Terlipressin or norepinephrine in hyperdynamic septic shock: a prospective, randomized study. Vasopressin in pediatric vasodilatory shock: a multicenter randomized controlled trial. Vasopressin versus norepinephrine infusion in patients with septic shock. The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis. Effects of epinephrine compared with the combination of dobutamine and norepinephrine on gastric perfusion in septic shock. Low-dose vasopressin in the treatment of vasodilatory septic shock. Terlipressin versus norepinephrine to correct refractory arterial hypotension after general anesthesia in patients chronically treated with renin-angiotensin system inhibitors. Cutaneous vascular reactivity and flow motion response to vasopressin in advanced vasodilatory shock and severe postoperative multiple organ dysfunction syndrome. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Effects of short-term simultaneous infusion of dobutamine and terlipressin in patients with septic shock: the DOBUPRESS study. Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Comparison of dopamine and norepinephrine in the treatment of shock. Regional blood flow and oxygen transport in septic shock. A comparison of epinephrine and norepinephrine in critically ill patients. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Efficacy and safety of dopamine versus norepinephrine in the management of septic shock. Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study. Vasopressin or norepinephrine in early hyperdynamic septic shock: a randomized clinical trial. Terlipressin as a rescue therapy for catecholamine-resistant septic shock in children. Continuous terlipressin versus vasopressin infusion in septic shock (TERLIVAP): a randomized, controlled pilot study.
To compare, in patients with hyperdynamic septic shock, the effects of norepinephrine or terlipressin on hemodynamic variables and renal function.
                Prospective, randomized, open-label study.
                Intensive care unit of a university, tertiary, and referral center.
                Twenty adult patients with hyperdynamic septic shock, after fluid resuscitation.
                Patients were randomized to receive norepinephrine or terlipressin. Global hemodynamic variables, oxygen consumption, urine flow, creatinine clearance, and arterial blood lactate levels were measured.
                Mean arterial pressure, systemic vascular resistance, pulmonary vascular resistance, and left and right ventricular stroke work were significantly increased with both drugs. With terlipressin, but not with norepinephrine, a significant decrease in heart rate (from 113 +/- 17 to 104 +/- 11 beats.min(-1), p < .01) and cardiac index (from 5.1 +/- 1.7 to 4.2 +/- 1.6 L.min(-1).m(-2)) was observed, with no change in stroke volume. Oxygen delivery index (from 784 +/- 131 to 701 +/- 92 mL.min(-1).m(-2)) and consumption index (from 244 +/- 69 to 210 +/- 54 mL.min(-1).m(-2)) were significantly decreased with terlipressin, but not with norepinephrine. Blood lactate concentrations were significantly decreased with both drugs. Urine flow and creatinine clearance were increased with both drugs.
                In patients with hyperdynamic septic shock, both norepinephrine and terlipressin were effective to raise mean arterial blood pressure. With terlipressin, but not norepinephrine, the improvement in blood pressure was achieved at the expense of cardiac index and oxygen consumption, which were significantly decreased. Renal function was improved with both drugs. In further studies, alternative strategies to maintain cardiac index should be explored, such as a synergy between low-dose terlipressin and dobutamine. Vasopressin has been proposed as a potent vasoactive agent in the treatment of vasodilatory shock in adults and children. The objective of this trial was to evaluate the efficacy and safety of vasopressin as an adjunctive agent in pediatric vasodilatory shock.
                In this multicenter, double-blind trial, children with vasodilatory shock were randomized to receive low-dose vasopressin (0.0005-0.002 U/kg/min) or placebo in addition to open-label vasoactive agents. Vasoactive infusions were titrated to clinical endpoints of adequate perfusion. The primary outcome was time to vasoactive-free hemodynamic stability. Secondary outcomes included mortality, organ-failure-free days, length of critical care unit stay, and adverse events.
