Benzodiazepine Infusions Research Articles

Reducing Deep Sedation and Delirium in Acute Lung Injury Patients

Deep sedation and delirium are common in the ICU. Mechanically ventilated patients with acute lung injury are at especially high risk for deep sedation, delirium, and associated long-term physical and neuropsychiatric impairments. We undertook an ICU-wide structured quality improvement project to decrease sedation and delirium. Prospective quality improvement project in comparison with a retrospective acute lung injury control group. Sixteen-bed medical ICU in an academic teaching hospital with pre-existing use of goal-directed sedation with daily interruption of sedative infusions. Consecutive acute lung injury patients. A "4Es" framework (engage, educate, execute, evaluate) was used as part of the quality improvement process. A new sedation protocol was created and implemented, which recommends a target Richmond Agitation Sedation Scale score of 0 (alert and calm) and requires failure of intermittent sedative dosing prior to starting continuous infusions. In addition, twice-daily delirium screening using the Confusion Assessment Method for the ICU was introduced into routine practice. Sedative use and delirium status in acute lung injury patients after implementation of the quality improvement project (n = 82) were compared with a historical control group (n = 120). During the quality improvement vs. control periods, use of narcotic and benzodiazepine infusions were substantially lower (median proportion of medical ICU days per patient: 33% vs. 74%, and 22% vs. 70%, respectively, both p < 0.001). Further, wakefulness increased (median Richmond Agitation Sedation Scale score per patient: -1.5 vs. -4.0, p < 0.001), and days awake and not delirious increased (median proportion of medical ICU days per patient: 19% vs. 0%, p < 0.001). Through a structured quality improvement process, use of sedative infusions can be substantially decreased and days awake without delirium significantly increased, even in severely ill, mechanically ventilated patients with acute lung injury.

Palliative sedation (PS) given to patients treated at the Fundación Santa Fe de Bogotá.

9541 Background: Around 50% of advanced-stage cancer patients have inadequate control of symptoms during the final period of life; palliative sedation (PS) would seem to be appropriate in such scenario. Methods: A retrospective cohort analytical study was carried out for determining the effectiveness of PS, evaluating the non-reduction of the number of final days of life in patients suffering advanced-stage cancer. PS therapy consisted of using a continuous infusion of benzodiazepines, opioids, antipsychotics and/or anaesthetics. Results: The study included 145 patients recorded between July 2008 and October 2012. Median age was 68 years (24% of the patients being aged over 80). The main motives for considering PS were dyspnoea (30%), uncontrolled pain (25%), delirium (26%) and presenting more than one of these symptoms (19%). The drugs used were opioids (in 87% of the patients), benzodiazepines (54%) and anaesthetics (2%). Using PS led to symptoms becoming controlled in 79% of the cases compared to 53% without it; symptoms became controlled in 85% of the cases in less than 24 hours when PS was used compared to 15% when it was not used (p&lt;0.001). Mean overall survival (OS) was 6.8 days for those who received PS and 7.2 for those who did not (RR 0.94, 0.97-1.33 95%CI; p=0.72) and final days of life after starting PS was 2.2 days (&lt;1-16 days). Multivariate analysis showed that using PS (HR 1.49, 1.08-2.07 95%CI; p=2.04) and the presence of oedema (RR 0.79, 0.61-1.0 95%CI; p=0.01) modified the course of controlling symptoms. Conclusions: PS improved the time to controlled cancer symptoms in patients suffering terminal illness, and their presentation profile without modifying the OS.

Reduction of Group II Metabotropic Glutamate Receptors during Development of Benzodiazepine Dependence

