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EFFICACY AND SAFETY OF DOPAMINE VERSUS NOREPINEPHRINE IN THE MANAGEMENT OF SEPTIC SHOCK
Gourang P. Patel, Jaime Simon Grahe, Mathew Sperry, Sunit Singla, Ellen Elpern, Omar Lateef, and Robert A. Balk
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rush University Medical Center and Rush Medical College, Chicago, Illinois
Received 23 Jun 2009; first review completed 13 Jul 2009; accepted in final form 10 Aug 2009 ABSTRACTThe 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 G 0.0001), respectively. Logistic regression analysis identified Acute Physiologic and Chronic Health Evaluation II score (P G 0.0001) and arrhythmia (P G 0.015) as significant predictors of outcome. In this protocoldirected vasopressor support strategy for septic shock, DA and NE were equally effective as initial agents as judged by 28day 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). KEYWORDSDopamine, norepinephrine, septic shock, vasopressor therapy, arrhythmia, safety

INTRODUCTION Septic shock continues to be a significant cause of morbidity and mortality despite the use of broad-spectrum antibiotics, modern intensive care unit (ICU) management, and treatment based on specific guidelines (1Y5). Current guidelines stress the importance of early recognition of sepsis, prompt institution of effective antibiotics, and aggressive source control when indicated (6, 7). In addition, studies have emphasized the importance of early goal-directed resuscitation and the use of specific bundles of care designed to improve compliance and early administration of effective therapeutic support strategies (8, 9). After initial fluid resuscitation, the use of vasopressor support to achieve and maintain adequate blood pressure and organ perfusion is the cornerstone of the hemodynamic support strategy (3). Optimum hemodynamic support would be expected to maintain organ perfusion and function, therefore reducing the development of one of the most common causes of death in the ICU, multiple organ dysfunction syndrome (10, 11). Currently, the optimum vasopressor agent for patients with septic shock remains an area of controversy (7, 12Y14). Although almost all agree that vasopressor therapy should not be
Address reprint requests to Robert A. Balk, MD, Division of Pulmonary and Critical Care Medicine, 1653 West Congress Parkway, Chicago, IL 60612. E-mail: Robert_A_Balk@rush.edu. The dopamine versus norepinephrine trial was not funded. None of the authors have any financial involvement or commercial association that might pose a real or perceived conflict of interest in connection with this study. DOI: 10.1097/SHK.0b013e3181c6ba6f Copyright 2010 by the Shock Society

started until there has been adequate volume resuscitation, currently defined by a central venous pressure (CVP) of 8- to 12-mmHg measurement, there is no current consensus as to the best vasopressor drug (3, 7). In 2004, the Society of Critical Care Medicine published consensus guidelines for hemodynamic support in septic shock (3). The guideline recommended initiation of either dopamine (DA) or norepinephrine (NE). If further hemodynamic support is necessary, the recommendation is to add NE (if not initially started), fixed, low-dose vasopressin (0.01 Y 0.04 U minj1), phenylephrine, or epinephrine. In 2008, the Surviving Sepsis Campaign pronounced that DA and NE were equally effective first-line agents to use for vasopressor support in septic shock (7). The dominance of DA began to change as observational trials demonstrated improved outcome with NE use, and at the same time, there were reports of increased rhythm disturbances and lack of a renal protection benefit associated with DA use (13, 15, 16). Two of the studies that suggested a potential survival benefit associated with NE treatment were conducted by Martin et al. (17, 18). One study randomized 32 septic shock patients to receive either DA or NE (17). If the hemodynamic goals were not achieved within 6 h, another agent was added. In the DA group, NE was added. The survival rate was 59% in the NE group compared with 17% with DA treatment; however, the small number of patients limited the strength of this observation (17). In a subsequent observational study of 97 septic shock patients treated with highdose DA, the patients either continued on high-dose DA with epinephrine or were changed to NE (18). The patients who received NE had a significantly lower mortality rate
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TABLE 1. Inclusion and exclusion criteria

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ET AL.

