Propofol is used for treating refractory status epilepticus, which has high rate of mortality. Propofol infusion syndrome is a rare but often fatal syndrome, characterized by lactic acidosis, lipidemia, and cardiac failure, associated with propofol infusion over prolonged periods of time. We investigated the clinical factors that characterize propofol infusion syndrome to know the risk of them in refractory status epilepticus.
This retrospective observation study was conducted in Samsung medical center from Jan. 2005 to Dec. 2009. Thirty two patients (19 males, 13 females, aged between 16 and 64 years), with refractory status epilepsy were included. Their clinical findings and treatment outcomes were evaluated retrospectively. We divided our patients into established status epilepticus (ESE) and refractory status epilepticus (RSE). And then the patients with RSE was further subdivided into propofol treatment group (RSE-P) and the other anesthetics treatment group (RSE-O). We analyzed the clinical characteristics by comparison of the groups.
There were significant differences of hypotension and lipid change between ESE and RSE (
RSE is very critical disease with high mortality, which may show as many clinical changes as propofol infusion syndrome. Therefore propofol infusion syndrome might be considered as one of the clinical manifestations of RSE.
The operational definition of status epilepticus is based on the length of time. Recent many trials were introduced, but 9–30% of status epilepticus remains to be refractory to treatment.
In refractory status epilepticus, when phenytoin is failed to stop status epilepticus, barbiturate, benzodiazepines, ketamine, and propofol have been used according to treatment guideline of status epilepticus of ILAE and other recent reports.
The incidence of propofol infusion syndrome is about 39%, and mortality rate is up to 6%. Propofol infusion syndrome is characterized as the occurrence of acute bradycardia resistant to treatment and progressing to asystole, lipemia, hepatomegaly due to fat infiltration, severe metabolic acidosis, and muscle involvement with evidence of rhabdomyolysis or myoglobinuria and so on.
We enrolled all the patients who had admitted at Samsung Medical Center and diagnosed with status epilepticus from Jan. 2005 to Dec. 2009. Status epilepticus was defined as no recovery of mental status or seizures over 30 minutes, and RSE is defined as failure of first line and second line treatments with no time limit. Nonconvulsive status epilepticus was defined as presence of EEG of status epilepticus or improved patient with treatment of status epilepticus. We excluded patients without definite electrographic abnormalities or specific clinical features. And the patients who had not currently status epilepticus and under 16 years old were also excluded.
Thirty two patients were included. Female was 13 (40.6%) and male was 19 (59.4%). The median age was 28.5 years old (range, 16–81). Among them, 21 (65.5%) patients had refractory status epilepticus and 11 (34.4%) patients had status epilepticus that was terminated by the first- and second line treatments. The classification of status epilepticus was convulsive type in 31 patients and non-convulsive type in 1 patient. Among the 21 patients with refractory status epilepticus, 13 (61.9%) patients were treated with propofol and 8 (38.1%) patients with the other anesthetics such as midazolam and pentobarbital. The median days of hospitalization was 12.5 days (2–240 days). According to the outcome, 9 (28.1%) patients were death, 15 (46.9%) patients did not return to baseline state, and 11 (25.0%) patients returned to baseline state. The history of epilepsy was in 10 (31.3%) patients (
We retrospectively reviewed the patients’ medical records. We collected the data on presence of previous history of epilepsy, clinical feature of status epilepticus (convulsive, non-convulsive), the causes of status epilepticus (infection, vascular, neoplasm, unknown), the numbers of concurrent antiepileptic drugs (AED) and clinical features of propofol infusion syndrome including metabolic acidosis, heart abnormalities, rhabdomyolysis, lipid change, hepatic change, renal change, death.
We evaluated the changes of clinical features on each category, based on the diagnostic criteria of Iyer et al.
We classified the patients with status epilepticus into established status epilepticus (ESE) and refractory status epilepticus (RSE) groups. And then the RSE group was further divided into propofol treatment (RSE-P) group and the other anesthetics treatment (RSE-O) group. The other intravenous anesthetics were midazolam and pentobarbital.
