Systemic therapeutic hypothermia (TH) is a medical therapy with a wide variety of clinical applications.Reference Kamps, Horn and Oddo 1 - Reference Wu and Grotta 4 From post cardiac arrest,Reference Kamps, Horn and Oddo 1 to neonatal hypoxemic encephalopathy,Reference Alkarfy 2 to intracranial pressure control in traumatic brain injury (TBI)Reference Sandestig, Romner and Grande 3 and stroke,Reference Wu and Grotta 4 TH has been trialed.
Some of the potential neurological benefits of TH include: reduction in cerebral metabolic rate and oxygen consumption, reduction in free radical formation, inhibition of apoptosis,Reference Rivera-Lara, Zhang and Muehlschledel 5 and slowing of action potential propagation.Reference Motamedi, Lesser and Vicini 6 It is with these mechanisms and more, that TH has the potential to impact seizure control in the setting of refractory status epilepticus (RSE).Reference Motamedi, Lesser and Vicini 6 , Reference Rossetti 7
To date, the majority of literature on TH for RSE focuses on animal models.Reference Motamedi, Lesser and Vicini 6 , Reference Kowski, Kanaan, Schmitt and Holtkamp 8 However, a small number of manuscripts exist on the application of TH in human subjects with RSE with promising results.Reference Cereda, Berger and Rossetti 9 - Reference Vastola, Homan and Rosen 21
Our goal was to perform of systematic review of the literature on the use of systemic TH in the setting of RSE, in order to comment on its effectiveness in seizure control.
Materials and Methods
A systematic review using the methodology outlined in the Cochrane Handbook for Systematic ReviewersReference Higgins and Green 22 was conducted. The data was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).Reference Moher, Liberati, Tetzlaff, Altman and Group 23 The review questions and search strategy were decided upon by the primary author and supervisor.
Search Question, Population, Inclusion and Exclusion Criteria
The question posed for systematic review was: What is the effectiveness of systemic TH on control of RSE in humans? All studies, prospective and retrospective of any size based on human subjects were included. The reason for an all-inclusive search was based on the small number of studies of any type identified by the primary author during a preliminary search of MEDLINE.
The primary outcome measure was electrographic seizure control. Secondary outcome measures were patient outcome (if reported), and adverse effects of the TH.
Inclusion criteria were: All studies including human subjects whether prospective or retrospective, all study sizes, any age category, and the use of systemic TH for seizure control in RSE. Exclusion criteria were: animal and non-English studies, any study not describing the seizure response to TH, TH for resistant epilepsy (i.e. must describe the use of TH in status epilepticus), and focal cortical hypothermia treatment for RSE or resistant epilepsy.
Search Strategy
MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, SCOPUS, and Cochrane Library from inception to May 2014 were searched using individualized search strategies for each database. The search strategy for MEDLINE can be seen in Appendix A of the supplementary material, with a similar search strategy utilized for the other databases. In addition, the World Health Organizations International Clinical Trials Registry Platform was searched looking for studies planned or underway.
As well, meeting proceedings for the past five years looking for ongoing and unpublished work based on TH for seizures were examined. The meeting proceedings of the following professional societies were searched: Canadian Neurological Sciences Federation (CNSF), American Association of Neurological Surgeons (AANS), Congress of Neurological Surgeons (CNS), European Neurosurgical Society (ENSS), World Federation of Neurological Surgeons (WFNS), American Neurology Association (ANA), American Academy of Neurology (AAN), European Federation of Neurological Science (EFNS), World Congress of Neurology (WCN), American Epilepsy Society (AES), International League Against Epilepsy (ILAE), Society of Critical Care Medicine (SCCM), Neurocritical Care Society (NCS), World Federation of Societies of Intensive and Critical Care Medicine (WFSICCM), American Society for Anesthesiologists (ASA), World Federation of Societies of Anesthesiologist (WFSA), Australian Society of Anesthesiologists, International Anesthesia Research Society (IARS), Society of Neurosurgical Anesthesiology and Critical Care (SNACC), Society for Neuroscience in Anesthesiology and Critical Care, and the Japanese Society of Neuroanesthesia and Critical Care (JSNCC).
