Electrocardiographic QTc Interval Research Articles

Usefulness of electrocardiography QT interval for prediction of left ventricular diastolic dysfunction: a cross-sectional study.

A cross-sectional at Holy-family Hospital, Rawalpindi Medical University, Pakistan. One thousand five hundred patients were referred for electrocardiography (ECG) for clinical suspicion of HF between May and July 2022. Ejection fraction (EF), lateral mitral annulus velocity (e'), mitral inflow early (E) and late (A) velocities, left ventricular filling pressure (E/e' ratio), and QT interval (QTc) was calculated. Odds ratios with a 95% CI (odds) were obtained by comparing QTc with all variables. The patients were mostly middle-aged adults with a mean age of 30.27 (±7.64). Male to female ratio was nearly balanced, with 771 (51.4%) males included in the clinical survey. The ECG parameters were; QT interval-494.07 (±63.61), EF-57.11 (±11.96), early to atrial filling velocity ratio-0.71 (±0.20), and lateral mitral annulus velocity-8.29 (±1.64). The promising results for correlation between QT interval and ECG parameters, particularly EF and lateral mitral annulus velocity, should not be considered as the alternative in diagnosing left ventricular diastolic dysfunction thus far. Prolonged electrocardiographic QTc interval in patients with HF is useful in predicting diastolic dysfunction.

Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

Tp-Te interval prolongs in hypertension independent of the left ventricular geometry

Background/Aim: Hypertension (HT) may modulate left ventricular (LV) geometry. Electrocardiographic Tp-Te, QT and QTc interval, and Tp-Te/QTc ratio are among the parameters of ventricular repolarization (VR) that may predict ventricular arrhytmogenic potential and possess prognostic significance. It is well known that left ventricular hypertrophy is associated with increase in the parameters of VR; however, little is known about the association of these parameters with other forms of LV geometry in HT. Our aim was to assess this association. Methods: A total of 162 newly diagnosed essential HT patients were enrolled and divided into those with concentric LV remodeling (n=79) and those with normal LV geometry (n=83). Healthy normotensive subjects (n=76) comprised the control group. Data were gathered retrospectively from electrocardiographic, echocardiographic, and demographic records. Results: QT interval, P-wave duration, and QRS duration were similar among the 3 groups (P>0.05). Tp-Te, QTc and Tp-Te/QTc were greater in the HT group compared with the controls (P 0.05). There was no correlation between Tp-Te interval, LV mass and LV mass index among the study population. Conclusion: Tp-Te may be useful in prognostic stratification of HT. Regardless of the LV geometry, HT patients have prolonged Tp-Te and QTc intervals, and increased Tp-Te/QTc ratio compared to the healthy subjects. Our findings may suggest possible utilization of Tp-Te as HT-related end-organ damage in the future.

β-blockers in advanced cirrhosis: More friend than enemy

Nonselective beta-adrenergic blocker (NSBB) therapy for the prevention of initial and recurrent gastrointestinal bleeding in cirrhotic patients with gastroesophageal varices has been used for the past four decades. NSBB therapy is considered the cornerstone of treatment for varices, and has become the standard of care. However, a 2010 study from the group that pioneered β-blocker therapy suggested a detrimental effect of NSBBs in decompensated cirrhosis, especially in patients with refractory ascites. Since then, numerous additional studies have incompletely resolved whether NSBBs are deleterious, although more recent evidence weighs against a harmful effect. The possibility of a “therapeutic window” has also been raised. We aimed to review the literature to analyze the pros and cons of using NSBBs in patients with cirrhosis, not only with respect to bleeding or mortality but also to other potential benefits and risks. β-blockers are highly effective in preventing first bleeding and recurrent bleeding. Furthermore, NSBBs improve congestion/ischemia of the gut mucosa, decrease intestinal permeability, and therefore indirectly alleviate systemic inflammation. β-blockers shorten the electrocardiographic prolonged QTc interval and may also decrease the incidence of hepatocellular carcinoma. On the other hand, the possibility of deleterious effects in cirrhosis has not been completely eliminated. NSBBs may be associated with an increased risk of portal vein thrombosis, although this could be correlational artifact. Overall, we conclude that β-blockers in cirrhosis are much more of a friend than enemy.

