at 2.5-min intervals for the first 20 min, then at 30, 45, 60 min, and 4 h. Local tolerance was defined as the absence of irritation or phlebitis at the site of injection. Patients were asked to grade pain at the site of injection on a scale of 0 to 10. Patients were asked to report any other sensations on a similar scale. These assessments were recorded before and during drug administration and continuously thereafter until the patient reported return to baseline scores. The interval between the onset of discomfort and its cessation defined the duration of local intolerance. Laboratory monitoring and determination of valproate plasma concentrations Ammonia, complete blood count with platelets, total bilirubin, direct bilirubin, calculated indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, amylase, and lipase were measured at baseline (before infusion), 1 h and 24 h after rapid infusion of valproic acid. Plasma concentrations of VPA (total and unbound) were measured at baseline, 5, 10, 15, 30, 60, and 240 min postinfusion in the first 20 patients. Based on pharmacokinetic analysis from the cohort of first 20 patients, the frequency for drug concentration monitoring was reduced to the baseline, at 30, 60, and 240-min time points. All samples were shipped at room temperature to MedTox (St. Paul, MN, U.S.A.). VPA concentrations were determined by ultrafiltration immunoassay. The lower limits of quantification for both total and unbound VPA in plasma were 0.7 µg/ml. All blood samples were collected by direct venipuncture or a second indwelling catheter (not used for drug administration) into appropriately labeled collection tubes. In the latter case the initial volume (5 ml) was discarded to ensure reliability of the blood sample. Statistical analysis Chi-square tests were used to assess differences in the frequencies in categorical variables and one-way analysis of variance (ANOVA) was used to assess differences in the continuous variables between the two dose groups (20 mg/kg and 30 mg/kg) and two infusion rates (6 and 10 mg/kg/min). Differences in continuous variables exhibiting unequal variances were evaluated using Welch- ANOVA. Wilcoxon rank sum test statistics are reported where appropriate. Changes in vital signs and local intolerance scores were compared across time (baseline to 1 h) using repeated measures ANOVA. All analyses were performed using JMP version 5.1 (SAS Institute, Cary, NC, U.S.A.) at a nondirectional α-level of RESULTS Forty patients (27 men, mean age 39 [SD ± 14.6, range 19 77] years) received VPA loading doses as part of their treatment. The majority of the patients were white (n = 28) or black (n = 9). Two patients were Hispanic and one was Asian. The average weight was 81.6 ± 23.1 kg and average dose was 1,993.8 ± mg. There were no differences by race or gender between dose groups (20 mg/kg and 30 mg/kg, p > 0.1) or infusion rate groups (6 mg/kg/min or 10 mg/kg/min, p > 0.3). Patients on concomitant therapy with enzyme-inducing antiepileptic drugs (EIAEDs) were more likely to receive higher loading dose (30 mg/kg) of VPA (p = 0.016). Fifteen patients (11 in the 20 mg/kg dose group) were on prior VPA therapy. VPA concentrations did not differ at baseline (Table 1) although the large variance and small sample size make this comparison tenuous. Plasma VPA total and unbound concentration-time profiles are shown in Fig. 1A. Changes in total VPA concentrations were significantly influenced by time since administration (p < ), dose (p = ), and cotherapy

3 480 N. A. LIMDI ET AL. TABLE 1. VPA dose, total, and unbound valproic acid concentrations by dose group Dose, Dose, 20 mg/kg 30 mg/kg (n = 20) (n = 20) p-value Weight 91.8 (27.8) 73.2 (14.2) Cotherapy with enzyme-inducing AED No 17 (85.0%) 10 (50.0%) Yes 3 (15.0%) 10 (50.0%) Valproate dose (mg) 1,834.0 (556.1) 2,190.6 (439.3) Total VPA concentration ( µg/ml) Baseline 12.0 (12.7) 28.8 (35.9) min (29.4) (33.2) min (25.1) (37.0) min (25.5) (40.1) min (18.4) (41.3) min (20.9) (47.7) min 118 (20.6) (35.1) h 75.7 (19.3) 79.2 (26.3) 0.65 Unbound VPA concentration (6 20 µg/ml) Baseline 1.4 (0.63) 19.1 (14.4) min 34.3 (11.5) 77.1 (43.5) min 30.6 (9.5) 69.6 (37.6) min 30.1 (10.1) 62.9 (43.0) min 24.6 (6.4) 50.2 (23.5) min 22.2 (5.8) 40.9 (23.0) min 21.5 (7.2) 39.1 (27.8) h 10.1 (5.6) 17.5 (18.5) 0.1 Two Hispanics, one Asian. VPA concentrations at 5, 10, 15, and 45 min determined in the first 20 patients only. Continuous variables are denoted as mean (SD). Four patients in the 30 mg/kg and 11 patients in the 20 mg/kg group were on prior VPA therapy. Enzyme-inducing AEDs: phenytoin, phenobarbital, carbamazepine, primidone. VPA concentrations were determined by MedTox laboratories (St. Paul, MN, U.S.A.). Patients with missing laboratory