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Objective: To analyze the incidence and factors associated with constipation in critically ill children., Study Design: We performed a prospective observational study that included children admitted to the pediatric intensive care unit for more than 3 days. Constipation was defined as more than 3 days without a bowel movement. Relationships between constipation and demographic data; clinical severity score; use of mechanical ventilation, use of vasoconstrictors, sedatives, and muscle relaxants; nutritional data; electrolyte disturbances; and clinical course were analyzed., Results: Constipation developed in 46.7% of the 150 patients studied (mean age, 34.3 ± 7.1 months). It was most common in postoperative, older, and higher-body-weight patients, and in those with fecal continence (P < .01). Compared with patients without constipation, patients with constipation had higher severity scores and more frequently received midazolam, fentanyl, muscle relaxants, and inotropic support (P < .05). Patients with constipation also started nutrition later and with a lower volume of nutrition (P < .01). There were no between-group differences in mortality or length of pediatric intensive care unit stay. In multivariate analysis, independent factors associated with constipation were body weight (OR, 1.08; 95% CI, 1.03-1.13), Pediatric Index of Mortality 2 score (OR, 1.05; 95% CI, 1.02-1.09), admission after surgery (OR, 7.64; 95% CI, 2.56-22.81), and treatment with vasoconstrictors (OR, 10.28; 95% CI, 3.53-29.93)., Conclusion: Constipation is common in critically ill children. Body weight, Pediatric Index of Mortality 2 clinical severity score, admission after surgery, and the need for vasoconstrictor therapy are major independent risk factors associated with constipation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Baclofen is increasingly being used as an off label anti-craving agent in alcohol use disorders in various parts of the world. The lack of proper recommendations regarding the dosage has important implications for safety in clinical management. In this context, we report two patients who were started with Baclofen as an anti-craving agent, and later developed serious complications following acute self inflicted overdose. We also highlight the important mechanisms of such complications and precautions that needs to be exerted while prescribing., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In recent years, there has been a growing interest in using baclofen for the management of alcohol use disorder. This off-label indication usually involves high doses of the medication. We report a case of severe baclofen overdose in a 66-year-old man. The patient was found severely agitated, and he presented with delirium and auditory hallucinations. At hospital admission, his daily dose was 180 mg baclofen. He was admitted to the intensive care unit for sedation and supportive care. When sedation was withdrawn, the patient presented with a normal neurological status. In this clinical context, baclofen intoxication was suspected. This was confirmed by measuring blood baclofen levels. This intoxication was probably mediated by a combination of risk factors including a high daily dose of baclofen and acute renal failure, conducive to drug accumulation., (2015 BMJ Publishing Group Ltd.)

Background: Dantrolene is neuroprotective in animal models and may attenuate cerebral vasospasm (cVSP) in human aneurysmal subarachnoid haemorrhage (aSAH). We evaluated safety, feasibility and tolerability of intravenous dantrolene (IV-D) in patients with aSAH., Methods: In this single-centre, randomised, double blind, placebo-controlled trial, 31 patients with aSAH were randomised to IV-D 1.25 mg every 6 h for 7 days (n=16) or equiosmolar free water/5% mannitol (placebo; n=15). Primary safety end points were incidence of hyponatraemia (sNa≤132 mmol/L) and liver toxicity (proportion of patients alanine transaminase, aspartate aminotransferase and AlkPhos >5× upper-limit-of-normal). Secondary end points included tolerability, systemic hypotension and intracranial hypertension. Efficacy was explored for clinical/radiological cVSP, delayed cerebral ischaemia (DCI), and 3-month functional outcomes. Quantitative analyses of angiograms and daily transcranial Doppler (TCD) were performed., Results: Between IV-D versus placebo, no differences were observed in the primary outcomes (hyponatremia 44% vs 67% (p=0.29); liver toxicity 6% vs 0% (p=1.0)). Three patients in the IV-D versus two in the placebo group had severe adverse events possibly attributable to infusion and reached stop criteria: one IV-D patient developed liver toxicity; two patients in each group developed brain oedema requiring osmotherapy. The majority of adverse events were not related to infusion (17 vs 5 (RR 2.2; 95% CI 0.7 to 6.7; p=0.16) in IV-D vs placebo). No differences in any categorical cVSP outcomes, DCI, 3-month outcomes or quantitative angiogram and TCD analyses were seen in this small safety trial not powered to detect efficacy., Conclusions: In this small trial, IV-D after aSAH was feasible, tolerable and safe., Trial Registration Number: http://clinicaltrials.gov NCT01024972., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Intrathecal baclofen (ITB) delivered by programmable pump devices represents an important modality for long-term treatment of severe spinal spasticity., Objective: One of the serious adverse events is a withdrawal syndrome after sudden interruption of ITB delivery. In this study, we analyzed the frequency and severity of this complication. Treatment recommendations follow., Study Design: Case study., Setting: Academic medical center., Methods: A total of 54 ITB pumps were successfully implanted in 39 patients with severe intractable spasticity (24 with spinal cord injury, 15 with multiple sclerosis, 24 men, age range 21-59 years)., Results: Eight patients developed a withdrawal syndrome on total a daily dose of ITB between 90-420 μg/day. Seven patients had catheter-related complications. In one patient, pump failure was observed due to its corrosion. Within the group, baclofen withdrawal syndrome occurred once in 20.1 pump-years counted out of 160.4 pump-years of ITB treatment., Limitations: Small sample size., Conclusions: ITB withdrawal syndrome is a rare but life-threatening event and prompt diagnosis before treatment initiation is critical. The reported events were mostly mild due to the acute treatment regime and probably due to a lower dose of ITB. A prerequisite for successful ITB treatment is a deep knowledge of complications and their prompt management in the hands of a multidisciplinary team in specialized centers.

