J Neurol (2003) 250 : 1237–1240 DOI 10.1007/s00415-003-0180-7
Jikke-Mien F. Niermeijer Cuno S. P. M. Uiterwaal Cees A. van Donselaar
Received: 18 November 2002 Received in revised form: 21 February 2003 Accepted: 13 May 2003
C. S. P. M. Uiterwaal Julius Centre for Health Sciences and Primary Care University Medical Centre Utrecht Utrecht, the Netherlands J. M. F. Niermeijer · Cees A. van Donselaar () Rudolf Magnus Institute of Neuroscience Dept. of Neurology Section Epilepsy University Medical Centre Utrecht PO Box 85500 3508 GA Utrecht, The Netherlands E-Mail:
[email protected]
ORIGINAL COMMUNICATION
Propofol in status epilepticus: little evidence, many dangers?
■ Abstract Introduction Several guidelines recommend the use of propofol for the treatment of refractory status epilepticus. An increased mortality rate in high dose, long-term treatment with propofol in adult patients was published recently. This prompted us to assess the literature on the scientific evidence for the efficacy and safety of propofol in the treatment of refractory status epilepticus. Methods Medline was searched and the three authors independently reviewed all Medline abstracts for selection of papers. Results We included 22 articles with original data on the use of propofol in refractory status epilepticus. Randomised clinical trials were lacking. Two non-randomised studies compared propofol with barbiturates and midazolam respectively.
Introduction
■ Key words refractory status epilepticus · treatment · death · propofol
in treating refractory status epilepticus, partly owing to its favourable pharmacokinetic profile that allows more rapid awakening for neurological assessment [46]. Data on the efficacy and safety of propofol in the treatment of status epilepticus are scarce, contradictory, and indicate possible serious side effects. It all concerns “off-label use” as propofol is not licensed for the treatment of refractory status epilepticus. In spite of this, several recent guidelines consider propofol as the drug of first choice in refractory convulsive status epilepticus in adults and children [36, 42, 50], whereas others warn against its use in children [15]. An increased mortality rate in high dose long-term treatment with propofol in adult patients was published
JON 1180
The use of propofol as an anaesthetic in patients undergoing electroconvulsive therapy (ECT) revealed its antiepileptic capacities; seizures induced by ECT lasted for a shorter period of time [39, 40, 43]. Propofol was then reported as a successful treatment of refractory status epilepticus [11, 29, 57, 58]. Two small non-controlled studies showed a markedly increased mortality rate in the propofol treatment groups (87.5 %), compared with the reference treatment (50 %) in 1998 and 2001 [36, 46]. This difference did not reach statistical significance. Surprisingly, propofol was considered a promising agent
Both studies reported a higher risk of mortality for propofol. In addition, case reports and case series on the use of propofol as anaesthetic or sedative in children and adults reported several lethal cases. Conclusions Serious doubts may be raised on the safety of propofol in the treatment of refractory status epilepticus. The two non-randomised studies and several case reports show an increased risk of mortality. Guidelines should not recommend the use of propofol as a routine treatment in refractory status epilepticus before a proper randomised trial has been performed.
1238
recently [13]. Fatal outcome was reported in two children treated with propofol for refractory nonconvulsive status epilepticus [18]. In addition, several fatal outcomes were reported when propofol was used as a sedative in adults [2, 25, 26, 28, 32, 49, 52, 55] or children [3, 7, 9, 31, 35, 47]. In addition, neurological sequelae after propofol anaesthesia were noted in children as well as adults [23, 48, 51, 52]. This prompted us to assess the reports in the literature on the scientific evidence for the efficacy and safety of propofol in the treatment of refractory status epilepticus.
