Multiple-crossover Trial Research Articles

N-of-1 trials in epilepsy: A systematic review and lessons paving the way forward.

Defined as prospective single-patient crossover studies with repeated paired cycles of active and control intervention, N-of-1 trials have gained attention as an option to obtain high-quality evidence of efficacy, particularly for patients with rare epilepsies in whom conduction of well-powered randomized controlled trials can be challenging. The objective of this systematic review is to provide an appraisal of the literature on N-of-1 trials in individuals with epilepsy. We searched PubMed and Embase on January 12, 2024, for studies meeting the following criteria: prospectively planned, within-patient, multiple-crossover design in individuals with epilepsy and outcomes related to comorbidities. Information on design, outcome measurements, intervention, and analyses was retrieved. Risk of bias assessment was performed using the Risk of Bias in N-of-1 Trials (RoBiNT) scale. We highlighted methodological aspects of the N-of-1 trials identified and discuss future recommendations. Five studies met our inclusion criteria. An additional multiple-crossover trial that evaluated treatment effects exclusively at group level was also included because of its relevance to N-of-1 study methodology. The studies enrolled individuals with focal seizures, absences or cognitive impairement and electrographic discharges. Treatments included established or investigational antiseizure medications, off-label medications, neurostimulation or lifestyle intervention. Three of the five N-of-1 trials reported on individual cases. The studies' strengths were the use of individualized treatment dosages and symptom-specific patient-reported outcomes. Limitations were related to minimal reporting of baseline characteristics and seizure burden. The trials identified by our search exemplify how the N-of-1 design can be applied to assess interventions in individuals with epilepsy-related disorders. Future N-of-1 trials of antiseizure interventions should take into account baseline seizure frequency, should apply statistical models suited to capture seizure frequency changes reliably and make predefined interim assessments. Non-seizure outcome measures evaluable over short periods should be considered. Tailored N-of-1 methodology could pave the way to evidence-based, treatment selection for patients with rare epilepsies.

Video Laryngoscopy vs Direct Laryngoscopy for Endotracheal Intubation in the Operating Room

Endotracheal tubes are typically inserted in the operating room using direct laryngoscopy. Video laryngoscopy has been reported to improve airway visualization; however, whether improved visualization reduces intubation attempts in surgical patients is unclear. To determine whether the number of intubation attempts per surgical procedure is lower when initial laryngoscopy is performed using video laryngoscopy or direct laryngoscopy. Cluster randomized multiple crossover clinical trial conducted at a single US academic hospital. Patients were adults aged 18 years or older having elective or emergent cardiac, thoracic, or vascular surgical procedures who required single-lumen endotracheal intubation for general anesthesia. Patients were enrolled from March 30, 2021, to December 31, 2022. Data analysis was based on intention to treat. Two sets of 11 operating rooms were randomized on a 1-week basis to perform hyperangulated video laryngoscopy or direct laryngoscopy for the initial intubation attempt. The primary outcome was the number of operating room intubation attempts per surgical procedure. Secondary outcomes were intubation failure, defined as the responsible clinician switching to an alternative laryngoscopy device for any reason at any time, or by more than 3 intubation attempts, and a composite of airway and dental injuries. Among 8429 surgical procedures in 7736 patients, the median patient age was 66 (IQR, 56-73) years, 35% (2950) were women, and 85% (7135) had elective surgical procedures. More than 1 intubation attempt was required in 77 of 4413 surgical procedures (1.7%) randomized to receive video laryngoscopy vs 306 of 4016 surgical procedures (7.6%) randomized to receive direct laryngoscopy, with an estimated proportional odds ratio for the number of intubation attempts of 0.20 (95% CI, 0.14-0.28; P < .001). Intubation failure occurred in 12 of 4413 surgical procedures (0.27%) using video laryngoscopy vs 161 of 4016 surgical procedures (4.0%) using direct laryngoscopy (relative risk, 0.06; 95% CI, 0.03-0.14; P < .001) with an unadjusted absolute risk difference of -3.7% (95% CI, -4.4% to -3.2%). Airway and dental injuries did not differ significantly between video laryngoscopy (41 injuries [0.93%]) vs direct laryngoscopy (42 injuries [1.1%]). In this study among adults having surgical procedures who required single-lumen endotracheal intubation for general anesthesia, hyperangulated video laryngoscopy decreased the number of attempts needed to achieve endotracheal intubation compared with direct laryngoscopy at a single academic medical center in the US. Results suggest that video laryngoscopy may be a preferable approach for intubating patients undergoing surgical procedures. ClinicalTrials.gov Identifier: NCT04701762.

