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Vasopressors in Sepsis: Do They Change the Outcome?
Marco A. González and Cristhiaan D. Ochoa
Sepsis is the second most common disease in the intensive care unit (ICU), with a mortality rate between 32% and 60%. The major cause of death among these patients is multiorgan failure syndrome (MOFS), which takes place after a period of systemic and regional hypoperfusion that keeps active the systemic infl amma- tory and antiinfl ammatory systems.1,2
This hypoperfusion is caused by either an endothelial infl ammatory process or by a systemic vasodilatation in response to (1) nitric oxide (NO) production by the inducible form of NO synthase (iNOS); (2) the ATP-dependent activation of a potassium (K+) channel; or (3) insuffi ciency of vasopressin, as a consequence of depletion of its stores.3 If this infl ammatory process continues, it could lead to a refractory vasodilatation, which is manifested by systemic hypotension, a decrease in mixed venous oxygen saturation, lactic acidosis, bases defi cit, and clinical manifestations of organ hypoperfusion.
Besides targeting the underlying pathogen disease, the main goal should be centered on aggressive resuscitation, an immunological intervention with current therapies (i.e., activated protein C), optimal control of glycemia, and the diagnosis and treatment of adrenal gland failure.4
Every treatment that has had a positive impact on the mortality of septic patients used vasopressors; the most frequently used are noradrenaline, followed by dobutamine, dopamine, and adrenaline.5–7 These medications are coadjuvants in the treatment to maintain vascular tone, preventing vasodilatation and hypoten- sion, which would contribute to multiorgan hypoperfusion.
The fl uid status must be aggressively corrected in a shock patient while imple- menting the antibiotic therapy and treating the infection. This adjustment should be directed by a pulmonary artery catheter. After the volume status is corrected the vasopressor that will be used should be selected. Options available are dobu- tamine, dopamine, noradrenaline, adrenaline, and vasopressin.
The surviving sepsis guidelines for management of severe sepsis and septic shock recommend inotropes and vasopressors with little scientifi c evidence;
however, in their daily practice intensivists use them to improve blood pressure measurements of patients in septic shock.8 The question then is: Which vasoactive should be used in order to have a positive impact on patient survival and to prevent deleterious effects?
The answer is still open to discussion since the experience that an intensivist has with these types of patients is still the prevailing factor for selecting vasopres- sors. The authors’ group, in particular, has decided that after achieving an ade- quate volume status, noradrenaline is the fi rst-line vasopressor to use. The justifi cation for this choice is explained below.
Noradrenaline
Noradrenaline (NE) constitutes 10% to 20% of suprarenal gland medulla cate- cholamines; the difference with adrenaline centers in the lack of a methyl substi- tute in the amine group. It has less adverse effects than adrenaline and it activates α-adrenergic postsynaptic receptors 1 and 2 (α-1 and α-2), leading to vasocon- striction. Additionally, it has a beta 1 (β-1) inotropic action. The pulmonary artery vasoconstrictor effect is not important (an average of 5 to 10 torr increase), which is why it could be used if heart failure is present in septic patients.9 Furthermore, its vasoconstrictory effects do not affect the splanchnic bed fl ow as it is shown in a large animal experiment by Bellomo and Giantomasso in which they docu- mented that noradrenaline infusion increased blood fl ow in the splanchnic, hepatic, and renal beds.10
NE dosage varies; it could be started as low as 0.05 µg/kg/min and may be increased until reaching the goal preferred by the physician. Doses as high as 3.3µg/kg/min have been described, but this is extremely rare in everyday practice and could lead to a vasoconstrictor effect in peripheral beds, resulting in distal necrosis.2
There is increasing evidence in the literature showing the benefi ts of NE in comparison to other vasopressors. Martin et al. compared two groups of patients:
one received dopamine plus NE and the other received adrenaline and dopamine.
