Anesth Analg 2011;113: 751-757

Cardiac output (CO) monitoring based on pulse contour analysis (Vigileo-FloTrac) has the potential to be used for goal-directed fluid therapy in the perioperative setting. However, factors such as vasopressor usage may impact Vigileo-FloTrac’s reliability in tracking CO changes. We tested third-generation Vigileo-FloTrac system’s ability to accurately measure the changes in CO induced by vasopressor administration and increased preload in comparison with esophageal Doppler measurements.

Methods
In 33 anesthetized patients, CO was monitored simultaneously by the third-generation Vigileo-FloTrac and esophageal Doppler. Hemodynamic challenges included phenylephrine (to increase vasomotor tone), ephedrine (to increase myocardial contractility and heart rate), and whole-body tilting (to increase preload). Measurements were performed before and after each intervention.

Results
Overall, 176 pairs of CO measurements were obtained. The difference between paired pulse contour and Doppler measurements of CO was 0.14 ± 2.13 L/min (mean ± SD), and the percentage error (2 SD of the difference divided by the mean CO of the reference method) was 66%. The trending ability of pulse contour versus Doppler was 23% (concordance, the percentage of the total number of data points that are in 1 of the 2 quadrants of agreement) after phenylephrine treatment, 69% (concordance) after ephedrine treatment, and 96% (concordance) after whole-body tilting.

Conclusions
The pulse contour method of measuring CO, as implemented in the third-generation Vigileo-FloTrac device, accurately tracks changes in CO when preload changes. However, the pulse contour method does not accurately track changes in CO induced with phenylephrine and ephedrine.

NEJM 2010;362:779-789

Both dopamine and norepinephrine are recommended as first-line vasopressor agents in the treatment of shock. There is a continuing controversy about whether one agent is superior to the other.

Methods
In this multicenter, randomized trial, we assigned patients with shock to receive either dopamine or norepinephrine as first-line vasopressor therapy to restore and maintain blood pressure. When blood pressure could not be maintained with a dose of 20 µg per kilogram of body weight per minute for dopamine or a dose of 0.19 µg per kilogram per minute for norepinephrine, open-label norepinephrine, epinephrine, or vasopressin could be added. The primary outcome was the rate of death at 28 days after randomization; secondary end points included the number of days without need for organ support and the occurrence of adverse events.

Results
The trial included 1679 patients, of whom 858 were assigned to dopamine and 821 to norepinephrine. The baseline characteristics of the groups were similar. There was no significant between-group difference in the rate of death at 28 days (52.5% in the dopamine group and 48.5% in the norepinephrine group; odds ratio with dopamine, 1.17; 95% confidence interval, 0.97 to 1.42; P=0.10). However, there were more arrhythmic events among the patients treated with dopamine than among those treated with norepinephrine (207 events [24.1%] vs. 102 events [12.4%], P<0.001). A subgroup analysis showed that dopamine, as compared with norepinephrine, was associated with an increased rate of death at 28 days among the 280 patients with cardiogenic shock but not among the 1044 patients with septic shock or the 263 with hypovolemic shock (P=0.03 for cardiogenic shock, P=0.19 for septic shock, and P=0.84 for hypovolemic shock, in Kaplan–Meier analyses).

Conclusions
Although there was no significant difference in the rate of death between patients with shock who were treated with dopamine as the first-line vasopressor agent and those who were treated with norepinephrine, the use of dopamine was associated with a greater number of adverse events.

AACN Advanced Critical Care 2008;19:281-287

Septic shock continues to be one of the leading causes of death in the intensive care unit today. The confluence of many factors contributes to the deterioration of patients’ condition in septic shock. Increased levels of nitric oxide, in part, mediate the cardiovascular effects of septic shock. Nitric oxide is major mediator of vasodilation and hypotension as well as myocardial depression. It also contributes to decreased production and release of endogenous vasopressin. Vasopressin effects are actualized by stimulation …

Crit Care Med 2009;37:811-818

Vasopressin and corticosteroids are often added to support cardiovascular dysfunction in patients who have septic shock that is nonresponsive to fluid resuscitation and norepinephrine infusion. However, it is unknown whether vasopressin treatment interacts with corticosteroid treatment.

