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Introduction: Ultrasonography as a guide for intravenous (IV) fluid therapy is increasingly accepted within the spheres of acute care. Initial investigations and protocols often focused on measures of arterial flow as an objective approach for personalising organ 'perfusion.' More recently, and with literature associating excessive IV fluid with adverse outcomes, venous ultrasound as a measure of organ 'congestion' is taking hold. Yet, arterial (i.e., 'perfusion') and venous (i.e., 'congestion') Doppler ultrasound measures are often performed separately and can be time‐consuming, especially for novices. Methods: We report a case, wherein venous and arterial Doppler were simultaneously measured using a wireless, wearable ultrasound as a means to optimise flow without congestion. Results: Before IV volume expansion, the patient had Doppler measures consistent with low central venous pressure (CVP) and stroke volume (SV). Following IV volume expansion, venous Doppler remained the same; however, carotid corrected flow time (ccFT) increased significantly. Conclusion: A framework for venous‐arterial Doppler enhanced resuscitation (VADER) can be used to guide IV volume in patients at risk for venous congestion. [ABSTRACT FROM AUTHOR]

Cardiac excitation‐contraction (E‐C) coupling is influenced by (at least) three dynamic systems that couple and feedback to one another (see Abstract Figure). Here we review the mechanical effects on cardiomyocytes that include mechano‐electro‐transduction (commonly referred to as mechano‐electric coupling, MEC) and mechano‐chemo‐transduction (MCT) mechanisms at cell and molecular levels which couple to Ca2+‐electro and E‐C coupling reviewed elsewhere. These feedback loops from muscle contraction and mechano‐transduction to the Ca2+ homeodynamics and to the electrical excitation are essential for understanding the E‐C coupling dynamic system and arrhythmogenesis in mechanically loaded hearts. This white paper comprises two parts, each reflecting key aspects from the 2018 UC Davis symposium: MEC (how mechanical load influences electrical dynamics) and MCT (how mechanical load alters cell signalling and Ca2+ dynamics). Of course, such separation is artificial since Ca2+ dynamics profoundly affect ion channels and electrogenic transporters and vice versa. In time, these dynamic systems and their interactions must become fully integrated, and that should be a goal for a comprehensive understanding of how mechanical load influences cell signalling, Ca2+ homeodynamics and electrical dynamics. In this white paper we emphasize current understanding, consensus, controversies and the pressing issues for future investigations. Space constraints make it impossible to cover all relevant articles in the field, so we will focus on the topics discussed at the symposium. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether percentage changes in pulse wave transit time (PWTT%Δ) induced by mini‐fluid challenges predict fluid responsiveness in mechanically ventilated anesthetized dogs. Design: Prospective experimental trial. Setting: University teaching hospital. Animals: Twelve Harrier hounds. Intervention: Each dog was anesthetized with propofol and isoflurane after premedication with acepromazine, mechanically ventilated, and had a fluid challenge. This was repeated 4 weeks later. The fluid challenge, 10 mL/kg of colloid administration over 13 minutes, consisted of 3 intermittent mini‐fluid challenges (1 mL/kg of each over a minute) with a minute interval, and the remaining colloid administration (7 mL/kg) over 7 minutes. Measurements and Main Results: Percentage change in velocity time integral of pulmonary arterial flow by echocardiography was calculated as an indication of change in stroke volume. Fluid responsiveness was defined as percentage change in velocity time integral ≥ 15% after 10 mL/kg colloid. Dogs responded on 14 fluid challenges and did not on 10. After 1, 2, 3, and 10 mL/kg of fluid challenge, PWTT%Δ1, 2, 3, 10 were measured. Receiver operator characteristic (ROC) curves were generated and areas under ROC curve were calculated for PWTT%Δ1, 2, 3. A gray zone approach was used to identify the clinically inconclusive range. The area under the ROC curve for PWTT%Δ3 was 0.91 (P = 0.001). Cutoff value for PWTT%Δ3 was −2.5% (sensitivity: 86%, specificity: 90%). The gray zone for PWTT%Δ3 was identified as between −2.9% to −1.9% for which fluid responsiveness could not be predicted reliably in 6 out of 24 fluid challenges. Conclusions: In mechanically ventilated anesthetized dogs given a mini‐fluid challenge of 3 mL/kg of colloid, PWTT%Δ could predict fluid responsiveness although the gray zone should be considered. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate whether pulse pressure variation (PPV) and pleth variability index (PVI) are more accurate than central venous pressure (CVP) for predicting fluid responsiveness in mechanically ventilated isoflurane‐anesthetized dogs after premedication with acepromazine. Design: Prospective experimental trial. Setting: University teaching hospital. Animals: Twelve Harrier hound dogs. Interventions: Each dog was anesthetized and had a fluid challenge performed. This was repeated 4 weeks later for a total of 24 fluid challenges. After premedication with intramuscular acepromazine, anesthesia was induced with propofol and maintained with isoflurane. The dogs were mechanically ventilated with constant settings. The fluid challenge consisted of 10 mL/kg of 6% hydroxyethyl starch intravenously over 13 minutes. Measurements and Main Results: Before and after the fluid challenge, PPV, PVI, CVP, and other hemodynamics were recorded. Change in velocity time integral of pulmonary arterial blood flow by echocardiography was calculated as an indication of change in stroke volume. A fluid responder was defined as an increase in velocity time integral ≥ 15%. Receiver operator characteristic (ROC) curves were used to determine cutoff values. Areas under ROC curve were calculated and compared. Dogs responded on 14 fluid challenges and did not on 10. Cutoff values for PPV and PVI were 11% (sensitivity 79%; specificity 80%) and 9.3% (sensitivity 86%; specificity 70%), respectively. The areas under the ROC curve of PPV [0.85, 95% confidence interval (CI): 0.70–1.00, P = 0.038] and PVI (0.84, 95% CI: 0.68–1.00, P = 0.043) were significantly higher than CVP (0.56, 95% CI: 0.32–0.81). Conclusions: PPV and PVI predicted fluid responsiveness more accurately than CVP and may be useful to guide fluid administration in mechanically ventilated isoflurane‐anesthetized dogs after premedication with acepromazine. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the effects of dexmedetomidine (DEX) on changes in pulse pressure variation (PPV) induced by hemorrhage followed by volume replacement (VR) during isoflurane (ISO) anesthesia. Design Prospective, randomized, crossover study. Setting Research laboratory at a veterinary teaching hospital. Animals Eight adult dogs. Interventions Anesthesia was maintained with 1.3 times the minimum alveolar concentration (MAC) of ISO alone or ISO with DEX (ISO-DEX, 1.6 μg/kg [bolus], followed by 2 μg/kg/h). Atropine was administered 30 minutes prior to hemorrhage in the ISO-DEX treatment. Ventilation was controlled (tidal volume of 12 mL/kg, positive end-expiratory pressure of 7 cm H2O, respiratory rate of 16-20/min) under neuromuscular blockade. After recording baseline data, progressive withdrawal of 10%, 20%, and 30% of blood volume (HV10, HV20, and HV30, respectively [measurements during hemorrhage, indicating x% of blood volume removed]) was followed by VR with autologous blood. Measurements and Main Results In 4 of 8 ISO dogs, hemorrhage decreased mean arterial pressure (MAP) < 60 mm Hg. Based on mean arterial pressure after hemorrhage, dogs were assigned to hypotensive (HG) and normotensive (NG) groups post hoc. During ISO, stroke index and cardiac index decreased with hemorrhage ( P < 0.05), while VR normalized or increased these variables. The PPV (%, mean [range]) was increased by hemorrhage from 7 (5-9) to 20 (12-27) and 27 (17-40) at HV20 and HV30, respectively, only in ISO dogs in the HG; PPV returned to baseline after VR. Dexmedetomidine caused increases in systemic vascular resistance (in dogs in HG and NG), and prevented the increase in PPV with hemorrhage. Conclusions During ISO anesthesia, PPV increases in individuals prone to developing hypotension from hypovolemia. Because DEX prevents the increase in PPV associated with hypovolemia, PPV should not be used to guide VR in dogs that have been given DEX. [ABSTRACT FROM AUTHOR]

