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. Author manuscript; available in PMC: 2010 Mar 23.
Published in final edited form as: Epilepsia. 2007 Oct 15;49(2):248–255. doi: 10.1111/j.1528-1167.2007.01384.x

A combination of ketamine and diazepam synergistically controls refractory status epilepticus induced by cholinergic stimulation

Brandon S Martin 1, Jaideep Kapur 1
PMCID: PMC2844443  NIHMSID: NIHMS185518  PMID: 17941842

SUMMARY

Purpose

New treatments are needed for status epilepticus (SE) that is refractory to drugs modulating GABAA receptors, and NMDA receptor antagonists are candidate drugs.

Methods

Clinically available NMDA receptor antagonist ketamine was tested for effectiveness in terminating prolonged SE induced by a combination of lithium and pilocarpine. Animals were treated 10 min after first grade 5 behavioral seizure (Racine scoring scale) by intraperitoneal administration of ketamine, diazepam, or saline. Seizure termination was determined by electroencephalogram (EEG) recordings from the hippocampus and the cortex.

Results

Animals treated with normal saline or either 20 mg/kg diazepam, or 50 mg/kg ketamine continued in SE for the next 300 min. However, combined treatment with diazepam and ketamine rapidly terminated prolonged cholinergic stimulation-induced SE. Detailed study of dose response relationships demonstrated that diazepam enhanced efficacy and potency of ketamine in terminating SE.

Discussion

This study demonstrated synergistic action of diazepam and ketamine in terminating SE. It suggests that a ketamine–diazepam combination might be a clinically useful therapeutic option for the treatment of refractory SE.

Keywords: Status epilepticus, NMDA receptor, Ketamine, Diazepam

Prolonged, self-sustaining seizures are commonly referred to as status epilepticus (SE). Benzodiazepines are currently the mainstay of treatment of SE. In randomized clinical trials of treatment of convulsive SE, benzodiazepines such as lorazepam and diazepam are effective in terminating seizures in 59–78% of patients (Leppik et al., 1983; Treiman et al., 1998; Alldredge et al., 2001). Currently, there are no therapies that have been demonstrated to control seizures in 22–41% of the patients who were refractory to benzodiazepines. Therapies such as phenobarbital and phenytoin were ineffective in controlling SE refractory to first line treatment in the Veteran’s Administration cooperative trial. It is a common practice to use general anesthetics such as midazolam, propofol, or pentobarbitone, etc. to terminate refractory SE. These treatments terminate SE but require prolonged hospitalization and intensive care (Bleck 2005).

N-methyl-d-aspartate (NMDA) antagonists are candidate treatments for refractory SE. Some of these compounds, such as ketamine and MK-801 (dizocilpine), have been demonstrated to terminate prolonged, GABA-refractory SE induced by electrical stimulation in experimental animals (Bertram & Lothman 1990; Mazarati & Wasterlain 1999; Borris et al., 2000). In addition, NMDA receptor antagonists offer the possibility of protecting neurons from seizure-induced neuronal damage and the development of epilepsy (Fujikawa et al., 1994; Prasad et al., 2002). However, in contrast to their efficacy in terminating SE in an electrical stimulation model, NMDA receptor antagonists are not effective in terminating cholinergic stimulation-induced diazepam-refractory SE. In addition, one study found that NMDA receptor antagonists were ineffective in controlling SE induced by organophosphate cholinesterase inhibitors, also known as nerve agents (Shih et al., 1999). In commonly used cholinergic models of SE induced by pilocarpine or lithium followed by pilocarpine, NMDA receptor antagonists were effective in terminating SE only if administered prior to the induction of SE (Ormandy et al., 1989). However, they were less effective in terminating ongoing SE when administered 30 or 60 min following administration of pilocarpine. Another study found that a combination of a single dose (4 mg/kg) of noncompetitive NMDA receptor antagonist, MK 801, with diazepam (10 mg/kg) was superior to diazepam alone in terminating SE when administered 60 min postseizure onset (Rice & DeLorenzo 1999).

Several issues related to the treatment of diazepam-refractory SE with NMDA receptor antagonists remain to be explored. For example, the drug efficacy is in part influenced by the dose used. The efficacy of various doses of NMDA receptor antagonists administered alone has not been investigated in the cholinergic activation model of SE. Previous studies on the treatment of SE caused by electrical stimulation have demonstrated that increasing doses of NMDA receptor antagonists control SE in a larger fraction of animals up to a peak effective dose; further increases diminished the efficacy (Yen et al., 2004). Therefore, it is possible that the efficacy of NMDA receptor antagonists in treating refractory SE could be improved by varying its dose. Additionally, the combination therapy of NMDA antagonist and diazepam was not systematically explored. The doses of NMDA receptor antagonist, MK-801(dizocilpine), and diazepam were not varied and this could impact the efficacy of the combination therapy. Importantly, NMDA receptor antagonist dizocilpine is not clinically available.

