S. Lendemans

Influence of surgical intervention in the immune response of severely injured patients

Objective Primary events such as severe injury and elective surgery cause a deterioration of the immune response measurable by reduction of expression of HLA-DR on monocytes or ex vivo LPS-induced TNFα production. The further influence of secondary surgery after severe injury on the immune response remains unresolved.Design Prospective observation study.Setting Surgical intensive care unit of an university hospital.Patients Sixteen severely injured patients with an ISS >25 points.Measurements and results On day 1 after trauma and immediately before secondary surgery, mean fluorescence intensity (MFI) of HLA-DR expression on monocytes and TNFα ex vivo synthesis was significantly reduced compared to healthy donors. Overall, surgical intervention during the second week after trauma caused no further reduction of HLA-DR expression on monocytes and of the ex vivo TNFα-synthesis. However, major surgery such as intramedullary nailing or pelvic osteosynthesis caused reduction of the HLA-DR expression and TNFα-synthesis, whereas, minor surgical interventions such as osteosynthesis on peripheral joints exhibited no significant effects on the immune response. Surgical intervention performed to clear septic foci normalised immune response by elevating HLA-DR expression on monocytes and ex vivo TNFα synthesis. Severe injury caused elevated serum IL-10 levels, whereas secondary surgery did not induce a further increase in serum IL-10 levels.Conclusion This study shows that initial trauma as well as major secondary surgery causes a suppression of immune functions, whereas minor secondary surgery does not cause significant immune disturbance.

Effect of granulocyte-macrophage colony-stimulating factor on the immune response of circulating monocytes after severe trauma.

ObjectiveSevere injury compromises functions of the antigen-presenting immune cells, resulting in an increased vulnerability toward bacterial sepsis. Support of the immune capabilities contributes a desirable therapeutic option in high-risk patients. Factors possessing immunostimulating properties such as granulocyte-macrophage colony-stimulating factor (GM-CSF) may serve as potential tools to compensate immunosuppression caused by severe trauma. In the present study, therefore, GM-CSF was examined with regard to its capacity to overcome trauma-induced down-regulation of immune functions. DesignProspective clinical experimental study. SettingUniversity hospital intensive care unit and research facility. PatientsSeverely injured patients with >25 points on the Injury Severity Score. InterventionsBlood samples of severely injured patients were incubated in vitro with 10 ng/mL GM-CSF for 6 hrs. MeasurementsHuman leukocyte antigen (HLA)-DR expression on monocytes was analyzed by flow cytometry, lipopolysaccharide-induced tumor necrosis factor (TNF)&agr; and interleukin-10 production of blood samples was measured by means of enzyme-linked immunoabsorbent assay. Main ResultsCompared with blood specimens of healthy donors, ex vivo endotoxin-induced TNF&agr; production and HLA-DR expression on monocytes were significantly reduced in blood of trauma patients. Ex vivo treatment of blood specimens with GM-CSF increased HLA-DR expression and TNF&agr; production stimulated by lipopolysaccharides in both healthy volunteers and patients on day 1 after trauma. Blood samples of patients with an uneventful recovery showed nearly normal TNF&agr; synthesis and HLA-DR expression after 2–3 wks, whereas TNF&agr; production and HLA-DR expression of patients with sepsis and multiple organ failure remained at low levels. In the sepsis/multiple organ failure group, GM-CSF also enhanced HLA-DR expression and TNF&agr; production, although the levels of the volunteers’ blood were not reached. ConclusionsThe presented data show that trauma- and sepsis-induced depression of monocyte functions can be counteracted by GM-CSF in vitro, suggesting that this substance may serve as support of immune functions in severely injured patients.

Administration of fibrinogen concentrate in exsanguinating trauma patients is associated with improved survival at 6 hours but not at discharge.

