Detection of Pentobarbital Using High- Performance Liquid Chromatography (Reference ) Notice of Assessment

Transcription

1 Detection of Pentobarbital Using High- Performance Liquid Chromatography (Reference ) Notice of Assessment December 2013 DISCLAIMER: This document was originally drafted in French by the Institut national d'ecellence en santé et en services sociau (INESSS), and that version can be consulted at barbital_chromatographie_liquide_haute_performance.pdf. It was translated into English by the Canadian Agency for Drugs and Technologies in Health (CADTH) with INESSS s permission. INESSS assumes no responsibility with regard to the quality or accuracy of the translation. While CADTH has taken care in the translation of the document to ensure it accurately represents the content of the original document, CADTH does not make any guarantee to that effect. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the information in this document, the original document, or in any of the source documentation.

2 1 GENERAL INFORMATION 1.1 Requestor: CHU Sainte-Justine 1.2 Application Sent to MSSS: January 7, Application Received by INESSS: July 1, Notice Issued: October 31, 2013 Note: This notice is based on the scientific and commercial information (submitted by the requestor[s]) and on a complementary review of the literature according to the data available at the time that this test was assessed by INESSS. 2 TECHNOLOGY, COMPANY, AND LICENCE(S) 2.1 Name of the Technology High-performance liquid chromatography (HPLC) with post-column photochemical reaction and diodearray detection. 2.2 Brief Description of the Technology, and Technical and Clinical Specifications HPLC is a chromatographic technique used to separate, identify and quantify the components in a miture. The method consists of passing a sample solution through a solid absorbent material, by forcing it through a column with a liquid under high pressure. The sample s components (analytes) interact with the absorbent material, which causes them to separate. Photochemical reaction in HPLC can improve both sensitivity and specificity. It causes several barbiturates, including pentobarbital, to significantly shift in the ultraviolet (UV) spectrum [Wolf and Schmid, 1990; Schmid and Wolf, 1989]. Without irradiation, pentobarbital is detected at a wavelength of < 220 nm (nanometres). With maimum irradiation of 25 s to 35 s, a photochemical reaction of pentobarbital is observed at a wavelength of 270 nm [Wolf and Schmid, 1990; Schmid and Wolf, 1989]. Pentobarbital is a sedative used when there is no response to first- or second-line drug therapy in children [Friedman, 2012] and adults [Stecker, 2013] with refractory status epilepticus. It is also used in patients with severe brain injury to induce coma and to alleviate intracranial pressure. The therapeutic drug monitoring of pentobarbital allows plasma concentrations of the drug to be titrated and monitored during use, in light of its potential toicity and risk of overdose [Kochanek et al., 2012; Molina et al., 2009; Miller et al., 2008] as well as the variability of patients pentobarbital plasma levels throughout treatment [Wermerling et al., 1987; Heinemeyer et al., 1986; Bayliff et al., 1985]. 2.3 Company or Developer: Based on the method published by Wolf and Schmid [1990] and Schmid and Wolf [1989]. 2.4 Licence: Not applicable. 2.5 Patent, If Any: Not applicable. 2.6 Approval Status (Health Canada, FDA) The test does not employ reagents and kits approved by Health Canada. 1

