Increased complement activation 3 to 6 h after trauma is a predictor of prolonged mechanical ventilation and multiple organ dysfunction syndrome: a prospective observational study.

BACKGROUND: Complement activation is a central mechanism in systemic inflammation and remote organ dysfunction following major trauma. Data on temporal changes of complement activation early after injury is largely missing. We aimed to describe in detail the kinetics of complement activation in individual trauma patients from admission to 10 days after injury, and the association with trauma characteristics and outcome. METHODS: In a prospective cohort of 136 trauma patients, plasma samples obtained with high time resolution (admission, 2, 4, 6, 8 h, and thereafter daily) were assessed for terminal complement complex (TCC). We studied individual TCC concentration curves and calculated a summary measure to obtain the accumulated TCC response 3 to 6 h after injury (TCC-AUC3-6). Correlation analyses and multivariable linear regression analyses were used to explore associations between individual patients' admission TCC, TCC-AUC3-6, daily TCC during the intensive care unit stay, trauma characteristics, and predefined outcome measures. RESULTS: TCC concentration curves showed great variability in temporal shapes between individuals. However, the highest values were generally seen within the first 6 h after injury, before they subsided and remained elevated throughout the intensive care unit stay. Both admission TCC and TCC-AUC3-6 correlated positively with New Injury Severity Score (Spearman's rho, p-value 0.31, 0.0003 and 0.21, 0.02) and negatively with admission Base Excess (- 0.21, 0.02 and - 0.30, 0.001). Multivariable analyses confirmed that deranged physiology was an important predictor of complement activation. For patients without major head injury, admission TCC and TCC-AUC3-6 were negatively associated with ventilator-free days. TCC-AUC3-6 outperformed admission TCC as a predictor of Sequential Organ Failure Assessment score at day 0 and 4. CONCLUSIONS: Complement activation 3 to 6 h after injury was a better predictor of prolonged mechanical ventilation and multiple organ dysfunction syndrome than admission TCC. Our data suggest that the greatest surge of complement activation is found within the first 6 h after injury, and we argue that this time period should be in focus in the design of future experimental studies and clinical trials using complement inhibitors.

The autoimmune basis of hypopituitarism in traumatic brain injury: fiction or reality?

Post-traumatic hypopituitarism has remained as an obscured cause of worsening morbidity and mortality in head injury patients. Researchers have for decades been puzzled by the mechanism of pituitary dysfunction in these cases. Amongst other causes like direct injury, vascular injury etc, an immunological basis of hypopituitarism has been suggested in some animal studies as well as human research. In this article, we have reviewed the latest articles and compiled the evidence which suggests for or against the role of autoimmunity in post-traumatic hypopituitarism or which defines the strength to which autoimmunity has been established as a cause of head-injury induced pituitary dysfunction.

Early immune response regulated by a bone marrow mesenchymal stem cell model of multiple trauma in rats.

AIM: To explore whether transplantation of bone marrow mesenchymal stem cells (BMSCs) would reduce the immune response and protect vital organs in a rat model of femur shaft fracture combined with craniocerebral injury. METHODS: The rats were divided into an experimental group (multiple traumas and receiving BMSCs injection, n = 25), a positive control group (only received the combination injuries, n = 25) and a negative group (n = 5). RESULTS: Compared with the positive control group, plasma IL-6 and IL-8 were significantly lower at the early stage, and IL-10 was higher at the late period in the experimental group (p < 0.05). TNF-α ex-vivo synthesis descended quickly after trauma. CONCLUSION: BMSCs reduced the inflammatory response and were effective in immunomodulations during severe trauma.

Changes in phagocytosis and expression of microglial cells in craniocerebral injury mice models.

The objective of this study was to investigate the changes in phagocytic function and expression quantities of CD11b and tumor necrosis factor-α (TNF-α) among microglia cells of craniocerebral injury mice. Modified Feeney method was used to establish the craniocerebral injury mice models. Twenty-one male SPF mice were divided into a control group and a trauma group. The scalp was incised and a bone window was opened in the control group without cerebral injury. In the trauma group, the mice were sacrificed after the craniocerebral injury at 1, 3, 6, 12, 24 and 48 h to make frozen sections of cerebral tissues. The phagocytic rate of microglia cells was observed by using fluorescent microsphere. The changes in the expression quantities of CD11b and TNF-α were detected by enzyme-linked immuno sorbent assay (ELISA). The phagocytic ability of the microglia cells after the craniocerebral injury increased at 1 h after injury compared with that of the control group (P less than 0.01). The expression of surface antigen CD11b of the microglia cells and the expression of TNF-α increased at 1, 3, 6, 12, 24 and 48 h after the injury compared with those of the control group (P less than 0.01). The phagocytic ability of the microglia cells increased. The expressions of CD11b and TNF-α were also gradually enhanced in the acute phase after craniocerebral injury, and then gradually decreased to the normal level. The expressions of CD11b and TNF-α indicated a high consistency with the changing trend of the phagocytic ability, suggesting that the microglia cells may participate in the regulation of the inflammatory process of the central nervous system through absorbing apoptotic cells and increasing and secreting inflammatory and anti-inflammatory factors.