BACKGROUND Despite poor evidence and high costs, fibrinogen concentrate (FC) represents one of the most frequently used hemostatic agents in exsanguinating trauma. The aim was to assess whether the administration of FC in severely injured patients was associated with improved outcomes. METHODS Patients documented in the Trauma Registry of the German Society for Trauma Surgery (primary admissions, Injury Severity Score [ISS] ≥16) who had received FC during initial care between emergency department (ED) arrival and intensive care unit admission (FC+) were matched with patients who had not received FC (FC−). RESULTS The matched-pairs analysis yielded two comparable cohorts (n = 294 in each group) with a mean ISS of 37.6 ± 13.7 (FC+) and 37.1 ± 13.3 (FC−) (p = 0.73); the mean age was 40 ± 17 versus 40 ± 16 (p = 0.72), respectively. Patients were predominantly male (71.1% in both groups, p = 1.0). On emergency department arrival, hypotension (systolic blood pressure, ⩽90 mm Hg) occurred in 51.4% (FC+) and 48.0% (FC−) (p = 0.41), and base excess was −7.4 ± 5.3 mmol/L for FC+ and was −7.5 ± 6.2 mmol/L for FC− (p = 0.96). Patients were administered 12.8 ± 14.3 (FC+) versus 11.3 ± 10.0 (FC−) packed red blood cell units (p = 0.20). Thromboembolism occurred in 6.8% (FC+) versus 3.4% (FC−) (p = 0.06), and multiple organ failure occurred in 61.2% versus 49.0% (p = 0.003), respectively. Whereas 6-hour mortality was 10.5% for FC+ versus 16.7% for FC− (p = 0.03), the mean time to death was 7.5 ± 14.6 days versus 4.7 ± 8.6 days (p = 0.006). The overall hospital mortality rate was 28.6% versus 25.5% (p = 0.40), respectively. CONCLUSION This is the first study to investigate the effect of FC administration in bleeding trauma. In our large population of severely injured patients, the early use of FC was associated with a significantly lower 6-hour mortality and an increased time to death, but also an increased rate of multiple organ failure. A reduction of overall hospital mortality was not observed in patients receiving FC. LEVEL OF EVIDENCE Therapeutic study, level IV.

Influence of prehospital fluid resuscitation on patients with multiple injuries in hemorrhagic shock in patients from the DGU trauma registry.

Background: Severe bleeding as a result of trauma frequently leads to poor outcome by means of direct or delayed mechanisms. Prehospital fluid therapy is still regarded as the main option of primary treatment in many rescue situations. Our study aimed to assess the influence of prehospital fluid replacement on the posttraumatic course of severely injured patients in a retrospective analysis of matched pairs. Materials and Methods: We reviewed data from 35,664 patients recorded in the Trauma Registry of the German Society for Trauma Surgery (DGU). The following patients were selected: patients having an Injury Severity Score >16 points, who were ≥16 years of age, with trauma, excluding those with craniocerebral injuries, who were admitted directly to the participating hospitals from the accident site. All patients had recorded values for replaced volume and blood pressure, hemoglobin concentration, and units of packed red blood cells given. The patients were matched based on similar blood pressure characteristics, age groups, and type of accident to create pairs. Pairs were subdivided into two groups based on the volumes infused prior to hospitalization: group 1: 0-1500 (low), group 2: ≥2000 mL (high) volume. Results: We identified 1351 pairs consistent with the inclusion criteria. Patients in group 2 received significantly more packed red blood cells (group 1: 6.9 units, group 2: 9.2 units; P=0.001), they had a significantly reduced capacity of blood coagulation (prothrombin ratio: group 1: 72%, group 2: 61.4%; P≤0.001), and a lower hemoglobin value on arrival at hospital (group 1: 10.6 mg/dL, group 2: 9.1 mg/dL; P≤0.001). The number of ICU-free days concerning the first 30 days after trauma was significantly higher in group 1 (group 1: 11.5 d, group 2: 10.1 d; P≤0.001). By comparison, the rate of sepsis was significantly lower in the first group (group 1: 13.8%, group 2: 18.6%; P=0.002); the same applies to organ failure (group 1: 36.0%, group 2: 39.2%; P≤0.001). Conclusion: The high amounts of intravenous fluid replacement was related to early traumatic coagulopathy, organ failure, and sepsis rate.