measurements at specific time points were excluded from analysis at that specific time point. Significant p-values are denoted in bold. EIAEDs (p < ). Loading doses of 30 mg/kg produced higher total (difference 20 µg/ml, p = 0.002) and unbound VPA concentrations (difference 23.2 µg/ml, p < ) compared to 20 mg/kg (Fig. 1B). At 4 h total and unbound VPA concentrations were similar in both dose groups (Table 1, Fig. 1B). Patients on EIAEDs achieved lower total VPA concentrations compared to patients not on EIAEDs (Fig. 1C). Among patients receiving 30 mg/kg dose total VPA concentrations were significantly higher in patients not on EIAEDs than those on EIAEDs (difference = 30.5 µg/ml, p = 0.023). Among patients receiving 20 mg/kg dose total VPA concentrations were not influenced by co-therapy with EIAEDs (difference = 8.9 µg/ml). Changes in unbound VPA concentrations were significantly influenced by time (p < ), age (p = ), and dose (p < ). Unbound VPA concentrations were marginally higher in patients on EIAEDs than in patients not on concurrent EIAEDs (Fig. 1C). FIG. 1. Mean plasma total and unbound VPA concentration-time profiles. Error bars represent standard deviation. (A) Unbound vs. total plasma VPA concentration profile over time. (B) Unbound vs. total plasma VPA concentration profile over time comparing 20mg/kg vs. 30 mg/kg loading dose. (C) Unbound vs. total plasma VPA concentration profile over time stratified by concomitant therapy with enzyme inducing AEDs. Patients in the two dosing groups did not differ with regard to laboratory parameters at baseline. There were no significant changes in platelets, bilirubin, hepatic transaminases, alkaline phosphatase, amylase, or lipase following VPA administration. Local tolerance Most patients (n = 38) received the dose through a peripheral IV of 20 (n = 35) or 22 (n = 3) gauge. The characteristics of peripheral access did not differ by dose group (p = 0.68) or by infusion rate group (p = 0.61). Two patients who received loading dose through central IV access were excluded from the analysis for local intolerance. Of the 38 patients evaluated, 31 (81.5%) patients complained of pain/burning (n = 23) and or paresthesias (n = 23) during the rapid administration of loading doses. Paresthesias were described as numbness, tingling, and chilling sensations and were more frequent in the

4 RAPID INTRAVENOUS LOADING OF VALPROATE 481 TABLE 2. Severity and duration of local intolerance in patients (n = 38) with peripheral IV access Dose group (mg/kg) Infusion rate (mg/kg/min) All Characteristic (n = 38) 20 (n = 20) 30 (n = 20) p-value 6 (n = 20) 10 (n = 20) p-value Any pain/burning or paresthesias Pain/burning (n = 23) 5.6 (2.4) 5.5 (2.5) 5.9 (2.3) (2.2) 5.9 (2.7) 0.63 Paresthesias (n = 23) 2.7 (3.2) 2.9 (3.2) 2.3 (3.3) (2.5) 4.5 (2.9) Duration (minutes) 2.1 (0.5) 2.1 (0.5) 2.3 (0.4) (0.6) 2.1 (0.2) 0.47 Both pain/burning and paresthesias Pain/burning (n = 11) 5.8 (2.3) 6.3 (2.1) 5.0 (2.7) (2.8) 5.8 (2.4) 0.91 Paresthesias (n = 11) 5.6 (2.0) 5.8 (1.5) 5.2 (3.0) (2.8) 5.0 (2.0) 0.79 Duration (minutes) 2.3 (0.5) 2.3 (0.6) 2.4 (0.5) (0.1) 2.4 (0.5) 0.36 Significant p-value is denoted in bold. Paresthesias were described as numbness, tingling, and chilling sensations. All effects were graded on a scale of 1 to 10 (with 0 being none and 10 being the worst). Scores presented as mean and standard deviation (in parenthesis). faster infusion rate group (10 mg/kg/min, p = 0.005). All effects were graded on a scale of 0 to 10 (with 0 being no irritation and 10 being the worst, Table 2). Most patients recognized the initiation of these effects during the infusion, peaking toward the end of infusion and subsiding soon thereafter, lasting less than 3 min after the end of infusion. Rapid administration was well tolerated as the infusion did not have to slowed or discontinued. Reexamination of injection site at 4-h and 24-h postadministration showed no indication of redness, irritation, or phlebitis. Among patients complaining of pain, burning, or paresthesias, the duration of these effects did not differ by size (gauge) of peripheral IV (p = 0.13, Wilcoxon rank sum). The duration of local intolerance was independent of rate of administration (p = 0.77), dose (p = 0.72), age (0.66), and gender (p = 0.13). Systemic tolerance Overall the rapid administration of VPA was well tolerated with no significant changes in respiratory rate, oxygen saturation, HR, or MAP. There were no disturbances in cardiac conduction or arrhythmias as indicated by normal ECG in all patients at all time points. There were no significant differences in MAP (all p-values > 0.1) or HR (all p-values > 0.2) at any time point by dose group or infusion rate group (Fig. 1A, B). Repeated measures analysis