In an attempt to determine the presence of additional predictors of mortality, a multiple logistic regression analysis was performed. The logistic regression analysis demonstrated that the APACHE II score (P < 0.0001) and arrhythmias (P < 0.015) were significant predictors of mortality.
This study was designed to evaluate both the efficacy and safety of NE and DA in the treatment of adults with fluid-resuscitated 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 (3-5, 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 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 Australia-New 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.
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 β1 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. 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., >70 mmHg) or SBP (e.g., >100 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.
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.
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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