Best Practice Alerts: A Poke in the Eye or an Efficient Method for Safer Prescribing?

Best Practice Alerts: A Poke in the Eye or an Efficient Method for Safer Prescribing?

Influence of food matrix delivery system on the bioavailability of vitamin D3: A randomized crossover trial in postmenopausal women

ObjectivesVitamin D insufficiency (blood 25-hydroxyvitamin D <50 nmol/L) is a global health problem. Vitamin D food fortification might be a solution, but knowledge is sparse on which food matrices yield the highest bioavailability. The aim of this study was to investigate the influence of different food matrices including complex formations with whey proteins on the human bioavailability of vitamin D. MethodsIn this randomized, multiple crossover trial, we enrolled 30 postmenopausal women 60 to 80 y of age with vitamin D insufficiency. We measured changes in serum concentrations of vitamin D3 (D3) postprandially for 24 h in response to the intake of 500 mL of different food matrices with 200 µg D3 added compared with a control (500 mL of water). Foods included apple juice with whey protein isolate (WPI), apple juice, semi-skim milk, and water (with D3). The food matrices were provided in a randomized order with ≥10-d washout period between them. On each intervention day, blood samples were collected at 0, 2, 4, 6, 8, 10, 12 and 24 h. ResultsD3 with WPI in juice did not enhance area under the curve (AUC) of serum D3 compared with juice without WPI (370 nmol × 24 h/L; 95% confidence interval [CI], 321–419 versus 357 nmol × 24 h/L; 95% CI, 308–406 nmol × 24 h/L; P = 0.65). However, compared with juice, the AUC was significantly higher in response to the intake of D3 in milk (452 nmol × 24 h/L; 95% CI, 402–502 nmol × 24 h/L) and water with D3 (479 nmol × 24 h/L; 95% CI, 430–527 nmol × 24 h/L; P < 0.05). No difference was observed between milk and water (P = 0.34). ConclusionsThe bioavailability of D3 was superior in milk and water compared with juice, regardless of whether WPI was added.

LACTATED RINGER'S VS SALINE AMONG CRITICALLY ILL ADULTS WITH CIRRHOSIS: A SECONDARY ANALYSIS OF THE ISOTONIC SOLUTIONS AND MAJOR ADVERSE RENAL EVENTS TRIAL

TOPIC: Critical Care TYPE: Original Investigations PURPOSE: The use of balanced crystalloids has been suggested to improve clinical outcomes among critically ill adults, compared to saline. However, some balanced crystalloids, such as lactated Ringer’s, include a significant concentration of lactate that could adversely impact patients with cirrhosis, who have an impaired ability to metabolize lactate. The purpose of this study was to determine, among critically ill patients with cirrhosis, the effect of lactated Ringer's, compared to saline, on plasma lactate levels, cirrhosis-related complications, and clinical outcomes. METHODS: We performed a secondary analysis of Isotonic Solutions and Major Adverse Renal Events Trial (SMART) using data from patients admitted to the medical intensive care unit with cirrhosis. A diagnosis of cirrhosis was determined using a screening algorithm that employed ICD-10 codes, followed by manual confirmation through chart review. SMART was a cluster-randomized, multiple-crossover trial that compared balanced crystalloids to saline for intravenous fluid administration among critically ill adults. The primary outcome of the SMART trial and this secondary analysis was major adverse kidney events (MAKE30), a composite of new renal replacement therapy, persistent renal dysfunction, or death. Secondary outcomes included plasma lactate levels and cirrhosis-related complications such as new ascites, variceal and nonvariceal bleeding, hepatorenal syndrome Type 1, hepatic encephalopathy, spontaneous bacterial peritonitis, or cerebral edema. Outcomes were compared using Pearson Chi-square test for categorical variables and Mann-Whitney U test for continuous variables. RESULTS: Of the 15,802 patients enrolled in SMART, 375 patients were admitted to the medical intensive care unit with a diagnosis of cirrhosis. Among the 169 patients with cirrhosis in the lactated Ringer’s group, 47 (28%) had a major adverse kidney event, compared to 78 (38%) of the 206 patients in the saline group (P = 0.04). In the lactated Ringer’s group, 31 patients (18%) developed a cirrhosis-related complication versus 46 (22%) in the saline group (P = 0.34). There was no significant difference in lactate levels between the two groups (P = 0.74). CONCLUSIONS: Among critically ill adults with cirrhosis in the medical intensive care unit, the use of lactated Ringer’s resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline. There was no significant difference in cirrhosis-related complications or lactate levels between the two groups. CLINICAL IMPLICATIONS: Lactated Ringer’s appears to be associated with improved clinical outcomes compared to saline and may be the crystalloid of choice for many critically ill adults with cirrhosis. DISCLOSURES: No relevant relationships by Jonathan Casey, source=Web Response No relevant relationships by Taylor Coston, source=Web Response No relevant relationships by Muhammad Hashim Hayat, source=Web Response No relevant relationships by Michael Koenig, source=Web Response No relevant relationships by Rishi Naik, source=Web Response No relevant relationships by Matthew Semler, source=Web Response No relevant relationships by Li Wang, source=Web Response