indicated that changes in MAP (p = 0.7) and HR (p = 0.9) were not significant across time. Moderate to severe local irritation (pain, burning, or paresthesias) associated with rapid administration can result in changes in MAP and HR. To delineate the effects of transient irritation on vital signs we reanalyzed the changes in HR and MAP using two different strategies: 1. Although overall changes in MAP and HR were nonsignificant, Fig. 2A, B indicates that there may be an acute effect of rapid infusion on HR and MAP. Therefore we restricted analysis 1 to include measurements from baseline up to 5 min. Results of analysis 1: Acute changes in HR and MAP are influenced by occurrence of pain/burning and paresthesias. Early changes in HR are influenced by occurrence of paresthesias (p = 0.02), dose (mg/kg, p = 0.024), and age (p = 0.026) but not by gender (p = 0.9), occurrence of pain or burning (p = 0.87), time postadministration (p = 0.83), rate of infusion (p = 0.61), or the size of the IV (p = 0.31). Acute changes in MAP are influenced by age (p = 0.001), gender (p = 0.043), and occurrence of pain or burning (p < ) but not by dose (mg/kg, p = 0.64), occurrence of paresthesias (p = 0.63), rate of infusion (p = 0.45), time postadministration (p = 0.18), or size of the IV (p = 0.18). 2. Although not statistically significant, Fig. 2A, B also indicates that there are differences in HR by dose group and MAP by infusion rate group at baseline. Therefore we conducted a separate repeated measures analysis (analysis 2) including clinically relevant time points (end of infusion, 15, 30, and 60 min postadministration) using baseline measurements as predictor variables. Results of analysis 2: Change in HR across time was not influenced by dose (p = 0.35) or time since administration (p = 0.28). Age (p < ), HR at baseline (p < ), gender (p = ), and administration rate (p < ) were significant predictors of changes in HR. Women exhibited higher HR than men (difference 3.8, 95% CI [1.8, 5.9]). Patients receiving VPA at 6 mg/kg/min exhibited higher HR than those receiving VPA at 10 mg/kg/min (difference 5.9, 95% CI [3.8, 8.0]). Change in MAP across time was not influenced by dose (p = 0.68), age (p = 0.60), administration rate (p = 0.39), or gender (p = 0.17). Time since dose administration (p < ) and baseline MAP (p < ) were significant

5 482 N. A. LIMDI ET AL. FIG. 2. (A) Changes in heart rate (HR) and mean arterial pressure (MAP) by dose group (20 mg/kg, 30 mg/kg) across time (baseline to 60 min). End: denotes end of infusion. Repeated measures ANOVA indicates no significant changes in HR or MAP across time postadministration of loading dose. Although not significant, HR differed across dose groups at baseline (p = 0.31). This difference was maintained from baseline to 1 h postinfusion. (B) Changes in HR and MAP by infusion rate group (6 mg/kg/min, 10 mg/kg/min) across time (baseline to 60 min). End: denotes end of infusion. Repeated measures ANOVA indicates no significant changes in HR or MAP across time postadministration of loading dose. Although not significant, MAP differed across dose groups at baseline (p = 0.14). This difference was maintained from baseline to 1 h postinfusion. predictors. As depicted in Fig. 1A, B, the change in MAP was significant only between the end of infusion and 15-min time points. Other adverse effects LOC was evaluated at baseline and again at min after dose administration. No patient exhibited a decline in LOC. Three patients (7.5%) complained of sedation and one complained of nausea. DISCUSSION In our study the rapid IV administration of undiluted VPA was safe and well tolerated at infusion rates up to 10 mg/kg/min and doses of up to 30 mg/kg in inpatients with epilepsy. A loading dose of 30 mg/kg produced higher VPA concentrations (total and unbound) at 30 and 60 min compared to a dose of 20 mg/kg. The difference in VPA concentration was not significant at 4 h. In our study, the unbound fraction was 7.5% at a total VPA concentration of 50 mg/l or an unbound concentration of 4 mg/l. As total VPA concentration increases, saturation of albumin-binding sites results in a greater proportion of unbound drug. At a total VPA concentration of 150 mg/l, the mean unbound fraction rose to 22%, resulting in an unbound concentration of 34 mg/l. In addition to concentration-dependent alterations in binding, the unbound fraction varied among subjects by 2- to 4-fold, particularly at higher concentrations. As expected, peak VPA concentrations were not different between enzyme-induced and -uninduced patients because they depend primarily on the rate of drug administration and extent of drug distribution in the body (typically characterized by pharmacokinetic parameter apparent volume of distribution ). In contrast to previous reports (Scheyer et al., 1990; MacKichan and JJ, 1992), in our study the unbound VPA concentrations were higher in patients on EIAEDs up to 1 h post-vpa administration probably because a majority, 10 of 13, enzyme-induced patients were in the higher (30 mg/kg) dose group. However, the rate of decline in unbound concentrations is faster in patients on EIAEDs compared to patients not on EIAEDs with insignificant differences at 4 h (Fig. 1C), consistent with an increased VPA clearance due to enzyme induction. The safety and tolerability of large IV VPA doses have been documented by several studies. The safety of rapid infusion of high loading doses of IV VPA (range mg/kg, mean 24.2 mg/kg) was prospectively demonstrated in a study of 21 patients (age 2 54 years). Doses were administered at a rate of 3 or 6 mg/kg/min after dilution with 5% dextrose solution (Venkataraman and Wheless, 1999). Ramsay et al. (2003) established the safety of rapid infusion of VPA loading doses in 112 patients in an open-label, multicentered, randomized, prospective trial. An extensive list of exclusion criteria was instituted for patient screening. Patients received loading doses of up to 15 mg/kg at rates of 1.5 or 3.0 mg/kg/min. Doses were diluted with normal saline or 5% dextrose solution and administered through peripheral IV access. Patients were followed for up to a week with extensive documentation of pharmacokinetics of VPA, physical, cardiac and neurological exam, and laboratory findings. Although studies have evaluated the safety of IV VPA some have assessed the safety of large doses at relatively slow rates of infusion (Wheless and Venkataraman, 1998) while others have assessed the safety of relatively rapid administration of smaller doses (Devinsky et al., 1995;

6 RAPID INTRAVENOUS LOADING OF VALPROATE 483 Ramsay et al., 2003). Few studies have combined large doses and rapid infusion (Venkataraman and Wheless, 1999; Uberall et al., 2000; Ramsay et al., 2003) but none have documented the safety of rapid administration of large undiluted loading doses. In our study patients received 20 or 30 mg/kg loading doses of VPA at either 6 mg/kg/min (first 20 patients) or 10 mg/kg/min (second 20 patients). A total of 60.5% (23 of 38) patients complained of pain, burning, or both at the injection site. Although all patients received the doses without dilution, no serious local irritation was encountered. Local intolerance did not result in discontinuation of dose administration in any patient. Local intolerance was transient, with pain, burning, and paresthesias lasting less than 3 min in all patients and was found to be independent of the gauge of the IV catheter used for peripheral access, VPA dose, infusion rate, age, and gender. To our knowledge this is first study to report tolerability of rapid administration of undiluted loading doses. These findings support the tolerability of rapid administration of IV VPA. Vital signs and cardiac rhythm were monitored closely (every 2.5 min for the first 20 min). We did not encounter any serious adverse effects on vital signs, cardiac rhythm, or LOC. Only three patients (7.5%) complained of feeling sedated postinfusion. This was surprising given that some patients had been sleep deprived. The small number of patients with sedation did not permit analysis of the relationship of sedation with VPA dose or rate of administration. In the past 5 years, several studies have demonstrated the efficacy (ranging from 66% to 100%) of VPA in acute repetitive seizures and SE in both adult (Giroud, 1993; Naritoku and Mueed, 1999; Limdi et al., 2005; Peters and Pohlmann-Eden, 2005) and pediatric populations (Uberall et al., 2000; Yu et al., 2003). Although the current study excluded patients with SE, we have demonstrated safety of rapid administration of undiluted loading doses known to be effective against SE supporting its usefulness in emergent situations with minimal dose preparation. These findings suggest that IV VPA provides physicians with an alternative drug for the rapid resolution of seizures in an emergency setting with minimal adverse effects. CONCLUSION Rapid administration of undiluted of VPA is safe and well tolerated at infusion rates up to 10 mg/kg/min and doses up to 30 mg/kg. Transient local irritation due to rapid administration of undiluted loading doses may cause transient, clinically nonsignificant changes in MAP in some patients. The lack of serious cardiovascular, neurological, hepatic, or local adverse effect and the rapid achievement of therapeutic concentrations support the use of VPA in emergent situations. Acknowledgments: We are grateful to all the patients who participated in the study. 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