Thor Allan Stenberg

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

IntroductionArginine 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.MethodsCardiac 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).ResultsAVP 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 Finally, these effects were reversed 40 min after AVP was withdrawn.ConclusionLow dose AVP induced a pronounced reduction in vital organ blood flow in pigs after transient cardiac ischemia.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.

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.

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 μg/kg loading and 0.04 μg · kg−1 · min−1 infusion) or an equipotent dose of dobutamine (1.25 μg · kg−1 · 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 μg · kg−1 · min−1 and 48 μg/kg loading with 0.2 μg · kg−1 · 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). Conclusion— 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. Received March 17, 2009; accepted November 16, 2009.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 &mgr;g/kg loading and 0.04 &mgr;g·kg−1·min−1 infusion) or an equipotent dose of dobutamine (1.25 &mgr;g·kg−1·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 &mgr;g·kg−1·min−1 and 48 &mgr;g/kg loading with 0.2 &mgr;g·kg−1·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). Conclusion—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.

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 InotropyCLINICAL PERSPECTIVE

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 μg/kg loading and 0.04 μg · kg−1 · min−1 infusion) or an equipotent dose of dobutamine (1.25 μg · kg−1 · 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 μg · kg−1 · min−1 and 48 μg/kg loading with 0.2 μg · kg−1 · 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). Conclusion— 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. Received March 17, 2009; accepted November 16, 2009.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 &mgr;g/kg loading and 0.04 &mgr;g·kg−1·min−1 infusion) or an equipotent dose of dobutamine (1.25 &mgr;g·kg−1·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 &mgr;g·kg−1·min−1 and 48 &mgr;g/kg loading with 0.2 &mgr;g·kg−1·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). Conclusion—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.

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.

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.

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.

Microvascular occlusions and coronary microembolization

The aim of percutaneous coronary interventions (PCI) in both acute coronary syndromes and stable coronary artery disease is a complete revasculariza-tion of the hypoperfused myocardium. Recanaliza-tion of epicardial coronary arteries or saphenous vein grafts can occur without a corresponding reperfusion of the microcirculation. The underlying pathology is either ischemic damage to the myocardium with edema and plugging of small vessels i.e the “ no-refl ow phenomenon ” (1), or a more abrupt micro-occlusive process due to embolic debris passing down to the microvasculature during PCI (2,3). This may mani-fest itself as a reduced “ thrombolysis in myocardial infarction (TIMI) ” fl ow in the epicardial artery or, sometimes, normal or nearly normal TIMI fl ow with reduced myocardial perfusion grade, both indi-cating insuffi cient perfusion of the corresponding microcirculation (2). Coronary microembolization (CME) describes a process where platelet aggregates, atherothrombotic debris and vasoconstrictive substances induce micro-vascular occlusion distal to a site of plaque disruption, and CME has been associated with subendocardial perfusion defi cits and microinfarctions following acute coronary syndromes (3–6). Importantly, several lines of evidence indicate that CME is a frequent complication after PCI. Post-procedural microinfarc-tions, cardiac biomarker elevations and myocardial perfusion reserve impairments following routine PCI have all been attributed to CME (7–9). A recent esti-mate indicates that peri-procedural microemboliza-tion occurs in approximately 25% of all PCI procedures, with incidence numbers spanning 0–70% depending on the complexity of the procedure and the cardiac marker assay being used (10). Of notice, the highest occurrence of microembolization is reported after saphenous vein graft interventions. Some reports state that a relatively minor elevation of the creatine kinase-myocardial band (CK-MB) after elective revasculariza-tion entails a worsened outcome, however this is still a matter of controversy (11–13). Previous large-scale autopsy studies have shown that 10–20% of patients suffering from sudden death due to coronary heart disease have platelet thrombi in the coronary microcir-culation as the only manifestation of acute myocardial infarction (14,15). What are the long term effects of acute or per-petual CME on ventricular function? In patients with an observed “ no-refl ow ” phenomenon a progressive dilatation of the left ventricle and a reduced ejection fraction have been observed (16,17). Experimentally, contractile impairment after CME is partly related to the embolic burden and the size of the microem-boli, however, the relation between embolic burden and left ventricular dysfunction is variable (18,19). Interestingly, the initial progressive contractile dys-function after CME is not related to the extent of microinfarction, but is determined by the infl amma-tory response as seen by the infi ltration of leucocytes, monocytes and macrophages. Particularly, a tran-sient reduction in contractile function has been related to the release of nitric oxide, tumor necrosis factor α and reactive oxygen species (4,20). CME has classically been studied in experimental animals by intracoronary injection of microspheres of varying sizes. However, these are biochemically inert particles, and the thrombogenic, vasoconstric-tor and infl ammatory cascades initiated by throm-bus-rich emboli mixed with atheromatous debris and activated platelets cannot be mimicked. Impor-tantly, the microspheres per se do not respond to antiplatelet and thrombolytic drugs that are used in

Oxygen-Wasting Effect of InotropyCLINICAL PERSPECTIVE: 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 μg/kg loading and 0.04 μg · kg−1 · min−1 infusion) or an equipotent dose of dobutamine (1.25 μg · kg−1 · 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 μg · kg−1 · min−1 and 48 μg/kg loading with 0.2 μg · kg−1 · 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). Conclusion— 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. Received March 17, 2009; accepted November 16, 2009.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 &mgr;g/kg loading and 0.04 &mgr;g·kg−1·min−1 infusion) or an equipotent dose of dobutamine (1.25 &mgr;g·kg−1·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 &mgr;g·kg−1·min−1 and 48 &mgr;g/kg loading with 0.2 &mgr;g·kg−1·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). Conclusion—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.