Intramedullary nailing of femoral shaft fractures in polytraumatized patients. a longitudinal, prospective and observational study of the procedure-related impact on cardiopulmonary- and inflammatory responses
© Husebye et al; licensee BioMed Central Ltd. 2012
Received: 28 September 2011
Accepted: 5 January 2012
Published: 5 January 2012
Early intramedullary nailing (IMN) of long bone fractures in severely injured patients has been evaluated as beneficial, but has also been associated with increased inflammation, multi organ failure (MOF) and morbidity. This study was initiated to evaluate the impact of primary femoral IMN on coagulation-, fibrinolysis-, inflammatory- and cardiopulmonary responses in polytraumatized patients.
Twelve adult polytraumatized patients with femoral shaft fractures were included. Serial blood samples were collected to evaluate coagulation-, fibrinolytic-, and cytokine activation in arterial blood. A flow-directed pulmonary artery (PA) catheter was inserted prior to IMN. Cardiopulmonary function parameters were recorded peri- and postoperatively. The clinical course of the patients and complications were monitored and recorded daily.
Mean Injury Severity Score (ISS) was 31 ± 2.6. No procedure-related effect of the primary IMN on coagulation- and fibrinolysis activation was evident. Tumor necrosis factor alpha (TNF-α) increased significantly from 6 hours post procedure to peak levels on the third postoperative day. Interleukin-6 (IL-6) increased from the first to the third postoperative day. Interleukin-10 (IL-10) peaked on the first postoperative day. A procedure-related transient hemodynamic response was observed on indexed pulmonary vascular resistance (PVRI) two hours post procedure. 11/12 patients developed systemic inflammatory response syndrome (SIRS), 7/12 pneumonia, 3/12 acute lung injury (ALI), 3/12 adult respiratory distress syndrome (ARDS), 3/12 sepsis, 0/12 wound infection.
In the polytraumatized patients with femoral shaft fractures operated with primary IMN we observed a substantial response related to the initial trauma. We could not demonstrate any major additional IMN-related impact on the inflammatory responses or on the cardiopulmonary function parameters. These results have to be interpreted carefully due to the relatively few patients included.
Keywordsintramedullary reaming intramedullary nailing inflammatory response femoral shaft fracture long bone fracture polytrauma coagulation and fibrinolysis cytokine activation cardiopulmonary response to trauma
The appropriate timing of internal stabilization of long bone fractures has been and still seems to be controversial [1–5]. Early fracture stabilization has, in several studies, been associated with reduced pulmonary complications and mortality [6–11], whereas in other studies early intramedullary nailing (IMN) has been associated with increased inflammation, multi organ failure (MOF) and morbidity [12–14]. Severe trauma results in a generalized inflammatory response that can pose a threat to the organism. This response results in vasodilatation with leakage of fluids from the blood vessels, aggregation of platelets and leukocytes with clogging of small capillaries and dysfunction of involved organs. The lungs are most frequently affected, with function failure spanning from mild dysfunction to grave failure (adult respiratory distress syndrome (ARDS)). In patients with severe chest trauma Pape et al. found a higher incidence of posttraumatic ARDS and mortality when early femoral IMN was done. In trauma patients, operative procedures, such as IMN, represent a second insult, and the ideal time for such treatment, to pose as little harm as possible, has been a topic of discussion [6, 15]. The aim of the study was to evaluate the additional procedure-related impact of primary femoral IMN on coagulation-, fibrinolysis-, inflammatory- and cardiopulmonary responses in polytraumatized patients.
This study was approved by the Regional Committee for Medical and Health Research (ref. 02066). Informed consent or assent was obtained from the patients or their representative prior to inclusion in this study. In cases when the patients were unable to give personal consent at hospital admission, the personal consent was given posterity.
Inclusion criteria were patients, 18-65 years of age, admitted to the hospital between May 2003 and December 2004 with femoral diaphyseal fracture suitable for initial IMN within 24 hours post injury. The exclusion criteria were previous femoral shaft fracture, pathological fracture, femoral deformities or pregnancy.
The injury severity was assessed according to the Abbreviated Injury Scale (AIS) and scored by a certified AIS-registrar [16, 17]. The overall severity of the injuries was calculated according to the Injury Severity Score (ISS) and New Injury Severity Score (NISS) [18, 19]. The time from injury to hospital admittance and to IMN, AO classification, Gustilo Anderson classification of open fractures, and amount of blood products transfused were recorded. The clinical course of the patients and complications were monitored and recorded daily. Number of days in the intensive care unit (ICU) was also noted. Severely injured patients were defined as patients with ISS ≥ 16 [20, 21]. The definitions of systemic inflammatory response syndrome (SIRS) and sepsis were according to the Consensus Conference of the American College of Chest Physicians and the Society of Critical Care Medicine of 1992 . The definitions of acute lung injury (ALI) and ARDS were according to the American-European Consensus Conference on Acute Respiratory Distress Syndrome of 1994 .