Evaluation of a new concept of immune-enhancing diet in a model of head-injured rat with infectious complications: A proof of concept study.

Immune-enhancing diet (IED) utilization in critically ill septic patients is still debated. A new concept of IED has been proposed combining extra glutamine sequentially with either antioxidants or other amino acids, in order to match patient requirements according to their response to injury. We evaluated whether this new IED elicits a more favorable response to stress when compared with two existing IEDs both enriched in arginine but with different levels of anti-oxidants, in a validated rat model combining head injury (HI) and infectious complications. Forty-eight HI rats were randomized into four groups (n = 11-13 per group) to receive, for 4 days, standard enteral nutrition (S), one of the two existing IEDs (IED1, IED2), or the new IED (IED3; providing glutamine and antioxidants for two days and glutamine and specific amino acids for two days). Two days after HI, the rats received an enteral bolus of luminescent Escherichia coli Xen14 to induce infection, and bacterial dissemination was evaluated. Body weight (BW) was recorded daily. Four days after HI, animals were euthanized; blood was sampled; organs were weighed; cumulated nitrogen balance (CNB) and nitrogen efficiency were determined. IED3 was more efficient than IED1 and IED2 in improving BW recovery from D3 (D3 vs. D1, p < 0.05) after HI. It significantly improved CNB and net protein utilization (IED3 vs. S, IED1, IED2, p < 0.05). An IED with sequential administration of anti-oxidants and glutamine may be better suited to meeting nutritional requirements in severe catabolic states.

Anaphylaxis due to head injury.

Both anaphylaxis and head injury are often seen in the emergency department, but they are rarely seen in combination. We present a case of a 30-year-old woman who presented with anaphylaxis with urticaria and angioedema following a minor head injury. The patient responded well to intramuscular epinephrine without further complications or airway compromise. Prior case reports have reported angioedema from hereditary angioedema during dental procedures and maxillofacial surgery, but there have not been any cases of first-time angioedema or anaphylaxis due to head injury.

Solitary Cranial Langerhans Cell Histiocytosis: Two case reports.

Langerhans cell histiocytosis (LCH) is a proliferation of Langerhans cells intermixed with inflammatory cells, in particular eosinophils, that may manifest as a unisystem (unifocal or multifocal) or multisystem disease. We describe the clinical and histologic spectrum of LCH of the orbit and skull in our two cases. Both cases had unifocal erosive skull lesions with a history of trauma. Typical histologic features included numerous histiocytes with varying degrees of giant cell formation and scattered eosinophilic granulocytes. The presence of Langerhans cells was confirmed by CD1a and S100 immunohistochemistry. LCH has an excellent prognosis when treated with surgical resection, steroids and radiotherapy or chemotherapy. One of our patients is disease free at 7 year follow-up and one patient had regression of lesion on follow-up.

Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease.

Glia of the central nervous system (CNS) help to maintain homeostasis in the brain and support efficient neuronal function. Microglia are innate immune cells of the brain that mediate responses to pathogens and injury. They have key roles in phagocytic clearing, surveying the local microenvironment and propagating inflammatory signals. An interruption in homeostasis induces a cascade of conserved adaptive responses in glia. This response involves biochemical, physiological and morphological changes and is associated with the production of cytokines and secondary mediators that influence synaptic plasticity, cognition and behavior. This reorganization of host priorities represents a beneficial response that is normally adaptive but may become maladaptive when the profile of microglia is compromised. For instance, microglia can develop a primed or pro-inflammatory mRNA, protein and morphological profile with aging, traumatic brain injury and neurodegenerative disease. As a result, primed microglia exhibit an exaggerated inflammatory response to secondary and sub-threshold challenges. Consequences of exaggerated inflammatory responses by microglia include the development of cognitive deficits, impaired synaptic plasticity and accelerated neurodegeneration. Moreover, impairments in regulatory systems in these circumstances may make microglia more resistant to negative feedback and important functions of glia can become compromised and dysfunctional. Overall, the purpose of this review is to discuss key concepts of microglial priming and immune-reactivity in the context of aging, traumatic CNS injury and neurodegenerative disease. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'.

