Support for cardiovascular dysfunction, a frequent presenting symptom defining outcome in sepsis, continues to be debated. Cardiovascular failure can present in a variety of ways. After standard volume resuscitation, patients in hyperdynamic or "warm" shock are peripherally vasodilated with high cardiac output. Patients in a hypodynamic state (traditional cold shock) present with increased vascular tone and low cardiac output. Adults more often present in hyperdynamic shock, whereas children may present with warm or cold shock (1).
Despite an increase in cardiac output during the hyperdynamic phase of sepsis, the myocardium is dysfunctional. Both right and left ventricles can dilate, contractile function may decrease, and ventricular compliance is reduced. Work at the NIH by Parker and associates demonstrate a depression of ejection fraction in patients with sepsis despite normal or elevated cardiac index. Dysfunction peaks soon after the onset of sepsis and resolves within 7 to 10 days in survivors. Many studies have investigated cardiovascular dysfunction in sepsis but its etiology remains unclear (1, 2).
With hypotension as the initial trigger, there is universal agreement that aggressive fluid resuscitation is the initial intervention in cardiovascular support of the patient in septic shock. Following adequate intravascular volume repletion, continued presence of hypotension warrants the consideration of vasoactive drug therapy either through drugs directly raising blood pressure or a combination of vasopressor and inotropic agents. Minimal data exist to guide the initiation of vasoactive drug therapy. Arbitrary values frequently given include maintenance of systolic blood pressure of 90 mmHg or a mean arterial blood pressure of 50 to 60 mmHg. A more important physiologic endpoint, one more difficult to describe, is adequacy of end organ function. Dopamine and norepinephrine have received the greatest amount of attention among vasoactive drugs for patients in septic shock. Do pamine is more likely to induce or exacerbate tachycardia than norepinephrine. Because of vasoconstriction and right atrial baroreceptor stimulation, norepinephrine usually does not induce or exacerbate tachycardia. Dopamine typically raises both blood pressure and cardiac index, as does norepinephrine, although the increase in cardiac output with dopamine is greater (3).
Systemic and regional hemodynamic effects of dopamine in patients with septic shock are well established. Dopamine increases MAP by increasing cardiac index with limited impact on systemic vascular resistance. Increase in cardiac index is due to an increase in stroke volume and, to a lesser extent, heart rate. Patients receiving dopamine at rates of greater than 20 μg/kg/min show increases in right heart pressure and in heart rate. The effect of dopamine on gastric tonometric and splanchnic variables has been evaluated with conflicting results. At low doses, dopamine increases splanchnic oxygen delivery but shows minimal change in splanchnic oxygen consumption. In fact, dopamine may decrease gastric mucosal pH suggesting inadequate perfusion-related nutrient delivery. Other work suggests that dopamine may adversely affect the inflammatory response to septic shock by decreasing the release of a number of hormones including prolactin. Potentially harmful endocrine effects have been demonstrated in trauma patients (2, 3).
Norepinephrine is a potent α-agonist with some β-adrenergic properties (2). The effects of norepinephrine have been examined in a number of studies on patients with septic shock. Norepinephrine has been shown to increase MAP in patients with hypotension resistant to fluid resuscitation and dopamine. Recent experience with the use of norepinephrine in patients with septic shock suggests that it can successfully increase blood pressure without causing deterioration in end organ dysfunction. In particular, concern has been expressed with respect to the effect of norepinephrine on the kidney. In patients with hypotension and hypovolemia during hemorrhagic shock, for example, norepinephrine and other vasoconstrictor agents may have detrimental effects on renal hemodynamics. In hyperdynamic septic shock, during which urine flow is believed to decrease mainly as a result of lowered glomerular perfusion pressure, administration of norepinephrine may result in an increase in renal blood flow. Norepinephrine increased MAP and improved parameters such as serum creatinine, blood urea nitrogen, free water clearance, and fractional excretion of sodium. Another perfusion-related concern associated with the use of norepinephrine is change in lactate level as a reflection of perfusion. Small studies suggest a trend toward a lower lactate level with norepinephrine compared with dopamine. Clinical data supporting norepinephrine use in sepsis come from single-center studies and a larger observational European trial favoring norepinephrine over dopamine in shock of varied etiologies (4-6).
Vasopressin use may also be considered in patients with refractory shock despite adequate fluid resuscitation and high-dose conventional vasopressors. At present, vasopressin is not recommended as a replacement for norepinephrine or dopamine as a first-line agent. If used in adults, low infusion rates should be used. Support for vasopressin comes from several small case series at present. There are some data that suggest that vasopressin may be more effective than norepinephrine in support of the splanchnic circulation. There is still inadequate understanding as to the mechanism or potential therapeutic benefit of vasopressin use in septic shock (7).
In patients with low cardiac output despite adequate fluid resuscitation and blood pressure, dobutamine is the agent of choice to increase cardiac output. If increase in cardiac output is desired in the presence of low blood pressure, dobutamine may be combined with vasopressor therapy (2, 3, 8). Dobutamine as an adrenergic agent stimulating both β-1 and β-2 receptors has been investigated in a number of studies of cardiac function during sepsis or septic shock. These small trials used a range of doses and found increases in cardiac index combined with stroke volume and heart rate. Leone and coworkers (9) ask whether isoproterenol is also an acceptable β-agonist in the septic patient on vasopressor therapy. Impressive hemodynamic benefit is seen in a small group of patients through outcome; immunologic and endocrine assessment is absent. They appropriately note that shock in sepsis is not comparable to that of coronary artery disease where this agent is not favored.
Regardless of the vasoactive drug therapy used, increasing cardiac output above physiologic levels cannot be recommended. Two recent prospective clinical trials including critically ill patients with sepsis have failed to demonstrate benefit from increasing oxygen delivery to supranormal levels. The goal of resuscitation should be to achieve adequate levels of oxygen delivery to avoid flow-dependent tissue hypoxia (2).
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