Hands-free continuous carotid Doppler ultrasound for detection of the pulse during cardiac arrest in a porcine model.

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.

The ß3 Adrenergic Receptor Antagonist L-748,337 Attenuates Dobutamine-Induced Cardiac Inefficiency While Preserving Inotropy in Anesthetized Pigs.

Excessive myocardial oxygen consumption (MVO2) is considered a limitation for catecholamines, termed oxygen cost of contractility. We hypothesize that increased MVO2 induced by dobutamine is not directly related to contractility but linked to intermediary myocardial metabolism. Furthermore, we hypothesize that selective ß3 adrenergic receptor (ß3AR) antagonism using L-748,337 prevents this. In an open-chest pig model, using general anesthesia, we assessed cardiac energetics, hemodynamics and arterial metabolic substrate levels at baseline, ½ hour and 6 hours after onset of drug infusion. Cardiac efficiency was assessed by relating MVO2 to left ventricular work (PVA; pressure-volume area). Three groups received dobutamine (5 µg/kg/min), dobutamine + L-748,337 (bolus 50 µg/kg), or saline for time-matched controls. Cardiac efficiency was impaired over time with dobutamine infusion, displayed by persistently increased unloaded MVO2 from ½ hour and 47% increase in the slope of the PVA-MVO2 relation after 6 hours. Contractility increased immediately with dobutamine infusion (dP/dtmax; 1636 ± 478 vs 2888 ± 818 mmHg/s, P < 0.05) and persisted throughout the protocol (2864 ± 1055 mmHg/s, P < 0.05). Arterial free fatty acid increased gradually (0.22 ± 0.13 vs 0.39 ± 0.30 mM, P < 0.05) with peak levels after 6 hours (1.1 ± 0.4 mM, P < 0.05). By combining dobutamine with L-748,337 the progressive impairment in cardiac efficiency was attenuated. Interestingly, this combined treatment effect occurred despite similar alterations in cardiac inotropy and substrate supply. We conclude that the extent of cardiac inefficiency following adrenergic stimulation is dependent on the duration of drug infusion, and ß3AR blockade may attenuate this effect.

Hemodynamic Effects of a Soluble Guanylate Cyclase Stimulator, Riociguat, and an Activator, Cinaciguat, During NO-Modulation in Healthy Pigs.

Cardiovascular diseases are often characterized by dysfunctional endothelium. To compensate for the related lack of nitric oxide (NO), a class of soluble guanylate cyclase (sGC) stimulators and activators have been developed with the purpose of acting downstream of NO in the NO-sGC-cGMP cascade. These drugs have been discovered using photoaffinity labeling of sGC and high-throughput screening of a vast number of chemical compounds. Therefore, an understanding of the integrated physiological effects of these drugs in vivo is necessary on the path to clinical application. We have characterized the integrated hemodynamic impact of the sGC stimulator riociguat and the activator cinaciguat in different NO-states in healthy juvenile pigs (n = 30). We assessed the vascular effects in both systemic and pulmonary circulation, the contractile effects in the right and left ventricles, and the effects on diastolic cardiac functions. Nitric oxide-tone in these pigs were set by using the NO-blocker l-NAME and by infusion of nitroglycerine. The studies show a more pronounced vasodilatory effect in the systemic than pulmonary circulation for both drugs. Riociguat acts integrated with NO in an additive manner, while cinaciguat, in principle, completely blocks the endogenous NO effect on vascular control. Neither compound demonstrated pronounced cardiac effects but had unloading effect on both systolic and diastolic function. Thus, riociguat can potentially act in various disease states as a mean to increase NO-tone if systemic vasodilation can be balanced. Cinaciguat is a complicated drug to apply clinically due to its almost complete lack of integration in the NO-tone and balance.

The effect of Riociguat on cardiovascular function and efficiency in healthy, juvenile pigs.

