Pathophysiology in patients with polytrauma.

The pathophysiology after polytrauma represents a complex network of interactions. While it was thought for a long time that the direct and indirect effects of hypoperfusion are most relevant due to the endothelial permeability changes, it was discovered that the innate immune response to trauma is equally important in modifying the organ response. Recent multi center studies provided a "genetic storm" theory, according to which certain neutrophil changes are activated at the time of injury. However, a second hit phenomenon can be induced by activation of certain molecules by direct organ injury, or pathogens (damage associated molecular patterns, DAMPS - pathogen associated molecular patterns, PAMPS). The interactions between the four pathogenetic cycles (of shock, coagulopathy, temperature loss and soft tissue injuries) and cross-talk between coagulation and inflammation have also been identified as important modifiers of the clinical status. In a similar fashion, overzealous surgeries and their associated soft tissue injury and blood loss can induce secondary worsening of the patient condition. Therefore, staged surgeries in certain indications represent an important alternative, to allow for performing a "safe definitive surgery" strategy for major fractures. The current review summarizes all these situations in a detailed fashion.

Validation of current procedural terminology codes for surgical stabilization of rib fractures.

INTRODUCTION: Current procedural terminology (CPT) codes for surgical stabilization of rib fractures (SSRF) are based solely on the number of ribs fixed, tricotomized at 1-3, 4-6, and ≥ 7. Our objective was to validate CPT codes against operative time at our institution, as well as further stratify complexity by rib fracture location and surgical approach. The purpose of this study is to validate the current CPT coding schema for SSRF, and to identify potential modifiers that are associated with increased case complexity. We hypothesized that operative time is associated with CPT code, number of fractures repaired, exposure technique, and fracture location. METHODS: Retrospective review of SSRF cases from October 2010 to March 2020. The primary outcome was the length of the operation (minutes). Predictor variables were CPT code, number of fractures repaired (grouped similarly to CPT codes), fractures repaired:ribs repaired ratio > 1, fracture location (sub-scapular vs. other), and positioning/exposure (supine, lateral, prone, and multiple). Kaplan-Meier time-to-event analyses were used to assess relationship with operative time. RESULTS: 188 patients underwent repair of 904 fractures. Operative time was significantly associated with both number of ribs repaired and number of fractures repaired (p<0.01). Although operative time varied significantly by CPT group (p<0.01), there was no significant difference between the 4-6 rib and the ≥ 7 rib groups (p = 0.33). By contrast, each group was significantly different from the others when organized by number of fractures repaired (p = 0.04). Operative time was significantly longer when the fractures repaired:ribs repaired ratio was > 1 (p<0.01), even after stratifying by number of ribs repaired. Both multiple positions/exposures (p<0.01), and repair of ≥ 1 sub-scapular fracture (p<0.01) were significantly associated with operative time. CONCLUSION: Number of fractures repaired provided a more accurate estimation of operative time as compared to number of ribs repaired. Based on these data, we recommend altering the CPT schema for SSRF to involve number of fractures repaired, with modifiers for both multiple positions/exposures and repair of sub-scapular fractures.

Proceedings of resources for optimal care of acute care and emergency surgery consensus summit Donegal Ireland.

BACKGROUND: Opportunities to improve emergency surgery outcomes exist through guided better practice and reduced variability. Few attempts have been made to define optimal care in emergency surgery, and few clinically derived key performance indicators (KPIs) have been published. A summit was therefore convened to look at resources for optimal care of emergency surgery. The aim of the Donegal Summit was to set a platform in place to develop guidelines and KPIs in emergency surgery. METHODS: The project had multidisciplinary global involvement in producing consensus statements regarding emergency surgery care in key areas, and to assess feasibility of producing KPIs that could be used to monitor process and outcome of care in the future. RESULTS: Forty-four key opinion leaders in emergency surgery, across 7 disciplines from 17 countries, composed evidence-based position papers on 14 key areas of emergency surgery and 112 KPIs in 20 acute conditions or emergency systems. CONCLUSIONS: The summit was successful in achieving position papers and KPIs in emergency surgery. While position papers were limited by non-graded evidence and non-validated KPIs, the process set a foundation for the future advancement of emergency surgery.

Erratum to: The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections.

[This corrects the article DOI: 10.1186/s13017-017-0141-6.].

Erratum to: Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA).

[This corrects the article DOI: 10.1186/s13017-016-0089-y.].

Viscoelastic measurements of platelet function, not fibrinogen function, predicts sensitivity to tissue-type plasminogen activator in trauma patients.

BACKGROUND: Systemic hyperfibrinolysis is a lethal phenotype of trauma-induced coagulopathy. Its pathogenesis is poorly understood. Recent studies have support a central role of platelets in hemostasis and in fibrinolysis regulation, implying that platelet impairment is integral to the development of postinjury systemic hyperfibrinolysis. OBJECTIVE: The objective of this study was to identify if platelet function is associated with blood clot sensitivity to fibrinolysis. We hypothesize that platelet impairment of the ADP pathway correlates with fibrinolysis sensitivity in trauma patients. METHODS: A prospective observational study of patients meeting the criteria for the highest level of activation at an urban trauma center was performed. Viscoelastic parameters associated with platelet function (maximum amplitude [MA]) were measured with native thrombelastography (TEG), and TEG platelet mapping of the ADP pathway (ADP-MA). The contribution of fibrinogen to clotting was measured with TEG (angle) and the TEG functional fibrinogen (FF) assay (FF-MA). Another TEG assay containing tissue-type plasminogen activator (t-PA) (75 ng mL(-1) ) was used to assess clot sensitivity to an exogenous fibrinolytic stimulus by use of the TEG lysis at 30 min (LY30) variable. Multivariate linear regression was used to identify which TEG variable correlated with t-PA-LY30 (quantification of fibrinolysis sensitivity). RESULTS: Fifty-eight trauma patients were included in the analysis, with a median injury severity score of 17 and a base deficit of 6 mEq L(-1) . TEG parameters that significantly predicted t-PA-LY30 were related to platelet function (ADP-MA, P = 0.001; MA, P < 0.001) but not to fibrinogen (FF-MA, P = 0.773; angle, P = 0.083). Clinical predictors of platelet ADP impairment included calcium level (P = 0.001), base deficit (P = 0.001), and injury severity (P = 0.001). RESULTS AND CONCLUSIONS: Platelet impairment of the ADP pathway is associated with increased sensitivity to t-PA. ADP pathway inhibition in platelets may be an early step in the pathogenesis of systemic hyperfibrinolysis.

Viscoelastic hemostatic fibrinogen assays detect fibrinolysis early.

PURPOSE: Viscoelastic hemostatic assays are emerging as the standard-of-care in the early detection of post-injury coagulopathy. TEG and ROTEM are most commonly used. Although similar in technique, each uses different reagents, which may affect their sensitivity to detect fibrinolysis. Therefore, the purpose of this study is to determine the ability of each device to detect fibrinolysis. METHODS: TEG (Rapid, Kaolin, Functional Fibrinogen) and ROTEM (EXTEM, INTEM, FIBTEM) were run simultaneously on normal blood as well as blood containing tPA from healthy volunteers (n = 10). A two-tailed, paired t-test and ANOVA were used to determine the significance between parameters obtained from normal blood and blood with tPA, and individual TEG and ROTEM assays, respectively. RESULTS: TEG detected significant changes in clot strength and 30-min lysis after the addition of tPA (p < 0.0001). All ROTEM assays detected changes in the 30-min lysis (p < 0.0001), but only INTEM detected changes in clot strength (p < 0.05). Kaolin and Rapid TEG assays detected greater changes in clot strength and lysis, but INTEM and EXTEM had decreased lysis onset times compared to TEG (p < 0.001). Functional Fibrinogen and FIBTEM assays detected lysis sooner than other TEG/ROTEM assays, and were comparable. CONCLUSIONS: TEG assays detect greater changes in clot strength compared to ROTEM. Despite this, Functional Fibrinogen and FIBTEM assays detect fibrinolysis sooner than their corresponding intrinsic and extrinsic assays. Therefore, fibrinogen assays should be employed in actively bleeding trauma patients in order to provide timely antifibrinolytic therapy.