Background: Baclofen is a centrally acting gamma-aminobutyric acid agonist used for the symptomatic relief of skeletal muscle spasm and spasticity in traumatic spinal cord lesions, multiple sclerosis, cerebral palsy, and stroke. It is also used in the treatment of chronic hiccups and cocaine abuse. Baclofen-induced central nervous system depression is rare at the usual therapeutic doses. However, patients with impaired renal function are at a higher risk of developing baclofen toxicity, even at a lower dose., Case Report: A 57-year-old woman with end-stage renal disease on hemodialysis was admitted to our emergency department with progressive confusion and a generalized decrease in muscular tone. There was no obvious metabolic or infectious etiology that could have explained her condition. A comprehensive laboratory and imaging workup was negative. A review of her medication showed that she had recently been prescribed baclofen for muscular spasm. She was diagnosed with baclofen toxicity and was treated with emergent hemodialysis, which improved her mental status and her decreased muscle tone. Repeated sessions of hemodialysis administered on her second and third days of admission ultimately produced sustained clinical improvement and a complete return to her baseline mental status. She was subsequently discharged home with instructions to stay off baclofen., Conclusions: Baclofen toxicity is an under-diagnosed condition, especially in patients with renal dysfunction. Physicians should consider baclofen toxicity in patients with suboptimal kidney function on baclofen who present with altered mental status. Emergent hemodialysis and intensive care unit monitoring is recommended.

Background: Muscle cramps can occur anywhere and for many reasons. Quinine has been used to treat cramps of all causes. However, controversy continues about its efficacy and safety. This review was first published in 2010 and searches were updated in 2014., Objectives: To assess the efficacy and safety of quinine-based agents in treating muscle cramps., Search Methods: On 27 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE. We searched reference lists of articles up to 2014. We also searched for ongoing trials in November 2014., Selection Criteria: Randomised controlled trials of people of all ages with muscle cramps in any location and of any cause, treated with quinine or its derivatives., Data Collection and Analysis: Three review authors independently selected trials for inclusion, assessed risk of bias and extracted data. We contacted study authors for additional information. For comparisons including more than one trial, we assessed the quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE)., Main Results: We identified 23 trials with a total of 1586 participants. Fifty-eight per cent of these participants were from five unpublished studies. Quinine was compared to placebo (20 trials, n = 1140), vitamin E (four trials, n = 543), a quinine-vitamin E combination (three trials, n = 510), a quinine-theophylline combination (one trial, n = 77), and xylocaine injections into the gastrocnemius muscle (one trial, n = 24). The most commonly used quinine dosage was 300 mg/day (range 200 to 500 mg). We found no new trials for inclusion when searches were updated in 2014.The risk of bias in the trials varied considerably. All 23 trials claimed to be randomised, but only a minority described randomisation and allocation concealment adequately.Compared to placebo, quinine significantly reduced cramp number over two weeks by 28%, cramp intensity by 10%, and cramp days by 20%. Cramp duration was not significantly affected.A significantly greater number of people suffered minor adverse events on quinine than placebo (risk difference (RD) 3%, 95% confidence interval (CI) 0% to 6%), mainly gastrointestinal symptoms. Overdoses of quinine have been reported elsewhere to cause potentially fatal adverse effects, but in the included trials there was no significant difference in major adverse events compared with placebo (RD 0%, 95% CI -1% to 2%). One participant suffered from thrombocytopenia (0.12% risk) on quinine.A quinine-vitamin E combination, vitamin E alone, and xylocaine injections into gastrocnemius were not significantly different to quinine across all outcomes, including adverse effects. Based on a single trial comparison, quinine alone was significantly less effective than a quinine-theophylline combination but with no significant differences in adverse events., Authors' Conclusions: There is low quality evidence that quinine (200 mg to 500 mg daily) significantly reduces cramp number and cramp days and moderate quality evidence that quinine reduces cramp intensity. There is moderate quality evidence that with use up to 60 days, the incidence of serious adverse events is not significantly greater than for placebo in the identified trials, but because serious adverse events can be rarely fatal, in some countries prescription of quinine is severely restricted.Evidence from single trials suggests that theophylline combined with quinine improves cramps more than quinine alone, and the effects of xylocaine injections into gastrocnemius are not significantly different to quinine across all outcomes. Low or moderate quality evidence shows no significant difference between quinine and vitamin E or quinine and quinine-vitamin E mixture. Further research into these alternatives, as well other pharmacological and non-pharmacological treatments, is thus warranted.There is no evidence to judge optimal dosage or duration of quinine treatment. Further studies using different dosages and measurement of serum quinine levels will allow a therapeutic range to be defined for muscle cramp. Because serious adverse events are not common, large population studies are required to more accurately inform incidence. Longer lengths of follow-up in future trials will help determine the duration of action following cessation of quinine as well as long-term adverse events. The search for new therapies, pharmacological and nonpharmacological, should continue and further trials should compare vitamin E, quinine-vitamin E combination, and quinine-theophylline mixture with quinine.

