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Introduction: Bone marrow embolization may complicate orthopedic surgery, potentially causing fat embolism syndrome. The inflammatory potential of bone marrow emboli is unclear. We aimed to investigate the inflammatory response to femoral intramedullary nailing, specifically the systemic inflammatory effects in plasma, and local tissue responses. Additionally, the plasma response was compared to that following intravenous injection of autologous bone marrow. Methods: Twelve pigs underwent femoral nailing (previously shown to have fat emboli in lung and heart), four received intravenous bone marrow, and four served as sham controls. Blood samples were collected hourly and tissue samples postmortem. Additionally, we incubated bone marrow and blood, separately and in combination, from six pigs in vitro. Complement activation was detected by C3a and the terminal C5b-9 complement complex (TCC), and the cytokines TNF, IL-1ß, IL-6 and IL-10 as well as the thrombin-antithrombin complexes (TAT) were all measured using enzyme-immunoassays. Results: After nailing, plasma IL-6 rose 21-fold, compared to a 4-fold rise in sham (p=0.0004). No plasma differences in the rest of the inflammatory markers were noted across groups. However, nailing yielded 2-3-times higher C3a, TCC, TNF, IL-1ß and IL-10 in lung tissue compared to sham (p<0.0001-0.03). Similarly, heart tissue exhibited 2-times higher TCC and IL-1ß compared to sham (p<0.0001-0.03). Intravenous bone marrow yielded 8-times higher TAT than sham at 30 minutes (p<0.0001). In vitro, incubation of bone marrow for four hours resulted in 95-times higher IL-6 compared to whole blood (p=0.03). Discussion: A selective increase in plasma IL-6 was observed following femoral nailing, whereas lung and heart tissues revealed a broad local inflammatory response not reflected systemically. In vitro experiments may imply bone marrow to be the primary IL-6 source.
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Embolia Gordurosa , Interleucina-6 , Pulmão , Animais , Suínos , Interleucina-6/sangue , Embolia Gordurosa/etiologia , Embolia Gordurosa/sangue , Embolia Gordurosa/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/metabolismo , Medula Óssea/metabolismo , Fixação Intramedular de Fraturas/efeitos adversos , Miocárdio/metabolismo , Miocárdio/patologia , Miocárdio/imunologia , Inflamação/sangue , Inflamação/imunologia , Feminino , Citocinas/sangue , Citocinas/metabolismo , Pinos Ortopédicos , Ativação do Complemento , Fêmur/metabolismo , Modelos Animais de DoençasRESUMO
Aim: Current guidelines for cardiopulmonary resuscitation (CPR) recommend a one-size-fits-all approach in relation to the positioning of chest compressions. We recently developed RescueDoppler, a hands-free Doppler ultrasound device for continuous monitoring of carotid blood flow velocity during CPR. The aim of the present study is to investigate whether RescueDoppler via real-time hemodynamic feedback, could identify both optimal and suboptimal compression positions. Methods: In this model of animal cardiac arrest, we induced ventricular fibrillation in five domestic pigs. Manual chest compressions were performed for ten seconds at three different positions on the sternum in random order and repeated six times. We analysed Time Average Velocity (TAV) with chest compression position as a fixed effect and animal, position, and sequential time within animals as random effects. Furthermore, we compared TAV to invasive blood pressure from the contralateral carotid artery. Results: We were able to detect changes in TAV when altering positions. The positions with the highest (range 19 to 48 cm/s) and lowest (6-25 cm/s) TAV were identified in all animals, with corresponding peak pressure 50-81 mmHg, and 46-64 mmHg, respectively. Blood flow velocity was, on average, highest at the middle position (TAV 33 cm/s), but with significant variability between animals (SD 2.8) and positions within the same animal (SD 9.3). Conclusion: RescueDoppler detected TAV changes during CPR with alternating chest compression positions, identifying the position yielding maximal TAV. Future clinical studies should investigate if RescueDoppler can be used as a real-time hemodynamical feedback device to guide compression position.