Prolonged use of benzodiazepines often leads to dependence and withdrawal syndrome. However, the cellular mechanisms underlying benzodiazepine dependence have not been fully clarified. Several investigators have shown an involvement of metabotropic glutamate receptors (mGluRs) in the pathophysiology of dependence or withdrawal. This study was performed to elucidate the role of mGluRs in benzodiazepine dependence. Withdrawal signs were precipitated in mice by flumazenil injection (25 mg/kg) after continuous subcutaneous infusion of benzodiazepines for 7 days, and the effects of several Gi-coupled receptor ligands on forskolin-stimulated cyclic AMP accumulation were examined in the cerebral cortex of mice. The mRNA expression for mGluRs was determined by RT-PCR. A single injection of flumazenil precipitated typical withdrawal signs such as tail elevation and tremor in mice treated with diazepam or alprazolam, but not quazepam. The inhibitory effect of nonselective mGluR ligands on adenylate cyclase activity was diminished in mice that showed signs of benzodiazepine withdrawal. The mRNA expression levels of mGluR2 and mGluR3 were lowered in the cerebral cortex of mice pretreated with diazepam or alprazolam. Our findings suggest that the reduction in the expression of group II mGluRs subunits may be involved in the development of benzodiazepine dependence.

Daily Sedation Interruption in Mechanically Ventilated Critically Ill Patients Cared for With a Sedation Protocol

Protocolized sedation and daily sedation interruption are 2 strategies to minimize sedation and reduce the duration of mechanical ventilation and intensive care unit (ICU) stay. We hypothesized that combining these strategies would augment the benefits. To compare protocolized sedation with protocolized sedation plus daily sedation interruption in critically ill patients. Randomized controlled trial of 430 critically ill, mechanically ventilated adults conducted in 16 tertiary care medical and surgical ICUs in Canada and the United States between January 2008 and July 2011. Continuous opioid and/or benzodiazepine infusions and random allocation to protocolized sedation (n = 209) (control) or to protocolized sedation plus daily sedation interruption (n = 214). Using validated scales, nurses titrated infusions to achieve light sedation. For patients receiving daily interruption, nurses resumed infusions, if indicated, at half of previous doses. Patients were assessed for delirium and for readiness for unassisted breathing. Time to successful extubation. Secondary outcomes included duration of stay, doses of sedatives and opioids, unintentional device removal, delirium, and nurse and respiratory therapist clinical workload (on a 10-point visual analog scale [VAS]). Median time to successful extubation was 7 days in both the interruption and control groups (median [IQR], 7 [4-13] vs 7 [3-12]; interruption group hazard ratio, 1.08; 95% CI, 0.86-1.35; P = .52). Duration of ICU stay (median [IQR], 10 [5-17] days vs 10 [6-20] days; P = .36) and hospital stay (median [IQR], 20 [10-36] days vs 20 [10-48] days; P = .42) did not differ between the daily interruption and control groups, respectively. Daily interruption was associated with higher mean daily doses of midazolam (102 mg/d vs 82 mg/d; P = .04) and fentanyl (median [IQR], 550 [50-1850] vs 260 [0-1400]; P < .001) and more daily boluses of benzodiazepines (mean, 0.253 vs 0.177; P = .007) and opiates (mean, 2.18 vs 1.79; P < .001). Unintentional endotracheal tube removal occurred in 10 of 214 (4.7%) vs 12 of 207 patients (5.8%) in the interruption and control groups, respectively (relative risk, 0.82; 95% CI, 0.36-1.84; P = .64). Rates of delirium were not significantly different between groups (53.3% vs 54.1%; relative risk, 0.98; 95% CI, 0.82-1.17; P = .83). Nurse workload was greater in the interruption group (VAS score, 4.22 vs 3.80; mean difference, 0.41; 95% CI, 0.17-0.66; P = .001). For mechanically ventilated adults managed with protocolized sedation, the addition of daily sedation interruption did not reduce the duration of mechanical ventilation or ICU stay. clinicaltrials.gov Identifier: NCT00675363.

