Continuous Intravenous Infusion Of Midazolam Research Articles

Convulsioni e gastroenterite: un caso che insegna

The article reports a case of convulsions with gastroenteritis (CWG) and briefly reviews the related literature. A 2-year-old girl presented with four short episodes of focal afebrile seizures within 12 hours. She had fever with vomiting in the previous 2 days and she developed diarrhoea during her hospital stay, after the fifth seizure. She had no significant past medical history and showed neither neurological signs nor signs of dehydration. Serum electrolytes were normal, cerebrospinal fluid examination was negative for meningoencephalitis and contrast-enhanced CT Brain scan showed no evidence of intracranial lesion. Stool investigation was positive for rotavirus. Therefore, the diagnosis of CWG was made. Repeated convulsions were handled with continuous intravenous infusion of midazolam. The main cause of CWGs in viral gastroenteritis is due to rotavirus or norovirus. The convulsions are usually focal seizure clusters, with secondary generalization. CWGs are associated with a benign prognosis.

Super-refractory status epilepticus and pharmacoresistant epilepsy in an infant with hemorrhagic shock and encephalopathy syndrome

Introduction. Hemorrhagic shock and encephalopathy syndrome (HSES) is a rare disorder with prevalence at an early age. The main features of HSES are acute diarrhea, shock, disseminated intravascular coagulation, multisystem impairment, and encephalopathy. The prognosis is very poor, with high mortality, especially in cases with status epilepticus. Case outline. The presented infant had typical features of HSES associated with super-refractory status epilepticus as de novo epileptic event, followed by pharmacoresistant epilepsy. Clinical course of the disease was very severe and required urgent circulatory and respiratory support, and simultaneous management of super-refractory status epilepticus by continuous intravenous infusion of midazolam, barbiturate, and levetiracetam. The outcome was very poor with serious neurological consequence and resistant epileptic seizures. Conclusion. The treatment of the presented patient with HSES was very challenging due to a lifethreatening condition associated with super-refractory status epilepticus, and further pharmacoresistant epilepsy. Additionally, the choice of antiepileptic drugs is limited due to multisystem impairment and adverse effects which might worsen the already severe course of the disease.

The Oral Bioavailability and Metabolism of Midazolam in Stable Critically Ill Children: A Pharmacokinetic Microtracing Study.

Midazolam is metabolized by the developmentally regulated intestinal and hepatic drug‐metabolizing enzyme cytochrome P450 (CYP) 3A4/5. It is frequently administered orally to children, yet knowledge is lacking on the oral bioavailability in term neonates up until 1 year of age. Furthermore, the dispositions of the major metabolites 1‐OH‐midazolam (OHM) and 1‐OH‐midazolam‐glucuronide (OHMG) after oral administration are largely unknown for the entire pediatric age span. We aimed to fill these knowledge gaps with a pediatric [14C]midazolam microtracer population pharmacokinetic study. Forty‐six stable, critically ill children (median age 9.8 (range 0.3–276.4) weeks) received a single oral [14C]midazolam microtracer (58 (40–67) Bq/kg) when they received a therapeutic continuous intravenous midazolam infusion and had an arterial line in place enabling blood sampling. For midazolam, in a one‐compartment model, bodyweight was a significant predictor for clearance (0.98 L/hour) and volume of distribution (8.7 L) (values for a typical individual of 5 kg). The typical oral bioavailability in the population was 66% (range 25–85%). The exposures of OHM and OHMG were highest for the youngest age groups and significantly decreased with postnatal age. The oral bioavailability of midazolam, largely reflective of intestinal and hepatic CYP3A activity, was on average lower than the reported 49–92% for preterm neonates, and higher than the reported 21% for children> 1 year of age and 30% for adults. As midazolam oral bioavailability varied widely, systemic exposure of other CYP3A–substrate drugs after oral dosing in this population may also be unpredictable, with risk of therapy failure or toxicity.

Ketamine Infusion as a Counter Measure for Opioid Tolerance in Mechanically Ventilated Children: A Pilot Study.