In this study, we examined the efficacy of clinically-available NMDA receptor antagonist (ketamine) in terminating diazepam-refractory SE induced by cholinergic stimulation. Multiple doses of ketamine ranging from ineffective to toxic were examined for their efficacy in terminating diazepam-refractory SE. Furthermore, the same range of ketamine doses was used in combination with two doses of diazepam. These studies provide a comprehensive evaluation of a therapy for refractory SE by a combination of two clinically available drugs.

METHODS

All procedures on animals were performed according to a protocol approved by the institutional Animal Care and Use Committee. Adult male Sprague–Dawley rats (Taconic) weighing 250–350 g were housed with food and water ad libitum. A bipolar insulated stainless steel electrode was implanted stereotaxically, under ketamine/xylazine anesthesia, in the left posterior ventral hippocampi (−5.3 mm anterior-posterior, ±4.9 mm media lateral, −5.0 depth from touch point) and another pair of electrodes was placed over the cortex. The assembly was secured to the skull with dental acrylic, as previously described (Lothman et al., 1988). After a 5 to 7-day recovery period, the rats were administered 3 mmol/kg lithium chloride intraperitoneally (i.p.) 2-h later, SE was induced by i.p. injection of 50 mg/kg pilocarpine. Thirty minutes prior to pilocarpine administration, 2 mg/kg scopolamine was given to each rat to reduce the peripheral effects of the pilocarpine. Electroencephalogram (EEG) activity was monitored continuously for 6 h by EEG recordings and behavior was observed visually. Only those animals that developed a grade 5 seizure on the Racine scale (Racine, 1972) within 60 min of pilocarpine administration were included in the study, at which time they were either treated with drug or vehicle.

Five animals treated with saline formed the control group. For initial experiments, ketamine doses were chosen based on results of previous studies (Borris et al., 2000). Subsequently, doses were increased or decreased to obtain the full range of the drugs’ effects, from no response to maximal effect. In a subsequent experiment, animals were studied using doses of diazepam or a combination of diazepam and ketamine. All drugs were obtained from Sigma Aldrich (St. Louis, MO). Pilocarpine, scopolamine methyl bromide, and ketamine were dissolved in normal saline. Lithium chloride was dissolved in distilled water. Diazepam is insoluble in saline or water and an organic solvent has to be used to dissolve it. Diazepam was dissolved in 100% alcohol because the solution can be diluted in saline and delivered rapidly. Four rats undergoing seizures were injected with 0.5 mL ethanol vehicle, a volume equal to or greater than that used in diazepam treatments. Seizures in these rats were neither behaviorally nor electrographically controlled. All drugs were delivered i.p. In cases where ketamine and diazepam were delivered simultaneously, separate injections were given for each drug individually (drugs were not mixed in a single syringe).

EEG activity was recorded continuously for at least 5 h following drug injection to determine the effect of the drug on prolonged SE. SE was considered terminated when the EEG returned to normal baseline or showed irregular spikes without recurrence of seizures in a subsequent observation period of 5 h. Behavioral seizures were considered terminated when there was cessation of behavioral seizures and resumption of exploratory behavior. In some animals, end of behavioral seizures was accompanied by sedation where animal lay still in the cage.

RESULTS

Refractory SE induced by cholinergic stimulation

All the animals used in the study demonstrated continuous SE for at least 5 h, with seizures lasting 12 h or more in some animals. Animals exhibited some or all of these previously reported behaviors in response to seizure-inducing doses of pilocarpine: wet dog shakes, facial twitching and automatisms, chewing, staring, hind limb scratching, head bobbing, forelimb clonus, rearing, and rearing and falling with full body convulsions. Behaviorally, animals exhibiting class 2 (head bobbing), class 3 (forelimb clonus), class 4 (rearing), and class 5 (rearing and falling with generalized convulsions) seizures according to the Racine scale (Racine, 1972) were considered to be in SE. Animals spent most of their time exhibiting class 3–5 seizures, briefly interrupted by class 2 behaviors. This was in contrast to SE induced by hippocampal stimulation (Lothman et al., 1989), where animals exhibited, for a majority of the time, class 2 behavioral seizures interrupted by brief periods of rearing and/or falling. Electrographically, all the animals demonstrated continuous SE for at least 5 h. Initially, electrical seizures consisted of a rapid spiking pattern that decreased in frequency over the next hour. Later, the EEG changed to rapid repeated bursting. SE ended with conversion of these bursts to periodic discharges.

