Juliane Mohr

Induced hypothermia does not impair coagulation system in a swine multiple trauma model.

BACKGROUND Accidental hypothermia, acidosis, and coagulopathy represent the lethal triad in severely injured patients. Therapeutic hypothermia however is commonly used in transplantations, cardiac and neurosurgical surgery, or after cardiac arrest. However, the effects of therapeutic hypothermia on the coagulation system following multiple trauma need to be elucidated. METHODS In a porcine model of multiple trauma including blunt chest injury, liver laceration, and hemorrhagic shock followed by fluid resuscitation, the influence of therapeutic hypothermia on coagulation was evaluated. A total of 40 pigs were randomly assigned to sham (only anesthesia) or trauma groups receiving either hypothermia or normothermia. Each group consisted of 10 pigs. Analyzed parameters were cell count (red blood cells, platelets), pH, prothrombin time (PT), fibrinogen concentration, and analysis with ROTEM and Multiplate. RESULTS Trauma and consecutive fluid resuscitation resulted in impaired coagulation parameters (cell count, pH, PT, fibrinogen, ROTEM, and platelet function). During hypothermia, coagulation parameters measured at 37°C, such as PT, fibrinogen, thrombelastometry measurements, and platelet function, showed no significant differences between normothermic and hypothermic animals in both trauma groups. Additional analyses of thrombelastometry at 34°C during hypothermia showed significant differences for clotting time and clot formation time but not for maximum clot firmness. We were not able to detect macroscopic or petechial bleeding in both trauma groups. CONCLUSION Based on the results of the present study we suggest that mild hypothermia can be safely performed after stabilization following major trauma. Mild hypothermia has effects on the coagulation system but does not aggravate trauma-induced coagulopathy in our model. Before hypothermic treatment can be performed in the clinical setting, additional experiments with prolonged and deeper hypothermia to exclude detrimental effects are required.

Increased age is not associated with higher incidence of complications, longer stay in acute care hospital and in hospital mortality in geriatric hip fracture patients

The number of agile patients in the 10th decade with a strong need for postoperative mobility will increase in the following decades. The present prospective study sought to prove if very old patients with hip-related fractures are disadvantaged according to incidence of complications, length of ICU and in-hospital stay, and in-hospital mortality. We included 402 patients, age 60 years and older, with hip related fractures. Operative treatment consisted of osteosynthesis or endoprothesis. ASA score, body mass index, Charlson Comorbidity Index, Barthel Index and Mini-Mental-Status were documented. We noted length of in-hospital stay and ICU stay as well as readmission to ICU and complications, including their dispersal according to Clavien-Dindo Classification. After univariate analysis, a multivariate analysis was performed. The examined cohorts were 85 patients aged 60-74 years, 253 75-90 years old and 64 >90 year old patients. In-hospital periods (13-14 days) mean stay on ICU (2 days) and frequency of readmission on ICU did not significantly differ statistically. Most complications were grade II, with comparable frequency and modality, displaying no significant difference throughout age-related groups (p=0.461). In-hospital mortality showing significance (p=0.014) only between 75-89 (4.4%) and >90-year-old (12.5%) cohort. Nevertheless, according to multivariate analysis, including the common risk factors, increased age was not an independent risk factor for dying (p=0.132). Patients at an advanced age with hip-related fractures showed neither a prolonged in-hospital nor ICU stay. There was no significant relation of advanced age to number and type of complications.

A Combined Trauma Model of Chest and Abdominal Trauma With Hemorrhagic Shock—description of a New Porcine Model

ABSTRACT Despite the high incidence and prognostic relevance of hemorrhagic shock and abdominal and blunt chest trauma in multiply injured patients, there are no animal models combining these injuries. Therefore, we established a new porcine multiple trauma model consisting of blunt chest trauma, penetrating abdominal trauma (two incisions in the right upper liver lobe using a four-edged scalpel and subsequent liver packing), and pressure-controlled hemorrhagic shock with a mean arterial pressure of 30 ± 5 mmHg (a maximum of 45% of the total blood volume). The combined traumatic insult led to severe signs of hemorrhagic shock and impaired pulmonary function. In conclusion, a consistent, reproducible, and clinically relevant porcine model of multisystem injury with controlled (pressure-controlled blood withdrawal) and uncontrolled components of hemorrhage (liver laceration) with the potential for rebleeding was established.