INTRODUCTION: Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of pulmonary hypertension. Its effect on cardiometabolic efficiency is unknown. A potential cardiac energy sparing effect of this drug could imply a positive prognostic effect, particularly in patients with right heart failure from pulmonary hypertension. METHOD: We infused Riociguat in six healthy juvenile pigs and measured the integrated cardiovascular effect and myocardial oxygen consumption. To assess the interplay with NO-blockade on cardiac function and efficiency we also administered the NO-blocker L- NAME to the animals after Riociguat. RESULTS AND DISCUSSION: Infusion of 100 µg/kg Riociguat gave modest systemic vasodilatation seen as a drop in coronary and systemic vascular resistance of 36% and 26%, respectively. Right and left ventriculoarterial coupling index (Ees/Ea), stroke work efficiency (SWeff), and the relationship between left ventricular myocardial oxygen consumption (MVO2 ) and total mechanical work (pressure-volume area; PVA) were unaffected by Riociguat. In contrast, systemic and pulmonary vasoconstriction induced by L-NAME (15 mg/kg) shifted the Ees/Ea ratio toward reduced SWeff in both systemic and pulmonary circulation. However, there was no surplus oxygen consumption, that was measured by the MVO2 /PVA relationship after L-NAME in Riociguat-treated pigs. This suggests that Riociguat can reduce the NO-related cardiometabolic inefficiency previously observed by blocking the NO pathway.

Combined Therapy With Dobutamine and Omecamtiv Mecarbil in Pigs With Ischemic Acute Heart Failure Is Attributed to the Effect of Dobutamine.

Inotropic support in ischemic acute heart failure (AHF) is controversial. We tested a therapeutic principle for AHF by combining a low dose of omecamtiv mecarbil (OM; 0.25 mg/kg bolus plus 0.25 mg/kg/h) with a low dose of dobutamine (Dobut; 1.25 µg/kg/min). In 10 pigs subjected to myocardial ischemia by left coronary microembolization, this cotreatment increased cardiac power (CP) from 0.48 ± 0.14 to 0.81 ± 0.22 W (P < .05). When the drugs were given as a monotherapy, CP increased from 0.57 ± 0.11 to 0.65 ± 0.15 W (OM; n = 5; not significant) and from 0.40 ± 0.07 to 0.70 ± 0.10 W (Dobut; n = 5; P < .05). Dobut counteracted OM-mediated impairments in early relaxation and diastolic shortening. In a second protocol using the same doses, we assessed cardiac efficiency in 5 healthy pigs by relating myocardial oxygen consumption (MVO2) to the pressure-volume area. Here, the increases in cardiac work and MVO2 were matched, leaving cardiac efficiency unaltered by this drug combination. Low-dose cotreatment with OM + Dobut produces an appropriate hemodynamic effect with improved CP at doses that do not affect cardiac efficiency. This outcome is mainly attributed to the inotropic effect of Dobut.

Opposite diastolic effects of omecamtiv mecarbil versus dobutamine and ivabradine co-treatment in pigs with acute ischemic heart failure.

Acute ischemic cardiogenic shock is associated with poor prognosis, and the impact of inotropic support on diastolic function in this context is unclear. We assessed two suggested new inotropic strategies in a clinically relevant pig model of ischemic acute heart failure (AHF): treatment with the myosin activator omecamtiv mecarbil (OM) or dobutamine and ivabradine (D+I). Left ventricular (LV) ischemia was induced in anesthetized pigs by coronary microembolization (n = 12). The animals then received OM (bolus 0.75 mg/kg, followed by 0.5 mg/kg per h) (n = 6) or D+I (5 µg/kg per min + 0.29 ± 0.16 mg/kg) (n = 6), respectively. Ischemia reduced the stroke volume (SV), despite the increased left atrial pressure associated with impaired LV early relaxation, systolic dilatation, and LV late diastolic stiffness. Both treatments improved systolic ejection, but only D+I increased the SV from 26 ± 5 to 33 ± 5 mL. D+I enhanced LV early relaxation (Tau; from 45 ± 11 to 29 ± 4 msec) and prolonged the diastolic time (DT) from 338 ± 60 to 352 ± 40 msec. In contrast, OM prolonged Tau (42 ± 5 to 62 ± 10 msec) and shortened the DT (from 326 ± 68 to 248 ± 84 msec). Our data suggest that enhanced early relaxation by D+I improves LV pump function in postischemic acute heart failure. In contrast, OM worsened lusitropy in this model.

