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Propofol in status epilepticus: little evidence, many dangers? Introduction. The use of propofol as an anaesthetic in patients under- going electroconvulsive ...
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]

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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

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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.

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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

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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.

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