We estimated the overall rate of the data of each clinical parameter. And then we compared those based first on the refractoriness of status epilepticus and then on use of propofol. So we analyzed the differences of clinical features between ESE and RSE groups. Also among RSE patients, RSE-P group was compared to RSE-O group. Finally we focused on the comparison of hospital days and treatment outcome between RSE-P and RSE-O groups. We used SPSS 14.0k for statistical analysis. We used Fisher’s exact two-tailed test for comparing sex, hypotension, metabolic acidosis, cardiac change, rhabdomyolysis, hepatic change, lipemia, renal change, death, previous history of epilepsy between groups. We also used Mann-Whitney U-test to analyze the age, numbers of AED. Analytical significance level was
The propofol infusion therapy was performed in 13 patients. The method of propofol treatment was that the medial value of initial loading dose of propofol was 80 mg (range, 0–180 mg), the median value of maximal infusion rate of propofol was 8 mg/kg/hr (range, 0.3–15 mg/kg/hr), the median rate of maintenance of propofol infusion was 5.6 mg/kg/hr (range, 0.3–9.7 mg/kg/hr) and median duration of propofol infusion was 78 hours (range, 8–426 hours).
Analyzing the clinical features during the status epilepticus, hypotension was in 14 (56.3%) patients, metabolic acidosis in 7 (43.8%), cardiac change including arrhythmia in 15 (21.9%), rhabdomyolysis in 11 (46.9%), hepatic change in 6 (34.4%), lipid change in 8 (18.8%), and renal change in 10 (25.0%) (
When we compared the clinical features between ESE and RSE, there was no significant difference in sex, age, metabolic acidosis, cardiac change, rhabdomyolysis, hepatic change, renal change, and number of antiepileptic drugs. The death rate was higher in RSE group (38.1%) than in ESE group (9.1%), while the previous epilepsy history was higher in ESE group (54.5%) than in RSE group (19.0%). But the death rate and previous epilepsy history did not show statistical significant differences (
According to the anesthetic treatments, we compared the clinical features of refractory status epilepticus. When we compared RSE-P group to RSE-O group, there were not any significant differences in sex, age, hypotension, metabolic acidosis, cardiac change, rhabdomyolysis, hepatic change, lipid change, renal change, lipid change, the previous history of epilepsy and the number of antiepileptic drugs. In hypotension, RSE-P group (92.3%) had a higher rate than RSE-O group (62.5%). But it did not reach statistical significant difference (
We compared the duration of admission between the groups. When we compared SE group with RSE group, the hospital days were significantly longer in RSE group (median, range; 41, 2–240) than in ESE group (median, range; 7, 3–60) (
The outcomes after the treatment of status epilepticus showed statistically difference between ESE and RSE groups, having tendency to get worse outcome more in RSE group than in ESE group (
In our study, RSE showed longer hospital days and worse treatment outcome than ESE. That is not strange results because RSE is main cause of fatality in SE. Also RSE had significantly higher rate in hypotension and dyslipidemia than ESE. Interestingly our data suggest that cardiovascular problem and lipid profile changes could be prominent clinical parameters to indicating worse prognosis in RSE. However, Comparison of clinical features between RSE-P and RSE-O subgroups did not show any significant differences. This means that using propofol can cause propofol infusion syndrome, but RSE itself can cause the similar clinical features to propofol infusion syndrome.
Propofol has been used since the early 1980s for anesthesia in the operation room and sedation in the intensive care unit as well as currently for refractory status epilepticus.
Known risk factors of propofol infusion syndrome are using high dose propofol (>83 μg/kg/min), more than 48 hours, concomitant use of vasopressor.
In conclusion, our study did not demonstrate any significant differences in clinical features of propofol infusion syndrome between RSE-P and RSE-O groups. It may suggest that the clinical features of propofol infusion syndrome can be the clinical features of RSE regardless of using propofol. We need to be more careful in diagnosing propofol infusion syndrome whether those findings are due to propofol or RSE per se. This study is limited retrospective study and has the small numbers of patients, so that a more comprehensive prospective study could make the propofol infusion syndrome clear. Until further data become available, caution should be recommended when using high dose and long term propofol treatment.
The change of clinical features during the status epilepticus.