Treatment was initiated 10 min after the first grade 5 seizures because previous studies demonstrated refractoriness to diazepam at this time point (Jones et al., 2002). Five rats, treated with normal saline 10 min after first grade 5 seizure, continued to exhibit continuous seizures for the next 5 h. Refractoriness to diazepam was confirmed in another experiment, five animals were treated with 20 mg/kg diazepam 10 min after the first grade 5 seizure and they too continued to have seizures for the next 5 h.

Partial control of SE by ketamine monotherapy

In a previous study on electrical stimulation-induced SE, 100 mg/kg ketamine controlled SE in all animals when administered 60 min after termination of stimulation (Borris et al., 2000). Therefore, we first tested whether this dose of ketamine would control cholinergic SE refractory to diazepam. The drug abolished behavioral seizures in seven of eight animals within 5 min of administration and one animal died of respiratory arrest. Analysis of electrographic activity demonstrated that, in four animals, the seizure activity ended within 60 min of drug administration. Three animals continued to have electrographic seizures for the remaining 5 h of observation. Animals whose electrographic seizures were controlled, regained normal behavior 2–3 h after drug administration. By contrast, those animals whose electrographic seizures continued demonstrated chewing and wet dog shakes upon awakening.

We tested whether increasing the ketamine dose to 150 mg/kg would control seizures in a larger percentage of animals. This dose of ketamine caused respiratory arrest in six out of seven animals treated and one continued to have seizures. When an intermediate dose (125 mg/kg) was administered to three animals, two animals died and one continued to exhibit electrographic and grade 1–2 behavioral seizures.

Effects of 50 and 75 mg/kg ketamine were studied in each of four animals. In all animals treated with 50 mg/kg ketamine, there was no grade 4 or 5 behavioral seizure, but grade 1–3 seizures continued in all the animals. Electrographic seizures were present continuously for the duration of the recording. Examples of EEG tracings obtained from an animal treated with 50 mg/kg ketamine are displayed in Fig. 1. Note that the frequency and amplitude of epileptiform activity increased following ketamine administration. Behavioral and electrographic seizures were controlled in one animal treated with 75 mg/kg ketamine for 1 h 5 min (electrographic frequency <1 Hz), but behavioral manifestations and electrographic frequency >2 Hz returned. Seizures continued unabated in the other three animals.

Figure 1.

Figure 1

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EEG tracings recorded from the hippocampus and cortex of an animal in SE treated with 50 mg/kg ketamine. Baseline recording was obtained prior to the administration of pilocarpine, animal was considered in SE when it experienced first stage 5 seizure. Ketamine was administered 10 min after first class 5 seizure and the tracing was obtained 5 min after ketamine treatment. Note that ketamine initially increased the frequency and amplitude of epileptiform activity which continued unabated for 5 h.

The dose response data were constructed based on electrographic and behavioral seizure termination within 60 min of drug administration. For this analysis, if the animal continued to have seizures past 1 h and subsequently became seizure-free, it was still considered a treatment failure. If the animal was seizure-free at the 1 h time point and then reverted back to SE, it was also considered a failure for this analysis. Doses of 50 mg/kg and 75 mg/kg were ineffective, and that of 100 mg/kg showed some efficacy but also the first signs of toxicity. Higher doses of ketamine were either ineffective or toxic. Thus, the ketamine dose SE termination (response) relationship demonstrated a very narrow therapeutic range of ketamine in terminating SE induced by cholinergic stimulation (Fig. 2).

Figure 2.

Figure 2

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Relationship between various doses of ketamine administered alone or in combination with diazepam and percentage of animals seizure-free at a time 60 min following drug administration. Note left and upward shift of curves as diazepam is combined with ketamine and its dose is increased.

The time course of electrographic seizure control was studied in each group at 15-min intervals in the first hour after treatment and on an hourly interval for the subsequent 4 h (Fig. 3 top panel). It took 45–60 min for 100 mg/kg ketamine to control SE and seizure-free animals did not revert to SE in the subsequent period of observation. Of the animals treated with 75 mg/kg, one became seizure-free after 45 min of treatment and this effect disappeared within 1 h.

Figure 3.

Figure 3

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Time course of ketamine control of electrographic seizures is displayed. The onset of ketamine action and persistence of seizure freedom were studied by analyzing seizure freedom at various time points following drug administration. When ketamine was administered alone (top panel), it acted slowly taking from 45 min to 1 h to terminate SE. In combination with 10 mg/kg diazepam (middle panel), the action became faster and more persistent. A combination of 20 mg/kg diazepam and ketamine was rapidly acting and its effect was persistent (bottom panel).