Time schedule for analysis, registrations and calculations
Blood sample analyses
Cardiopulmonary registrations and calculations
Blood gases, Hb, cytokines, coagulation, fibrinolysis, complement
Blood gases, Hb, cytokines, coagulation, fibrinolysis, complement
After nail insertion
Blood gases, coagulation, fibrinolysis, complement
30 minutes after nail insertion
Blood gases, cytokines, coagulation, fibrinolysis, complement
2 hours after nail insertion
Blood gases, Hb, cytokines, coagulation, fibrinolysis, complement
6 hours after nail insertion
Blood gases, Hb, cytokines, coagulation, fibrinolysis, complement
1. postoperative day at 0800
Blood gases, Hb, cytokines, coagulation, fibrinolysis, complement
1. postoperative day at 1800
2. postoperative day at 0800
Blood gases, Hb, cytokines, coagulation, fibrinolysis, complement
2. postoperative day at 1800
3. postoperative day at 0800
Blood gases, Hb, cytokines, coagulation, fibrinolysis, complement
All patients had general anesthesia with the exception of one, who received spinal anesthesia. A standard antegrade technique was used for reamed IMN (Bicut Intramedullary Reamer System, Stryker, Trauma GmbH, Schöhnkirchen, Germany), and the femur was sequentially reamed 1-2 mm greater than the applied nail diameter. In 11/12 patients a T2 nail (Stryker) was used. In one patient a Groβe-Kempf nail (Stryker) was used. Cephalotine 2 g × 3-4 (Keflin®, 50 mg/ml, Lilly, Florence, Italy) was given intravenously as antibiotic prophylaxis according to the hospital routines.
Hemoglobin (Hb) was measured in peripheral blood. Arterial- and mixed venous blood gas analyzes were collected according to Table 1. Serial blood samples were collected for determination of coagulation-, fibrinolytic-, complement- and cytokine activation in arterial (sample time A-I) and mixed venous (sample time B-I) blood (Table 1). The samples were collected in Stabylite® (Biopool AB, Umeå, Sweden) tubes, and vacutainer tubes containing ethylenediaminetetraacetic acid (K2EDTA) or 1/10 vol 0.13 M trisodium citrate. The tubes were immediately placed on ice and centrifuged within 30 minutes at 2000 g for 12 minutes at 4°C. Plasma was aliquoted, transferred to 1.5 mL polypropylene tubes, and stored at -70°C until assayed. The samples were thawed only once.
Citrated plasma was used for the determination of thrombin-antithrombin-complexes (TAT) (Enzygnost TAT Micro, Behringwerke AG, Marburg, Germany), plasminogen activator inhibitor (PAI-1) (TriniLIZE PAI-1 activity, Trinity Biotech, Jamestown, NY, USA), tissue plasminogen activator (t-PA) antigen (TriniLIZE t-PA antigen, Trinity Biotech), soluble tissue factor (sTF) (Imubind TF Elisa, American Diagnostica Inc., Greenwich, CT, USA) and terminal SC5b-9 complement complex (TCC) (by using an enzyme-linked immunosorbent assay (ELISA) as described by Mollnes et al. ). Stabylite plasma was used for determination of t-PA activity (TriniLIZE t-PA activity, Trinity Biotech). When analyzed with the described assays the median plasma levels in healthy humans are; t-PA activity 0.2-2 IU/ml, t-PA antigen 4.0 (women) and 5.5 (men) ng/ml (age 25 - 34), PAI-1 activity 2.60 IU/ml, the normal reference range for TAT complex is 1.0 - 8.0 ug/L, and sTF is normally not present at measurable levels.
The following cytokines were analyzed in EDTA plasma by using commercially available ELISA kits; TNF-α (R&D Systems Europe, Abingdon, UK, Human TNF-α QuantiGlo Chemiluminescent Sandwich ELISA), IL-6 (R&D, Human IL-6 QuantiGlo Chemiluminescent Sandwich ELISA), IL-1β (R&D, Human IL-1β QuantiGlo Chemiluminescent Sandwich ELISA), IL-8 (R&D, Human CXCL8/IL-8 Quantikine colorimetric Sandwich ELISA) and IL-10 (R&D, Human IL-10 QuantiGlo Chemiluminescent Sandwich ELISA). Samples from apparently healthy volunteers evaluated with the applied assays demonstrated the following mean levels; TNF-α 2.88 pg/mL, IL-6 1.32 pg/mL, and IL-10 7.15 pg/mL.
Statistical analyzes were performed using the Statistical Package for Social Science (SPSS) software, version 16.0 (SPSS Inc, Chicago, IL, USA). Normally distributed data are presented as group means and standard error of the mean (S.E.M.). Paired-samples t-test was used for evaluation of increasing or decreasing levels between two measuring points. Non-parametric statistics were used when Kolmogorov-Smirnov test and histograms demonstrated not normally distributed data, as shown for RBCT, coagulation-, fibrinolysis- and cytokine activation. Median levels are then presented. Wilcoxon Signed Rank Test was used as the non-parametric test describing increasing and decreasing levels between two measuring points. Differences were considered significant at P levels ≤ 0.05.