Hanft LM, McDonald KS. Sarcomere length dependence of power output is increased after PKA treatment in rat cardiac myocytes. Am J Physiol Heart Circ Physiol 296: H1524-H1531, 2q09. First published February 27, 2009; doi: 10.11 52/ajpheart.00864.2008. The Frank-Starling relationship of the heart yields increased stroke volume with greater end-diastolic volume, and this relationship is steeper after β-adrenergic stimulation. The underlying basis for the Frank-Starling mechanism involves length-dependent changes in both Ca[sup2+] sensitivity of myofibrillar force and power output. In this study, we tested the hypothesis that PKA-induced phosphorylation of myofibrillar proteins would increase the length dependence of myofibrillar power output, which would provide a myofibrillar basis to, in part, explain the steeper Frank-Starling relations after β-adrenenic stimulation. For these experiments, adult rat left ventricles were mechanically disrupted, permeabilized cardiac myocyte preparatkrns were attached between a force transducer and position motor, and the length dependence of loaded shortening and power output were measured before and after treatment with PKA. PKA increased the phosphorylation of myosin binding protein C and cardiac troponin I, as assessed by autoradiography. In terms of myocyte mechanics, PKA decreased the Ca[sup2+] sensitivity of force and increased loaded shortening and power output at all relative loads when the myocyte preparations were at long sarcomere length (-2.30 μm). PKA had less of an effect on loaded shortening and power output at short sarcomere length (-2.0 μm). These changes resulted in a greater length dependence of myocyte power output after PKA treatment; peak normalized power output increased -20% with length before PKA and -40% after PKA. These results suggest that PKA-induced phosphorylation of myofibrillar proteins explains, in part, the steeper ventricular function curves (i.e., Frank-Starling relationship) after β-adrenergic stimulation of the left ventricle. [ABSTRACT FROM AUTHOR]

The present study examined the contribution of myofilament contractile proteins to regional function in guinea pig myocardium. We investigated the effect of stretch on myofilament contractile proteins, Ca2+ sensitivity, and cross-bridge cycling kinetics ( K tr) of force in single skinned cardiomyocytes isolated from the sub-endocardial (ENDO) or sub-epicardial (EPI) layer. As observed in other species, ENDO cells were stiffer, and Ca2+ sensitivity of force at long sarcomere length was higher compared with EPI cells. Maximal K tr was unchanged by stretch, but was higher in EPI cells possibly due to a higher α-MHC content. Submaximal Ca2+-activated K tr increased only in ENDO cells with stretch. Stretch of skinned ENDO muscle strips induced increased phosphorylation in both myosin-binding protein C and myosin light chain 2. We concluded that transmural MHC isoform expression and differential regulatory protein phosphorylation by stretch contributes to regional differences in stretch modulation of activation in guinea pig left ventricle. [ABSTRACT FROM AUTHOR]

Abstract: Myocardial contractile reserve is significantly attenuated in patients with advanced heart failure. The aim of this study was to identify mechanisms of impaired contractile reserve in a large animal model that closely mimics human myocardial failure. Progressive right ventricular hypertrophy and failure were induced by banding the pulmonary artery in kittens. Isometric contractile force was measured in right ventricular trabeculae (n =115) from age-matched Control and Banded feline hearts. Rapid cooling contractures (RCC) were used to determine sarcoplasmic reticulum (SR) Ca2+ load while assessing the ability of changes in rate, adrenergic stimulation and bath Ca2+ to augment contractility. The positive force–frequency relationship and robust pre- and post-receptor adrenergic responses observed in Control trabeculae were closely paralleled by increases in RCC amplitude and the RCC2/RCC1 ratio. Conversely, the severely blunted force–frequency and adrenergic responses in Banded trabeculae were paralleled by an unchanged RCC amplitude and RCC2/RCC1 ratio. Likewise, supraphysiologic levels of bath Ca2+ were associated with severely reduced contractility and RCC amplitude in Banded trabeculae compared to Controls. There were no differences in myofilament Ca2+ sensitivity or length-dependent increases in contractility between Control and Banded trabeculae. There was a significant decrease in SR Ca2+-ATPase pump abundance and phosphorylation of phospholamban and ryanodine receptor in Banded trabeculae compared with Controls. A reduced ability to increase SR Ca2+ load is the primary mechanism of reduced contractile reserve in failing feline myocardium. The similarity of impaired contractile reserve phenomenology in this feline model and transplanted hearts suggests mechanistic relevance to human myocardial failure. [Copyright &y& Elsevier]