Cardiogenic Shock: Dopamine or Norepinephrine? It's a Question : Cardiology Plus

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Cardiogenic Shock: Dopamine or Norepinephrine? It's a Question

He, Ben1; Kong, Lingcong1; Ge, Junbo2

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Cardiology Plus 2(1):p 1-4, January 2017. | DOI: 10.4103/2470-7511.248216
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Fatal as cardiogenic shock may be, it is of great importance to administer vasoactive agents appropriately for the purpose of correcting shock. Various reasons for shock, differences between the matching status of cardiac output (CO) and peripheral resistance, the diverse mechanism of vasoactive agents as well as the dose-dependent response of drugs, all play a critical decision-making role for physicians. Appropriate administration of combined medications for hemodynamic stability is common. Dopamine and norepinephrine, as vasoactive agents with different mechanisms, could both increase blood pressure. However, the latter is not regarded as a first-line choice for cardiologists, as it agitates α receptors and constricts peripheral vessels and coronary arteries, which burden left ventricle afterload and increases the risk of coronary spasm.

Nevertheless, the 2015 guidelines in emergency medicine recommendations for the management of adult patients with cardiogenic shock[1] strongly suggest the administration of norepinephrine for restoring perfusion pressure during cardiogenic shock, which subverted the prescribing habits for years.

The Evidence of Experts Recommendations

On what clinical evidence is the recommendation based? It was mainly drawn from a multi-center randomized control trial published in 2010 which compared dopamine and norepinephrine use for the treatment of shock.[2] The conclusion is that, although no significant difference was seen between shock patients prescribed dopamine as the first-line agent and those prescribed norepinephrine, the former agent was associated with more arrhythmia and an increasing rate of death in the subgroup analysis on cardiogenic shock (cardiogenic shock P = 0.03).

A total of 1679 study patients with shock were randomly assigned to a dopamine arm (858 cases) and a norepinephrine arm (821 cases) and received a maximum dose of 20 μg/kg of body weight per minute for dopamine or a maximum dose of 0.19 μg/kg per minute for norepinephrine, respectively. When blood pressure could not be maintained with the maximum dose of agents, open-label vasopressors such as norepinephrine, epinephrine, or vasopressin were added. The primary outcome of the study was a rate of death at 28 days after randomization, whereas the secondary outcomes included some days without the need for organ support as well as the occurrence of adverse events. The study concluded that there was no significant between-group difference in the rate of death at 28 days (dopamine arm 52.5% versus norepinephrine arm 48.5%, odds ratio 1.17, confidence interval 0.97˜1.42, P = 0.10). Nevertheless, more arrhythmic events occurred in the dopamine group than the norepinephrine group (207 events [24.1%] vs. 102 events [12.4%], P < 0.001), with respectively 52 cases and 13 cases withdrawn from the trial due to serious arrhythmia, including rapid atrial fibrillation (>160 beats/min) or ventricular tachycardia (P < 0.001). The results of subgroup analysis demonstrated that dopamine, when compared with norepinephrine, was related to an increased rate of death at 28 days in the cardiogenic shock group, which was not the case in septic shock group or hypovolemic shock group (280 patients, P = 0.03 for cardiogenic shock; 1044 patients, P = 0.19 for septic shock; 263 patients, P = 0.84 for hypovolemic shock, in the Kaplan-Meier analyses). In the discussion section, the authors questioned the current guidelines published by the American College of Cardiology/American Heart Association, which recommend dopamine as the first-line agent for increasing arterial pressure among post-acute myocardial infarction patients who suffered from hypertension.

The Interpretation of the Article

Is this conclusion reliable? There are some concerns and questions as proposed below, especially about the design and results:

  1. The target blood pressure after medication was not defined but was determined solely by the patient's doctor in charge, which may be a confounding factor and could lead to bias. Besides, the maximum dose of dopamine was 20 μg/kg of body weight per minute followed by open-label vasopressors if the patient was still hypotensive, so it is conceivable that a majority of patients in the dopamine arm was prescribed dopamine at an effective vasoconstrictive dose, rather than inotropic dose. Would the results have differed if the maximum dose of dopamine was 10 μg/kg body weight per minute in this study?
  2. In the cardiogenic shock subgroup, there are only 135 cases and 145 cases in dopamine and norepinephrine arms, respectively, which comprised <18% of the population. Moreover, acute myocardial infarction accounted for merely half of the so-called “cardiogenic shock,” with the rest caused by tamponade, pulmonary embolism, valvular heart disease, etc., which suggests that a group of patients at extreme medical status with hemodynamic changes due to various mechanisms and with diverse confounding factors was classified as “cardiogenic shock” patients, and then were randomly assigned to receive two vasopressors of different mechanisms to reach a conclusion of the better treatment, which begs many questions. What is the clinical value of the treatment? Was the study designed humanely and ethically? Should medical decisions and prescribed medications be based on pathophysiological changes, or according to “evidence-based medicine?” As we know, it is contraindicated to administrate norepinephrine as a first-choice medication for increasing peripheral resistance in patients with left ventricular valvular regurgitation diseases (e.g., mitral valve, aortic valve regurgitation, and septal rupture) because of the risk of further hemodynamics deterioration. In patients with left heart obstructive disease, such as mitral stenosis and aortic stenosis or hypertrophic obstructive cardiomyopathy, the main method to increase BP is to relieve the obstruction; any vasoactive agents are of limited effect. For patients who suffer from massive myocardial infarction and consequent cardiogenic shock, the peripheral resistance has been increased compensatively, and burdens the afterload of the left ventricle by using vasoconstrictors. Furthermore, the use of salvage drugs to treat shock, especially cardiogenic shock, is based on the clinical status acquired by a physician's observation and bedside practice, which frequently results in a combination of medications that meet different needs and mechanisms (e.g., inotropes and vasopressors). Addressing the problem by a single drug is unreasonable
  3. The dopamine arm was reported to have a higher rate of arrhythmia, most of which was atrial fibrillation. Since dopamine mainly activates β receptors, a higher dosage resulting in more atrial arrhythmia are predictable. However, it is unclear whether the patients were diagnosed with atrial fibrillation before inclusion. The numbers of patients with arrhythmia and subsequent withdrawn cases within subgroups were not mentioned
  4. Although no significant difference was found between the rate of drug-induced myocardial infarction (dopamine arm 2.2% vs. norepinephrine arm 3.0%), the effect of norepinephrine on coronary artery (e.g., constriction and spasm) is dubious/doubtful/doubtless. Furthermore, data suggest that high-dose vasoconstrictors (e.g., norepinephrine) would increase the mortality of patients with cardiogenic shock[3]
  5. Last but not least, the rate of skin ischemia, as one of the secondary outcomes, were higher in the dopamine arm (5.6% vs. 4.1%, though P = 0.09), which suggests that the dopamine was used at a vasoconstrictive dose rather than an inotropic dose. Therefore, we conclude that the use of dopamine at this large dose should be contraindicated and no longer expected to be the inotropes “dopamine.”

Pathophysiology of Cardiogenic Shock

Cardiogenic shock is defined as critical end-stage organ hypoperfusion due to impaired or reduced CO, which is a life-threatening clinical status among emergency rooms and cardiology departments. Up to 70% of cardiogenic shock cases were related to ST-segment elevation myocardial infarction, with or without mechanical complications. In two-thirds of cases, shock is not present at admission and occurs in the first 48 h following admission for MI.[4]

Physiology helps to reveal the basic mechanism for maintenance of arterial blood pressure: mean arterial pressure (MAP) = CO × total peripheral resistance (TPR), CO = stroke volume × heart rate (HR). Thus, the initial compensating reaction of decreasing CO is the increasing HR, followed by TPR.

Amore comprehensive understanding of this issue can be guided by reviewing the established criteria for the diagnosis of cardiogenic shock:[1]

  1. Systolic blood pressure <90 mmHg for 30 min or mean arterial pressure <65 mmHg for 30 min or vasopressors required to achieve a blood pressure >90 mmHg
  2. Pulmonary congestion or elevated left-ventricular filling pressures
  3. Signs of impaired organ perfusion with at least one of the following criteria: (a) altered mental status; (b) cold, clammy skin; (c) oliguria; (d) increased serum lactate.

For this reason, the main pathophysiological features and process include: pump failure driven by myocardial injury would lead to the sharp decrease in CO and cause blood storage in the left ventricle, which then enlarges left ventricular volume and results in an increase of end-diastolic pressure. The rest uninvolved myocardium would compensate the heart function according to the Frank-Starling mechanism.

However, CO lower than 2.2 L per decimeter would lead to hypo-perfusion and cause a series of symptoms such as hypovolemic shock. Besides, stress and inadequate arterial filling would activate the sympathetic system and increase catecholamine, which can lead to more peripheral resistance, increasing return volume, central venous pressure, and consequent pulmonary edema and congestion. Unfortunately, these changes burden the cardiac load, cause hypoxia, and worsen the pump function.

Pharmacology of Dopamine and Norepinephrine

Although both are categorized as catecholamines and could increase blood pressure, dopamine, and norepinephrine share totally different mechanisms of action.

Dopamine, as a pre-drug of norepinephrine, has a dose-dependent effect on the cardiovascular system. Dopamine at low doses (<2 μg/kg/min) activates dopamine receptor D1 and dilates renal vessels, which then helps increase renal blood flow and urine output, while intermediate doses (2-10 μg/kg/min) of dopamine also increase cardiac contractility and HR by agitating β receptors. At higher doses (10-20 μg/kg/min), dopamine results in increased afterload through alpha-adrenergic stimulation, which may be detrimental and cause in heart failure.[5] Thus it was recommended not to use dopamine at a dose higher than 10 μg/kg/min. Previously, dopamine was thought to be renal protective besides its hypertensive effect. Low-dose dopamine improves renal perfusion by increasing CO, which contributes to ameliorating urination and creatinine clearance.[6] In the meantime, dopamine promotes diuresis by inhibiting both the Na+/K+ -ATPase activity in renal cortical tubule cells and the production of aldosterone.[7] However, a meta-analysis demonstrated that low dose dopamine administration cannot reduce the incidence or severity of acute kidney failure or improve the survival rate of patients with critical illness.[8] Furthermore, some studies suggested that although dopamine promoted diuresis, it added to the oxygen consumption of renal medulla, which was deleterious by increasing the risk of medulla ischemia rather than improving it.[9] Finally, 2008 international guidelines for management of severe sepsis and septic shock[10] suggested that low dose dopamine has no effect on renal protection in patients with septic shock.

In comparison, norepinephrine, acting as a strong α receptor agonist, could cause extreme vessels constriction to increase blood pressure and coronary blood flow. Meanwhile, it agitates β receptors to a certain extent which theoretically helps increase myocardial contractility and cardiac output. At a low dose of 0.4μg per kilogram body weight, norepinephrine dominantly stimulates β receptors, while α receptor gets agonized at a higher dose. Generally, reflexive vagus nerve stimulation due to blood pressure increase overwhelmed the direct effect on accelerating heart rate, which finally presented as a reduction in heart rate. Still, strong vasocontraction effect contributes to high peripheral and cardiac ejection resistance, which means cardiac output won't increase obviously, but likely decrease in some degree. Moreover, splanchnic blood flow could be reduced and hypo-perfusion would damage renal function, norepinephrine influences blood flow by constricting both afferent and efferent arterioles (latter is stronger) in animal models, resulting in improved glomerular perfusion pressure, effective filtration pressure and increased urination.[11,12] However, the studies were based on patients with septic shock. There are no data available on patients with cardiogenic shock.

According to the mechanism, dopamine should be the first-line choice for correcting hemodynamic disorder if hypotension is induced by decreased cardiac output; norepinephrine should be used for decreased peripheral resistance.

The Usage of Vasoactive Agents in Cardiogenic Shock

In patients diagnosed with cardiogenic shock, pump failure brings about decreased CO and peripheral hypoperfusion, so the essence and core of correcting cardiogenic shock is the decision on how to increase and maintain blood pressure by inotropes or vasoconstrictors. In fact, it is of critical importance to address the primary problem and initial factor-pump failure. Hence, it is justifiable to administer inotropes instead of norepinephrine to correct pump failure, which could raise peripheral resistance due to its excessively strong vasoconstriction effect, burden the afterload, cause renal hypo-perfusion, resulting in pre-renal acute kidney injury, and deleterious cardiogenic shock.

Alternatively, for patients with cardiogenic shock, it is the balance between CO and TPR that also affects the choice between dopamine and norepinephrine. Patients would suffer at different stages, changes and unexpected adjustments, unexplained symptoms, low peripheral resistance or impaired CO. Dopamine is well-established as an effective treatment to correct CO while norepinephrine's efficacy for TPR is undisputed. They function as are “partners” not “competitors.” The use of only a single drug in the whole course is inappropriate. It is supported by the evidence reported in the trial. Why not make combination therapy of the two drugs as early as possible?

Evidence-based medication should be the result of dialectic and objective research designed to optimize and expedite therapeutic and clinical practice.

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Conflicts of interest

There are no conflicts of interest.


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