Rectal Administration Of Diazepam Research Articles

Use of benzodiazepines in patients with status epilepticus requiring second-line antiseizure medication treatment.

Status epilepticus (SE) is a life-threatening state that needs rapid and adequate treatment. Benzodiazepines (BZD) are used as a first-line treatment for SE, and if the desired effect is not achieved, second-line antiseizure medications are used. To investigate whether the treatment with BZDs is performed adequately in patients with different subtypes of SE requiring second-line ASM treatment and, if not, to identify the factors influencing the suboptimal treatment. This is a retrospective single centre study from the patient register of Tampere University Hospital including patients over 16 years of age with a diagnosis of SE, seizure or epilepsy and who received intravenous (IV) ASM during a one-year period in 2015. Treatment was considered to be suboptimal if it was not in line with the latest European, Finnish or American guidelines. In total, 109 episodes were registered. The largest group was that with convulsive SE with 56 episodes, followed by postictal with 23 episodes, nonconvulsive status epilepticus (NCSE) with 22 episodes, and focal awareness SE (FASE) with eight episodes. Overall, in 77 % of the episodes, BZDs were administered, and in 43 % of the episodes, treatment was in line with guidelines. In the NCSE group, BZD was administered less often and was less often in line with the guidelines than in the CSE group (27.3 % vs. 89.3 %, p < 0.001 and 4.5 % vs. 55.4 %, p < 0.001). For FASE episodes, the concordance with the guidelines was low. After IV administration, the mean BZD dose was lower than that after buccal administration of midazolam (2.1 mg vs. 8.7 mg) or after rectal administration of diazepam (4.5 mg vs. 10.0 mg). Lorazepam was administered only via the IV route, with mean dosage of 2.6 mg. Clinical characteristics did not influence the dosing of BZDs. BZDs were both underdosed and underused for all subtypes of SE. In particular, their use for NCSE was infrequent and suboptimal. The divergence from the guidelines was influenced especially by low IV dosages.

Out-of-hospital rescue medication in dogs with emergency seizure disorders: an owner perspective.

Emergency seizure disorders such as status epilepticus and cluster seizures are unlikely to cease spontaneously while prolonged seizure activity become progressively more resistant to treatment. Early administration of rescue medication in canine epileptic patients, in particular benzodiazepines, at seizure onset by the owners can be life-saving and brain protecting. Clinical studies in dogs evaluating the use of rescue medication in hospital environment exist, however, the owner perspective has not been assessed to date. To evaluate the use of rescue medication in dogs with seizure emergencies by the owner at home. Observational study based on online surveys of owners of dogs with emergency seizure disorders. The questionnaire was answered by 1,563 dog owners, of which 761 provided complete and accurate answers suitable for analysis. Of these, 71% administered diazepam, 19% midazolam, 6% levetiracetam, 3% lorazepam, and 4% more than one rescue or other medication. Overall, the success rates based on owners' perspective for intranasal midazolam and rectal diazepam were 97 and 63%, respectively. Owners reported a compliance level of 95 and 66% for intranasal midazolam and rectal diazepam administration, respectively. Even though rectal diazepam was the most used rescue medication in this survey population, intranasal midazolam was perceived by the owners as a better option regarding effectiveness, time to seizure cessation and owner compliance.