Inclusion criteria Q18 yr Admission to MICU Diagnosis of septic shock requiring vasopressor therapy after adequate fluid resuscitation (clinical examination and/or CVP 9 8 mmHg) Exclusion criteria Lack of infectious cause of shock (e.g., hypovolemic, hemorrhagic, cardiogenic, anaphylactic, and/or obstructive shock) Noninfectious etiology of the SIRS response Allergy to DA or NE Vasopressor therapy for 96 h

(62% vs. 82%; P G 0.001) compared with high-dose DA treatment (18). Unfortunately, the treatment choice was not randomized or controlled. The European Sepsis Occurrence in Acutely Ill Patients study of 1,058 patients with shock, of which only 462 had septic shock, reported an increase in mortality associated with DA treatment (15). Levy et al. (19) reported on a two-phase, prospective, observational study of 110 patients with septic shock. Phase 1 of the study assigned all patients to DA (5Y20mcg kgj1 minj1) to achieve and maintain a MAP greater than 70 mmHg within a 30-min window. Phase 2 evaluated those patients who did not achieve the target MAP and were classified as DAresistant shock. These patients required the addition of either NE or epinephrine to achieve the MAP goal. The DA resistance patients had a significantly higher mortality rate of 78% (52/66) versus 16% (7/44; P = 0.0006) (19). Dopamine and NE have been the most commonly used initial vasopressors agents in the United States. The objective of this trial was to determine if there was an efficacy or safety benefit to the use of DA versus NE as the initial vasopressor in patients with septic shock. The primary outcome variable was 28-day all-cause mortality between the two treatment strategies. MATERIALS AND METHODS
This trial was a single-center, prospective, randomized, protocol-controlled, open-label comparison of DA versus NE as the initial vasopressor for adult patients presenting with septic shock. This study took place from September 1, 2003 to June 30, 2008 at Rush University Medical Center, a 750-bed, tertiarycare, academic institution located in Chicago, Ill. The study was approved by the institutional review board for human experimentation. All of the patients in this study were managed in the 14-bed medical ICU (MICU) of Rush University Medical Center. The enrollment criteria are displayed in Table 1. Patients were eligible for inclusion in the study if they were 18 years or older, presented with a diagnosis of systemic inflammatory response syndrome (SIRS) plus a suspected or documented source of infection, and were admitted to the medical ICU (10). Eligible patients had to be in shock (MAP G60 mmHg and/or systolic blood pressure G90 mmHg) after adequate fluid resuscitation, as determined by a CVP greater than 8 mmHg for nonmechanically ventilated patients (12Y15 mmHg for patients requiring mechanical ventilation) and require the administration of a vasopressor for management. Patients were excluded from the study if they were found to have alternative causes of their shock (i.e., hypovolemic, hemorrhagic, cardiogenic, anaphylactic, and/or obstructive shock) or another cause of their SIRS. Patients who were allergic to DA or NE were excluded, as were patients who were on vasopressors for more than 6 h before enrollment (see Fig. 1 for study flow). This study was approved by our Institutional Human Use Committee and informed consent was obtained. Adult patients with septic shock were randomized to receive either DA (5Y20 mcg kgj1 minj1) or NE (5Y20 mcg minj1) as the first-line vaso-

