Assuntos
Carcinoma de Células Escamosas/cirurgia , Colostomia/métodos , Exenteração Pélvica/métodos , Úlcera por Pressão/complicações , Neoplasias Cutâneas/cirurgia , Adulto , Carcinoma de Células Escamosas/etiologia , Evolução Fatal , Humanos , Masculino , Úlcera por Pressão/cirurgia , Neoplasias Cutâneas/etiologiaRESUMO
BACKGROUND: Bone marrow dysfunction is common in severely injured trauma patients, with release of hematopoietic progenitor cells (HPC) into the peripheral blood. Granulocyte colony stimulating factor (G-CSF) is a potent stimulator of HPC mobilization. We hypothesized that plasma G-CSF levels are elevated after trauma and correlate with postinjury anemia and infection. STUDY DESIGN: Blood from 83 severely injured patients was collected at several time points for determination of G-CSF levels and HPC mobilization and compared with that from healthy volunteers. Data were categorized by age, sex, Injury Severity Score (ISS), and whether the patient was in shock. Hemoglobin and transfusion requirements and hospital-acquired infection data were recorded. Data are expressed as mean ± SEM. RESULTS: After trauma, there is a 50-fold increase in plasma levels of G-CSF in trauma patients compared with controls (1,640.4 ± 304.3 pg/mL vs 33.0 ± 6.8 pg/mL, p < 0.001). Patients who presented in shock had 5-times higher G-CSF levels than nonshock trauma patients and a 75-fold increase compared with controls (2,528.7 ± 536.4 pg/mL vs 728.0 ± 191.0 pg/mL vs 33.0 ± 6.8 pg/mL, p < 0.001). Age, sex, and ISS had no effect on G-CSF levels. Mobilization of HPC was sustained for up to 10 days after injury and involved multiple cells types. Higher G-CSF levels were also associated with lower hemoglobin levels and greater transfusion requirements 3 weeks after injury and a higher incidence of hospital-acquired pneumonia and bacteremia. CONCLUSIONS: Plasma G-CSF is markedly elevated after injury and is greater in patients who present in shock. The rise in G-CSF was also associated with prolonged mobilization of HPC. Elevation of G-CSF in humans after severe trauma may play a significant role in the development of post-traumatic bone marrow dysfunction, anemia, and infection.
Assuntos
Medula Óssea/fisiopatologia , Fator Estimulador de Colônias de Granulócitos/sangue , Células-Tronco Hematopoéticas/metabolismo , Ferimentos e Lesões/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Anemia/etiologia , Anemia/fisiopatologia , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Escala de Gravidade do Ferimento , Masculino , Pessoa de Meia-Idade , Choque Traumático/sangue , Choque Traumático/fisiopatologia , Ferimentos e Lesões/complicações , Ferimentos e Lesões/fisiopatologia , Adulto JovemRESUMO
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.
RESUMO
BACKGROUND: ß-blockade (BB) has been shown to prevent bone marrow (BM) dysfunction after trauma and hemorrhagic shock (HS). The impact of the sympathetic system and the role of BB on shock-induced distant organ injury is not known. This study will determine if BB has systemic effects and can diminish gut and lung injury after trauma and HS. METHODS: Male Sprague-Dawley rats were subjected to lung contusion (LC) followed by 45 minute of HS. Animals (n = 6 per group) were then randomized to either receive propranolol (LCHS + BB) immediately after resuscitation or not (LCHS). Gut permeability was evaluated in by diffusion of Mr 4,000 of fluorescein dextran (FD4) from a segment of small bowel into peripheral blood. Villous injury and lung injury were graded histologically by a blinded reader. Plasma-mediated effects of BB were evaluated in vitro by an assessment of BM progenitor growth. RESULTS: Animals undergoing LCHS had significantly higher plasma levels of FD4 compared with control animals (mean [SEM], 2.8 [0.4] µg/mL vs. 0.8 [0.2] µg/mL). However, animals receiving BB had a significant reduction in plasma FD4 compared with the LCHS group. With the use of BB after LCHS, both ileal and lung injury scores were similar to control. In addition, BM progenitor growth was inhibited by the addition of LCHS plasma, and LCHS + BB plasma showed no inhibition of BM progenitor growth. CONCLUSION: Propranolol can protect against the detrimental effects of trauma and HS on gut permeability, villous, and lung injury. The effects of BB are likely systemic and appear to be mediated through plasma. BB likely blunts the exaggerated sympathetic response after shock and injury. Propranolol's reduction of both BM dysfunction and distant organ injury further demonstrates the importance of the sympathetic nervous system and its role in potentiating end organ dysfunction after severe trauma.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Trato Gastrointestinal/efeitos dos fármacos , Lesão Pulmonar/tratamento farmacológico , Propranolol/farmacologia , Choque Hemorrágico/tratamento farmacológico , Animais , Células da Medula Óssea/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Trato Gastrointestinal/lesões , Imuno-Histoquímica , Lesão Pulmonar/metabolismo , Lesão Pulmonar/prevenção & controle , Masculino , Insuficiência de Múltiplos Órgãos/patologia , Insuficiência de Múltiplos Órgãos/prevenção & controle , Permeabilidade/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Valores de Referência , Medição de Risco , Sensibilidade e Especificidade , Choque Hemorrágico/fisiopatologia , Células-Tronco/metabolismo , Taxa de Sobrevida , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologiaRESUMO
BACKGROUND: Following severe trauma, there is a profound elevation of catecholamine that is associated with a persistent anemic state. We have previously shown that ß-blockade (ßB) 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 ßB protection of BM following trauma. METHODS: Male Sprague-Dawley rats were subjected to either unilateral lung contusion (LC) ± ßB, hemorrhagic shock (HS) ± ßB, or both LC/HS ± ßB. Propranolol (ßB) was given immediately following resuscitation. Animals were sacrificed at 3 and 24 h 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-9 was measured in plasma by ELISA. RESULTS: BM cellularity is decreased at 3 h following LC, HS, and LC/HS. HS and LC/HS resulted in significant HPC mobilization in the peripheral blood. The addition of ßB 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. ßB significantly decreased G-CSF in both HS and LC/HS. Similarly, MMP-9 is elevated following LC/HS, and ßB prevents this elevation (390 ± 100 pg/mL versus 275 ± 80 pg/mL). CONCLUSION: ßB 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 ßB and suggests a possible mechanism how ßB decreases HPC mobilization thus preserving BM cellularity. In contrast, ßB protection 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.