                Sixty-five of 69 children (94%) who were randomized received the study drug (33 vasopressin, 32 placebo) and were included in the analysis. There was no significant difference in the primary outcome between the vasopressin and placebo groups (49.7 vs. 47.1 hours; P = 0.85). There were 10 deaths (30%) in the vasopressin group and five (15.6%) in the placebo group (relative risk, 1.94; 95% confidence interval, 0.75-5.05; P = 0.24). There were no significant differences with respect to organ failure-free days (22 vs. 25.5 days; P = 0.11), ventilator-free days (16.5 23 days; P = 0.15), length of stay (8 vs. 8.5 days; P = 0.93), or adverse event rate ratios (12.0%; 95% confidence interval, -2.6 to 26.7; P = 0.15).
                Low-dose vasopressin did not demonstrate any beneficial effects in this pediatric trial. Although not statistically significant, there was a concerning trend toward increased mortality. Clinical trial registered with www.controlled-trials.com (ISRCTN11597444). Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors.
                In this multicenter, randomized, double-blind trial, we assigned patients who had septic shock and were receiving a minimum of 5 microg of norepinephrine per minute to receive either low-dose vasopressin (0.01 to 0.03 U per minute) or norepinephrine (5 to 15 microg per minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. The primary end point was the mortality rate 28 days after the start of infusions.
                A total of 778 patients underwent randomization, were infused with the study drug (396 patients received vasopressin, and 382 norepinephrine), and were included in the analysis. There was no significant difference between the vasopressin and norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P=0.26) or in 90-day mortality (43.9% and 49.6%, respectively; P=0.11). There were no significant differences in the overall rates of serious adverse events (10.3% and 10.5%, respectively; P=1.00). In the prospectively defined stratum of less severe septic shock, the mortality rate was lower in the vasopressin group than in the norepinephrine group at 28 days (26.5% vs. 35.7%, P=0.05); in the stratum of more severe septic shock, there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively; P=0.76). A test for heterogeneity between these two study strata was not significant (P=0.10).
                Low-dose vasopressin did not reduce mortality rates as compared with norepinephrine among patients with septic shock who were treated with catecholamine vasopressors. (Current Controlled Trials number, ISRCTN94845869 [controlled-trials.com].).
                Copyright 2008 Massachusetts Medical Society. To compare the effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in patients with hyperdynamic sepsis.
                A randomized short-term, interventional study.
                An intensive care unit of a university hospital.
                Twenty septic patients with a cardiac index greater than 3.2 L-min-1.m-2 and either a mean arterial pressure (MAP) less than 60 mm Hg or a systemic vascular resistance index less than 1200 dyne.s.cm-5.m-2.
                Patients were randomized to receive an infusion of either dopamine or norepinephrine titrated to increase the MAP to greater than 75 mm Hg. The hemodynamic profile, oxygen delivery, oxygen consumption (determined by indirect calorimetry), and gastric intramucosal pH (pHi) (determined by gastric tonometry) were determined at baseline and after 3 hours of achieving the target MAP.
                Dopamine increased the MAP largely by increasing the cardiac index whereas norepinephrine increased the MAP by increasing the systemic vascular resistance index while maintaining the cardiac index. Although oxygen delivery and oxygen consumption increased in both groups of patients, the pHi increased significantly in those patients treated with norepinephrine whereas the pHi decreased significantly in those patients receiving dopamine (P < .001, for corrected 3-hour value).
                This study suggests that dopamine may cause an uncompensated increase in splanchnic oxygen requirements in septic patients. Norepinephrine, however, may have a more favorable hemodynamic profile and improve splanchnic tissue oxygen utilization in sepsis. In septic shock, the alteration of the gut barrier contributes to the development of multiple organ failure. The aim of the study was to compare epinephrine with the combination of dobutamine and norepinephrine on gastric perfusion in patients with septic shock.
                In a prospective randomized study on 2 parallel groups, systemic and pulmonary hemodynamics (arterial and Swan-Ganz catheters), gastric mucosal blood flow (laser Doppler flowmetry technique), hepatic function (indocyanine green clearance), and blood gases were evaluated just before catecholamine infusion and when mean arterial pressure reached 70 to 80 mm Hg. Epinephrine or norepinephrine were titrated (from 0.1 microg/kg per minute, with 0.2 microg/kg per minute increases every 5 minutes). Dobutamine was continuously infused at 5 microg/kg per minute.