Design
Post hoc substudy of a multicenter randomized blinded controlled trial of vasopressin vs. norepinephrine in septic shock.

Setting
Twenty-seven Intensive Care Units in Canada, Australia, and the United States.

Patients
Seven hundred and seventy-nine patients who had septic shock and were ongoing hypotension requiring at least 5 μg/min of norepinephrine infusion for 6 hours.

Interventions
Patients were randomized to blinded vasopressin (0.01-0.03 units/min) or norepinephrine (5-15 μg/min) infusion added to open-label vasopressors. Corticosteroids were given according to clinical judgment at any time in the 28-day postrandomization period.

Measurements
The primary end point was 28-day mortality. We tested for interaction between vasopressin treatment and corticosteroid treatment using logistic regression. Secondary end points were organ dysfunction, use of open-label vasopressors and vasopressin levels.

Main results
There was a statistically significant interaction between vasopressin infusion and corticosteroid treatment (p = 0.008). In patients who had septic shock and were also treated with corticosteroids, vasopressin, compared to norepinephrine, was associated with significantly decreased mortality (35.9% vs. 44.7%, respectively, p = 0.03). In contrast, in patients who did not receive corticosteroids, vasopressin was associated with increased mortality compared with norepinephrine (33.7% vs. 21.3%, respectively, p = 0.06). In patients who received vasopressin infusion, use of corticosteroids significantly increased plasma vasopressin levels by 33% at 6 hours (p = 0.006) to 67% at 24 hours (p = 0.025) compared with patients who did not receive corticosteroids.

Conclusions
There is a statistically significant interaction between vasopressin and corticosteroids. The combination of low-dose vasopressin and corticosteroids was associated with decreased mortality and organ dysfunction compared with norepinephrine and corticosteroids.

BJA 2009;102:198-204

The calcium sensitizer levosimendan has anti-ischaemic effects mediated via the opening of sarcolemmal and mitochondrial ATP-sensitive potassium channels. These properties suggest potential application in clinical situations where cardioprotection would be beneficial, such as cardiac surgery. We thus decided to investigate whether pharmacological pre-treatment with levosimendan reduces intensive care unit (ICU) length of stay in patients undergoing elective myocardial revascularization under cardiopulmonary bypass.

Methods
One hundred and six patients undergoing elective coronary artery bypass grafting were randomly assigned in a double-blind manner to receive levosimendan or placebo. Levosimendan (24 µg kg–1) or placebo was administered as a slow i.v. bolus over a 10 min period before the initiation of bypass.

Results
Tracheal intubation time and the length of ICU stay were significantly reduced in the levosimendan group (P<0.01). The number of patients needing inotropic support for >12 h was significantly higher in the control group (18.0% vs 3.8%; P=0.021). Compared with control patients, levosimendan-treated patients had lower postoperative troponin I concentrations (P<0.0001) and a higher cardiac power index (P<0.0001).

Conclusions
Pre-treatment with levosimendan in patients undergoing surgical myocardial revascularization resulted in less myocardial injury, a reduction in tracheal intubation time, less requirement for inotropic support, and a shorter length of ICU stay.

Intensive Care Med 2008:34;2226-2234

To determine whether there was a difference between epinephrine and norepinephrine in achieving a mean arterial pressure (MAP) goal in intensive care (ICU) patients.

Design
Prospective, double-blind, randomised-controlled trial.

Setting
Four Australian university-affiliated multidisciplinary ICUs.

Patients and participants
Patients who required vasopressors for any cause at randomisation. Patients with septic shock and acute circulatory failure were analysed separately.

Interventions
Blinded infusions of epinephrine or norepinephrine to achieve a MAP =70 mmHg for the duration of ICU admission.

