Statistical methods for primary and secondary outcomes {20a}
death, critically ill, hyperhydration, STEC, STEC-HUS, HUS
REGRESSION, CRITICALLY ILL, COMPLICATIONS, KIDNEY DYSFUNCTION
Baseline characteristics of subjects will be summarized by intervention group. Counts and proportions will be used for categorical variables and means, standard deviations, medians, and quartiles will be used for numeric variables.We will adhere to the ITT principle. The primary outcome, the MAKE30, will be compared between children allocated to hyperhydration vs. those allocated to conservative fluid management. We will use logistic regression with generalized estimating equation (GEE) methods to account for clustering at the site level. Fixed model terms will include treatment effect and period effect. Other baseline terms in the model will be age (as a continuous variable), serum creatinine, and hematocrit. These variables have been associated with adverse kidney outcomes in this population. The superiority test of null treatment effect will be carried out at the 0.05 level. Parameter estimates and 95% confidence intervals will be provided for all model terms. Carry-over effect will not be present in our crossover design in the traditional sense as patients themselves, and therefore, their outcomes will only be subject to one type of treatment. The only possible “carryover” effect would be a lack of adherence to the new treatment protocol after the crossover at the site level. We will monitor this closely and its potential effect which would be to reduce power.The primary outcome, MAKE30, is a composite measure that includes (1) death, (2) new initiation of RRT, and (3) persistent kidney dysfunction. The latter is traditionally defined by a persistent increase in creatinine from a known baseline value at 30-day follow-up. However, most children with STEC-HUS are previously healthy and do not have baseline serum creatinine values available. As such, we will compare 30-day values to estimated, pre-illness values. Although imputation methods have been used previously in critically ill children to estimate baseline serum creatinine values, most of these require patient height. However, as children managed as outpatients under the conservative fluid management strategy will not routinely have height documented, this approach also would be a challenge to our study. Pottel et al. [Secondary outcomes will be analyzed in a similar manner as the primary outcome, with the dichotomous outcomes of extrarenal complications and HUS utilizing the same logistic regression model. Only patients without HUS at baseline will be included in the latter analysis. Additional details can be found in the HIKO STEC Statistical Analysis Plan.