                Twenty-two patients were included (11 in each group). At randomization there was no significant difference between groups. At the time of evaluation, mean arterial pressure was 78 +/- 3 and 77 +/- 5 mm Hg in the epinephrine and dobutamine-norepinephrine groups, respectively. There was no significant difference between groups regardless of the systemic and pulmonary hemodynamic or blood gas variable considered. Nevertheless, compared with dobutamine-norepinephrine, epinephrine tended to induce greater values for cardiac index (5.0 +/- 1.6 versus 4.2 +/- 1.5 L/min per square meter; P =.078) and oxygen transport (617 +/- 166 versus 481 +/- 229 mL/min per square meter; P =.068). Epinephrine also induced significantly greater values of gastric mucosal blood flow (662 +/- 210 versus 546 +/- 200 units; P =.011) but did not modify indocyanine green clearance.
                In patients with septic shock, at doses that induced the same mean arterial pressure, epinephrine enhanced more gastric mucosal blood flow than the combination of dobutamine at 5 microg/kg per minute and norepinephrine. This effect was probably a result of higher cardiac index. Despite appropriate therapy, refractory hypotension often occurs in septic shock. A double-blinded placebo controlled clinical trial was performed to assess the role of low-dose vasopressin (VP) as a pressor agent in septic shock.
                Patients admitted to a trauma intensive care unit with vasodilatory septic shock were randomized to receive either VP at 0.04 U/min (n = 5) or placebo (n = 5). Vasodilatory septic shock was defined as a need for catecholamine agents to maintain a mean arterial pressure more than or equal to 70 mm Hg, despite a cardiac index more than 2.5 L/min and a minimal pulmonary artery wedge pressure more than 12 mm Hg. After 1 hour of initiation of the study drug, attempts to discontinue norepinephrine, phenylephrine, and/or dopamine, in respective order, were undertaken provided that the mean arterial pressure remained more than or equal to 70 mm Hg.
                A vasopressin infusion increased systolic arterial pressure (98 +/- 5 to 125 +/- 8 mm Hg, p < 0.008) because of peripheral vasoconstriction (systemic vascular resistance increased from 878 +/- 218 to 1,190 +/- 213 dynes/s per cm(-5) p < 0.05). Arterial pressure and systemic vascular resistance were statistically unaffected in the placebo group. Before study termination, measured at 24 hours after drug initiation, two patients in the placebo group died of refractory hypotension. However, all patients receiving VP survived the 24-hour study period and had all other catecholamine pressors withdrawn and blood pressure maintained solely with a low-dose VP infusion.
                A VP infusion improved arterial pressure and permitted the withdrawal of catecholamine vasopressors. VP is a useful agent in the treatment of refractory septic shock. Terlipressin, a precursor that is metabolized to lysine-vasopressin, has been proposed as a drug for treatment of intraoperative arterial hypotension refractory to ephedrine in patients who have received long-term treatment with renin-angiotensin system inhibitors. The authors compared the effectiveness of terlipressin and norepinephrine to correct hypotension in these patients.
                Among 42 patients scheduled for elective carotid endarterectomy, 20 had arterial hypotension following general anesthesia that was refractory to ephedrine. These patients were the basis of the study. After randomization, they received either 1 mg intravenous terlipressin (n = 10) or norepinephrine infusion (n = 10). Beat-by-beat recordings of systolic arterial blood pressure and heart rate were stored on a computer. The intraoperative maximum and minimum values of blood pressure and heart rate, and the time spent with systolic arterial blood pressure below 90 mmHg and above 160 mmHg, were used as indices of hemodynamic stability. Data are expressed as median (95% confidence interval).
                Terlipressin and norepinephrine corrected arterial hypotension in all cases. However, time spent with systolic arterial blood pressure below 90 mmHg was less in the terlipressin group (0 s [0-120 s] vs. 510 s [120-1011 s]; P < 0.001). Nonresponse to treatment (defined as three boluses of terlipressin or three changes in norepinephrine infusion) occurred in zero and eight cases (P < 0.05), respectively.