Sublingual lorazepam as rescue therapy for seizure emergencies in adults

ObjectiveLimited acute home treatments are available for patients with prolonged (>5 minutes) or repetitive (≥2 in 24 hours) seizures. While this early seizure treatment may reduce the need for emergency care, intermittent intranasal benzodiazepine formulations are expensive and rectal diazepam administration is often socially unacceptable. We determined whether caregivers could use sublingual lorazepam oral concentrate solution effectively as acute treatment for adults with prolonged and repetitive seizures. MethodsPatients prescribed sublingual lorazepam solution at the Johns Hopkins Epilepsy Center for acute seizure treatment during a 5-year period (2012–2017) were screened. We determined clinical history of seizure patterns and number of antiseizure medications (ASMs) through patient and caregiver surveys, and we verified this history in patients’ medical records and charts. During a 2-year span (2017–2018), patients and caregivers were surveyed on responses to their most recent use of sublingual lorazepam solution, including seizure cessation (prolonged seizure stopping <5 minutes or ≤1 repetitive seizure), presence of sedation and adverse events within 24 hours of administration, and whether refrigeration limited use. ResultsIn total, 52 patients used sublingual lorazepam for treatment of acute seizures during the study period (median dose 1 mg, range 0.5 to 2 mg). Of them, 48 patients participated in treatment survey interviews. Family caregivers usually administered lorazepam (88%); 3 self-administered. Patients were surveyed on responses to their most recent use of sublingual lorazepam treatment: 66% (23/35) of patients with repetitive seizures reported no further seizure activity after administering treatment; 70% (7/10) with prolonged seizures reported seizure activity ceased within 5 minutes of treatment. Three patients treated auras and had no seizures. There were no serious adverse events during most recent use: 31% of patients developed moderate/severe sedation. Of note, 98% refrigerated lorazepam, often with coolers; 44%, however, said this limited treatment access. There was high treatment satisfaction; 79% reported that having the emergency treatment available made them feel safer. SignificanceThis patient survey and retrospective chart review demonstrates that home treatment with sublingual lorazepam solution may be effective for interrupting prolonged and repetitive seizures. No patients had sedation complications with home doses of 0.5 to 2 mg, and patients report high satisfaction with the treatment.

Formulation and Evaluation of Diazepam as a Rectal Preparation

Diazepam has become a commonly used drug for treatment of acute repetitive epileptic seizures and febrile convulsions in children. Considering the advantages of rectal administration of diazepam, the objective of this study was to formulate and evaluate rectal hydrogels containing diazepam as a drug substance in combination with suitable co - solvents and preservatives.Prepared HPMC (hydroxypropyl methylcellulose) hydrogels containing different concentrations of diazepam (2, 4 and 6 mg I ml) manifested good quality in respect to physicochemical parameters (pH value, drug content, ingredients content and viscosity), antimicrobial efficiency and microbiological quality. Under the proposed HPLC conditions, satisfactory separation of diazepam and the preservatives used was achieved. In vitro release studies have shown that the total amount ofdiazepam was released in a period of 3 hours. Prepared formulations were stable for four months at 26 C (ambient temperature characteristic of the second climate zone

Change in the strategy for prophylactic diazepam use for febrile seizures and the impact on seizure recurrence within 24 h

PurposeTo investigate the association between reduced prophylactic diazepam usage and short-term recurrence of febrile seizures (FSs) after the FS practice guideline was updated in Japan. MethodIn this single-center, retrospective study, children (6–60 months of age) with FS who were transported to our center by ambulance from January 2011 through December 2018 were included. Rectal administration of diazepam (0.3-0.5 mg/kg) after the first seizure and seizure recurrence within 24 h were compared between 2011–2015 (pre-guideline revision) and 2016–2018 (post-guideline revision). ResultsAmong the total of 509 children, 297 were transported to our hospital in 2011–2015 and 212 in 2016–2018. Rectal diazepam administration was decreased in 2016–2018 (17 %) compared to 2011–2015 (53 %, P < 0.0001), while seizure recurrence was increased in 2016–2018 (20 %) compared to 2011–2015 (12 %, P = 0.0087). Similarly, hospital revisits (23 %) and hospital admissions (26 %) were increased in 2016–2018 compared to 2011–2015 (15 %, P = 0.031 and 18 %, P = 0.026, respectively). Multiple logistic regression analyses showed that prophylactic diazepam administration was the only factor related to preventing seizure recurrence. FS recurrence after the initial seizure was significantly less frequent with diazepam use (6 %) than without diazepam use (21 %, P < 0.0001; relative risk reduction, 70 %; number needed to treat, 6.8 children). ConclusionThe FS practice guideline revision was associated with reduced prophylactic diazepam usage and increased FS recurrence within 24 h in Japan. Prophylactic diazepam use should be determined based on clinical safety, local health infrastructure, and parental anxiety.