[Comparative evaluation of effectiveness of the combined immunocorrection in patients suffering severe craniocerebral trauma].

Comparative estimation of clinical efficacy of various immunocorrection schemes for the immune state correction was conducted in 106 patients in conditions ofsevere craniocerebral trauma (SCCT), combined application of immunofan and intravenous laser irradiation of blood (IVLIB). In 32 patients (I group) a standard intensive therapy (SITH) was conducted: in 21 (II group)--immunofan was applied additionally; in 25 (III group)--in addition to SITH IVLIB was conducted; in 28 (IV group)--immunofan solution was infused and sessions of IVLIB (3 - 4 sessions a day) on a background of SITH were conducted. The immunity indices were analyzed on the 1 - 2, 5 - 6-th and 9 -10-th days after trauma. Estimation of the combined therapy efficacy have shown, that in SCCT she renders a significant immunocorrecting effect on the 5 - 6-th days already, on the 9 - 10-th days the immune state parameters were really normalized, reduction of the complications rate by 26% and of lethality by 8.6% was noted.

[The dynamics of the immune status indices in conditions of cranio-cerebral trauma on background of a streptozotocin-induced diabetes mellitus in experiment].

Peculiarities of changes in the immune status in a cranio-cerebral trauma (CCT) on a background of a streptozotocin-induced diabetes mellitus (DM) were studied up. After CCT there are noted the inhibition of predominantly cellular link of immunity, accompanied by reduction of the CD3+ lymphocytes quantity, as well as lymphocytes of the main subpopulations CD4+ and CD8+, CD16+, reduction of the neutrophils phagocytic activity, a complement titer enhancement. Experimental CCT do not cause the essential changes in a CD19+ lymphocytes quantity. The CCT modelling on a background of a streptozotocin-induced DM causes the immune deficiency deepening, in a cellular and humoral links together, significant reduction of activity of a phagocytosis system and complement as well.

[The humoral immunity changes in experimental cranio-cerebral trauma, concurrent with diabetes mellitus].

The results of studying in dynamics of the humoral immunity indices were adduced in experimental cranio-cerebral truma (CCT) in conjunction with diabetes mellitus (DM). Peculiarities of the immune answer while the period of an acute reaction on trauma and early signs of posttraumatic period have been characterized by reduction of content in the main classes of immunoglobulins IgA, IgM, IgG and enhancement of the circulating immune complexes (CIC) concentration. Experimental DM was accompanied by raising of functional activity of humoral immunity in accordance with immunoglobulins level and CIC. The specificity of changes in humoral immunity in conditions of CCT on the DM background consisted of more profound lowering of the immunoglobulins level and rapid enhancement of the CIC content.

Damage control immunoregulation: is there a role for low-volume hypertonic saline resuscitation in patients managed with damage control surgery?

Hypertonic saline (HTS) is beneficial in the treatment of head-injured patients as a result of its potent cytoprotective effects on various cell lines. We hypothesize that low-volume resuscitation with 3 per cent HTS, when used after damage control surgery (DCS), improves outcomes compared with standard resuscitation with isotonic crystalloid solution (ICS). This is a 4-year retrospective review from two Level I trauma centers. Patients included had 10 units or more of packed red blood cells during initial DCS. On arrival to the trauma intensive care unit (TICU), patients were resuscitated with low-volume 3 per cent HTS or with conventional ICS. A cohort analysis was performed comparing resuscitation strategies. Univariate analysis of continuous data was done with Student t test followed by multivariate analysis. Of 188 patients included, 76 were in the low-volume HTS group and 112 in the ICS group. Demographics were similar between the groups. Over the next 48 hours after DCS in HTS versus ISC groups, intravenous fluids were given: 1920 ± 455 mL versus 8400 ± 1200 mL (P < 0.0001); urine output was 4320 ± 480 mL versus 1940 ± 480 mL(P < 0.0001); mean TICU length of stay was 10 ± 8 versus 16 ± 15 days (P < 0.01); prevalence of acute respiratory distress syndrome was 4.0 versus 13.4 per cent (P = 0.02); sepsis was 6.6 versus 15.2 per cent (P = 0.06); multisystem organ failure was: 2.6 versus 16.1 per cent (P < 0.01); and 30-day mortality was 5.3 versus 15.2 per cent (P = 0.03). There was no difference for prevalence of renal failure at 5.3 versus 3.6 per cent (P = 0.58). Low-volume resuscitation with HTS administered after DCS on arrival to the TICU may have a protective effect on the polytrauma patient. We believe that this study demonstrates a role for low-volume resuscitation with HTS to improve outcomes in patients undergoing DCS.

