Prognosis of status epilepticus in patients requiring intravenous anesthetic drugs (a single center experience)

Accepted Manuscript Title: Prognosis of status epilepticus in patients requiring intravenous anesthetic drugs (a single center experience) Author: Estevo Santamarina Gloria M. Gonz´alez-Cuevas Anna Sanchez Rosa M. Gracia Isabel Porta Manuel Toledo Manuel Quintana Mar´ıa Sueiras Lorena Guzm´an Javier Salas-Puig PII: DOI: Reference:

S1059-1311(16)30302-8 http://dx.doi.org/doi:10.1016/j.seizure.2016.12.001 YSEIZ 2863

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Seizure

Received date: Revised date: Accepted date:

15-10-2016 29-11-2016 2-12-2016

Please cite this article as: Santamarina Estevo, Gonz´alez-Cuevas Gloria M, Sanchez Anna, Gracia Rosa M, Porta Isabel, Toledo Manuel, Quintana Manuel, Sueiras Mar´ıa, Guzm´an Lorena, Salas-Puig Javier.Prognosis of status epilepticus in patients requiring intravenous anesthetic drugs (a single center experience).SEIZURE: European Journal of Epilepsy http://dx.doi.org/10.1016/j.seizure.2016.12.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Prognosis of status epilepticus in patients requiring intravenous anesthetic drugs (a single center experience). Estevo Santamarina MD PhD 1, Gloria M González-Cuevas MD 1, Anna Sanchez MD 2,

Rosa M Gracia MD 2, Isabel Porta MD 2, Manuel Toledo MD PhD 1, Manuel

Quintana 1, María Sueiras MD 3, Lorena Guzmán MD 3, Javier Salas-Puig MD PhD 1.

1-

Epilepsy Unit. Hospital Vall Hebron. Barcelona

2-

Intensive Care Unit. Hospital Vall Hebron. Barcelona

3-

Neurophysiology department. Hospital Vall Hebron. Barcelona

Word count abstract: 249 Word count paper: 2933 Correspondence author: Dr. Estevo Santamarina, Epilepsy Unit. Hospital Vall Hebron Pg Vall Hebron 119 – 129 Barcelona (Spain) Mob: +34687762325 Fax: +34934894257 e-mail: [email protected]

HIGHLIGHTS - Factors associated with prognosis in Status Epilepticus (SE) requiring IVADs are evaluated. - Functional status at discharge is associated with duration, STESS and etiology. - Mortality is related with duration, the level of consciousness and the presence of complications.

Abstract Purpose: There is concern about the safety of anesthetic drugs (IVADs) in the management of status epilepticus (SE). To clarify this aspect, we aimed to assess the factors associated with a poor prognosis in SE requiring anesthetics. Method: We analyzed all SE requiring IVADs between October 2011 and December 2015. Demographics, clinical data, etiology, SE duration, indications for sedation, electroencephalography features, complications and the prognosis at discharge were collected. Hypoxic etiology was ruled out. Results:73 patients needed IVADs. These were indicated as third-line treatment for SE in 58.9%, for decreased level of consciousness result from previous treatments in 27.4%, and for the underlying etiology in 13.7%. At discharge 41(56.2%) patients showed a bad outcome and 32 a good outcome. This was poorer in patients with higher STESS (p=0.003), lower level of consciousness (p=0.025), non-convulsive SE in coma (p=0.040), potentially fatal etiology-PFE- (p=0.006), longer duration (p=0.026), presence of complications (p=0.022), use of IVADs due to the underlying etiology (p=0.020), and periodic epileptiform discharges on electroencephalography (p=0.032). Following multivariate analysis, SE duration>12 hours (OR=3.266;95%CI=1.0779.908;p=0.037), STESS≥3 (OR=4.816;95%CI=1.435-16.165;p=0.011), and PFE (OR=3.526;95%CI=1.184-10.506;p=0.024) were independently associated with a poor

functional

prognosis.

