Unmasking the Confounder: The Inherent Physiologic Variability of Swine During an Automated Experimental Model of Ischemia-Reperfusion Injury

Martin, Symonne C; Hauser, Nathaniel; Renaldo, Antonio C.; Lane, Magan R.; Jordan, James; Qadri, Hisham I; Mouser, Nicholas; Rahbar, Elaheh; Williams, Timothy K.; Neff, Lucas P.

doi:10.1177/00031348221084967

Cited by 4 publications

(4 citation statements)

References 19 publications

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“…Furthermore, sample sizes should be determined a priori based on robust power calculations. However, we found consistency in cardiac function measurements at baseline and end of hemorrhage across groups, which demonstrates the rigor of instrumentation and automated experimental methodology to enable a reproducible hemorrhagic shock model ( 28 ). While there was decreased variability for most parameters after the controlled hemorrhage in all groups, there were some notable exceptions such as HR.…”

Section: Discussionmentioning

confidence: 62%

“…The elevated HR variability was not expected in a state of shock as others, such as Batchinsky et al and Carrara et al ( 29 , 30 ), have shown that acute stress from hemorrhagic shock can impair the autonomic nervous system and its modulation of heart rate. The consistency in cardiac function measurements at baseline and end of hemorrhage also demonstrates the rigor of the instrumentation and automated experimental methodology to enable a reproducible hemorrhagic shock model ( 28 , 30 , 31 ). Collectively, the results from this suggest that an n = 6 pigs/group is only adequately powered to detect a twofold increase in cardiac performance metrics (e.g., SV, CO).…”

Section: Discussionmentioning

confidence: 84%

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Investigating the variability in pressure–volume relationships during hemorrhage and aortic occlusion

Mobin,

Renaldo,

Carrasco Perez

et al. 2023

Front. Cardiovasc. Med.

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IntroductionThe pressure–volume (P-V) relationships of the left ventricle are the classical benchmark for studying cardiac mechanics and pumping function. Perturbations in the P-V relationship (or P-V loop) can be informative and guide the management of heart failure, hypovolemia, and aortic occlusion. Traditionally, P-V loop analyses have been limited to a single-beat P-V loop or an average of consecutive P-V loops (e.g., 10 cardiac cycles). While there are several algorithms to obtain single-beat estimations of the end-systolic and end-diastolic pressure–volume relations (i.e., ESPVR and EDPVR, respectively), there remains a need to better evaluate the variations in P-V relationships longitudinally over time. This is particularly important when studying acute and transient hemodynamic and cardiac events, such as active hemorrhage or aortic occlusion. In this study, we aim to investigate the variability in P-V relationships during hemorrhagic shock and aortic occlusion, by leveraging on a previously published porcine hemorrhage model.MethodsBriefly, swine were instrumented with a P-V catheter in the left ventricle of the heart and underwent a 25% total blood volume hemorrhage over 30 min, followed by either Zone 1 complete aortic occlusion (i.e., REBOA), Zone 1 endovascular variable aortic control (EVAC), or no occlusion as a control, for 45 min. Preload-independent metrics of cardiac performance were obtained at predetermined time points by performing inferior vena cava occlusion during a ventilatory pause. Continuous P-V loop data and other hemodynamic flow and pressure measurements were collected in real-time using a multi-channel data acquisition system.ResultsWe developed a custom algorithm to quantify the time-dependent variance in both load-dependent and independent cardiac parameters from each P-V loop. As expected, all pigs displayed a significant decrease in the end-systolic pressures and volumes (i.e., ESP, ESV) after hemorrhage. The variability in response to hemorrhage was consistent across all three groups. However, upon introduction of REBOA, we observed significantly high levels of variability in both load-dependent and independent cardiac metrics such as ESP, ESV, and the slope of ESPVR (Ees). For instance, pigs receiving REBOA experienced a 342% increase in ESP from hemorrhage, while pigs receiving EVAC experienced only a 188% increase. The level of variability within the EVAC group was consistently less than that of the REBOA group, which suggests that the EVAC group may be more supportive of maintaining healthier cardiac performance than complete occlusion with REBOA.DiscussionIn conclusion, we successfully developed a novel algorithm to reliably quantify the single-beat and longitudinal P-V relations during hemorrhage and aortic occlusion. As expected, hemorrhage resulted in smaller P-V loops, reflective of decreased preload and afterload conditions; however, the cardiac output and heart rate were preserved. The use of REBOA and EVAC for 44 min resulted in the restoration of baseline afterload and preload conditions, but often REBOA exceeded baseline pressure conditions to an alarming level. The level of variability in response to REBOA was significant and could be potentially associated to cardiac injury. By quantifying each P-V loop, we were able to capture the variability in all P-V loops, including those that were irregular in shape and believe that this can help us identify critical time points associated with declining cardiac performance during hemorrhage and REBOA use.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 84%

Investigating the variability in pressure–volume relationships during hemorrhage and aortic occlusion

Mobin,

Renaldo,

Carrasco Perez

et al. 2023

Front. Cardiovasc. Med.