Prehospital intubation of the moderately injured patient: a cause of morbidity? A matched-pairs analysis of 1,200 patients from the DGU Trauma Registry

IntroductionHypoxia and hypoxemia can lead to an unfavorable outcome after severe trauma, by both direct and delayed mechanisms. Prehospital intubation is meant to ensure pulmonary gas exchange. Limited evidence exists regarding indications for intubation after trauma. The aim of this study was to analyze prehospital intubation as an independent risk factor for the posttraumatic course of moderately injured patients. Therefore, only patients who, in retrospect, would not have required intubation were included in the matched-pairs analysis to evaluate the risks related to intubation.MethodsThe data of 42,248 patients taken from the trauma registry of the German Association for Trauma Surgery (Deutsche Gesellschaft für Unfallchirurgie (DGU)) were analyzed. Patients who met the following criteria were included: primary admission to a hospital; Glasgow Coma Scale (GCS) of 13 to 15; age 16 years or older; maximum injury severity per body region (AIS) ≤ 3; no administration of packed red blood cell units in the emergency trauma room; admission between 2005 and 2008; and documented data regarding intubation. The intubated patients were then matched with not-intubated patients.ResultsThe study population included 600 matched pairs that met the inclusion criteria. The results indicated that prehospital intubation was associated with a prolonged rescue time (not intubated, 64.8 minutes; intubated, 82.3 minutes; P ≤ 0.001) and a higher volume replacement (not intubated, 911.3 ml; intubated, 1,573.8 ml; P ≤ 0.001). In the intubated patients, coagulation parameters, such as the prothrombin time ratio (PT) and platelet count, declined, as did the hemoglobin value (PT not intubated: 92.3%; intubated, 85.7%; P ≤ 0.001; hemoglobin not intubated, 13.4 mg/dl; intubated, 12.2 mg/dl; P ≤ 0.001). Intubation at the scene resulted in an elevated sepsis rate (not intubated, 1.5%; intubated, 3.7%; P ≤ 0.02) and an elevated prevalence of multiorgan failure (MOF) and organ failure (OF) (OF not intubated, 9.1%; intubated, 23.4%; P ≤ 0.001).ConclusionsPrehospital intubation in trauma patients is associated with a number of risks and should be critically weighed, except in cases with clear indicators, such as posttraumatic apnea.

Differential immunostimulating effect of Granulocyte-macrophage colony-stimulating factor (GM-CSF), Granulocyte colony-stimulating factor (G-CSF) and Interferon γ (IFNγ) after severe trauma

Abstract.Objective:Severe trauma leads to an increased vulnerability to bacterial sepsis. In the present study, we compared the immunostimulating potential of granulocyte-colony stimulating-factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-γ).Design:Prospective clinical experimental study.Setting:University hospital intensive care unit and research facility.Patients:6 Patients with an Injury Severity Score (ISS) of more than 25 points.Interventions:Heparinized blood samples of severely injured patients and 12 healthy volunteers were incubated in vitro with 10 ng/ml GM-CSF, 10 ng/ml G-CSF or 10 ng/ml IFN-γ for 6h.Measurements:Flow cytometry: HLA-DR expression on monocytes, B- and T-lymphocytes.ELISA:LPS-induced TNFα and IL-10 production.Results:In all patients reduced cytokine production and HLA-DR expression on monocytes was established. After administration of GM-CSF and IFN-γ it in vitro, the level of HLA-DR expression on monocytes and the it ex vivo TNFα-synthesis increased while only GM-CSF increased significantly IL-10-liberation after LPS-stimulation. However, only IFN-γ had the capacity to enhance HLA-DR on B- and T-Lymphocytes. G-CSF it in vitro had no significant effect on the measured parameter.Conclusions:These data suggest that GM-CSF and IFN-γ may serve to support immune functions in severely injured patients.