The effects of Rhizoma drynariae on interleukin-2 and T-lymphocyte levels in rats after severe head injury.

OBJECTIVE: To investigate the effects of Rhizoma drynariae on the levels of interleukin-2(IL-2) and T-lymphocyte subset in rats with severe head injury (SHI). METHODS: 72 Sprague Dawley (SD) rats were randomly divided into 3 groups: control group, model group, and R. drynariae group. The experimental group received intragastrical infusions of with aqueous R. drynariae extract four hours after SHI while the other groups were administered with equivalent volumes of physiological saline. Infusions were administered to the 3 groups once a day for 7 d. IL-2 and T-lymphocyte (CD3, CD4, CD8) levels were measured at 24, 72, and 168 h after initial infusion. RESULTS: The levels of IL-2 and CD4 T cells reduced obviously after 24 h in the model group (P<0.05), but recovered to the levels of the control group after 72 h, and remained elevated after 168 h. In the R. drynariae group, IL-2 and CD4 levels were did not decrease while the level of CD8 T cells was reduced significantly (P<0.05). CONCLUSIONS: R. drynariae can protect against immune dysfunction or improve immunity in rats with severe head injury (SHI).

Severe traumatic head injury affects systemic cytokine expression.

BACKGROUND: The neuroimmunologic effect of traumatic head injury remains ill-defined. This study aimed to characterize systemic cytokine profiles among traumatically injured patients to assess the effect of traumatic head injury on the systemic inflammatory response. STUDY DESIGN: For 5 years, 1,022 patients were evaluated from a multi-institutional Trauma Immunomodulatory Database. Patients were stratified by presence of severe head injury (SHI; head Injury Severity Score ≥4, n = 335) vs nonsevere head injury (NHI; head Injury Severity Score ≤3, n = 687). Systemic cytokine expression was quantified by ELISA within 72 hours of admission. Patient factors, outcomes, and cytokine profiles were compared by univariate analyses. RESULTS: SHI patients were more severely injured with higher mortality, despite similar ICU infection and ventilator-associated pneumonia rates. Expression of early proinflammatory cytokines, interleukin-6 (p < 0.001) and tumor necrosis factor-α (p = 0.02), was higher among NHI patients, and expression of immunomodulatory cytokines, interferon-γ (p = 0.01) and interleukin-12 (p = 0.003), was higher in SHI patients. High tumor necrosis factor-α levels in NHI patients were associated with mortality (p = 0.01), increased mechanical ventilation (p = 0.02), and development of ventilator-associated pneumonia (p = 0.01). Alternatively, among SHI patients, high interleukin-2 levels were associated with survival, decreased mechanical ventilation, and absence of ventilator-associated pneumonia. CONCLUSIONS: The presence of severe traumatic head injury significantly alters systemic cytokine expression and exerts an immunomodulatory effect. Early recognition of these profiles can allow for targeted intervention to reduce patient morbidity and mortality.

[Invasive trichosporonosis caused by Trichosporon asahii in a polytraumatized neurosurgical patient: case report]. / Invazivna trihosporonoza uzrokovana gljivom Trichosporon asahii u politraumatiziranog neurokirurskog bolesnika.

Trichosporon asahii (formerly T. beigelii) is a rare cause of human infections with very varied clinical manifestations ranging from superficial infections to severe and systemic diseases. T. asahii is a life-threatening opportunistic pathogen especially for granulocytopenic, immunocompromised and immunodeficient patients. It is the possible cause of summer-type hypersensitivity pneumonitis in Japan and systemic infections in transplant patients, patients on corticosteroid therapy, patients with solid tumors and burn patients. Cases of infection in non-immunocompromised surgical patients and patients with long-term stay in ICU are described in the literature. We report on T. asahii fungemia in a polytraumatized neurosurgical patient with long-term stay in the hospital. Urinary tract was the source of fungemia, with the same pathogen isolated from urine and blood at the same time. In the Referral Center for Systemic Mycoses, Croatian Institute of Public Health, Zagreb, the strain from the urine and blood culture was identified as T. asahii, with good susceptibility to fluconazole, voriconazole and 5 fluorocytosine, reduced susceptibility to itraconazole and resistance to amphotericin B. The patient responded to fluconazole therapy very well. Since systemic trichosporonoses are generally associated with immunocompromised patients (hematologic, granulocytopenic and AIDS patients), this case confirms the possibility of infection with this pathogen in patients with long-term hospital stay and reduced local immunity, but without classic immunodeficiency.