Drug rotation to prevent opioid tolerance is well recognized in chronic pain management. However, ketamine infusion as a counter measure for opioid tolerance is rarely described in mechanically ventilated children developing tolerance from prolonged opioid infusion. We performed a retrospective study in a 14-bed medical-surgical-cardiac pediatric intensive care unit. Thirty-two mechanically ventilated children who had developed tolerance from prolonged intravenous infusion of opioids received a continuous intravenous infusion of ketamine as an opioid substitute for more than 2days, scheduled in a drug rotation protocol. Thirty-two children (median age 2.5years, range 0.1-16.0; weight 11.2kg [3.8-62.0]) were included. Patients had received continuous intravenous infusion of opioids and benzodiazepines for 16.0days (4.0-34.0) when drug rotation was started. The median dose of continuous intravenous infusion of ketamine was 4.0mg·kg-1·h-1 (1.8-6.0) and the median duration was 3.0days (2.0-6.0). After having restarted opioids, fentanyl doses were significantly lower compared with the time before the drug rotation began (after, 2.9µg·kg-1·h-1 [0.8-4.9] vs before, 4.15µg·kg-1·h-1 [1.2-10.0]; p<0.001). Continuous intravenous infusion of midazolam and clonidine were unchanged during drug rotation. COMFORT-B scoring was significantly lower after having started drug rotation (after, 14.5 [8-19] vs before, 16 [11-22]; p<0.001). Drug rotation with ketamine in mechanically ventilated children with opioid tolerance is feasible and seems to reduce the rate of fentanyl infusion.

An audit of the predictors of outcome in status epilepticus from a resource-poor country: a comparison with developed countries.

Status epilepticus is a neurological emergency with significant morbidity and mortality. This study describes the clinical profile, treatment, and predictors of outcome of status epilepticus in a tertiary referral centre in a developing country and aims to highlight the similarities and differences from data available from the western world. A retrospective analysis of data of patients treated for status epilepticus was conducted from prospectively maintained records, between January2000 and September2010. The demographic data, clinical profile and investigations (including neuroimaging and EEG), aetiology, treatment, and outcomes were studied and compared with data available from the western world. The analysis included 108 events in 84 patients. A single episode of status epilepticus was treated in 72 patients (86%) and multiple status epilepticus events, ranging from two to six per patient, were managed in 12 patients (14%). Mean age was 24.1±20.3 years and 63% were males. The types of status epilepticus included convulsive status in 98 (90.7%), non-convulsive status in seven (6.5%), and myoclonic status in three (2.8%). The majority of events (60%) were remote symptomatic, 16% were acute symptomatic, 16% were of unexplained aetiology, and 8% were progressive symptomatic. In 85 events (79%), status epilepticus could be aborted with first and second-line drugs. The remaining 23 events (21%) progressed to refractory status epilepticus, among which, 13 (56%) were controlled with continuous intravenous midazolam infusion. Case fatality rate was 11%, neurological sequelae were reported in 22%, and 67% returned to baseline. Acute symptomatic status, older age, altered sensorium at the time of admission, and delayed hospitalisation were predictors of poor outcome. Aetiology was the most important determinant of outcome of status epilepticus, as in reports from the western world, with remote symptomatic aetiology secondary to gliosis being the most common. Treatment delay was frequent and adversely affected the outcome.