Methods ■ Search strategy, inclusion and exclusion criteria Medline was searched for the following items In “Any field” from 1987–2001: “propofol” and “status epilepticus”, “propofol” and “epilepsy" (not status epilepticus),“propofol” and “death”,“propofol” and “mortality”, and in title only from 2000–2001: “status epilepticus”. Lists of references were hand-searched for additional publications. Papers had to be written in English, French, or German and had to concern the use of propofol in status epilepticus, or propofol causing death either as anaesthetic agent or as antiepileptic drug (AED). Both adult and paediatric cases were included. ■ Data abstraction and classification The three authors independently reviewed all Medline abstracts and selected papers according to the above-mentioned criteria. Papers were included after consensus. Papers were categorised as reviews, or reports of original data further classified as: (non) randomised clinical trial, case series study (at least 4 cases), case report (maximum 3 cases), and animal study. Since randomised clinical trials were lacking we could not apply formal quality assessment scales [4, 24].
Results We included 22 articles with original data on the use of propofol in refractory status epilepticus (Table 1). Twelve case reports and seven case series concerned 43 adults and 9 children. The status was treated “successfully” in all. However, five patients died. In addition, a child and an adolescent with nonconvulsive status epilepticus died from major complications due to propofol [18]. Only two non-randomised studies compared two treatments for refractory status epilepticus [37, 46]. Seizure control (clinical or EEG) was achieved in 5/8 through propofol (62 %), compared with 9/11 (82 %) after high dose barbiturates. The mortality rate was higher in the propofol group 87.5 % (7 out of 8 patients), versus 50 % (4 out of 8 patients) in the barbiturate treated group (n. s.) [46]. Propofol was nevertheless held to be a promising agent because of its more rapid seizure control. The second study on refractory status epilepticus [37] reported a clinical success rate of 9/14 (64 %) after
Table 1 Propofol in status epilepticus Author
Study design
Age
Outcome successful
Stecker, 1998 [46] Prasad, 2001 [37] Wood, 1988 [57] Yanny, 1988 [58] Chilvers, 1990 [11] Mackenzie, 1990 [29] Campostrini, 1991 [8] Natale, 1993 [59] Borgeat, 1994 [6] Hantson, 1994 [19] Pitt-Miller, 1994 [33] Prause, 1994 [38] Merigian, 1995 [30] Exil, 1995 [60] Kuisma, 1995 [27] Huff, 1996 [22] Walker, 1996 [54] Harrison, 1997 [20] Hanna, 1998 [18] Begemann, 2000 [4] Fernandez, 2000 [16] Sahin, 2001 [41] Total number of patients
NET Comp NET Comp Case report Case report Case report Case report Case series Case series Case report Case report Case report Case series Case report Case series Case series Case report Case series Case report Case report Case report Case report Case series
A A A A A A A A A A A A A A A A? A C C A A C
5/8 11/14 1 1 1 2 4 4 1 1 1 11 1 5 8 2 7 1 2 1 1 3 74
death 7/8 8/14 1/1
3/4
2/2
1/3 22
A Adult; C Children; NET Comp Non experimental treatment comparison; case report: n < 4; case series: n = 4 or more
propofol and 4/6 (67 %) after midazolam treatment. The same applied to the electrophysiological success rate: 11/14 (78 %) in the propofol group versus 4/6 (67 %) in the midazolam group. Importantly, 8 (57 %) of the propofol treated patients died versus one (17 %) of the midazolam treated group (n. s.). However in patients with an APACHE II score of > 20, the proportion of deaths in the propofol treated group was significantly higher than in the midazolam group. In addition, alarming case reports and case series on the use of propofol as anaesthetic or sedative in children [7, 9, 31, 34, 35, 47] and adults [2, 13, 25, 26, 28, 32, 49, 52, 55] reported other lethal cases.
