Early propranolol administration to severely injured patients can improve bone marrow dysfunction.
Bible LE, Pasupuleti LV, Alzate WD, Gore AV, Song KJ, Sifri ZC, Livingston DH, Mohr AM.
Division of Trauma, Department of Surgery, Rutgers-New Jersey Medical School, Newark, New Jersey, USA.
BACKGROUND: Bone marrow (BM) dysfunction is common in severely injured trauma patients, resulting from elevated catecholamines and plasma granulocyte colony-stimulating factor (G-CSF) as well as prolonged mobilization of hematopoietic progenitor cells (HPCs). We have previously shown that propranolol (β-blocker [BB]) reduces HPC mobilization in a rodent model of injury and hemorrhagic shock. We hypothesize that BB would prevent BM dysfunction in humans following severe injury.
METHODS: Forty-five severely injured trauma patients were studied in a prospective, randomized pilot trial. Twenty-five patients received BB, and 20 served as untreated controls. The dose of propranolol was adjusted to decrease the heart rate by 10% to 20% from baseline. Blood was analyzed for the presence of HPC (blast-forming unit erythroid cells [BFU-E] and colony-forming unit erythroid cells) and G-CSF. Demographic data, Injury Severity Score (ISS), hemoglobin, reticulocyte number, and outcome data were obtained.
RESULTS: The mean age of the study population was 33 years; 87% were male, with a mean ISS of 29. There is a significant increase in BFU-E in peripheral blood immediately following traumatic injury, and this mobilization persists for 30 days. The use of BB significantly decreases BFU-E and colony-forming unit erythroid cells at all time points. G-CSF is significantly elevated in both groups on admission; the use of BB decreases G-CSF levels by 51% as compared with 37% for controls. The average hemoglobin is nearly 1 g higher on the day of discharge with propranolol treatment (BB, 9.9 ± 0.4 g/dL vs. no BB, 9.1 ± 0.6 g/dL).
CONCLUSION: Following severe trauma, early treatment with propranolol following resuscitation is safe. The use of propranolol blunts early tachycardia, reduces HPC mobilization, and results in a faster return to baseline of the G-CSF peak seen after injury. There is also a trend toward faster recovery and resolution of anemia. Propranolol may be the first therapeutic agent to show improved BM function after severe injury.
Among severely injured trauma patients, an injury-associated anemia persists for several weeks following their initial injury. Often, this anemia leads to several blood transfusions, which in turn is an independent risk factor for infections, organ failure, and death (1-2). A key concomitant finding with persistent anemia is the prolonged hypercatecholamine state. Severe traumatic injury is coupled to a stress response that is regulated by the sympathetic nervous system and following severe trauma injury there is bone marrow (BM) dysfunction which is associated with both enhanced HPC mobilization and inhibited hematopoietic progenitor cell (HPC) growth (Figure 1). Previous work with in vitro and vivo models demonstrated that norepinephrine (NE) rather than epinephrine was a key modulator of inhibition of BM growth and HPC mobilization (3). NE has been shown to mediate this effect via beta-2 and beta-3 adrenergic receptors (4). In severely injured trauma patients, this persistent elevation of catecholamines leads to BM dysfunction but is clinically manifest as a persistent injury-associated anemia (Figure 1).
Based on the above findings, we investigated the role of propranolol, a nonselective beta blocker (BB), as a potential protective and therapeutic treatment for severely injured trauma patients. Previous work has supported the use of BB in patients after burns, non-cardiac operations, and traumatic brain injuries (5-8). Benefits varied from improved wound healing, reversal of catabolic states, and prevention of stress cardiomyopathy (5-8). In our initial animal models, of injury and shock we discovered that the use of propranolol improved BM function. Figure 2 and Table 1 show the use of propranolol in a rodent model improved BM HPC growth and restored hemoglobin (Hb) levels (9).
Figure 2. Improved bone marrow CFU-E colony growth with use of beta blockade. (N = 4-6/group) UC=unmanipulated control; LC=lung contusion; LC/HS=lung contusion followed by hemorrhagic shock; LC/HS/BB=LC/HS followed by beta blockade after resuscitation * P
|RBC (106/ µl)||7.2±0.3||6.9±0.5||5.3±0.9*||6.7±0.5**|
Table 1. Peripheral blood hematologic parameters seven days after injury. (N = 4-6/group) UC=unmanipulated control; LC=lung contusion; LC/HS=lung contusion followed by hemorrhagic shock; LC/HS/BB=LC/HS followed by beta blockade after resuscitation WBC=white blood cell; RBC=red blood cell; Hb=hemoglobin; MCV=mean corpuscular volume *P
Up to this point, the hematological benefits of propranolol had yet to be tested among severely injured trauma patients with anemia. In this manuscript, we prospectively randomized patients to receive propranolol or not following severe injury. Within 24 hours of admission, 45 trauma patients were enrolled and assigned to either the propranolol treated group or untreated control group. Propranolol dosing was titrated to cause a reduction in initial heart rate of 10-20%; doses were adjusted accordingly to achieve goal HR. This dosing protocol was effective in two-thirds of the treated group. HPC mobilization was measured by assessing BFU-E and CFU-E HPC growth in the peripheral blood and plasma G-CSF, a key inducer of HPC mobilization from to the BM to periphery. The hematological effects of propranolol on trauma patients mirrored our previous work with rodent models. The effect of propranolol resulted in a clinically significant increase in Hb levels, on the day of discharge, in the treated group when compared to the untreated group. The lack of statistical significance could be attributed to our small sample size or lack of a consistent thiryt day hemoglobin measurement. Yet, as pilot, this is the first study to evaluate the potential use of propranolol therapy to improve BM dysfunction and resolve persistent injury-associated anemia following trauma. This study demonstrated that the early use of propranolol therapy is a safe, efficient, and can potentially improve persistent injury-associated anemia following trauma.
Importance of This Work
The significance of understanding the pathophysiology of injury-associated persistent anemia following severe trauma has three key elements. First, critically ill patients remain anemic in the absence of any blood loss for several weeks following their initial injury and anemia itself is associated with a higher degree of organ failure, longer lengths of stay, and higher mortality rates. Second, the only available treatment of injury-associated persistent anemia is blood transfusions and the search for alternative treatments has been unsuccessful. Third, the role of bone marrow dysfunction in injury-associated persistent anemia is not well understood and this is the first study to demonstrate the potential effectiveness of propranolol.
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Acknowledgements: This work has been supported by NIH T32 GM069330, K08 NIH GM078304, and the Clowes American College of Surgeons/American Association for the Surgery of Trauma Award.