Continuous infusion pentobarbital for refractory status epilepticus in children

The purpose of this retrospective medical chart review was to describe dosing regimens and outcomes in children who received continuous pentobarbital therapy for refractory status epilepticus. Thirty patients (age = 6.5 ± 5.1 years; 67% male) received a mean loading dose of 5.4 ± 2.8 mg/kg with an initial infusion of 1.1 ± 0.4 mg/kg/h. Maximum infusion dose was 4.8 ± 2 mg/kg/h. Thirty-three percent of patients achieved sustained burst suppression without relapse; 66.7% experienced relapse, but 60% of those (n = 12) eventually reachieved burst suppression. Children achieving burst suppression within 24 hours of pentobarbital initiation and those older than age 5 years were 1.5 times more likely to have a positive outcome. None of these variables, however, achieved significance (Fisher exact test). Ninety-three percent of patients required inotropes; 66% acquired an infection; 10% had metabolic acidosis; and 10% experienced pancreatitis. Poor outcomes (death, encephalopathy) were observed in 33% of patients.     

Continuous midazolam infusion for refractory nonconvulsive status epilepticus in children

We examined efficacy of continuous midazolam (MDL) infusion in seven episodes of refractory nonconvulsive status epilepticus (NCSE) in five children. Diagnosis included Lennox-Gastaut syndrome (two cases), and symptomatic generalized epilepsy, ring chromosome 20 syndrome, and epilepsy with continuous spike-waves during slow-wave sleep (one case each). One patient with Lennox-Gastaut syndrome and another with ring chromosome 20 syndrome had two episodes of NCSE. MDL was given as an initial bolus of 0.15 to 0.3 mg/kg, followed by continuous intravenous infusion at 0.1 to 0.2 mg/kg/hr. The infusion rate was increased slowly by 0.1 mg/kg/hr every 0.5 to 1.0 hr, up to 0.4 mg/kg/hr or until NCSE was controlled. The electroencephalogram, vital signs, blood pressure, and oxygen saturation were monitored during therapy. Electrical status epilepticus was abolished within a few hours in five of the seven episodes, and two patients could maintain wakefulness, oral intake, and bowel and bladder control throughout the continuous infusion. In one patient in whom NCSE recurred, it then remained uncontrolled even at a maximum dose. Serious complications such as respiratory depression or hypotension were not observed. Continuous intravenous infusion of MDL was effective and safe for NCSE in children, and can be used as firstline therapy for this condition.     

Continuous midazolam versus diazepam infusion for refractory convulsive status epilepticus

The objective of this study was to compare the efficacy of continuous midazolam and diazepam infusion for the control of refractory status epilepticus. An open-label, randomized control study was undertaken at the Pediatric Emergency and Intensive Care Service of a multidisciplinary teaching and referral hospital. Subjects included 40 children, 2 to 12 years of age, with refractory status epilepticus (motor seizures uncontrolled after two doses of diazepam, 0.3 mg/kg per dose, and phenytoin infusion, 20 mg/kg). Either continuous midazolam (n = 21) or diazepam infusion (n = 19) in incremental doses was administered. The primary outcome measure was the proportion of children in each group with successful control of refractory status epilepticus. The secondary outcome measure was the time to control seizure activity, recurrence of seizure after initial control, if any, the frequency of hypotension, and the need for ventilation. The two groups were similar in age (mean +/- SD = 4.9 +/- 43.6 months) and etiology. Twenty-three (57.5%) patients had acute central nervous system infection. Refractory status epilepticus was controlled in 18 (86%) and 17 (89%) patients in the midazolam and diazepam groups, respectively (P = not significant). The median time to seizure control was 16 minutes in both groups, but in the midazolam group, seizures recurred in more children (57% versus 16% in diazepam group; P < .05). The maximum dose (mean +/- SD) of midazolam and diazepam required was 5.3 +/- 2.6 microg/kg/min and 0.04 +/- 0.02 mg/kg/min, respectively. About half of the patients needed mechanical ventilation and 40% had hypotension in both groups, but the mortality was higher in the midazolam group (38%) as compared to the diazepam group (10.5%, P < .1 > .05). Continuous midazolam and diazepam infusions were equally effective for control of refractory status epilepticus. However, midazolam was associated with more seizure recurrence and higher mortality in refractory status epilepticus predominantly caused by central nervous system infections.     

Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review

BACKGROUND: New continuous infusion antiepileptic drugs (cIV-AEDs) offer alternatives to pentobarbital for the treatment of refractory status epilepticus (RSE). However, no prospective randomized studies have evaluated the treatment of RSE. This systematic review compares the efficacy of midazolam (MDL), propofol (PRO), and pentobarbital (PTB) for terminating seizures and improving outcome in RSE patients. METHODS: We performed a literature search of studies describing the use of MDL, PRO, or PTB for the treatment of RSE published between January 1970 and September 2001, by using MEDLINE, OVID, and manually searched bibliographies. We included peer-reviewed studies of adult patients with SE refractory to at least two standard AEDs. Main outcome measures were the frequency of immediate treatment failure (clinical or electrographic seizures occurring 1 to 6 h after starting cIV-AED therapy) and mortality according to choice of agent and titration goal (cIV-AED titration to "seizure suppression" versus "EEG background suppression"). RESULTS: Twenty-eight studies describing a total of 193 patients fulfilled our selection criteria: MDL (n = 54), PRO (n = 33), and PTB (n = 106). Forty-eight percent of patients died, and mortality was not significantly associated with the choice of agent or titration goal. PTB was usually titrated to EEG background suppression by using intermittent EEG monitoring, whereas MDL and PRO were more often titrated to seizure suppression with continuous EEG monitoring. Compared with treatment with MDL or PRO, PTB treatment was associated with a lower frequency of short-term treatment failure (8 vs. 23%; p < 0.01), breakthrough seizures (12 vs. 42%; p < 0.001), and changes to a different cIV-AED (3 vs. 21%; p < 0.001), and a higher frequency of hypotension (systolic blood pressure <100 mm Hg; 77 vs. 34%; p < 0.001). Compared with seizure suppression (n = 59), titration of treatment to EEG background suppression (n = 87) was associated with a lower frequency of breakthrough seizures (4 vs. 53%; p < 0.001) and a higher frequency of hypotension (76 vs. 29%; p < 0.001). CONCLUSIONS: Despite the inherent limitations of a systematic review, our results suggest that treatment with PTB, or any cIV-AED infusion to attain EEG background suppression, may be more effective than other strategies for treating RSE. However, these interventions also were associated with an increased frequency of hypotension, and no effect on mortality was seen. A prospective randomized trial comparing different agents and titration goals for RSE with obligatory continuous EEG monitoring is needed.     

Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus

BACKGROUND: Although cIV-MDZ has emerged as a popular alternative to barbiturate therapy for refractory status epilepticus (RSE), experience with its use for this indication is limited. OBJECTIVE:- To evaluate the efficacy of continuous intravenous midazolam (cIV-MDZ) for attaining sustained seizure control in patients with RSE. METHODS: The authors reviewed 33 episodes of RSE treated with cIV-MDZ in their neurologic intensive care unit over 6 years. All patients were monitored with continuous EEG (cEEG). MDZ infusion rates were titrated to eliminate clinical and EEG seizure activity; cIV-MDZ was discontinued once patients were seizure-free for 24 hours. Acute treatment failures (seizures 1 to 6 hours after starting cIV-MDZ), breakthrough seizures (after 6 hours of therapy), post-treatment seizures (within 48 hours of discontinuing therapy), and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) were identified. RESULTS: All patients were in nonconvulsive SE at the time cIV-MDZ was started; the mean duration of SE before treatment was 3.9 days (range 0 to 17 days). In addition to benzodiazepines, 94% of patients had received at least two antiepileptic drugs (AED) before starting cIV-MDZ. The mean loading dose was 0.19 mg/kg, the mean maximal infusion rate was 0.22 mg/kg/h, and the mean duration of cIV-MDZ therapy was 4.2 days (range 1 to 14 days). Acute treatment failure occurred in 18% (6/33) of episodes, breakthrough seizures in 56% (18/32), post-treatment seizures in 68% (19/28), and ultimate treatment failure in 18% (6/33). Breakthrough seizures were clinically subtle or purely electrographic in 89% (16/18) of cases and were associated with an increased risk of developing post-treatment seizures (p = 0.01). CONCLUSIONS: Although most patients with RSE initially responded to cIV-MDZ, over half developed subsequent breakthrough seizures, which were predictive of post-treatment seizures and were often detectable only with cEEG. Titrating cIV-MDZ to burst suppression, more aggressive treatment with concurrent AED, or a longer period of initial treatment may reduce the high proportion of patients with RSE who relapse after cIV-MDZ is discontinued.     