Finally, reference lists of any review articles or systematic reviews on seizure management were reviewed for relevant studies on TH for seizure control.
Study Selection
Utilizing two reviewers, a two-step review of all articles returned by our search strategies was performed. First, the reviewers independently screened all titles and abstracts of the returned articles to decide if they met the inclusion criteria. Second, full text of the chosen articles was then assessed to confirm if they met the inclusion criteria and that the primary outcome of seizure control was reported in the study. Any discrepancies between the two reviewers were resolved by a third party.
Data Collection
Data was extracted from the selected articles and stored in an electronic database. Data fields included: patient demographics, type of study (prospective or retrospective), number of patients, details of TH administration and management, how many other anti-epileptic drugs (AEDs) were utilized prior to implementation of TH, degree of seizure control, adverse effects, and patient outcome.
Quality of Evidence Assessment
Assessment of the level of evidence for each included study was conducted by two independent reviewers, utilizing the Oxford criteriaReference Phillips, Ball, Sackett, Straus, Haynes and Dawes 24 and the Grading of Recommendation Assessment Development and Education (GRADE) criteriaReference Guyatt, Oxman and Vist 25 - Reference Jaeschke, Guyatt and Dellinger 30 for level of evidence. We elected on utilizing two different systems to grade level of evidence as these two systems are amongst the most commonly used. We believe this would allow a larger audience to follow our systematic approach in the setting of unfamiliarity with a particular grading system.
The Oxford criterion consists of a five level grading system for literature. Level 1 is split into subcategories 1a, 1b, and 1c which represent a systematic review of randomized control trials (RCT) with homogeneity, individual RCT with narrow confidence interval, and all or none studies respectively. Oxford level 2 is split into 2a, 2b, and 2c representing systematic review of cohort studies with homogeneity of data, individual cohort study or low quality RCT, and outcomes research respectively. Oxford level 3 is split into 3a and 3b representing systematic review of case-control studies with homogeneity of data and individual case-control study respectively. Oxford level 4 represents case-series and poor cohort studies. Finally, Oxford level 5 represents expert opinion.
The GRADE level of evidence is split into 4 levels: A, B, C and D. GRADE level A represents high evidence with multiple high quality studies having consistent results. GRADE level B represents moderate evidence with one high quality study, or multiple low quality studies. GRADE level C evidence represents low evidence with one or more studies with severe limitations. Finally, GRADE level D represents very low evidence based on either expert opinion or few studies with severe limitations.
Any discrepancies between the grading of the three reviewers were resolved via a third party.
Statistical Analysis
A meta-analysis was not performed in this study due to the heterogeneity of data within the articles and the presence of a small number of low quality retrospective studies.