Measurements
Primary outcome was achievement of MAP goal >24 h without vasopressors. Secondary outcomes were 28 and 90-day mortality. Two hundred and eighty patients were randomised to receive either epinephrine or norepinephrine. Median time to achieve the MAP goal was 35.1 h (interquartile range (IQR) 13.8ñ70.4 h) with epinephrine compared to 40.0 h (IQR 14.5ñ120 h) with norepinephrine (relative risk (RR) 0.88; 95% confidence interval (CI) 0.69ñ1.12; P = 0.26). There was no difference in the time to achieve MAP goals in the subgroups of patients with severe sepsis (n = 158; RR 0.81; 95% CI 0.59ñ1.12; P = 0.18) or those with acute circulatory failure (n = 192; RR 0.89; 95% CI 0.62ñ1.27; P = 0.49) between epinephrine and norepinephrine. Epinephrine was associated with the development of significant but transient metabolic effects that prompted the withdrawal of 18/139 (12.9%) patients from the study by attending clinicians. There was no difference in 28 and 90-day mortality.

Conclusions
Despite the development of potential drug-related effects with epinephrine, there was no difference in the achievement of a MAP goal between epinephrine and norepinephrine in a heterogenous population of ICU patients.

Critical Care Med 2008;37:7-18

Fluid refractory septic shock can develop into a hypodynamic cardiovascular state in both children and adults. Despite management of these patients with empirical inotropic therapy (with or without a vasodilator), mortality remains high.

Objectives
The effect of cardiovascular support using intra-aortic balloon counterpulsation was investigated in a hypodynamic, mechanically ventilated canine sepsis model in which cardiovascular and pulmonary support were titrated based on treatment protocols.

Methods
Each week, three animals (n = 33, 10-12 kg) were administered intrabronchial Staphylococcus aureus challenge and then randomized to receive intra-aortic balloon counterpulsation for 68 hrs or no intra-aortic balloon counterpulsation (control). Bacterial doses were increased over the study (4-8 x 109 cfu/kg) to assess the effects of intra-aortic balloon counterpulsation during sepsis with increasing risk of death.

Main results
Compared with lower bacterial doses (4-7 x 109 colony-forming units/kg), control animals challenged with the highest dose (8 x 109 colony-forming units/kg) had a greater risk of death (mortality rate 86% vs. 17%), with worse lung injury ([A - a]o2), and renal dysfunction (creatinine). These sicker animals required higher norepinephrine infusion rates to maintain blood pressure (and higher Fio2) and positive end-expiratory pressure levels to maintain oxygenation (p <= 0.04 for all). In animals receiving the highest bacterial dose, intra-aortic balloon counterpulsation improved survival time (23.4 +/- 10 hrs longer; p = 0.003) and lowered norepinephrine requirements (0.43 +/- 0.17 [mu]g/kg/min; p = 0.002) and systemic vascular resistance index (1.44 +/- 0.57 dynes/s/cm5/kg; p = 0.0001) compared with controls. Despite these beneficial effects, intra-aortic balloon counterpulsation was associated with an increase in blood urea nitrogen (p = 0.002) and creatinine (p = 0.12). In animals receiving lower doses of bacteria, intra-aortic balloon counterpulsation had no significant effects on survival or renal function.

Conclusions
In a canine model of severe septic shock with a low cardiac index, intra-aortic balloon counterpulsation prolongs survival time and lowers vasopressor requirements.

Critical Care Medicine 2008:36:2257-2266

Cardiogenic shock is the leading cause of death in patients hospitalized for acute myocardial infarction. The objectives were to investigate the effects of levosimendan, a novel inodilator, compared with the phosphodiesterase-III inhibitor enoximone in refractory cardiogenic shock complicating acute myocardial infarction, on top of current therapy.

Design
Prospective, randomized, controlled single-center clinical trial.

Setting
Medical and coronary intensive care unit in a university hospital.

Patients
Thirty-two patients with refractory cardiogenic shock for at least 2 hrs requiring additional therapy.

Interventions
Infusion of either levosimendan (12 ug/kg over 10 min, followed by 0.1 ug/kg/min over 50 min, and of 0.2 ug/kg/min for the next 23 hrs) or enoximone (fractional loading dose of 0.5 mg/kg, followed by 2-10 ug/kg/min continuously) after initiation of current therapy, always including revascularization, intra-aortic balloon pump counterpulsation, and inotropes.