Deltoid-split or deltopectoral approaches for the treatment of displaced proximal humeral fractures?

BackgroundProximal humeral fractures are mainly associated with osteoporosis and are becoming more common with the aging of our society. The best surgical approach for internal fixation of displaced proximal humeral fractures is still being debated.Questions/purposesIn this prospective randomized study, we aimed to investigate whether the deltoid-split approach is superior to the deltopectoral approach with regard to (1) complication rate; (2) shoulder function (Constant score); and (3) pain (visual analog scale [VAS]) for internal fixation of displaced humeral fractures with a polyaxial locking plate.MethodsWe randomized 120 patients with proximal humeral fractures to receive one of these two approaches (60 patients for each approach). We prospectively documented demographic and perioperative data (sex, age, fracture type, hospital stay, operation time, and fluoroscopy time) as well as complications. Followup examinations were conducted at 6 weeks, 6 months, and 12 months postoperatively, including radiological and clinical evaluations (Constant score, activities of daily living, and pain [VAS]). Baseline and perioperative data were comparable for both approaches. The sample size was chosen to provide 80% power, but it reached only 68% as a result of the loss of followups to detect a 10-point difference on the Constant score, which we considered the minimum clinically important difference.ResultsComplications or reoperations between the approaches were not different. Eight patients in the deltoid-split group (14%) needed surgical revisions compared with seven patients in the deltopectoral group (13%; p = 1.00). Deltoid-split and deltopectoral approaches showed similar Constant scores 12 months postoperatively (Deltoid-split 81; 95% confidence interval [CI], 74–87 versus deltopectoral 73; 95% CI, 64–81; p = 0.13), and there were no differences between the groups in terms of pain at 1 year (deltoid-split 1.8; 95% CI, 1.2–1.4 versus deltopectoral 2.5; 95% CI, 1.7–3.2; p = 0.14). No learning-curve effects were noted; fluoroscopy use during surgery and function and pain scores during followups were similar among the first 30 patients and the next 30 patients treated in each group.ConclusionsThe treatment of proximal humeral fractures with a polyaxial locking plate is reliable using both approaches. For a definitive recommendation for one of these approaches, further studies with appropriate sample size are necessary.Level of EvidenceLevel II, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Induced hypothermia reduces the hepatic inflammatory response in a swine multiple trauma model

BACKGROUND Mild therapeutic hypothermia following trauma has been introduced in several studies to reduce the posttraumatic inflammation and organ injury. In this study, we analyzed the effects of induced mild hypothermia (34°C) on the inflammation of the shock organs liver and kidney. METHODS In a porcine model of multiple trauma including blunt chest trauma, liver laceration, and hemorrhagic shock followed by fluid resuscitation, the influence of induced hypothermia on hepatic and renal damage and organ-specific inflammation were evaluated. A total of 40 pigs were randomly assigned to four groups, which were sham (anesthesia only) or trauma groups receiving either hypothermia or normothermia. The parameters analyzed were laboratory parameters (aspartate transaminase [AST], lactate dehydrogenase, urea, creatinine) as well as hepatic and renal cytokine expression determined by real-time polymerase chain reaction (interleukin 6 [IL-6], IL-8). Blinded analysis of histologic changes in the liver and kidney was performed. RESULTS Fifteen and a half hours following combined trauma, hepatic cytokine expression and liver damage were significantly increased in animals with normothermia compared with the respective sham group. Hypothermia, however, resulted in a fivefold reduced hepatic expression of IL-8 (mean ± SE, 2.4 ± 1.3; p = 0.01) when compared with the normothermic trauma group (IL-8, 12.8 ± 4.7). Accordingly, granulocyte infiltration and a histologic, semiquantitative score for liver injury were significantly higher in the normothermic trauma group. Serum AST levels raised significantly after trauma and normothermia compared with the respective sham group, while AST levels showed no difference from the sham groups in the hypothermic trauma group. In contrast, neither trauma nor hypothermia influenced the expression of IL-6 and IL-8 and tissue injury in the kidney. CONCLUSION Therapeutic hypothermia seems to attenuate the hepatic inflammatory response and the associated liver injury after severe trauma. Therefore, induced hypothermia might represent a potential therapeutic strategy to avoid posttraumatic organ dysfunction.