Results
The results of the search strategy across all databases and other sources are summarized in Figure 1. After removal of duplicates a total of 554 articles were identified, with 546 from the database search, 6 from the search of published meeting proceedings, and 2 ongoing clinical trials identified in the World Health Organization (WHO) database. By applying the inclusion/exclusion criteria to the title and abstract of the articles, we identified 32 articles that fit these criteria. Of the 32 identified, 27 were from the database search, 3 were from published meeting proceedings, and 2 were ongoing clinical trials. Applying the inclusion/exclusion criteria to the full text documents, only 13 articles were eligible for inclusion in the systematic review, with 10 from database and 3 from meeting proceeding sources. Given the lack of published data, the 2 ongoing clinical trials are listed within for completeness. The 17 articles that were excluded either did not report details around the administration of TH for seizure control, or because they were review articles. Reference sections from these review articles were searched for any other articles missed in the database search, with none being identified. Of the 13 articles included in the review,Reference Cereda, Berger and Rossetti 9 - Reference Vastola, Homan and Rosen 21 all were original studies. Three articles were published meeting abstracts.Reference Czeisler, Manvar and De Marchis 11 , Reference Hakimi, Talsania, Fesler and Fields 14 , Reference Svoronos, Kilbride and Mendoza 20
Figure 1 Flow Diagram of Search Results
All studies were retrospective: eight were retrospective case seriesReference Corry, Dhar, Murphy and Diringer 10 , Reference Czeisler, Manvar and De Marchis 11 , Reference Guilliams, Rosen, Buttram, Zempel, Pineda and Miller 13 , Reference Hakimi, Talsania, Fesler and Fields 14 , Reference Lin, Lin, Hsia and Wang 16 , Reference Orlowski, Erenberg, Lueders and Curse 18 , Reference Svoronos, Kilbride and Mendoza 20 , Reference Vastola, Homan and Rosen 21 and the remaining five were retrospective case reports.Reference Cereda, Berger and Rossetti 9 , Reference Elting, van der Naalt and Fock 12 , Reference Ito, Mori, Toda, Sugimoto, Takahashi and Kuroda 15 , Reference Missert, Qazi and Ionita 17 , Reference Shein, Reynolds, Gedela, Kochanek and Bell 19 The retrospective case series were all single center reviews. Five articles described the use of inhaled anesthetic in adults.Reference Cereda, Berger and Rossetti 9 - Reference Czeisler, Manvar and De Marchis 11 , Reference Missert, Qazi and Ionita 17 , Reference Vastola, Homan and Rosen 21 Six studies described pediatric patients.Reference Elting, van der Naalt and Fock 12 , Reference Guilliams, Rosen, Buttram, Zempel, Pineda and Miller 13 , Reference Ito, Mori, Toda, Sugimoto, Takahashi and Kuroda 15 , Reference Lin, Lin, Hsia and Wang 16 , Reference Orlowski, Erenberg, Lueders and Curse 18 , Reference Shein, Reynolds, Gedela, Kochanek and Bell 19 Two studies failed to mention patient age.Reference Hakimi, Talsania, Fesler and Fields 14 , Reference Svoronos, Kilbride and Mendoza 20
Across all studies, a total of 40 patients were studied utilizing systemic TH for control of their RSE (mean: 3.1 patients/study; range: 1–7 patients/study). Fourteen patients were pediatric (age range: 4 months to 18 years). Eighteen patients were adult (age range: 19 to 75 years). A variety of underlying etiologies for RSE existed in both the adult and pediatric populations. Eight patients, in two studies, were of unknown age.Reference Hakimi, Talsania, Fesler and Fields 14 , Reference Svoronos, Kilbride and Mendoza 20
Study demographics and patient characteristics for all studies can be seen in Table 1, while treatment characteristics and seizure outcome are reported in Table 2.
Table 1 Study Characteristics and Patient Demographics
ICU=intensive care unit, NMDA=n-methyl d-aspartate, yrs=years, hrs=hours, AED=anti-epileptic drugs, CJD=Creutzfeldt Jakob Disease, CLL=chronic lymphocytic leukemia, SBE=subacute bacterial endocarditis.
Table 2 Treatment Characteristics, Seizure Response, and Outcome
hrs=hours, IVC=inferior vena cava, DVT=deep venous thrombosis, UTI=urinary tract infection, PA=pulmonary artery, TBI=traumatic brain injury, GOS=Glasgow Outcome Score.