Early Withdrawal of Life Support in Severe Burn Injury

Despite many advances in modern burn care, deaths still occur in the burn intensive care unit. For patients with severe burns, providers may advocate to withdraw life support early during hospitalization when the extent of injury makes survival highly unlikely or when the patient's condition deteriorates during resuscitation. Our regional burn center has implemented a stepwise withdrawal protocol since 2001 in an effort to standardize symptoms palliation at the end of life. In this study, the authors evaluated the frequency of early withdrawal and the protocol impact on end-of-life processes of care in burn patients who died within 72 hours of hospitalization. A 13-year review of all burn patients aged ≥18 years admitted to our burn center to identify all patients who died within 72 hours of hospitalization was performed. Patients were dichotomized to the periods before (1995 to mid-2001) and after implementation of standardized withdrawal protocol (mid-2001 to 2007). Descriptive analyses were performed to compare end-of-life care processes between the two periods. A total of 4374 adult patients with acute burns were admitted during the 13-year study period, of which 252 (6%) died during hospitalization. Of the patients who died within 72 hours, 106 (84%) had withdrawal of life support compared with 20 (16%) who died with ongoing life support. Higher mean TBSA distinguished patients who died by withdrawal (61 vs 48%, P = .06). Since mid-2001, all 61 patients who had life support withdrawn were by protocol. Implementation of the protocol has led to more frequent use of opioid infusion (98 vs 87%, P = .07) and benzodiazepine infusion (95 vs 49%, P < .01), without hastening time to death (median 5.0 vs 5.5 hours, P = .70). The large majority of early burn deaths at our regional center occur via withdrawal of life support. Implementation of a protocolized withdrawal has resulted in more consistent provision of analgesia and sedation without hastening death. Burn centers should consider using a protocol for withdrawal of life support to improve consistency in end-of-life symptoms palliation.

Involvement of endothelium-dependent and -independent mechanisms in midazolam-induced vasodilation

Benzodiazepine (BDZ) infusion has been shown to reduce blood pressure in both humans and animals. Although the inhibitory effects of BDZ on the central nervous system have been well documented, less is known about the direct effects of BDZ on the vascular bed. The aims of this study were to assess the effects of the BDZ midazolam on the vascular system in C57/BL6 mouse aortic rings and to investigate the mechanisms of its direct vascular action. We found that midazolam induced reversible, dose-dependent vasodilation in potassium- and phenylephrine-precontracted rings. In rings that were precontracted with potassium or phenylephrine, treatment with 10 μmol l(-1) midazolam increased vasodilation by 15 and 60%, respectively, compared with baseline. Vasodilation increased by 80 and 87%, respectively, after treatment with 50 μmol l(-1) midazolam. Only the low concentration of midazolam (10 μmol l(-1)) induced endothelium-dependent vasodilation in phenylephrine-precontracted rings. Vasodilation increased by 60% in rings with endothelium and by 20% in rings without endothelium. Conversely, only the high concentration of midazolam (50 μmol l(-1)) reduced the CaCl(2)-induced vasoconstriction of aortic rings with EC(50) (the concentration giving 50% of the maximal effect) values of 1 and 6 mmol l(-1) for vehicle- and midazolam-treated rings, respectively. Furthermore, the incubation of phenylephrine-precontracted rings with an inhibitor of the nitric oxide synthase (NOS) NG-nitro-L-arginine methyl ester or the inhibitors of central or peripheral type BDZ receptors (flumazenil or PK 11195, respectively) produced no change in midazolam-induced vasodilation. Thus, low concentrations of midazolam induce vasodilation via an endothelium-dependent mechanism that does not involve NO production. In contrast, high concentrations of midazolam induce vasodilation via an endothelium-independent mechanism that implies reduced sensitivity of aortic rings to calcium ions. Additionally, neither the central γ-amino-butyric acid receptor type A nor the peripheral type BDZ receptors seem to be involved in the mechanism of midazolam-induced vasodilation.

Nursing Considerations for Children Undergoing Delayed Sternal Closure After Surgery for Congenital Heart Disease

Nursing Considerations for Children Undergoing Delayed Sternal Closure After Surgery for Congenital Heart Disease