The cell fate determinant Scribble is required for maintenance of hematopoietic stem cell function

Cell fate determinants influence self-renewal potential of hematopoietic stem cells. Scribble and Llgl1 belong to the Scribble polarity complex and reveal tumor-suppressor function in drosophila. In hematopoietic cells, genetic inactivation of Llgl1 leads to expansion of the stem cell pool and increases self-renewal capacity without conferring malignant transformation. Here we show that genetic inactivation of its putative complex partner Scribble results in functional impairment of hematopoietic stem cells (HSC) over serial transplantation and during stress. Although loss of Scribble deregulates transcriptional downstream effectors involved in stem cell proliferation, cell signaling, and cell motility, these effectors do not overlap with transcriptional targets of Llgl1. Binding partner analysis of Scribble in hematopoietic cells using affinity purification followed by mass spectometry confirms its role in cell signaling and motility but not for binding to polarity modules described in drosophila. Finally, requirement of Scribble for self-renewal capacity also affects leukemia stem cell function. Thus, Scribble is a regulator of adult HSCs, essential for maintenance of HSCs during phases of cell stress.

JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation

JAK2-V617F–positive chronic myeloproliferative neoplasia (CMN) commonly displays dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes, and leukocytes. However, the mechanism by which the 2 major leukocyte integrin chains, &bgr;1 and &bgr;2, may contribute to CMN pathophysiology remained unclear. &bgr;1 (&agr;4&bgr;1; VLA-4) and &bgr;2 (&agr;L&bgr;2; LFA-1) integrins are essential regulators for attachment of leukocytes to endothelial cells. We here showed enhanced adhesion of granulocytes from mice with JAK2-V617F knockin (JAK2+/VF mice) to vascular cell adhesion molecule 1– (VCAM1-) and intercellular adhesion molecule 1–coated (ICAM1-coated) surfaces. Soluble VCAM1 and ICAM1 ligand binding assays revealed increased affinity of &bgr;1 and &bgr;2 integrins for their respective ligands. For &bgr;1 integrins, this correlated with a structural change from the low- to the high-affinity conformation induced by JAK2-V617F. JAK2-V617F triggered constitutive activation of the integrin inside-out signaling molecule Rap1, resulting in translocation toward the cell membrane. Employing a venous thrombosis model, we demonstrated that neutralizing anti–VLA-4 and anti–&bgr;2 integrin antibodies suppress pathologic thrombosis as observed in JAK2+/VF mice. In addition, aberrant homing of JAK2+/VF leukocytes to the spleen was inhibited by neutralizing anti-&bgr;2 antibodies and by pharmacologic inhibition of Rap1. Thus, our findings identified cross-talk between JAK2-V617F and integrin activation promoting pathologic thrombosis and abnormal trafficking of leukocytes to the spleen.

Hypothermia does not influence liver damage and function in a porcine polytrauma model