Metabolomics of AS-5 RBC supernatants following routine storage.

BACKGROUND AND OBJECTIVES: The safety and efficacy of stored red blood cells (RBCs) transfusion has been long debated due to retrospective clinical evidence and laboratory results, indicating a potential correlation between increased morbidity and mortality following transfusion of RBC units stored longer than 14 days. We hypothesize that storage in Optisol additive solution-5 leads to a unique metabolomics profile in the supernatant of stored RBCs. MATERIALS AND METHODS: Whole blood was drawn from five healthy donors, RBC units were manufactured, and prestorage leucoreduced by filtration. Samples were taken on days 1 and 42, the cells removed, and mass spectrometry-based metabolomics was performed. RESULTS: The results confirmed the progressive impairment of RBC energy metabolism by day 42 with indirect markers of a parallel alteration of glutathione and NADPH homeostasis. Moreover, oxidized pro-inflammatory lipids accumulated by the end of storage. CONCLUSION: The supernatants from stored RBCs may represent a burden to the transfused recipients from a metabolomics standpoint.

Strategies for the management of haemorrhage following pelvic fractures and associated trauma-induced coagulopathy.

Exsanguination is the second most common cause of death in patients who suffer severe trauma. The management of haemodynamically unstable high-energy pelvic injuries remains controversial, as there are no universally accepted guidelines to direct surgeons on the ideal use of pelvic packing or early angio-embolisation. Additionally, the optimal resuscitation strategy, which prevents or halts the progression of the trauma-induced coagulopathy, remains unknown. Although early and aggressive use of blood products in these patients appears to improve survival, over-enthusiastic resuscitative measures may not be the safest strategy. This paper provides an overview of the classification of pelvic injuries and the current evidence on best-practice management of high-energy pelvic fractures, including resuscitation, transfusion of blood components, monitoring of coagulopathy, and procedural interventions including pre-peritoneal pelvic packing, external fixation and angiographic embolisation.

Trauma-Induced Coagulopathy: An Institution's 35 Year Perspective on Practice and Research.

INTRODUCTION: Injury is the second leading cause of death worldwide, and as much as 40% of injury-related mortality is attributed to uncontrollable hemorrhage. This persists despite establishment of regionalized trauma systems and advances in the management of severely injured patients. Trauma-induced coagulopathy has been identified as the most common preventable cause of postinjury mortality. METHODS: A review of the current literature was performed by collecting PUBMED references related to trauma-induced coagulopathy. Data were then critically analyzed and summarized based on the authors' clinical and research perspective, as well as that reported by other institutions and researchers interested in trauma-induced coagulopathy. A particular focus was placed on those aspects of coagulopathy in which agreement among clinical and basic scientists is currently lacking; these include, pathophysiology, the role of blood components and factor therapy, and goal-directed assessment and management. RESULTS: Trauma-induced coagulopathy has been recognized in approximately one-third of trauma patients. There is a vast range of severity, and the emergence of viscoelastic assays, such as thrombelastography and rotational thromboelastogram, has refined its diagnosis and management, particularly through the establishment of goal-directed massive transfusion protocols. Despite advancements in the diagnosis and management of trauma-induced coagulopathy, much remains to be understood regarding its pathophysiology. The cell-based model of hemostasis has allowed for characterization of endothelial dysfunction, impaired thrombin generation, platelet dysfunction, fibrinolysis, endogenous anticoagulants such as protein-C, and antifibrinolytic proteins. These concepts collectively compose the contemporary, but still partial, understanding of trauma-induced coagulopathy. CONCLUSION: Trauma-induced coagulopathy is a complex pathophysiological condition, of which some mechanisms have been characterized, but much remains to be understood in order to translate this knowledge into improved outcomes for the injured patient.