Levetiracetam Rectal Administration in Healthy Dogs

BackgroundLevetiracetam is used to manage status epilepticus (SE) and cluster seizures (CS) in humans. The drug might be absorbed after rectal administration and could offer a practical adjunct to rectal administration of diazepam in managing SE and CS.HypothesisLevetiracetam is rapidly absorbed after rectal administration in dogs and maintains target serum concentrations for at least 9 hours.AnimalsSix healthy privately owned dogs between 2 and 6 years of age and weighing 10–20 kg.MethodsLevetiracetam (40 mg/kg) was administered rectally and blood samples were obtained immediately before (time zero) and at 10, 20, 40, 60, 90, 180, 360, and 540 minutes after drug administration. Dogs were observed for signs of adverse effects over a 24‐hour period after drug administration.Results C LEV at 10 minutes was 15.3 ± 5.5 μg/mL (mean, SD) with concentrations in the target range (5–40 μg/mL) for all dogs throughout the sampling period. C max (36.0 ± 10.7 μg/mL) and T max (103 ± 31 minutes) values were calculated and 2 disparate groups were appreciated. Dogs with feces in the rectum at the time of drug administration had lower mean C max values (26.7 ± 3.4 μg/mL) compared with those without (45.2 ± 4.4 μg/mL). Mild sedation was observed between 60 and 90 minutes without other adverse effects noted.Conclusions and Clinical ImportanceThis study supports the use of rectally administered levetiracetam in future studies of clinical effectiveness in the management of epileptic dogs.

Management of Patients With Status Epilepticus Treated at a Pediatric Intensive Care Unit in Turkey

We investigated the etiology, treatment, and prognosis of patients treated for status epilepticus at a pediatric intensive care unit. Medical records of 89 patients admitted to a pediatric intensive care unit with status epilepticus were reviewed retrospectively. Patients ranged in age from 2 months to 18 years (mean age ± S.D., 4.7 ± 3.8 years). Seizure etiologies comprised remote symptomatic in 47 (52.7%), febrile in 15 (16.9%), acute symptomatic in 12 (13.5%), and unknown in 15 (16.9%). Seizure durations ranged from 30-60 minutes in 58 patients, whereas 31 manifested refractory seizures longer than 60 minutes. Seizure control was achieved within 30 minutes in 55 patients, from 30-60 minutes in 19, and after 60 minutes in 15. Rectal diazepam was administered to 38 (42.7%) patients before admission to the hospital. Length of intensive care unit stay increased with increasing seizure duration (P < 0.05). The total mortality rate was 3.4%. This lower mortality rate may be considered evidence of the effectiveness and reliability of the status epilepticus treatment protocol in our pediatric intensive care unit. Prehospital rectal diazepam administration and the treatment of brain edema in the intensive care unit may be useful in the management of patients with status epilepticus.

Diazepam pharmacokinetics after nasal drop and atomized nasal administration in dogs

The standard of care for emergency therapy of seizures in veterinary patients is intravenous (i.v.) administration of benzodiazepines, although rectal administration of diazepam is often recommended for out-of-hospital situations, or when i.v. access has not been established. However, both of these routes have potential limitations. This study investigated the pharmacokinetics of diazepam following i.v., intranasal (i.n.) drop and atomized nasal administration in dogs. Six dogs were administered diazepam (0.5 mg/kg) via all three routes following a randomized block design. Plasma samples were collected and concentrations of diazepam and its active metabolites, oxazepam and desmethyldiazepam were quantified with high-performance liquid chromatography (HPLC). Mean diazepam concentrations >300 ng/mL were reached within 5 min in both i.n. groups. Diazepam was converted into its metabolites within 5 and 10 min, respectively, after i.v. and i.n. administration. The half lives of the metabolites were longer than that of the parent drug after both routes of administration. The bioavailability of diazepam after i.n. drop and atomized nasal administration was 42% and 41%, respectively. These values exceed previously published bioavailability data for rectal administration of diazepam in dogs. This study confirms that i.n. administration of diazepam yields rapid anticonvulsant concentrations of diazepam in the dog before a hepatic first-pass effect.