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Introduction: Hyperosmotic agents are the mainstay of therapy for intra-cranial hypertension. However, little is known about the cerebral metabolic response to different hyper-osmotic agents. Methods: Pigs (35–45 Kg), anesthetized using a continuous intravenous infusion of midazolam, fentanyl and rocuronium, were managed to achieve normal cardiac output and mean arterial pressure and ventilated to maintain normoxia, normocapnia and normal cerebral perfusion. A balloon catheter was used to increase intracranial pressure (ICP). When ICP reached 30 mmHg, animals were randomized to receive one iso-osmolar load of 255 mOsm/dose of either 20% mannitol (M20%) or 7.45% hypertonic saline (HS 7.45%) as a 30 min bolus through a central vein. The effectiveness of the solution to decrease ICP was arbitrarily defined as an ICP decrease of ≥3 mmHg after the infusion. Measurements of cerebral perfusion (intra-parenchymal pressure, cerebral perfusion pressure, brain oxygen tension, PtO2), systemic perfusion (mean arterial pressure [MAP], cardiac output (CO), serum lactate) and neuronal response (lactate/pyruvate ratio, L/P) were taken at baseline (twice), at ICPs of 15 and 30 mmHg and at T30, T60, T120 and T180 min after the end of the infusion. After 5 hours, the animal was sacrificed. A linear mixed model was used to analyze the time courses of considered variables. Results: All values are express as mean (SD). HS 7.45% administration resulted in lower ICP at T180 min: 27.1 mmHg (11.64) vs. 36.1 mmHg (11.9); mean difference: 9 mmHg ±4.2;p=0.04) and higher PtO2 at T180: 41.0 (14.9) vs. 21.7 (13.1); mean difference: 19.2 mmHg ±7.1 mmHg, p=0.01. We found no significant difference in the L/P ratio at T180 min: 67.5 (31.8) vs. 65.4 (115.41); mean difference: 2.1 ± 34.2, p=0.95, or on MAP, CO or lactate levels between the two groups. Conclusions: In this model, administration of HS 7.45% was more effective than M20% in reducing ICP and increasing PtbO2. These differences were not associated with significant differences in systemic variables or regional metabolism.

Refractory Metabolic Acidosis as a Complication of High-Dose Midazolam Infusion for Pediatric Status Epilepticus

The use of midazolam for the treatment of status epilepticus in children has generally been shown to be well tolerated and safe. Furthermore, encouraging efficacy has been observed when pediatric patients with status epilepticus have received continuous intravenous infusions of midazolam. A 9-year-old girl was treated with high-dose, continuous intravenous infusion of midazolam for the management of refractory status epilepticus. The patient developed a severe hyperchloremic, non-anion gap metabolic acidosis and resultant hemodynamic compromise, necessitating significant inotropic support and the initiation of a vasopressor infusion. We speculate that this complication was due to the preparation of parenteral midazolam with hydrochloric acid. The midazolam infusion was stopped, and, in less than 5 hours, the patient's metabolic acidosis resolved. The patient's inotropic and vasopressor infusions could only be weaned after discontinuing the use of high-dose midazolam. Although this complication was observed in only 1 pediatric patient with cortical dysplasia, caution and close clinical and laboratory surveillance should be exercised when administering continuous intravenous infusions of midazolam to pediatric patients.

Midazolam Efficacy and Side Effects in Generalized and Partial Refractory Status Epilepticus in Children

Objective Midazolam is a significant and effective drug for control of a life-threatening condition, generalized and partial refractory convulsive status epilepticus. The goal of this study was evaluation of midazolam efficacy for management of this serious disease and its two side effects, hypotension and respiratory failure. Materials & Methods Our study was done using a quasi experimental method; 22 children with generalized refractory convulsive status epilepticus and 13 with partial refractory convulsive status epilepticus were enrolled for the study. All patients received 0.2mg/kg/dose as a bolus intravenous midazolam followed by 1-6 mcg/kg/min continuous intravenous midazolam. Following this, termination of seizures as well as hypotension and respiratory failure were evaluated. Results Midazolam ceased stop convulsions in 81.81% (18) patients with generalized seizures, and in 76.92% (10) patients with partial seizures, showing no significant difference between these two types of seizures (p=0.52) Hypotension was induced in 18.18% (4) patients with generalized seizures and in 30.70% (4) patients with partial seizures, again difference not significant (p=0.14). There was respiratory failure in 21.73% (5) patients with generalized seizure and in 7.69% (1) patients with partial seizure, difference not significant.(p=0.09) Conclusion There was no significant difference in efficacy and creation of hypotension and respiratory failure after continuous intravenous infusion of midazolam between generalized and partial refractory convulsive status epilepticus.