Electrocardiographic safety evaluation of extended artemether-lumefantrine treatment in patients with uncomplicated Plasmodium falciparum malaria in Bagamoyo District, Tanzania

BackgroundExtended artemisinin-based combination therapy (ACT) for treatment of uncomplicated Plasmodium falciparum malaria with already existing drug regimens, such as artemether-lumefantrine, might be effective in tackling the emerging ACT resistance. However, given the history of cardiotoxicity among anti-malarial drugs structurally similar to lumefantrine, the potential effect of extended artemether-lumefantrine treatment on the electrocardiographic (ECG) QTc interval is of high concern.MethodsMale and non-pregnant females aged 1–65 years, diagnosed with uncomplicated P. falciparum malaria in Bagamoyo district, Tanzania, were randomized into two arms. The intervention arm received an extended, i.e. 6-day, course of artemether-lumefantrine and an additional single low-dose primaquine (0.25 mg/kg) administered together with the last artemether-lumefantrine dose. The control arm received the standard weight-based 3-day course. ECGs were performed at day 0 and 4–5 h after the last dose at day 5. QT intervals were read manually using the tangent method and automatically. Bazett’s (QTcB) and Fridericia’s (QTcF) formulae were used for correction for heart rate. Descriptive statistics were used to calculate baseline characteristics and the number of supra-thresholds QTc intervals (QTc prolongation > 500, change in QTc interval (ΔQTc) > 60 ms). The mean change in QTc interval in and between the two arms was compared using the paired t-test and independent samples t-test, respectively.ResultsA total of 195 patients were enrolled, 103 and 92 in the intervention and control arm, respectively. No patient experienced QTc intervals > 500 ms on day 5 by both formulae. Patients with ΔQTc > 60 ms, for QTcF were 6/103 (5.8%) vs 2/92 (2.2%) and for QTcB 2/103 (1.9%) vs 1/92 (1.1%) in the intervention and control arms, respectively. The mean difference in ΔQTc interval was statistically significant between the two arms with both correction formulae, 11.4 ms (95% CI 2.7–20.0, p = 0.010) and 13.4 ms (95% CI 5.3–21.5, p = 0.001), for QTcB and QTcF, respectively.ConclusionThe extended 6-day course of artemether-lumefantrine did not reveal clinically relevant QTc prolonging effects. However, significant QTcF prolongation and presence of patients with supra-threshold QTc values observed in the intervention arm underscore the importance of further monitoring of QTc parameters in extended artemether-lumefantrine treatment.Trial registration ClinicalTrials.gov, NCT03241901. Registered July 27, 2017. https://clinicaltrials.gov/show/NCT03241901

An actionable KCNH2 Long QT Syndrome variant detected by sequence and haplotype analysis in a population research cohort