Efficacy of continuous midazolam infusion and mortality in childhood refractory generalized convulsive status epilepticus.

PURPOSE: Continuous midazolam infusion is commonly used for the management of status epilepticus (SE). The purpose of this study was to assess the efficacy of midazolam and mortality in childhood refractory generalized convulsive SE. METHODS: We included 27 children with refractory generalized convulsive SE. Midazolam was given 0.2 mg/kg as bolus, followed by 1-5 microg/kg/min as continuous infusion. Clinical data and response to treatment were recorded for each patient. RESULTS: Acute symptomatic SE accounted for 52%, and central nervous system (CNS) infections were the most frequently associated etiologic condition (44%). Complete control of seizures was achieved with midazolam infusion in the 26 (96%) children within 65 min; at a mean midazolam infusion rate of 3.1 microg/kg/min. Adverse effects such as hypotension, bradycardia or respiratory depression did not occur during midazolam infusion. In one (4%) patient with acute meningoencephalitis, SE could not be controlled. Five (19%) patients died; four had acute symptomatic aetiology and one had progressive encephalopathy. CONCLUSION: Midazolam is effective and safe in the control of refractory generalized convulsive SE. The response to treatment and mortality were related to the underlying aetiology.     

Very-high-dose phenobarbital for childhood refractory status epilepticus

This report describes the management of three children, ranging in age from 7 to 9 years, who had refractory status epilepticus. This condition was likely the result of viral encephalitis; it manifested initially as generalized tonic-clonic seizure and later frequent subtle eye staring and twitching of mouth or limbs as well as tachycardia and dilatation of pupils. The seizures were not responsive to treatment with conventional doses of intravenous phenobarbital, phenytoin, and midazolam infusion. Very-high-dose phenobarbital was administered at accumulated daily doses up to 80 mg/kg, with a resulting serum level of more than 1000 mumol/L. It was effective in achieving seizure control, with milder adverse effects compared with thiopental infusion.     

Midazolam and pentobarbital for refractory status epilepticus.

Status epilepticus, a serious, life-threatening emergency characterized by prolonged seizure activity, occurs most commonly in pediatric patients. Although initial therapies with agents such as diazepam, phenytoin, or phenobarbital generally terminate seizure activity within 30-60 minutes, patients with refractory status epilepticus (RSE) lasting longer require additional intervention. High-dose pentobarbital has been the most commonly prescribed agent for the management of RSE in children; however, midazolam has emerged as a new treatment option. This review compares the use of midazolam with pentobarbital in published reports of pediatric RSE. Both drugs effectively terminated refractory seizure activity, although pentobarbital use was complicated by hypotension, delayed recovery, pneumonia, and other adverse effects. Midazolam use was effective and well tolerated, affirming its value in pediatric RSE management.     