3 The analytical reagents are certified for HPLC, and certificates are issued for each lot. 2.7 Weighted Value: (estimate in 2012). 3 CLINICAL INDICATIONS, PRACTICE SETTINGS, AND TESTING PROCEDURES 3.1 Targeted Patient Group Children with intractable epilepsy, severe traumatic brain injury, or intracranial hypertension, who receive strong doses of pentobarbital to prevent brain damage. 3.2 Targeted Disease(s) Convulsive status epilepticus is defined as continuous generalized tonic-clonic seizure activity with loss of consciousness for longer than 30 minutes, or two or more successive seizures without a return to consciousness [Friedman, 2012]. It is estimated that one in three cases of status epilepticus is refractory to treatment with two different antiepileptic medications, for eample, a benzodiazepine (first-line) and phenytoin (second-line) [Friedman et al., 2012; Fisher, 2009]. In these cases, pentobarbital is indicated [Friedman et al., 2012]. Overall morbidity (e.g., newly diagnosed neurological disorders) in these children is estimated at 10% to 20%, and mortality is reported to be between 2.7% and 8% [Friedman et al., 2012]. The annual incidence of status epilepticus in children is estimated to range between 10 and 73 episodes per 100,000 children [Friedman et al., 2012], which suggests that 175 to 1,278 episodes occur in Quebec annually (estimates based on data from the 2011 Census). Traumatic brain injury is a leading cause of death in children and adolescents in North America, and it is often associated with multiple trauma and cervical spine injury [Vavilala and al., 2013]. The resulting disability is significant and related to the severity of the injuries [Vavilala et al., 2013; Michaud et al., 1992]. The pathophysiology of severe traumatic brain injury involves direct injury to the brain and cerebral edema, which generally occurs 24 hours to 72 hours after the injury [Vavilala et al., 2013]. Seizures may also occur post-trauma. Barbiturates are indicated in certain cases to reduce intracranial pressure. Canadian pediatric guidelines for acute severe traumatic brain injury [Farrell et al., 2013] refer to the guidelines for the treatment of convulsive status epilepticus in case of post-traumatic seizures. The current estimate of the incidence of pediatric severe traumatic brain injury in Quebec lacks precision. According to Dr. Gilles Bourgeois (Medical Advisor, Trauma Care Continuum Assessment Team, INESSS 24 ), between 275 and 300 cases of severe traumatic brain injury are reported each year in Quebec (children, adolescents and adults). 3.3 Number of Patients Targeted According to the requestor, the number of patients targeted for Quebec ranges between 30 and 50 per year. As this test will be used for therapeutic monitoring, more than one test will likely be performed for each patient. A study dating from 1986 describes the monitoring of pentobarbital plasma concentrations in 16 patients with intracranial hypertension who were hospitalized in intensive care [Heinemeyer et al., 1986]. On average, these patients were tested twelve times during their treatment. Assuming monitoring for epilepsy is the same, the number of anticipated tests will range from 360 to 600 per year. 24.Personal communication September 5,

4 As the requestor's establishment is not the only establishment to treat intractable epilepsy and traumatic brain injuries, and as pentobarbital may be used for these indications in adults, this test may be performed in other establishments if it is included in the Inde. Pentobarbital usage is unknown in Quebec. At the Hôpital du Sacré-Cœur de Montréal 25, this test has not been performed in over five years; the samples are sent to the CHU Sainte-Justine for analysis. The only other centres that could use pentobarbital assays are the Hôpital de l Enfant-Jésus of the CHU de Québec, the Montreal General Hospital, and the Montreal Neurological Institute and Hospital. The majority of cases of intracranial hypertension in children are associated with traumatic brain injury [Brasher and Tasker, 2013]. In adults, there are numerous causes of intracranial hypertension, including intracranial lesions (e.g., tumour, hematoma), cerebral edema, an increase in cerebrospinal fluid, decreased absorption of cerebrospinal fluid, obstructive hydrocephalus, impaired venous outflow, or an idiopathic condition [Smith and Amin-Hanjani, 2013]. 3.4 Medical Specialties Involved (and Other Professions, If Any) Intensivists, traumatologists, neurologists, neurosurgeons, anesthesiologists, pharmacists, respiratory therapists. 3.5 Testing Procedure The specimen is collected at the hospital by venipucture. 4 TECHNOLOGY BACKGROUND 4.1 Nature of the Diagnostic Technology: Unique. 4.2 Brief Description of the Current Technological Contet In Quebec, the frequency with which pentobarbital assays are used to treat patients with traumatic brain injury or refractory epilepsy is unknown. The drug is not on the list of medications covered by Quebec s publicly funded drug plan, nor in the formularies of public drug coverage in other Canadian provinces. Moreover, the drug is not approved by Health Canada and is available only through the Special Access Programme [Health Canada]. This programme does not provide any data on the use of special access drugs. The Canadian Paediatric Society s (CPS s) position on the management of convulsive status epilepticus [Friedman et al., 2012] is that pentobarbital can be used in refractory cases; however, the author notes that there are no published randomized trials. Specific dosages of pentobarbital are recommended, but reference values are not mentioned. The CPS guidelines for the treatment of children with acute head trauma [Farrell et al., 2013] are in accordance with international clinical practice guidelines [Kochanek et al., 2012], which indicate that high-dose barbiturates may be considered for patients with refractory intracranial hypertension who are hemodynamically stable (low level of evidence: two case-series studies). The monitoring of pentobarbital concentrations is not mentioned in any of the clinical practice guidelines reviewed. 25. Dr. François Bédard, personal communication September 15,