12 patients were included, 11 men and 1 woman, aged 27.6 ± 2.5 (range 18-44) years. The mechanisms of injury were car accident (10/12) and fall from heights (2/12). ISS was 31 ± 2.6, NISS was 34.3 ± 2.1, and AIS thorax was 3.7 ± 0.2. The time from injury to admission was 95 ± 11 (range 22 - 365) minutes. One patient had bilateral femoral shaft fractures. The fractures were classified according to AO; 3 A-fractures, 3 B-fractures and 7 C-type fractures. Two fractures were open (Gustilo Anderson 2 and 3A), and in 3 cases the fracture was openly reduced. All included patients had additional extremity- and thoracic injuries, 50% (6/12) abdominal, and 42% (5/12) had head injuries. The time from injury to femoral IMN was 544 ± 42 (range 330 - 830) minutes. The IMN operating time was 106 ± 7 (range 60 - 155) minutes. Number of days in the intensive care unit (ICU) was 16 ± 4 (range 4 - 48). The postoperative course was prolonged by pneumonia (7/12), ALI (3/12), ARDS (3/12) and sepsis (3/12). All except one patient fulfilled the SIRS criteria.
Blood product transfusions.
Admission - IMN (A-B)
IMN - 6 hours post IMN (B-F)
Admission - 1. postoperative day (A-G1)
1. - 2. postoperative day (G1 - H1)
2. - 3. postoperative day (H1 - I)
Coagulation and fibrinolysis
In all patients a marked activation of the coagulation- and fibrinolytic systems was seen at hospital admission, but no significant procedure-related effect could be detected.
sTF is normally not present at measurable levels in the circulation. Arterial sTF (Figure 2b) levels were increased at hospital admission and increased during the study period. The increase reached significance from nail insertion (C) to 72 hours (I) post nail insertion (p = 0.011). The highest sTF levels were present at the second and third postoperative day.
The arterial t-PA activity (data not shown) levels were low at admission and stayed low during the study period, and the arterial t-PA antigen (Figure 2c) levels were high at admission and stayed elevated until decreasing from day one post IMN.
Arterial PAI-1(Figure 2d) levels were high at admission and increased further significantly from admission (A) to skin incision (B) (p = 0.001) and from nail insertion (C) to six hours (F) post nail insertion (p = 0.012). From six (F) to 48 hours (H1) post nail insertion (p = 0.005) the PAI-1 activity levels decreased. Peak PAI-1 activity levels were demonstrated at skin incision (B) and at six hours post IMN (F). A procedure-related effect participating in the PAI-1 peak level response could not be ruled out.
No significant differences were demonstrated between arterial and mixed venous blood levels for TAT, sTF, t-PA activity or PAI-1 (data not shown).
Coagulation and fibrinolysis in patients that were primary external fixated demonstrated similar levels as related to IMN. At secondary IMN a procedure-related increase of TAT, sTF and t-PA activity and antigen were present and the PAI-1 response was almost absent.
Arterial TCC levels were studied in 6 patients. The TCC levels were slightly increased in most patients at admission and increased further (ns) from hospital admission (A) to the third postoperative day (I) (data not shown).
No significant differences were demonstrated between arterial and mixed venous blood levels for TNF-α, IL-6, IL-10, IL-1β, or IL-8.
Arterial IL-6 levels were elevated already at hospital admission, and for the whole study period the IL-6 levels exceeded 200 pg/mL. Peak levels were observed the third postoperative day (Figure 3b). The increase from skin incision (B) to peak level at the third day post procedure was not significant (p = 0.39).
Arterial IL-10 levels were elevated at hospital admission. A decrease from hospital admission to skin incision (p = 0.009) and a non-significant increase from skin incision to the first post IMN day (p = 0.28) was observed (Figure 3c).
IL-1β levels at all sampling locations were mostly below the lowest detectable level at 0.4 pg/mL (data not shown). IL-8 levels demonstrated no significant increases or decreases within the study group (data not shown).
Cytokine release in patients that were primary external fixated and secondary nailed were both significantly lower and peak levels occurred earlier when compared to the response after initial IMN.
The SVRI (Figure 5b) levels were lower than normal at skin incision and the levels, with the exception of a minor procedure-related (ns) increase, continued to decrease (ns) during the study period. The changes in the filling pressures in the right (CVP) and the left (PCWP) side of the heart were modest, but with levels in the upper range of normal levels (data not shown). Both CVP and PCWP demonstrated peak levels at 30 minutes post IMN (D), the increases, however, were not significant. The MPAP (Figure 5c) levels were high at skin incision (B), had a minor transient procedure-related increase, and increased further from the first (G1) to the third postoperative day (I) (ns, p = 0.07). The PVRI levels (Figure 5d) were high at skin incision (B) and increased (ns, p = 0.057) further from skin incision (B) until peaking at 2 hours after the nail was inserted (E).