Very-high-dose phenobarbital for refractory status epilepticus in children

Status epilepticus refractory to initial anticonvulsant therapy is a serious condition with a high morbidity and mortality. We present 50 cases with refractory status epilepticus (RSE) treated with very-high-dose phenobarbital (VHDPB) without reference to a predetermined maximum level or dose. Maximum serum levels ranged from 70 to 344 micrograms/ml (median, 114 micrograms/ml). VHDPB controlled seizures in all cases where no limits were imposed upon maximum dose (47/50). We found no maximum dose beyond which further doses are likely to be ineffective. Forty patients were intubated prior to VHDPB, but recovered respiratory drive and could be removed from the ventilator despite very high serum levels. This is explained by acute drug tolerance. Hypotension was unusual, related to the highest levels, and easily controlled. VHDPB has many relative advantages over other therapies presently used for RSE.     

Continuous infusion of midazolam in the treatment of refractory generalized convulsive status epilepticus

We studied the efficacy and safety of midazolam given as a continuous infusion in the treatment of refractory generalized convulsive status epilepticus (RGCSE). We carried out a prospective, open study, in 19 patients (11 men) with RGCSE in the intensive care unit at Firat Medical Center in Elazig. When intravenous administration of 0.3 mg/kg diazepam (three times at 5-min intervals), 20 mg/kg phenytoin, and 20 mg/kg phenobarbital failed to bring the episode under control, patients were administered an intravenous bolus of midazolam (200 μg/kg) followed by a continuous infusion at 1 μg/kg min. The dose was increased by 1 μg/kg min every 15 min until the episode of seizure was brought under control. The time from beginning of treatment to control of seizures, infusion rate, and side-effects were monitored. The mean age of the patients was 40.4 years (range 16–87 years). The clinical etiology of RGCSE was idiopathic epilepsy (6 cases), anoxicischemic cerebral insult due to cardiac arrest (3), viral encephalitis (2), intrahemispheric hematoma due to hemorrhagic stroke (1), cerebral infarct due to ischemic stroke (1), pituitary adenoma (1), post-traumatic epilepsy (1), renal failure (1), tuberculous meningitis (1), and unknown (2). In eighteen (94.7%) patients, seizures were completely controlled in a mean time of 45 min (range, 5–120 min) at a mean infusion rate of 8 μg/kg min (range, 3–21 μg/kg min). In one patient seizures did not stop. Midazolam administration did not cause any significant change in blood pressure, heart rate, oxygen saturation, or respiratory status. The mean time to full consciousness for patients after stopping the infusion was 1.6 hours (range, 2.0–8.5 hours). The mean infusion duration of midazolam was 14.5 hours (range, 12–25 hours). Midazolam is an effective and safe drug to control RGCSE, and may represent a substantial improvement over current therapeutic approaches such as pentobarbital anesthesia. Received: 15 December 2001 / Accepted in revised form: 10 July 2002 Correspondence to B. Müngen     

Mega‐dose phenobarbital therapy for super‐refractory status epilepticus

Aims. To evaluate the efficacy and safety of mega‐dose phenobarbital (MDPB; enteral or parenteral phenobarbital >10 mg/kg/day) for treating super‐refractory status epilepticus (SRSE; continuous or recurrent status epilepticus for ≥24 hours after the onset of continuous anaesthetic treatment) in adult patients. Methods. Adult patients with SRSE who were treated with MDPB in our institution from March 2005 to September 2014 were reviewed. We collected data on basic demographics, clinical features, functional status, anticonvulsant treatment, and possible adverse events. SRSE outcome was divided into six categories: successful therapy, initial failure, breakthrough seizures, withdrawal seizures, intolerable side effects, and death during treatment. Results. Ten adult patients with SRSE received MDPB. Median age at seizure onset was 38 years (range: 18‐59), and half were male. All patients had no history of seizures and had symptoms suggestive of viral encephalitis. Median duration of status epilepticus was 17.5 days (range: 6–60) and anaesthetics were used for a median of 14.0 days (range: 2–54) before MDPB. Successful control of SRSE was achieved in half of the patients, however, only one of ten patients was able to fully recover at discharge. Median duration of the MDPB was 45.5 days and the maximum serum phenobarbital level reached a median of 151.5 μg/ml. Patients with successful MDPB therapy had normal brain imaging (80% vs. 0%; p=0.048) and better functional outcome at discharge and after three months of follow‐up. Infection was the most critical complication, along with cardiorespiratory depression. Conclusion. MDPB is a therapeutic option for control of SRSE when other choices are exhausted.     