Propulsion of blood through the right heart circulatory system.

Venous return, the right heart function and the pulmonary circulation is an integrated functional unit. The right ventricle is particularly load sensitive, and will be influenced directly by the venous and pulmonary physiology. In this paper we present important physiological principles that govern the diagnosis and treatment of dysfunctions affecting the return of blood to the heart and the transfer of the cardiac output from the right to the left side. We do evaluate both basic science and the clinical literature pointing to practical aspects of physiological knowledge.

Myosin Activator Omecamtiv Mecarbil Increases Myocardial Oxygen Consumption and Impairs Cardiac Efficiency Mediated by Resting Myosin ATPase Activity.

BACKGROUND: Omecamtiv mecarbil (OM) is a novel inotropic agent that prolongs systolic ejection time and increases ejection fraction through myosin ATPase activation. We hypothesized that a potentially favorable energetic effect of unloading the left ventricle, and thus reduction of wall stress, could be counteracted by the prolonged contraction time and ATP-consumption. METHODS AND RESULTS: Postischemic left ventricular dysfunction was created by repetitive left coronary occlusions in 7 pigs (7 healthy pigs also included). In both groups, systolic ejection time and ejection fraction increased after OM (0.75 mg/kg loading for 10 minutes, followed by 0.5 mg/kg/min continuous infusion). Cardiac efficiency was assessed by relating myocardial oxygen consumption to the cardiac work indices, stroke work, and pressure-volume area. To circumvent potential neurohumoral reflexes, cardiac efficiency was additionally assessed in ex vivo mouse hearts and isolated myocardial mitochondria. OM impaired cardiac efficiency; there was a 31% and 23% increase in unloaded myocardial oxygen consumption in healthy and postischemic pigs, respectively. Also, the oxygen cost of the contractile function was increased by 63% and 46% in healthy and postischemic pigs, respectively. The increased unloaded myocardial oxygen consumption was confirmed in OM-treated mouse hearts and explained by an increased basal metabolic rate. Adding the myosin ATPase inhibitor, 2,3-butanedione monoxide abolished all surplus myocardial oxygen consumption in the OM-treated hearts. CONCLUSIONS: Omecamtiv mecarbil, in a clinically relevant model, led to a significant myocardial oxygen wastage related to both the contractile and noncontractile function. This was mediated by that OM induces a continuous activation in resting myosin ATPase.

Prolonged observation time reveals temporal fluctuations in the sublingual microcirculation in pigs given arginine vasopressin.