Discussion Although propofol most probably has an antiepileptic effect, serious doubts may be raised about its safety in the treatment of status epilepticus. Positive evidence for its efficacy and safety is based only on small case series and case reports in both adults and children. In fact this all concerns “off-label use”, as propofol is not licensed
1239
for the treatment of refractory status epilepticus, neither in the USA nor in countries of the European Union. Publication bias (reluctance to publish ‘negative results’) or hesitation to publish fatalities may have further hampered our scientific knowledge of possible bad news on this topic. The data from two small non-randomised studies lack statistical power but point to a substantially increased mortality risk. This needs further study. A non-significant difference in mortality risk in a small study may be clinically very relevant [37, 46]. One may argue that refractory status epilepticus is a rather heterogeneous emergency with high mortality rates, often related to the underlying pathology. Therefore, interpretation of these results is hazardous. However, the significantly increased mortality in the propofol treated cases with APACHE II score > 20 is worrying. Prognostic group incomparability would hamper all inference, both of success rates and of side effects. For instance, patients given propofol might have had worse prognoses to begin with. In any case, it is not from the absence of statistical significance with respect to the mortality risk differences between treatments, that equivalence concerning mortality risks can be concluded.Along similar lines of reasoning, it may be stated that both studies simply lacked the statistical power to detect mortality risk differences if these actually do exist. Despite group incomparability, publication bias, and lack of statistical power, there seem to be insufficient data to justify strongly advising the use of propofol in refractory status epilepticus. In fact, data from the litera-
ture seem to justify great concern on the safety of propofol in the treatment of refractory status epilepticus. In our opinion it is very surprising that these alarming signals have not raised clinical awareness and that its use is advocated in several recently published guidelines and reviews [5, 10, 12, 17, 36, 42, 44, 45, 56]. Only two guidelines concerning the use of propofol for status epilepticus in children warn for possible serious complications [1, 14]. To suggest the use of propofol as a possible firstline agent in humans on the basis of an animal model study ignores the fact that results from animal studies should not be generalized to humans without question [21]. Moreover, propofol may induce epilepsy-like phenomena [23, 48, 52, 53]. We realise that other treatments such as barbiturates or midazolam may have serious side effects as well. However, warnings have been published recently on the use of propofol.A detailed discussion on the use of these other agents is beyond the scope of this paper. Could Dearlove ‘s statement that “the use of propofol for the treatment of status epilepticus is controversial and that the death of one patient is enough argument to discontinue the prescription of a drug, as it would be inhumane and unethical to have a randomised trial with such a drug” [15] still be relevant? In our opinion this statement is too strong and more solid research into the benefits and particularly the risks of propofol in status epilepticus is needed. Collaboration between clinical groups in this field is indicated, before advocating its use in guidelines.