Cardiopulmonary function in patients operated with external fixation and secondary nailing
PAO2 - PaO2 difference after external fixation was comparable to the levels after primary IMN. Related to secondary nailing, the PAO2 - PaO2 difference was elevated at skin incision, and demonstrated decreasing levels during the study period. The SaO2 levels after external fixation and secondary nailing were comparable to the levels after primary IMN. Minor increases of PVRI, MPAP and PCWP values were seen between 30 minutes and two hours after secondary IMN.
In this study on 12 polytraumatized patients with femoral shaft fractures we investigated the impact of IMN on cardiopulmonary function and inflammation- and coagulation/fibrinolytic responses. The main observation was that an additional effect of the primary IMN, a second hit, on the activation of coagulation and fibrinolysis could not be clearly identified. A transient procedure-related PVRI increase was present. This may be a result of intravasation of intramedullary content. Delayed peak levels of arterial TNF-α, IL-6 and IL-10 levels were observed and might be the result of a second hit phenomenon. Primary IMN did not demonstrate a negative impact on pulmonary shunting.
In the present study systemic activation of the coagulation system, represented by arterial TAT level increase, was present at patient admission to the hospital. The high TAT levels were mainly related to the injury per se, and primary IMN did not result in additional TAT generation. Activation of fibrinolysis, measured as elevation of t-PA activity, was low. However, the t-PA antigen levels were high at hospital admission and stayed high before it dropped at 48 hours after IMN, which verify an increased fibrinolytic activity for much longer than the evaluation of t-PA activity alone suggests. The inhibition of the fibrinolysis, measured as augmented PAI-1 activity levels, was present at admission, and increased further. PAI-1 is produced upon stimulation by endothelial cells, platelets, fibroblasts and smooth muscle cells and functions as an acute phase reactant , and also binds circulating t-PA rapidly. Despite the prolonged increase in t-PA antigen levels, the functional effect of the PAI-1 increase (which is faster than other acute phase reactants like CRP and fibrinogen), combined with the nearly absent t-PA activity increase (neutralized by PAI-1) definitely represent a fibrinolytic shutdown and a prothrombotic state, which is often prevailing after orthopedic surgery or trauma.
Tissue factor (TF) is the most potent trigger of the coagulation system known . sTF is normally not present at measurable levels in the circulation . Marked peaks of plasma TF activity have been demonstrated during bone preparation in total hip replacement surgery , which indicates release of TF-rich material to the systemic circulation from traumatized tissues, mainly the bone marrow which is a rich source of TF. This mechanism may also explain the sTF levels found in the present study; elevated arterial sTF blood levels were demonstrated at hospital admission (A), which decreased slightly until skin incision (B) and then increased significantly until the third postoperative day (I), indicating an enduring procoagulant state.
Generation of proinflammatory cytokines has been demonstrated to be proportional to the extent of tissue injury and hypoxia [29–32]. TNF-α levels in our study were steady and slightly elevated until six hours post procedure (F) and were still increasing at day three post IMN. The still increasing levels at day three are not in agreement with other studies. Spielmann et al.  demonstrated the highest TNF-α level in trauma patients 12 hours post injury, Kobbe et al. , however, demonstrated no significant elevation of TNF-α. Great variations in TNF-α levels (when measured) are observed in clinical studies, which can be explained by the short half-life of TNF-α .
The IL-6 levels in the present study were in general higher than 200 pg/mL, a level which is associated with SIRS . In the one patient without SIRS, peak IL-6 level (at 6 hours post procedure) was 106 pg/mL. The elevated IL-6 levels in the present study were in agreement with other investigations demonstrating a post injury association between increased levels of IL-6, and high ISS and postoperative complications [29–32]. The IL-6 level peak in the present study occurred later than peak levels observed in other studies [13, 14, 29, 31, 35] in which IL-6 peaked 4 - 24 hours post injury or post procedure and persisted for 3 - 10 days [31, 35]. Orthopedic surgery has in particular been associated with local release of IL-6 . Pape et al.  investigated patients with femoral shaft fractures and found venous IL-6 peak levels 24 hours after IMN. When the femoral fracture was initially stabilized with external fixation and secondarily converted to an intramedullary implant, they did not, however, observe a surgery-related IL-6 increase . These results are inconsistent with the results in the present study demonstrating arterial IL-6 peak level at the second postoperative day after primary IMN and also a procedure-related IL-6 response after secondary IMN. The IL-6 levels after secondary nailing in our study were significantly lower than the levels after primary IMN. The results from the study of Pape et al.  were also inconsistent with the results from the study of Morley et al.  in which blood samples from the femoral canal before and after reaming of the canal showed very high levels of IL-6 after intramedullary reaming (median 3947 at opening and 15903 pg/mL after reaming). These very high levels indicated a significant local inflammatory reaction following the dual trauma (fracture and IMN). Due to intravasation and pulmonal sequestering of bone marrow content at intramedullary pressure increase during femoral canal reaming, an additional pulmonary IL-6 activation has been suggested in an experimental porcine study . Levels of IL-6 in both mixed venous and arterial blood were analyzed in the present study, but the results did not confirm the suggestion.