Immune status and apoptosis activation during brain death.

The present study evaluates the role of the inflammatory status and apoptosis activation in the development of organ dysfunction after brain death using plasma assays and macroarray analysis on skeletal muscle biopsies to look for evidence of remote tissue damage in two intensive care units in France and one in Belgium. As controls, we used patients undergoing hip surgery and healthy volunteers. Causes of brain death in the 85 consecutive patients included in the study were cardiac arrest (n = 29; 34%), stroke (n = 42; 49%, with 38 patients having hemorrhagic stroke), and head injury (n = 14; 17%). Of the 85 patients, 45 donated 117 organs. Plasma endotoxin and cytokine levels indicated a marked systemic inflammatory response in brain-dead patients, which was strongest in the cardiac arrest group. Leukocyte dysfunction, as assessed by cytokines production in response to various stimuli, was noted in a subgroup of patients with brain death after stroke. Interestingly, skeletal muscle biopsies showed no increase in mRNAs for genes related to inflammation, whereas mRNAs for both antiapoptotic and proapoptotic genes were increased, the balance being in favor of apoptosis induction. The increased activation of the proapoptotic caspase 9 was further confirmed by Western blot. In conclusion, the presence of inflammation and apoptosis induction may explain the rapid organ dysfunction seen after brain death. Both abnormalities may play a role in organ dysfunction associated with brain death. However, the level of systemic inflammation or the presence of circulating endotoxin was not associated with lower graft survival.

Intramedullary nailing as a 'second hit' phenomenon in experimental research: lessons learned and future directions.

BACKGROUND: The 'second hit' phenomenon is based on the fundamental concept that sequential insults, which are individually innocuous, can lead to overwhelming physiologic reactions. This response can be expressed in several organic systems and can be examined by measurement of several parameters. PURPOSES: The purpose of this study was to evaluate the incidence of systemic effects of intramedullary nailing and the role of concurrent head and thoracic injuries as they have been recorded in vivo. We also wanted to determine what would be the optimal animal model for future research and what variables should be investigated. METHODS: We reviewed the available literature of animal studies that used surgery, and particularly nailing, as a second hit. The reviewed studies were retrieved through an electronic search of the MEDLINE database. We analyzed the methods of creating the first and second hits (nailing), the characteristics of the animal models, the variables examined, and the pathophysiologic responses, which appeared after the second hit. RESULTS: Second hit reamed intramedullary nailing was found to provoke consumption of coagulation factors, whereas the effect of unreamed nailing on coagulation factors appears inconsistent. Hemodynamic factors were affected only transiently by the second hit, whereas the pulmonary function was affected only when the first hit included lung injury. CONCLUSIONS: Thoracic and head injuries predispose to an aggravated second hit. Primate animal models are considered to be closer to clinical reality and should be preferred for future studies. Future studies should include measurements of proinflammatory and antiinflammatory markers.

Predictive value of leucocytosis in head trauma.

AIM: Head trauma is associated with an acute phase response which is characterized by leucocytosis due to increased levels of catecholamine and cortisol. Early edema formation following severe head injury may also be associated with microglia activation. Therefore, increased white blood cell (WBC) count after head trauma may be a predictive parameter of the severity of craniocerebral trauma. MATERIAL AND METHODS: We retrospectively studied 59 patients with severe, moderate and minor injury between February 2007 and March 2009. WBC counts of all patients were obtained within the first day of their admission. All patients were divided into separate groups according to their Glasgow Coma Scale (GCS) scores and hospital stay durations. Their CT progressions and Glasgow Outcome Scale (GOS) scores were also assessed. The relationship between these parameters and WBC counts were evaluated by statistical methods. RESULTS: There was a favorable correlation between WBC counts of the patients and GCS scores (pI0.01), hospital stay (p=0.006), CT progression (p < 0.01) and GOS scores (p < 0.01). CONCLUSION: AWBC count exceeding 17.5 x 106/l has a predictive value for poor GCS score, and long hospital stay. CT progression tends to be seen in patients with moderate and severe head injury.