                In patients who received long-term treatment with renin-angiotensin system inhibitors, intraoperative refractory arterial hypotension was corrected with both terlipressin and norepinephrine. However, terlipressin was more rapidly effective for maintaining normal systolic arterial blood pressure during general anesthesia. Disturbances in microcirculatory homeostasis have been hypothesized to play a key role in the pathophysiology of multiple organ dysfunction syndrome and vasopressor-associated ischemic skin lesions. The effects of a supplementary arginine vasopressin (AVP) infusion on microcirculation in vasodilatory shock and postoperative multiple organ dysfunction syndrome are unknown.
                Included in the study were 18 patients who had undergone cardiac or major surgery and had a mean arterial blood pressure below 65 mmHg, despite infusion of more than 0.5 microg/kg per min norepinephrine. Patients were randomly assigned to receive a combined infusion of AVP/norepinephrine or norepinephrine alone. Demographic and clinical data were recorded at study entry and after 1 hour. A laser Doppler flowmeter was used to measure the cutaneous microcirculatory response at randomization and after 1 hour. Reactive hyperaemia and oscillatory changes in the Doppler signal were measured during the 3 minutes before and after a 5-minute period of forearm ischaemia.
                Patients receiving AVP/norepinephrine had a significantly higher mean arterial pressure (P = 0.047) and higher milrinone requirements (P = 0.025) than did the patients who received norepinephrine only at baseline. Mean arterial blood pressure significantly increased (P < 0.001) and norepinephrine requirements significantly decreased (P < 0.001) in the AVP/norepinephrine group. Patients in the AVP/norepinephrine group exhibited a significantly higher oscillation frequency of the Doppler signal before ischaemia and during reperfusion at randomization. During the study period, there were no differences in either cutaneous reactive hyperaemia or the oscillatory pattern of vascular tone between groups.
                Supplementary AVP infusion in patients with advanced vasodilatory shock and severe postoperative multiple organ dysfunction syndrome did not compromise cutaneous reactive hyperaemia and flowmotion when compared with norepinephrine infusion alone. International guidelines for management of septic shock recommend that dopamine or norepinephrine are preferable to epinephrine. However, no large comparative trial has yet been done. We aimed to compare the efficacy and safety of norepinephrine plus dobutamine (whenever needed) with those of epinephrine alone in septic shock.
                This prospective, multicentre, randomised, double-blind study was done in 330 patients with septic shock admitted to one of 19 participating intensive care units in France. Participants were assigned to receive epinephrine (n=161) or norepinephrine plus dobutamine (n=169), which were titrated to maintain mean blood pressure at 70 mm Hg or more. The primary outcome was 28-day all-cause mortality. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148278.
                There were no patients lost to follow-up; one patient withdrew consent after 3 days. At day 28, there were 64 (40%) deaths in the epinephrine group and 58 (34%) deaths in the norepinephrine plus dobutamine group (p=0.31; relative risk 0.86, 95% CI 0.65-1.14). There was no significant difference between the two groups in mortality rates at discharge from intensive care (75 [47%] deaths vs 75 [44%] deaths, p=0.69), at hospital discharge (84 [52%] vs 82 [49%], p=0.51), and by day 90 (84 [52%] vs 85 [50%], p=0.73), time to haemodynamic success (log-rank p=0.67), time to vasopressor withdrawal (log-rank p=0.09), and time course of SOFA score. Rates of serious adverse events were also similar.
                There is no evidence for a difference in efficacy and safety between epinephrine alone and norepinephrine plus dobutamine for the management of septic shock. Terlipressin bolus infusion may reduce cardiac output and global oxygen supply. The present study was designed to determine whether dobutamine may counterbalance the terlipressin-induced depression in mixed-venous oxygen saturation (Svo) in patients with catecholamine-dependent septic shock.
                Prospective, randomized, controlled study performed in a university hospital intensive care unit. Septic shock patients requiring a continuous infusion of norepinephrine (0.9 microg kg(-1) min(-1)) to maintain mean arterial pressure (MAP) at 70 (sd 5) mm Hg were randomly allocated to be treated either with (i) sole norepinephrine infusion (control, n=20), (ii) a single dose of terlipressin 1 mg (n=19), or (iii) a single dose of terlipressin 1 mg followed by dobutamine infusion titrated to reverse the anticipated reduction in Svo2 (n=20). Systemic, pulmonary, and regional haemodynamic variables were obtained at baseline and after 2 and 4 h. Laboratory surrogate markers of organ (dys)function were tested at baseline and after 12 and 24 h.