Regarding

(OR=7.07;95%CI=1.836-27.220;p=0.004), (OR=6.97;95%CI=1.194-40.718;p=0.031),

mortality, low

and

level presence

duration>12 of of

hours

consciousness complications

(OR=21.32;95%CI=2.440-186.295;p=0.006) were independent predictors of death. Conclusions: Lengthy duration of SE in patients requiring IVADs is associated with a poorer prognosis and death. A STESS≥3 and the etiology seem mainly related to

the functional status at discharge, whereas more severely impaired consciousness and complications during sedation are related to mortality.

Refractory status epilepticus (SE) is defined as SE that cannot be controlled with benzodiazepines, the first-line treatment, and one AED, the second-line treatment 1.

SE refractoriness has been linked with mortality; hence, various opinion leaders

have recommended the use of IVADs (midazolam, propofol, thiopental, phenobarbital) as the next treatment option to rapidly suppress seizure activity 2-4. Prompt sedation may be important, as the duration of the SE episode has been related to brain damage in animal models 5-8 and is suggested in studies in humans 9-14.

There is currently no consensus regarding the optimal IVAD for this purpose or the level of sedation that should be achieved: suppression only of critical activity, a burst-suppression pattern, or an isoelectric pattern. The related clinical guidelines do not specify whether the choice of IVAD should be adapted to the specific type of SE, and they conclude that there is a lack of strong evidence and a need for further studies and clinical trials to support anesthetic use in these patients

15-16.

Furthermore, some recent observational studies have reported an association between IVAD use and a poorer prognosis, generating concern about the safety of these agents in refractory SE

17-19.

In addition to increased mortality, the use of

anesthetics has been linked to prolonged ICU stays and the development of related complications (higher infection rates, hemodynamic instability). This raises questions about whether different types or etiologies of SE may be more sensitive to the side effects of anesthesia use, and whether the increased mortality risk exceeds the mortality directly derived from the situation of SE in a particular patient. To provide answers to these questions, it would be helpful to know what factors are associated with a poor outcome in SE patients who ultimately require sedation in the management of their condition. Thus, the aim of this study was to describe the factors associated with a poor prognosis in a sample of consecutive SE patients requiring IVAD use, treated in our center. SE: Status Epilepticus; IVAD: Intravenous Anesthetics Drugs; AED: Antiepileptic Drug; ICU: Intensive Care Unit; EEG: electroencephalography; NCSEC: Non-convulsive status epilepticus in coma; STESS: Status Epilepticus Severity Score; PED:

periodic epileptiform discharges

METHODS In our hospital, all patients with SE older than 16 years are prospectively recorded in a database, which has been approved by the hospital ethics committee. The present study includes all patients with SE who required sedation attending our hospital from October 2011 to December 2015. All were admitted to the ICU. Patients with post-anoxic etiologies are not included in the registry. Status epilepticus was defined as a continuous seizure lasting at least 5 minutes or repetitive seizures between which there was incomplete recovery of the baseline clinical condition

20.

In case of non-convulsive SE, the working criteria used were

the proposed by Kaplan and subsequently modified by Beniczky et al 21 The patients’ demographic data and history of previous seizures were prospectively recorded on admission. The etiology of SE was determined based on the ILAE classification (acute, remote, progressive symptomatic, or cryptogenic) 2223.

In addition, an etiology that might lead to death independently of SE if not

specifically treated was categorized as “potentially fatal” in accordance with the definition of other publications 24. The patient’s level of consciousness before treatment was categorized as arousable upon a clear clinical contact (implying an alert or confused patient) or as severely impaired. The type of SE was classified based on the worst clinical seizure in the specific episode and was retrospectively adapted according to the latest ILAE classification 23

as SE with prominent motor symptoms (including generalized convulsive SE

[GCSE], and myoclonic or focal motor SE), and SE without prominent motor symptoms (including NCSEC and complex, partial, focal SE with or without impaired consciousness). The STESS was calculated for each patient at admission 25 . The duration of SE was

