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.

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.

Inhibition of NF-κB activation by ß-glucan is not associated with protection from global ischemia-reperfusion injury in pigs.

BACKGROUND: Pretreatment with ß-glucan has been shown to protect against regional ischemia-reperfusion injury, through inhibition of myocardial NF-κB activation. The aim was to examine whether ß-glucan pretreatment could protect against the global ischemia-reperfusion injury, which is encountered in the clinical setting during open heart surgery. MATERIALS AND METHODS: Twenty-one pigs were randomized to pretreatment with oral ß-glucan (SBGo, n = 7), pretreatment with i.p. ß-glucan (SBGip, n = 7), and untreated controls (n = 7). The pigs were subjected to cardiopulmonary bypass (CPB) with 1 h of global cardioplegic ischemia followed by wean from CPB and reperfusion for 4 h. Cardiac function was determined by a conductance catheter, and troponin T was sampled from the coronary sinus. Atrial biopsies obtained at baseline, following 30 min, and 3 h of reperfusion were analyzed for phosphorylated NF-κB by Western blot. RESULTS: Following reperfusion, phosphorylated NF-κB increased by 210% in the control group, 197% in the SBGo group, but was reduced by 5% in the SBGip group (P < 0.01 versus control). After 4 h of reperfusion, preload recruitable stroke work dropped by 19% in the control group and 25% in the SBGo group compared with 60% in the SBGip group (P < 0.01 versus control). The area under the curve for troponin T was larger in the SBGip group compared with the control group (P < 0.05) and the SBGo group (P < 0.01). CONCLUSION: Inhibition of NF-κB activation by i.p. ß-glucan does not protect against ischemia-reperfusion injury in pigs subjected to global ischemia and reperfusion, and may be associated with aggravation of ischemia-reperfusion injury.

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.

Mechanoenergetic function and troponin T release following cardioplegic arrest induced by St Thomas' and histidine-tryptophan-ketoglutarate cardioplegia--an experimental comparative study in pigs.

The study compares the single dose histidine-tryptophan-ketoglutarate (HTK) cardioplegia to the repeatedly delivered St Thomas' Hospital Solution (STHS) with respect to preservation of left ventricular mechanoenergetics and leakage of troponin T in a porcine experimental model. Fourteen pigs were randomized to a single infusion of 30 ml/kg HTK cardioplegia (n=7) or 500 ml STHS (n=7) followed by 200 ml after 20 and 40 min. After 1 h of aortic cross-clamping on cardiopulmonary bypass (CPB), the pigs were weaned and the hearts reperfused for 4 h. Stroke work (SW) was determined by a conductance catheter in the left ventricle. Myocardial oxygen consumption (MvO(2)) was measured as a function of coronary blood flow and arterial-to-coronary sinus oxygen saturation difference. Troponin T was sampled from the coronary sinus. The slope of the SW-MvO(2) relationship increased by 1.09 (+/-0.53) in the HTK group compared with 0.33 (+/-0.70) in the STHS group following ischemia and 4 h of reperfusion (P=0.04). Troponin T was significantly higher in the HTK group compared with the STHS group (P=0.04). Repeatedly delivered STHS gives better preservation of postischemic mechanoenergetic function and lower troponin T release compared with single dose HTK cardioplegia, indicating improved cardioprotection with STHS.

Vasopressin impairs brain, heart and kidney perfusion: an experimental study in pigs after transient myocardial ischemia.

INTRODUCTION: Arginine vasopressin (AVP) is increasingly used to restore mean arterial pressure (MAP) in low-pressure shock states unresponsive to conventional inotropes. This is potentially deleterious since AVP is also known to reduce cardiac output by increasing vascular resistance. The effects of AVP on blood flow to vital organs and cardiac performance in a circulation altered by cardiac ischemia are still not sufficiently clarified. We hypothesised that restoring MAP by low dose, therapeutic level AVP would reduce vital organ blood flow in a setting of experimental acute left ventricular dysfunction. METHODS: Cardiac output (CO) and arterial blood flow to the brain, heart, kidney and liver were measured in nine pigs using transit-time flow probes. Left ventricular pressure-volume catheter and central arterial and venous catheters were used for haemodynamic recordings and blood sampling. Transient left ventricular ischemia was induced by intermittent left coronary occlusions resulting in a 17% reduction in cardiac output and a drop in MAP from 87 +/- 3 to 67 +/- 4 mmHg (p < 0.001). A low-dose therapeutic level of AVP (0.005 U/kg/min) was used to restore MAP to pre-ischemic values (93 +/- 4 mmHg). RESULTS: AVP further impaired systemic perfusion (CO and brain, heart and kidney blood flow reduced by 29, 18, 23 and 34%, respectively) due to a 2.0-, 2.2-, 1.9- and 2.1-fold increase in systemic, brain, heart and kidney specific vascular resistances. The hypoperfusion induced by AVP was associated with an increased systemic oxygen extraction. Oxygen saturation in blood drawn from the great cardiac vein fell from 29 +/- 1 to 21 +/- 3% (p = 0.01). Finally, these effects were reversed 40 min after AVP was withdrawn. CONCLUSION: Low dose AVP induced a pronounced reduction in vital organ blood flow in pigs after transient cardiac ischemia. This indicates a potentially deleterious effect of AVP in patients with heart failure or cardiogenic shock due to impaired coronary perfusion.