Bleeding is a severe complication of critical illness in children, which has been associated with longer hospital stays, increased blood product and vasoactive utilization, as well as increased mortality (1, 2). Despite the burden bleeding places on the critically ill pediatric community, to date there remains little clarity regarding its incidence, with wide variations recorded in pediatric populations of different ages (2, 3). Additionally, adult studies make use of different clinical definitions of bleeding, which when coupled with the intrinsic differences in incidence and physiology of disease states in the adult population, make generalization to the pediatric population difficult (4). This lack of pediatric epidemiological data presents a major obstacle in designing studies that evaluate interventions to prevent or stop bleeding.

Patient blood management programs have effectively reduced incidence of transfusions, with restrictive transfusion strategies being employed in part because of a better understanding of the physiologic impact of bleeding (5–8). It is not known if restrictive transfusion strategies in bleeding adult patients can be extrapolated to children, in part because of the challenge of an objective description of bleeding and lack of epidemiological background (8). Our objective in this study was to describe the epidemiology of bleeding in the critically ill population, using a clinical tool validated specifically for use in critically ill children (9).

We conducted a prospective longitudinal observational study in a tertiary 20-bed pediatric intensive care unit (PICU) in Richmond, Virginia. From November 2019 to October 2020, we enrolled all consecutive critically ill children (1 month to 18 years of age) admitted to the PICU. We excluded preterm infants (<44 weeks gestation at age of enrollment) or term infants <28 days old, as bleeding etiologies are specific to the neonatal period and the bleeding assessment tool is not calibrated for this population. In addition, we excluded patients with known limitations of care at enrollment. The study was approved by the Institutional Review Board (HM20016435) with a waiver of individual consent.

Due to logistical constraints, clinical data was only collected Monday through Friday. For all critically ill children, we collected demographics (such as reason for admission, age, weight, surgical status), severity at admission as evaluated by the Pediatric Index of Mortality, length of mechanical ventilation and 28-day ventilator-free days, PICU length of stay and 28-day PICU-free days, and 28-day mortality (10). To avoid potential biases due to the unavailability of floor beds delaying transfers of children no longer critically ill, PICU discharge was based on two consecutive Pediatric Early Warning Score (PEWS) <3 (11).

Our study, which sought to describe the epidemiology and clinical burden of bleeding in the critically ill pediatric population, suggested that bleeding occurs in ~18% of patients, and that disease severity at admission was the most significant predictor of severity of bleeding in both medical and surgical patients. In medical patients, an admission diagnosis of gastrointestinal bleeding was the most significant predictor of bleeding severity, while for surgical patients, bleeding severity was predicted by trauma or infection admission diagnosis, as well as total length of surgery. Furthermore, bleeding severity was independently associated with fewer ventilator-free days, fewer PICU-free days, and increased mortality risk. This study also provides further validation of BASIC bleeding definition, indicating association between degree of bleeding severity and clinical outcomes.

Due to the heterogeneity of the concept of “clinically significant bleeding,” the epidemiology and outcomes of bleeding are difficult to accurately quantify. Adult studies have reported bleeding incidence at 30% in BMT patients, while some studies report bleeding incidence as high as 90% in critically ill populations, with subsequent longer ICU stays, albeit variable survival (4, 12, 13). Pinto et al. (2) showed that in critically ill adolescents, this incidence was 30%, and when studying specifically critically ill children, White et al. (3) estimated the bleeding incidence to be 37%, with clinically significant bleeds only occurring in 9% of patients. Greenway et al. (14) identified a similar incidence of clinically relevant bleeds in critically ill children; 10% using the ISTH definition. It should be noted that White et al. excluded patients bleeding at admission, which eliminated a large number of surgical patients from the bleeding cohort, and was likely contributory to the subsequently decreased risk of bleeding associated with surgery when compared to our cohort. It should also be noted that both of these studies defined clinical relevant bleeding using the International Society on Thrombosis and Hemostasis (ISTH) categories of bleeding, which were designed to standardize outcomes in clinical trials of anticoagulation (15, 16). These definitions fail to account for differences in pediatric physiology, and are highly dependent on subjective assessments as the definition links the decision to transfuse blood products to the severity of bleeding. As such, the ISTH definition may not completely capture all nuances of bleeding in a critical care setting or may overemphasize the severity of a bleed.