TH Treatment Characteristics
Within the 13 studies identified utilizing systemic TH for control of RSE, the technique of achieving hypothermia involved: external cooling blanket,Reference Cereda, Berger and Rossetti 9 , Reference Elting, van der Naalt and Fock 12 , Reference Guilliams, Rosen, Buttram, Zempel, Pineda and Miller 13 , Reference Lin, Lin, Hsia and Wang 16 , Reference Orlowski, Erenberg, Lueders and Curse 18 , Reference Shein, Reynolds, Gedela, Kochanek and Bell 19 , Reference Vastola, Homan and Rosen 21 endovascularly,Reference Corry, Dhar, Murphy and Diringer 10 and unknown.Reference Czeisler, Manvar and De Marchis 11 , Reference Hakimi, Talsania, Fesler and Fields 14 , Reference Ito, Mori, Toda, Sugimoto, Takahashi and Kuroda 15 , Reference Missert, Qazi and Ionita 17 , Reference Svoronos, Kilbride and Mendoza 20 One study utilized concurrent thiopental infusions during their hypothermia protocol,Reference Orlowski, Erenberg, Lueders and Curse 18 while another utilized cooled ventilator gas in addition to external cooling.Reference Shein, Reynolds, Gedela, Kochanek and Bell 19
The target temperature for TH therapy varied across studies, with a range from 30 to 36 degrees Celsius. The most common target temperature reported was 33 degrees Celcius. Bladder temperature was the most common site of measurement. The time to reach target temperature was only reported in three studies,Reference Corry, Dhar, Murphy and Diringer 10 , Reference Guilliams, Rosen, Buttram, Zempel, Pineda and Miller 13 , Reference Shein, Reynolds, Gedela, Kochanek and Bell 19 with a mean of 3.9 hours (range: 1 to 13 hours). Similarly, the duration of TH at target temperature ranged from 11 to 240 hours (mean=89.0 hours, median=67.2 hours).Reference Corry, Dhar, Murphy and Diringer 10 , Reference Elting, van der Naalt and Fock 12 , Reference Guilliams, Rosen, Buttram, Zempel, Pineda and Miller 13 , Reference Ito, Mori, Toda, Sugimoto, Takahashi and Kuroda 15 - Reference Shein, Reynolds, Gedela, Kochanek and Bell 19 , Reference Vastola, Homan and Rosen 21 Finally the mean rewarming period was also variable within the six studies in which it was reported,Reference Corry, Dhar, Murphy and Diringer 10 , Reference Guilliams, Rosen, Buttram, Zempel, Pineda and Miller 13 , Reference Lin, Lin, Hsia and Wang 16 - Reference Shein, Reynolds, Gedela, Kochanek and Bell 19 with a range from 31.5 to 84 hours (mean=54.5 hours, median=48 hours).Reference Corry, Dhar, Murphy and Diringer 10 , Reference Lin, Lin, Hsia and Wang 16 , Reference Missert, Qazi and Ionita 17 Furthermore, a rate of rewarming was quoted from 0.5 to 1 degree Celcius every three hours to daily.Reference Guilliams, Rosen, Buttram, Zempel, Pineda and Miller 13 , Reference Lin, Lin, Hsia and Wang 16 , Reference Orlowski, Erenberg, Lueders and Curse 18 , Reference Shein, Reynolds, Gedela, Kochanek and Bell 19
Duration of treatment prior to implementation of systemic TH was documented in seven studies, ranging from 2.5 hours to two months (mean=11.4 days, median=4 days), with patients on various numbers of AEDs prior to TH, ranging from one to nine (mean=6.0, median=6). The majority of patients were likely on intravenous anesthetic drugs, though it was not clear within the reports for the majority of studies included in the review. Treatment characteristics for the adult studies can be seen in Table 2.
Seizure Response
Seizure control with TH was documented as excellent (burst suppression or absence of seizure activity electrographically) in 25 of 40 (62.5%) patients. The electroencephalogram (EEG) monitoring utilized was not mentioned in the majority of cases. Reduction in seizure frequency, or a partial response, was documented in six (15%) of patients. Finally, failure of treatment response occurred in nine (22.5%) patients.
After optimization of other AED’s, acute recurrence of seizures upon rewarming occurred in three (7.5%) patients and appeared temporally related to the patients return to normothermia.