                Terlipressin (with and without dobutamine) infusion preserved MAP at 70 (5) mm Hg, while allowing to reduce norepinephrine requirements to 0.17 (0.2) and 0.2 (0.2) microg kg(-1) min(-1), respectively [vs1.4 (0.3) microg kg(-1) min(-1) in controls at 4 h; each P<0.001]. The terlipressin-linked decrease in Svo2 was reversed by dobutamine at a mean dose of 20 (8) microg kg(-1) min(-1) [Svo2 at 4 h: 59 (11)% vs 69 (12)%, P=0.028].
                In human catecholamine-dependent septic shock, terlipressin (with and without concomitant dobutamine infusion) increases MAP and markedly reduces norepinephrine requirements. Although no adverse events were noticed in the present study, potential benefits of increasing Svo2 after terlipressin bolus infusion need to be weighted against the risk of cardiovascular complications resulting from high-dose dobutamine. To compare the ability of dopamine and norepinephrine to reverse hemodynamic and metabolic abnormalities of human hyperdynamic septic shock.
                Prospective, double-blind, randomized trial.
                An ICU in a university hospital.
                Adult patients with hyperdynamic septic shock after fluid resuscitation.
                Patients were assigned to receive either dopamine (2.5 to 25 micrograms/kg/min) or norepinephrine (0.5 to 5.0 micrograms/kg/min). If hemodynamic and metabolic abnormalities were not corrected with the maximum dose of one drug, the other was added.
                The aim of therapy was to achieve and maintain for at least 6 h all of the following: (1) systemic vascular resistance index > 1,100 dynes.s/cm5.m2 and/or mean systemic blood pressure > or = 80 mm Hg; (2) cardiac index > or = 4.0 L/min/m2; (3) oxygen delivery > 550 ml/min/m2; and (4) oxygen uptake > 150 ml/min/m2. With the use of dopamine 10 to 25 micrograms/kg/min, 5 of 16 patients (31 percent) were successfully treated, as compared with 15 of 16 patients (93 percent) by norepinephrine at a dose of 1.5 +/- 1.2 micrograms/kg/min (p < 0.001). Ten of 11 patients who did not respond to dopamine and remained hypotensive and oliguric were successfully treated with the addition of norepinephrine.
                At the doses tested, norepinephrine was found, in the present study, to be more effective and reliable than dopamine to reverse the abnormalities of hyperdynamic septic shock. In the great majority of the study patients, norepinephrine was able to increase mean perfusing pressure without apparent adverse effect on peripheral blood flow or on renal blood flow (since urine flow was reestablished). At the same time, oxygen uptake was increased. 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.
                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 microg per kilogram of body weight per minute for dopamine or a dose of 0.19 microg 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.
                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).
                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. (ClinicalTrials.gov number, NCT00314704.)
                2010 Massachusetts Medical Society To measure the blood flow distribution and regional oxygen transport in hyperdynamic septic shock during hypotension and after correction by vasopressor doses of dopamine or norepinephrine.
                Prospective, randomized, controlled trial.
                Tertiary care center.
                Ten patients with hyperdynamic septic shock (ages ranging from 45.1 +/- 16.6 yrs) and a control group of 11 postoperative cardiac surgery patients (ages ranging from 54.8 +/- 7.9 yrs).
                Systemic and regional hemodynamics and oxygen transport were measured in ten patients with hyperdynamic septic shock during hypotension and after vasopressor therapy (norepinephrine or dopamine). Oxygen consumption (VO2) was measured by indirect calorimetry and splanchnic and leg blood flow with indocyanine green infusion.
                Splanchnic blood flow and VO2 (p < .05) were increased in septic shock during hypotension and during vasopressor therapy. Both dopamine and norepinephrine increased systemic blood flow and VO2 independently of the arterial lactate level. Despite the relatively small changes in systemic oxygen transport, major regional changes occurred in oxygen delivery and VO2, and these changes were unpredictable from systemic changes.