Measurements and main results
Survival rate at 30 days was significantly higher in the levosimendan-treated group (69%, 11 of 16) compared with the enoximone group (37%, 6 of 16, p = 0.023). Invasive hemodynamic parameters during the first 48 hrs were comparable in both groups. Levosimendan induced a trend toward higher cardiac index, cardiac power index, left ventricular stroke work index, and mixed venous oxygen saturation. In addition, lower cumulative values for catecholamines at 72 hrs and for clinical signs of inflammation were seen in the levosimendan-treated patients. Multiple organ failure leading to death occurred exclusively in the enoximone group (4 of 16 patients).

Conclusions
In severe and refractory cardiogenic shock complicating acute myocardial infarction, levosimendan, added to current therapy, may contribute to improved survival compared with enoximone.

Critical Care 2008;12:R99

The multifactorial etiology of septic cardiomyopathy is not fully elucidated. Recently, high catecholamine levels have been suggested to contribute to impaired myocardial function.

Methods
This retrospective analysis summarizes our preliminary clinical experience with the combined use of milrinone and enteral metoprolol therapy in 40 patients with septic shock and cardiac depression. Patients with other causes of shock or cardiac failure, patients with beta-blocker therapy initiated more than 48 hours after shock onset, and patients with pre-existent decompensated congestive heart failure were excluded. In all study patients, beta blockers were initiated only after stabilization of cardiovascular function (17.7 ± 15.5 hours after shock onset or intensive care unit admission) in order to decrease the heart rate to less than 95 beats per minute (bpm). Hemodynamic data and laboratory parameters were extracted from medical charts and documented before and 6, 12, 24, 48, 72, and 96 hours after the first metoprolol dosage. Adverse cardiovascular events were documented. Descriptive statistical methods and a linear mixed-effects model were used for statistical analysis.

Results
Heart rate control (65 to 95 bpm) was achieved in 97.5% of patients (n = 39) within 12.2 ± 12.4 hours. Heart rate, central venous pressure, and norepinephrine, arginine vasopressin, and milrinone dosages decreased (all P < 0.001). Cardiac index and cardiac power index remained unchanged whereas stroke volume index increased (P = 0.002). In two patients (5%), metoprolol was discontinued because of asymptomatic bradycardia. Norepinephrine and milrinone dosages were increased in nine (22.5%) and six (15%) patients, respectively. pH increased (P < 0.001) whereas arterial lactate (P < 0.001), serum C-reactive protein (P = 0.001), and creatinine (P = 0.02) levels decreased during the observation period. Twenty-eight-day mortality was 33%.

Conclusion
Low doses of enteral metoprolol in combination with phosphodiesterase inhibitors are feasible in patients with septic shock and cardiac depression but no overt heart failure. Future prospective controlled trials on the use of beta blockers for septic cardiomyopathy and their influence on proinflammatory cytokines are warranted.

Crit Care Med 2008;36:1886-1891

To determine the effects of norepinephrine and levosimendan on microvascular perfusion and oxygenation in a rat model of septic shock.

Design
Controlled laboratory animal study.

Setting
Research laboratory in a university hospital.

Subjects
Forty Sprague-Dawley rats.

Interventions
Sepsis was induced in 32 animals by cecal ligation and puncture. Eight animals served as sham controls. Animals were randomly assigned to five groups: 1) fluid resuscitation (25 ml.kg^-1.h^-1), 2) fluid resuscitation plus norepinephrine (0.5 ug.kg^-1.min^-1), 3) fluid resuscitation plus levosimendan (0.3 ug.kg^-1.min^-1), 4) no treatment and 5) sham control.

Measurements and Main Results
Microvascular perfusion was quantitated using sidestream darkfield imaging and microvascular oxygenation (uPO2) was assessed by oxygen-dependent quenching of phosphorescence. Measurements were obtained on the buccal mucosa at baseline and at hourly intervals thereafter. In parallel, cardiac output (CO) was recorded. After induction of sepsis microvascular perfusion and uPO2 were impaired early followed by significant decreases in CO. Although levosimendan and norepinephrine were equally effective in restoring CO, only treatment with levosimendan significantly improved uPO2 after 1 and 2 hours of treatment (9.7 +/- 2.0 vs. 15.1 +/- 2.6 and 16.0 +/- 3.7 mmHg; p < 0.05). Microvascular perfusion was not significantly influenced by any of the treatment strategies.