Proteomic analysis of the supernatant of red blood cell units: the effects of storage and leucoreduction.

BACKGROUND: Red blood cell (RBC) transfusion is a life-saving intervention for critically ill patients; however, it has been linked to increased morbidity and mortality. We hypothesize that a number of important proteins accumulate during routine storage of RBCs, which may explain some of the adverse effects seen in transfused patients. STUDY DESIGN: Five RBC units were drawn and divided (half prestorage leucoreduced (LR-RBC) and half left as an unmodified control (RBC). The supernatant was separated on days 1 and 42 of storage and proteomic analyses completed with in-gel tryptic digestion and nano-liquid chromatography tandem mass spectrometry. RESULTS: In RBC supernatants, 401 proteins were identified: 203 increased with storage, 114 decreased, and 84 were unchanged. In LR-RBC supernatant, 231 proteins were identified: 84 increased with storage, 30 decreased, and 117 were unchanged. Prestorage leucoreduction removed many platelet- and leucocyte-derived structural proteins; however, a number of intracellular proteins accumulated including peroxiredoxins (Prdx) 6 and latexin. The increases were confirmed by immunoblotting, including the T-phosphorylation of Prdx-6, indicating that it may be functioning as an active phospholipase. Active matrix metalloproteinase-9 also increased with a coinciding decrease in the metalloproteinase inhibitor 1 and cystatin C. CONCLUSION: We conclude that a number of proteins increase with RBC storage, which is partially ameliorated with leucoreduction, and transfusion of stored RBCs may introduce mediators that result in adverse events in the transfused host.

The Glue Grant experience: characterizing the post injury genomic response.

Despite ongoing improvements in resuscitation, care, and outcomes, traumatic injury remains a significant health care and economic burden. The causes are multifactorial, but our approach to the clinical management of these patients remains limited by our current understanding of the pathobiology of the disease. A multicenter, multidisciplinary program known as the "Inflammation and the Host Response to Injury" Large Scale Collaborative Research Program was created by the National Institute of General Medical Sciences (NIGMS, U54 GM062119-10) in 2001 in a 10-year effort to address some of these issues. Its primary goal is to describe the human genomic response to severe trauma and burns, and to examine changes in gene expression in the context of different clinical outcomes. The Program has not only successfully implemented clinical care guidelines for managing the severe trauma patient based on the best available evidence to minimize iatrogenic variability, but it has also examined the genome-wide, immune-inflammatory response in total and isolated blood leukocyte populations. This review will address current milestones as well as future directions for the Program.

Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritis and a primary cause of disability, however, there are no treatments that can slow disease progression or repair damaged joint cartilage. Fibroblast growth factor-18 (FGF18) has been reported to have significant anabolic effects on cartilage. We therefore examined its effects on repair of cartilage damage in a rat meniscal tear model of OA. DESIGN: Surgical damage to the meniscus in rats leads to joint instability and significant damage to the articular cartilage at 3 weeks post-surgery. At this time, animals received bi-weekly intra-articular injections of FGF18 for 3 weeks, and the knee joints were then harvested for histologic examination. RESULTS: FGF18-induced dose-dependent increases in cartilage thickness of the tibial plateau, due to new cartilage formation at the articular surface and the joint periphery. The generation of new cartilage resulted in significant reductions in cartilage degeneration scores. The highest dose of FGF18 also induced an increase in chondrophyte size and increased remodeling of the subchondral bone. CONCLUSIONS: The results of this study demonstrate that FGF18 can stimulate repair of damaged cartilage in a setting of rapidly progressive OA in rats.

Hypotension and acute pulmonary insufficiency following transfusion of autologous red blood cells during surgery: a case report and review of the literature.

