Antiplatelet therapy in bleeding trauma patients: tales of the unexpected.

Critical Care Medicine www.ccmjournal. org e187 To the Editor: We read with interest the results from the study of Harr et al (1), which reports on the association between preinjury antiplatelet therapy (APT) and a decreased risk of lung dysfunction and multiple organ failure in severely injured blunt trauma patients who received blood transfusions. These results are in line with evidence from preclinical studies on the role of platelets in lung injury, and we acknowledge the authors for their effort to further explore the role of APT in inflammatory states and transfusion in a clinical setting. A potential recommendation arising from the results of this trial may be to expose bleeding trauma patients to APT. Given the potential of worsening bleeding from APT, associations should be interpreted with caution. We would like to raise some uncertainties in the presentation of the model. The purpose of the logistic regression model used was to quantify the net relationship of APT with lung injury and multiple organ failure and mortality as dependent variables. In the results, we read: “after the adjustment for possible confounders, we identified a significant interaction between blood transfusion and APT,” suggesting that interaction is investigated after adjustment for possible confounders (1). However, interaction must be assessed before assessment of confounding. If a covariate contributes to effect modification as shown by the significance of the interaction term, it cannot also be used as a confounder. If significant interaction is found, an adjustment for confounding for that same variable is inappropriate (2). Furthermore, results are drawn from a secondary cohort analysis, which carries a considerable risk of confounders not accounted for. Of these, we would like to address transfusion practice. No description of the transfusion protocols in the different centers was given. There are many possible confounders related to transfusion, including use of packed RBCs versus leukocyte-reduced RBCs, age of blood products, the ratio of transfused blood products, and the use of tranexamic acid (3–5). Most likely of all transfusion-related confounders, platelet transfusion may supposedly influence the effect of APT on outcome. Thereby, we would like to suggest that analysis of the predictive than others in relation to clinical outcomes. However, all five methods (1, 2) of measuring cell-free hemoglobin described in patients with sepsis have shown significant associations with poor clinical outcomes, adding strength to the argument that this association is real rather than an effect of measurement technique. More importantly, cell-free hemoglobin was consistently detectable in the majority of patients with sepsis, a finding that had not been previously described in sepsis. Our use of the Hemocue device (HemoCue, Angelholm, Sweeden) for measurement of cell-free hemoglobin is in no way an endorsement of this method but does provide evidence that a point-of-care device that can produce results within seconds may be useful in future clinical trials in patients with sepsis that require rapid determination of cell-free hemoglobin levels. Hartmann and de Groot’s summary of our current knowledge of the role of cell-free hemoglobin in the pathophysiology of sepsis points out the large gaps in the understanding of this topic. Specifically, neither our analysis (2) nor past analyses (1) of patients with sepsis have been able to delineate a potential mechanism for the associated increase in mortality. Although studies of free hemoproteins in animals and nonseptic humans suggest that acute kidney injury due to lipid peroxidation (3), nitric oxide consumption, and vasoconstriction (4) are potential mechanisms, our study did not show an association of cellfree hemoglobin with acute kidney injury. In addition, more detailed mechanistic studies are needed to determine why hemoglobin is released from red cells in sepsis and what role endogenous scavengers of cell-free hemoglobin, such as haptoglobin, play in the development of poor outcomes. Finally, looking ahead, it is important to remember that the pathophysiologic mechanisms underlying disease associated with cell-free hemoglobin are many, and a variety of potential therapeutic scavengers and inhibitors of cell-free hemoglobin are available. Therefore, future studies may need to involve multiple interventions, perhaps through factorial designs, to better elucidate the most important mechanisms and parsimonious therapeutic options. Acetaminophen, haptoglobin, hemopexin, and albumin are all potential therapeutic options for study and also may provide impetus for reanalysis of past studies that have shown potential protective effects of these hemoprotein scavengers and inhibitors in patients with sepsis (5). Drs. Janz and Ware received funding support from the National Institutes of Health.