Phenobarbital Treatment in a Patient with Resistant Alcohol Withdrawal Syndrome

Alcohol withdrawal syndrome (AWS) is a major cause of morbidity and mortality in the acute care setting. We describe a 28-year-old man who was brought to the emergency department with a new-onset seizure and clinical signs and symptoms consistent with advanced delirium tremens. A symptom-triggered intensive care unit treatment protocol consisting of a benzodiazepine and antiadrenergic agents was started. The manifestations of delirium tremens persisted with titration of a lorazepam infusion in excess of 40 mg/hour. Intravenous phenobarbital was administered in escalating doses of 65 mg followed by 130 mg 15 minutes later, resulting in control of severe agitation in the face of benzodiazepine resistance. Subsequent scheduled phenobarbital administration allowed for a successful and orderly weaning of the continuous benzodiazepine infusion and adjunctive agents used in AWS management. With continued clearing of consciousness, the patient was successfully discharged. The administration of phenobarbital in this patient allowed improved symptom control, minimized the potential for propylene glycol toxicity, was not associated with respiratory depression, and facilitated successful weaning of benzodiazepines. Barbiturates offer a mechanism of action that is different from that of benzodiazepines. Although the cornerstone of treatment for AWS remains benzodiazepines, this case highlights the potential utility of phenobarbital in patients with resistant AWS.

Reassessment of phenytoin for treatment of late stage progressive myoclonus epilepsy complicated with status epilepticus

In order to find an effective treatment option for status epilepticus in progressive myoclonus epilepsy (PME), we reviewed the clinical course of 9 patients with PME. Initially, epilepsy was successfully treated with antiepileptics. However, it gradually became refractory to medication, and status epilepticus emerged 3-19 years after the onset of epilepsy. In these patients, status epilepticus in PME was classified into (1) myoclonic status epilepticus (MSE), (2) myoclonic-generalized status epilepticus (MGSE), and (3) generalized status epilepticus (GSE). MSE was common in patients with neuronal ceroid lipofuscinosis, and GSE was common in those with dentatorubral-pallidoluysian atrophy. MGSE was characterized by the mixture of escalating myoclonus and generalized seizures, and was observed in patients with Gaucher disease or unspecified PME. All patients were often refractory to infusion of benzodiazepines and barbiturates but phenytoin was able to terminate status epilepticus in 7 patients. Oral phenytoin administration as preventive therapy was effective in 6 patients. Aggravation of myoclonus was not provoked by these treatments. We propose that phenytoin should be considered as a treatment choice for PME patients at late stages to prevent the detrimental effects of prolonged or repeated status epilepticus on the brain tissues.

The use of boluses of propofol for the management of severe tetanus in a child

Tetanus is endemic in many developing countries. Although propofol has been proposed for sedation in tetanus, the routine use of this drug has not been clearly documented in published reports. A few studies have reported its beneficial effects but no randomized studies are available. We describe the case of a five-year-old boy who presented with severe tetanus in East Africa. The antispastic therapy consisted of benzodiazepine infusion with the addition of titrated boluses of propofol. Intubation and mechanical ventilation were avoided.

Alcohol Withdrawal Requiring Massive Prolonged Benzodiazepine Infusion

The objective of this case report is to describe a patient with prolonged alcohol withdrawal requiring massive standing doses of benzodiazepines. The setting is the medical intensive care unit of the Tripler Army Medical Center, Honolulu, Hawaii. The patient is a 58-year-old alcohol-dependent male presenting with mental status changes and agitation following an uncomplicated cystoprostatectomy, who ultimately required massive doses of benzodiazepines to treat his symptoms effectively. We conclude that symptom-triggered therapy proved ineffective in this case due to inability to achieve adequate frequency of assessments. Ultimately, a lengthy, high-dose, fixed interval benzodiazepine regimen was required. The 5-week period of intensive care illustrated that scheduled doses of benzodiazepines may be required and massive and prolonged doses are sometimes necessary. Adherence to a slow-weaning protocol understood by an interdisciplinary team was critical to this patient's recovery. Additionally, toxicity from the high-dose medication was not observed.

Symptom‐Driven Lorazepam Protocol for Treatment of Severe Alcohol Withdrawal Delirium in the Intensive Care Unit