Combination therapy with 10 mg/kg diazepam

We tested whether a combination of diazepam (10 mg/kg) with varying doses of ketamine would be less toxic, more efficacious, and faster acting than ketamine alone. Animals (n = 8) were treated 10 min after first grade 5 seizure with a combination of diazepam and 75 mg/kg ketamine; electrographic and behavioral seizures were controlled in two animals, and death due to respiratory arrest occurred in six animals.

A combination of diazepam and a smaller dose of ketamine (50 mg/kg) was more efficacious. Electrographic and behavioral seizures were terminated in three out of seven animals. One animal died of respiratory arrest and in the remaining animals, behavioral seizures were attenuated and electrographic seizures continued. Ketamine controlled seizures in 42.9% of animals at a dose of 50 mg/kg with one animal experiencing respiratory arrest (Fig. 2). All animals (n = 6) treated with diazepam and 25 mg/kg ketamine experienced alleviation of behavioral seizures but electrographic seizures continued unabated for at least 4 h (Fig 2 and Fig 3, middle panel). One animal died of respiratory arrest at this dose.

The ketamine dose response relationship demonstrated a widening and left shift when 10 mg/kg diazepam was combined with it (Fig. 2). Increasing the dose beyond 50 mg/kg diminished efficacy and increased toxicity. When successful, diazepam and 75 mg/kg ketamine combination controlled seizures in 15–30 min and animals did not revert to SE once they were treated (Fig. 3, middle panel). The combination containing a lower dose of ketamine (50 mg/kg) was faster, with seizures coming under control in all animals treated within 15 min and none of the treated animals reverted back to seizures.

Combination therapy with 20 mg/kg diazepam

We tested whether a higher dose of diazepam, 20 mg/kg combined with various doses of ketamine would control SE. A combination of 50 mg/kg ketamine with 20 mg/kg diazepam controlled behavioral and electrographic seizures in all five animals tested (Fig 2 and Fig 4). In seven animals treated with a ketamine dose of 25 mg/kg, behavioral and electrographic seizures were terminated in three animals, while two died of respiratory arrest. Behavioral and electrographic seizures were controlled in one out of six animals treated with 10 mg/kg ketamine with diazepam (Fig. 2).

Figure 4.

Figure 4

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EEG tracings recorded from the hippocampus and cortex of an animal in SE treated with 50 mg/kg ketamine and 20 mg/kg diazepam. Baseline recording was obtained prior to the administration of pilocarpine, animal was considered in SE when it experienced first stage 5 seizure. A combination of ketamine 50 mg/kg with 20 mg/kg diazepam abolished SE. Compare this response to that shown in Fig. 1.

The ketamine dose response relationship was broader when it was combined with 20 mg/kg diazepam; effective doses ranged from 10 to 50 mg/kg with respiratory arrest only at the 25 mg/kg dose. Seizures were terminated within 30 min of drug administration in all animals treated with 50 mg/kg ketamine with 20 mg/kg diazepam (Fig. 3, bottom panel). In the subsequent observation period of 5 h, none of the animals reverted back to seizures. A lower dose of ketamine, 25 mg/ kg, was slower and took 30–180 min to terminate seizures. The lowest dose combination with 10 mg/kg of ketamine gradually controlled seizures in an increasing number of animals reaching a peak of 60% in 4 h.

DISCUSSION

The principal finding of this study is that a combination of diazepam and ketamine rapidly terminates prolonged cholinergic stimulation-induced SE in a synergistic fashion. Diazepam shifted the ketamine dose response (SE termination) relationship to the left and increased the maximal effect of ketamine. A ketamine–diazepam combination might be a clinically useful treatment of refractory SE.

This study demonstrated synergistic action of diazepam and ketamine in controlling prolonged SE. In classical pharmacological terminology, synergism refers to interaction between two drugs that individually produce very similar effects, and yield a superadditive effect when present with each other (Tallarida, 2007). Synergism or a superadditive effect is present when the effect of the combination is superior to the sum of the effects of individual drugs. The most dramatic example of synergism between ketamine and diazepam was illustrated by the combination of 50 mg/kg ketamine and 20 mg/kg diazepam. The current study demonstrated that when administered 10 min after the first class 5 seizure, 20 mg/kg diazepam did not control seizures in any animal (0% response). Ketamine at a dose of 50 mg/kg also had a 0% response. The additive effect of these drugs in combination is expected to be 0%; however, the experimentally observed effect was 100%, clearly demonstrating superadditive or synergistic action.