Physiological impact of wearing a surgical face mask during walking in the COVID-19 pandemic

Background and Study Aim. Common use of surgical face masks is recommended for social and individual health due to the COVID-19 pandemic. However, there is no systematic report for responses of organism to wearing a surgical face mask during different exercises. In this context the purpose of this study was to examine the impacts of wearing a surgical face mask during a one-hour brisk walking.&#x0D; Material and Methods. A total of thirty male (n=16) and female (n=14) volunteers (mean age and BMI of 32±1.07 years and 25.1±0.68 kg/m2, respectively) completed the protocol. This was a multiple cross-over trial for healthy volunteers. All participants took a one-hour brisk walking with and without a surgical face mask. Specific physiological measurements (HR - heart rate; BP - blood pressure, SaO2 - arterial oxygen content) were compared before and immediately after two brisk walking. Each subject served their own control.&#x0D; Results. The evaluation found that there was no statistically significant difference between the mean HR and blood pressure values during the brisk walking with and without a surgical face mask, while there was a statistically significant difference in the SaO2 values on behalf of no-mask-walking (p&lt;0.05).&#x0D; Conclusions. The use of surgical face masks in healthy volunteers causes a decrease in SaO2 during brisk walking. However, it does not affect the mean pulse rate and blood pressure. Although there was a statistically significant decrease in the SaO2 parameter during mask-walking, it is possible to state that brisk walking with a surgical face mask does not have a physiologically negative impact, because this decrease is in ranges that are accepted to be normal.

Tolerability and efficacy of two doses of aerosolized albuterol in ventilated infants with BPD: A randomized controlled crossover trial.

Aerosolized albuterol is widely used, but its tolerability and efficacy in infants with severe bronchopulmonary dysplasia (sBPD) is not well established. To compare the tolerability and efficacy of two dose levels of aerosolized albuterol to saline placebo in infants with sBPD. Single-center, multiple-crossover trial in 24 ventilated very preterm infants with sBPD. Albuterol (1.25 mg, 2.5 mg) and 3 ml of normal saline were administered every 4 h during separate 24-htreatment periods assigned in random order with a 6-hwashout phase between periods. The primary outcome was the absolute change (post and pretherapy) in expiratory flow at 75% of exhalation (EF75). Secondary endpoints were changes in ventilator parameters, vital signs, and heart arrhythmia. Average within subject EF75 values improved with each therapy: saline placebo ( + 0.45 L/min ± 2.5, p = .04), 1.25 mg of albuterol ( + 0.70 L/min ± 2.4, p < .001), and 2.5 mg of albuterol ( + 0.38 L/min ± 2.4, p = .06). However, 1.25 mg of albuterol (0.26 L/min; 95% CI -0.19, 0.72) and 2.5 mg (-0.10 L/min; 95% CI -0.77, 0.57) produced similar changes in EF75 when compared to saline. All secondary outcomes were similar between saline and 1.25 mg of albuterol. Peak inspiratory pressure needed to deliver goal tidal volumes (7.5% relative decrease, 95% CI 2.6, 12.3) and heart rate (6.5% increase, 95% CI 2.2, 10.8) differed significantly between albuterol 2.5 mg and saline. Albuterol at 1.25 mg and 2.5 mg, compared to aerosolized saline, did not affect EF75 in infants with sBPD receiving invasive ventilation. Greater improvement in peak inspiratory pressures with albuterol 2.5 mg suggests benefit, but close heart monitoring may be indicated.

Time to First Culture Positivity for Gram-Negative Rods Resistant to Ceftriaxone in Critically Ill Adults.