Diazepam autoinjector intramuscular delivery system versus diazepam rectal gel: A pharmacokinetic comparison

Rectal administration of diazepam (DZ) has been used effectively in patients with epilepsy who experience acute repetitive seizures, but rectal gel may be difficult to administer during a seizure and is subject to variable drug absorption. An intramuscular (IM) autoinjector DZ formulation may offer a practical alternative to rectal DZ. This single-center, open-label, 3-treatment, 3-period crossover study compared the pharmacokinetic and safety profiles of 10mg DZ administered rectally in 24 healthy, fasted and fed subjects versus IM autoinjector delivery in fasted subjects. Blood samples were collected at baseline and for up to 24h postdose and plasma DZ concentrations were determined by liquid chromatography and tandem mass spectrometry. There were no significant differences between plasma concentrations for rectal administration of DZ in fasted and fed subjects at any time point. Intramuscular DZ administration resulted in more rapid and less variable drug absorption than rectal delivery. At 30min postdose and at all subsequent evaluations, IM administration resulted in significantly higher areas under the curve versus rectal administration in fasted subjects (p<0.05). This significant difference was sustained throughout the remainder of the 24-h study period (p<0.05). All reported adverse events were considered mild, and none required treatment.

Rectal Diazepam Gel in the Home Management of Seizures in Children

This study assessed the utility of rectal diazepam gel in the home management of prolonged or repetitive seizures in children. Thirty-eight children being prescribed rectal diazepam gel by their clinician were prospectively recruited. Seizures, rectal diazepam use, emergency department visits, and quality of life data before and after study entry were recorded. The 38 children included 14 (37%) with complex febrile seizures, and 24 with epilepsy (n = 22) or a single seizure (n = 2). There were 23 (61%) children with prolonged seizures and 15 (39%) with repetitive seizures. During the 6-month follow-up period, 12 children experienced 26 seizures which met the criteria for rectal diazepam administration. Rectal diazepam gel was administered to 8 children on 19 occasions. In 16 (84%) of these episodes, seizures stopped and no emergency department visit was required. Parental stress was decreased between baseline and 6 months in both the overall group and in all the subgroups. Home use of rectal diazepam gel is effective in aborting seizure activity, often avoiding an emergency department visit. Its use reduces morbidity and costs associated with hospital visits and provides parents a treatment option for home management of prolonged or repetitive seizures.

Adjustment in children with intractable epilepsy: importance of seizure duration and family factors.

Seventy-five families of children with intractable epilepsy but without a severe learning disability (mean age 7 years 1 month, SD 2 years 6 months; range 2 to 12 years) who attended a regional paediatric neurology service, were surveyed. A postal questionnaire was used which included standardized measures of child and family adjustment; forty-eight families responded (64%; 31 males, 17 females). There was no significant difference between responders and non-responders in terms of age, sex, number of other chronic illnesses and disabilities, age at epilepsy diagnosis, seizure type, nor number of antiepileptic drugs currently prescribed (p > 0.05). The importance of including multidimensional measures of outcome was highlighted by the finding that epilepsy, pharmacological, and psychosocial factors were differentially associated with specific adjustment difficulties. Two factors appeared to be most pervasively implicated across a range of adjustment problems: frequency of rectal diazepam administration and family patterns of relating to each other (p < 0.05). It appeared that duration of seizures (as indicated by frequency of rectal diazepam administration), rather than the frequency of seizures per se, was more pernicious in terms of poor adjustment. Intrafamilial relations (degree of conflict/cohesion and soon) were not only associated with adjustment difficulties in the child, but also with the frequency of seizures themselves. Implications for psychological interventions in intractable epilepsy in childhood are highlighted.