5 4.3 Brief Description of the Advantages Cited for the New Technology A case study reported a case of propylene glycol (a vehicle in the formulation of several intravenous drugs, such as pentobarbital) toicity [Miller et al., 2008]. Monitoring pentobarbital plasma levels may prevent toicity or overdose, which may cause death [Molina et al., 2009]. 4.4 Cost of Technology and Options Based on the information provided by the requestor, the weighted value of the test is It is not known whether the requestor has the equipment required to perform the HPLC test. Based on a nonsystematic Internet search, the cost of this equipment ranges from approimately $5,000 to $30,000 per unit. 5 EVIDENCE 5.1 Clinical Relevance Other Tests Replaced This test replaces the thiopental assay (code 30772). Thiopental was taken off the North American market in 2011, and is not approved by Health Canada Diagnostic or Prognostic Value The literature review did not identify any studies assessing the effect of this test on patients in terms of morbidity, mortality or quality of life Therapeutic Value The test is intended for the therapeutic monitoring of a drug that can have serious consequences in case of overdose. 5.2 Clinical Validity: No studies of clinical validity were identified. 5.3 Analytical (or Technical) Validity Only one study, published by the researchers who developed the test, provides information on analytical validity [Schmid and Wolf, 1989]. PARAMETER PRESENCE ABSENCE NOT APPLICABLE Repeatability X Reproducibility Analytical sensitivity Analytical specificity Matri effect Concordance Correlation between test and comparator Others depending on type of test X 4

6 Coefficient of Variation (CV) Within-day: < 3.7% (8 samples; concentration of 20 μg ml -1 ). Day-to-day: 4.4% (8 samples; concentration of 20 μg ml -1 ). Analytical Sensitivity and Specificity Without photochemical reaction, the UV wavelength required to detect pentobarbital is < 220 nm (nanometres). According to Schmid and Wolf [1989], photochemically induced absorbance allows pentobarbital to be detected at a wavelength of 270 nm with a sensitivity 100 times greater (0.2 mcg ml -1 ) and greater specificity as a result of a reduced matri effect (details not shown)[schmid and Wolf, 1989]. Area Versus Concentrations The regression calculation for area versus pentobarbital concentrations indicates: intercept: mcg ml -1, slope: That of thiopental was: intercept: mcg ml -1, slope: Recommendations for Listing in Other Jurisdictions The practice guidelines identified do not address the monitoring of pentobarbital with HPLC. 6 POSSIBLE OUTCOMES OF INTRODUCING THE TEST 6.1 Impact on Material and Human Resources: Not assessed. 6.2 Economic Consequences of Introducing the Test Into Quebec's Health Care and Social Services System: Not assessed. 5

7 6.3 Main Organizational, Ethical, and Other (Social, Legal, Political) Issues Pentobarbital is a metabolite of thiopental. Thiopental was used for the same indications in Canada until 2011, when it was taken off the market as a result of the controversy surrounding its use for eecutions in the United States. Pentobarbital has not been approved by Health Canada, and its therapeutic use is currently controlled by Health Canada's Special Access Programme. 7 IN BRIEF 7.1 Clinical Relevance Useful test for the therapeutic monitoring of potentially toic last-resort treatments in cases of refractory epilepsy and traumatic brain injury. 7.2 Clinical Validity: No data available. 7.3 Analytical Validity: Very little information suggesting good analytical sensitivity and specificity. 7.4 Recommendations for Listing in Other Jurisdictions No guidelines on the use of the test for the monitoring of pentobarbital treatment have been found. 6