The optimal timing for the de-escalation of broad-spectrum antibiotics with activity against Pseudomonas aeruginosa and resistant Gram-negative rods (GNRs) in critically ill adults remains unknown. We tested the hypothesis that cultures will identify GNRs that ultimately demonstrate resistance to ceftriaxone within 48 hours, potentially allowing safe de-escalation at this time point. We conducted a secondary analysis of data from the Isotonic Solutions and Major Adverse Renal Events Trial: a pragmatic, cluster-randomized, multiple-crossover trial comparing balanced crystalloids versus saline for intravenous fluid administration in 15,802 critically ill adults at 5 intensive care units (ICUs) at Vanderbilt University Medical Center in Nashville, TN, USA. The primary endpoint was the time-to-positivity of respiratory and blood cultures that ultimately demonstrated growth of GNRs resistant to ceftriaxone. Multivariable logistic regression modeling was used to examine risk factors for the growth of cultures after 48 hours. A total of 524 respiratory cultures had growth of GNRs, of which 284 (54.2%) had resistance to ceftriaxone. A total of 376 blood cultures grew GNRs, of which 70 (18.6%) had resistance to ceftriaxone. At 48 hours, 87% of respiratory cultures and 85% of blood cultures that ultimately grew GNRs resistant to ceftriaxone had demonstrated growth. Age, gender, predicted risk of inpatient mortality and prior use of antibiotics did not predict the growth of cultures after 48 hours. Among a cohort of critically ill adults, 13% of respiratory cultures and 15% of blood cultures that ultimately grew GNRs resistant to ceftriaxone did not demonstrate growth until at least 48 hours after collection. Further work is needed to determine the ideal time for critically ill adults to de-escalate from broad-spectrum antibiotics targeting Pseudomonas aeruginosa and extended-spectrum β-lactamase-producing gram-negative pathogens.

Return to training in the COVID‐19 era: The physiological effects of face masks during exercise

COVID‐19 outbreak has a profound impact on almost every aspect of life. Universal masking is recommended as a means of source control. Routinely exercising in a safe environment is an important strategy for healthy living during this crisis. As sports clubs and public spaces may serve a source of viral transmission, masking may become an integral part of physical activity. This study aimed to assess the physiological effects of wearing surgical masks and N95 respirators during short‐term strenuous workout. This was a multiple cross‐over trial of healthy volunteers. Using a standard cycle ergometry ramp protocol, each subject performed a maximal exercise test without a mask, with a surgical mask, and with an N95 respirator. Physiological parameters and time to exhaustion were compared. Each subject served his own control. Sixteen male volunteers (mean age and BMI of 34 ± 4 years and 28.72 ± 3.78 kg/m2, respectively) completed the protocol. Heart rate, respiratory rate, blood pressure, oxygen saturation, and time to exhaustion did not differ significantly. Exercising with N95 mask was associated with a significant increase in end‐tidal carbon dioxide (EtCO2) levels. The differences were more prominent as the load increased, reaching 8 mm Hg at exhaustion (none vs N95, P = .001). In conclusion, in healthy subjects, short‐term moderate‐strenuous aerobic physical activity with a mask is feasible, safe, and associated with only minor changes in physiological parameters, particularly a mild increase in EtCO2. Subjects suffering from lung diseases should have a cautious evaluation before attempting physical activity with any mask.

Effect of dried fruit on postprandial glycemia: a randomized acute-feeding trial

Background/ObjectivesTo investigate the effect of dried fruit in modifying postprandial glycemia, we assessed the ability of 4 dried fruits (dates, apricots, raisins, sultanas) to decrease postprandial glycemia through three mechanisms: a glycemic index (GI) effect, displacement effect, or ‘catalytic’ fructose effect.Subjects/MethodsWe conducted an acute randomized, multiple-crossover trial in an outpatient setting in 10 healthy adults. Participants received 3 white bread control meals and 12 dried fruit test meals in random order. The test meals included each of 4 dried fruits (dates, apricots, raisins, sultanas) alone (GI effect), 4 of the dried fruits displacing half the available carbohydrate in white bread (displacement effect), or 4 of the dried fruits providing a small ‘catalytic’ dose (7.5 g) of fructose added to white bread (‘catalytic’ fructose effect). The protocol followed the ISO method for the determination of GI (ISO 26642:2010). The primary outcome was mean ± SEM GI (glucose scale) for ease of comparison across the three mechanisms.ResultsTen healthy participants (7 men, 3 women; mean ± SD age and BMI: 39 ± 12 years and 25 ± 2 kg/m2) were recruited and completed the trial. All dried fruit had a GI below that of white bread (GI = 71); however, only dried apricots (GI = 42 ± 5), raisins (GI = 55 ± 5), and sultanas (51 ± 4) showed a significant GI effect (P < 0.05). When displacing half the available carbohydrate in white bread, all dried fruit lowered the GI; however, only dried apricots (GI = 57 ± 5) showed a significant displacement effect (P = 0.025). None of the dried fruits showed a beneficial ‘catalytic’ fructose effect.ConclusionsIn conclusion, dried fruits have a lower GI and reduce the glycemic response of white bread through displacement of half of the available carbohydrate. Longer-term randomized trials are needed to confirm whether dried fruit can contribute to sustainable improvements in glycemic control.Trial registrationClinicalTrials.gov identifier, NCT02960373

Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized, multiple crossover trial.