pressor therapy for septic shock. Randomization was based on whether the patient presented on an odd or even calendar day of the month. For example, if the patient had presented on the third day of the month, then they would be randomized to DA, and if they had presented on the fourth day of the month, then they would be randomized to the NE treatment arm. This randomization scheme was chosen to facilitate rapid institution of assigned vasopressor therapy and to avoid either delay in administration of vasopressor or the need to switch vasopressor therapy associated with use of a more time-consuming randomization system. All patients were treated according to our sepsis management algorithm that incorporated early goal-directed therapy, including fluid resuscitation, early and appropriate antimicrobial therapy (with a goal of G1 h for administration), source control as indicated, glycemic control (blood glucose concentration G150 mg dLj1), and consideration of steroid replacement for patients with relative adrenal insufficiency. Suspected or confirmed septic shock patients were initially resuscitated with either crystalloid or colloid infusions to a CVP greater than or equal to 8 mmHg. If they continued to have a MAP less than 60 mmHg or a systolic blood pressure less than 90 mmHg after adequate fluid resuscitation, they were considered candidates for randomized to receive vasopressor therapy and enrolled in our study. A vasopressor administration protocol (Fig. 2) guided the administration and dosing titration of vasopressor agents to achieve a MAP greater than or equal to 60 mmHg or a systolic pressure greater than or equal to 90 mmHg. If the predetermined maximum dose was reached for the initial vasopressor (DA, 20 mcg kgj1 minj1 or NE, 20 mcg minj1), then the addition of vasopressin at a continuous infusion dose (0.04 U minj1) was initiated. Patients who required additional hemodynamic support to meet the goals were then started on an infusion of phenylephrine (25Y200 mcg minj1), which was titrated to reach the goal hemodynamic parameters (Fig. 2). Those patients who were found to have a low central venous oxygen saturation (ScvO2 G70%) were given dobutamine. Activated protein C was used when indicated based on Acute Physiologic and Chronic Health Evaluation (APACHE) II score and patient characteristics on day of entry into the clinical trial. To ensure similarity in ventilator management strategies, patients in the study were managed with our sedation and analgesia, acute lung injury/adult respiratory distress syndrome, and weaning protocols, as indicated. The primary end point was all-cause 28-day mortality. Secondary end points included length of stay in the ICU, organ dysfunction/failure (as measured by Sequential Organ Failure Assessment [SOFA] score), length of stay in the hospital, and the occurrence of cardiac arrhythmias. Data collected included baseline characteristics (sex, age, underlying illness, site of infection, organism, history of previous cardiac disease or cardiac arrhythmia), laboratory parameters and APACHE II score (20), occurrence of arrhythmias, and survival. Arrhythmias were defined as sinus tachycardia, atrial fibrillation and flutter, ventricular fibrillation and flutter, and premature ventricular contractions

FIG. 1. Enrollment diagram.

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FIG. 2. Vasopressor protocol. Hemodynamic goal, MAP greater than or equal to 60 mmHg and/or SBP greater than or equal to 90 mmHg.

(PVCs). Sinus tachycardia was defined as greater than 20% increase in heart rate from baseline after the start of vasopressor for a period of greater than 8 to 12 h. Atrial arrhythmia was defined as the presence of an abnormal atrial rhythm such as atrial fibrillation, atrial flutter, or paroxysmal supraventricular tachycardia. Ventricular arrhythmia was defined as ventricular tachycardia, ventricular fibrillation, or torsade de pointes. Ventricular tachycardia was recorded if greater than six consecutive beats with a coinciding heart rate greater than 100. Premature ventricular contractions (defined as more than two consecutive PVCs during the course of a nursing shift of 8- to 12-h period) based on electrocardiograph record. All patients were continuously monitored via electrocardiogram leads and the Solar 7000/8000 system, which alerts the nurse via an alarm mechanism for abnormal cardiac rhythms. Patients enrolled in this trial were followed for 28 days, until discharge from the hospital, or death, whichever came first.