Conclusions
In this model, treatment with levosimendan and norepinephrine showed comparable effects in restoring CO and had no significant influence on microvascular perfusion. However, only levosimendan significantly improved uPO2, suggesting that a mechanism relatively independent of macrocirculatory hemodynamics and overall microvascular perfusion might account for these observations.

Critical Care 2008, 12:R35

During septic shock, resistance to the hemodynamic effects of catecholamine vasopressors/inotropes is a well-recognized marker of mortality risk. However, the specific cardiovascular/metabolic response elements that are most closely associated with outcome have not been well defined. The objective of this study was to assess cardiovascular/metabolic responses to dobutamine as correlates of outcome in patients with severe sepsis/septic shock.

Methods
A prospective, non-randomized, non-blinded interventional study of graded dobutamine challenge (0, 5, 10, and 15 ug/kg/min) in adult patients who had undergone pulmonary artery catheterization within 48 hours of onset of severe sepsis or septic shock (8 survivors/15 non-survivors) was performed. Radionuclide cineangiography during graded infusion was used to determine biventricular ejection fractions at each increment of dobutamine.

Results
In univariate analysis, a variety of cardiovascular/hemodynamic and oxygen transport/metabolic variables (at the point of maximum cardiac index response for a given subject) were associated with survival including increased stroke volume index (p=0.0003), right ventricular end-diastolic volume index (p=0.0047), left ventricular stroke work index (p=0.0054), oxygen delivery index (p=0.0084), cardiac index (p=0.0093), systolic blood pressure/left ventricular end-systolic volume index ratio (sbp/lvesvi) (p=0.0188), left ventricular ejection fraction (p=0.0160), venous oxygen content (p=0.0208), mixed venous oxygen saturation (p=0.0234) and pulse pressure (p=0.0403); and decreased pulmonary artery diastolic pressure (p=0.0133), systemic vascular resistance index (p=0.0154), extraction ratio (p=0.0160) and pulmonary vascular resistance index (p=0.0390). Increases of SVI of greater than or less than 8.5 ml/m2 were concordant with survival or death in 21 of 23 cases. Multivariate profile construction showed stroke volume index as the dominant discriminating variable for survival with the sBP/LVESVI ratio alone among all other variables significantly improving the model.

Conclusions
Survivors maintain cardiac responsiveness to catecholamine stimulation during septic shock. Survival from severe sepsis/septic shock is associated with increased cardiac performance and contractility indices during dobutamine infusion. Further studies are required to determine whether these parameters are predictive of outcome in a larger severe sepsis/septic shock population.

Chest 2003;124:90S

Despite the current definition of septic shock, patients with normal or high blood pressure may still display global tissue hypoxia. The following study evaluates early, goal-directed therapy (EGDT) in patients with severe sepsis in the absence of hypotension.

METHODS
This is a post-hoc anlysis of patients presenting to an urban ED in severe sepsis and septic shock. Patients were included if they had SIRS critieria, lactic acidosis (> 4 mmol/liter), and mean arterial pressure (MAP) > 100 mm Hg. Patients were randomized to conventional care (inclusive of central venous pressure (CVP) monitoring) or EGDT. EGDT consisted of 6 hours of resuscitation to goals of CVP between 8–12, MAP between 65–90, and central venous oximetry (ScvO₂) greater than 70%.

RESULTS
There was no difference in mean MAP (116.0 mm Hg in the control and 117.6 mm Hg in the treatment group), and there was no difference in APACHE, MODS, and SAPS scores between groups. Forty-eight patients (23 in the control group and 25 in the EGDT group) were analyzed. The mortality was 60.9% in the control group compared to 20% in the EGDT group [p < 0.004]. The mean initial ScvO₂ was 45 % and 44 % in the control and treatment groups respectively. At six hours, ScvO₂ was higher in the EGDT (76% versus 59%), whereas the lactate and MODS score were reduced (p < 0.05). The EGDT group received more total intravenous fluids than the treatment group (p < 0.05) during the first six hours. At sixty days, mortality in the control (70%) and in the treament group (24%) remained significant (p=0.002).