Purpose: Leg cramps are common in patients with heart failure. Quinine is frequently prescribed in low doses to these patients, but safety of this practice is unknown. We studied the outcomes associated with use of quinine in a nationwide cohort of patients with heart failure., Methods: Through individual-level-linkage of Danish national registries, we identified patients discharged from first-time hospitalization for heart failure in 1997-2010. We estimated the risk of mortality associated with quinine treatment by time-dependent Poisson regression models., Results: A total of 135 529 patients were included, with 14 510 patients (11%) using quinine at some point. During a median time of follow-up of 989 days (interquartile range 350-2004) 88 878 patients (66%) died. Patients receiving quinine had slightly increased mortality risk, adjusted incidence rate ratio (IRR) 1.04 (95% confidence interval [CI] 1.01 to 1.07). The risks differed according to concomitant β-blocker treatment. For patients treated with both quinine and β-blockers IRR was 1.15 (95% CI 1.09 to 1.21) vs. 0.99 (95% CI 0.96 to 1.03) for patients treated with quinine but not β-blockers. The risks were highest shortly after initiation of therapy: for the first 14 days of treatment IRR was 2.12 (95% CI 1.54 to 2.93) for patients in treatment with β-blockers and 1.17 (95% CI 0.86 to 1.59) for patients not treated with β-blockers., Conclusions: Use of quinine was common and associated with increased mortality in heart failure, especially if administered together with β-blockers and shortly after treatment initiation. Mechanisms underlying the findings remain to be established., (Copyright © 2015 John Wiley & Sons, Ltd.)

Introduction: An acute discontinuation of tizanidine, an alpha-2-agonistic muscle relaxant, is associated with reflex tachycardia, hypertension, tremor, hypertonicity and anxiety., Case Report: We describe a 53-year-old patient with broken-heart syndrome, who developed serious tizanidine withdrawal symptoms after high-dosed long-term treatment within the framework of stress cardiomyopathy., Conclusion: Central muscle relaxants like tizanidine might have an impact on the development of delirium. Tizanidine withdrawal should be considered in patients who manifest signs and symptoms of withdrawal from medications. The drug should be gradually reduced in dosage under observation by a psychiatrist. When prescribing tizanidine, the possible pharmacological side effects and interactions should be taken into careful account., (© Georg Thieme Verlag KG Stuttgart · New York.)

Intrathecal baclofen (ITB), administered by an implanted pump, has emerged as an efficacious therapy for the treatment of hypertonicity in pediatrics. Although ITB has been used for more than 20 years clinically, much is still unknown about the most optimal dosing regimens and intrathecal catheter tip placement. Clinician experience, animal research, and advanced imaging is guiding the use of ITB. The rationale for high cervical catheter tip placement and pulsating flex dosing is described., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Treatment of severe spasticity and dystonia with intrathecal baclofen (ITB) in children has been shown to be effective and has therefore been employed in the Region of Southern Denmark. The aim of this retrospective study was to analyse the efficacy and adverse events since ITB was introduced in 2003., Methods: A total of 46 children who had a baclofen pump from April 2003 to January 2013 were included. The children's medical records were reviewed and clinical characteristics, efficacy and adverse events were registered. The efficacy of treatment experienced by parents was ascertained by telephone interviews, and data were rated on a Likert scale ranging from one to five, where one was no effect and five was marked improvement., Results: After ITB, spasticity was reduced from a median of four to two in the upper extremities and from a median of four to one in the lower extremities. Baclofen infusion was 105.1-2,000 micrograms/day (mean 494.9 micrograms/day). Oral baclofen was reduced from 27.3 to 17.7 mg/day after ITB (p < 0.01). The parents' assessment of improvement in well-being, function and ease of care of their child had a mean score of 3.7, 2.2 and 3.4, respectively. 87.1% of parents stated that ITB had been worthwhile, and 90.3% would recommend it to other parents. Most infectious and mechanical adverse events were experienced during the first 200 days after pump implantation. The total complication rate was 0.40 per pump year., Conclusion: ITB resulted in reduced spasticity in children with severe spasticity and dystonia, and ITB could be considered safe. Parents' satisfaction with ITB was rated as good and most parents would recommend ITB to others., Funding: not relevant., Trial Registration: not relevant.