Intravital videomicroscopy of sublingual microcirculation is used to monitor critically ill patients. Existing guidelines suggest averaging handheld video recordings of ∼20 s in duration from five areas. We assessed whether an extended observation time may provide additional information on the microcirculation. Pigs (n = 8) under general anesthesia were divided between two groups, one with manually held camera, in which microcirculation was assessed continuously for 1 min in five areas, and one with a fixed camera, in which the observation time was extended to 10 min in a single area. The microcirculation was challenged by infusing arginine vasopressin (AVP). In the fixed group, ischemic acute heart failure was induced by left coronary microembolization, and the AVP infusion was repeated. All recordings were divided into 20-s sequences, and the small-vessel microvascular flow index (MFI) was scored and averaged for each measurement point. When administering 0.003, 0.006, and 0.012 IU·kg(-1)·min(-1) of AVP, we observed that the small-vessel MFI in the fixed 10-min group was significantly reduced (2.03 ± 0.38, 0.98 ± 0.18, and 0.48 ± 0.11) compared with both the initial 20 s (2.77 ± 0.04, 2.06 ± 0.04, and 1.74 ± 0.06; P < 0.05) and the 1-min total (2.63 ± 0.09, 1.70 ± 0.07, and 1.33 ± 0.16; P < 0.05) in the handheld group. In acute heart failure, the cardiac output decreased to half of the preischemic values. Interestingly, the small-vessel MFI was more affected by the administration of 0.001 and 0.003 IU·kg(-1)·min(-1) of AVP in acute heart failure (1.62 ± 0.60 and 1.16 ± 0.38) compared with preischemic values (2.86 ± 0.09 and 2.03 ± 0.38; P < 0.05). In conclusion, a prolonged recording time reveals temporal heterogeneity that may impact the assessment of microcirculatory function.

The acute phase of experimental cardiogenic shock is counteracted by microcirculatory and mitochondrial adaptations.

The mechanisms contributing to multiorgan dysfunction during cardiogenic shock are poorly understood. Our goal was to characterize the microcirculatory and mitochondrial responses following ≥ 10 hours of severe left ventricular failure and cardiogenic shock. We employed a closed-chest porcine model of cardiogenic shock induced by left coronary microembolization (n = 12) and a time-matched control group (n = 6). Hemodynamics and metabolism were measured hourly by intravascular pressure catheters, thermodilution, arterial and organ specific blood gases. Echocardiography and assessment of the sublingual microcirculation by sidestream darkfield imaging were performed at baseline, 2 ± 1 and 13 ± 3 (mean ± SD) hours after coronary microembolization. Upon hemodynamic decompensation, cardiac, renal and hepatic mitochondria were isolated and evaluated by high-resolution respirometry. Low cardiac output, hypotension, oliguria and severe reductions in mixed-venous and hepatic O2 saturations were evident in cardiogenic shock. The sublingual total and perfused vessel densities were fully preserved throughout the experiments. Cardiac mitochondrial respiration was unaltered, whereas state 2, 3 and 4 respiration of renal and hepatic mitochondria were increased in cardiogenic shock. Mitochondrial viability (RCR; state 3/state 4) and efficiency (ADP/O ratio) were unaffected. Our study demonstrates that the microcirculation is preserved in a porcine model of untreated cardiogenic shock despite vital organ hypoperfusion. Renal and hepatic mitochondrial respiration is upregulated, possibly through demand-related adaptations, and the endogenous shock response is thus compensatory and protective, even after several hours of global hypoperfusion.

Cardiomyocyte-restricted inhibition of G protein-coupled receptor kinase-3 attenuates cardiac dysfunction after chronic pressure overload.