No correlation between target temperature and seizure response could be determined. Similarly, given the heterogeneous pathology leading to RSE in the patient identified, we are unable to comment on the effectiveness of TH for specific pathology.
Adverse Effects of TH
Adverse effects were seldom described within the 13 articles reviewed. Four studies reported complications during the patient’s intensive care unit (ICU) course, that may or may not be attributable to TH treatment.Reference Cereda, Berger and Rossetti 9 , Reference Corry, Dhar, Murphy and Diringer 10 , Reference Guilliams, Rosen, Buttram, Zempel, Pineda and Miller 13 , Reference Lin, Lin, Hsia and Wang 16 Giulliams et alReference Guilliams, Rosen, Buttram, Zempel, Pineda and Miller 13 and Corry et alReference Corry, Dhar, Murphy and Diringer 10 described complicated patient ICU courses with the following complications: deep venous thrombosis (three patients), infections (five patients), non-hemodynamically significant arrhythmias (two patients), ischemic/perforated bowel (one patient), acidosis (four patients), and electrolyte disturbances (one patient). Cereda et alReference Cereda, Berger and Rossetti 9 and Lin et alReference Lin, Lin, Hsia and Wang 16 reported bowel perforation in one patient and hypokalemia in one patient, respectively. Based on the complexity and duration of critical illness in the patients identified in the review, it is difficult to know if the complications described can be attributed to TH alone.
Outcome
Patient outcome was reported in most studies, with some documentation in 8 of the 13 articles. Five manuscripts failed to document patient functional outcome.Reference Czeisler, Manvar and De Marchis 11 , Reference Elting, van der Naalt and Fock 12 , Reference Hakimi, Talsania, Fesler and Fields 14 , Reference Missert, Qazi and Ionita 17 , Reference Vastola, Homan and Rosen 21
The overall outcome of the patients was variable, and recorded in only 15 patients. Glasgow Outcome Score (GOS) was calculated in those 15 patients with adequate data available. A GOS of 1, 2, 3, 4, or 5 occurred in five, one, two, six, and one patient(s) respectively.
Only five patients were reported as deceased.Reference Corry, Dhar, Murphy and Diringer 10 , Reference Guilliams, Rosen, Buttram, Zempel, Pineda and Miller 13 , Reference Svoronos, Kilbride and Mendoza 20 The majority of patients suffered moderate to severe disability. Often there was failure to document functional status, and focus on seizure control was the only outcome reported. Patient outcomes can be seen in Table 2.
Level of Evidence for TH
Based on two independent reviewers, there were a total of 13 studies reviewed with all representing Oxford level 4 evidence supporting the trend to seizure improvement or control with systemic TH in RSE. Similarly, within the adult and pediatric population all studies met the criteria for GRADE D level of evidence, very low evidence, in support of the use of systemic TH for RSE.
Overall we can recommend Oxford level 4 and GRADE D evidence for the use of systemic TH for RSE. Summary of the level of evidence can be seen in Table 3.
Table 3 Oxford and GRADE Level of Evidence
Trials Ongoing
Through our search of the WHO International Clinical Trials Registry Platform we identified two ongoing prospective trials utilizing systemic TH for status epilepticus. 31 , 32
First, there is a French based prospective single arm study 31 looking at moderate hypothermia therapy for convulsive status epilepticus in patients 18 years or older. The goal recruitment is 270 patients, with enrollment having begun in 2010. Primary outcome is functional status at three months. Secondary outcomes are: length of hospital stay, length of ICU stay, mortality, and incidence of functional sequelae. Currently, enrollment is suspended.
Second, a Chinese based prospective randomized trial 32 looking at intravenous anesthetic in combination with TH for patients 14 years or older in RSE, currently receiving benzodiazepines and one other AED. The goal recruitment is 40 patients; 20 in the treatment arm, and 20 in the control arm. Enrollment began in January 2013 and is ongoing. Primary outcomes are: clinical and(or) EEG termination of seizures, decrease of seizures, recurrence of seizures, mortality at three months, GOS score at three months, and post-status epilepticus symptomatic epilepsy at three months. Secondary outcomes are: change in EEG during hypothermia, length of ICU stay, and length of hospital stay.