characteristics at the time of enrollment were balanced in terms of patient demographics, severity of illness (APACHE II scores), multiorgan dysfunction/failure (SOFA scores), immunosuppressive disease states (i.e., cancer), and type of bacterial infection (gram-positive and gram-negative; see Table 2). In addition, the use of corticosteroids and recombinant activated protein C was similar in both groups. The overall mortality from the septic shock was 47% (118/252). The mortality rate in the patients who received DA as the initial vasopressor was 50% (67/134) as compared with 43% (51/118) for NE treatment (P = 0.282). Kaplan-Meier survival curves for the 28-day study period are displayed in Figure 3. The secondary end points of multiorgan dysfunction (as assessed by SOFA scores) and length of stay (ICU and hospital) were not significantly different between the DA and NE treatment arms (Table 3). A similar number of patients in both groups required the addition of vasopressin and phenylephrine to the initial vasopressor strategy. Importantly, there was a significant difference in the occurrence of arrhythmias between the two vasopressor treatment arms. This difference is reflected in the increased need to change vasopressors in the DA-treated arm of the study (Table 4). The incidence of arrhythmias in the DA-treated group was 38% (51/134) versus 11.8% (14/118) in the NE-treated patients (P G 0.0001). Table 5depicts the arrhythmias that were noted in the two study populations. The presence of a previous cardiac history and/or arrhythmia was not significantly different between the DA and NE treatment arms (P = 0.975 and P = 0.842, respectively; Table 5). In an attempt to determine the presence of additional predictors of mortality, a multiple logistic regression analysis was performed. The logistic regression analysis demonstrated
TABLE 2. Demographics and baseline characteristics Category DA, n = 134 64 70 28 T 6.7 12 T 3.3 5,435 T 2,084 53 42 NE, n = 118 52 66 27 T 6.1 12 T 3.2 5,643 T 2,304 52 43 0.548 0.754 0.452 0.468 0.441 Significance P value 0.557

Statistical analysis
The primary outcome variable was 28-day survival. The exposure variable was whether the patient received DA or NE for hemodynamic support in the setting of septic shock. All statistical evaluations were performed using intention-to-treat analysis. The sample size for this study was based on a power analysis that assumed the expected mortality of septic shock was approximately 40% to 60%. We were looking for 20% reduction in mortality rate that would require n = 240 for our sample size to achieve a power of 80% (21). The primary outcome of survival was compared via a chi-square test. Comparison of baseline categorical and continuous data was completed using a chi-square and Student t test, respectively. The continuous secondary outcome parameters such as length of ICU and hospital stay and SOFA score (as a measure of organ dysfunction/failure) were analyzed using a t test. The development of arrhythmias was compared in both groups using a chi-square test. Kaplan-Meier survival curves were constructed and compared via logrank analysis for the NE and DA treatment groups. Multivariate analysis was performed by constructing a model consisting of variables commonly known to affect mortality and variables significant at the P G 0.2 in univariate analysis with a plausible relationship with morbidity and mortality. All statistical analyses were performed using SPSS software (v15; Chicago, Ill), and statistical significance was judged by a P e 0.05.

Male, n Female, n APACHE II, mean T SD SOFA, mean T SD First 6 h fluids, mL; mean T SD Cancer, n Corticosteroids, n Infection Gram-positive bacteria, n Gram-negative bacteria, n Culture negative, n Site of infection

46 41 28

36 43 20

0.518 0.326 0.426

RESULTS A total of 252 consecutive septic shock patients were enrolled in this trial during a 5-year period (Fig. 1). Baseline

Respiratory tract, n Bloodstream, n Urine, n

23 54 19

27 50 16

0.328 0.798 0.887

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TABLE 4. Vasopressor requirements DA NE Vasopressin Vasopressin and phenylephrine 23 28 32 23 8 P 0.110 0.400

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ET AL.

RR (95% CI)

Change secondary to arrhythmia 32 RR indicates relative risk.

G0.0001 3.52 (1.69 Y 7.30)

FIG. 3. Kaplan-Meier survival curve. *P value calculated based on logrank test.

that the APACHE II score (P G 0.0001) and arrhythmias (P G 0.015) were significant predictors of mortality.