Transgenic mice with cardiac-specific expression of a peptide inhibitor of G protein-coupled receptor kinase (GRK)3 [transgenic COOH-terminal GRK3 (GRK3ct) mice] display myocardial hypercontractility without hypertrophy and enhanced α(1)-adrenergic receptor signaling. A role for GRK3 in the pathogenesis of heart failure (HF) has not been investigated, but inhibition of its isozyme, GRK2, has been beneficial in several HF models. Here, we tested whether inhibition of GRK3 modulated evolving cardiac hypertrophy and dysfunction after pressure overload. Weight-matched male GRK3ct transgenic and nontransgenic littermate control (NLC) mice subjected to chronic pressure overload by abdominal aortic banding (AB) were compared with sham-operated (SH) mice. At 6 wk after AB, a significant increase of cardiac mass consistent with induction of hypertrophy was found, but no differences between GRK3ct-AB and NLC-AB mice were discerned. Simultaneous left ventricular (LV) pressure-volume analysis of electrically paced, ex vivo perfused working hearts revealed substantially reduced systolic and diastolic function in NLC-AB mice (n = 7), which was completely preserved in GRK3ct-AB mice (n = 7). An additional cohort was subjected to in vivo cardiac catheterization and LV pressure-volume analysis at 12 wk after AB. NLC-AB mice (n = 11) displayed elevated end-diastolic pressure (8.5 ± 3.1 vs. 2.9 ± 1.2 mmHg, P < 0.05), reduced cardiac output (3,448 ± 323 vs. 4,488 ± 342 µl/min, P < 0.05), and reduced dP/dt(max) and dP/dt(min) (both P < 0.05) compared with GRK3ct-AB mice (n = 16), corroborating the preserved cardiac structure and function observed in GRK3ct-AB hearts assessed ex vivo. Increased cardiac mass and myocardial mRNA expression of ß-myosin heavy chain confirmed the similar induction of cardiac hypertrophy in both AB groups, but only NLC-AB hearts displayed significantly elevated mRNA levels of brain natriuretic peptide and myocardial collagen contents as well as reduced ß(1)-adrenergic receptor responsiveness to isoproterenol, indicating increased LV wall stress and the transition to HF. Inhibition of cardiac GRK3 in mice does not alter the hypertrophic response but attenuates cardiac dysfunction and HF after chronic pressure overload.

Adrenomedullin-epinephrine cotreatment enhances cardiac output and left ventricular function by energetically neutral mechanisms.

Adrenomedullin (AM) used therapeutically reduces mortality in the acute phase of experimental myocardial infarction. However, AM is potentially deleterious in acute heart failure as it is vasodilative and inotropically neutral. AM and epinephrine (EPI) are cosecreted from chromaffin cells, indicating a physiological interaction. We assessed the hemodynamic and energetic profile of AM-EPI cotreatment, exploring whether drug interaction improves cardiac function. Left ventricular (LV) mechanoenergetics were evaluated in 14 open-chest pigs using pressure-volume analysis and the pressure-volume area-myocardial O(2) consumption (PVA-MVo(2)) framework. AM (15 ng·kg(-1)·min(-1), n = 8) or saline (controls, n = 6) was infused for 120 min. Subsequently, a concurrent infusion of EPI (50 ng·kg(-1)·min(-1)) was added in both groups (AM-EPI vs. EPI). AM increased cardiac output (CO) and coronary blood flow by 20 ± 10% and 39 ± 14% (means ± SD, P < 0.05 vs. baseline), whereas controls were unaffected. AM-EPI increased CO and coronary blood flow by 55 ± 17% and 75 ± 16% (P < 0.05, AM-EPI interaction) compared with 13 ± 12% (P < 0.05 vs. baseline) and 18 ± 31% (P = not significant) with EPI. LV systolic capacitance decreased by -37 ± 22% and peak positive derivative of LV pressure (dP/dt(max)) increased by 32 ± 7% with AM-EPI (P < 0.05, AM-EPI interaction), whereas no significant effects were observed with EPI. Mean arterial pressure was maintained by AM-EPI and tended to decrease with EPI (+2 ± 13% vs. -11 ± 10%, P = not significant). PVA-MVo(2) relationships were unaffected by all treatments. In conclusion, AM-EPI cotreatment has an inodilator profile with CO and LV function augmented beyond individual drug effects and is not associated with relative increases in energetic cost. This can possibly take the inodilator treatment strategy beyond hemodynamic goals and exploit the cardioprotective effects of AM in acute heart failure.

Changes in cardiovascular effects of dopamine in response to graded hypothermia in vivo.