Discusson
Systemic TH poses a potential treatment option for RSE. The anti-epileptic activity of hypothermia therapy is based on a variety of changes at the molecular level.Reference Motamedi, Lesser and Vicini 6 First, alteration in potassium ion exchange via sodium-potassium pumps has been demonstrated with hypothermia, impeding action potential propagation.Reference Volgushev, Vidyasagar, Chistiakova, Yousef and Eysel 33 Second, hypothermia can alter glutamate binding affinity and reduce glutamate mediated excitotoxicity.Reference Boucher, Kroger and Sik 34 It has also been linked to a reduction in glutamate release.Reference Boucher, Kroger and Sik 34 Finally, cooling has been demonstrated to reduce synaptic vesicle release, thus reducing neurotransmission and epileptic activity.Reference Yang, Ouyang, Kennedy and Rothman 35
One of the major limiting factors to implementation of TH is its complications. Complications of systemic TH include, but are not limited to: venous thrombosis, increased infection rates, cardiac arrhythmias, electrolyte disturbances, and coagulopathy.Reference Motamedi, Lesser and Vicini 6 Such complications of treatment are seen in the literature on TH for other neurological pathology, outside of RSE.Reference Kamps, Horn and Oddo 1 - Reference Wu and Grotta 4
Given the small number of studies in existence quoting the use of systematic TH for RSE,Reference Cereda, Berger and Rossetti 9 - Reference Vastola, Homan and Rosen 21 we elected to perform a systematic review of the literature to determine its effectiveness on seizure control. In addition we wished to provide a reference article for those deciding to trial TH therapy in the setting of RSE. Through our review we identified 13 articles,Reference Cereda, Berger and Rossetti 9 - Reference Vastola, Homan and Rosen 21 10 manuscripts and 3 meeting proceedings utilizing systemic TH to control refractory seizures. A total of 40 patients were described in these articles with 18 being adult, 14 pediatric, and 8 were of unknown age. All of the studies were retrospective case reports/series. Intravascular cooling was utilized in one studyReference Corry, Dhar, Murphy and Diringer 10 , while seven studies utilized external cooling blankets.Reference Cereda, Berger and Rossetti 9 , Reference Elting, van der Naalt and Fock 12 , Reference Guilliams, Rosen, Buttram, Zempel, Pineda and Miller 13 , Reference Lin, Lin, Hsia and Wang 16 , Reference Orlowski, Erenberg, Lueders and Curse 18 , Reference Shein, Reynolds, Gedela, Kochanek and Bell 19 , Reference Vastola, Homan and Rosen 21 Five studies failed to document their technique of achieving systemic TH.Reference Czeisler, Manvar and De Marchis 11 , Reference Hakimi, Talsania, Fesler and Fields 14 , Reference Ito, Mori, Toda, Sugimoto, Takahashi and Kuroda 15 , Reference Missert, Qazi and Ionita 17 , Reference Svoronos, Kilbride and Mendoza 20 The common target temperature was 33 degrees Celsius, as measured by bladder temperatures. This was achieved over a mean of 3.9 hours, and maintained for a median of 48 hours. Rewarming was typically by 0.5 to 1 degree over a median of 48 hours. Seizure control (burst suppression or absence of seizures electrographically) with systemic TH occurred in 62.5%, while reduction in the number of seizures occurred in another 15%. Overall 22.5% of patients reviewed demonstrated no seizure response to systemic TH and were deemed failures of treatment. In the secondary outcomes, adverse events were reported in four studies, with two studies quoting significant complications.Reference Corry, Dhar, Murphy and Diringer 10 , Reference Guilliams, Rosen, Buttram, Zempel, Pineda and Miller 13 The commonly reported adverse events were: acidosis, deep venous thrombosis, and infections. However, the complications may not entirely be related to TH alone and may reflect the severity of the critical illness in general. Unfortunately, patient outcome data was too sparingly documented for any strong conclusion. Overall, 12.5% of patients were reported as deceased. The remaining outcomes reported were heterogeneous, with the majority displaying moderate to severe disability. All studies were an Oxford level 4, GRADE D level of evidence supporting improvement in seizure control with systemic TH for RSE. A meta-analysis was not possible given the heterogeneous, retrospective nature of the majority of studies available.