The prospective multicenter open noncomparative pharmaco-epidemiological observational project on the use of mydocalm in real clinical practice has been completed in 2013. The project has been performed in 2090 clinical/rehabilitation settings in 284 cities of 13 countries using the results of 35,383 patients. The project aimed to assess the safety of treatment (percentage of patients with adverse-effects) and pain relieving efficacy as well as patient's satisfaction with the treatment. In total, 6603 (19%) adverse-effects were recorded. Their severity was evaluated as mild in 84,48%, no serious adverse-effects were noted. The high efficacy of mydocalm in the treatment of pain syndromes with the muscle spasm has been demonstrated. The high level of tolerability and absence of the clinically significant increase of adverse effects in the combination with nonsteroidal anti-inflammatory drugs have been confirmed.

Purpose: In 2005, the Food and Drug Administration approved Qualaquin (quinine) for treatment of malaria and later ordered unapproved quinine formulations off the market. In 2009, labeling for Qualaquin added a warning for use for leg cramps, as serious hematologic reactions could occur. We examined quinine use trends among Medicare beneficiaries focusing on indications for use and associations with adverse hematologic outcomes., Methods: Medicare beneficiaries, aged 65 years and older, in 2006-2012, were included in incident quinine or comparator, diltiazem, cohorts if 183 days prior to dispensing, they were enrolled in Medicare, had no dispensing of quinine, diltiazem, ticlodipine, clopidogrel, and sulfonamide drugs, and had no diagnoses of thrombocytopenia, immune thrombocytopenic purpura (ITP), thrombotic microangiopathy (TMA), or hemolytic-uremic syndrome (HUS). Diagnoses of malaria or leg cramps were observed during 183 days prior to index dispensing. Outcomes of ITP, TMA, or HUS in inpatient or emergency room settings were then observed during drug use., Results: Prevalent use of quinine decreased by 99%, from 419 675 to 6036 users during 2006-2012. Of 88 066 quinine users, 9 had diagnoses of malaria and 36 218 had leg cramps. Incidence rates (per 1000 person-years) for ITP were quinine 1.67 and diltiazem 0.40 [incidence rate ratio 4.2 (95% confidence interval 2.5, 6.5)], for TMA were quinine 0.23 and diltiazem 0.03 [incidence rate ratio 6.9 (95% confidence interval 1.3, 24.0)], and for HUS were quinine 0 and diltiazem 0.01., Conclusions: Use of quinine decreased substantially, although diagnoses of leg cramps persist. To our knowledge, this is the first demonstration of an association for quinine and ITP and TMA in claims data., (Copyright © 2014 John Wiley & Sons, Ltd.)

Continuous infusion of intrathecal baclofen (ITB), via implanted pump, is a powerful tool in the management of severe spasticity in neurological disorders. The advantages of ITB therapy are that it is non-destructive, reversible, and programmable, allowing for neuromodulation. Patients reported significant subjective improvements and decreases in muscle tone after baclofen injection, but excessive doses of ITB resulted in motor weakness. Few complications and adverse effects were reported. ITB therapy appears to be a promising treatment to improve residual motor control in patients with severe spasticity.

What Is Known and Objective: Dantrolene can be combined with baclofen to better treat spasticity, but may cause muscular weakness and dysphagia. We instead describe a pharyngeal spasm due to dantrolene., Case Summary: A 12-year-old male received dantrolene 3 mg/kg/day in adjunct to baclofen 2 mg/kg/day, to improve spasticity. After 5 days of full-dose dantrolene, his dysphagia worsened and he developed pharyngeal spasm. Dantrolene was suspected for an adverse reaction and removed. The patient subsequently improved., What Is New and Conclusion: Causality analysis determined a probable relationship between dantrolene and pharyngeal spasm. This may be due to direct muscle contraction by dantrolene, an effect seen previously in vitro., (© 2014 John Wiley & Sons Ltd.)

Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous reaction, which is mostly due to drugs, but which has also been described as occurring after infections. We report a case of severe AGEP with extensive blistering mimicking toxic epidermal necrolysis (TEN) in a 47-year-old woman. This was associated with a life-threatening primary mumps infection, complicated by perimyocarditis and encephalitis. The recent increase in the incidence of mumps should lead physicians to be aware of the uncommon clinical features and complications of this disease., (© 2014 British Association of Dermatologists.)