CONCLUSIONS
This study confirms that patients with severe sepsis accompanied by lactic acidosis may display global tissue hypoxia in the absence of hypotension. Early identification and goal-directed therapy of this subgroup leads to a reduction in morbidity and mortality.

Critical Care Medicine 2007;35:S609-S615

Vasopressin is an endogenously released stress hormone that is important in shock. However, there is a deficiency of vasopressin in patients who have septic shock. To date, studies of animal models of septic shock, small clinical studies, and proof of principle randomized, controlled trials show that exogenously administered low-dose vasopressin infusion restores vascular tone, increases blood pressure, spares the use of conventional catecholamines (e.g., norepinephrine), and may improve renal function (urine output and creatinine clearance) in septic shock. However, both vasopressin and conventional vasopressors, such as norepinephrine, have potentially important adverse effects, such as decreased cardiac output, mesenteric ischemia, and skin lesions.

Despite apparently widespread clinical use of vasopressin in septic shock, there are considerable gaps in the literature regarding vasopressin in septic shock. For example, there are few studies of vasopressin infusion that are >4-12 hrs in duration, yet the duration of vasopressin infusion in clinical use is often for several days or longer. Second, there are no studies of the efficacy of vasopressin that are adequately powered for mortality and organ dysfunction. Third, there are no large randomized, controlled trials of low-dose vasopressin in septic shock that carefully address safety and the adverse effects of vasopressin vs. norepinephrine in septic shock. Finally, there are no studies of the pharmacokinetics of prolonged (several days as opposed to 4-12 hrs) low-dose vasopressin infusion in septic shock.

Arginine vasopressin belongs to the oldest substances in the pharmacologic armament of critical care physicians. The effects of purified pituitary extract on blood pressure were first recognized in the early 20th century. Although vasopressin and its analogs have emerged as standard drugs in the treatment of central diabetes insipidus and gastroesophageal hemorrhage, there is still no consensus on the use of vasopressin analogs in counteracting arterial hypotension. In cases of severe upper gastrointestinal bleeding, physicians often do not hesitate to administer several milligrams of terlipressin to terminate hemorrhage. Conversely, we are still very cautious with low-dose vasopressin infusion in septic shock patients, especially when such a concept yields to supraphysiologic plasma levels. And we are right to do so because several studies revealed severe complications after vasopressin administration in shock states. In this context, it is of note that most of these unwanted side effects are dose dependent. For example, van Haren et al. reported a proportional increase in the gastric mucosal Pco2 gap of septic shock patients in response to increased vasopressin plasma levels. On the contrary, several other clinical studies did not notice a negative effect of vasopressin therapy on organ function or outcome. Landry et al. even suggested relative vasopressin deficiency as a key factor in the pathogenesis of vasodilatory shock. In addition, the same authors noticed a pressor hypersensitivity in response to infusion of low vasopressin doses without obvious side effects.

Just recently, the results of the Vasopressin and Septic Shock Trial (unpublished) were presented at several major critical care meetings. These data provide evidence for the safety of a low-dose arginine vasopressin infusion (≤0.03 units/min), though the investigators did not observe an overall reduction in mortality. However, the results of an a priori analysis showed an improved survival rate of patients allocated to the vasopressin group in the less severe state of the disease (i.e., baseline norepinephrine dosage of <15 μg/min).

Critical Care Medicine 2006;34:2814-2819

A transient increase in pulmonary arterial (PA) pressure can persistently depress right ventricular (RV) contractility. We investigated the effects of dobutamine and levosimendan on RV-PA coupling in this model of RV failure.

Design
Prospective, controlled, randomized animal study.

Setting
University research laboratory.

Subjects
Fifteen anesthetized dogs.