Retrospective clinical data and case studies support a therapeutic effect of ketamine in suppression of spreading depolarization (SD) following brain injury. Preclinical data strongly support efficacy in terms of frequency of SD as well as recovery from electrocorticography (ECoG) depression. The authors present the results of the first prospective controlled clinical trial testing the role of ketamine used for clinical sedation on occurrence of SD. Ten patients with severe traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH) were recruited for this pilot trial. A standard ECoG strip was placed at the time of craniotomy, and the patients were then placed on an alternating every-6-hour schedule of ketamine or other sedation agent. The order of treatment was randomized. The ketamine dose was adjusted to clinical effect or maintained at a subanesthetic basal dose (0.1 mg/kg/hr) if no sedation was required. SD was scored using standard criteria, blinded to ketamine dosing. Occurrence of SD was compared with the hourly dose of ketamine to determine the effect of ketamine on SD occurrence. Successful ECoG recordings were obtained in all 10 patients: 8 with SAH and 2 with TBI. There were a total of 1642 hours of observations with adequate ECoG: 833 hours off ketamine and 809 hours on ketamine. Analysis revealed a strong dose-dependent effect such that hours off ketamine or on doses of less than 1.15 mg/kg/hr were associated with an increased risk of SD compared with hours on doses of 1.15 mg/kg/hr or more (OR 13.838, 95% CI 1.99-1000). This odds ratio decreased with lower doses of 1.0 mg/kg/hr (OR 4.924, 95% CI 1.337-43.516), 0.85 mg/kg/hr (OR 3.323, 95% CI 1.139-16.074), and 0.70 mg/kg/hr (OR 2.725, 95% CI 1.068-9.898) to a threshold of no effect at 0.55 mg/kg/hr (OR 1.043, 95% CI 0.565-2.135). When all ketamine data were pooled (i.e., on ketamine at any dose vs off ketamine), a nonsignificant overall trend toward less SD during hours on ketamine (χ2 = 3.86, p = 0.42) was observed. Ketamine effectively inhibits SD over a wide range of doses commonly used for sedation, even in nonintubated patients. These data also provide the first prospective evidence that the occurrence of SD can be influenced by clinical intervention and does not simply represent an unavoidable epiphenomenon after injury. These data provide the basis for future studies assessing clinical improvement with SD-directed therapy.Clinical trial registration no.: NCT02501941 (clinicaltrials.gov).

Balanced Crystalloids versus Saline in Critically Ill Adults

BackgroundBoth balanced crystalloids and saline are used for intravenous fluid administration in critically ill adults, but it is not known which results in better clinical outcomes.MethodsIn a pragmatic, cluster-randomized, multiple-crossover trial conducted in five intensive care units at an academic center, we assigned 15,802 adults to receive saline (0.9% sodium chloride) or balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) according to the randomization of the unit to which they were admitted. The primary outcome was a major adverse kidney event within 30 days — a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) — all censored at hospital discharge or 30 days, whichever occurred first.ResultsAmong the 7942 patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04). In-hospital mortality at 30 days was 10.3% in the balanced-crystalloids group and 11.1% in the saline group (P=0.06). The incidence of new renal-replacement therapy was 2.5% and 2.9%, respectively (P=0.08), and the incidence of persistent renal dysfunction was 6.4% and 6.6%, respectively (P=0.60).ConclusionsAmong critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SMART-MED and SMART-SURG ClinicalTrials.gov numbers, NCT02444988 and NCT02547779.)

Balanced Crystalloids versus Saline in Noncritically Ill Adults

BackgroundComparative clinical effects of balanced crystalloids and saline are uncertain, particularly in noncritically ill patients cared for outside an intensive care unit (ICU).MethodsWe conducted a single-center, pragmatic, multiple-crossover trial comparing balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) with saline among adults who were treated with intravenous crystalloids in the emergency department and were subsequently hospitalized outside an ICU. The type of crystalloid that was administered in the emergency department was assigned to each patient on the basis of calendar month, with the entire emergency department crossing over between balanced crystalloids and saline monthly during the 16-month trial. The primary outcome was hospital-free days (days alive after discharge before day 28). Secondary outcomes included major adverse kidney events within 30 days — a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) — all censored at hospital discharge or 30 days, whichever occurred first.ResultsA total of 13,347 patients were enrolled, with a median crystalloid volume administered in the emergency department of 1079 ml and 88.3% of the patients exclusively receiving the assigned crystalloid. The number of hospital-free days did not differ between the balanced-crystalloids and saline groups (median, 25 days in each group; adjusted odds ratio with balanced crystalloids, 0.98; 95% confidence interval [CI], 0.92 to 1.04; P=0.41). Balanced crystalloids resulted in a lower incidence of major adverse kidney events within 30 days than saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P=0.01).ConclusionsAmong noncritically ill adults treated with intravenous fluids in the emergency department, there was no difference in hospital-free days between treatment with balanced crystalloids and treatment with saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SALT-ED ClinicalTrials.gov number, NCT02614040.)