monitored by EEG, and was estimated as the interval from the moment SE was clinically diagnosed by a neurologist up to the time EEG monitoring registered seizure suppression or burst suppression as the target. The indication for IVAD administration and endotracheal intubation was recorded in all patients and categorized into 3 situations: 1) as third-line treatment for SE; 2) for impaired consciousness occurring as an adverse event of first- or secondline therapies (airway protection) after EEG verification that it was not due to the presence or a recurrence of NCSE; and 3) for the underlying cause of SE, before the onset or diagnosis of SE. The clinical outcome at discharge was prospectively categorized into 3 groups: return to baseline status, new disability (defined as development of new neurological impairment and a decrease in the Glasgow Outcome Scale-Extended score), or death. Occurrence of new disability or death was considered a negative outcome. Medical comorbidities were assessed using the Charlson Comorbidity Index (CCI) 26.

Conditions considered to be the etiology of SE for the specific episode were

excluded. Complications, defined as those arising during IVAD treatment, included infectious complications

requiring

antibiotics

(respiratory

tract,

urinary

tract

or

bloodstream), severe hemodynamic instability, and respiratory failure. Those directly due to the etiology of SE and those appearing before sedation were excluded. Firstly, we compared the group of patients with bad outcome with those who return to baseline status (good outcome). Subsequently, we focused on mortality, and compared those patients who eventually died in hospitalization with those who did not die to assess the factors related with mortality. Statistical Analysis

Descriptive and frequency statistics were obtained. Statistical significance for intergroup differences was assessed by the Pearson chi-square or Fisher exact text for categorical variables and the Student t or Mann-Whitney U test for continuous variables. A receiver characteristic operator (ROC) curve was configured to calculate a cut-off point for SE duration with the best sensitivity and specificity for predicting a poor prognosis at discharge. Significant variables in the univariate analysis were entered in adjusted multivariate logistic regression models to identify factors independently associated with a negative outcome at discharge. Pvalues less than 0.05 were considered statistically significant. Statistical analyses were carried out with SPSS for Windows, version 17.0. RESULTS In total, 73 SE patients required IVAD administration and endotracheal intubation during the study period. The mean age was 58.8 years old and 48 (65.8 % were male. Twenty-eight (38.4 %) had a previous history of epilepsy. Forty-three (58.9%) were considered to have an acute symptomatic SE etiology, and 36 (49.3%) had a potentially fatal etiology. IVADs were applied as third-line therapy in 43 (58.9%) patients, for impaired consciousness following first and second-line treatments in 20 (27.4%) patients, and for the underlying etiology in 10 (13.7%) patients. The median duration of SE was 11.5 hours (0.5 – 720 h). Major complications were present in 45 patients (61.6%). All the patients had been treated according to the same protocol for sedation—midazolam followed by propofol—and only 2 required barbiturates. As to the outcome, 22 patients (30.2%) showed a functional decline at discharge, and the mortality rate was 26% (n=19). Thus, the overall negative outcome rate was 56% (41 patients). The discharge timing ranged from 4 days to 72 days. Functional Outcome No associations were found with the patients’ demographic profile. The following variables were found to be significantly associated with a poor functional outcome on univariate analysis: higher STESS score (p=0.003), lower baseline level of

consciousness (p=0.025), potentially fatal etiology (p=0.006), progression to NCESC (p=0.040), major complications during sedation (p=0.022), IVAD use due to the etiology (p=0.020), and PEDs on EEG (p=0.032). In addition, the duration of SE was significantly longer in patients with a poor functional outcome at discharge (21 hours vs. 41 hours, p=0.026). ROC curve analysis, used to calculate the cut-off point for SE duration that would best predict a poor prognosis, yielded a value of 12 hours. SE duration exceeding that point was significantly more frequent in patients with a poor prognosis (73.3% vs 42.9%; p=0.01) (Table 1). Following multivariate analysis of these variables, only SE duration >12h (OR=3.266, 95% CI=1.077-9.908; p=0.037), STESS score ≥3 (OR=4.816, 95% CI=1.435-16.165; p=0.011), and the presence of a potentially fatal etiology (OR=3.526, 95% CI=1.184-10.506; p=0.024) were independently associated with a poor functional outcome at discharge (Table 2). Mortality The mortality rate was found to be significantly higher in patients with a lower level of consciousness at admission (p=0.029), progression to NCSEC (p=0.05), development of complications during sedation (p<0.0001), IVAD use for the etiology of SE (p=0.016), duration of SE >12 hours (p=0.036), and PEDs detected on the baseline EEG (p=0.036), whereas a higher STESS score showed a trend toward significance (p=0.058) (Table 3). Following logistic regression analysis, SE duration >12h (OR=7.07, 95% CI=1.83627.220; p=0.004), low baseline level of consciousness (OR=6.97, 95% CI=1.19440.718; p=0.031), and presence of complications (OR=21.32, 95% CI=2.440186.295; p=0.006) were independent predictors of mortality.