Interventions
Transient (90-min) PA constriction to induce persistent RV failure. Random assignment to dobutamine 5 and 10 µg/kg/min or levosimendan 12 µg/kg for 10 mins followed by 0.1 and 0.2 µg/kg/min.

Measurements and Main Results
We measured PA distal resistance and proximal elastance by pressure-flow relationships and vascular impedance. We measured RV contractility by the end-systolic pressure-volume relationship (Ees), PA effective elastance by the end-diastolic to end-systolic relationship (Ea), and RV-PA coupling efficiency by the Ees/Ea ratio. PA constriction persistently increased PA resistance and elastance, increased Ea from 0.95 ± 0.07 to 3.01 ± 0.28 mm Hg/mL, decreased Ees from 1.17 ± 0.09 to 0.58 ± 0.07 mm Hg/mL, and decreased Ees/Ea from 1.26 ± 0.09 to 0.22 ± 0.03 (p < .05). Dobutamine did not affect pulmonary hemodynamics, markedly increased RV contractility, and improved RV-PA coupling. Levosimendan decreased PA resistance and elastance, increased RV contractility, and restored RV-PA coupling. Compared with dobutamine, levosimendan decreased RV afterload and therefore better restored RV-PA coupling at similar inotropic state.

Conclusions
A transient increase in PA pressure persistently worsens PA hemodynamics, RV contractility, RV-PA coupling, and cardiac output. Levosimendan restores RV-PA coupling better than dobutamine because of similar inotropic effects and additional pulmonary vasodilatory effects.

N Engl J Med 2006;355:1922-25

Heart failure is increasing in incidence and prevalence, is expensive to treat, and is associated with substantial morbidity and mortality.1 In the nomenclature of the guidelines of the American Heart Association and the American College of Cardiology, the majority of patients with heart failure are classified as having stage C heart failure, characterized by structural heart disease that is or has been symptomatic.2 Numerous drugs (e.g., angiotensin converting–enzyme [ACE] inhibitors or angiotensin-receptor blockers, beta-blockers, and aldosterone blockers) and electrophysiological devices may temporarily halt, slow, or even reverse the pathophysiological processes in patients with stage C heart failure. Reversion of the heart toward more normal shape and function is called reverse remodeling.

N Engl J Med 2006;355:1873-84

In patients with severe heart failure, prolonged unloading of the myocardium with the use of a left ventricular assist device has been reported to lead to myocardial recovery in small numbers of patients for varying periods of time. Increasing the frequency and durability of myocardial recovery could reduce or postpone the need for subsequent heart transplantation.

Methods
We enrolled 15 patients with severe heart failure due to nonischemic cardiomyopathy and with no histologic evidence of active myocarditis. All had markedly reduced cardiac output and were receiving inotropes. The patients underwent implantation of left ventricular assist devices and were treated with lisinopril, carvedilol, spironolactone, and losartan to enhance reverse remodeling. Once regression of left ventricular enlargement had been achieved, the 2-adrenergic–receptor agonist clenbuterol was administered to prevent myocardial atrophy.

Results
Eleven of the 15 patients had sufficient myocardial recovery to undergo explantation of the left ventricular assist device a mean (±SD) of 320±186 days after implantation of the device. One patient died of intractable arrhythmias 24 hours after explantation; another died of carcinoma of the lung 27 months after explantation. The cumulative rate of freedom from recurrent heart failure among the surviving patients was 100% and 88.9% 1 and 4 years after explantation, respectively. The quality of life as assessed by the Minnesota Living with Heart Failure Questionnaire score at 3 years was nearly normal. Fifty-nine months after explantation, the mean left ventricular ejection fraction was 64±12%, the mean left ventricular end-diastolic diameter was 59.4±12.1 mm, the mean left ventricular end-systolic diameter was 42.5±13.2 mm, and the mean maximal oxygen uptake with exercise was 26.3±6.0 ml per kilogram of body weight per minute.

Conclusions
In this single-center study, we found that sustained reversal of severe heart failure secondary to nonischemic cardiomyopathy could be achieved in selected patients with the use of a left ventricular assist device and a specific pharmacologic regimen.