He clearly showed that the group receiving NE had a higher survival rate.11 Bellomo and Giantomasso10 demonstrated that the mortality rate, based on the Simplifi ed Acute Physiology Scale (SAPS) II score, of patients receiving NE was lower than patients on adrenaline. The average dose received by the former group was 0.86 µg/kg/min. The average infusion time was 88 hours. These studies support the authors’ recommendation for using NE as the fi rst-line vasopressor in patients with refractory septic shock.12
Dobutamine
Dobutamine is a synthetic catecholamine with beta-1 and beta-2 (β-1; β-2) activity. Dobutamine has less adverse effects that dopamine. The author’s group uses it in combination with NE either when the resuscitation endpoints are not reached or when the attending physician desires a higher cardiac index. The dose utilized is 5 to 15 µg/kg/min. The pharmacological effect starts a few minutes after the IV infusion and ends when the delivery is stopped.8
Dobutamine has a coadjuvant role with the vasopressors in septic shock treat- ment. The fi nal goal of this mixture is to improve the cardiac index and mixed venous oxygen saturation. Dobutamine has a chronotropic effect in addition to its inotropic one, both of which could improve the systolic performance of a septic heart. However, when the heart rate is disproportionately high, it increases the systemic vasodilation, worsening the hypotension.8 Dobutamine improves cardiac index and reduces pulmonary vascular resistance in patients with sepsis. These effects restore the right heart contractility and increase splanchnic blood fl ow.
There are no studies showing improvement in mortality rates when dobutamine was used in septic patients, but it was used by Rivers et al. in their classic paper to achieve a higher mixed venous oxygen saturation endpoint after utilizing intravenous fl uids and vasopressors.5
Dopamine
Dopamine is the most popular catecholamine used in septic shock after adrena- line. Its activity spectrum encompasses, depending upon the dosage, alpha, beta, and dopa receptors. Vincent recommended dopamine as the fi rst-line vasopressor for septic shock in 2001.13 Dopaminergic effects that favor renal blood fl ow, with low doses of 5 µg/kg/min and below, have been described. Unfortunately, an Australian randomized, double-blind clinical trial showed that this catecholamine did not prevent renal failure in septic shock patients.14 Subsequently, a metaanaly- sis published in 2001 reported that there is no evidence to support its use in septic shock.15 The surviving sepsis guidelines do not support dopamine as a renal pro- tective agent. Dopamine has a grade-B evidence-based recommendation.8
The beta-1 stimulatory effect is reached with doses within the 5- to 10-µg/mL/
min range. At this point inotropic and chronotropic effects are both favored. This, however, has deleterious consequences such as the increase in myocardium oxygen consumption.16
In addition to its chronotropic effects, dopamine has immunologic and metabolic effects. It diminishes cyclic adenosine monophosphate (cAMP) and inhibits prolif- eration in lymphocytes, as well as immunoglobulins, cytokines, growth hormone, and thyroid-stimulating hormone (TSH) production. It has been reported that dopa- mine allows lymphocyte apoptosis. A number of studies have reported intestinal ischemia as a consequence of dopamine infusions at different dosages.17
Vasopressin
Vasopressin (VP) levels are usually low in the late phase of septic shock. This contributes to the refractory status of some vasodilatory shock. VP has anti- diuretic effects when it binds V2 receptors in renal tubules; it also results in vasoconstriction when it acts on V1 receptors present in vascular smooth muscle cells.18
VP blocks directly ATP-dependent K+ channels in vascular smooth muscle cells, preventing the vasodilatory status from continuing in septic shock. It also blunts the cyclic guanosine monophosphate (cGMP) receptors’ response to nitric oxide and atrial natriuretic peptide. The dosage for refractory hypotension due to septic shock is 0.01 to 0.04 U/min. Larger doses show no benefi t and may lead to adverse effects.18–20
Laudry’s studies3 demonstrated that at this dosage, VP increases arterial pressure, renal blood fl ow, and diuresis, but it did not increase the cardiac index.
There are no studies to report an increase in survival in septic patie nts treated with VP.
Conclusion
The fi nal event in septic shock is multiorgan failure syndrome as a consequence of hypoperfusion resulting from a late, refractory vasodilatory shock. Before starting vasoactive agents, the underlying infectious disease must be under treat- ment, the volume status aggressively corrected, the immunomodulatory therapy started, and adrenal gland failure ruled out. NE is the vasoactive agent with the best results in refractory shock, and it is probably the vasoconstrictor that most improves mortality in septic patients. VP levels are depleted in the late phase of septic shock. If the patient is hypotensive, even though vasoactive agents and inotropes are used, VP should be started at low doses.
References
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