References 1. Appleton R, Choonara I, Martland T, Phillips B, Scott R, Whitehouse W (2000) The treatment of convulsive status epilepticus in children. The Status Epilepticus Working Party, Members of the Status Epilepticus Working Party. Arch Dis Child 83:415–419 2. Badr AE, Mychaskiw G 2nd, Eichhorn JH (2001) Metabolic acidosis associated with a new formulation of propofol. Anesthesiology 94:536–538 3. Barclay K, Williams A, Major E (1992) Letter to the editor. BMJ 305:953 4. Begemann M, Rowan AJ, Tuhrim S (2000) Treatment of refractory complex-partial status epilepticus with propofol: case report. Epilepsia 41: 105–109 5. Beyenburg S, Bauer J, Elger CE (2000) Therapy of generalized tonic-clonic status epilepticus in adulthood. Nervenarzt 71:65–77
6. Borgeat A, Wilder-Smith OH, Jallon P, Suter PM (1994) Propofol in the management of refractory status epilepticus: a case report. Intensive Care Med 20:148–149 7. Bray RJ (1995) Fatal myocardial failure associated with a propofol infusion in a child. Anaesthesia 50:94 8. Campostrini R, Bati MB, Giorgi C, Palumbo P, Serra P, Vinattieri A, Cantini A, Martini E (1991) Propofol in the treatment of convulsive status epilepticus: a report of four cases. Riv Neurol 61:176–179 9. Cannon ML, Glazier SS, Bauman LA (2001) Metabolic acidosis, rhabdomyolysis, and cardiovascular collapse after prolonged propofol infusion. J Neurosurg 95:1053–1056 10. Chapman MG, Smith M, Hirsch NP (2001) Status epilepticus. Anaesthesia 56:648–659 11. Chilvers CR, Laurie PS (1990) Successful use of propofol in status epilepticus. Anaesthesia 45:995–996
12. Claassen J, Hirsch LJ, Emerson RG, Mayer SA (2002) Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 43:146–153 13. Cremer OL, Moons KG, Bouman EA, Kruijswijk JE, de Smet AM, Kalkman CJ (2001) Long-term propofol infusion and cardiac failure in adult head-injured patients. Lancet 357:117–118 14. De Negri M, Baglietto MG (2001) Treatment of status epilepticus in children. Paediatr Drugs 3:411–420 15. Dearlove O, Dobson A (1995) Does propofol cause deaths in children? Anaesthesia 50:916 16. Fernandez-Torre JL, Gonzalez C, Sanchez JM (2000) Nonconvulsive status epilepticus of frontal origin. A case report. Rev Neurol (Paris) 30: 1040–1043 17. Hanhan UA, Fiallos MR, Orlowski JP (2001) Status epilepticus. Pediatr Clin North Am 48:683–694
1240
18. Hanna JP, Ramundo ML (1998) Rhabdomyolysis and hypoxia associated with prolonged propofol infusion in children. Neurology 50:301–303 19. Hantson P, Van Brandt N, Verbeeck R, Guerit JM, Mahieu P (1994) Propofol for refractory status epilepticus. Intensive Care Med 20:611–612 20. Harrison AM, Lugo RA, Schunk JE (1997) Treatment of convulsive status epilepticus with propofol: case report. Pediatr Emerg Care 13:420–422 21. Holtkamp M, Tong X, Walker MC (2001) Propofol in subanesthetic doses terminates status epilepticus in a rodent model. Ann Neurol 49:260–263 22. Huff JS, Bleck TP (1996) Propofol and midazolam in status epilepticus. Acad Emerg Med 3:179 23. Islander G, Vinge E (2000) Severe neuroexcitatory symptoms after anaesthesia – with focus on propofol anaesthesia. Acta Anaesthesiol Scand 44: 144–149 24. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12 25. Kelly DF (2001) Propofol-infusion syndrome. J Neurosurg 95:925–926 26. Konarzewski W, De’Ath S (2001) Unrecognised fatal anaphylactic reaction to propofol or fentanyl. Anaesthesia 56:497–498 27. Kuisma M, Roine RO (1995) Propofol in prehospital treatment of convulsive status epilepticus. Epilepsia 36: 1241–1243 28. Mackay P (1996) Fatal cardiovascular collapse following propofol induction in high-risk patients. Anaesth Intensive Care 24:125–126 29. Mackenzie SJ, Kapadia F, Grant IS (1990) Propofol infusion for control of status epilepticus. Anaesthesia 45: 1043–1045 30. Merigian KS, Browning RG, Leeper KV (1995) Successful treatment of amoxapine-induced refractory status epilepticus with propofol (diprivan). Acad Emerg Med 2:128–133 31. Parke TJ, Stevens JE, Rice AS, Greenaway CL, Bray RJ, Smith PJ, Waldmann CS, Verghese C (1992) Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. BMJ 305:613–616 32. Perrier ND, Baerga-Varela Y, Murray MJ (2000) Death related to propofol use in an adult patient. Crit Care Med 28:3071–3074