OBJECTIVE: Inotropic drugs are frequently administered in hypothermic patients to support an assumed inadequate circulation, but their pharmacologic properties at reduced temperatures are largely unknown. Thus we estimated dopamine pharmacokinetics as well as left ventricular function and global hemodynamics after dopamine infusions at various core temperatures in a pig model of surface cooling and rewarming. DESIGN: Prospective, randomized, open, placebo-controlled experimental study. SETTING: University-affiliated animal research laboratory. SUBJECTS: Sixteen healthy, anesthetized juvenile (2-3 months) castrated male pigs. INTERVENTIONS: After normothermic infusions of dopamine at different doses (4, 8, and 16 µg/kg/min), effects of dopamine (n = 8) or saline (n = 8) were tested at 25 °C and during rewarming (30-34 °C). MEASUREMENTS AND MAIN RESULTS: Dopamine half-time was 5.4 ± 0.7 min at normothermia, increased to 11.6 ± 0.8 min at 25 °C, but returned to control during rewarming at 34-35 °C. Dopamine infusion at 25 °C elevated dopamine plasma concentration four-fold compared to the same infusion rate at normothermia, leading to increased systemic vascular resistance index not seen at normothermia. Also, in contrast to the dopamine-mediated increase in cardiac index observed at normothermia, high-dose dopamine at 25 °C left cardiac index unchanged despite a concomitant increase in heart rate, since stroke index decreased by 43%. During rewarming, cardiovascular effects of dopamine at moderate hypothermia (30-34 °C) were principally similar to responses during normothermia. CONCLUSIONS: Pharmacodynamic effects and pharmacokinetics of dopamine are maintained during the rewarming phase at moderate hypothermia. However, at 25 °C dopamine pharmacokinetics were seriously altered and dopamine failed to increase cardiac index since stroke index was reduced with incrementing dosages. Properties of the low-flow, high-viscosity circulatory state, combined with altered pharmacokinetics of dopamine, may explain lack of beneficial--and potentially harmful--effects from dopamine administration at 25 °C.

Effect of angiotensin II on the left ventricular function in a near-term fetal sheep with metabolic acidemia.

We tested the hypothesis that, in acute metabolic acidemia, the fetal left ventricle (LV) has the capacity to increase its contractility in response to angiotensin II infusion. Eleven ewes and their fetuses were instrumented at 127-138/145 days of gestation. The effect of angiotensin II on fetal LV function was assessed using intraventricular pressure catheter and tissue Doppler imaging (TDI). Angiotensin II increased fetal arterial blood pressure, whereas pH and pO(2) decreased. The heart rate and systemic venous pressure were not affected significantly. The LV end-diastolic and end-systolic pressures, as well as dP/dt(max), increased. The TDI-derived LV longitudinal myocardial isovolumic contraction velocity and its acceleration and velocity during early filling were higher than those at baseline. The incidence of absent isovolumic relaxation velocity was greater during angiotensin II infusion. In summary, during acute metabolic acidemia, the fetal left ventricle could increase its contractility in response to inotropic stimulus even in the presence of increased afterload. The diastolic LV function parameters were altered by angiotensin II.

Inflammation and reduced endothelial function in the course of severe acute heart failure.

Systemic inflammation and elevated circulating levels of the endogenous nitric oxide inhibitor asymmetrical dimethylarginine (ADMA) have been associated with increased risk in cardiogenic shock (CS). In this prospective study, we assessed, over 4 consecutive days, the changes and possible associations between vascular function, markers of inflammation, and circulating ADMA levels in patients with CS (n = 12) and postcardiotomy heart failure (n = 12, PC-HF). Vasodilator function was measured as a reactive hyperemia index (RH-index) using a finger plethysmograph. Blood samples were analyzed for plasma ADMA, interleukine-6, interleukine-8, intracellular adhesion molecule-1, and vascular adhesion molecule-1. Baseline RH-index was significantly attenuated compared with healthy controls (2.28) for both CS and PC-HF (1.35 and 1.45, respectively, P = 0.001). Although vasodilator function improved in PC-HF patients, it remained attenuated in CS. Inflammatory markers were markedly elevated followed by a significant fall during the observation period in both groups. ADMA levels increased significantly during the observation period for PC-HF, whereas no pattern of change was observed for CS. No association was found between the longitudinal changes in RH-index, markers of inflammation, or ADMA in CS. However, an improved RH-index was associated with decreasing inflammatory markers in PC-HF. ADMA correlated to arterial lactate levels and the degree of organ dysfunction in CS. In conclusion, CS and PC-HF were characterized by a marked inflammatory activation accompanied by an attenuated vasodilator function. ADMA was related to organ dysfunction and degree of hypoperfusion during CS but showed no correlations to inflammation or hampered vasodilator function. The pathogenic significance of these responses needs clarification.