Delayed Recovery after Continuous Infusion of Midazolam in Hepatic Dysfunction: A case report

Benzodiazepines are frequently administered for sedation to surgical intensive care unit patients who require postoperative intubation and mechanical ventilation. Midazolam is the most commonly used drug, which is water soluble, short-acting benzodiazepine and rapidly metabolized by the liver. Continuous intravenous infusion of midazolam was administered to the man who was 40 years old for mechanical ventilation in the intensive care unit for 58 hours. After discontinued midazolam, patient who had acute hepatic dysfunction had been sedated with endotracheal intubation for 5 days. Even flumazenil was tried twice to reverse the effect of midazolam, the response was limited by the time. Finally he awaked as recovery of his hepatic function.

Possibility of influence of midazolam sedation on the diagnosis of brain death: concentrations of active metabolites after cessation of midazolam.

Midazolam and its active metabolites have a depressant effect on respiration and consciousness level, and therefore their effects should be considered in all patients for whom brain death testing is contemplated. The concentrations of midazolam and its active metabolites were measured in critically ill patients on a ventilator during and after continuous intravenous infusion of midazolam. Three days after cessation of midazolam infusion, the concentrations of midazolam and 1-hydroxymidazolam decreased to below the therapeutic range (100-1000 ng/ml) in all patients, although the concentrations of 1-hydroxymidazolam glucuronide remained extremely high in a patient who showed deteriorating renal function. The concentrations of 1-hydroxymidazolam glucuronide (19,497-29,761 ng/ml) were measured in this patient. When it is impossible to confirm factors consistent with irreversible brain death, such as the lack of cerebral blood flow, until 3 days after cessation of midazolam infusion, monitoring of the concentration of these substances should be carried out in all patients in whom suspicion exists prior to the evaluation of brain death. It is particularly imperative that monitoring of the 1-hydroxymidazolam glucuronide concentration be carried out in patients with poor renal function.

Propofol and Midazolam versus Propofol Alone for Sedation following Coronary Artery Bypass Grafting: A Randomized, Placebo-controlled Trial

The aim was to compare the efficacy and side-effects of propofol combined with a constant, low dose of midazolam versus propofol alone for sedation. In a prospective, randomized and double-blinded study, 60 male patients scheduled for elective coronary bypass grafting were enrolled. Postoperatively, patients were stratified to receive either a continuous intravenous infusion of midazolam 1 mg/h or placebo. Target Ramsay sedation score was 3 to 5 corresponding to conscious sedation. An intention-to-treat design for propofol was performed to reach target sedation. Efficacy of sedation was statistically significantly higher in the group midazolam + intention-to-treat with propofol compared with the group placebo + intention-to-treat with propofol (91% vs 79%; P=0.0005). Nine of 27 patients in the midazolam group (33.4%) and nine of 26 patients in the placebo group (34.6%) needed no supplementary propofol. Weaning time from mechanical ventilation was longer in the midazolam group whether or not they required supplemental propofol when compared with placebo group (all: 432 +/- 218 min vs 319 +/- 223 min; P=0.04; supplementary propofol: 424 +/- 234 min vs 265 +/- 175 min; P=0.03). The cumulative number of patients remaining intubated was significantly higher in the group midazolam + propofol compared with the group placebo + propofol (P=0.03). In conclusion, target sedation is reached slightly more often by the co-administration of propofol and a low dose of midazolam, but weaning time from mechanical ventilation is prolonged by the co-administration of propofol and a low dose of midazolam.

Continuous Intravenous Midazolam Infusion for Centruroides exilicauda Scorpion Envenomation