33. Pitt-Miller PL, Elcock BJ, Maharaj M (1994) The management of status epilepticus with a continuous propofol infusion. Anesth Analg 78:1193–1194 34. Plotz FB, Waalkens HJ, Verkade HJ (1997) Fatal outcome after propofol sedation in children. Anaesth Intensive Care 25:585 35. Plotz FB, Waalkens HJ, Verkade HJ, Strengers JL, Knoester H, Mandema JM (1996) Fatal side-effects of continuous propofol infusion in children may be related to malignant hyperthermia. Anaesth Intensive Care 24:724 36. Pourrat X, Serekian JM, Antier D, Grassin J (2001) Generalized tonicclonic status epilepticus: therapeutic strategy. Presse Med 30:1031–1036 37. Prasad A, Worrall BB, Bertram EH, Bleck TP (2001) Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 42:380–386 38. Prause G, Kaloud H, RatzenhoferKomenda B (1994) Propofol in emergency care – areas of application and initial experiences. Wien Klin Wochenschr 106:645–648 39. Rampton AJ, Griffin RM, Durcan JJ, Stuart CS (1988) Propofol and electroconvulsive therapy. Lancet 1:296–297 40. Rampton AJ, Griffin RM, Stuart CS, Durcan JJ, Huddy NC, Abbott MA (1989) Comparison of methohexital and propofol for electroconvulsive therapy: effects on hemodynamic responses and seizure duration. Anesthesiology 70:412–417 41. Sahin M, Riviello JJ Jr. (2001) Prolonged treatment of refractory status epilepticus in a child. J Child Neurol 16:147–150 42. Shorvon S (2001) The management of status epilepticus. J Neurol Neurosurg Psychiatry 70 (Suppl 2):II22–II27 43. Simpson KH, Halsall PJ, Carr CM, Stewart KG (1988) Propofol reduces seizure duration in patients having anaesthesia for electroconvulsive therapy. Br J Anaesth 61:343–344 44. Smith BJ (2001) Treatment of status epilepticus. Neurol Clin 19:347–369 45. Starreveld E, Starreveld AA (2000) Status epilepticus. Current concepts and management. Can Fam Physician 46: 1817–1823 46. Stecker MM, Kramer TH, Raps EC, O’Meeghan R, Dulaney E, Skaar DJ (1998) Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia 39:18–26
47. Strickland RA, Murray MJ (1995) Fatal metabolic acidosis in a pediatric patient receiving an infusion of propofol in the intensive care unit: is there a relationship? Crit Care Med 23:405–409 48. Sutherland MJ, Burt P (1994) Propofol and seizures. Anaesth Intensive Care 22:733–737 49. Tramer MR, Moore RA, McQuay HJ (1997) Propofol and bradycardia: causation, frequency and severity. Br J Anaesth 78:642–651 50. Treiman DM (2001) Therapy of status epilepticus in adults and children. Curr Opin Neurol 14:203–210 51. Trotter C, Serpell MG (1992) Neurological sequelae in children after prolonged propofol infusion. Anaesthesia 47:340–342 52. Valente JF, Anderson GL, Branson RD, Johnson DJ, Davis K Jr., Porembka DT (1994) Disadvantages of prolonged propofol sedation in the critical care unit. Crit Care Med 22:710–712 53. Walder B, Tramer MR, Seeck M (2002) Seizure-like phenomena and propofol: a systematic review. Neurology 58: 1327–1332 54. Walker MC, Howard RS, Smith SJ, Miller DH, Shorvon SD, Hirsch NP (1996) Diagnosis and treatment of status epilepticus on a neurological intensive care unit. Qjm 89:913–920 55. Warden JC, Pickford DR (1995) Fatal cardiovascular collapse following propofol induction in high-risk patients and dilemmas in the selection of a short-acting induction agent. Anaesth Intensive Care 23:485–487 56. Waterhouse EJ, DeLorenzo RJ (2001) Status epilepticus in older patients: epidemiology and treatment options. Drugs Aging 18:133–142 57. Wood PR, Browne GP, Pugh S (1988) Propofol infusion for the treatment of status epilepticus. Lancet 1:480–481 58. Yanny HF, Christmas D (1988) Propofol infusions for status epilepticus. Anaesthesia 43:514 59. Natale E, Mattaliano A, Alia G, Daniele O (1993) Propofol in treatment of status epilepticus: report of four cases successfully treated, Epilepsia 34(suppl2):124–125 60. Exil G, Clancy RR, Hyder DJ (1995) Propofol treatment of status epilepticus: a report of five pediatric cases, Epilepsia 36(suppl4):124