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“…Interindividual variability in response to surgical setup may have contributed to some of our findings. Our group has already highlighted the unexpected variability in response to a similar model 74 . Regardless, blood pressure alone is not a good marker of microperfusion overall.…”

Section: Discussionmentioning

confidence: 91%

Elamipretide mitigates ischemia-reperfusion injury in a swine model of hemorrhagic shock

Patel

Johnson

Vapniarsky

et al. 2023

Sci Rep

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Abstractischemia-reperfusion injury (IRI) after hemorrhage is potentiated by aortic occlusion or resuscitative endovascular balloon occlusion of the aorta (REBOA). Given the central role of mitochondrial injury in shock, we hypothesized that Elamipretide, a peptide that protects mitochondria, would mitigate IRI after hemorrhagic shock and REBOA. Twelve pigs were subjected to hemorrhagic shock and 45 min of REBOA. After 25 min of REBOA, animals received either saline or Elamipretide. Animals were transfused with autologous blood during balloon deflation, and pigs were resuscitated with isotonic crystalloids and norepinephrine for 4.25 h. Elamipretide-treated animals required less crystalloids than the controls (62.5 [50–90] and 25 [5–30] mL/kg, respectively), but similar amounts of norepinephrine (24.7 [8.6–39.3] and 9.7 [2.1–12.5] mcg/kg, respectively). Treatment animals had a significant reduction in serum creatinine (control: 2.7 [2.6–2.8]; Elamipretide: 2.4 [2.4–2.5] mg/dL; p = 0.04), troponin (control: 3.20 [2.14–5.47] ng/mL, Elamipretide: 0.22 [0.1–1.91] ng/mL; p = 0.03), and interleukin-6 concentrations at the end of the study. There were no differences in final plasma lactate concentration. Elamipretide reduced fluid requirements and protected the kidney and heart after profound IRI. Further understanding the subcellular consequences of REBOA and mitochondrial rescue will open new therapeutic avenues for patients suffering from IRI after hemorrhage.

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“…Our group has previously investigated the inherent physiologic variability in an automated ischemia-reperfusion swine model and found significant differences in cardiovascular and biological response. Although this confounder seems to be unavoidable in preclinical in vivo models, it may offer a translational advantage as it effectively models clinical practice (41).…”

Section: Discussionmentioning

confidence: 99%

Investigating the Relationship Between Bleeding, Clotting, and Coagulopathy During Automated Partial Reboa Strategies in a Highly Lethal Porcine Hemorrhage Model

Renaldo,

Soudan,

Gomez

et al. 2024

Shock

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Background Death due to hemorrhagic shock, particularly, non-compressible truncal hemorrhage (NCTH), remains one of the leading causes of potentially preventable deaths. Automated partial and intermittent resuscitative endovascular balloon occlusion of the aorta (i.e., pREBOA and iREBOA, respectively) are lifesaving endovascular strategies aimed to achieve quick hemostatic control while mitigating distal ischemia. In iREBOA, the balloon is titrated from full occlusion to no occlusion intermittently whereas in pREBOA, a partial occlusion is maintained. Therefore, these two interventions impose different hemodynamic conditions, which may impact coagulation and the endothelial glycocalyx layer (EGL). In this study, we aimed to characterize the clotting kinetics and coagulopathy associated with iREBOA and pREBOA, using thromboelastography (TEG). We hypothesized that iREBOA would be associated with a more hypercoagulopathic response compared to pREBOA due to more oscillatory flow. Methods Yorkshire swine (n = 8/group) were subjected to an uncontrolled hemorrhage by liver transection, followed by 90 minutes of automated partial REBOA (pREBOA), intermittent REBOA (iREBOA), or no balloon support (Control). Hemodynamic parameters were continuously recorded, and blood samples were serially collected during the experiment (i.e., 8 key time points: baseline (BL), T0, T10, T30, T60, T90, T120, T210 minutes). Citrated kaolin heparinase (CKH) assays were run on a TEG 5000 (Haemonetics, Niles, IL). General linear mixed models were employed to compare differences in TEG parameters between groups and over time using STATA (v17; College Station, TX), while adjusting for sex and weight. Results As expected, iREBOA was associated with more oscillations in proximal pressure (and greater magnitudes of peak pressure) because of the intermittent periods of full aortic occlusion and complete balloon deflation, compared to pREBOA. Despite these differences in acute hemodynamics, there were no significant differences in any of the TEG parameters between iREBOA and pREBOA groups. However, animals in both groups experienced a significant reduction in clotting times (R-time: p < 0.001; K-time: p < 0.001) and clot strength (MA: p = 0.01; G: p = 0.02) over the duration of the experiment. Conclusions Despite observing acute differences in peak proximal pressures between iREBOA and pREBOA groups, we did not observe any significant differences in TEG parameters between iREBOA and pREBOA. The changes in TEG profiles were significant over time, indicating that a severe hemorrhage followed by both pREBOA and iREBOA can result in faster clotting reaction times (i.e., R-times). Nevertheless, when considering the significant reduction in transfusion requirements and more stable hemodynamic response in the pREBOA group, there may be some evidence favoring pREBOA usage over iREBOA.

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Unmasking the Confounder: The Inherent Physiologic Variability of Swine During an Automated Experimental Model of Ischemia-Reperfusion Injury

Cited by 4 publications

References 19 publications

Investigating the variability in pressure–volume relationships during hemorrhage and aortic occlusion

Investigating the variability in pressure–volume relationships during hemorrhage and aortic occlusion

Elamipretide mitigates ischemia-reperfusion injury in a swine model of hemorrhagic shock

Investigating the Relationship Between Bleeding, Clotting, and Coagulopathy During Automated Partial Reboa Strategies in a Highly Lethal Porcine Hemorrhage Model

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