Post-hypothermic cardiac left ventricular systolic dysfunction after rewarming in an intact pig model.

INTRODUCTION: We developed a minimally invasive, closed chest pig model with the main aim to describe hemodynamic function during surface cooling, steady state severe hypothermia (one hour at 25°C) and surface rewarming. METHODS: Twelve anesthetized juvenile pigs were acutely catheterized for measurement of left ventricular (LV) pressure-volume loops (conductance catheter), cardiac output (Swan-Ganz), and for vena cava inferior occlusion. Eight animals were surface cooled to 25°C, while four animals were kept as normothermic time-matched controls. RESULTS: During progressive cooling and steady state severe hypothermia (25°C) cardiac output (CO), stroke volume (SV), mean arterial pressure (MAP), maximal deceleration of pressure in the cardiac cycle (dP/dt(min)), indexes of LV contractility (preload recruitable stroke work, PRSW, and maximal acceleration of pressure in the cardiac cycle, dP/dt(max)) and LV end diastolic and systolic volumes (EDV and ESV) were significantly reduced. Systemic vascular resistance (SVR), isovolumetric relaxation time (Tau), and oxygen content in arterial and mixed venous blood increased significantly. LV end diastolic pressure (EDP) remained constant. After rewarming all the above mentioned hemodynamic variables that were depressed during 25°C remained reduced, except for CO that returned to pre-hypothermic values due to an increase in heart rate. Likewise, SVR and EDP were significantly reduced after rewarming, while Tau, EDV, ESV and blood oxygen content normalized. Serum levels of cardiac troponin T (TnT) and tumor necrosis factor-alpha (TNF-α) were significantly increased. CONCLUSIONS: Progressive cooling to 25°C followed by rewarming resulted in a reduced systolic, but not diastolic left ventricular function. The post-hypothermic increase in heart rate and the reduced systemic vascular resistance are interpreted as adaptive measures by the organism to compensate for a hypothermia-induced mild left ventricular cardiac failure. A post-hypothermic increase in TnT indicates that hypothermia/rewarming may cause degradation of cardiac tissue. There were no signs of inadequate global oxygenation throughout the experiments.

Dobutamine-norepinephrine, but not vasopressin, restores the ventriculoarterial matching in experimental cardiogenic shock.

We assessed the hemodynamic effects of guideline therapy in experimental cardiogenic shock and compared this treatment with a combination containing an alternative vasopressor (arginine vasopressin, AVP). Our hypothesis was that combined dobutamine-norepinephrine still is the superior inopressor therapy assessed by ventriculoarterial matching in both systole and diastole. Cardiogenic shock (CS) was induced by coronary microembolization in 16 pigs. Dobutamine (Dobu, 2ug/kg/min) alone and combined with either norepinephrine (NE, 100 ng/kg/min) or the pure vasopressor AVP (0.001 u/kg/min) were infused. In CS, Dobu increased cardiac output (CO) and central venous oxygen saturation (SVO2) from 74 ± 3 mL/kg and 37 ± 2% to 103 ± 8 mL/kg and 49 ± 3%. Adding NE resulted in a further improvement of CO (125 ± 9 mL/kg) and SVO2 (59 ± 4%) because of an increased heart rate and contractility with minimal change in systemic vascular resistance. Also, energy transfer from the ventricle to the arterial system was restored partly by Dobu and was normalized by supplementing NE. In contrast, supplemental AVP further worsened the shock state by decreasing CO (70 ± 6 mL/kg) and SVO2 (45 ± 5%) compared with Dobu alone. Combined Dobu-NE has an efficient hemodynamic profile in CS. A pure afterload increasing substance used in acute ischemic CS aggravates the shock state by causing a ventriculoarterial mismatch despite its use in combination with an inotropic compound.

