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Abstract & Commentary
Synopsis: In a prospective, comparative trial of norepinephrine against high-dose dopamine, norepinephrine, as a part of the hemodynamic management of patients in septic shock, was associated with a highly significant decrease in hospital mortality.
Source: Martin C, et al. Effect of norepinephrine on the outcome of septic shock. Crit Care Med 2000;28:2758-2765.
Martin and colleagues used a prospective ob-servational design to identify factors associated with outcome in a cohort of 97 consecutive critically ill patients with septic shock at a major referral center in France. Nineteen clinical, biological, and hemodynamic variables were analyzed using stepwise logistic regression analysis and a model building strategy to identify variables independently and significantly associated with outcome. Septic shock was defined according to the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference on Sepsis and Organ Failure: sepsis-induced hypotension, persisting despite adequate fluid resuscitation, along with the presence of hypoperfusion abnormalities, or organ dysfunction (oliguria < 30 mL/hr, lactic acidosis, and alteration in mental status evaluated without use of sedative drugs).
All patients in the study received a protocol of broad-spectrum antibiotic coverage, mechanical ventilation, and pulmonary artery catheterization. A strict hemodynamic management protocol was used in which all patients were given fluid resuscitation (³ 12 mL/kg) to maintain the pulmonary artery wedge pressure (PAWP) between 12-15 mm Hg. Hematocrit (Hct) was maintained at 30% with packed red blood cells. Dopamine was initiated at a dose of 5 mcg/kg/min followed by 5 mcg/kg/min increments up to a dose of 15 mcg/kg/min. Dobutamine was added at a dose of 5 mcg/kg/min with 5 mcg/kg/min increments if SvO2 was less than 70% (provided SpO2 > 95%, Hct > 30%). This vasoactive and inotropic support was titrated to keep MAP greater than 70 mm Hg, SvO2 at 70% or greater, and urine output greater than 0.7 mL/kg/hr.
Hypotension persisted in all 97 patients despite this protocol. Patients were then nonrandomly assigned to one of two treatment protocols: 1) high dose dopamine (16-25 mcg/kg/min, n = 40) or 2) dopamine 15 mcg/kg/min and norepinephrine (started at 0.5 mcg/kg/min) with 0.3 mcg/kg/min increments, up to a maximal dose of 5.0 mcg/kg/min (n = 57). If the treatment failed to correct abnormalities in MAP, epinephrine was added to both protocols (n = 7 in high-dose dopamine protocol; n = 10 in norepinephrine protocol). When the hemodynamic status of patients was stable for at least 24 hours, progressive weaning of the drugs was begun.
The 97 patients included 29 women and 68 men with a mean age of 53 ± 12 years. The mean APACHE II score was 28 ± 4. Causes of septic shock were 50 pneumonia (52%), 33 peritonitis (34%), and 14 miscellaneous etiologies (11%). The hospital mortality was 73%. Patients treated with norepinephrine had lower mortality than patients treated with high dose dopamine on day 7 (28% vs 40%, P < 0.005), on day 28 (55% vs 8%, P < 0.001), and on hospital discharge (62% vs 84%, P < 0.001). Patients in both treatment protocols were analyzed and found to have similar characteristics.
Multivariate analysis revealed the use of norepinephrine was the only factor associated with a favorable outcome. Three factors were independently and significantly associated with an unfavorable outcome: pneumonia as the cause of septic shock (P < 0.05), high lactate concentrations (> 4 mmol/L) before treatment was started (P < 0.001), and organ system failure index of 3 or more (P < 0.001).
COMMENT BY KAREN JOHNSON, RN, PhD, CCRN
This study contributes to an increasing body of knowledge of factors that are associated with an increased mortality in septic shock of which two are known: a) high blood lactate concentration at the time of onset of shock, and b) dysfunction in three or more organ systems. The results of this study make us challenge our long held clinical assumptions that norepinephrine is a potent vasoconstrictor and potentiator of end organ hypoperfusion. We have to ask ourselves whether or not norepinephrine (Levophed) deserves its nickname, "leave em dead."
When multiple vasopressors are used in the management of shock, it is the last drug physicians typically order and the first drug nurses titrate down. Dopamine has typically been the vasopressor of choice in the management of patients with hypotension, despite adequate fluid resuscitation. However, this study revealed the use of norepinephrine as part of a hemodynamic support protocol that was strongly related to a favorable outcome and was statistically considered a protective factor that markedly decreased hospital mortality.
A critical point must be made here. Martin et al paid special attention to achieving effective circulating volume before prescribing vasopressor therapy. Patients were subjected to strict fluid resuscitation protocols with specific resuscitation end points that included PAWP, Hct, MAP, urine output, SvO2, and SpO2. They carefully point out that the present study underscores some benefits of norepinephrine in patients who have received adequate fluid resuscitation. These results must be interpreted with extreme caution because the study’s open label, nonrandomized design could have led to a potential bias. It is not clear how decisions were made as to what vasopressor agent patients received.
Large, prospective, randomized clinical trials are needed to answer additional questions this study raises: 1) Should dopamine or norepinephrine be used as the "first-line" vasopressor?; 2) Does the choice of one vasopressor over another truly affect survival?; 3) Should dopamine and norepinephrine be used as combination therapy? If so, when and how should these drugs be titrated? Perhaps this study will challenge us to pursue efforts to identify a standardized approach to resuscitation end points and vasopressor therapy in the management of septic shock. (Karen Johnson works at the School of Nursing, University of Arizona, Tucson, Ariz.)