Important trends can be seen within our review. First, we documented a 62.5% seizure cessation and 15% seizure reduction rates in the studies identified. For patients with RSE, a 77.5% chance of some degree of seizure response is impressive, thus reinforcing systemic TH as a viable option in RSE. A cautionary note, however; it is suspected that most of these patients were receiving intravenous anesthetic agents in concert with TH, thus the seizure response reported may reflect the combination of therapies on board at the time. Second, the preferred technique for TH in the review is external cooling. This is important, since the newer endovascular devices are expensive, require technical expertise for placement and are not as readily available in most centers compared to cooling blankets. However, we are unable to comment on whether one method is superior to another at this time. Third, the target temperature of 33 degrees Celsius seems to be common target in the studies identified. No correlation between target temperature and seizure control could be identified. Fourth, despite a small number of patients displaying seizure recurrence on rewarming, it is important to emphasize that TH is a bridge to optimization of oral AEDs, similar to intravenous sedatives and volatile inhalational anesthetics. Fifth, complications related to TH treatment cannot be underestimated. Despite only four studies documenting complications, two displayed severe complications.Reference Corry, Dhar, Murphy and Diringer 10 , Reference Guilliams, Rosen, Buttram, Zempel, Pineda and Miller 13 Given the complexity of the critical illness in this patient population, it is difficult to know if all complications described can be solely attributed to systemic TH. Finally, two prospective trials utilizing TH for seizures have been identified, both of which will hopefully shed further light on the utility of systemic TH in RSE.
Our review has significant limitations. First, the small number of studies identified, all with small patient populations, makes it difficult to generalize to all RSE patients. Second, the retrospective heterogeneous nature of the data (both patient disease characteristics and treatment regimens) makes it difficult to perform a meaningful meta-analysis, resulting in a strictly descriptive analysis. Third, the heterogeneity of prior treatments, time to implementation of systemic TH, and variable target temperature, time to target and duration of therapy at target leave the data on seizure responsiveness difficult to interpret. Fourth, the potential for publication bias in the articles reviewed is high. It is likely that only those cases displaying positive results after systemic TH treatment have appeared in the literature. Fifth, even though burst suppression appears attainable in some of these cases of RSE, this treatment provides only a means to achieve seizure control, with the transition to oral medication still required. Despite these limitations, we believe the data provides evidence for the potential benefit of systemic TH, in both the adult and pediatric RSE populations.
We believe this systematic review provides a good reference for the use of systemic TH in RSE. Consideration should be made for future prospective study of TH in RSE. Upon publication of the two ongoing prospective trials utilizing TH in RSE, our ability to comment more definitively on the role of this technique should improve. However, regardless of the results of these trials, the small number of cases identified in this review highlights the need for multi-center databases for RSE in order to better outline the role of non-conventional therapies.
Conclusions
There currently exists Oxford level 4, GRADE D evidence to support the use of systemic TH to achieve seizure reduction in RSE. Further prospective study of systemic TH in RSE is warranted.
Disclosure
Fred Zeiler has the following disclosures:
Health Sciences Center Foundation, Researcher, Research grant for project on optic nerve sheath diameter. Kaitlin Zeiler, Jeanne Teitelbaum, Lawrence Gillman, and Michael West do not have anything to disclose.
Supplementary material
To view supplementary material for this article, please visit http://dx.doi.org/10.1017/cjn.2015.31