To compare outcomes of treating alcohol withdrawal delirium (AWD) with a symptom-driven benzodiazepine protocol versus nonprotocol benzodiazepine infusions in the intensive care unit (ICU). Retrospective observational study of a quality improvement project. Medical intensive care unit at a Veterans Affairs medical center. Thirty-six patients who had 40 ICU admissions for AWD between January 1, 1994, and May 31, 2003. Sixteen episodes (15 patients [historical controls]) occurred before implementation of the symptom-driven protocol in 1998, and 24 episodes (21 patients) occurred after implementation. Outcomes evaluated were time to reach symptom control, total dose of benzodiazepine, amount of time receiving continuous benzodiazepine infusion, length of ICU and hospital stay, polypharmacy (use of multiple benzodiazepines), and complications of treatment. The historical control group was treated according to physician preference, which consisted of continuous-infusion midazolam without a protocol. The symptom-driven protocol used lorazepam administered initially as intermittent intravenous doses, progressing to a continuous intravenous infusion according to a locally developed symptom scale. The mean +/- SD values for the outcomes in the historical control group versus the protocol group were as follows: time to control symptoms 19.4 +/- 9.7 versus 7.7 +/- 4.9 hours (p=0.002), cumulative benzodiazepine dose in lorazepam equivalents 1677 +/- 937 versus 1044 +/- 534 mg (p=0.014), time receiving benzodiazepine continuous infusion 122.1 +/- 64.4 versus 52.0 +/- 35.1 hours (p=0.001), length of stay in the ICU 7.7 +/- 6.3 versus 5.6 +/- 1.7 days (p=0.21), and length of hospital stay 15.3 +/- 8.9 versus 11.2 +/- 3.4 days (p=0.43). Use of a symptom-driven protocol was associated with significantly decreased time to symptom control, amount of sedative required, and time spent receiving benzodiazepine infusion compared with historical controls. The use of the protocol is effective but requires close monitoring to ensure protocol compliance and to avoid potential propylene glycol toxicity.

An evaluation of two subcutaneous infusion devices in children receiving palliative care

Children and young people with advanced cancer frequently have a central venous access device (central line) in place which can be used for intravenous medication for symptom management. Those that do not may need a subcutaneous device for medication infusion. Two subcutaneous devices were evaluated in four children requiring infusion of opioids, anti-emetics, anti-muscarinic agents and benzodiazepines during their palliative care. The length of time the device was in situ and local skin reactions were monitored and the views of children, parents and nurses obtained. Out of 32 evaluations, 28 (88 per cent) indicated that the Thalaset s/c device was preferred to the winged device in terms of child comfort and nurse satisfaction. Although limited by the number of children in the evaluation, the results support the use of the Thalaset s/c device as part of symptom management for children and young people who do not have central lines.

Myocardial Ischemia as a Result of Severe Benzodiazepine and Opioid Withdrawal

Long-term infusion of benzodiazepines and opioids is strongly associated with dependence and withdrawal syndromes. We report the first case of severe benzodiazepine and opioid withdrawal resulting in transient myocardial ischemia.A 6-month-old female born at 25 weeks gestation with severe opioid and benzodiazepine dependence resulting from multiple operative procedures and chronic ventilatory support was receiving continuous intravenous infusion of fentanyl and midazolam after trials of enteral methadone and diazepam had been unsuccessful due to gastric intolerance. On postoperative day 5 following Nissen fundoplication and gastrostomy tube placement, she acutely developed tachycardia, hypertension, agitation, loose stools, and yawning. Attempts to provide boluses of benzodiazepines and opioids revealed a very sluggish port in her subclavian central venous catheter. Prompt replacement of the catheter occurred without complication. After resuming infusions and providing additional sedatives and opioids, the loose stools, yawning, and agitation resolved. However, the tachycardia persisted. A 12-lead ECG was notable for significant ST depression in anterior leads. Laboratory studies revealed significantly elevated cardiac enzymes. The patient was transfused with packed red blood cells to optimize oxygen-carrying capacity. Echocardiography demonstrated a small region of dyskinetic apical endocardium. Cardiac enzymes normalized within 48 h. The ECG and echocardiographic findings fully resolved after approximately 70 h.We believe that the sluggish central venous catheter port limited delivery of the midazolam and fentanyl to our patient. The resultant tachycardia and hypertension limited diastolic filling of the coronary arteries, resulting in myocardial ischemia. As the withdrawal was treated, heart rate and blood pressure returned to baseline, myocardial perfusion normalized, and the ST depression and the cardiac enzyme values normalized. This report underscores the significant morbidity associated with withdrawal syndromes and the need to recognize withdrawal early and to treat it aggressively.