High resolution speckle tracking dobutamine stress echocardiography reveals heterogeneous responses in different myocardial layers: implication for viability assessments.

BACKGROUND: Speckle-tracking echocardiography (STE) can be used to quantify wall strain in 3 dimensions and thus has the potential to improve the identification of hypokinetic but viable myocardium on dobutamine stress echocardiography (DSE). However, if different myocardial layers respond heterogeneously, STE-DSE will have to be standardized according to strain dimension and the positioning of the region of interest. Therefore, the aim of this study was to create a high-resolution model for ejection time (ET) strain and tissue flow in 4 myocardial layers at rest, during hypoperfusion, and during dobutamine challenge to assess the ability of STE-DSE to detect deformation and functional improvement in various layers of the myocardium. METHODS: In 10 open chest pigs, the left anterior descending coronary artery was constricted to a constant stenosis, resulting in 35% initial flow reduction. Fluorescent microspheres were used to measure tissue flow. High-resolution echocardiography was performed epicardially to calculate ET strain in 4 myocardial layers in the radial, longitudinal, and circumferential directions using speckle-tracking software. Images were obtained at rest, during left anterior descending coronary artery constriction (hypoperfusion), and during a subsequent dobutamine stress period. RESULTS: Dobutamine stress at constant coronary stenosis increased flow in all layers. ET strain increased predominantly in the midmyocardial layers in the longitudinal and circumferential directions, whereas subendocardial strain did not improve in either direction. CONCLUSION: Dobutamine stress influences ET strain differently in the various axes and layers of the myocardium and only partially in correspondence to tissue flow. Longitudinal and circumferential functional reserve opens the potential for the specific detection of midsubendocardial viable tissue by high-resolution STE.

Oxygen-wasting effect of inotropy: is there a need for a new evaluation? An experimental large-animal study using dobutamine and levosimendan.

BACKGROUND: We addressed the hypothesis that the inotropic drugs dobutamine and levosimendan both induce surplus oxygen consumption (oxygen wasting) relative to their contractile effect in equipotent therapeutic doses, with levosimendan being energetically more efficient. METHODS AND RESULTS: Postischemically reduced left ventricular function (stunning) was created by repetitive left coronary occlusions in 22 pigs. This contractile dysfunction was reversed by infusion of either levosimendan (24 microg/kg loading and 0.04 microg x kg(-1) x min(-1) infusion) or an equipotent dose of dobutamine (1.25 microg x kg(-1) x min(-1)). Contractility and cardiac output were normalized by both drug regimens. The energy cost of drug-induced contractility enhancement was assessed by myocardial oxygen consumption related to the mechanical indexes tension-time index, pressure-volume area, and total mechanical energy. ANCOVA did not reveal any increased oxygen cost of contractility for either drug in these doses. However, both dobutamine and levosimendan at supratherapeutic levels (10 microg x kg(-1) x min(-1) and 48 microg/kg loading with 0.2 microg x kg(-1) x min(-1) infusion, respectively) induced a highly significant increase in oxygen consumption related to mechanical work, compatible with the established oxygen-wasting effect of inotropy (P<0.001 for all mechanical indexes with dobutamine; P=0.007 for levosimendan as assessed by pressure-volume area). CONCLUSIONS: Therapeutic levels of neither dobutamine nor levosimendan showed inotropic oxygen wasting in this in vivo pig model. Thus, relevant hemodynamic responses can be achieved with an adrenergic inotrope without surplus oxygen consumption.