The Viking Health Study Shetland is a population-based research cohort of 2,122 volunteer participants with ancestry from the Shetland Isles in northern Scotland. The high kinship and detailed phenotype data support a range of approaches for associating rare genetic variants, enriched in this isolate population, with quantitative traits and diseases. As an exemplar, the c.1750G > A; p.Gly584Ser variant within the coding sequence of the KCNH2 gene implicated in Long QT Syndrome (LQTS), which occurred once in 500 whole genome sequences from this population, was investigated. Targeted sequencing of the KCNH2 gene in family members of the initial participant confirmed the presence of the sequence variant and identified two further members of the same family pedigree who shared the variant. Investigation of these three related participants for whom single nucleotide polymorphism (SNP) array genotypes were available allowed a unique shared haplotype of 1.22 Mb to be defined around this locus. Searching across the full cohort for this haplotype uncovered two additional apparently unrelated individuals with no known genealogical connection to the original kindred. All five participants with the defined haplotype were shown to share the rare variant by targeted Sanger sequencing. If this result were verified in a healthcare setting, it would be considered clinically actionable, and has been actioned in relatives ascertained independently through clinical presentation. The General Practitioners of four study participants with the rare variant were alerted to the research findings by letters outlining the phenotype (prolonged electrocardiographic QTc interval). A lack of detectable haplotype sharing between c.1750G > A; p.Gly584Ser chromosomes from previously reported individuals from Finland and those in this study from Shetland suggests that this mutation has arisen more than once in human history. This study showcases the potential value of isolate population-based research resources for genomic medicine. It also illustrates some challenges around communication of actionable findings in research participants in this context.

Significance of Electrocardiographic QTc Interval on Assessment of Left Ventricular Diastolic Dysfunction in Hypertensive Patient: A Simple Screening Tool

Background: Diastolic dysfunction as part of heart failure with preserved ejection fraction (HFpEF) has gain interests, due to the increasing prevalence rate and poor prognosis. Besides the mechanism is not fully understood, there are some difficulties in detecting the presence of diastolic dysfunction. Previous studies have shown correlation between some electrocardiographic parameters and diastolic function. Furthermore, the aim of this study is to assess the diagnostic value of the QTc interval in detecting left ventricular diastolic dysfunction.Methods: A cross sectional study was conducted on patients with clinical suspicion of heart failure. Electrocardiographic examination was performed to obtain QTc interval (msec) using the Bazett formula. Left ventricular diastolic function was assessed using Tissue Doppler Imaging by echocardiography. Using correlation test and ROC method, the relationships between QTc interval and LV diastolic function were investigated.Results: Of 82 patients analyzed, there were 62 patients (75.9%) known to have diastolic dysfunction. The QTc interval was found to be longer in the group with diastolic dysfunction compared to the normal group (442.9±27 vs. 402.1±18.2, p &lt;0.001). There was a strong negative correlation between the QTc interval and diastolic function (r = -0.619; p &lt;0.001). Using ROC analysis, the cut off point for QTc interval was 410 ms with 91% sensitivity, 70% specificity, and 90% positive predictive value.Conclusion: The QTc interval is an accurate, simple and highly feasible electrocardiographic parameter as a screening tool to determine the presence of left ventricular diastolic dysfunction.

Methadone and the QTc Interval: Paucity of Clinically Significant Factors in a Retrospective Cohort.

Methadone is associated with prolongation of the electrocardiographic QTc interval. QTc prolongation may be linked to cardiac dysrhythmia and sudden cardiac death. The rate of these events is unknown in methadone-maintained patients. This retrospective cohort study of 749 patients with opioid use disorder receiving methadone maintenance therapy through a single safety-net hospital, queried the electronic health record for electrocardiogram results, demographics, methadone dose, and diagnostic codes consistent with cardiac conduction disorder (International Classification of Disease, Ninth Revision [ICD-9] 426) and cardiac dysrhythmia (ICD-9 427). Factors associated with QTc interval were explored; Cox proportional-hazards regression models were used to analyze time to an event that may predispose to sudden cardiac death. One hundred thirty-four patients had an electrocardiogram while on methadone, 404 while off methadone, and 211 both while on and off methadone. Mean QTc interval while on methadone (436 ms, SD 36) was significantly greater than while off methadone (423 ms, SD 33). Age and methadone dose were weakly associated with increased QTc interval (P < 0.01 and P < 0.0005, respectively, adjusted R = 0.05). There were 44 ICD-9 426 and 427 events over 7064 patient-years (6.3 events/1000 patient-yrs). Having a QTc greater than sex-specific cut-off values was significantly associated with time to event (hazard ratio 3.32, 95% confidence interval 1.25-8.81), but being on methadone was not. Methadone is associated with QTc prolongation in a nonclinically significant dose-related manner. Cardiac events were rare and the sudden cardiac death rate was below that of the general population. Current recommendations for cardiac risk assessment in methadone-maintained patients should be reconsidered.

Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

The mechanisms underlying chronic kidney disease (CKD)–associated higher risks for life-threatening ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood urea nitrogen and creatinine levels and a longer electrocardiographic QTc interval than did the sham group. Patch-clamp studies revealed epicardial (EPI)-predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to sham EPI cardiomyocytes. A significant reduction of the transient outward potassium current (Ito) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of Ito. The reduction of Ito currents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4 protein expression. Incubation of plasma electronegative low-density lipoprotein (LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of Ito via downregulation of KChIP2 proteins in the EPI region, which may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD.

Ventricular Repolarization in Patients with Decompensated Liver Cirrhosis and its Relation to the in-Hospital Outcome: Electrocardiographic Study

Background: Prolonged ventricular repolarization has been documented in patients with chronic liver disease. The objective of this study was to study the electrocardiographic QTc interval in patients with decompensated liver disease and its relation to the in-hospital outcome. Methods: We retrospectively studied 75 patients with hepatic encephalopathy. The QTc interval was measured in a 12-lead electrocardiogram obtained on admission. Results: Patients were divided into two groups according to their clinical outcome during hospitalization. The first group included 53 (70.7%) patients who survived, and the second group included 22 (29.3%) patients who died. QTc interval was significantly prolonged in died patients than patients who survived (p<0.001). There was insignificant difference between two groups regarding age, sex, smoking status, hypertension, diabetes mellitus and basal laboratory findings except for serum creatinine level (p = 0.006) and MELD score (p = 0.033). Conclusions: In patients with hepatic encephalopathy, QTc interval was significantly higher in patients who died than in patients who survived, however, in multivariate logistic regression analysis, QTc interval, was not predictors of survival.

Electrocardiographic Abnormalities and QTc Interval in Patients Undergoing Hemodialysis.

BackgroundSudden cardiac death is one of the primary causes of mortality in chronic hemodialysis (HD) patients. Prolonged QTc interval is associated with increased rate of sudden cardiac death. The aim of this article is to assess the abnormalities found in electrocardiograms (ECGs), and to explore factors that can influence the QTc interval.MethodsA total of 141 conventional HD patients were enrolled in this study. ECG tests were conducted on each patient before a single dialysis session and 15 minutes before the end of dialysis session (at peak stress). Echocardiography tests were conducted before dialysis session began. Blood samples were drawn by phlebotomy immediately before and after the dialysis session.ResultsBefore dialysis, 93.62% of the patients were in sinus rhythm, and approximately 65% of the patients showed a prolonged QTc interval (i.e., a QTc interval above 440 ms in males and above 460ms in females). A comparison of ECG parameters before dialysis and at peak stress showed increases in heart rate (77.45±11.92 vs. 80.38±14.65 bpm, p = 0.001) and QTc interval (460.05±24.53 ms vs. 470.93±24.92 ms, p<0.001). After dividing patients into two groups according to the QTc interval, lower pre-dialysis serum concentrations of potassium (K+), calcium (Ca2+), phosphorus, calcium* phosphorus (Ca*P), and higher concentrations of plasma brain natriuretic peptide (BNP) were found in the group with prolonged QTc intervals. Patients in this group also had a larger left atrial diameter (LAD) and a thicker interventricular septum, and they tended to be older than patients in the other group. Then patients were divided into two groups according to ΔQTc (ΔQTc = QTc peak-stress- QTc pre-HD). When analyzing the patients whose QTc intervals were longer at peak stress than before HD, we found that they had higher concentrations of Ca2+ and P5+ and lower concentrations of K+, ferritin, UA, and BNP. They were also more likely to be female. In addition, more cardiac construction abnormalities were found in this group. In multiple regression analyses, serum Ca2+ concentration before HD and LAD were independent variables of QTc interval prolongation. UA, ferritin, and interventricular septum were independent variables of ΔQTc.ConclusionProlonged QT interval is very common in HD patients and is associated with several risk factors. An appropriate concentration of dialysate electrolytes should be chosen depending on patients’ clinical conditions.