When the two

possibly modifiable factors were combined, 63.6% of patients with SE duration >12 hours plus major complications eventually died. Mortality decreased to 18.2% in patients with shorter SE duration experiencing complications, whereas none of the patients without complications died (Figure 1). DISCUSSION

In our sample of patients with SE requiring IVAD administration, SE duration was related to both a poor functional prognosis and death on multivariate analysis. Other factors associated with a poor prognosis were the STESS score and a potentially fatal etiology, whereas other factors related to death were greater consciousness impairment at baseline and complications during treatment. Several studies

17-19 have

reported a relationship between IVAD use and death in

SE patients, but their findings may have been influenced by possible bias related to the indication for this treatment. In all the related reports, the comparison has been performed between patients treated or not with IVADs, but patients with more severe etiologies are more likely to receive these agents. For this reason, we focused only on SE patients receiving sedation and investigated what factors indicate a high risk of a negative outcome in this population. In all these studies, IVAD use is considered one of the lines of treatment for SE patients, but in the present study, we additionally examined other indications and determined whether IVAD use exclusively to treat SE was related to the prognosis. The additional indications included were 1) treatment of decreased level of consciousness directly resulting from the use of first- and second-line SE treatments in patients whose epileptic activity had improved or ceased on EEG monitoring, and 2) treatment of decreased level of consciousness secondary to the cause of SE. In this case, NCSE was diagnosed on EEG when the patient was receiving anesthetics. Although at times it may be difficult to clearly distinguish between the indications leading to a medical intervention in a retrospective study, data collection was prospective in our case, and the indication that prompted the decision to administer IVADs was used in the analysis. None of the previous studies in this line have analyzed prognostic associations according to the IVAD indication. We reasoned that the results regarding IVAD use could be affected by the indication as a confounding factor and that they might be reinterpreted if the actual reason for sedating the patient were taken into account.

For example, in the case of loss of consciousness after the first and second line of treatment, the patient probably needs low doses of propofol or midazolam for tube tolerance, and therefore the degree of sedation is low; this probably explains that this indication is not clearly related with outcome. With regard to the indication due to the underlying cause of SE, it seemed to be related to a poor functional prognosis (Tables 1 and 3), but it did not remain as an independent predictive factor on multivariate analysis. This is likely because this indication is closely related to the level of consciousness and the most severe etiologies. In addition, the duration of IVAD use may differ depending on the indication, with the most severe etiologies requiring lengthier sedation. Therefore, these patients would be more prone to experiencing complications and morbidity, factors related to mortality, as has been reported 27. According to our results, SE duration was clearly related to both a poor functional prognosis and mortality in patients requiring IVADs. Other authors have reported various timing cut-off points related to outcome. In a study by Drislane et al, SE duration <10 hours was associated with a better outcome 14, whereas Madzar et al suggested that duration over 10 days was the limit point for a poor outcome in refractory SE 28. The classic study on the prognostic significance of SE duration by Towne et al 29 described a significant increase in mortality in episodes lasting more than one hour, but it was not clear whether duration beyond 24 hours led to a further increase in mortality. The 12-hour cut-off established in our study is longer than that reported by Towne, but the difference is likely due to the specific subgroup comprising our sample: patients requiring anesthetics and having more severe etiologies. Regardless of the precise time limit, most related studies have suggested a link between SE duration and mortality or functional outcome 29-30, and the duration of the seizure is a modifiable factor even in patients requiring IVADs. As some authors have suggested, delays in controlling seizure activity because of an excessively conservative approach when performing coma induction and maintenance may be one of the main factors that determine the patient’s prognosis 30.