Transfusion of autologous blood is associated with fewer complications, although all untoward events of transfusion may not be negated with this strategy. We report a case of acute pulmonary insufficiency and hypotension following transfusion of autologous packed red blood cells (PRBCs) in a patient, who was undergoing major surgery. Anti-HLA class-I and class-II and anti-granulocyte antibodies were measured in the unit and in the recipient. Neutrophil (PMN)-priming activity was measured as the augmentation of the formyl-Met-Leu-Phe-activated respiratory burst. No immunoglobulins were identified; however, significant lipid-priming activity was present in the implicated, autologous PRBC unit that primed PMNs from both healthy people and the recipient. In addition, lipids, identical to those that accumulate during PRBC storage, caused significant hypotension when infused into rats at similar concentrations found in stored PRBCs. We conclude that the observed transfusion-related acute lung injury reaction with significant hypotension may be the result of two independent events: the first is related to inherent host factors, in this case major surgery, and the second is the infusion of lipids that accumulate during the routine storage of PRBCs.

Large volume polymerized haemoglobin solution in a Jehovah's Witness following abruptio placentae.

Severe anaemia, with haemoglobin (Hb) levels < or =3 g dL(-1), is associated with mortality rates of 50-95%. Although accepted transfusion targets have been debated in the literature (Carson et al., 2002; Practice guidelines for blood component therapy. 1996; Consensus Conference. 1988; Hebert et al., 1999), few would argue the risks associated with Hb levels less than 5 g dL(-1) in critically ill patients. In patients who are unable to receive red blood cell transfusions, the utility of Hb solutions is an attractive solution. We describe a Jehovah's Witness patient who exemplifies the marked physiologic derangements of severe anaemia and subsequent clinical resolution with large volume polymerized human Hb transfusion. The Hb-based oxygen carrier, PolyHeme, provided adequate oxygen transport, acting as a bridge until endogenous production could compensate for red cell loss. Practicing physicians need to be aware of current therapeutic options for use in these complicated patients.

Routine preoperative laboratory analyses are unnecessary before elective laparoscopic cholecystectomy.

BACKGROUND: We formulated a clinical pathway (CP) for elective laparoscopic cholecystectomy (LC), which included the following preoperative evaluation: history and physical (H&P), right upper quadrant ultrasound (US), and liver function tests (LFTs). We hypothesized that routine LFTs did not alter management beyond that dictated by H&P and US, and could be excluded from the CP. METHODS: The study involved 387 consecutive patients undergoing elective LC. Abnormalities in the preoperative evaluation were compared with the finding of choledocholithiasis or other unexpected outcomes. RESULTS: In 187 (48%) patients, abnormalities were found by H&P (n = 7), US (n = 13), and LFTs (n = 177). Seven patients (2%) had documented choledocholithiasis; two had abnormal H & P; three had abnormal US; and four had abnormal LFTs. No patient with choledocholithiasis had abnormal LFTs but normal H&P and US. CONCLUSIONS: Routine LFTs before elective LC are not cost effective. Before LC H&P and US are warranted, but LFTs do not add any useful information and should not be routinely measured.

Fibroblast growth factor-18 is a trophic factor for mature chondrocytes and their progenitors.