Validity of Electrocardiographic QT Interval in Predicting Left Ventricular Diastolic Dysfunction in Patients with Suspected Heart Failure.

To determine the validity of electrocardiographic QT interval in predicting left ventricular diastolic dysfunction in patients with suspected heart failure using echocardiogram as the gold standard. Cross-sectional validation study. AFIC-NIHD, Rawalpindi, from December 2012 to June 2013. Patients with suspected heart failure undergoing 12-lead electrocardiogram and echocardiography were inducted. All electrocardiograms were analyzed by a single trained reader unaware of the echocardiographic findings. QTc interval was calculated according to the published guidelines. All patients underwent a complete M mode, 2 dimensional, Doppler, and tissue Doppler echocardiography using aiE33 ultrasound system and diastolic dysfunction was calculated. Three hundred patients were studied. Descriptive statistics of age was 61.42 years ±10.43. Of all the patients 218 patients (72.7%) were male and 82 patients were female (27.3%). Mean QT interval (msec) was 427.29 ±54.69. One hundred and eighty patients (60.0%) had diastolic dysfunction and 120 patients (40%) had no diastolic dysfunction. The sensitivity of electrocardiographic QTc interval in predicting diastolic dysfunction was 71.11% and specificity was 88.11%. Prolonged electrocardiographic QTc interval in patients with suspected heart failure is a useful tool in predicting diastolic dysfunction.

Metabolomic patterns associated to QTc interval in shiftworkers: an explorative analysis

Objectives: 1H NMR-metabolomic approach was used to investigate QTc interval correlation with plasma metabolic profiles in shiftworkers.Methods: Socio-demographic data, electrocardiographic QTc interval and plasma metabolic profiles from 32 male shiftworkers, were correlated by multivariate regression analysis.Results: We found a positive correlation between QTc interval values, body mass index, glycemia and lactate level and a negative correlation between QTc interval and both pyroglutamate and 3-hydroxybutyrate plasma level.Conclusions: Our analysis provides evidence of the association between clinical, metabolic profiles and QTc interval values. This could be used to identify markers of early effects and/or susceptibility in shiftworkers.

Methadone Safety: A Clinical Practice Guideline From the American Pain Society and College on Problems of Drug Dependence, in Collaboration With the Heart Rhythm Society

Methadone is used for the treatment of opioid addiction and for treatment of chronic pain. The safety of methadone has been called into question by data indicating a large increase in the number of methadone-associated overdose deaths in recent years that has occurred in parallel with a dramatic rise in the use of methadone for chronic pain. The American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, commissioned an interdisciplinary expert panel to develop a clinical practice guideline on safer prescribing of methadone for treatment of opioid addiction and chronic pain. As part of the guideline development process, the American Pain Society commissioned a systematic review of various aspects related to safety of methadone. After a review of the available evidence, the expert panel concluded that measures can be taken to promote safer use of methadone. Specific recommendations include the need to educate and counsel patients on methadone safety, use of electrocardiography to identify persons at greater risk for methadone-associated arrhythmia, use of alternative opioids in patients at high risk of complications related to corrected electrocardiographic QTc interval prolongation, careful dose initiation and titration of methadone, and diligent monitoring and follow-up. Although these guidelines are based on a systematic review, the panel identified numerous research gaps, most recommendations were based on low-quality evidence, and no recommendations were based on high-quality evidence. PerspectiveThis guideline, based on a systematic review of the evidence on methadone safety, provides recommendations developed by a multidisciplinary expert panel. Safe use of methadone requires clinical skills and knowledge in use of methadone to mitigate potential risks, including serious risks related to risk of overdose and cardiac arrhythmias.