Critical Care Medicine 2003;31(9):2408-2409

The life expectancy of patients with congestive heart failure is shortened or, at best, unchanged by long-term exposure to currently available positive inotropic agents (1). All positive inotropic agents currently available enhance myocardial contractility by increasing intracellular calcium concentration. Increased intracellular calcium may be caused by an increase in the intracellular concentration of cyclic adenosine monophosphate, which can be caused by ß-adrenergic stimulation or by decreasing the catabolism of cyclic adenosine monophosphate via phosphodiesterase inhibition (2). Increasing intracellular calcium also can promote after-potential depolarizations and, thereby, ventricular tachyarrhythmias and sudden death……

Critical Care Medicine 2006;34(9):2287-2293

Acute respiratory distress syndrome (ARDS) is frequently associated with increased pulmonary vascular resistance and thus with systolic load of the right ventricle. We hypothesized that levosimendan, a new calcium sensitizer with potential pulmonary vasodilator properties, improves hemodynamics by unloading the right ventricle in patients with ARDS.

Design
Prospective, randomized, placebo-controlled, pilot study.

Setting
Twenty-two-bed multidisciplinary intensive care unit of a university hospital.

Patients
Thirty-five patients with ARDS in association with septic shock.

Interventions
Patients were randomly allocated to receive a 24-hr infusion of either levosimendan 0.2 ug/kg/min (n = 18) or placebo (n = 17). Data from right heart catheterization, cardiac magnetic resonance, arterial and mixed venous oxygen tensions and saturations, and carbon dioxide tensions were obtained before and 24 hrs after drug infusion.

Measurements and Main Results
At a mean arterial pressure between 70 and 80 mm Hg (sustained with norepinephrine infusion), levosimendan increased cardiac index (from 3.8 +/- 1.1 to 4.2 +/- 1.0 L/min/m²) and decreased mean pulmonary artery pressure (from 29 +/- 3 to 25 +/- 3 mm Hg) and pulmonary vascular resistance index (from 290 +/- 77 to 213 +/- 50 dynes/s/cm⁵/m²; each p < .05). Levosimendan also decreased right ventricular end-systolic volume and increased right ventricular ejection fraction (p < .05). In addition, levosimendan increased mixed venous oxygen saturation (from 63 +/- 8 to 70 +/- 8%; p < .01).

Conclusions
This study provides evidence that levosimendan improves right ventricular performance through pulmonary vasodilator effects in septic patients with ARDS. A large multiple-center trial is needed to investigate whether levosimendan is able to improve the overall prognosis of patients with sepsis and ARDS.

Critical Care 2006, 10:R72

Preventing perioperative tissue oxygen debt contributes to a better postoperative recovery. Whether the beneficial effects of fluids and inotropes during optimization of the oxygen delivery index (DO₂I) in high-risk patients submitted to major surgeries are due to fluids, to inotropes, or to the combination of the two is not known. We aimed to investigate the effect of DO₂I optimization with fluids or with fluids and dobutamine on the 60-day hospital mortality and incidence of complications.

Methods
A randomized and controlled trial was performed in 50 high-risk patients (elderly with coexistent pathologies) undergoing major elective surgery. Therapy consisted of pulmonary artery catheter-guided hemodynamic optimization during the operation and 24 hours postoperatively using either fluids alone (n = 25) or fluids and dobutamine (n = 25), aiming to achieve supranormal values (DO₂I > 600 ml/minute/m²).

Results
The cardiovascular depression was an important component in the perioperative period in this group of patients. Cardiovascular complications in the postoperative period occurred significantly more frequently in the volume group (13/25, 52%) than in the dobutamine group (4/25, 16%) (relative risk, 3.25; 95% confidence interval, 1.22–8.60; P < 0.05). The 60-day mortality rates were 28% in the volume group and 8% in the dobutamine group (relative risk, 3.00; 95% confidence interval, 0.67–13.46; not significant).

Conclusion
In patients with high risk of perioperative death, pulmonary artery catheter-guided hemodynamic optimization using dobutamine determines better outcomes, whereas fluids alone increase the incidence of postoperative complications.