OBJECTIVE: The aim of this study was to examine the effects of recombinant human Fgf18 on chondrocyte proliferation and matrix production in vivo and in vitro. In addition, the expressions of Fgf18 and Fgf receptors (Fgfr) in adult human articular cartilage were examined. METHODS: Adenovirus-mediated transfer of Fgf18 into murine pinnae and addition of FGF18 to primary cultures of adult articular chondrocytes were used to assess the effects of FGF18 on chondrocytes. In situ hybridization was used to examine the expression of Fgf18 and Fgfr s in adult human articular cartilage. RESULTS: Expression of Fgf18 by adenovirus-mediated gene transfer in murine pinnae resulted in a significant increase in chondrocyte number. Chondrocytes were identified by staining with toluidine blue and a monoclonal antibody directed against type II collagen. Fgf18, Fgfr 2-(IIIc), Fgfr 3-(IIIc), and Fgfr 4 mRNAs were detected within these cells by in situ hybridization. The nuclei of the chondrocytes stained with antibodies to PCNA and FGF receptor (FGFR) 2. Addition of FGF18 to the culture media of primary articular chondrocytes increased the proliferation of these cells and increased their production of extracellular matrix. To assess the receptor selectivity of FGF18, BaF3 cells stably expressing the genes for the major splice variants of Fgfr1-3 were used. Proliferation of cells expressing Fgfr 3-(IIIc) or Fgfr 2-(IIIc) was increased by incubation with FGF18. Using FGFR-Fc fusion proteins and BaF3 cells expressing Fgfr 3-(IIIc), only FGFR 3-(IIIc)-Fc, FGFR 2-(IIIc)-Fc or FGFR 4-Fc reduced FGF18-mediated cell proliferation. Expression of Fgf18, Fgfr 3-(IIIc) and Fgfr 2-(IIIc) mRNAs was localized to chondrocytes of human articular cartilage by in situ hybridization. CONCLUSION: These data demonstrate that Fgf18 can act as a trophic factor for elastic chondrocytes and their progenitors in vivo and articular chondrocytes cultured in vitro. Expression of Fgf18 and the genes for two of its receptors in chondrocytes suggests that Fgf18 may play an autocrine role in the biology of normal articular cartilage.

Mesenteric lymph is responsible for post-hemorrhagic shock systemic neutrophil priming.

BACKGROUND: Hemorrhagic shock-induced splanchnic hypoperfusion has been implicated as a priming event in the two event model of multiple organ failure (MOF). We have previously shown that early postinjury neutrophil (PMN) priming identifies the injured patient at risk for MOF. Recent in vitro studies have demonstrated that postshock mesenteric lymph primes isolated human neutrophils. We hypothesize that lymphatic diversion before hemorrhagic shock abrogates systemic PMN priming and subsequent lung injury. METHODS: Sprague-Dawley rats (n >or= 5 per group) underwent hemorrhagic shock (MAP 40 mm Hg x 30 min) and resuscitation (shed blood + 2x crystalloid) with and without mesenteric lymphatic duct diversion. Sham animals underwent anesthesia and laparotomy. Whole blood was taken 2 hours after resuscitation, heparinized, and incubated for 5 min at 37 degrees C. Surface expression of CD11b (a marker for PMN priming) was determined by flow-cytometry compared with isotype controls. In addition, lung myeloperoxidase (MPO) was measured for PMN sequestration, and Evans blue lung leak was assessed in the bronchoalveolar lavage fluid in sham, and shock +/- lymph diversion animals. RESULTS: Hemorrhagic shock resulted in increased surface expression of PMN CD11b relative to sham (23.8 +/- 6.7 vs. 9.9 +/- 0.6). Mesenteric lymphatic diversion before hemorrhagic shock abrogated this effect (8.0 +/- 2.6). Lung PMN accumulation, as assessed by MPO, was greater in the lungs of nondiverted (113 +/- 14 MPO/mg lung) versus sham (55 +/- 4 MPO/mg lung, p < 0.05); lymph diversion reduced lung PMNs to control levels (71 +/- 6.5 MPO/mg lung, p < 0.05). Evans blue lung leak was 1.6 times sham in the hemorrhagic shock group; this was returned to sham levels after lymph diversion (p < 0.05). CONCLUSION: Post-hemorrhagic shock mesenteric lymph primes circulating PMNs, promotes lung PMN accumulation, and provokes acute lung injury. Lymphatic diversion abrogates these pathologic events. These observations further implicate the central role of mesenteric lymph in hemorrhagic shock-induced lung injury. Characterizing the PMN priming agents could provide insight into the pathogenesis of postinjury MOF and ultimately new therapeutic strategies.