A prospective study of adverse reactions to the weaning of opioids and benzodiazepines among critically ill children

The aim of this study was to identify the optimal rates at which opioids and benzodiazepines should be weaned in order to prevent withdrawal reactions in the pediatric intensive care unit (PICU). This study follows an earlier investigation that developed a graphical analysis method for examining behavioral signs of withdrawal in relation to changes in opioid and benzodiazepine administration. This method was utilized in this present study for a prospective sample of all patients admitted to a tertiary/quaternary level PICU within a 4-week interval (n=27). The findings of this study indicate that the required rate of weaning (in order to prevent withdrawal reactions) is related to the number of days the child has been on a continuous infusion of opioids and/or benzodiazepines. Adverse withdrawal reactions were prevented when the daily rate of weaning did not exceed: 20% for children receiving continuous infusions for 1-3 days; 13-20% for 4-7 days; 8-13% for 8-14 days; 8% for 15-21 days; and 2-4% for more than 21 days of infusions. The authors recommend that the rate of weaning of opioids and benzodiazepines in critically ill children be tailored to the length of time the child received continuous infusions of these agents.

Myocardial Ischemia as a Result of Severe Benzodiazepine and Opioid Withdrawal

Long-term infusion of benzodiazepines and opioids is strongly associated with dependence and withdrawal syndromes. We report the first case of severe benzodiazepine and opioid withdrawal resulting in transient myocardial ischemia.Case Report: A 6-month-old female born at 25 weeks gestation with severe opioid and benzodiazepine dependence resulting from multiple operative procedures and chronic ventilatory support was receiving continuous intravenous infusion of fentanyl and midazolam after trials of enteral methadone and diazepam had been unsuccessful due to gastric intolerance. On postoperative day 5 following Nissen fundoplication and gastrostomy tube placement, she acutely developed tachycardia, hypertension, agitation, loose stools, and yawning. Attempts to provide boluses of benzodiazepines and opioids revealed a very sluggish port in her subclavian central venous catheter. Prompt replacement of the catheter occurred without complication. After resuming infusions and providing additional sedatives and opioids, the loose stools, yawning, and agitation resolved. However, the tachycardia persisted. A 12-lead ECG was notable for significant ST depression in anterior leads. Laboratory studies revealed significantly elevated cardiac enzymes. The patient was transfused with packed red blood cells to optimize oxygen-carrying capacity. Echocardiography demonstrated a small region of dyskinetic apical endocardium. Cardiac enzymes normalized within 48 h. The ECG and echocardiographic findings fully resolved after approximately 70 h.Discussion: We believe that the sluggish central venous catheter port limited delivery of the midazolam and fentanyl to our patient. The resultant tachycardia and hypertension limited diastolic filling of the coronary arteries, resulting in myocardial ischemia. As the withdrawal was treated, heart rate and blood pressure returned to baseline, myocardial perfusion normalized, and the ST depression and the cardiac enzyme values normalized. This report underscores the significant morbidity associated with withdrawal syndromes and the need to recognize withdrawal early and to treat it aggressively.

Focal nonconvulsive status epilepticus associated to PLEDs and intense focal hyperemia in an AIDS patient

Purpose: Periodic lateralised epileptiform discharges (PLEDs) can be seen associated to nonconvulsive status epilepticus (NCSE), although their pathophysiological meaning remains questionable. Functional neuroimaging has suggested that, in this setting, PLEDs may indeed be an ictal pattern. In this report we describe perfusional changes in a patient with AIDS, PLEDs and NCSE. Methods: A 37-year-old man with AIDS, cryptococcosis and recurrent epileptic seizures was admitted. After initial treatment, he remained comatose, and had MRI and serial EEG recordings performed. Technetium-99m-ethyl cysteinate dimer (99mTc-ECD) SPECT scans were also obtained, before and after continuous benzodiazepine infusion. Results: EEG disclosed PLEDs over the right fronto-polar region while MRI revealed meningeal thickening and scattered unspecific findings. SPECT revealed marked focal hyperperfusion overlapping the areas with PLEDs, both resolved after continuous midazolam infusion and clinical improvement. Conclusions: This report demonstrates association of PLEDs, NCSE, and focal hyperperfusion on SPECT, additionally supporting the concept of PLEDs as an ictal pattern. Considering that status epilepticus may eventually not be detected by conventional approaches alone, we advocate the use of functional neuroimaging to assess suspected patients with impaired consciousness.