Balanced Crystalloids vs Saline for Critically Ill Adults

SESSION TITLE: Late-Breaking Abstracts 1 SESSION TYPE: Late-Breaking Abstract Slide PRESENTED ON: Tuesday, October 31, 2017 at 02:45 PM - 04:15 PM PURPOSE: Saline is the intravenous fluid most commonly administered to critically ill adults, but may be associated with acute kidney injury and death. The purpose of this study was to determine the effect of balanced crystalloids compared to saline on patient outcomes. METHODS: In a pragmatic, cluster-randomized, multiple-crossover trial in five intensive care units at a single academic center, we assigned 15802 adults to receive saline (0.9% sodium chloride) or balanced crystalloids (lactated Ringer’s solution or Plasmalyte A) for intravenous fluid administration, according to the randomization assignment of the unit to which they were admitted. The primary outcome was Major Adverse Kidney Events within 30 days (MAKE30), the composite of death, new renal replacement therapy, or persistent creatinine elevation ≥ 200% of baseline. RESULTS: Patients in the balanced crystalloid group received a median of 1470 mL [IQR 100 – 3625 mL] of balanced crystalloid and 0 mL [IQR 0 – 0 mL] of saline (P<0.001), whereas patients in the saline group received a median of 0 mL [IQR 0 – 100 mL] of balanced crystalloid and 1180 mL [IQR 125 – 300 mL] of saline (P<0.001). A total of 1,139 patients (14.3%) in the balanced crystalloid group experienced the primary outcome of MAKE30, compared with 1,211 patients (15.4%) in the saline group (adjusted odds ratio, 0.90; 95% confidence interval, 0.82 to 0.99; P=0.04). A total of 818 patients (10.3%) in the balanced crystalloid group died prior to hospital discharge or 30 days, compared with 875 (11.1%) in the saline group (adjusted odds ratio, 0.90; 95% confidence interval, 0.80 to 1.01; P=0.06). CONCLUSIONS: Among critically ill adults, use of balanced crystalloids for intravenous fluid administration reduced the composite of death, new renal replacement therapy, and persistent renal dysfunction compared with use of saline. (SMART-MED and SMART-SURG ClinicalTrials.gov numbers, NCT02444988 and NCT02547779.) CLINICAL IMPLICATIONS: Using balanced crystalloids rather than saline for intravenous fluid administration among critically ill adults can reduce the incidence of death, new renal replacement therapy, or persistent renal dysfunction. No Product/Research Disclosure Information

Saline versus balanced crystalloids for intravenous fluid therapy in the emergency department: study protocol for a cluster-randomized, multiple-crossover trial

BackgroundPrior studies in critically ill patients suggest the supra-physiologic chloride concentration of 0.9% (“normal”) saline may be associated with higher risk of renal failure and death compared to physiologically balanced crystalloids. However, the comparative effects of 0.9% saline and balanced fluids are largely unexamined among patients outside the intensive care unit, who represent the vast majority of patients treated with intravenous fluids.Methods/designThis study, entitled Saline Against Lactated Ringer’s or Plasma-Lyte in the Emergency Department (SALT-ED), is a pragmatic, cluster, multiple-crossover trial at a single institution evaluating clinical outcomes of adults treated with 0.9% saline versus balanced crystalloids for intravenous fluid resuscitation in the emergency department. All adults treated in the study emergency department receiving at least 500 mL of isotonic crystalloid solution during usual clinical care and subsequently hospitalized outside the intensive care unit are included. Treatment allocation of 0.9% saline versus balanced crystalloids is assigned by calendar month, with study patients treated during the same month assigned to the same fluid type. The first month (January 2016) was randomly assigned to balanced crystalloids, with each subsequent month alternating between 0.9% saline and balanced crystalloids. For balanced crystalloid treatment, clinicians can choose either Lactated Ringer’s or Plasma-Lyte A©. The study period is set at 16 months, which will result in an anticipated estimated sample size of 15,000 patients. The primary outcome is hospital-free days to day 28, defined as the number of days alive and out of the hospital from the index emergency department visit until 28 days later. Major secondary outcomes include proportion of patients who develop acute kidney injury by creatinine measurements; major adverse kidney events by hospital discharge or day 30 (MAKE30), which is a composite outcome of death, new renal replacement therapy, and persistent creatinine elevation >200% of baseline; and in-hospital mortality.DiscussionThis ongoing pragmatic trial will provide the most comprehensive evaluation to date of clinical outcomes associated with 0.9% saline compared to physiologically balanced fluids in patients outside the intensive care unit.Trial registrationClinicalTrials.gov, NCT02614040. Registered on 18 November 2015.

