Page 577 - ACCCN's Critical Care Nursing

554 P R I N C I P L E S A N D P R A C T I C E O F C R I T I C A L C A R E

important adjunct in managing the acute shock phase, Drotrecogin alfa-activated (rhu), a recombinant form
other drug therapies remain controversial. of activated protein C, was developed using DNA
recombinant technology as a treatment for sepsis. Previ-
Inotropes and vasopressors ous drug trials had targeted particular aspects of the host
response to sepsis but had not yielded positive results.
A goal of maintaining MAP greater than 65 mmHg is Preclinical studies devised dose-dependent reductions in
common, with inotropes and vasopressors commenced the markers of fibrinolysis (D-dimer) and inflammation
when fluid resuscitation is considered adequate. Ad mini- (Interleukin 6) leading to a Phase III clinical trial which
stration of these drugs requires continuous blood pres- resulted in drotrecogin alfa-activated rhu being the first
sure monitoring and enables effective titration to meet drug approved for the treatment of severe sepsis. The
the treatment goal. Australian practice preferences published phase III trial was a large multi-centre, double-
noradrenaline (for its specific alpha-receptor effects) and blind randomised controlled trial (PROWESS); this
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adrenaline as the vasopressors of choice. Dobutamine landmark study was the first drug trial to demonstrate a
(2.5–10 mcg/kg) is often added to support patients positive result in the treatment of severe sepsis. PROWESS
with myocardial dysfunction to increase myocardial was conducted in 11 countries with the hypothesis that
90
contractility and oxygen delivery to the tissues. Refrac- administration of drotrecogin alfa at 24 mcg/kg/min for
tory hypotension, resistant to vasopressors, has been 96 hours would reduce 28-day all-cause mortality in
linked to downregulation of receptors. Vasopressin (0.4– patients with severe sepsis, with an acceptable safety
0.6 units/hour) has been shown to reduce the require- profile.
ments of other vasopressor agents.
Controversy followed publication of the PROWESS
Administration of arginine vasopressin in vasodilatory paper and licensing of drotrecogin alfa. A further study,
shock may help maintain blood pressure despite the ADDRESS, mandated by the Food and Drug Administra-
relative ineffectiveness of other vasopressor hormones. tion in the USA to investigate the effect of the drug on
99
Specifically, arginine vasopressin may inactivate the KATP patients with a low risk of death, was stopped prema-
channels and thereby lessen vascular resistance to nor- turely due to futility and an increased risk of significant
adrenaline and angiotensin II. It also decreases the bleeding. Studies on children were also stopped due to
synthesis of nitric oxide (as a result of a decrease in the unacceptable risk profile. An open label trial,
the expression of nitric oxide synthase) as well as cyclic ENHANCE, was then conducted to replicate the results
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guanosine monophosphate (cGMP) signalling by nitric of PROWESS; the Australian data indicated that depend-
99
oxide. The sites of major arterial vasodilation in sepsis ing on the selection criteria used, up to 8% of patients
– the splanchnic circulation, the muscles and the skin may be eligible for treatment with drotrecogin alfa (acti-
– are vascular beds that contain abundant arginine vated). Evidence for use remains equivocal. Use is cur-
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vasopressin receptors. In sepsis, vasopressin stores are rently rare and where used in severe sepsis, preparation
quickly depleted. Administration of exogenous arginine and administration requires additional education and
vasopressin (0.04–0.06 units/min) can raise blood pres- continual assessment and specific attention to signs of
sure by 25–50 mmHg by returning plasma concentra- bleeding including cerebral haemorrhage.
tions of antidiuretic hormones to their earlier high
levels. 99
Other adjuncts
Steroids Adequate nutritional support to offset high caloric and
protein demands is relevant with enteral feeding pre-
The use of steroid therapy in severe sepsis remains con- ferred. Translocation of gut bacteria due to splanchnic
troversial. At times, steroid replacement therapy may be hypoperfusion and increased permeability is a factor in
used when patients display resistance to increasing doses secondary septic insults and stress ulceration. Equally
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of adrenergic agonists, i.e. adrenal insufficiency. Some important to patient-specific measures is institution of
research indicates that patients with septic shock that are diligent infection control practices in ICU. For more
117
unable to increase cortisol levels in response to a chal- information on organ support refer to the relevant chap-
lenge may benefit from administration of low-dose cor- ters in Section II and Chapter 21.
ticosteroids (see Chapters 19 and 21 for further
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information).
ANAPHYLAXIS
Recombinant human activated protein C Anaphylaxis is the most severe, potentially life-threatening
118–121
Activated protein C is a plasma protease produced in form of an allergic reaction, usually as a type I hyper-
response to thrombin formulation. Actions of activated sensitivity classification (IgE-mediated hypersensitiv-
121
120
protein C include: ity). Anaphylaxis appears rare, although data are
sporadic in the literature; 0.01–0.02% of the general pop-
121
● decreased inflammation through reduced levels of ulation is affected. Anaphylaxis appears more common
TNFα and NFKβ in Western countries, but this may be related to more
122
● decreased thrombin production leading to thorough reporting mechanisms. The prevalence of
anticoagulation allergy with anaphylaxis has been documented as high as
● profibrinolytic action through modulation of fibrino- 7% in one Australian study of children, with insect stings,
lysis inhibitors. oral medications or food the most often cited causes.