Adjustment in children with intractable epilepsy: importance of seizure duration and family factors

Seventy‐five families of children with intractable epilepsy but without a severe learning disability (mean age 7 years 1 month, SD 2 years 6 months; range 2 to 12 years) who attended a regional paediatric neurology service, were surveyed. A postal questionnaire was used which included standardized measures of child and family adjustment; forty‐eight families responded (64%; 31 males, 17 females). There was no significant difference between responders and non‐responders in terms of age, sex, number of other chronic illnesses and disabilities, age at epilepsy diagnosis, seizure type, nor number of antiepileptic drugs currently prescribed (p&gt;0.05). The importance of including multidimensional measures of outcome was highlighted by the finding that epilepsy, pharmacological, and psychosocial factors were differentially associated with specific adjustment difficulties. Two factors appeared to be most pervasively implicated across a range of adjustment problems: frequency of rectal diazepam administration and family patterns of relating to each other (p&lt;0.05). It appeared that duration of seizures (as indicated by frequency of rectal diazepam administration), rather than the frequency of seizures per se, was more pernicious in terms of poor adjustment. Intrafamilial relations (degree of conflict/cohesion and so on) were not only associated with adjustment difficulties in the child, but also with the frequency of seizures themselves. Implications for psychological interventions in intractable epilepsy in childhood are highlighted.

Pharmacological management of convulsive status epilepticus in children

Pharmacological management of convulsive status epilepticus in children

Chronic phenobarbital therapy reduces plasma benzodiazepine concentrations after intravenous and rectal administration of diazepam in the dog.

Disposition of diazepam (DZ) 2 mg/kg after single bolus intravenous (i.v.) and rectal (p.r.) administration before and after 30 day oral phenobarbital therapy was investigated in normal dogs. Adverse cardiovascular and neurologic effects for each drug, dosage and route of administration were evaluated. Plasma benzodiazepine concentrations were determined by fluorescence polarization immunoassay. This assay measured DZ and its active metabolites, oxazepam and nordiazepam to provide a total benzodiazepine concentration. Mean peak plasma concentrations after i.v. administration were 5963 and 5565 ng/mL, before and after phenobarbital treatment, respectively. After p.r. administration, mean peak concentrations were 629 ng/mL and 274 ng/mL and were reached within 30 min before and after phenobarbital treatment, respectively. The target concentration for potential seizure control (i.e. 150 ng/mL) was attained in five dogs in the post phenobarbital p.r. group with a median time to attainment of target concentration of 8 min. The administration of phenobarbital resulted in significantly lower areas under the plasma concentration vs. time curves (AUC) for both i.v. and p.r. administration. Similarly, there was a reduction in maximal plasma concentration, bioavailability (F), mean residence time, and time to target and peak concentrations in the postphenobarbital p.r. group, as compared to the prephenobarbital p.r. group. Adverse cardiovascular and neurologic effects were short-lived and were considered of minor clinical significance. Overall, chronic phenobarbital therapy in the dog reduces total benzodiazepine concentration after i.v. and p.r. administration presumably due to increased hepatic clearance of DZ and its metabolites oxazepam and nordiazepam. Despite this finding, administration of DZ rectally at 2 mg/kg may be a clinically useful alternative to i.v. administration to treat emergency seizures when i.v. therapy is not possible in dogs on chronic phenobarbital therapy.

Antiepileptic drug therapy

Successful treatment of seizure disorders in small animals requires proper patient assessment, understanding the principles of antiepileptic drug (AED) therapy, designing a strategy for pharmacotherapy, and plans for emergency treatment. Several levels of assessment are needed in managing an epileptic patient to include the diagnosis, effectiveness of therapy, and health-related quality of life assessments. Three levels of diagnosis are important in determining the appropriate AED therapy: 1) confirmation that an epileptic seizure has occurred, and if so, the seizure type(s) manifested; 2) diagnosis of the seizure etiology; and 3) determination of an epileptic syndrome. Monotherapy is the initial goal of treating any cat or dog with epilepsy to reduce possible drug-drug interactions and adverse effects. Unfortunately, many of the AEDs useful in people cannot be prescribed to small animals either due to inappropriate pharmacokinetics (too rapid of an elimination), and potential hepatotoxicity. Thus, the most commonly used AEDs in veterinary medicine are from the same mechanistic category, that of enhancing inhibition of the brain. Antiepileptic drugs can be classified into three broad mechanistic categories: 1) enhancement of inhibitory processes via facilitated action of gamma amino-butyric acid (GABA); 2) reduction of excitatory transmission; and 3) modulation of membrane cation conductance. Pharmacotherapy strategies should be designed based on the decision when to start treatment, choice of the appropriate AED, and proper AED monitoring and adjustment. Information is presented for the current AEDs of choice, phenobarbital and bromide. Additional guidelines are provided for administration of newer AEDs, felbamate and gabapentin. All owners should be aware that emergency therapy may be necessary if recurrent or severe seizures occur in their pet. A rapid, reliable protocol is presented for the emergency management of seizuring cats and dogs in the hospital and at home. Home treatment with per rectal administration of diazepam in the dog has proven to be an effective means of reducing seizure frequency and owner anxiety. Treating each animal as an individual, applying the philosophy that seizure prevention is better than intervention, and consulting specialists to help formulate or revise treatment plans will lead to improved success in treating seizure disorders in the cat and dog.