8 8 INESSS NOTICE IN BRIEF Detection of Pentobarbital Using High-Performance Liquid Chromatography Status of the Diagnostic Technology Established Innovative Eperimental (for research purposes only) Replacement for technology:, which becomes obsolete INESSS Recommendation Add test to the Inde Do not add test to the Inde There is no data on clinical validity and little information on analytical validity. The test Barbiturates (other than strip) (Quantitative) is already in the Inde (code 30620). This test includes pentobarbital, and its weighted value is 6.6. It is difficult to justify use of a new test with a weighted value of Reassess test Additional Recommendation Draw connection with listing of drugs, if companion test Production of an optimal use guide Production of indicators, when monitoring is required NOTE Code Thiopental (Pentothal ) should be removed from the Inde. The drug is no longer on the market. 7

9 REFERENCES Bayliff CD, Schwartz ML, Hardy BG. Pharmacokinetics of high-dose pentobarbital in severe head trauma. Clin Pharmacol Ther 1985;38(4): Brasher WK and Tasker RC. Elevated intracranial pressure (ICP) in children Waltham, MA Wolters Kluwer Health; Available from Farrell CA. Management of the paediatric patient with acute head trauma. Paediatr Child Health 2013;18(5): from Fisher RS. Refractory seizures. Epilepsy.com spotlight newsletter, April Available Friedman JN. Emergency management of the paediatric patient with generalized convulsive status epilepticus. Paediatr Child Health 2013;16(2):91-7. Heinemeyer G, Roots I, Dennhardt R. Monitoring of pentobarbital plasma levels in critical care patients suffering from increased intracranial pressure. Ther Drug Monit 1986;8(2): Kochanek PM, Carney N, Adelson PD, Ashwal S, Bell MJ, Bratton S, et al. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents--second edition. Pediatr Crit Care Med 2012;13(Suppl 1):S1-82. Michaud LJ, Rivara FP, Grady MS, Reay DT. Predictors of survival and severity of disability after severe brain injury in children. Neurosurgery 1992;31(2): Miller MA, Forni A, Yogaratnam D. Propylene glycol-induced lactic acidosis in a patient receiving continuous infusion pentobarbital. Ann Pharmacother 2008;42(10): Molina DK, McCutcheon JR, Rulon JJ. Head injuries, pentobarbital, and the determination of death. Am J Forensic Med Pathol 2009;30(1):75-7. from Health Canada; Available Santé Canada.Programme d'accès spécial.ottawa, ON ile/cl _sap-table_( )_fr.pdf. Schmid RW and Wolf C. Simultaneous determination of thiopental and its metabolite, pentobarbital, in blood by high-performance liquid chromatography and post-column photochemical reaction. J Pharm Biomed Anal 1989;7(12): Smith ER and Amin-Hanjani S. Evaluation and management of elevated intra-cranial pressure in adults. Waltham, MA Wolters Kluwer Health; Availabe from from Wolters Kluwer Health; Available Stecker MM. Status epilpeticus in adults.waltham, MA Vavilala MS, Waitayawinyu P, Dooney NM.Initial approach to severe traumatic brain injury in children.waltham, MA Wolters Kluwer Health; Available from Ward JD, Becker DP, Miller JD, Choi SC, Marmarou A, Wood C, et al. Failure of prophylactic barbiturate coma in the treatment of severe head injury. J Neurosurg 1985;62(3): Wermeling DP, Blouin RA, Porter WH, Rapp RP, Tibbs PA. Pentobarbital pharmacokinetics in patients with severe head injury. Drug Intell Clin Pharm 1987;21(5): Wolf C and Schmid RW. Enhanced UV-detection of barbituates in HPLC analysis by on-line photochemical reaction. Journal of Liquid Chromatography 1990;13(1):