Study objective: We sought to describe the effects of continuous intravenous midazolam infusion as therapy for severe bark scorpion (Centruroides exilicauda) envenomation. Methods: A retrospective chart review from July 1, 1993, through January 1, 1998, identified all patients treated at a university hospital with International Classification of Diseases, Ninth Revision, codes 989.5 (toxic effect of venom) or E905.2 (scorpion sting causing poisoning). By using standardized collection forms, data were extracted from the medical record of every patient who had a grade III or IV envenomation and was treated with a continuous intravenous midazolam infusion. Results: Our search identified 104 patients; 34 had grade III or IV envenomation. Of these, 33 were treated in the ICU with continuous intravenous midazolam infusion. Median patient age was 4 years (range, 1 to 68 years). Midazolam dosage was adjusted to induce a light sleep state to control agitation and involuntary motor activity. The median amount of midazolam resulting in the first recorded decrease in agitation and involuntary motor activity was 0.30 mg/kg (range, 0.03 to 1.76 mg/kg). This first evidence of clinical improvement was recorded as 1.00 hour (median), with a range of 0.00 to 3.75 hours. The initial midazolam infusion rate was 0.10 mg·kg –1·h –1 (median), with a range of 0.01 to 0.31 mg·kg –1·h –1. The maximal midazolam infusion rate was 0.30 mg·kg –1·h –1 (median), with a range of 0.06 to 1.29 mg·kg –1·h –1. The median time until the maximal midazolam infusion rate was 2.5 hours (range, 0.00 to 8.50 hours). The median duration of infusion was 9.50 hours (range, 4.25 to 20.50 hours). The median length of stay in the ICU was 15.17 hours (range, 6.0 to 28.0 hours), and 85% of patients were discharged directly home. All patients had resolution of abnormal motor activity and agitation during their midazolam infusion. Transient hypoxemia without evidence of end-organ dysfunction was documented in 4 patients during midazolam therapy. Conclusion: A continuous intravenous midazolam infusion can be a safe, effective, and readily available treatment option for patients with grade III or IV C exilicauda envenomation. [Gibly R, Williams M, Walter FG, McNally J, Conroy C, Berg RA: Continuous intravenous midazolam infusion for Centruroides exilicauda scorpion envenomation. Ann Emerg Med November 1999;34:620-625.]

Conservative treatment of tracheal rupture

J Thorac Cardiovasc Surg 1999;117:399-401

Efficacy of Continuous Intravenous Infusion of Midazolam in the Treatment of Status Epilepticus in Children

Efficacy of Continuous Intravenous Infusion of Midazolam in the Treatment of Status Epilepticus in Children

Tolerability profile on continuous intravenous midazolam in critical care patients

This review summarizes the tolerability profile of midazolam administered as a continuous intravenous (IV) infusion to patients in the intensive care unit (ICU) who are receiving mechanical ventilation. Midazolam is a short-acting benzodiazepine indicated for intramuscular administration for preoperative sedation; for IV administration for conscious sedation prior to short diagnostic, therapeutic, or endoscopic procedures; and for IV administration for induction of general anesthesia. The drug can also be used for short surgical procedures as a component of IV supplementation. Because of its favorable properties (short half-life, ease of titration of infusion, and favorable tolerability profile), midazolam is used as a sedative agent for critically ill patients requiring mechanical ventilatory support. No clinically significant differences with respect to laboratory, hemodynamic, respiratory, neurologic, or monitoring variables have been reported between continuous IV midazolam and propofol, lorazepam, or diazepam. No adverse events were reported in association with the administration of midazolam by continuous infusion other than those previously identified in the short-term use of midazolam. Mortality rates for midazolam were no greater than those previously reported for critically ill patients receiving mechanical ventilation. The tolerability profile indicates that the continuous IV infusion of midazolam in critically ill patients who require mechanical ventilation in the ICU will not result in any significant clinical problems.

Sedation during Artificial Ventilation by Continuous Intravenous Infusion of Midazolam: Effects of Hepatocellular or Renal Damage