Bioavailability of benzodiazepines following rectal administration of diazepam in dogs

Bioavailability of benzodiazepines following rectal administration of diazepam in dogs

Rectal Administration of Diazepam

Rectal Administration of Diazepam

Prehospital Administration of Rectal Diazepam in Pediatric Status Epilepticus

Seizures are a common pediatric problem encountered by prehospital personnel. Status epilepticus is defined as seizure activity lasting longer than 15 minutes, or recurrent seizures that occur close together without a period of consciousness between ictal periods. It is estimated that 60,000 to 160,000 cases of status epilepticus occur each year within the United States. Prior to 1960, status epilepticus carried a 50% morbidity rate. However, improved anticonvulsive medications, aggressive airway management, and the spread of EMS Systems throughout the nation have reduced the morbidity rate to a range of 8% to 12%.Prompt and vigorous treatment is paramount in the successful management of status epilepticus because delays can result in neuronal damage and death. Although intravenous diazepam currently is the drug of choice to terminate seizure activity, it may be difficult to rapidly establish a patent intravenous (IV) line during status epilepticus in young children with vigorous motor activity. Alternate routes, such as intramuscular injections, are unreliable due to unpredictable absorption. Rectal administration of diazepam may provide an useful alternate route for delivery of the drug during status epilepticus when IV attempts fail.In this review, the authors discuss a case of status epilepticus wherein intravenous access could not be established rapidly and the patient was given diazepam rectally with favorable results.

Tratamiento del estado epiléptico con diazepam por vía rectal: Rectal administration in the treatment of status epilepticus

Rectal administration of diazepam is a good alternative to intravenous acute treatment in severe epileptic crises, but there is scarce information about its usefulness in status epilepticus. Treatment with rectal diazepam, 0.6 to 0.8 mg x kg of body weight as a single drug, in 10 children with 13 episodes of status epilepticus, defined as epileptic crises lasting 30 or more minutes (ten of these were generalized tonic and clonic, two were unilateral tonic and clonic, and one was of the partial complex type) is described. Nine status epilepticus episodes subsided at an average 4.4 minutes after the drug was given; in 3 cases there were no favourable effects, and one case recurred after initial response. There were no significant complications, with the exception of slight respiratory depression in a patient with encephalitis. In spite of the small size of the sample, these results suggest that rectal diazepam is an effective alternative to intravenous drug administration in the management of status epilepticus whenever venous access is difficult.

LOCAL IRRITATION AFTER ADMINISTRATION OF DIAZEPAM IN A RECTAL SOLUTION

The extent of local irritation after rectal administration of diazepam in solution was studied in 24 adults (mean weight of 70 kg). The trial was randomized using a triple cross-over design. A burning sensation was reported in 60%, 12% and 0% of subjects up to 15 min after administration of diazepam 35 mg, diazepam 10 mg and placebo, respectively. Endoscopic assessment 24 h after medication showed mechanical irritation in three subjects and local irritation probably caused by diazepam, the vehicle, or both, in four. No correlation was found between subjective complaints and objective findings. Control endoscopy 7 days after medication revealed no pathology. It is suggested that a rectal solution of diazepam in doses up to 0.5 mg kg-1 is a safe form of medication in respect of irritation of the rectal mucosa.