For the evaluation of the anti-inflammatory response IL-10 was studied. IL-10 levels were elevated during the study period, and peak IL-10 level was observed at the first day post primary IMN. This IL-10 response was delayed compared to other studies demonstrating an IL-10 response after 1 - 6 hours post injury [34, 40].
In this study we have used the non-parametric tests for evaluation of coagulation-, fibrinolysis- and cytokine activation. Both effect size and power calculations of the results have demonstrated large variations, which indicate a possibility for a Type 2 error and insignificant results due to the limited sample size.
In the literature, there is no uniform understanding of the effect of IMN on hemodynamics and pulmonary function. Early operative fracture treatment, especially of large long bones (femur), has empirically been associated with reduction in the occurrence of pulmonary failure (ARDS) [2, 41, 42]. However, some data also indicate that the early internal stabilization of these fractures in itself can have negative impacts on pulmonary function. The total effect of IMN on morbidity seems, however, to be beneficial.
The reported incidences of ALI and ARDS in severely injured patients with femoral shaft fractures are not uniform [2, 43, 44]; a higher incidence is suggested if the fractures are accompanied by thoracic injuries . In the present study 6/12 patients had ALI or ARDS (3/12 ALI and 3/12 ARDS), and all the patients had thoracic injury. The pathophysiology of the early ALI after trauma is fluid leakage and pulmonary edema combined with inflammatory cell infiltration of pulmonary tissue. In addition, a hypoxemic vasoconstriction and capillary microthrombosis creates a ventilation-perfusion mismatch, clinically manifested as hypoxemia. The PAO2 - PaO2 difference increased in the severely injured patients in this study as a surrogate indicator for increased pulmonary shunting. Pulmonary vascular changes may cause an increased pulmonary vascular resistance and increase the MPAP . In the present study MPAP was elevated already at skin incision, and demonstrated a minor procedure-related increase, before continuously increasing towards the end of the study period. Simultaneously, a procedure-related PVRI level increase was observed. In previous human studies increased MPAP, PVR and CVP plus decreased PaO2 have been associated with pulmonary embolism . These associations, however, have to be interpreted carefully as pressure increases in previous normal, easily distendable, pulmonary blood vessels may retain undetectable until at least 30% of the vessels are occluded . In pre-injured lungs the effect of compensatory dilatation will not occur equivalently, and the flow in the still open pulmonary vessels will increase and create significantly elevated PVR levels. The filling pressures of the heart, CVP and PCWP, are influenced by treatment, quantum of intravenous fluid/blood administration and the titration of ventilator volumes, pressures and rates. As strict control of these parameters is impossible in a clinical setting, CVP and PCWP are not suitable for the evaluation of impact of surgical interventions on cardiac function.
Polytraumatized patients usually consist of a heterogeneous group of patients, and firm conclusions from clinical studies are difficult to draw. Differences in the extent of injury, time from injury to hospital admission, time from admission to operation, extent of further operations and amount of blood product transfusions induce a wide range of variance. The included patients in the present study were extensively examined, which also made the patient inclusion and follow-up challenging. The present patient material consisted of patients with high ISS, femoral shaft fractures equally treated, and all registrations, calculations and analyzes were strictly related to IMN. However, the included patients were relatively few. We did not differentiate and relate the observations and calculations to specific organ system injuries. For such differentiation, larger studies and multi-centre trials are needed.
In the severely injured patients with femoral shaft fractures operated with primary IMN we observed a substantial response related to the initial trauma. We could not demonstrate any major additional IMN-related impact on the inflammation or the cardiopulmonary function parameters. A transient cardiopulmonary response related to IMN, however, was demonstrated. Delayed arterial TNF-α, IL-6 and IL10 peak levels were observed, and it could be questioned whether these changes were related to the procedure. These results have to be interpreted carefully due to the relatively few patients included in the study. The inflammation-associated complication rate was high.
Abbreviated Injury Scale
Acute lung injury
Adult respiratory distress syndrome
Indexed cardiac output
Central venous pressure
Intensive care unit
Injury severity score
Mean arterial pressure
Multi Organ Failure
Mean pulmonary artery pressure
New injury severity score
Plasminogen activator inhibitor-1
Partial pressure of arterial oxygen
Alveolo-arterial oxygen difference
Pulmonary capillary wedge pressure
Pulmonary vascular resistance
Indexed pulmonary vascular resistance
Red blood cell transfusion
Standard error of the mean
Systemic inflammatory response syndrome
Statistical Package for Social Science
Soluble tissue factor
Mixed venous oxygen saturation
Systemic vascular resistance
Indexed systemic vascular resistance
Terminal complement complex
Tumor necrosis factor-alpha
Tissue plasminogen activator.