DISCUSSION This study was designed to evaluate both the efficacy and safety of NE and DA in the treatment of adults with fluidresuscitated septic shock. There was no difference observed in the primary end point, 28-day mortality rate. However, the use of DA was associated with significantly increased rate of arrhythmias. The management of septic shock entails many different components that focus on appropriate and timely administration of antimicrobial agents, fluid resuscitation, source control, hemodynamic and respiratory support as indicated, and prevention of common complications of critical illness (3Y5, 7). The controversy concerning superiority of one vasopressor strategy over others continues. This trial demonstrated that both DA and NE as initial vasopressors in a vasopressor treatment algorithm lead to similar 28-day survival rates. Despite the similarity in overall survival, NE seemed to be the safer agent as evidenced by a reduced number of cardiac arrhythmias. The significant difference in the occurrence of arrhythmias between the DA and NE treatment arms does raise some important safety considerations. The increased occurrence of
TABLE 3. Outcome data Outcome Mortality DA 50% (67/134) NE P RR (95% CI) 1.16 (0.886Y1.51)

excessive sinus tachycardia, atrial fibrillation, and premature ventricular contractions may potentially pose additional risks for critically ill patients with septic shock requiring vasopressor agents for hemodynamic support. In a study of 1,341 critically ill patients, Annane et al. (22) found sustained arrhythmias occurred in 12% of the population. Supraventricular arrhythmias occurred in 8%, ventricular arrhythmias occurred in 2%, and conduction abnormalities occurred in 2% of the patients. The mortality rate in patients without arrhythmias was 17% but increased to 73% in those patients with ventricular arrhythmias and 60% in those with conduction abnormalities. Both of these arrhythmias significantly increased the risk of death. Neurologic complications were also more likely to occur in those patients who manifested ventricular arrhythmias (22). The occurrence of increased arrhythmias associated with the use of DA is not a new finding. The AustraliaYNew Zealand Critical Care Trials group found that the use of renal dose DA was associated with increased arrhythmias (16). Similarly, Argalious et al. (23) noted an odds ratio of 1.74 for the development of atrial fibrillation when renal dose DA was given to patients after coronary artery bypass surgery. However, it should be noted that Levy et al. (19) did not demonstrate an increased risk for cardiac arrhythmias with the use of DA in the trial. The use of NE and epinephrine in the French vasopressor study did not pose an increase risk for the development of cardiac arrhythmias or adverse neurologic or ischemic events (24). The vasopressin study of Russell et al. (25) also reported a low incidence of cardiac arrhythmias. Our finding of arrhythmias in 38% of the DA group in contrast to approximately 12% of the NE group we think is noteworthy and should prompt a change in vasopressor selection. The 12% incidence of arrhythmias in the NE group was similar to those results reported by Annane et al. (22) in their study of sustained arrhythmias in critically ill patients.
TABLE 5. Arrhythmia analysis DA (n) NE (n) Sinus tachycardia A-fib PVC VT Total Previous cardiac history Cardiac disease 60 18 53 15 0.975 0.842 33 18 6 2 51 7 3 0 1 14 P RR (95% CI)

G0.0001 4.15 (1.91Y9.03) 0.002 0.031 1 G0.0001 3.21 (1.88Y5.49) 5.28 (1.60Y17.49)

43% 0.282 (51/118) 7.5 T 7.6 0.469 0.695

ICU length of stay 6.8 T 7.3 (d T SD)

Hospital length of 14.2 T 16.3 13.5 T 13.3 stay (d T SD) Incidence of arrhythmias 38% (51/134)

11.8% G0.0001 (14/118)

3.21 (1.88Y5.49)

Arrhythmia

RR indicates relative risk.

A-fib indicates atrial fibrillation; RR, relative risk; VT, ventricular tachycardia.