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Background: Shaft fractures of the femur are commonly treated with intramedullary nailing, which can release bone marrow emboli into the bloodstream. Emboli can travel to the lungs, impairing gas exchange and causing inflammation. Occasionally, emboli traverse from the pulmonary to the systemic circulation, hindering perfusion and resulting in injuries such as heart and brain infarctions, known as fat embolism syndrome. We studied the extent of systemic bone marrow embolization in a pig model. Methods: Twelve anesthetized pigs underwent bilateral intramedullary nailing of the femur, while 3 animals served as sham controls. Monitoring included transesophageal echocardiography (TEE), pulse oximetry, electrocardiography, arterial blood pressure measurement, and blood gas and troponin-I analysis. After surgery, animals were monitored for 240 minutes before euthanasia. Post mortem, the heart, lungs, and brain were biopsied. Results: Bone marrow emboli were found in the heart and lungs of all 12 of the pigs that underwent intramedullary nailing and in the brains of 11 of them. No emboli were found in the sham group. The pigs subjected to intramedullary nailing exhibited significant hypoxia (PaO2/FiO2 ratio, 410 mm Hg [95% confidence interval (CI), 310 to 510) compared with the sham group (594 mm Hg [95% CI, 528 to 660]). The nailing group exhibited ST-segment alterations consistent with myocardial ischemia and a significant increase in the troponin-I level compared with the sham group (1,580 ng/L [95% CI, 0 to 3,456] versus 241 ng/L [95% CI, 0 to 625] at the 240-minute time point; p = 0.005). TEE detected emboli in the right ventricular outflow tract, but not systemically, in the nailing group. Conclusions: Bilateral intramedullary nailing caused bone marrow emboli in the lungs and systemic emboli in the heart and brain in this pig model. The observed clinical manifestations were consistent with coronary and pulmonary emboli. TEE detected pulmonary but not systemic embolization. Clinical Relevance: Femoral intramedullary nailing in humans is likely to result in embolization as described in our pig model. Focused monitoring is necessary for detection of fat embolism syndrome. Absence of visual emboli in the left ventricle on TEE does not exclude the occurrence of systemic bone marrow emboli.
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Background/Purpose: Pulse palpation is an unreliable method for diagnosing cardiac arrest. To address this limitation, continuous hemodynamic monitoring may be a viable solution. Therefore, we developed a novel, hands-free Doppler system, RescueDoppler, to detect the pulse continuously in the carotid artery. Methods: In twelve pigs, we evaluated RescueDopplers potential to measure blood flow velocity in three situations where pulse palpation of the carotid artery was insufficient: (1) systolic blood pressure below 60 mmHg, (2) ventricular fibrillation (VF) and (3) pulseless electrical activity (PEA). (1) Low blood pressure was induced using a Fogarty balloon catheter to occlude the inferior vena cava. (2) An implantable cardioverter-defibrillator induced VF. (3) Myocardial infarction after microembolization of the left coronary artery caused True-PEA. Invasive blood pressure was measured in the contralateral carotid artery. Time-averaged blood flow velocity (TAV) in the carotid artery was related to mean arterial pressure (MAP) in a linear mixed model. Results: RescueDoppler identified pulsatile blood flow in 41/41 events with systolic blood pressure below 60 mmHg, with lowest blood pressure of 19 mmHg. In addition the absence of spontaneous circulation was identified in 21/21 VF events and true PEA in 2/2 events. The intraclass correlation coefficient within animals for TAV and MAP was 0.94 (95% CI. 0.85-0.98). Conclusions: In a porcine model, RescueDoppler reliably identified pulsative blood flow with blood pressures below 60 mmHg. During VF and PEA, circulatory arrest was rapidly and accurately demonstrated. RescueDoppler could potentially replace unreliable pulse palpation during cardiac arrest and cardiopulmonary resuscitation.