The authors wish to express their gratitude to Lisbeth Sætre, Center for Clinical Research, Oslo University Hospital, Ullevaal, Norway, for carefully analyzing the blood samples.
- Enninghorst N, Toth L, King KL, McDougall D, Mackenzie S, Balogh ZJ: Acute definitive internal fixation of pelvic ring fractures in polytrauma patients: a feasible option. J Trauma. 2010, 68: 935-941. 10.1097/TA.0b013e3181d27b48.View ArticlePubMedGoogle Scholar
- O'Toole RV, O'Brien M, Scalea TM, Habashi N, Pollak AN, Turen CH: Resuscitation Before Stabilization of Femoral Fractures Limits Acute Respiratory Distress Syndrome in Patients With Multiple Traumatic Injuries Despite Low Use of Damage Control Orthopedics. J Trauma. 2009, 67: 1013-1021. 10.1097/TA.0b013e3181b890be.View ArticlePubMedGoogle Scholar
- Pape HC: Effects of changing strategies of fracture fixation on immunologic changes and systemic complications after multiple trauma: damage control orthopedic surgery. J Orthop Res. 2008, 26: 1478-1484. 10.1002/jor.20697.View ArticlePubMedGoogle Scholar
- Pape HC, Rixen D, Morley J, Husebye EE, Mueller M, Dumont C, Gruner A, Oestern HJ, Bayeff-Filoff M, Garving C, et al: Impact of the method of initial stabilization for femoral shaft fractures in patients with multiple injuries at risk for complications (borderline patients). Ann Surg. 2007, 246: 491-499; discussion 499-501. 10.1097/SLA.0b013e3181485750.PubMed CentralView ArticlePubMedGoogle Scholar
- Pape HC, Tornetta P, Tarkin I, Tzioupis C, Sabeson V, Olson SA: Timing of fracture fixation in multitrauma patients: the role of early total care and damage control surgery. J Am Acad Orthop Surg. 2009, 17: 541-549.PubMedGoogle Scholar
- Bone LB, Johnson KD, Weigelt J, Scheinberg R: Early versus delayed stabilization of femoral fractures. A prospective randomized study. J Bone Joint Surg Am. 1989, 71: 336-340.PubMedGoogle Scholar
- Bosse MJ, MacKenzie EJ, Riemer BL, Brumback RJ, McCarthy ML, Burgess AR, Gens DR, Yasui Y: Adult respiratory distress syndrome, pneumonia, and mortality following thoracic injury and a femoral fracture treated either with intramedullary nailing with reaming or with a plate. A comparative study. J Bone Joint Surg Am. 1997, 79: 799-809.PubMedGoogle Scholar
- Goris RJ, Gimbrere JS, van Niekerk JL, Schoots FJ, Booy LH: Early osteosynthesis and prophylactic mechanical ventilation in the multitrauma patient. J Trauma. 1982, 22: 895-903. 10.1097/00005373-198211000-00002.View ArticlePubMedGoogle Scholar
- Johnson KD, Cadambi A, Seibert GB: Incidence of adult respiratory distress syndrome in patients with multiple musculoskeletal injuries: effect of early operative stabilization of fractures. J Trauma. 1985, 25: 375-384. 10.1097/00005373-198505000-00001.View ArticlePubMedGoogle Scholar
- Riska EB, von Bonsdorff H, Hakkinen S, Jaroma H, Kiviluoto O, Paavilainen T: Prevention of fat embolism by early internal fixation of fractures in patients with multiple injuries. Injury. 1976, 8: 110-116. 10.1016/0020-1383(76)90043-7.View ArticlePubMedGoogle Scholar
- Waydhas C, Nast-Kolb D, Trupka A, Zettl R, Kick M, Wiesholler J, Schweiberer L, Jochum M: Posttraumatic inflammatory response, secondary operations, and late multiple organ failure. J Trauma. 1996, 40: 624-630. 10.1097/00005373-199604000-00018. discussion 630-621View ArticlePubMedGoogle Scholar
- Pape HC, Schmidt RE, Rice J, van Griensven M, das Gupta R, Krettek C, Tscherne H: Biochemical changes after trauma and skeletal surgery of the lower extremity: quantification of the operative burden. Crit Care Med. 2000, 28: 3441-3448. 10.1097/00003246-200010000-00012.View ArticlePubMedGoogle Scholar
- Giannoudis PV, Smith RM, Bellamy MC, Morrison JF, Dickson RA, Guillou PJ: Stimulation of the inflammatory system by reamed and unreamed nailing of femoral fractures. An analysis of the second hit. J Bone Joint Surg Br. 1999, 81: 356-361. 10.1302/0301-620X.81B2.8988.View ArticlePubMedGoogle Scholar
- Pape HC, Grimme K, van Griensven M, Sott AH, Giannoudis P, Morley J, Roise O, Ellingsen E, Hildebrand F, Wiese B, et al: Impact of intramedullary instrumentation versus damage control for femoral fractures on immunoinflammatory parameters: prospective randomized analysis by the EPOFF Study Group. J Trauma. 2003, 55: 7-13. 10.1097/01.TA.0000075787.69695.4E.View ArticlePubMedGoogle Scholar
- White TO, Clutton RE, Salter D, Swann D, Christie J, Robinson CM: The early response to major trauma and intramedullary nailing. J Bone Joint Surg Br. 2006, 88: 823-827. 10.1302/0301-620X.88B6.17359.View ArticlePubMedGoogle Scholar
- Association for the Advancement of Automotive medicine, 1998. The Abbreviated Injury Scale (1990 Revision) Update 98. Des Plaines, IL.