                Regional changes in oxygen transport in septic shock cannot be predicted from the changes in the whole body. The increased oxygen demand in the splanchnic region is the main risk factor for splanchnic tissue hypoxia in septic shock. To determine whether there was a difference between epinephrine and norepinephrine in achieving a mean arterial pressure (MAP) goal in intensive care (ICU) patients.
                Prospective, double-blind, randomised-controlled trial.
                Four Australian university-affiliated multidisciplinary ICUs.
                Patients who required vasopressors for any cause at randomisation. Patients with septic shock and acute circulatory failure were analysed separately.
                Blinded infusions of epinephrine or norepinephrine to achieve a MAP >or=70 mmHg for the duration of ICU admission.
                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) 13.8-70.4 h) with epinephrine compared to 40.0 h (IQR 14.5-120 h) with norepinephrine (relative risk (RR) 0.88; 95% confidence interval (CI) 0.69-1.12; 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 0.59-1.12; P = 0.18) or those with acute circulatory failure (n = 192; RR 0.89; 95% CI 0.62-1.27; 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.
                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. Vasodilatory shock is a potentially lethal complication of severe disease in critically ill patients. Currently, catecholamines are the most widely used vasopressor agents to support blood pressure, but loss of catecholamine pressor effects is a well-known clinical dilemma. Arginine vasopressin (AVP) has recently been shown to be a potent vasopressor agent to stabilize cardiocirculatory function even in patients with catecholamine-resistant vasodilatory shock.
                Forty-eight patients with catecholamine-resistant vasodilatory shock were prospectively randomized to receive a combined infusion of AVP and norepinephrine (NE) or NE infusion alone. In AVP patients, AVP was infused at a constant rate of 4 U/h. Hemodynamic, acid/base, single-organ, and tonometrically derived gastric variables were reported before the study and 1, 12, 24, and 48 hours after study entry. For statistical analysis, a mixed-effects model was used. AVP patients had significantly lower heart rate, NE requirements, and incidence of new-onset tachyarrhythmias than NE patients. Mean arterial pressure, cardiac index, stroke volume index, and left ventricular stroke work index were significantly higher in AVP patients. NE patients developed significantly more new-onset tachyarrhythmias than AVP patients (54.3% versus 8.3%). Gastrointestinal perfusion as assessed by gastric tonometry was better preserved in AVP-treated patients. Total bilirubin concentrations were significantly higher in AVP patients.
                The combined infusion of AVP and NE proved to be superior to infusion of NE alone in the treatment of cardiocirculatory failure in catecholamine-resistant vasodilatory shock. The optimum septic shock vasopressor support strategy is currently debated. This study was performed to evaluate the efficacy and safety of norepinephrine (NE) and dopamine (DA) as the initial vasopressor in septic shock patients who were managed with a specific treatment protocol. A prospective, randomized, open-label, clinical trial was used in a medical intensive care unit comparing DA with NE as the initial vasopressor in fluid-resuscitated 252 adult patients with septic shock. If the maximum dose of the initial vasopressor was unable to maintain the hemodynamic goal, then fixed-dose vasopressin was added to each regimen. If additional vasopressor support was needed to achieve the hemodynamic goal, then phenylephrine was added. The primary efficacy end point was all-cause 28-day mortality. Secondary end points included organ dysfunction, hospital and intensive care unit length of stay, and safety (primarily occurrence of arrhythmias). The 28-day mortality rate was 50% (67/134) with DA as the initial vasopressor compared with 43% (51/118) for NE treatment (P = 0.282). There was a significantly greater incidence of sinus tachycardia with DA (24.6%; 33/134) than NE (5.9%; 7/118) and arrhythmias noted with DA treatment (19.4%; 26/134) compared with NE treatment (3.4%; 4/118; P < 0.0001), respectively. Logistic regression analysis identified Acute Physiologic and Chronic Health Evaluation II score (P < 0.0001) and arrhythmia (P < 0.015) as significant predictors of outcome. In this protocol-directed vasopressor support strategy for septic shock, DA and NE were equally effective as initial agents as judged by 28-day mortality rates. However, there were significantly more cardiac arrhythmias with DA treatment. Patients receiving DA should be monitored for the development of cardiac arrhythmias (NCT00604019). To compare the effects of norepinephrine and dobutamine to epinephrine on hemodynamics, lactate metabolism, and gastric tonometric variables in hyperdynamic dopamine-resistant septic shock.