Should ranolazine be used for all patients with ischemic heart disease or only for symptomatic patients with stable angina or for those with refractory angina pectoris? A critical appraisal

Introduction: Ranolazine is a novel antianginal and anti-ischemic agent, that, unlike other available antianginal drugs in the United States (beta-blockers, organic nitrates, and calcium channel blockers), has no significant effect on either heart rate or blood pressure. Its exact mechanism of action is unknown. Ranolazine does increase electrocardiographic QTc interval in a dose-related manner, but at therapeutic doses it has no proarrhythmic effects. Ranolazine (ER) at doses of 500 and 1,000 mg twice daily is currently approved for the treatment of angina pectoris either as monotherapy or added to beta-blockers, nitrates, and calcium channel blockers. Ranolazine (ER) is currently not approved for the treatment of unstable angina, silent ischemia, or cardiac arrhythmias. The most common adverse effects reported in clinical trials during ranolazine (ER) treatment are dizziness, headaches, constipation, and nausea.Areas covered: Recent changes in ranolazine (ER) labeling have led to its increased use for treating patients with ischemic heart disease. This review addresses its appropriate use. All publications were reviewed and those relevant were included.Expert opinion: Ranolazine (ER) is an effective antianginal and anti-ischemic agent, but I restrict its use to treat patients with stable angina pectoris.

Comparison of Dexamethasone with Ondansetron or Haloperidol for Prevention of Patient‐Controlled Analgesia‐Related Postoperative Nausea and Vomiting: A Randomized Clinical Trial

Patient-controlled analgesia (PCA) with parenteral opioids is associated with a high incidence of postoperative nausea and vomiting (PONV). The aim of the present study was to compare the efficacy of dexamethasone plus haloperidol with dexamethasone plus ondansetron for the prevention of PCA-related PONV. Patients who received dexamethasone alone were used as controls. A total of 135 female patients (n = 45 in each of three groups) were eligible to participate in this randomized trial. A total of 135 female patients (n = 45 in each of three groups) were eligible to participate in this randomized trial. Dexamethasone 5 mg IV was administered after the induction of anesthesia in dexamethasone group (group D) patients. Patients in the dexamethasone plus haloperidol group (group DH) and in the dexamethasone plus ondansetron (group DO) further received haloperidol 2 mg IM or ondansetron 4 mg IV, respectively, 30 min before the end of surgery. The complete response rates, incidence of PONV, need for rescue medication, average pain and sedation scores, recovery times, and adverse events were observed postoperatively. The incidences of total PONV in the first 24 h in groups DH (35%) and DO (30%) were significantly lower than those of group D (57%) (p < 0.05 for each comparison). The differences between groups DH and DO were insignificant. The incidence of PONV was significantly smaller in the DH and DO groups than predicted by the patients’ underlying risks. Pain scores, sedation scores, and recovery times were similar among the three study groups, and no clinically relevant prolongation of the electrocardiographic QTc interval was observed in any patient. conclusions: Dexamethasone 5 mg with either haloperidol 2 mg or ondansetron 4 mg provides a better antiemetic effect than dexamethasone 5 mg alone in patients receiving postoperative morphine PCA.

SP5-33 Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the new world

IntroductionPentavalent antimonials are first-line drugs for the treatment of the cutaneous form of American tegumentary leishmaniasis. Second-line drugs include amphotericin B and pentamidine. Although these drugs have been used for...

What Can Large Simple Trials Do for Psychiatry?

What Can Large Simple Trials Do for Psychiatry?