Comparison of hospital stays between established status epilepticus (ESE) and refractory status epilepticus (RSE). There is significant difference of hospital stay between them (
Comparison of hospital stays between propofol and other anesthetics groups. There is no significant difference of hospital stay between those groups (
Comparison of outcomes after treatment between established status epilepticus (ESE) and refractory status epilepticus (RSE). There is significant difference of treatment outcome between SE and RES groups (
Comparison of outcomes after treatment between propofol and other anesthetics groups. There is no significant difference of treatment outcome between them (
Clinical features of the subjects with status epilepticus
N | Percent | |||
---|---|---|---|---|
Sex | Female | 13 | 40.6 | |
Male | 19 | 59.4 | ||
Age [yr, median (range)] | 28.5 (16–81) | |||
Etiology | infection | 16 | 50.0 | |
vascular | 6 | 18.8 | ||
neoplasm | 1 | 3.1 | ||
unknown | 9 | 28.1 | ||
Status epilepticus | ESE | 11 | 34.4 | |
RSE | 21 | 65.5 | ||
RSE-P | 13 | 61.9 | ||
RSE-O | 8 | 38.1 | ||
Hospital stays [d, median (range)] | 12.5 (2–240) | |||
Outcome | return to baseline | 8 | 25.0 | |
no return to baseline | 15 | 46.9 | ||
death | 9 | 28.1 | ||
Previous epilepsy | 10 | 31.3 |
ESS: established status epilepticus, RSE-P/O: refractory status epilepticus, treated with propofol/the other anesthetics.
Comparison of clinical characteristics between status epilepticus (SE) and refractory status epilepticus (RSE) groups
ESE (n=11) | RSE (n=21) | ||
---|---|---|---|
Male | 9 (47.4) | 10 (52.6) | 0.066 |
Age [yr, median (range)] | 35 (16–80) | 27 (16–81) | 0.611 |
Hypotension | 1 (9.1) | 17 (81.0) | 0.000 |
Acidosis | 5 (45.5) | 9 (42.9) | 0.298 |
Cardiac change | 2 (18.2) | 5 (23.8) | 0.544 |
Rhabdomyolysis | 5 (45.5) | 10 (47.6) | 0.500 |
Hepatic change | 2 (18.2) | 9 (42.9) | 0.158 |
Lipid change | 0 (0.0) | 6 (28.6) | 0.017 |
Death | 1 (9.1) | 8 (38.1) | 0.090 |
Arrhythmia | 1 (9.1) | 6 (28.6) | 0.212 |
Renal change | 3 (30.0) | 5 (23.8) | 0.575 |
Previous epilepsy | 6 (54.5) | 4 (19.0) | 0.050 |
Number of AED, median (range) | 4 (1–7) | 5 (1–8) | 0.628 |
AED; antiepileptic drug, numbers in the parentheses are percentile or range.
Comparison of clinical features between propofol (RES-P) and other anesthetics (RES-O) groups
RSE-P (n=13) | RSE-O (n=8) | ||
---|---|---|---|
Male | 6 (46.2) | 4 (50.0) | 0.608 |
Age [yr, median (range)] | 28 (17–81) | 25 (16–61) | 0.221 |
Hypotension | 12 (92.3) | 5 (62.5) | 0.133 |
Acidosis | 4 (30.8) | 5 (62.5) | 0.166 |
Cardiac change | 4 (30.8) | 1 (12.5) | 0.344 |
Rhabdomyolysis | 6 (46.2) | 4 (50.0) | 0.605 |
Hepatic change | 6 (46.2) | 3 (37.5) | 0.538 |
Lipid change | 3 (23.1) | 3 (37.5) | 0.738 |
Death | 5 (38.5) | 3 (37.5) | 0.664 |
Arrhythmia | 5 (38.5) | 1 (12.5) | 0.221 |
Renal change | 3 (23.1) | 2 (25.0) | 0.656 |
Previous epilepsy | 2 (15.4) | 2 (25.0) | 0.498 |
Number of AED, median (range) | 4 (2–8) | 5 (1–8) | 0.853 |
AED; antiepileptic drug, numbers in the parentheses are percentile or range.