Quantitatively, synergism is demonstrated by analysis of shifts in dose response (isobolic) curves (Tallarida, 2007). Synergism between ketamine and diazepam was further demonstrated by the left and upward shift of the ketamine dose–response relationship caused by increasing doses of diazepam. Ketamine alone and in combination with 10 mg/kg diazepam had a maximal efficacy of 50%; however, when combined with 20 mg/kg, its efficacy increased to 100%. Similarly, the dose of ketamine required to control seizures in 50% of animals decreased from 100 mg/kg to approximately 30 mg/kg when it was administered with diazepam (20 mg/kg). Synergism between a weak NMDA receptor antagonist budipine and topiramate in terminating SE was described in the past (Fisher et al., 2004). Neither drug alone at any dose-controlled self-sustaining SE induced by electrical stimulation. However, when the drugs were administered in combination, SE was terminated in all animals tested.

There are many possible mechanisms underlying synergistic action of drugs that block NMDA receptors and enhance GABAA receptors in the treatment of SE. Several studies have demonstrated that GABAA receptor-mediated inhibition is diminished during SE (Kapur & Lothman 1989; Kapur & Coulter, 1995; Goodkin et al., 2005; Naylor et al., 2005). Furthermore, during periods of intense neuronal activity, the reduction of GABAergic inhibition can be prevented by blocking NMDA receptors (Stelzer et al., 1987; Kapur & Lothman, 1990; Stelzer, 1990). During intense neuronal activity associated with SE, there is activation of NMDA and intracellular calcium accumulation (DeLorenzo et al., 1998; Pal et al., 1999; Raza et al., 2004) which can lead to the activation of calcium-dependent phophatases and kinases (Churn & DeLorenzo, 1998). Also, phosphorylation and dephosphorylation of GABAA receptors modulate their activity and trafficking (Connolly et al., 1999; Kittler & Moss, 2003; Jovanovic et al., 2004).

There is likely to be increased activation of NMDA receptors during SE. Glutamate release from presynaptic terminals is increased in certain models of SE and chronic epilepsy (Mangan & Kapur, 2004; Yang et al., 2006). Prolonged seizures and SE enhance the activity of calcium phosopholipid-dependent kinase (PKC) in the hippocampus (Kohira et al., 1992) which can modulate gating and trafficking of NMDA receptors (Lan et al., 2001). Finally, NMDA receptors undergo tyrosine phosphorylation during SE, which may alter their trafficking and surface availability (Huo et al., 2006). These studies suggest that there is increased activation of NMDA receptors during SE, which reduces GABAA receptor-mediated inhibition and reinforce seizures. A combination of GABAA receptor agonist and NMDA receptor antagonist counteracts two parts of this vicious cycle to terminate it.

In contrast to the current study, several previous studies demonstrated that NMDA receptor antagonists terminated prolonged, refractory SE evoked by electrical stimulation in all animals (Mazarati & Wasterlain, 1999; Borris et al., 2000; Prasad et al., 2002). These differences likely arise from the nature of SE induced by cholinergic stimulation and electrical stimulation. Behavioral and electrographic seizures and cell loss appear to be more intense in cholinergic stimulation-induced SE.

Respiratory arrest was observed in many animals treated with ketamine. This effect perhaps resulted from a combination of cholinergic stimulation and ketamine. Cholinergic stimulation increases bronchial secretions and can compromise the respiratory system. Similarly, ketamine can increase secretions to compromise respiration. Additional central effects of cholinergic stimulation and ketamine may combine to depress respiration.

These findings are clinically significant and raise the possibility of using ketamine as an adjunct to diazepam for the treatment of patients with refractory SE. Ketamine was initially introduced as an anesthetic but its undesired psychic effects have limited its use as an anesthetic. More recently, the drug has found use as an analgesic in a hospice setting and in the perioperative period (Bell et al., 2006; Legge et al., 2006). There are case reports of ketamine use to treat SE (Bleck et al., 2002; Mewasingh et al., 2003; Ubogu et al., 2003). However, it is difficult to compare clinical studies with those performed in experimental animals, because the range of doses of ketamine that were used in clinical studies may not be pharmacologically equivalent to those used in experimental animals. Once appropriate human dose range been determined, therapeutic efficacy and safety of ketamine in terminating refractory SE in humans should be determined in a prospective randomized clinical trial.

ACKNOWLEDGMENT

Public Health Service Grants from National Institutes of Health NINDS RO1 NS40337 and UO1 NS58204 supported this work.

Footnotes

Conflict of interest: Authors have no conflicts of interest to report. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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