- Ullevaal Trauma Registry. Ullevaal University Hospital Trauma Registry.
- Osler T, Baker SP, Long W: A modification of the injury severity score that both improves accuracy and simplifies scoring. J Trauma. 1997, 43: 922-925. 10.1097/00005373-199712000-00009. discussion 925-926View ArticlePubMedGoogle Scholar
- Balogh Z, Offner PJ, Moore EE, Biffl WL: NISS predicts postinjury multiple organ failure better than the ISS. J Trauma. 2000, 48: 624-627. 10.1097/00005373-200004000-00007. discussion 627-628View ArticlePubMedGoogle Scholar
- Boyd CR, Tolson MA, Copes WS: Evaluating trauma care: the TRISS method. Trauma Score and the Injury Severity Score. J Trauma. 1987, 27: 370-378. 10.1097/00005373-198704000-00005.View ArticlePubMedGoogle Scholar
- Champion HR, Copes WS, Sacco WJ, Lawnick MM, Keast SL, Bain LW, Flanagan ME, Frey CF: The Major Trauma Outcome Study: establishing national norms for trauma care. J Trauma. 1990, 30: 1356-1365. 10.1097/00005373-199011000-00008.View ArticlePubMedGoogle Scholar
- American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992, 20: 864-874. 10.1097/00003246-199206000-00025.
- Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, LeGall JR, Morris A, Spragg R: Report of the American-European Consensus conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee. J Crit Care. 1994, 9: 72-81. 10.1016/0883-9441(94)90033-7.View ArticlePubMedGoogle Scholar
- Mollnes TE, Redl H, Hogasen K, Bengtsson A, Garred P, Speilberg L, Lea T, Oppermann M, Gotze O, Schlag G: Complement activation in septic baboons detected by neoepitope-specific assays for C3b/iC3b/C3c, C5a and the terminal C5b-9 complement complex (TCC). Clin Exp Immunol. 1993, 91: 295-300.PubMed CentralView ArticlePubMedGoogle Scholar
- Kluft C, Verheijen JH, Jie AF, Rijken DC, Preston FE, Sue-Ling HM, Jespersen J, Aasen AO: The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma. Scand J Clin Lab Invest. 1985, 45: 605-610. 10.3109/00365518509155267.View ArticlePubMedGoogle Scholar
- Dahl OE, Westvik AB, Kierulf P, Lyberg T: Effect of monomethylmethacrylate on procoagulant activities of human monocytes and umbilical vein endothelial cells in vitro. Thromb Res. 1994, 74: 377-387. 10.1016/0049-3848(94)90153-8.View ArticlePubMedGoogle Scholar
- Esmon CT: Crosstalk between inflammation and thrombosis. Maturitas. 2004, 47: 305-314. 10.1016/j.maturitas.2003.10.015.View ArticlePubMedGoogle Scholar
- Giercksky KE, Bjorklid E, Prydz H, Renck H: Circulating tissue thromboplastin during hip surgery. Eur Surg Res. 1979, 11: 296-300. 10.1159/000128078.View ArticlePubMedGoogle Scholar
- Gebhard F, Pfetsch H, Steinbach G, Strecker W, Kinzl L, Bruckner UB: Is interleukin 6 an early marker of injury severity following major trauma in humans?. Arch Surg. 2000, 135: 291-295. 10.1001/archsurg.135.3.291.View ArticlePubMedGoogle Scholar
- Giannoudis PV, Harwood PJ, Loughenbury P, Van Griensven M, Krettek C, Pape HC: Correlation between IL-6 levels and the systemic inflammatory response score: can an IL-6 cutoff predict a SIRS state?. J Trauma. 2008, 65: 646-652. 10.1097/TA.0b013e3181820d48.View ArticlePubMedGoogle Scholar
- Hoch RC, Rodriguez R, Manning T, Bishop M, Mead P, Shoemaker WC, Abraham E: Effects of accidental trauma on cytokine and endotoxin production. Crit Care Med. 1993, 21: 839-845. 10.1097/00003246-199306000-00010.View ArticlePubMedGoogle Scholar
- Pape HC, Tsukamoto T, Kobbe P, Tarkin I, Katsoulis S, Peitzman A: Assessment of the clinical course with inflammatory parameters. Injury. 2007, 38: 1358-1364. 10.1016/j.injury.2007.09.026.View ArticlePubMedGoogle Scholar