Our study showed that 12% of bleeding pediatric patients received blood products, and that severity of bleeding was associated with higher doses of all blood products except plasma. In critically ill adults, transfusion rates are significantly higher, with 37% of patients receiving a transfusion during their ICU stay, and over two thirds of those patients requiring multiple transfusions (16). However, the need for transfusion was included in their definition of severe bleeding. Transfused patients had more ICU days, more severe organ failure, and higher mortality than non-transfused patients (17). Regarding plasma transfusions, a multicenter trial of 13,192 critically ill children identified that 1.5% received plasma to treat bleeding, compared to 2.1% in this current cohort (18).

Hemostatic transfusions are frequently administered to critically ill patients to prevent or stop bleeding. In critically ill adult patients with hypoproliferative thrombocytopenia, platelet transfusions occurred in over 44% of patients, but were of limited benefit, with poor post-transfusion improvement increments (19). Prophylactic transfusions are also extremely common in pediatric patients with oncologic disorders. Nellis et at. demonstrated that 43% of critically ill pediatric patients who receive a platelet transfusion have an underlying oncologic diagnosis. In these patients, 71% of the transfusions were administered prophylactically. Patients with oncologic diagnoses demonstrated impaired increment response to platelets, and while they received more transfusions overall, their total platelet dose over the admission was equivalent to their non-oncological cohorts, and mortality was not significantly different (20). This is consistent with our findings, that while a moderate number of bleeding patients had an oncologic diagnosis, this diagnosis did not independently increase the risk of a severe bleeding event. When looking at a general population of critically ill children, a large international study of 16,934 pediatric patients showed that 3.3% received platelets to treat bleeding, compared to 1.6% in our study (21).

We furthermore, showed that 3.6% of patients required surgical interventions, and that severity of bleeding was also associated with the need for surgical interventions. Previous studies have shown that some of the most frequent triggers for transfusion are preoperative, to correct laboratory values prior to an invasive procedure in the absence of clinical bleeding. Karam et al. (18) previously demonstrated that 34% of critically ill patients received plasma prior to a planned procedure.

Our study had several limitations. First, in the critically ill population, the nature of some critical interventions performed while resuscitating patients may have increased the odds of bleeding, in which case bleeding would be a marker of severity, instead of being independently associated with worse outcome. Therefore, we might have overestimated the real association between bleeding severity and outcomes. For example, bleeding from an endotracheal tube might be a consequence of the need for intubation and mechanical ventilation, which is itself a risk factor for worse outcome. Second, data was not collected on weekends and holidays, due to staffing restrictions, which might have led to a selection bias as elective surgeries are frequently done during the week. Third, while our center does encompass trauma, ECMO, cancer, BMT and solid organ transplants, our study was single center and as such may not be fully generalizable to other units. Finally, bedside nursing assessments and documentation likely led to variation in data capture, for example when different nurses would assess the same patient's clinical bleeding as less or more severe, or when documentation of blood loss was charted all at once, instead of hourly, making rate calculations unreliable.

In conclusion, bleeding in the critically ill pediatric population is frequent and represents a significant source of morbidity and mortality. Further, studies will be required to elaborate the importance of laboratory values and clinical findings in the decision of the clinician to intervene to address bleeding events, as well as the impact blood product administration has on outcomes.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Virginia Commonwealth University Institutional Review Board (HM20016435). Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

JS wrote the research project, analyzed data, and wrote the manuscript. OK wrote the research project, analyzed the data, and reviewed the manuscript. MN wrote the research project and reviewed the manuscript. JS and OK had full access to the data and take responsibility for its integrity. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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