                A prospective, intervention, randomized clinical trial.
                Adult medical/surgical intensive care unit in a university hospital.
                30 patients with a cardiac index (CI) > 3.51 x min(-1) x m(-2) and a mean arterial pressure (MAP) < or = 60 mmHg after volume loading and dopamine 20 microg/kg per min and either oliguria or hyperlactatemia.
                Patients were randomized to receive an infusion of either norepinephrine-dobutamine or epinephrine titrated to obtain an MAP greater than 80 mmHg with a stable or increased CI.
                Baseline measurements included: hemodynamic and tonometric parameters, arterial and mixed venous gases, and lactate and pyruvate blood levels. These measurements were repeated after 1, 6, 12, and 24 h. All the patients fulfilled the therapeutic goals. No statistical difference was found between epinephrine and norepinephrine-dobutamine for systemic hemodynamic measurements. Considering metabolic and tonometric measurements and compared to baseline values, after 6 h, epinephrine infusion was associated with an increase in lactate levels (from 3.1 +/- 1.5 to 5.9 +/- 1.0 mmol/l;p < 0.01), while lactate levels decreased in the norepinephrine-dobutamine group (from 3.1 +/- 1.5 to 2.7 +/- 1.0 mmol/l). The lactate/pyruvate ratio increased in the epinephrine group (from 15.5 +/- 5.4 to 21 +/- 5.8; p < 0.01) and did not change in the norepinephrine-dobutamine group (13.8 +/- 5 to 14 +/- 5.0). Gastric mucosal pH (pHi) decreased (from 7.29 +/- 0.11 to 7.16 +/- 0.07; p < 0.01) and the partial pressure of carbon dioxide (PCO2) gap (tonometer PCO2-arterial PCO2) increased (from 10 +/- 2.7 to 14 +/- 2.7 mmHg; p < 0.01) in the epinephrine group. In the norepinephrine-dobutamine group pHi (from 7.30 +/- 0.11 to 7.35 +/- 0.07) and the PCO2 gap (from 10 +/- 3.0 to 4 +/- 2.0 mmHg) were normalized within 6 h (p < 0.01). The decrease in pHi and the increase in the lactate/pyruvate ratio in the epinephrine group was transient, since it returned to normal within 24 h.
                Considering the global hemodynamic effects, epinephrine is as effective as norepinephrine-dobutamine. Nevertheless, gastric mucosal acidosis and global metabolic changes observed in epinephrine-treated patients are consistent with a markedly inadequate, although transient, splanchnic oxygen utilization. The metabolic and splanchnic effects of the combination of norepinephrine and dobutamine in hyperdynamic dopamine-resistant septic shock appeared to be more predictable and more appropriate to the current goals of septic shock therapy than those of epinephrine alone. To compare the effects of arginine-vasopressin (AVP) and norepinephrine (NE) on hemodynamic variables, organ dysfunction, and adverse events in early hyperdynamic septic shock.
                Randomized, controlled, open-label trial.
                Twenty-three patients with early (12h) hyperdynamic septic shock in two teaching hospitals.
                AVP (0.04-0.20 Umin(-1), n=13) as a single agent or NE (0.1-2.8microg kg(-1)min(-1), n=10) infusion for 48[Symbol: see text]h to achieve mean arterial pressure at or above 70mmHg.
                Hemodynamic parameters and Sequential Organ Failure Assessment (SOFA) score were measured. AVP and NE equally increased mean arterial pressure over 48h, but NE was required in 36% of AVP patients at 48h. Compared to baseline, AVP increased systemic vascular resistance, decreased exposure to NE, decreased cardiac output by decreasing heart rate, increased creatinine clearance, and improved SOFA score. The PrCO(2) - PaCO(2) difference remained stable throughout the study. One AVP patient developed acute coronary syndrome with dose-dependent ECG changes. Three patients in both groups died during their ICU stay.