BACKGROUND Previous studies revealed evidence that induced hypothermia attenuates ischemic organ injuries after severe trauma. In the present study, the effect of hypothermia on liver damage was investigated in a porcine long term model of multi-system injury, consisting of blunt chest trauma, penetrating abdominal trauma, musculoskeletal injury, and hemorrhagic shockMETHODS: In 30 pigs, a standardized polytrauma including blunt chest trauma, penetrating abdominal trauma, musculoskeletal injury, and hemorrhagic shock of 45% of total blood volume was induced. Following trauma, hypothermia of 33∘C was induced for 12 h and intensive care treatment was evaluated for 48 h. As outcome parameters, we assessed liver function and serum transaminase levels as well as a histopathological analysis of tissue samples. A further 10 animals served as controls. RESULTS Serum transaminase levels were increased at the end of the observation period following hypothermia without reaching statistical significance compared to normothermic groups. Liver function was preserved (p⩽ 0.05) after the rewarming period in hypothermic animals but showed no difference at the end of the observation period. In H&E staining, cell death was slightly increased hypothermic animals and caspase-3 staining displayed tendency towards more apoptosis in hypothermic group as well. CONCLUSIONS Induction of hypothermia could not significantly improve hepatic damage during the first 48 h following major trauma. Further studies focusing on multi-organ failure including a longer observation period are required to illuminate the impact of hypothermia on hepatic function in multiple trauma patients.

Diverging impact of cell fate determinants Scrib and Llgl1 on adhesion and migration of hematopoietic stem cells

PurposeCell fate determinants Scrib and Llgl1 influence self-renewal capacity of hematopoietic stem cells (HSCs). Scrib-deficient HSCs are functionally impaired and lack sufficient repopulation capacity during serial transplantation and stress. In contrast, loss of Llgl1 leads to increased HSC fitness, gain of self-renewal capacity and expansion of the stem cell pool. Here, we sought to assess for shared and unique molecular functions of Llgl1 and Scrib by analyzing their interactome in hematopoietic cells.MethodsInteractome analysis was performed by affinity purification followed by mass spectrometry. Motility, migration and adhesion were assessed on primary murine HSCs, which were isolated by FACS sorting following conditional deletion of Scrib or Llgl1, respectively. Imaging of Scrib-deficient HSCs was performed by intravital 2-photon microscopy.ResultsComparison of Scrib and Llgl1 interactome analyses revealed involvement in common and unique cellular functions. Migration and adhesion were among the cellular functions connected to Scrib but not to Llgl1. Functional validation of these findings confirmed alterations in cell adhesion and migration of Scrib-deficient HSCs in vitro and in vivo. In contrast, genetic inactivation of Llgl1 did not affect adhesion or migratory capacity of hematopoietic stem cells.ConclusionOur data provide first evidence for an evolutionarily conserved role of the cell fate determinant Scrib in HSC adhesion and migration in vitro and in vivo, a unique function that is not shared with its putative complex partner Llgl1.

Induced Hypothermia Preserves the Functional Enterocyte Mass in A Porcine Multiple Trauma Model: Retracted.

INTRODUCTION Multiple organ dysfunction syndrome (MODS) and the resulting multiple organ failure (MOF) following severe trauma are associated with increased morbidity and mortality. Due to intestinal mucosal lesions and gut barrier disorders, the intestine contributes decisively to how post-traumatic MOF develops. As mild therapeutic hypothermia has been found to have protective effects on post-traumatic organ injuries, we analysed its effects on the intestine. METHODS In a porcine model, Forty pigs were assigned to four groups: sham or trauma groups each with two sub-groups receiving either hypothermia or normothermia. The trauma was a combined trauma of blunt chest trauma, liver laceration and haemorrhagic shock. Functional enterocyte mass and enterocyte necrosis were evaluated by measuring plasma citrulline and iFABP. Mucosal lesions were assessed using a semi-quantitative histological scoring system. RESULTS In normothermic trauma animals, citrulline decreased significantly compared to both sham groups and to the hypothermic trauma group. However, citrulline levels did not differ significantly between the hypothermic trauma group and the hypothermic sham group. Although histological analysis demonstrated subepithelial lifting and mucosal oedema in the ileal mucosa of all trauma animals, the semi-quantitative score of the group treated with hypothermia was comparable to that of the hypothermic sham group. However, the score was significantly elevated in normothermic trauma animals in comparison to sham and hypothermic trauma animals. CONCLUSION Induced hypothermia preserves the functional enterocyte mass after severe trauma. Therefore induced hypothermia might represent a therapeutic strategy to avoid posttraumatic organ dysfunction, although further studies regarding the safety and long-term effects are required. LEVEL OF EVIDENCE Level III; therapeutic study.