To evaluate the effects of hepatocellular or renal damage on therapeutic doses of midazolam and emergence time after withdrawal of the drug, 87 patients under continuous sedation with midazolam on artificial ventilation were prospectively studied. They needed continuous sedation for 12 hours or more. They included 55 patients with normal hepatocellular and renal functions (C group), 21 patients with hepatocellular damage (II group), and 11 patients with hepatocellular and renal damage (HR group). Midazolam was initiated with an intravenous dose of 0.1 mg/kg followed by 0.05 mg/kg/hr. Dosage was regulated to maintain a state in which patients responded to verbal command and had bucking responses to endotracheal suctioning. The three groups were compared with respect to midazolam dosage, emergence time, aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine (Cr) levels and urine volume. The mean doses of midazolam in the C, H, and HR groups were 0.083 ± 0.038 mg/kg/hr, (mean ± standard deviation) 0.073 ± 0.037 mg/kg/hr, and 0.088 ± 0.048 mg/kg/hr, respectively, showing no differences among these groups. Emergence time was significantly longer in the H group (333 ± 263 min; p &lt; 0.005) and the HR group (305 ± 225 min; p &lt; 0.025) than in the C group (171 ± 106 min). No effect of midazolam administration was seen on AST, ALT, BUN, Cr, and urine volume in all groups. In conclusion, presence of hepatocellular or renal damage did not alter required dosage of midazolam. Hepatocellular damage prolonged emergence time, but renal damage had no more additive effect. There was no evidence of hepatocellular and renal damages during treatment.

Clinical experience with continuous intravenous sedation using midazolam and fentanyl in the paediatric intensive care unit

Twenty-four patients in a paediatric intensive care unit mostly undergoing cardiac surgery, received a midazolam dosage between 50-400 micrograms/kg per hour as a continuous intravenous infusion partly in combination with fentanyl [0,5-2,5 micrograms/kg per hour] for analgesia and sedation. The mean duration of midazolam infusion was 11.6 days (range 38 h-40 days). Blood samples for the HPLC assay of serum midazolam concentration were taken and the clearance estimated. The efficiency of sedation in correlation to the midazolam concentration was evaluated by a clinical sedation score. Serum midazolam concentrations between 100-400 micrograms/l were sufficient for sedation. Dosage had to be increased during therapy according to an increased midazolam clearance. The evaluation of the sedation score showed that sedation of artificially ventilated infants and young children can be established by continuous intravenous infusion of midazolam.

Isoflurane compared with midazolam for sedation in the intensive care unit.

To compare isoflurane with midazolam for sedation of ventilated patients. Randomised control study. Setting--Intensive care unit in university teaching hospital. Sixty patients aged 18-76 who required mechanical ventilation. Sedation with either 0.1-0.6% isoflurane in an air-oxygen mixture (30 patients) or a continuous intravenous infusion of midazolam 0.01-0.20 mg/kg/h (30 patients). Sedation was assessed initially and hourly thereafter on a six point scale. Incremental intravenous doses of morphine 0.05 mg/kg were given for analgesia as required. The trial sedative was stopped when the patient was judged ready for weaning from ventilatory support or at 24 hours (whichever was earlier). Achievement of a predetermined level of sedation for as much of the time as possible. Isoflurane produced satisfactory sedation for a greater proportion of time (86%) than midazolam (64%), and patients sedated with isoflurane recovered more rapidly from sedation. Isoflurane is a promising alternative technique for sedation of ventilated patients in the intensive care unit.

Clinical pharmacokinetics of midazolam in intensive care patients, a wide interpatient variability?

The pharmacokinetics of midazolam and its metabolites were studied in 17 patients on mechanical ventilation in a general intensive care unit who were receiving a continuous intravenous infusion of midazolam, adjusted according to the level of induced sedation. Three patients were studied twice. Serum midazolam and alpha-hydroxymidazolamglucuronide levels were determined during and after infusion. The sedation level was scored on a four-point scale. Half of the observed patients were still drowsy or asleep 10 hours after termination of midazolam infusion. In only one patient was midazolam serum elimination half-life less than 2 hours and in six patients the half-life was greater than 10 hours. A wide range of midazolam serum levels was associated with adequate sedation, and similarly the midazolam levels at the moment of awakening were highly variable. The serum concentration ratio of midazolam/alpha-hydroxymidazolamglucuronide at the end of the infusion varied from 0.03 to 15.6. Renal function could account for only a part of this variation.

Continuous Intravenous Midazolam Infusion for Sedation in the Pediatric Intensive Care Unit

Continuous Intravenous Midazolam Infusion for Sedation in the Pediatric Intensive Care Unit