Introduction: Intrathecal administration of baclofen (ITB) is widely recognized as an effective treatment for severe spasticity of both spinal and supraspinal origin with fewer side effects. The lower drug dosages used for spinal intrathecal administration, acting directly on the receptor sites, result in greater therapeutic efficacy with less systemic toxicity than with oral preparations., Aim: This study aims to prospectively evaluate the effects of ITB on erectile function in male patients affected by severe spasticity., Methods: Twenty adult male patients, with a 34.85 ± 10.27 mean age, affected by severe spasticity mainly due to spinal cord lesions (10 traumatic, three vascular, six degenerative, and one congenital in origin) and treated with ITB, were enrolled in the study. All participants underwent specific clinical scales to evaluate force, muscle tone, cognition and mood, and specific sexual questionnaires, including an accurate semi-structured interview., Main Outcome Measure: The International Index of Erectile Function (IIEF) was used to evaluate sexual function before and after pump implantation., Results: A comparative analysis of the neurological scales and psychometric scores at T1 (baseline) and T2 (follow-up) showed statistically significant differences before and after pump implantation. In particular, we noted a significant decrease in the IIEF median scores (from 0.42 ± 0.07 to 0.14 ± 0.02, P value < 0.0001) and a correlation between ITB dosage and IIEF scores (ρ = -0.60; P < 0.05)., Conclusions: This study supports previous findings on a possible negative effect of ITB on sexual function, with regard to erection. Patients who are considering ITB for treatment of severe spasticity should be informed about possible but reversible sexual side effects, especially at higher dosage. Future studies with larger samples should be fostered to confirm these findings for a better management of these, often young, patients., (© 2014 International Society for Sexual Medicine.)

Introduction: In July 2013, the European Medicines Agency suspended the marketing authorizations of tetrazepam across the European Union. Herein, we examine the various kinds of adverse drug reactions (ADRs) reported to be associated with tetrazepam., Areas Covered: We undertook a two-sided systematic approach. First, we conducted a search in Medline for all studies that have published about tetrazepam ADRs in peer-reviewed journals. Second, we collected tetrazepam ADRs from pharmacovigilance system databases. Our study reveals discrepancies in the information provided by these two different sources, both in the number of cases reported as well as in the kind of reported ADRs. Whereas cutaneous alterations are the only ADRs reported in peer-reviewed journals, pharmacovigilance system databases include others (hepatobiliary, neurological and psychiatric)., Expert Opinion: We noted the lack of randomized controlled clinical trials evaluating tetrazepam efficiency and safety. We failed to find a turning point in the amount of ADRs reported following tetrazepam withdrawal to underpin the validity of the withdrawal. We stress the importance of a better communication of knowledge in scientific literature, pharmacovigilance agencies, and from doctors to prevent marketed usage of drugs with well-established side effects during long periods.

Objective: To assess the frequency and types of adverse events (AEs) related to intrathecal baclofen (ITB) therapy in adults, and associated risk factors., Design: A prospective, observational cohort study of adults followed up from January 1 to December 31, 2010., Setting: A neurologic rehabilitation department in a university hospital., Participants: All consecutive adult subjects (N=158) receiving ITB via a pump, either implanted or followed up during the study period., Intervention: Not applicable., Main Outcome Measures: Frequency and type of AEs., Results: In 2010, 158 subjects were followed up for ITB therapy, of whom 128 were implanted before 2010 (nonsurgical subjects), and 30 underwent implantation in 2010 (surgical subjects). Of these 30 subjects, 20 were "newly implanted" and 10 were "replacements." The most frequent pathologic disorders were spinal cord injury (42%) and multiple sclerosis (28%). Twenty-eight subjects (18%) experienced a total of 38 AEs. The rate of AEs was .023 per month of ITB treatment. AEs were related to the surgical procedure in 53% of cases, to the device in 29% (predominantly catheter dysfunctions), and to adverse effects of baclofen in 18%. AEs related to the surgical incision (scar complications and collections) were more frequent in replacement than newly implanted subjects (P=.009). No significant association between occurrence of an AE and subject characteristics (age, gait capacity, spinal vs cerebral spasticity, duration of ITB therapy follow-up) was found. Nearly half of the AEs were serious, extending admission time by a mean of 16 days. No AE induced long-term morbidity or death., Conclusions: The AE rate was relatively low in this cohort. This has to be balanced against the clinical, functional, and quality-of-life improvements, which are expected from ITB therapy., (Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

A 41-year-old man presented with postcervical traumatic complete quadriparesis under intrathecal baclofen therapy (ITB) for refractory spasticity. Less than 24 h after having his baclofen pump substituted, he develops hyperthermia, seizures, cognitive depression, acute hypoxaemic respiratory failure and cardiovascular instability leading to mechanical ventilation and vasopressor support. He was transferred to an intensive care unit with diagnosis of community-acquired pneumonia leading to septic shock. He evolved with progressive clinical worsening and multisystem organ failure and cardiac arrest in non-shockable rhythm (pulseless electrical activity)--4 min resuscitation with return of spontaneous circulation. Considering the possible diagnosis of baclofen withdrawal syndrome and, in suspicion of ITB delivery disruption, the catheter system was surgically explored and a leaking tubule attachment was found. Despite aggressive cardiovascular, respiratory and renal support therapy, clinical improvement occurred only after restoration of intrathecal drug delivery. He was discharged from the hospital after 56 days, having returned to baseline status., (2014 BMJ Publishing Group Ltd.)