Hence, continuous monitoring of IVAD treatment is critical, and is advocated in

the Neurocritical Care Society guidelines 15. In several studies, one of the variables affecting the prognosis and mortality in SE patients is the etiology of SE

14, 29, 31-32Nonetheless,

in our SE patients requiring

IVADs, this factor mainly affected the functional outcome, but not mortality. The reason for this disparity may reside in the type of patients included. Our sample was exclusively comprised of patients requiring anesthetics, in whom the aggressiveness of the treatment was similar regardless of the etiology. There was only a slight trend showing more severe etiologies in patients who died. Since its proposal and validation, the STESS scale has shown prognostic value in patients with SE

25, 28, 33. Our

data provide further support of its value in the SE

population requiring IVADs. The related studies have proposed various cut-offs associated with a poor prognosis. We found that a STESS score ≥3 was associated with a poorer short-term prognosis in our specific SE population. In the evaluation of mortality alone, two factors in addition to SE duration gained importance. When considering etiologies of similar severity, mortality was related to a more pronounced decrease in the patient’s level of consciousness at admission and major complications during treatment management in the ICU. The depth of coma at presentation as a strong predictor of outcome has been reported in several publications on SE

14, 31, 34.

We have keep in mind that low level of

consciousness at the beginning is one component of STESS score, and therefore patients with an unfavorable STESS might have intrinsically a lower level of consciousness; however regarding mortality only this component was specifically associated in SE patients in need of IVADs, and no the other components (age, history of previous epilepsy). The association we found with major complications, which is mainly related to the ICU stay and indirectly derives from the care given, is also in line with the results of some recent publications

27 35.

This finding

underscores the importance of strictly following the recommendations for optimal care to prevent complications in the management of these patients. Thus, the two modifiable factors that greatly affect the outcome will require efforts for improvement: reducing the duration of SE and avoiding complications.

As to the limitations of this study, we did not collect information on the total dosage in bolus infusion, the total loading used, the maintenance dose and the timing of administration for each of the established indications, and this can be considered a limitation. Nonetheless, the maintenance dose and the length of sedation were related to other variables included in the analysis, such as the level of consciousness and presence of complications. Furthermore, we were unable to analyze the specific prognosis associated with each anesthetic used or the number of IVADs prescribed, largely because the same protocol was used in all patients and more than 30% received IVADs for reasons other than third-line treatment. The mostly used IVADs in our center are propofol and midazolam, the most widely used in the treatment of SE and barbiturates are reserved when these agents fail to control seizure activity. Our experience with ketamine is much limited and more recent and it was not included in this study. The use of other options such as barbiturate might have an effect in a higher presence of complications and/or the outcome, however in our study the number of patients receiving each anesthetic agent was too small to determine which was more effective or had the most negative outcome. A global registry is being performed to try to clarify this issue 36. We know that data on the pharmacotherapy of SE are most often observational, having a high degree of heterogeneity and high-class randomized controlled trials are lacking on this late-stage, and future studies should be addressed in this direction. CONCLUSION Lengthier duration of SE in patients requiring IVADs is associated with a poor functional prognosis and mortality. STESS score ≥3 and the underlying etiology mainly seem to have an impact on the functional status at discharge, whereas more severely impaired baseline consciousness and complications seem more related to mortality. Efforts to prevent complications and shorten the duration of SE may be key to improving survival in SE patients requiring anesthetics.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest: none for all authors

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Figure 1. Modifiable mortality-related factors in patients treated with IVADs

