Thromboprophylaxis using combined intermittent pneumatic compression and pharmacologic prophylaxis versus pharmacologic prophylaxis alone in critically ill patients: study protocol for a randomized controlled trial

Abstract Background Venous thromboembolism (VTE) remains a common problem in critically ill patients. Pharmacologic prophylaxis is currently the standard of care based on high-level evidence from randomized controlled trials. However, limited evidence exists regarding the effectiveness of intermittent pneumatic compression (IPC) devices. The Pneumatic compREssion for preventing VENous Thromboembolism (PREVENT trial) aims to determine whether the adjunct use of IPC with pharmacologic prophylaxis compared to pharmacologic prophylaxis alone in critically ill patients reduces the risk of VTE. Methods/Design The PREVENT trial is a multicenter randomized controlled trial, which will recruit 2000 critically ill patients from over 20 hospitals in three countries. The primary outcome is the incidence of proximal lower extremity deep vein thrombosis (DVT) within 28 days after randomization. Radiologists interpreting the scans are blinded to intervention allocation, whereas the patients and caregivers are unblinded. The trial has 80 % power to detect a 3 % absolute risk reduction in proximal DVT from 7 to 4 %. Discussion The first patient was enrolled in July 2014. As of May 2015, a total of 650 patients have been enrolled from 13 centers in Saudi Arabia, Canada and Australia. The first interim analysis is anticipated in July 2016. We expect to complete recruitment by 2018. Trial registration Clinicaltrials.gov: NCT02040103 (registered on 3 November 2013). Current controlled trials: ISRCTN44653506 (registered on 30 October 2013)

Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults

BACKGROUND The appropriate caloric goal for critically ill adults is unclear. We evaluated the effect of restriction of nonprotein calories (permissive underfeeding), as compared with standard enteral feeding, on 90-day mortality among critically ill adults, with maintenance of the full recommended amount of protein in both groups. METHODS At seven centers, we randomly assigned 894 critically ill adults with a medical, surgical, or trauma admission category to permissive underfeeding (40 to 60% of calculated caloric requirements) or standard enteral feeding (70 to 100%) for up to 14 days while maintaining a similar protein intake in the two groups. The primary outcome was 90-day mortality. RESULTS Baseline characteristics were similar in the two groups; 96.8% of the patients were receiving mechanical ventilation. During the intervention period, the permissiveunderfeeding group received fewer mean (±SD) calories than did the standardfeeding group (835±297 kcal per day vs. 1299±467 kcal per day, P<0.001; 46±14% vs. 71±22% of caloric requirements, P<0.001). Protein intake was similar in the two groups (57±24 g per day and 59±25 g per day, respectively; P = 0.29). The 90-day mortality was similar: 121 of 445 patients (27.2%) in the permissive-underfeeding group and 127 of 440 patients (28.9%) in the standard-feeding group died (relative risk with permissive underfeeding, 0.94; 95% confidence interval [CI], 0.76 to 1.16; P = 0.58). No serious adverse events were reported; there were no significant between-group differences with respect to feeding intolerance, diarrhea, infections acquired in the intensive care unit (ICU), or ICU or hospital length of stay. CONCLUSIONS Enteral feeding to deliver a moderate amount of nonprotein calories to critically ill adults was not associated with lower mortality than that associated with planned delivery of a full amount of nonprotein calories. 2399 Permissive Underfeeding in Critically Ill Adults N utritional support is an essential component of the care of critically ill adults. 1 Achieving caloric targets has been recommended with the premise that attenuating malnutrition and protein catabolism, which are associated with increased morbidity and mortality, will improve outcomes. 2 Observational studies examining various doses of enteral feeding have yielded conflicting results. 11 Conversely, caloric restriction may be beneficial; it has been shown to prolong life span in several species, 12-14 promote mammalian cell survival, 24 Such findings prompt the question of whether moderate caloric restriction while protein intake is preserved would improve the outcomes in critically ill adults. In a single-center, randomized, controlled trial of moderate caloric intake (60 to 70% of the estimated caloric requirement) versus standard caloric intake (90 to 100%), with maintenance of the full targeted protein intake in both groups, we observed that the lower caloric intake was associated with a reduction in in-hospital mortality, which was a secondary end point. Me thods Study Design The Permissive Underfeeding versus Target Enteral Feeding in Adult Critically Ill Patients (PermiT) trial was an unblinded, pragmatic, randomized, controlled trial conducted at seven tertiary care centers in Saudi Arabia and Canada between November 2009 and September 2014. The institutional review board at each participating center approved the study. Written informed consent was obtained from all the patients or their legal representatives. The study was sponsored by the King Abdullah International Medical Research Center, Riyadh, Saudi Arabia, and the investigators designed, managed, and analyzed the study independently. Patients were eligible for the trial if they were fed enterally within 48 hours after ICU admission. Inclusion and exclusion criteria are listed in Interventions Enrolled patients were randomly assigned to the permissive-underfeeding group or the standardfeeding group with the use of opaque, sealed, sequentially numbered envelopes. The randomization list was computer-generated. Randomization was performed in random permuted blocks and was stratified according to center. The feeding strategy was unblinded because of the need for adjustment of the nutritional support according to feeding tolerance and gastric residual volumes. ICU dietitians estimated patients' standard caloric requirements using the equation 2400 T h e ne w e ngl a nd jou r na l o f m e dicine University (the Penn State equation) for mechanically ventilated patients who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of less than 30 and using the 1992 Ireton-Jones equation for mechanically ventilated patients who had a BMI of 30 or higher and for spontaneously breathing patients 26-28 The caloric goal was 40 to 60% of caloric requirements in the permissive-underfeeding group and 70 to 100% of caloric requirements in the standard-feeding group. We set the caloric goal in the permissive-underfeeding group at a lower level than we did in the earlier trial, Cointerventions Protein requirements were calculated at 1.2 to 1.5 g per kilogram of body weight per day, in accordance with clinical practice guidelines. 1 To ensure that enteral protein and volume delivery in the permissive-underfeeding group would be similar to those in the standard-feeding group, the permissive-underfeeding group received additional protein (Beneprotein, Nestlé Nutrition) and normal saline or water at a dose of 2 ml per kilogram every 4 hours unless otherwise specified by the clinical team. Data Collection At baseline, we collected data on patient demographics, diabetes history, admission category (medical, surgical, or trauma), Acute Physiology and Chronic Health Evaluation (APACHE) II score, Daily during the intervention period, we obtained nutritional data (total calories and calories from enteral feeding, propofol, intravenous dextrose, and parenteral nutrition), laboratory data (levels of blood glucose, hemoglobin, creatinine, potassium, magnesium, and phosphate), and information on insulin dose, fluid intake and output, use of prokinetic agents, stool frequency and consistency, and duration of interruption in feeding. On a weekly basis, we recorded body weight; levels of lipids, prealbumin, and transferrin; and 24-hour urinary nitrogen excretion. We also recorded the use of selected medications during the ICU stay. Information on the monitoring of serious adverse events is provided in Outcomes The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality in the ICU, 28-day mortality, in-hospital mortality, 180-day mortality, and serial SOFA scores. Tertiary outcomes included days free from mechanical ventilation, ICU-free days, hospital length of stay, hypoglycemia, hypokalemia, hypomagnesemia, hypophosphatemia, transfusions of packed ), feeding intolerance (vomiting, abdominal distention, or a gastric residual volume of more than 200 ml), and diarrhea. Statistical Analysis On the basis of the findings of our previous randomized, controlled trial, For serial measurements, we tested the change over time and the difference between the two groups over time using a repeated-measures analysis of variance, with no imputation for missing values. The primary outcome was compared between the two study groups in the following prespecified subgroups: nonsurgical patients versus surgical patients, patients with diabetes versus patients without diabetes, patients with an APACHE II score of 18 or lower versus those with a score higher than 18, patients with a specific admission diagnosis (severe sepsis or traumatic brain injury) versus patients without either of those diagnoses, patients using vasopressors at baseline versus those not using them, and patients with a blood glucose level of no more than the median value at randomization versus those with a level higher than the median value. Tests were two-sided and at the 5% significance level. For serial measurements, we used a Bonferroni correction to account for multiple comparisons. To account for alpha spending by the interim analyses, we used the O'Brien-Fleming method. A final P value of less than 0.045 was considered to indicate statistical significance for the primary outcome. Analyses were performed with the use of SAS software, version 9.2 (SAS Institute). R esult s Patients A total of 894 patients underwent randomization Interventions and Cointerventions Throughout the intervention period, patients in the permissive-underfeeding group had a lower caloric intake than did patients in the standardfeeding group Outcomes Mortality The 90-day mortality (primary end point) was 27.2% (121 of 445 patients) in the permissiveunderfeeding group and 28.9% (127 of 440 patients) in the standard-feeding group (relative risk, 0.94; 95% confidence interval [CI], 0.76 to 1.16; P = 0.58) ( 2402 T h e ne w e ngl a nd jou r na l o f m e dicine ence in the probability of survival between the two groups (P = 0.43 by the log-rank test) Other End Points Serial SOFA scores, nitrogen balance, body weight, and levels of C-reactive protein, prealbumin, creatinine, bilirubin, partial pressure of arterial carbon dioxide, hemoglobin, lipids, potassium, magnesium, phosphate, transferrin, and urinary nitrogen excretion did not differ significantly between the two groups ( 2404 T h e ne w e ngl a nd jou r na l o f m e dicine days did not differ significantly between the two group

Statistical analysis plan for the Pneumatic CompREssion for PreVENting Venous Thromboembolism (PREVENT) trial: a study protocol for a randomized controlled trial

Abstract Background The Pneumatic CompREssion for Preventing VENous Thromboembolism (PREVENT) trial evaluates the effect of adjunctive intermittent pneumatic compression (IPC) with pharmacologic thromboprophylaxis compared to pharmacologic thromboprophylaxis alone on venous thromboembolism (VTE) in critically ill adults. Methods/design In this multicenter randomized trial, critically ill patients receiving pharmacologic thromboprophylaxis will be randomized to an IPC or a no IPC (control) group. The primary outcome is “incident” proximal lower-extremity deep vein thrombosis (DVT) within 28 days after randomization. Radiologists interpreting the lower-extremity ultrasonography will be blinded to intervention allocation, whereas the patients and treating team will be unblinded. The trial has 80% power to detect a 3% absolute risk reduction in the rate of proximal DVT from 7% to 4%. Discussion Consistent with international guidelines, we have developed a detailed plan to guide the analysis of the PREVENT trial. This plan specifies the statistical methods for the evaluation of primary and secondary outcomes, and defines covariates for adjusted analyses a priori. Application of this statistical analysis plan to the PREVENT trial will facilitate unbiased analyses of clinical data. Trial registration ClinicalTrials.gov, ID: NCT02040103. Registered on 3 November 2013; Current controlled trials, ID: ISRCTN44653506. Registered on 30 October 2013