Balanced crystalloids versus saline in the intensive care unit: study protocol for a cluster-randomized, multiple-crossover trial

BackgroundSaline, the intravenous fluid most commonly administered to critically ill adults, contains a high chloride content, which may be associated with acute kidney injury and death. Whether using balanced crystalloids rather than saline decreases the risk of acute kidney injury and death among critically ill adults remains unknown.MethodsThe Isotonic Solutions and Major Adverse Renal Events Trial (SMART) is a pragmatic, cluster-level allocation, cluster-level crossover trial being conducted between 1 June 2015 and 30 April 2017 in five intensive care units at Vanderbilt University Medical Center in Nashville, TN, USA. SMART compares saline (0.9% sodium chloride) with balanced crystalloids (clinician’s choice of lactated Ringer’s solution or Plasma-Lyte A®). Each intensive care unit is assigned to provide either saline or balanced crystalloids each month, with the assigned crystalloid alternating monthly over the course of the trial. All adults admitted to participating intensive care units during the study period are enrolled and followed until hospital discharge or 30 days after enrollment. The anticipated enrollment is approximately 14,000 patients. The primary outcome is Major Adverse Kidney Events within 30 days—the composite of in-hospital death, receipt of new renal replacement therapy, or persistent renal dysfunction (discharge creatinine ≥200% of baseline creatinine). Secondary clinical outcomes include in-hospital mortality, intensive care unit-free days, ventilator-free days, vasopressor-free days, and renal replacement therapy-free days. Secondary renal outcomes include new renal replacement therapy receipt, persistent renal dysfunction, and incidence of stage 2 or higher acute kidney injury.DiscussionThis ongoing pragmatic trial will provide the largest and most comprehensive comparison to date of clinical outcomes with saline versus balanced crystalloids among critically ill adults.Trial registrationFor logistical reasons, SMART was prospectively registered separately for the medical ICU (SMART-MED; ClinicalTrials.gov identifier: NCT02444988; registered on 11 May 2015; date of first patient enrollment: 1 June 2015) and the nonmedical ICUs (SMART-SURG; ClinicalTrials.gov identifier: NCT02547779; registered on 9 September 2015; date of first patient enrollment: 1 October 2015).

Famotidine, a Histamine H2 Receptor Antagonist, Does Not Reduce Levodopa‐Induced Dyskinesia in Parkinson's Disease: A Proof‐of‐Concept Study

The neural mechanisms underlying levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) may involve histamine (H2) receptors on striatopallidal pathways. We recently demonstrated that the clinically available oral histamine H2 receptor antagonist (H2 RA), famotidine, can reduce l-dopa-induced chorea in MPTP-lesioned macaques. We hypothesized that famotidine may be useful in the treatment of LID in PD patients. We performed a proof-of-concept, double-blind, randomized, multiple cross-over (4×) trial. Seven PD subjects with bothersome dyskinesia were randomized to oral famotidine 80, 120, and 160mg/day and placebo. Each subject was randomized to receive each of the four treatment phases for 14days followed by a 7-day wash-out period between each treatment phase. The primary outcome measure was change in the Unified Dyskinesia Rating Scale (UDysRS; part III) between placebo and famotidine. Secondary outcomes were UDysRS (parts I and II), Global Impression of Change, Lang-Fahn Activities of Daily Living Dyskinesia Scale, Unified Parkinson's Disease Rating part III, and adverse events (AEs). Outcomes were evaluated pre- and post-treatment per dose and analyzed using a mixed-effects linear model. There was no significant effect of famotidine treatment on any of the primary or secondary outcome measures compared to placebo (each dose and all doses combined). There were no significant AEs. Even though the sample size of the current study is limited, famotidine seems to be safe in patients with PD and LID, but showed no potential as an antidyskinetic agent.

Oral bioavailability of dabigatran etexilate (Pradaxa®) after co‐medication with verapamil in healthy subjects

To investigate the effect of the P-glycoprotein inhibitor verapamil on the pharmacokinetics and pharmacodynamics of dabigatran etexilate (DE). In this two part multiple crossover trial in 40 healthy subjects, DE 150 mg was given alone or with verapamil at different doses, duration of treatment (single vs. multiple dosing), formulations, and timings (before, concurrently or after DE). Primary pharmacokinetic endpoints were determined from concentrations of total dabigatran (unconjugated plus conjugated). Pharmacodynamic endpoints were determined from clotting time. The greatest effect was observed with single dose verapamil 120 mg immediate release given 1 h before single dose DE. Geometric mean area under the plasma concentration curve [AUC(0,∞)] and maximum analyte concentration in the plasma (Cmax ) were increased by 143% [90% confidence interval (CI) 91, 208] and 179% (90% CI 115, 262), respectively. The effect was reduced to a 71% and 91% increase in AUC and Cmax , respectively, when DE was administered with verapamil 240 mg extended release. After multiple verapamil dosing, DE AUC(0,∞) and Cmax increases were 54% and 63%, respectively. However, DE given 2 h before verapamil increased DE AUC(0,∞) and Cmax by <20%. With regard to clotting prolongation, the dabigatran plasma concentration-effect relationship was generally not affected by the co-administration of verapamil. Concomitant administration of DE and verapamil did not reveal any unexpected safety findings. Verapamil increased DE bioavailability, likely due to inhibition of P-glycoprotein. Our results suggest that an interaction between verapamil and DE can be minimized if DE is administered 2 h prior to verapamil.

Simvastatin decreases levodopa-induced dyskinesia in monkeys, but not in a randomized, placebo-controlled, multiple cross-over (“n-of-1”) exploratory trial of simvastatin against levodopa-induced dyskinesia in Parkinson's disease patients

BackgroundSimvastatin may improve levodopa-induced dyskinesia through striatal Ras-extracellular signal-regulated kinase pathway modulation. Methods(1) Six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques were assessed for parkinsonism and dyskinesia severity following acute co-administration of levodopa and simvastatin (0, 1.5, 3 and 6 mg/kg). (2) A “n-of-1” design randomized, placebo-controlled, 3 cross-over trial was then conducted in 10 Parkinson's disease patients with troublesome dyskinesia. The primary endpoint was a 7-point scale rating subjective discomfort caused by troublesome dyskinesia. Secondary endpoints related to dyskinesia severity and duration and functional impairment, severity and duration of OFF periods, motor scores and investigator- and patient-rated global impressions. (3) The pharmacodynamic variable for both studies consisted in a multiplex analysis of kinase-induced phosphorylation in T and B-lymphocytes by flow cytometry. Results(1) In the macaque, simvastatin reduced dyskinesia scores (45%), at the dose of 3 mg/kg (2) In the “n-of-1” trial no significant response was observed in the primary end point and all secondary endpoints. No serious adverse events were reported. (3) Simvastatin 3 mg/kg significantly reduce kinase-induced phosphorylation in monkeys but not simvastatin 40 mg in patients. ConclusionsSimvastatin reduced dyskinesia in primates using high doses over 3 mg/kg but the exploratory trial in patients revealed no effect at 40 mg/d suggesting that higher doses, not compatible with a safe prolonged administration, are necessary.

Discomfort and Exertion Associated with Prolonged Wear of Respiratory Protection in a Health Care Setting

The nature of discomfort and level of exertion associated with wearing respiratory protection in the health care workplace are not well understood. Although a few studies have assessed these topics in a laboratory setting, little is known about the magnitude of discomfort and the level of exertion experienced by workers while they deliver health care to patients for prolonged periods. The purpose of this study was to determine the magnitude of discomfort and level of exertion experienced by health care workers while wearing respiratory protection for periods up to 8 hr when performing their typical occupational duties. This project was a multiple cross-over field trial of 27 health care workers, aged 24–65, performing their typical, hospital-based occupational duties. Each participant served as his/her own control and wore one of seven respirators or a medical mask for 8 hr (or as long as tolerable) with interposed doffing periods every 2 hr. Self-perceived discomfort and exertion were quantified before each doffing: self-perceived level of discomfort using a visual analog scale, and self-perceived level of exertion using a Borg scale. Overall, and as would be expected, discomfort increased over time with continual respirator use over an 8-hr period. Interestingly, exertion increased only marginally over the same time period. The relatively low level of exertion associated with eight respiratory protective devices, including models commonly used in the U.S. health care workplace, is not likely to substantially influence workers’ tolerability or occupational productivity. However, the magnitude of discomfort does appear to increase significantly over time with prolonged wear. These results suggest that respirator-related discomfort, but not exertion, negatively influences respirator tolerance over prolonged periods. Discomfort may also interfere with the occupational duties of workers.