IntroductionBone 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.MethodsTwelve 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-1β, IL-6 and IL-10 as well as the thrombin-antithrombin complexes (TAT) were all measured using enzyme-immunoassays.ResultsAfter 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-1β and IL-10 in lung tissue compared to sham (p<0.0001-0.03). Similarly, heart tissue exhibited 2-times higher TCC and IL-1β 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).DiscussionA 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.

BackgroundIdentifying spontaneous circulation during cardiopulmonary resuscitation (CPR) is challenging. Current methods, which involve intermittent and time-consuming pulse checks, necessitate pauses in chest compressions. This issue is problematic in both in-hospital cardiac arrest and out-of-hospital cardiac arrest situations, where resources for identifying circulation during CPR may be limited. The fraction of chest compression plays a pivotal role in improving survival rates. To address this challenge, we evaluated a newly developed hands-free, continuous carotid Doppler system (RescueDoppler), designed to identify spontaneous circulation during chest compressions. In our study, we utilized a porcine model of cardiac arrest to investigate sequences of ventricular fibrillation, followed by defibrillation, and monitoring for the return of spontaneous circulation during chest compressions with the carotid Doppler system. We explored both manual compressions at 100 and 50 compressions per minute and mechanical compressions. To estimate the detection rate (i.e., sensitivity), we employed a logistic mixed model with animal identity as random effect.ResultsOffline analysis of Doppler color M-mode and spectral display successfully identified spontaneous circulation during chest compressions in all compression models. Spontaneous circulation was detected in 51 of 59 sequences, yielding an expected sensitivity of 98% with a 95% confidence interval of 59% to 99%.ConclusionThe RescueDoppler, a continuous hands-free carotid Doppler system, demonstrates an expected sensitivity of 98% for identifying spontaneous circulation during both manual and mechanical chest compressions. Clinical studies are needed to further validate these findings.

Background: During cardiopulmonary resuscitation (CPR), identifying the return of spontaneous circulation (ROSC) is challenging. Methods such as manual palpation, end-tidal carbon dioxide, and point-of-care ultrasound to detect ROSC are inaccurate, time-consuming, or intermittent. They may also require halting or prolonging no-compression time to identify signs of circulation. Maintaining a high compression fraction is associated with an increased likelihood of achieving ROSC. Aim: This study aimed to investigate if using a novel continuous hands-free carotid Doppler system (RescueDoppler (RD)) could identify ROSC during chest compressions by distinguishing between spontaneous and chest compression-generated carotid blood flow velocity. Methods: We used a porcine cardiac arrest model to investigate the RD. The RD probe was positioned and fixated over the carotid artery. An invasive blood pressure catheter was inserted in the contralateral carotid artery. An implantable cardioverter defibrillator (ICD) was utilized to induce sequences of ventricular fibrillation followed by defibrillation and chest compressions (cardiac arrest sequences). Compressions were administered manually at a rate of 100 or 50 compressions per minute or using a mechanical chest compression device (LUCAS). Doppler blood flow velocity curves were retrospectively analyzed for signs of ROSC by examining both spontaneous and/or compression-generated velocities (Fig. 1,2). We combined color M-mode and Doppler spectrum (Fig. 1) to differentiate between chest compression and spontaneous velocities. Results: Data from eight animals (mean weight 30 kg) and 56 cardiac arrest sequences were included. In the analysis, chest compressions were identified as tissue movements through the whole spectrum of the color M-mode, in the spectral display (Fig. 1), or both. Spontaneous velocities were identified in a specific carotid depth of the color M-mode and between compression-generated peak velocities in the Doppler specter (Fig. 1). ROSC was confirmed by pausing chest compressions and evaluating ECG and invasive blood pressure. We identified spontaneous circulation during manual and mechanical chest compressions in 55 of 56 sequences. Conclusions: In a porcine cardiac arrest model, with ROSC, we could differentiate between spontaneous circulation and chest compression-generated blood flow velocity of the carotid artery using RescueDoppler.