Objective: Initial outcome of intrathecal baclofen (ITB) treatment in Japan is being reported on., Methods: Chronological change of the Ashworth scale and complications after surgery were analyzed. Data were obtained from 71 children with severe spasticity who had received ITB screening tests by the end of March 2012., Results: Pump implantations for ITB treatment were performed in 43 children out of 62 whose spasticity reduced after baclofen injection at the screening tests. Postoperative evaluations of ITB treatment were carried out within one year and, in some cases, more than 2 years after surgery. Complications related to baclofen were reported on 19 occasions in 12 children within one year of ITB pump implantation, and on 9 occasions in 4 children of the 21 who were followed for more than 2 years. Main complications were hypertonia of muscle, liver dysfunction, and low blood pressure. The frequency of complications was lower than that reported previously. There was no apparent evidence to indicate that complications developed more in children than in adults in this study. The postoperative values of Ashworth scale in the upper and lower extremities were reduced markedly when compared with preoperative levels, and the improvements were statistically significant (P < 0.05)., Conclusions: This is the first report of outcome of ITB for severely disabled children with spasticity in Japan. It was confirmed that ITB for children with severe spasticity is a safe and effective treatment.

Objective: The γ-aminobutyric acid type B (GABA-B) receptor agonist baclofen is approved for spasticity up to the dose of 80 mg/d. Recently, off-label use of high-dose baclofen (HDB), up to 400 mg/d, has been increasing for treating alcohol use disorders (AUDs), although the efficacy and safety profiles of HDB are relatively unknown. We report 2 cases of tinnitus in patients treated with HDB for AUD., Case Summaries: The first case concerns a 60-year-old man who reported tinnitus when he reached a 180 mg/d dose of baclofen after 3 months of treatment. Tinnitus persisted until the dose was reduced to 90 mg/d. The second case concerns a 45-year-old woman who presented with tinnitus when she reached a 210 mg/d dose of baclofen after 4 months of treatment. Tinnitus persisted until the dose was reduced to 60 mg/d., Discussion: Using the Naranjo scale, imputability to baclofen was considered probable in both cases. GABA-B receptors have been reported to be implicated in both the etiology and the treatment of tinnitus. There may be an individual susceptibility to develop tinnitus under baclofen therapy because of some GABA-B genetic polymorphisms that remain to be determined., Conclusion: HDB may be responsible for the occurrence of severe tinnitus, possibly in a dose-dependent manner. This appears to be coherent with the previously known involvement of GABA-B receptors in the pathophysiology of tinnitus.

The pharmacokinetics of baclofen is well delineated in subjects with normal kidney function (KF); however, pharmacokinetics data in patients with chronic kidney disease (CKD) are not and dosage recommendations remain empirical. The effects of CKD on baclofen pharmacokinetics were assessed through a multi-center, open-label, single 5-mg dose, pharmacokinetics study. The KF was measured as the creatinine clearance (CrCL) calculated with the Cockroft-Gault (C-G) equation or as the estimated glomerular filtration rate (eGFR) using subjects' CKD-EPI equation. Subjects were assigned to 1 of 4 groups based on their CrCL (>80 mL/min, 50-80 mL/min; 30-50 mL/min and <30 mL/min). Cmax was not statistically different between the groups, while AUC and T1/2el increased, and CL/F decreased, with increasing severity of CKD. Baclofen's oral clearance and CrCL were statistically significantly correlated, and the trend was the same when classifying subjects either with the CKD-EPI or C-G equations. Linear equations using KF as variable were set to recommend individual dose reduction in CKD patients. Results suggest a mean dose reduction of 1/3, 1/2, and 2/3 in patients with mild, moderate, and severe CKD respectively, in order to achieve baclofen exposure comparable to that observed in healthy subjects., (© 2014, The American College of Clinical Pharmacology.)

Baclofen is a γ-aminobutyric acid (GABA) agonist that is commonly prescribed for the treatment of spasticity in children. The clinical indications for baclofen use in the pediatric population have increased in recent years. Prescribing baclofen mandates education regarding abrupt withdrawal and overdose because of the severe clinical reactions this can precipitate. This report highlights the case of a patient who presented with acute onset of coma and a flaccid paralysis after baclofen overdose. We reviewed the presentation, clinical course, diagnostic studies, and outcome of this patient. A review of prior literature regarding baclofen overdose is included. Baclofen overdose is heralded by dose-related alteration in consciousness and weakness, progressing to coma and a flaccid paralysis. Screening for baclofen overdose is accomplished through high-power liquid chromatography. Baclofen overdose is treated with supportive care and antiepileptic medications as indicated. There is usually full spontaneous recovery with elimination of the medication.