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SHOCK APRIL 2010

Although the recognition of increased cardiac rhythm disturbances associated with DA use did not result in an increase in mortality, this observation raises concern over the continued use of this agent when there are alternative vasopressors that do not seem to pose the same risk. Current Society of Critical Care Medicine guidelines do not recommend one catecholamine over another, but the consensus is that there are physiologic advantages of both medications in the setting of septic shock (7, 26, 27) The mechanism by which DA is thought to precipitate more arrhythmias has been linked to its properties and action on the myocardium via the "1 receptor activity. In addition to increased heart rate, there is also concern for the effects on the hormones controlled by the anterior pituitary and adverse effects from low-dose DA (26, 27). There are several strengths of this study that we would like to emphasize. First, there have been few prospective, randomized, protocol-controlled trials of NE versus DA in patients with septic shock. Previous trials included small numbers of patients and/or were observational studies that limit their clinical utility (17, 18). Our study prospectively evaluated DA versus NE in 252 patients with fluid-resuscitated septic shock. The study was performed in a single MICU that allowed for a more uniform approach to patient management and one that used a specific vasopressor dosing and titration protocol to minimize variation of management. In addition to the protocol to guide vasopressor management, this study incorporated protocols and bundles of care to guide sepsis management, ventilator management, sedation, and glucose control. Specific components of our sepsis protocol included goal-directed fluid administration, early administration of effective antibiotic treatment, assessment of adequacy of source control, adrenal assessment and replacement therapy when indicated, and assessment for use of activated protein C therapy, in addition to the goal-directed vasopressor administration protocol. We also included a safety analysis along with the efficacy evaluation. Because vasopressors may contribute to the development of arrhythmias and other untoward events, we evaluated the patients in this trial for the occurrence of rhythm changes or other cardiac events that might lead to a change in therapy or an adverse outcome. One of the limitations of this study was the use of a randomization scheme based on the date. Although this form of randomization has the potential to introduce bias, it was thought to be necessary for the successful conduct of this study and to facilitate the early administration of the necessary vasopressor support. A more complex randomization procedure may have produced a delay in the start of necessary vasopressor support and would have made it difficult to begin correct vasopressor support in the emergency room or hospital ward before the patient arrived in the MICU. Despite our use of the even/odd enrollment procedure, it does seem that the randomization was effective, as demonstrated by Table 2. Another potential limitation of our trial was the use of a single center. However, we would suggest that the external validity of our study was not compromised by this approach because our study population is representative of the typical university or tertiary-care MICU. Our patient population was critically ill with an APACHE II score in the 27 to 28 range.

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This high level of acuity is higher than typical multicenter trials investigating innovative therapeutic strategies in patients with severe sepsis and septic shock because we only enrolled patients with septic shock and did not exclude patients who had preexisting malignancy and/or immunocompromised state, or chronic organ dysfunction (28, 29). Therefore, it may be argued that our population is more reflective of a true MICU septic shock population as opposed to the patients enrolled in most multicenter pharmaceutical trials. In addition, the use of a MAP of greater than 60 mmHg or a systolic blood pressure greater than 90 mmHg both represent accepted guideline goals for resuscitation. The use of higher MAP (e.g., 970 mmHg) or SBP (e.g., 9100 mmHg), although possibly associated with improved perfusion, has not necessarily been associated with improved outcome (30, 31). Finally, it may be argued that a systematic search for arrhythmias was not conducted on a daily basis during the infusion of vasopressors. All of the patients enrolled in the trial underwent continuous electrocardiogram and hemodynamic monitoring. Any arrhythmia would have been recognized and printed by the arrhythmia monitoring system, and adverse hemodynamic outcomes were called to the attention of the nursing and medical staff by the alarm system. In addition, it is known that there can be some degree of sinus tachycardia that can result from NE infusions; however, there was a threshold set by the investigators of a 20% increase for a period of 8 to 12 h to stay consistent with the nursing monitoring and working shifts. CONCLUSION In clinical practice, there may be advantages to choosing one vasopressor over another. The results of this study of MICU patients with septic shock demonstrated no significant 28-day survival benefit for NE compared with DA as the initial vasopressor after adequate volume resuscitation. However, the finding of significantly more cardiac arrhythmias associated with DA administration is concerning and should prompt further study and caution when DA is used in patients with a history of cardiac disease or arrhythmia. ACKNOWLEDGMENTS
The authors thank the nurses and physicians (including the internal medicine interns and residents) who worked in our MICU and their adherence to the authors vasopressor protocol.

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