Influence of prehospital volume replacement on outcome in polytraumatized children

IntroductionSevere bleeding after trauma frequently results in poor outcomes in children. Prehospital fluid replacement therapy is regarded as an important primary treatment option. Our study aimed, through a retrospective analysis of matched pairs, to assess the influence of prehospital fluid replacement therapy on the post-traumatic course of severely injured children.MethodsThe data for 67,782 patients from the TraumaRegister DGU® of the German Trauma Society were analyzed. The following inclusion criteria were applied: injury severity score ≥16 points, primary admission, age 1 to 15 years old, systolic blood pressure ≥20 mmHg at the accident site and transfusion of at least one unit of packed red blood cells (pRBC) in the emergency trauma room prior to intensive care admission. As volume replacement therapy depends on age and body weight, especially in children, three subgroups were formed according to the mean value of the administered prehospital volume. The children were matched and enrolled into two groups according to the following criteria: intubation at the accident site (yes/no), Abbreviated Injury Scale (four body regions), accident year, systolic blood pressure and age group.ResultsA total of 31 patients in each group met the inclusion criteria. An increase in volume replacement was associated with an elevated need for a transfusion (≥10 pRBC: low volume, 9.7%; high volume, 25.8%; P = 0.18) and a reduction in the ability to coagulate (prothrombin time ratio: low volume, 58.7%; high volume, 55.6%; P = 0.23; prothrombin time: low volume, 42.2 seconds; high volume, 50.1 seconds; P = 0.38). With increasing volume, the mortality (low volume, 19.4%; high volume, 25.8%; P = 0.75) and multiple organ failure rates (group 1, 36.7%; group 2, 41.4%; P = 0.79) increased. With increased volume, the rescue time also increased (low volume, 62 minutes; high volume, 71.5 minutes; P = 0.21).ConclusionFor the first time, a tendency was shown that excessive prehospital fluid replacement in children leads to a worse clinical course with higher mortality and that excessive fluid replacement has a negative influence on the ability to coagulate.

[Significance of liver trauma for the incidence of sepsis, multiple organ failure and lethality of severely injured patients. An organ-specific evaluation of 24,771 patients from the trauma register of the DGU].

BACKGROUND The prognosis of multiple injured patients is mainly limited by initial severe hemorrhage causing hemorrhagic shock, subsequent sepsis and multiple organ failure (MOF). Although mechanisms of altered microcirculation, cytokine release etc. have been intensively investigated, little is known about the relevance of severe liver trauma as an independent predictive outcome factor in these patients. This study aimed to clarify the impact of severe liver trauma in one of the largest trauma databases. PATIENTS AND METHODS The study was based on data from the German trauma register within the German Society for Trauma Surgery (DGU) and 24,711 patients from 113 hospitals were collected for retrospective analysis between 1993 and 2005. Patients with an injury severity score (ISS) >16, no isolated head injury and primary admission to a trauma center were included. Data were allocated according to the injury pattern into I liver group (severe damage of the liver, AIS>3 and AIS abdomen <3), II Abdomen group (severe abdominal trauma AIS>3, AIS liver <3) and III Control group (liver and/or abdominal trauma AIS<3, other trauma AIS>3). RESULTS Out of 24,771 multiple injured patients from 113 trauma centers, 321 individuals were identified which matched the criteria of the liver group. Another 574 patients were allocated to the abdomen group while the majority of patients formed the trauma group (9574). Severe injury of the liver is associated with excessive demands for volume resuscitation and induces a significantly increased risk for sepsis and MOF compared to both other groups (sepsis 19.9% vs 11%; MOF 32.7% vs 16.6%). Furthermore, deleterious outcome is more frequent associated with patients with severe liver trauma (lethality 34.9%) compared to severe abdominal trauma (12%) and the control group (19.5%). CONCLUSIONS Severe liver trauma is an independent predictor for severe hemorrhage with a substantial increased risk of sepsis, MOF and trauma-related death. While conservative treatment of patients with severe liver trauma but no hemorrhage is effective, patients with hemodynamic instability seem to form a subgroup where contemporary treatment modalities are not yet sufficient.