There are 3 surgical procedures that patients with cerebral palsy (CP) undergo that may be considered major procedures: femoral osteotomies combined with pelvic osteotomies, spine fusion, and intrathecal baclofen pump implant for the treatment of spasticity. Many complications are known to occur at a higher rate in this population, and some may be avoided with prior awareness of the preoperative pathophysiology of the patient with CP., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Object: This single-center study investigated adverse events that occurred in children and adolescent patients treated with intrathecal baclofen (ITB) therapy for spasticity and/or dystonia., Methods: In a 14-year period, 430 consecutive patients with a mean age of 13.3 ± 5.9 years received ITB over a mean follow-up period of 8.6 ± 3.8 years (range 12 months to 14 years). Eighty-nine percent of these patients had cerebral palsy. Major complications, defined as those that required a surgical intervention, were infections, CSF leaks, and device problems related to the catheter or pump. Assessing infections, the authors compared the 2 groups of patients implanted with an ITB system by either the subcutaneous or subfascial technique. The temporal distribution of events related to the catheter was also considered., Results: At least 1 complication was present in 25% of the patients: 9.3% experienced an infection, 4.9% a CSF leak, 15.1% a problem with the catheter, and 1% a problem related to the pump. Five percent of the assessed patients suffered more than 1 complication. The rate of infections was significantly lower (p < 0.001) in patients with the pump placed subfascially compared with those with the pump placed subcutaneously. A higher rate of infection was found after pump replacement compared with the first pump implantation (10.6% vs 6%, respectively). Catheter problems were the most common complication and occurred more frequently during the 1st year after the implant., Conclusions: While ITB is an effective treatment to manage spasticity of different origins, adverse events may occur and need to be managed. The surgical procedure should be meticulous and different techniques may have a diverse impact on the infection rate, which is the most critical complication. Despite the adverse events that occurred in this study, the majority of patients were satisfied with the treatment received.

Aim: To investigate the effect of intrathecal baclofen (ITB) on sitting in children with cerebral palsy with severe spasticity; and identify potential sub-groups of patients at particular risk of deterioration., Method: Twenty three children with cerebral palsy, mean age 10 yrs 10 mo were assessed before and after ITB treatment using the Sitting dimension of the Gross Motor Function Measure. Sitting prior to treatment was compared to sitting following ITB treatment in the same children. Exploration of sub groups was also attempted to investigate affects of ITB on sitting according to age and severity of motor impairment., Results: No significant difference was found in sitting before ITB treatment compared to sitting following insertion of an ITB pump (p = 0.09). No specific age group or classification of motor impairment demonstrated significant deterioration in sitting following ITB treatment., Conclusion: Sitting does not improve or deteriorate in children following treatment with ITB, independent of age or severity of motor impairment., (Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: Eperisone hydrochloride is a centrally acting muscle relaxant prescribed for muscle stiffness that acts by depressing the activities of α and γ efferent neurons in the spinal cord and supraspinal structures. Although a case of eperisone-induced severe QT prolongation had been reported, the relationship between serum eperisone concentration and QT interval remains obscure., Objective: The aim of this study was to investigate the relationship between serum eperisone concentration and QT interval., Methods: Four patients who overdosed on eperisone were admitted to our hospital between January 2010 and December 2011. We took simultaneous serial measurements of serum eperisone concentration and QT interval in the intensive care unit. In total, 22 measurement points were plotted for these patients. We analyzed the correlation between the serum eperisone concentration and corrected QT (QTc) interval., Results: Three men and one woman (mean age, 50 years) overdosed on eperisone with an average dose of 3087.5 mg (therapeutic dose, 150 mg/day). The mean QTc interval at arrival was 592 ms (range, 444-825 ms), and the mean serum eperisone concentration at arrival was 1257.5 ng/mL (range, 14.5-4120.0 ng/mL). The correlation coefficient was 0.833 between serum eperisone concentration and QTc interval (P < .001)., Conclusion: Serum eperisone concentration correlates with QTc interval in patients who overdose on eperisone., (© 2013.)

Objective: To investigate the long-term dosage evolution and complication rate of intrathecal baclofen use in multiple sclerosis and spinal cord injury patients, based on a large population with a long follow-up., Design: Retrospective data analysis., Setting: Academic hospital., Subjects: Patients with multiple sclerosis (n = 81) or spinal cord injury (n = 49) having an intrathecal baclofen pump implanted at the University Hospitals Leuven between 1988 and 2009., Intervention: Medical records review of included patients in August 2010., Main Measures: Complications linked to intrathecal baclofen therapy. Daily baclofen dosage after 3 and 6 months, and yearly thereafter. Data on dosage evolution were analysed using a mixed-effect linear model., Results: In 130 patients with a mean follow-up of 63 months, comprising 797 pump years, 104 complications were recorded. This corresponds to a complication rate of 0.011 per month, equally divided among both groups. Seventy-eight of these complications were catheter related. The mean dosage of baclofen stabilizes two years after implantation at 323 µg/day in the multiple sclerosis population. In spinal cord injury patients the daily dose only stabilizes after five years at a significantly higher dosage (504 µg/day). No significant increase in dosage is seen in the long term., Conclusions: In multiple sclerosis and spinal cord injury patients, intrathecal baclofen therapy has a complication rate of 1% per month. Complications are mainly due to catheter-related problems (74%). The intrathecal baclofen dosage stabilizes in the long term, indicating that long-term tolerance, defined as progressive diminution of the susceptibility to the effects of a drug, is not present.