Topiramate and status epilepticus: report of three cases

OBJECTIVE: The goal of this study was to report the effectiveness of topiramate in treating status epilepticus. METHODS: Three patients with status epilepticus were treated with topiramate 500 mg twice daily for 2-5 days, with the dose gradually tapered thereafter to 200 mg twice daily. The patients' clinical status and EEG recordings were followed. RESULTS: Patient 1 was admitted for subacute encephalopathy that was complicated by secondarily generalized status epilepticus resistant to lorazepam, fosphenytoin, and pentobarbital coma. Topiramate was added and, 2 days later, pentobarbital was tapered with no recurrence of ictal discharges as the patient improved clinically. Patient 2 had end-stage liver disease and was hospitalized for peritonitis, and his course was complicated by partial status epilepticus. Topiramate was started and, 2 days later, his mental status improved as repeat EEG showed no further ictal discharges although periodic epileptiform discharges were seen in the left centroparietal area. The patient later died from complications of variceal bleeding. Patient 3 suffered cardiopulmonary arrest, and developed postanoxic seizures, which did not respond to lorazepam, fosphenytoin, valproate, and propofol coma as continuous EEG recordings showed recurrent generalized ictal discharges. Two days after topiramate was started, propofol was tapered and discontinued and EEG showed generalized slow wave activity and no ictal discharges. The patient was discharged to another facility 12 days later. CONCLUSIONS: Topiramate was effective in treating two patients with refractory generalized status epilepticus and one with complex partial status epilepticus. It should therefore be considered as an option in these situations, especially when other medications cannot be used.     

Prolongation of midazolam half-life after sustained infusion for status epilepticus

Midazolam clearance was examined in two patients with medically refractory convulsive status epilepticus. One patient received a constant infusion of midazolam for 68 hours and the other patient received a constant infusion of midazolam for 148 hours. In both patients the decline in level was, overall, much slower than expected. The half-lives of the terminal phase were longer than typically published (52.9 hours in Patient 1 and 20.1 hours in Patient 2). Thus, the data suggest that midazolam exhibits use-dependent pharmacokinetic changes that may be important clinically in situations that require prolonged midazolam therapy.     

Fosphenytoin vs. continuous midazolam for pediatric febrile status epilepticus

Background

Fosphenytoin (fPHT) and continuous intravenous midazolam (cMDL) had commonly been used as second-line treatments for pediatric status epilepticus (SE) in Japan. However, there is no comparative study of these two treatments.

Eight-year study of childhood status epilepticus: midazolam infusion in management and outcome

Sixty-eight children 2 months to 14 years of age were admitted with status epilepticus to Sultan Qaboos University Hospital from November 1993 to December 2001. Thirty-eight children (55.9%) had refractory status epilepticus and 30 (44.1%) had established status epilepticus. The children with refractory status epilepticus had received intravenous or per rectal diazepam and intravenous phenytoin/phenobarbital (either or both) before continuous infusion of midazolam was given. Fifty-one children received continuous midazolam infusion. In 38 children with refractory status epilepticus, the midazolam infusion was given in addition to the long-acting antiepilepsy drug, whereas 13 (18.8%) children needed only midazolam to control the established status epilepticus. Seventeen (25%) children were controlled with phenytoin sodium alone. Midazolam was given 0.15 mg/kg/minute initially as bolus in 1 minute, followed by 1 to 7 microg/kg/minute as continuous infusion. The status could not be controlled in one child (1.5%) suffering from neurodegenerative disease. Two children needed mechanical ventilation following prolonged apnea after diazepam administration in one and diazepam plus phenobarbital in the other. No metabolic derangements or compromise of vital functions was noted on midazolam infusion. All children made a complete recovery. There was one death related to meningoencephalitis.