Page 842 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 64: Sepsis, Severe Sepsis, and Septic Shock 573

this group found use of norepinephrine, as the vasopressor of choice, severe sepsis or septic shock. 155,156 Calcium supplementation has also
was associated with lower hospital mortality in septic shock patients. been proposed in the management of myocardial dysfunction in septic
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Most recently, a large prospective double blind multicenter randomized shock, but few studies have shown a consistent hemodynamic benefit.
controlled trial with 1600 patients with shock compared the efficacy of Most recently, levosimendan, a calcium sensitizer that acts through a
dopamine and norepinephrine. The study found that in patients with nonadrenergic pathway, has been studied in sepsis. It exerts beneficial
septic shock, although there was no significant difference in the rate of effects on the ventricles without changing intracellular calcium con-
death between the two groups, dopamine was associated with a greater centrations. Levosimendan increases cardiac output in septic shock by
number of adverse events. 27,139 increasing both systolic and diastolic function. In preclinical models,
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Vasopressin, an endogenous hormone synthesized in the hypothalamus, levosimendan has been shown to increase cardiac index and stroke vol-
has emerged as an adjunct to catecholamines for patients with septic shock. ume, while decreasing systemic vascular resistance with a resultant slight
Vasopressin levels have been found to be lower than expected in patients decrease in MAP. 158-160 Several clinical studies assessing levosimendan in
with septic shock, 140,141 suggesting a relative vasopressin deficiency patients with sepsis have reported improved cardiac performance and
state. In addition, vasopressin has been found to spare catecholamine oxygen transport. 161,162 Most recently, levosimendan was compared to
use and have other beneficial physiologic effects. 140-144 Recently, a large dobutamine in an open-label randomized clinical trial. Results showed
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multicenter randomized double blind trial of approximately 800 patients that although levosimendan decreased serum lactate to a greater
was conducted to determine whether low-dose norepinephrine (ie, degree, there was no significant difference between the two drugs with
<5 µg/min) and vasopressin at 0.03 units per minute decreased mortal- regard to their effect on Scv O 2 . This drug is currently not FDA approved
ity compared to using norepinephrine alone at 5 to 15 µg/min. There because discussions with the FDA revealed that the pharmaceutical com-
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was no difference in mortality, ICU and hospital length of stay, days alive pany would have to conduct another randomized control trial in order
and free of vasopressor use, corticosteroids, or organ dysfunction, but to approve the drug, which they decided they did not want to pursue.
the dose of norepinephrine infusion was significantly lower in the group ■
receiving vasopressin. Although there was no difference in the rates of CORTICOSTEROIDS
adverse events overall, there was a trend toward a higher rate of cardiac The past decade has seen a considerable debate and the emergence of new
arrest in the norepinephrine group and a trend toward a higher rate evidence regarding the utility of corticosteroids in septic shock. In the
of digital ischemia in the vasopressin plus norepinephrine group. An past, randomized clinical trials and meta-analyses have shown that high-
a priori defined subgroup analysis showed that survival was improved dose corticosteroid therapy for patients with severe sepsis or septic shock
with vasopressin in a subgroup of patients with less severe septic shock, is ineffective. 164-167 Generally, corticosteroids are considered for patients
but this effect was not statistically robust. This study demonstrated that with septic shock, as there are no studies suggesting benefit in less severe
although vasopressin is an effective second-line agent, it is not any more forms of sepsis (ie, sepsis or severe sepsis). Until recently, there was
effective than using norepinephrine alone. Vasopressin, however, may only one adequately powered trial to suggest better shock reversal and a
be used at low doses (0.03 units per minute), particularly for refrac- survival benefit in patients with vasopressor unresponsive septic shock
tory hypotension, and should generally be reserved for patients without and relative adrenal insufficiency, defined as post- adrenocorticotrophic
active coronary or mesenteric ischemia. hormone (ACTH) cortisol increase less than or equal to 9 µg/dL.
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A recent large European multicenter trial (CORTICUS) random-
Inotropes: Septic shock involves a complex interplay between vasodilata- ized 499 septic shock patients to receive either low-dose hydrocorti-
tion, relative and absolute hypovolemia, and direct myocardial depression. sone therapy or placebo for 5 days. The authors concluded that at
167
Even after restoration of intravascular volume and maintenance of cardiac 28 days, there was no significant difference in mortality between
index, there are microvascular abnormalities that preclude normal distri- patients in the two treatment groups, irrespective of any response to
bution of an often elevated cardiac output. This myocardial dysfunction ACTH. While corticosteroids did hasten the reversal of septic shock,
167
is complex and characterized by a depressed ejection fraction, impaired they were also associated with a greater risk for nosocomial infections
contractility, and low peak systolic pressure/end-diastolic volume. 146,147 It and recurrent sepsis. These results suggest that ACTH stimulation
167
is thought to be secondary to downregulation of adrenergic pathways, testing is not useful in predicting sepsis patients who may benefit from
alteration of intracellular calcium, and desensitization of the myofibrils to steroids, and that corticosteroid therapy in general for septic shock does
calcium. 148,149 In patients with decreased cardiac output, the goals of ther- not improve clinical outcomes.
apy are aimed at restoring normal physiology. Two large randomized con- Corticosteroids are not without their side effects. These drugs are
trolled trials that included patients with severe sepsis did not demonstrate immunosuppressive, potentially leading to secondary infections and
benefit to raising oxygen delivery to supranormal levels. 115,150 However, impaired wound healing, and additionally can cause myopathy, hyper-
these studies did not target the initial 6 hours of resuscitation where glycemia, and hypernatremia, 167,169,170 thus corticosteroids should be
hemodynamic goals are different than the latter stages of severe sepsis.
discontinued as early as possible. However, to date there has not been
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Dobutamine: Dobutamine is the inotrope most studied in severe sepsis/ any study comparing a fixed duration of steroids followed by tapering of
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septic shock. It is an adrenergic agonist that stimulates β1- and drug over several days 167,169 or abrupt discontinuation versus tapering
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β2-adrenergic receptors. β-Adrenergic stimulation is also associated with therapy after shock resolution, and so it remains uncertain whether
an increase in splanchnic perfusion. Many studies have evaluated the outcome is affected by tapering or not of steroids.
Many of these studies found an increase in cardiac index with an increase ■ SEPSIS BUNDLES
effect of dobutamine in patients with severe sepsis/septic shock.

93,151-153
in stroke volume and heart rate. It is recommended as the first choice ino- The last decade has seen an increasing application of care bundles
trope for patients with measured or suspected low cardiac output in the as part of sepsis management. A study by Rivers et al emphasized
presence of adequate left ventricular filling pressure and adequate MAP. the time-critical nature of sepsis. Their study designed a protocol for
91
Cardiac outputs may vary in patients who remain hypotensive after fluid sepsis management, which started in the emergency room and led to
resuscitation, therefore treatment with a combined inotrope/vasopressor a significant improvement in survival in patients with severe sepsis.
93
is recommended if cardiac output is not measured. 91 Since this milestone, sepsis care bundles have become an integral part
Although dobutamine is recommended as a first line inotrope, many are of the “Surviving Sepsis Campaign,” which aimed to improve survival
reluctant to use it for its adverse effects—notably cardiac arrhythmias and from severe infection by 25% by 2009. This multifaceted intervention
immunosuppression. Phosphodiesterase inhibitors (eg, amrinone was designed to facilitate compliance with selected guideline recom-
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and milrinone) have also been considered in patients with septic shock, mendations, which were “bundled” into two sets to be completed
but presently there is a limited role for these drugs in patients with within 6 hours and 24 hours (Table 64-5). Some factors depend on the

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