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Introduction: Air embolism may complicate invasive medical procedures. Bubbles trigger complement C3-mediated cytokine release, coagulation, and platelet activation in vitro in human whole blood. Since these findings have not been verified in vivo, we aimed to examine the effects of air embolism in pigs on thromboinflammation. Methods: Forty-five landrace pigs, average 17 kg (range 8.5-30), underwent intravenous air infusion for 300 or 360 minutes (n=29) or served as sham (n=14). Fourteen pigs were excluded due to e.g. infections or persistent foramen ovale. Blood was analyzed for white blood cells (WBC), complement activation (C3a and terminal C5b-9 complement complex [TCC]), cytokines, and hemostatic parameters including thrombin-antithrombin (TAT) using immunoassays and rotational thromboelastometry (ROTEM). Lung tissue was analyzed for complement and cytokines using qPCR and immunoassays. Results are presented as medians with interquartile range. Results: In 24 pigs receiving air infusion, WBC increased from 17×109/L (10-24) to 28 (16-42) (p<0.001). C3a increased from 21 ng/mL (15-46) to 67 (39-84) (p<0.001), whereas TCC increased only modestly (p=0.02). TAT increased from 35 µg/mL (28-42) to 51 (38-89) (p=0.002). ROTEM changed during first 120 minutes: Clotting time decreased from 613 seconds (531-677) to 538 (399-620) (p=0.006), clot formation time decreased from 161 seconds (122-195) to 124 (83-162) (p=0.02) and α-angle increased from 62 degrees (57-68) to 68 (62-74) (p=0.02). In lungs from pigs receiving air compared to sham animals, C3a was 34 ng/mL (14-50) versus 4.1 (2.4-5.7) (p<0.001), whereas TCC was 0.3 CAU/mL (0.2-0.3) versus 0.2 (0.1-0.2) (p=0.02). Lung cytokines in pigs receiving air compared to sham animals were: IL-1ß 302 pg/mL (190-437) versus 107 (66-120), IL-6 644 pg/mL (358-1094) versus 25 (23-30), IL-8 203 pg/mL (81-377) versus 21 (20-35), and TNF 113 pg/mL (96-147) versus 16 (13-22) (all p<0.001). Cytokine mRNA in lung tissue from pigs receiving air compared to sham animals increased 12-fold for IL-1ß, 121-fold for IL-6, and 17-fold for IL-8 (all p<0.001). Conclusion: Venous air embolism in pigs activated C3 without a corresponding C5 activation and triggered thromboinflammation, consistent with a C3-dependent mechanism. C3-inhibition might represent a therapeutic approach to attenuate this response.
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Embolia Aérea , Trombose , Animais , Complemento C3/genética , Complexo de Ataque à Membrana do Sistema Complemento , Citocinas , Inflamação , Interleucina-6 , Interleucina-8 , Suínos , TromboinflamaçãoRESUMO
BACKGROUND: Intraosseous cannulation can be life-saving when intravenous access cannot be readily achieved. However, it has been shown that the procedure may cause fat emboli to the lungs and brain. Fat embolization may cause serious respiratory failure and fat embolism syndrome. We investigated whether intraosseous fluid resuscitation in pigs in hemorrhagic shock caused pulmonary or systemic embolization to the heart, brain, or kidneys and if this was enhanced by open chest conditions. METHODS: We induced hemorrhagic shock in anesthetized pigs followed by fluid-resuscitation through bilaterally placed tibial (hind leg) intraosseous cannulas. The fluid-resuscitation was limited to intraosseous or i.v. fluid therapy, and did not involve cardiopulmonary resuscitation or other interventions. A subgroup underwent median sternotomy with pericardiectomy and pleurotomy before hemorrhagic shock was induced. We used invasive hemodynamic and respiratory monitoring including Swan Ganz pulmonary artery catheter and transesophageal echocardiography and obtained biopsies from the lungs, heart, brain, and left kidney postmortem. RESULTS: All pigs exposed to intraosseous infusion had pulmonary fat emboli in postmortem biopsies. Additionally, seven of twenty-one pigs had coronary fat emboli. None of the pigs with open chest had fat emboli in postmortem lung, heart, or kidney biopsies. During intraosseous fluid-resuscitation, three pigs developed significant ST-elevations on ECG; all of these animals had coronary fat emboli on postmortem biopsies. CONCLUSIONS: Systemic fat embolism occurred in the form of coronary fat emboli in a third of the animals who underwent intraosseous fluid resuscitation. Open chest conditions did not increase the incidence of systemic fat embolization.