                In early hyperdynamic septic shock, the administration of high-dose AVP as a single agent fails to increase mean arterial pressure in the first hour but maintains it above 70mmHg in two-thirds of patients at 48h. AVP decreases NE exposure, has no effect on the PrCO(2) - PaCO(2 )difference, and improves renal function and SOFA score. To evaluate the effect of terlipressin on oxygenation, PaO2/FIO2, heart rate, mean arterial pressure, and mortality in children with septic shock refractory to high doses of dopamine/dobutamine and adrenaline.
                A randomized, nonblind study in the pediatric intensive care unit of a university hospital.
                We studied 58 children with septic shock and refractory hypotension despite fluid loading and high doses of catecholamines, randomly enrolled to terlipressin (TP, n=30) or control (n=28). TP was administered as intravenous bolus doses of 20 microg/kg every 6 h for a maximum of 96 h. Hemodynamic changes, PaO2/FIO2 rates, length of stay, and mortality rate in PICU were recorded prospectively.
                Mean arterial pressure and PaO2/FIO2 significantly increased, and heart rate significantly decreased 30 min after each TP treatment, but mortality did not differ from control (67.3% vs. 71.4%). Mean stay in the PICU was shorter in the TP group (13.4+/-7.9 vs. 20.2+/-9.7 days and was longer among nonsurvivors of the TP group vs. control (10.4+/-6.9 vs. 6.2+/-3.4 days). Blood urea nitrogen, creatinine, AST, ALT, and urine output of patients in the TP group did not change after terlipressin.
                Although terlipressin infusion had no effect on mortality, it significantly increases mean arterial pressure, PaO2/FIO2, and survival time in nonsurvivors. Terlipressin seems to cause no adverse effect but warrants further evaluation as a rescue therapy in refractory septic shock. Recent clinical data suggest that early administration of vasopressin analogues may be advantageous compared to a last resort therapy. However, it is still unknown whether vasopressin and terlipressin are equally effective for hemodynamic support in septic shock. The aim of the present prospective, randomized, controlled pilot trial study was, therefore, to compare the impact of continuous infusions of either vasopressin or terlipressin, when given as first-line therapy in septic shock patients, on open-label norepinephrine requirements.
                We enrolled septic shock patients (n = 45) with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation. Patients were randomized to receive continuous infusions of either terlipressin (1.3 microg.kg-1.h-1), vasopressin (.03 U.min-1) or norepinephrine (15 microg.min-1; n = 15 per group). In all groups, open-label norepinephrine was added to achieve a mean arterial pressure between 65 and 75 mmHg, if necessary. Data from right heart and thermo-dye dilution catheterization, gastric tonometry, as well as laboratory variables of organ function were obtained at baseline, 12, 24, 36 and 48 hours after randomization. Differences within and between groups were analyzed using a two-way ANOVA for repeated measurements with group and time as factors. Time-independent variables were compared with one-way ANOVA.
                There were no differences among groups in terms of systemic and regional hemodynamics. Compared with infusion of .03 U of vasopressin or 15 microg.min-1 of norepinephrine, 1.3 microg.kg-1.h-1 of terlipressin allowed a marked reduction in catecholamine requirements (0.8 +/- 1.3 and 1.2 +/- 1.4 vs. 0.2 +/- 0.4 microg.kg-1.min-1 at 48 hours; each P < 0.05) and was associated with less rebound hypotension (P < 0.05). At the end of the 48-hour intervention period, bilirubin concentrations were higher in the vasopressin and norepinephrine groups as compared with the terlipressin group (2.3 +/- 2.8 and 2.8 +/- 2.5 vs. 0.9 +/- 0.3 mg.dL-1; each P < 0.05). A time-dependent decrease in platelet count was only observed in the terlipressin group (P < 0.001 48 hours vs. BL).
                The present study provides evidence that continuous infusion of low-dose terlipressin--when given as first-line vasopressor agent in septic shock--is effective in reversing sepsis-induced arterial hypotension and in reducing norepinephrine requirements.