Rapid Critical Period Induction by Tonic Inhibition in Visual Cortex

Mice lacking a synaptic isoform of glutamic acid decarboxylase (GAD65) do not exhibit ocular dominance plasticity unless an appropriate level of GABAergic transmission is restored by direct infusion of benzodiazepines into the brain. To better understand how intracortical inhibition triggers experience-dependent changes, we dissected the precise timing requirement for GABA function in the monocular deprivation (MD) paradigm. Diazepam (DZ) or vehicle solution was infused daily before and/or during 4 d of MD in GAD65 knock-out mice. Extracellular single-unit recordings from the binocular zone of visual cortex were performed at the end of deprivation. We found that a minimum treatment of 2 d near the beginning of MD was sufficient to fully activate plasticity but did not need to overlap the deprivation per se. Extended delay after DZ infusion eventually led to loss of plasticity accompanied by improved intrinsic inhibitory circuit function. Two day DZ treatment just after eye opening similarly closed the critical period prematurely in wild-type mice. Raising wild-type mice in complete darkness from birth delayed the peak sensitivity to MD as in other mammals. Interestingly, 2 d DZ infusion in the dark also closed the critical period, whereas equally brief light exposure during dark-rearing had no such effect. Thus, enhanced tonic signaling through GABA(A) receptors rapidly creates a milieu for plasticity within neocortex capable of triggering a critical period for ocular dominance independent of visual experience itself.

Questions and Answers from the F.I.X.; Psychiatric Emergencies; Digoxin Immune Fab (Ovine) (DigiFab); Doxorubicin as a Sclerosing Agent; Tapering Benzodiazepine Infusions

The Formulary Information Exchange (The F.I.X.) is an online drug information service available to subscribers to The Formulary Monograph Service at http://theformulary.com , or you may log on through drugfacts.com. In this column, we present samples of recent dialog on The F.I.X. If you would like more information on The Formulary Monograph Service or The F.I.X., please call 800-322-4349.

Abrupt withdrawal from intrathecal baclofen: Recognition and management of a potentially life-threatening syndrome

Coffey RJ, Edgar TS, Francisco GE, Graziani V, Meythaler JM, Ridgely PM, Sadiq SA, Turner MS. Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially life-threatening syndrome. 2002;83:735-41. Objective: To suggest guidelines for the prevention, recognition, and management of a life-threatening syndrome (high fever, altered mental status, profound muscular rigidity that sometimes progressed to fatal rhabdomyolysis) in patients who experience the abrupt withdrawal of intrathecal baclofen (ITB) therapy. Design: Retrospective literature and safety-file review. Setting: Expert panel drawn from physiatry, neurology, and neurosurgery. Participants: Experienced users of ITB therapy in the pediatric and adult populations in the United States. Interventions: Not applicable. Main Outcome Measures: We reviewed literature reports, MedWatch reports to the US Food and Drug Administration, and our own experiences. We critically analyzed patient management and drug therapy in the context of the pharmacology of baclofen and other antispastic agents. Results: An abrupt reduction in γ-aminobutyric acidB (GABA) agonist activity in the central nervous system can cause the ITB withdrawal syndrome, which is clinically and pathophysiologically distinct from autonomic dysreflexia, malignant hyperthermia, and neuroleptic-malignant syndrome. ITB withdrawal evolves over 1 to 3 days, but may become fulminant if not recognized and treated early. The syndrome can be interrupted by the restoration of ITB therapy. However, supportive measures and high-dose benzodiazepine infusion may be life saving in the interval before ITB therapy is resumed. Dantrolene infusion may relieve muscle rigidity but does not reverse the other manifestations of GABAergic agonist withdrawal. Conclusions: Most episodes of severe ITB withdrawal were preventable. Patients at risk can be identified and educated prospectively and given medication for emergency use. Treatment with GABAergic agonist drugs may prevent potentially fatal sequelae. © 2002 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation