Dopamine vs. norepinephrine for septic / distributive shock?
When New York rolled out a massive protocol update in 2014, our fire department was fortunate enough to be able to add a few more trays to our drug box. Among the newcomers was norepinephrine, which was not unreasonably placed next to our existing stores of dopamine. Prior to this point, we had relied on dopamine as a pressor in the prehospital setting (in large part due to a lack of options). Thus, when the choice was offered to us, providers began to question the preferred agent.
Mechanism of Action:
Before delving into the clinical data, let’s address the theoretical differences based on the mechanism of action of the drugs.
To start, we can quickly review the adrenergic receptors, as they are pertinent to our discussion:
- Alpha-1: Activation results in constriction of peripheral vasculature, and increase in blood pressure.
- Alpha-2: A generalized inhibitor, which tones down adrenergic effects in the body.
- Beta-1: Receptors heavily represented in the heart, where their activation results in increased rate (chronotropy), conduction speed (dromotropy), and strength of contraction (inotropy).
- Beta-2: Receptors present in many vascular beds and in the airways, where the effect is to relax smooth muscle (opens the vessels and the airways).
At lower concentrations (0.5 – 2.0 mcg/kg/min), the drug is believed to primarily activate dopamine-1 receptors in the renal vascular bed, resulting in vasodilation and increased blood flow through the kidneys. This effect is also believed to occur to some extent in the vessels of the intestines, heart, and brain. Although this theoretical benefit exists from animal studies, it has not been borne out in clinical trials.
At intermediate concentrations (2.0 – 10.0 mcg/kg/min), the drug is believed to primarily activate beta-1 receptors, largely located in the heart. This results in the aforementioned effects: increased rate, strength of contraction, and speed of conduction in the heart. There appears to be minimal beta-2 stimulation, and no pressor effect (as there is not yet much alpha-1 stimulation).
At high concentrations (10.0 – 20.0 mcg/kg/min), the drug is believed to primarily activate alpha-1 receptors in the peripheral vasculature, especially in the skeletal muscles. This results in a concomitant increase in blood pressure due to an increase in total peripheral resistance.
While the drug activates both beta and alpha receptors, it disproportionately activates alpha-1 receptors. The result of this is peripheral constriction of arteries, resulting in an increase in total peripheral resistance (and blood pressure), and peripheral constriction of veins, resulting in an increase in cardiac preload (and cardiac output). Thus, the effect of norepinephrine in the periphery is rather like the “pressor” dose of dopamine (10.0 – 20.0 mcg/kg/min).
As the pressor dose of dopamine appears to have the same physiologic effect as norepinephrine, it seems reasonable to conclude that both would be similarly efficacious as pressors.
Clinical Data: The Good Stuff
There is no paucity of data when it comes to the comparison of dopamine and norepinephrine as pressors. It is important to emphasize that treatment of shock is highly contingent upon the type of shock that is being treated. For example, in a patient with hypovolemic shock, the issue requiring correction is the circulating volume of blood. In a patient with obstructive shock, the issue requiring correction may be a pericardial tamponade or a tension pneumothorax. Pressors such as dopamine and norepinephrine are best used in cases of distributive shock (ie. septic, neurogenic, anaphylactic), in which there is generalized dilation of the ‘pipes’ in the body, which require the clamping effects of these drugs.
Study Sample: Twenty-three randomized-controlled trials were included in the review, comprising 3212 patients. Norepinephrine versus dopamine was the largest comparison, comprising 1400 patients from six trials.
No difference in mortality between any of the vasopressors or their combinations.
More arrhythmias were observed in patients given dopamine as compared to norepinephrine.
The risk of death with norepinephrine versus dopamine was found to be largely equivalent (RR CI 0.87 – 1.03).
The choice of vasopressor probably does not affect outcome, and there does not appear to be a superior drug.
“Cochrane Reviews are systematic reviews of primary research in human health care and health policy, and are internationally recognized as the highest standard in evidence-based health care. They investigate the effects of interventions for prevention, treatment and rehabilitation.”
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Since the publication of this equivocal Cochrane Review, there appears to be a growing body of evidence which discourages the use of dopamine as a vasopressor in sepsis. Foremost among these is the 2012 guidelines for the management of severe sepsis and septic shock, known colloquially as the ‘Surviving Sepsis Campaign’.
Particularly with respect to the increased propensity for tachyarrhythmia, this consensus committee of 68 international experts suggested that dopamine should only be used as an alternative vasopressor to norepinephrine in highly selected patients (ie. low risk of tachyarrhythmias and absolute or relative bradycardia), and even this was only a grade 2C recommendation (recommendations were graded as (1) Strong or (2) Weak, and evidence level was rated from A to D).
- Short-term mortality: RR 0.91 (0.83 – 0.99)
- Serious Supraventricular Arrhythmias: RR 0.47 (0.38 – 0.58)
- Serious Ventricular Arrhythmias: RR 0.35 (0.19-0.66)
In stark contrast, norepinephrine has emerged as the first choice of vasopressor in septic shock, with grade 1B recommendation. For a second vasopressor, epinephrine has been offered a weak recommendation (grade 2C).
Other Practical Considerations:
When dosing dopamine on most 9-1-1 ambulances (ie. in the absence of medication pumps), we must approximate the administration rate in an imperfect way (timing the drops in the IV’s drip chamber). If we underdose the drug, we will fail to achieve the desired pressor effect. In contrast, norepinephrine will always exert alpha-1 effects in a dose-responsive manner. Starting low, and raising it in slow increments will result in relatively quick systemic effect, which facilitates titration of MAP.
Another consideration is the way in which the drugs are dosed. Dopamine requires weight-based dosing, which necessitates an additional step for paramedics (as well as potential for error in calculation). Norepinephrine, however, can be dosed at either a simple rate (titrating up from 1mcg/min) or weight-based dosing, depending on your propensities. Although there are very strong proponents for ubiquitous use of weight-based dosing with resuscitation drugs, the uniquely resource-poor environment in the back of ambulance (ie. you and your two hands) presents a strong argument for the use of a drug that can be more quickly and easily initiated and maintained.
An example of a dosing chart using 1mg/250cc solution concentration and 60gtt/mL set is below: