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There are no proven methods to predict the risk of clinically significant bleeding in the PICU. A retrospective study identified platelet count as a risk marker for clinically significant bleeding. We conducted a study to examine any association of platelet count, international normalized ratio, and activated partial thromboplastin time with bleeding risk in PICU patients.Prospective observational cohort study.The PICU at the Children’s Hospital of Eastern Ontario, a university-affiliated tertiary care pediatric center.Consecutive patients admitted to the PICU. Exclusion criteria were prior inclusion, admission with bleeding, inherited bleeding disorders, weight less than 3 kg, and age less than 60 days or 18 years or more.There were no interventions in this observational study.Patients were monitored in real time for clinically significant bleeding, using a broadly inclusive definition of clinically significant bleeding, for up to 72 hours after admission to the PICU, or until death or discharge. All measurements of platelet count, international normalized ratio, and activated partial thromboplastin time obtained during the study period were included as time-varying covariates in Cox proportional hazard models. Two hundred thirty-four patients were eligible, and 25 (11%) had one or more episodes of clinically significant bleeding. Platelet count was associated with increased hazard of clinically significant bleeding (hazard ratio, 0.96 per 10 × 109/L increase in platelet count; 95% CI (0.93–0.997; p = 0.03). Increasing hazard for clinically significant bleeding was seen with decreasing platelet count. Neither international normalized ratio nor activated partial thromboplastin time was significantly associated with clinically significant bleeding.There is a statistically significant association in PICU patients between decrease in platelet count and clinically significant bleeding, and this association is stronger with lower platelet counts. Further study is required to determine whether platelet transfusion can reduce bleeding risk. International normalized ratio and activated partial thromboplastin time do not predict clinically significant bleeding, and these tests should not be used for this purpose in a general PICU patient population.