- Spielmann S, Kerner T, Ahlers O, Keh D, Gerlach M, Gerlach H: Early detection of increased tumour necrosis factor alpha (TNFalpha) and soluble TNF receptor protein plasma levels after trauma reveals associations with the clinical course. Acta Anaesthesiol Scand. 2001, 45: 364-370. 10.1034/j.1399-6576.2001.045003364.x.View ArticlePubMedGoogle Scholar
- Kobbe P, Vodovotz Y, Kaczorowski DJ, Mollen KP, Billiar TR, Pape HC: Patterns of cytokine release and evolution of remote organ dysfunction after bilateral femur fracture. Shock. 2008, 30: 43-47. 10.1097/SHK.0b013e31815d190b.View ArticlePubMedGoogle Scholar
- Lin E, Calvano SE, Lowry SF: Inflammatory cytokines and cell response in surgery. Surgery. 2000, 127: 117-126. 10.1067/msy.2000.101584.View ArticlePubMedGoogle Scholar
- Pape HC, Griensven MV, Hildebrand FF, Tzioupis CT, Sommer KL, Krettek CC, Giannoudis PV: Systemic inflammatory response after extremity or truncal fracture operations. J Trauma. 2008, 65: 1379-1384. 10.1097/TA.0b013e31818c8e8c.View ArticlePubMedGoogle Scholar
- Morley JR, Smith RM, Pape HC, MacDonald DA, Trejdosiewitz LK, Giannoudis PV: Stimulation of the local femoral inflammatory response to fracture and intramedullary reaming: a preliminary study of the source of the second hit phenomenon. J Bone Joint Surg Br. 2008, 90: 393-399.View ArticlePubMedGoogle Scholar
- Husebye EE, Opdahl H, Roise O, Aspelin T, Lyberg T: Coagulation, fibrinolysis and cytokine responses to intramedullary nailing of the femur: an experimental study in pigs comparing traditional reaming and reaming with a one-step reamer-irrigator-aspirator system. Injury. 2011, 42: 630-637. 10.1016/j.injury.2010.06.025.View ArticlePubMedGoogle Scholar
- Bone RC: Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome: what we do and do not know about cytokine regulation. Crit Care Med. 1996, 24: 163-172. 10.1097/00003246-199601000-00026.View ArticlePubMedGoogle Scholar
- Smith RM, Giannoudis PV, Bellamy MC, Perry SL, Dickson RA, Guillou PJ: Interleukin-10 release and monocyte human leukocyte antigen-DR expression during femoral nailing. Clin Orthop Relat Res. 2000, 233-240.Google Scholar
- Brundage SI, McGhan R, Jurkovich GJ, Mack CD, Maier RV: Timing of femur fracture fixation: effect on outcome in patients with thoracic and head injuries. J Trauma. 2002, 52: 299-307. 10.1097/00005373-200202000-00016.View ArticlePubMedGoogle Scholar
- Fakhry SM, Rutledge R, Dahners LE, Kessler D: Incidence, management, and outcome of femoral shaft fracture: a statewide population-based analysis of 2805 adult patients in a rural state. J Trauma. 1994, 37: 255-260. 10.1097/00005373-199408000-00018. discussion 260-251View ArticlePubMedGoogle Scholar
- Pape HC, Auf'm'Kolk M, Paffrath T, Regel G, Sturm JA, Tscherne H: Primary intramedullary femur fixation in multiple trauma patients with associated lung contusion--a cause of posttraumatic ARDS?. J Trauma. 1993, 34: 540-547. 10.1097/00005373-199304000-00010. discussion 547-548View ArticlePubMedGoogle Scholar
- Cannada LK, Taghizadeh S, Murali J, Obremskey WT, DeCook C, Bosse MJ: Retrograde intramedullary nailing in treatment of bilateral femur fractures. J Orthop Trauma. 2008, 22: 530-534. 10.1097/BOT.0b013e318183eb48.View ArticlePubMedGoogle Scholar
- Wheeler AP, Bernard GR: Acute lung injury and the acute respiratory distress syndrome: a clinical review. Lancet. 2007, 369: 1553-1564. 10.1016/S0140-6736(07)60604-7.View ArticlePubMedGoogle Scholar
- Wood KE: Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest. 2002, 121: 877-905. 10.1378/chest.121.3.877.View ArticlePubMedGoogle Scholar
- McIntyre KM, Sasahara AA: The hemodynamic response to pulmonary embolism in patients without prior cardiopulmonary disease. Am J Cardiol. 1971, 28: 288-294. 10.1016/0002-9149(71)90116-0.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.