Cisapride treatment for gastro-oesophageal reflux in children

Gastro-oesophageal reflux (GOR) is common and usually self-limiting in infants. Cisapride, a pro-kinetic agent, was commonly prescribed until reports of possible serious adverse events were associated with its use. To determine the effectiveness of cisapride versus placebo or non-surgical treatments for symptoms of GOR. We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Specialised Register and Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, reference lists of relevant review articles and searched in the Science Citation Index for all the trials identified. All searches were updated in February 2009. Randomised controlled trials comparing oral cisapride therapy with placebo or other non-surgical treatments for children diagnosed with GOR were included. We excluded trials with a majority of participants less than 28 days of age. Primary outcomes were a change in symptoms at the end of treatment, presence of adverse events, occurrence of clinical complications and weight gain. Secondary outcomes included physiological measures of GOR or histological evidence of oesophagitis. We dichotomised symptoms into 'same or worse' versus 'improved' and calculated summary odds ratios (OR). Continuous measures of GOR (for example reflux index) were summarised as a weighted mean difference. All outcomes were analysed using a random-effects method. Ten trials in total met the inclusion criteria. Nine trials compared cisapride with placebo or no treatment, of which eight (262 participants) reported data on symptoms of gastro-oesophageal reflux. There was no statistically significant difference between the two interventions (OR 0.34; 95% CI 0.10 to 1.19) for 'same or worse' versus 'improved symptoms' at the end of treatment. There was significant heterogeneity between the studies, suggesting publication bias. Four studies reported adverse events (mainly diarrhoea); this difference was not statistically significant (OR 1.80; 95% CI 0.87 to 3.70). Another trial found no difference in the electrocardiographic QTc interval after three to eight weeks of treatment. Cisapride significantly reduced the reflux index (weighted mean difference -6.49; 95% CI -10.13 to -2.85; P = 0.0005). Other measures of oesophageal pH monitoring did not reach significance. One included study compared cisapride with Gaviscon (with no statistically significant difference). One small study found no evidence of benefit on frequency of regurgitation or weight gain after treatment with cisapride versus no treatment, carob bean or corn syrup thickeners. We found no clear evidence that cisapride reduces symptoms of GOR. Due to reports of fatal cardiac arrhythmias or sudden death, from July 2000 in the USA and Europe cisapride was restricted to a limited access programme supervised by a paediatric gastrologist.

Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients

Nebulized solutions of long-acting bronchodilators provide an alternative to DPI and MDI delivery, particularly for COPD patients unable to use hand-held devices easily or correctly. The long-acting beta2-agonist, formoterol fumarate, is differentiated by its onset of significant bronchodilation within 5 min of administration. In a randomized, double-blind, double-dummy trial, COPD subjects (n=351, mean forced expiratory volume FEV1=1.3 L, 44% predicted) received nebulized formoterol fumarate (Perforomist inhalation solution; FFIS 20 microg) or DPI (Foradil Aerolizer; FA 12 microg), or placebo twice daily for 12 weeks. Efficacy was assessed with 12-h pulmonary function tests, and quality of life was assessed before and after treatment with the St. George's Respiratory Questionnaire (SGRQ). At the 12-week endpoint, FFIS significantly increased FEV1 AUC0-12h relative to placebo (p<0.0001). No evidence of tachyphylaxis was observed as indicated by maintained FEV1 AUC and reduced rescue albuterol use throughout treatment. FFIS also significantly increased peak FEV1, trough FEV1, and standardized FVC AUC0-12h compared with placebo. SGRQ assessment at Week 12 demonstrated significant and clinically meaningful improvements in total score (FFIS vs placebo, -4.9, p=0.0067), symptom, and impact scores. No significant differences in efficacy were observed between the two active treatments. Drug related AEs in the FFIS arm with a frequency > or = 1% and exceeding placebo were dry mouth, nausea, and insomnia. Nebulized FFIS provided significant improvement in respiratory status and quality of life in subjects with COPD relative to placebo and was well tolerated. The efficacy and safety profile of FFIS was comparable to FA DPI.