Drugs can lead to severe life-threatening thrombocytopenia. The mechanisms of drug-induced thrombocytopenia are increased destruction by immune-mediated platelet destruction or decreased platelet production by bone marrow suppression. Quinine is a drug used for the treatment of malaria and nocturnal leg cramps and is also an important ingredient in some herbal preparations. Quinine can very rarely cause thrombocytopenia by immune-mediated platelet destruction. In a patient with thrombocytopenia, a detailed history of all the medications including over-the-counter medications and herbal preparations is very important.

Objective: To evaluate, whether once-daily oral baclofen administration increases and/or sustains plasma insulin-like growth factor-1 (IGF-1) concentration in 11 men with chronic spinal cord injury (SCI) and IGF-1 deficiency (i.e. <250 ng/ml)., Design: Prospective, open-label, dose titration study. Baclofen was administered at 20 mg/day for 8 weeks; then increased to 40 mg/day for another 8 weeks. Plasma IGF-1 and self-reported side effects were measured at baseline and every other week for the duration of the study., Results: The subjects were 43 ± 12 years old, had duration of injury of 20 ± 12 years; eight subjects had a complete motor injury, and eight had paraplegia. Nine of 11 subjects completed the 20 mg/day treatment and 5 subjects completed the 40 mg/day treatment. Plasma IGF-1 levels improved with each baclofen dose; however, only one subject increased from baseline and remained above the targeted physiological range of 250 ng/ml throughout treatment. A significant increase in IGF-1concentration was observed between baseline and week 2 (154 ± 63 vs. 217 ± 69 ng/ml; P < 0.05), weeks 8 and 10 (188 ± 95 vs. 228 ± 93 ng/ml; P < 0.05), and weeks 8 and 16 (188 ± 95 vs. 259 ± 92 ng/ml; P < 0.05). No serious side effects were observed at 20 mg/day; the 40 mg/day dose was less well tolerated., Conclusion: Baclofen was not effective at sustaining plasma IGF-1 concentrations in the physiological range in men with chronic SCI.

Surgeries in general and cardiac procedures in particular are increasingly performed using catheter-based or minimally invasive techniques, often with sedation or general anesthesia. These new approaches require close cooperation and communication between the cardiologist and anesthesiologist to ensure patient safety. Anesthesia-related respiratory complications arising in the catheterization laboratory are more frequent and more severe than are seen in the operating room. The principals of safe anesthetic practice as they apply to procedures performed outside the operating room and suggestions to improve safety and outcome are reviewed in this article., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Fixed drug eruption is a common cutaneous adverse reaction in young patients with a characteristic clinical appearance. However, the diagnosis and identification of the substance may be difficult if food or food additives provoke the fixed eruption. A 26-year-old man had a history of two episodes of cutaneous erythema with residual pigmentation. Close examination of the history including his diet in addition to an oral challenge test and patch testing led to the diagnosis of fixed eruption secondary to quinine in tonic water. We examined for the presence of quinine in commercially available brands of tonic water using ultraviolet A and irradiation and high-performance liquid chromatography. Both Schweppes and CANADA DRY brands of tonic water emitted fluorescent light upon ultraviolet A irradiation, and contained quinine at concentrations of 67.9 and 61.3 mg/L, respectively. Quinine contained in some tonic waters may trigger fixed eruption., (© 2013 Japanese Dermatological Association.)

Background: Arbaclofen placarbil is a pro-drug of the gamma-aminobutyric acid-B agonist R-baclofen that has been shown to reduce reflux episodes in patients with gastro-oesophageal reflux disease (GERD)., Aim: To evaluate the efficacy and safety of arbaclofen placarbil vs. placebo as adjunctive therapy in subjects with troublesome GERD symptoms despite therapy with once-daily doses of a proton pump inhibitor (PPI) and to identify the characteristics of patients who were responders., Methods: Patients (n = 460) with symptomatic GERD experiencing troublesome symptoms on once-daily PPI therapy were enrolled in this phase II, randomised, multicentre, double-blind, placebo-controlled, dose-ranging study. Patients were randomised to receive placebo or arbaclofen placarbil (20 or 40 mg once daily, 20 or 30 mg twice daily) with their current PPI for 6 weeks. Patients recorded heartburn and other GERD symptoms in a daily diary and rated severity of each event. The primary endpoint was percent change from baseline in heartburn events per week., Results: In the primary analysis, there was no significant difference between arbaclofen placarbil and placebo. Post hoc analyses removing mild and very mild heartburn events resulted in greater percent reductions for all arbaclofen placarbil doses with nominal P values <0.05 for each dose compared with placebo. There was a dose-related increase for the most common adverse events., Conclusions: Arbaclofen placarbil was not superior to placebo in the primary analysis. Post hoc analyses suggest that subjects with more clinically relevant moderate or severe symptoms are more likely to respond to arbaclofen placarbil (clinicaltrials.gov NCT00978016)., (© 2013 John Wiley & Sons Ltd.)