Alicia M. Mohr

β-Blockade Protection of Bone Marrow Following Trauma: The Role of G-CSF

BACKGROUNDnFollowing severe trauma, there is a profound elevation of catecholamine that is associated with a persistent anemic state. We have previously shown that β-blockade (βB) prevents erythroid growth suppression and decreases hematopoietic progenitor cell (HPC) mobilization following injury. Under normal conditions, granulocyte colony stimulating factor (G-CSF) triggers the activation of matrix metalloprotease-9 (MMP-9), leading to the egress of progenitor cells from the bone marrow (BM). When sustained, this depletion of BM cellularity may contribute to BM failure. This study seeks to determine if G-CSF plays a role in the βB protection of BM following trauma.nnnMETHODSnMale Sprague-Dawley rats were subjected to either unilateral lung contusion (LC) ± βB, hemorrhagic shock (HS) ± βB, or both LC/HS ± βB. Propranolol (βB) was given immediately following resuscitation. Animals were sacrificed at 3xa0and 24xa0h and HPC mobilization was assessed by evaluating BM cellularity and flow cytometric analysis of peripheral blood for HPCs. The concentration of G-CSF and MMP-9xa0was measured in plasma by ELISA.nnnRESULTSnBM cellularity is decreased at 3xa0h following LC, HS, and LC/HS. HS and LC/HS resulted in significant HPC mobilization in the peripheral blood. The addition of βB restored BM cellularity and reduced HPC mobilization. Three h following HS and LC/HS, plasma G-CSF levels more than double, however LC alone showed no change in G-CSF. βB significantly decreased G-CSF in both HS and LC/HS. Similarly, MMP-9xa0is elevated following LC/HS, and βB prevents this elevation (390 ± 100xa0pg/mL versus 275 ± 80xa0pg/mL).nnnCONCLUSIONnβB protection of the BM following shock and injury may be due to reduced HPC mobilization and maintenance of BM cellularity. Following shock, there is an increase in plasma G-CSF and MMP-9, which is abrogated by βB and suggests axa0possible mechanism how βB decreases HPC mobilization thus preserving BM cellularity. In contrast, βBxa0protection of BM following LC is not mediated by G-CSF. Therefore, the mechanism of progenitor cell mobilization from the BM is dependent on the type of injury.

Does beta blockade postinjury prevent bone marrow suppression

BACKGROUNDnTrauma-induced hypercatecholaminemia negatively impacts bone marrow (BM) function by suppressing BM hematopoietic progenitor cell (HPC) growth and increasing HPC egress to injured tissue. Beta blockade (BB) given before tissue injury alone has been shown to reduce both HPC mobilization and restore HPC colony growth within the BM. In a clinically relevant model, this study examines the effect of BB given after both tissue injury and hemorrhagic shock (HS).nnnMETHODSnMale Sprague-Dawley rats underwent lung contusion (LC) with a blast wave percussion. HS was achieved after LC by maintaining the mean arterial blood pressure 30 mm Hg to 35 mm Hg for 45 minutes. Propranolol (10 mg/kg) was given once the mean arterial blood pressure>80 mm Hg and subsequent doses were given daily (LC/HS/BB). One-day and 7-day postinjury, analysis of BM and lung tissue for the growth of HPCs, hematologic parameters, and histology of lung injury were performed.nnnRESULTSnLC/HS significantly worsens BM CFU-E growth suppression (15±8 vs. 35±2) and increases CFU-E growth in injured tissue when compared with LC at 1 day and 7 days (33±5 vs. 22±9). The use of BB after LC/HS ameliorated BM suppression, the degree of anemia and HPC growth in the injured lung at 1 day and 7 days postinjury. Lung injury score shows that there was no worsening of lung healing with BB (LC/HS/BB 3.2±2 vs. LC/HS 3.8±0.8).nnnCONCLUSIONnIn an injury and shock model, administration of propranolol immediately after resuscitation significantly reduced BM suppression, and the protective effect is maintained at 7 days with daily BB. Although BB appears to improve BM function by decreasing HPC mobilization to injured tissue, there was no worsening of lung healing. Therefore, the use of propranolol after trauma and resuscitation may minimize long-term BM suppression after injury with no adverse impact on healing.

The role and value of surgical critical care, an essential component of Acute Care Surgery, in the Affordable Care Act: A report from the Critical Care Committee and Board of Managers of the American Association for the Surgery of Trauma

Heidi L. Frankel, MD, Karyn L. Butler, MD, Joseph Cuschieri, MD, Randall S. Friese, MD, Toan Huynh, MD, Alicia M. Mohr, MD, Miren A. Schinco, MD, Lena M. Napolitano, MD, L.D. Britt, MD, MPH, Raul Coimbra, MD, PhD, Martin A. Croce, MD, James W. Davis, MD, Gregory J. Jurkovich, MD, Ernest E. Moore, MD, John A. Morris, Jr., MD, Andrew B. Peitzman, MD, Basil A. Pruitt, MD, Grace S. Rozycki, MD, MBA, Thomas M. Scalea, MD, and J. Wayne Meredith, MD, Baltimore, Maryland

Beta Blockade Protection of Bone Marrow Following Injury: A Critical Link between Heart Rate and Immunomodulation.

Introduction Severe trauma induces a profound elevation of catecholamines that is associated with bone marrow (BM) hematopoietic progenitor cell (HPC) colony growth suppression, excessive BM HPC mobilization, and a persistent anemia. Previously, propranolol (BB) use after injury and shock has been shown to prevent this BM dysfunction and improve hemoglobin levels. This study seeks to further investigate the optimal therapeutic dose and timing of BB administration following injury and shock. Methods Male Sprague-Dawley rats were subjected to a combined lung contusion (LC), hemorrhagic shock (HS) model ± BB. In our dose response experiments, animals received BB at 1, 2.5, 5, or 10 mg/kg immediately following resuscitation. In our therapeutic window experiments, following LCHS rats were given BB immediately, 1 hour, or 3 hours following resuscitation. BM and peripheral blood (PB) were collected in all animals to measure cellularity, BM HPC growth, circulating HPCs, and plasma G-CSF levels. Results Propranolol at 5 and 10 mg/kg significantly reduced HPC mobilization, restored BM cellularity and BM HPC growth, and decreased plasma G-CSF levels. Propranolol at 5 and 10 mg/kg also significantly decreased heart rate. When BB was administered beyond 1 hour after LCHS, its protective effects on cellularity, BM HPC growth, HPC mobilization, and plasma G-CSF levels were greatly diminished. Conclusion Early Buse following injury and shock at a dose of at least 5mg/kg is required to maintain BM cellularity and HPC growth, prevent HPC mobilization, and reduce plasma G-CSF levels. This suggests that propranolol exerts its BM protective effect in a dose and time dependent fashion in a rodent model. Finally, heart rate may be a valuable clinical marker to assess effective dosing of propranolol.