Poor outcome (New disability) n=41 61.6±16.4 29 (70.7) 14 (34.1) 1

Good outcome (Return to baseline) n=32 55.2±15.5 19 (59.4) 14 (43.9) 1

p

Age, y, mean±SD 0.093 Sex, male, n (%) 0.310 History of epilepsy, n (%) 0.402 Baseline mRS, median 0.698 Baseline level of consciousness (stuporous or 35 (85.4) 20 (62.5) 0.025 comatose), n (%) Presence of NCSEC, n (%) 18 (43.9) 7 (21.9) 0.049 With prominent motor 24 (58.5) 25 (78.1) 0.077 symptoms, n (%) Baseline STESS, median 4 3 0.003 Charlson Index, median 2 (1 - 2) 1 (0 – 2) 0.146 Etiology, n (%) Acute symptomatic 27 (65.9) 16 (50.0) Delayed symptomatic 8 (19.5) 10 (31.2) 0.362 Progressive symptomatic 3 (7.3) 1 ( 3.1) Cryptogenic 3 (7.3) 5 (15.6) Potentially fatal etiology, n 26 (63.4) 10 (31.3) 0.006 (%) IVADs indicated only for SE 9 (22.0) 1 ( 3.1) 0.020 etiology, n (%) SE duration, h, median 17 7 0.028 Duration >12 h, n (%) 22 (55.0) 8 (25.0) 0.010 PEDs on EEG, n (%) 6 (14.6) 0 0.032 Major complications, n (%) 30 (73.2) 15 (46.9) 0.022 SE recurrence, n (%) 5 (12.2) 3 (9.4) 0.695 NCSEC: non-convulsive status epilepticus in coma; IVAD: intravenous anesthetic drugs; SE: status epilepticus; PED: periodic epileptiform discharges, SE: Status Epilepticus; EEG: Electroencephalography , mRS: modified Rankin Scale; STESS: Status Epilepticus Severity Score

Table 1. Factors associated with a poor outcome

Duration >12 hours STESS ≥3 Potentially fatal etiology

OR 3.266 4.816 3.526

95% CI 1.077 - 9.908 1.435 - 16.165 1.184 - 10.506

p 0.037 0.011 0.024

Table 2 - Variables independently associated with the clinical outcome on multivariate analysis

Died n=19 59.3±18.6 14 (73.7) 5 (26.3) 1

Survived n=54 58.7±15.6 34 (63.0) 23 (42.6) 1

p Age, y, mean±SD 0.888 Sex, male, n (%) 0.310 History of epilepsy, n (%) 0.210 Baseline mRS (median) 0.164 Baseline level of consciousness (stuporous or 18 (94.7) 37 (68.5) 0.029 comatose), n (%) Presence of NCSEC, n (%) 10 (52.6) 15 (27.8) 0.050 With prominent motor 13 (68.4) 36 (66.7) 0.889 symptoms, n (%) Baseline STESS, median 4 3 0.101 Charlson Index, median 2 (1-3) 2 (0-2) 0.387 (range) Etiology, n (%) Acute symptomatic 14 (73.7 %) 29 (53.7) Delayed symptomatic 1 (5.3) 16 (31.5) 0.245 Progressive symptomatic 1 (5.3) 3 (5.6) Cryptogenic 3 (15.8) 5 (9.3) Potentially fatal etiology, n 12 (63.2) 24 (44.4) 0.161 (%) IVADs due only to SE etiology, 6 (31.6) 4 (7.4) 0.016 n (%) SE duration, h, median 27.5 8 0.006 Duration >12 hours, n (%) 14 (77.8) 16 (29.6) <0.0001 PEDs on EEG, n (%) 4 (21.1) 2 ( 3.7) 0.036 Major complications, n (%) 19 (100) 26 (48.1) <0.0001 SE recurrence, n (%) 2 (10.5) 6 (11.1) 1 NCSEC: non-convulsive status epilepticus in coma; IVAD: intravenous anesthetic drugs; SE: status epilepticus; PED: periodic epileptiform discharges, SE: Status Epilepticus; EEG: Electroencephalography , mRS: modified Rankin Scale; STESS: Status Epilepticus Severity Score

Table 3. Factors associated with mortality