Bedeutung des Lebertraumas für die Inzidenz von Sepsis, Multiorganversagen und Letalität bei Schwerstverletzten

BACKGROUND The prognosis of multiple injured patients is mainly limited by initial severe hemorrhage causing hemorrhagic shock, subsequent sepsis and multiple organ failure (MOF). Although mechanisms of altered microcirculation, cytokine release etc. have been intensively investigated, little is known about the relevance of severe liver trauma as an independent predictive outcome factor in these patients. This study aimed to clarify the impact of severe liver trauma in one of the largest trauma databases. PATIENTS AND METHODS The study was based on data from the German trauma register within the German Society for Trauma Surgery (DGU) and 24,711 patients from 113 hospitals were collected for retrospective analysis between 1993 and 2005. Patients with an injury severity score (ISS) >16, no isolated head injury and primary admission to a trauma center were included. Data were allocated according to the injury pattern into I liver group (severe damage of the liver, AIS>3 and AIS abdomen <3), II Abdomen group (severe abdominal trauma AIS>3, AIS liver <3) and III Control group (liver and/or abdominal trauma AIS<3, other trauma AIS>3). RESULTS Out of 24,771 multiple injured patients from 113 trauma centers, 321 individuals were identified which matched the criteria of the liver group. Another 574 patients were allocated to the abdomen group while the majority of patients formed the trauma group (9574). Severe injury of the liver is associated with excessive demands for volume resuscitation and induces a significantly increased risk for sepsis and MOF compared to both other groups (sepsis 19.9% vs 11%; MOF 32.7% vs 16.6%). Furthermore, deleterious outcome is more frequent associated with patients with severe liver trauma (lethality 34.9%) compared to severe abdominal trauma (12%) and the control group (19.5%). CONCLUSIONS Severe liver trauma is an independent predictor for severe hemorrhage with a substantial increased risk of sepsis, MOF and trauma-related death. While conservative treatment of patients with severe liver trauma but no hemorrhage is effective, patients with hemodynamic instability seem to form a subgroup where contemporary treatment modalities are not yet sufficient.

GM-CSF priming of human monocytes is dependent on ERK1/2 activation.

The ability to augment monocyte functions such as TNF-α-producing capacities confers a high immunostimulating potential to GM-CSF. In the present investigation, the mechanism of the GM-CSF-mediated enhancement of monocyte cytokine production was analysed with regard to the involvement of intracellular signalling pathways. GM-CSF primes human monocytes dose- and time-dependently for enhanced LPS-stimulated TNF-α synthesis. Pre-incubation with 10 ng/ml GM-CSF for 6 h before LPS stimulation (10 ng/ml) caused a 3.4 ± 1.9-fold increase in TNF-α release compared to unprimed controls. This was associated with increased phosphorylation of IκBα and elevated nuclear levels of the NF-κB components p50 and p65 and NF-κB binding to DNA. LPS-induced AP-1 binding to DNA was also enhanced in GM-CSF-pre-incubated cells. GM-CSF treatment also caused a slight increase in TLR4 expression on monocytes while CD14 expression remained unchanged. GM-CSF-priming was unaffected by inhibitors of p38 MAPK (SB203580) and lipoxygenase (NDGA). In contrast, the broad-spectrum tyrosine kinase inhibitor genistein and the MEK-1 inhibitor (PD98059) abrogated GM-CSF priming of TNF-α release and activation of both NF-κB and AP-1. It is concluded that a tyrosine kinase of the GM-CSF-triggered ERK1/2 pathway augments the LPS-induced NF-κB and AP-1 activation.