Background: Real-time hemodynamic feedback devices provide information on cardiopulmonary resuscitation (CPR) quality. This can improve hand positioning and technique, thereby maximizing blood flow and potentially improve survival. Hypothesis: We hypothesize that a newly developed hands-free Doppler for carotid blood flow velocity (RescueDoppler, RD), can identify optimal vs. suboptimal chest compression sites during CPR. Aim: To assess the potential of the RD device to continuously monitor the effect of each compression by ultrasound metrics and waveforms in a porcine model. Methods: Ventricular fibrillation was induced in 5 pigs using an ICD. Manual CPR (blinded for hemodynamic data) was performed for 10 seconds at 3 different compression sites in random order (Fig.), and repeated 6 times. We analyzed ultrasound waveforms with Time Average Velocity (TAV) in a linear mixed model with site as fixed effect, and animal and site within animal as random effects. We further compared TAV to invasive systolic blood pressure (SBP) from the contralateral carotid artery. Results: Data from 5 pigs (mean weight 31.2 kg) and 29 of 30 sequences were included. Overall, blood flow velocity was highest at compression site 2 (TAV 33 cm/s, P<0.01), but there was significant variability (P<0.01) in animals (SD= 3.7) and at sites within animal (SD= 7). A compression site yielding the highest TAV (range 19 to 48 cm/s) or lowest TAV (6-25 cm/s) was successfully identified in all animals with corresponding SBPs 50-81 mmHg, and 46-64 mmHg, respectively. The correlation between TAV and SBP was 0.62-0.90 within animals. Conclusions In this animal study, a newly developed hands-free Doppler enabled assessment of blood flow velocity during CPR and detected significant variation according to chest compression site. RD identified the sites with both high and low blood flow velocities and is thus a promising device for effectively identifying the optimal and suboptimal chest compression sites during CPR.

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.

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 RescueDoppler ' s 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.

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-1β 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-1β, 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.

Introduction: Intermittent carotid pulse palpation (PP) is used to determine the return of spontaneous circulation (ROSC) during cardiopulmonary resuscitation (CPR). PP requires interruption of CPR and has low accuracy. Therefore, we investigated if a novel continuous non-invasive hands-free Doppler ultrasound system (RescueDoppler; RD) could detect the presence of pulse/no pulse and ROSC in an experimental setting with ventricular fibrillation (VF) and severe hypotension. Methods: RD was attached to the neck with a self-adhesive bandage onto twelve pigs (mean weight of 30.4 kg). RD used multirange Doppler, with 32 depth ranges over 8 - 45 mm. The transducer dimension was 30 x 6 mm. The RD probe was placed over the carotid artery, while invasive blood pressure was recorded on the contralateral side. Two profound circulatory disturbances were initiated; 1) severe hypotension by vena cava inferior occlusion (VCO) using a 7 Fr Fogarty catheter with gradual balloon inflation and 2) VF by applying a 7.5 V direct current in the myocardium for 2 seconds using an implantable cardioverter-defibrillator placed in the right ventricle apex. The pigs were defibrillated back to ROSC. Mean velocity over one cardiac cycle (time-averaged velocity; TAV) was compared with mean arterial pressure (MAP). Results: RD detected flow in the carotid artery in all 41 VCO sequences (figure), including the lowest induced systolic blood pressure of 19 mmHg. The intraclass correlation coefficient was 0.76 between TAV and MAP. ROSC was equally identified by RD and invasive blood pressure in all 21 VF sequences where the pigs were defibrillated from VF to sinus rhythm (figure). Conclusion: The RD system was simple and required no ultrasound knowledge. RD detected ROSC and blood flow at extremely low invasive carotid blood pressures during VF and VCO. TAV correlated well with MAP. RD could become an essential non-invasive, hands-free tool for continuous hemodynamic-guided CPR.

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.