Page 835 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

566 PART 5: Infectious Disorders

Cholestasis develops from inflammation of cytokines within hepato- and metabolites in and out of the brain. Compromise to this highly
cytes. The proinflammatory cascade represses hepatobiliary transporter regulated security system causes entry of inflammatory cells and toxic
gene expression. Hepatobiliary transport system is crucial for the uptake metabolites, which leads to neuronal tissue edema, limiting diffusion
and excretion of bile acids and so disruption in this process can result and oxygenation utilization. Astrocytes are important in inducing the
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in sepsis-associated cholestasis. blood-brain barrier properties and their damage will cause increased
■ KIDNEY DYSFUNCTION permeability. Astrocytes have receptors for inflammatory mediators. In
human astrocyte cultures, recombinant human gamma interferon and
The hypoperfusion state of sepsis with systemic vasodilatation can also IL-1β induce the formation of reactive oxygen intermediates that are
toxic, allowing vulnerability to free radical injury and hypoxic injury.
cause poor perfusion to the kidney, resulting in acute kidney injury
(AKI). Fifty percent of AKI in the intensive care unit (ICU) is caused Damaged astrocytes will impair the regulation of local blood flow and
the synaptic activity of neurons.
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by sepsis and the incidence rises with the severity of sepsis. Twenty-
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with septic shock develop AKI. Renal hypoperfusion can occur even ■ ENDOCRINE DYSFUNCTION
three percent of patients with sepsis have AKI and 51% of patients
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in the absence of severe hypotension, especially in high-risk patients It is well known that acute illness and injury results in insulin resistance
with baseline renal dysfunction. Aggressive fluid resuscitation can and consequential hyperglycemia. Critical illness is associated with
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cause capillary leaks that lead to tissue edema in the abdomen that increases in many counterregulatory hormones (glucagon, epinephrine,
can further impede blood flow to the kidneys. Decreased renal func- growth hormone) and cytokines (TNF-α, IL-1) resulting in a sustained
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tion has been associated with a 6.5-fold increase in odds of death. 43,44 increase in plasma glucose despite hyperinsulinemia. 54,55 Resultant
Those who require renal replacement therapy (RRT) have a mortality hyperglycemia can have significant side effects such as impaired
rate of 50% to 80%. 45 wound healing, vascular and endothelial dysfunction, and increased
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■ HEMATOPOIETIC CELL DYSFUNCTION proteolysis. Intensive insulin therapy has been shown to beneficially
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affect innate immunity by preventing catabolism and lactic acidosis,
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IL-6 and TNF-α decrease iron in the blood due to stimulation of ferritin exerting anti-inflammatory effects 59-61 and protecting endothelial and
synthesis, resulting in a decrease tissue iron release and consequential fall hepatocyte mitochondrial function. 63
in soluble transferring receptors, which are needed to stimulate erythroid Thyroid hormones regulate energy expenditure and orchestrate
growth. Inflammatory cytokines increase hepcidin expression, which metabolism. Early in acute stress, triiodothyronine (T3) rapidly declines.
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causes decreased absorption of iron from the intestine and diverts iron to Low T3 levels remain even after thyroid-stimulating hormone (TSH)
storage sites like the reticuloendothelial system (RES) and the liver. This normalizes, a condition called low T3 syndrome. Low T3 decreases the
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causes a decline in serum iron concentrations and transferrin saturation, pulsatile release of TSH, causing low levels of thyroxine (T4).
which results in decreased erythroid formation and shortened survival of Hillenbrand reported that adipokines and resistin, produced by
red cells. 47,48 Given that oxygen is transported by hemoglobin, decreased adipose tissue and macrophages respectively, contributed to insulin
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red blood cell production and cell life directly impact oxygen-carrying resistance in septic patients. The hypothalamic corticotropin-releasing
capacity to vital organs. This has a profound effect on oxygenation and hormone (CRH) stimulates the pituitary for release of adrenocortico-
perfusion, which can lead to multiorgan failure. tropic hormone (ACTH) and corticotropin, which trigger the adrenal
Endothelial cells and megakaryocytes, which are precursors to platelets, cortex to produce cortisol. Cortisol levels are usually increased in
come from the same bone marrow progenitor cells. Also, they share the early phase of sepsis and cause an increase in the release of CRH
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the same transcriptional and gene expression pathways such as von and ACTH. Elevated cortisol shifts carbohydrate, protein, and fat
Willebrand factor. There is a strong interplay of communication between metabolism to allow immediate energy availability to vital organs. Both
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endothelial cells and platelets. Platelets release signaling pathways to systemic and neural pathways activate the hypothalamic-pituitary
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the endothelium through cytokines like IL-1, transforming growth adrenal axis. Several studies have revealed that septic patients have
factor (TGF), and platelet-derived growth factor (PDGF). Conversely, elevated baseline cortisol levels and a lower cortisol response to ACTH
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endothelial cells can inhibit or promote platelet activation through NO or simulation test causing a relative adrenal insufficiency. This relative
PAF. Miscommunication between these cells can lead to thrombocytope- adrenal insufficiency has been associated with an increased length of
nia, which has an incidence of 35% to 59% in septic patients. 49 ICU and hospital stay. 65
■ CENTRAL NERVOUS SYSTEM DYSFUNCTION DIAGNOSIS, PROGNOSIS, AND MONITORING
encephalopathy. It is the most common form of encephalopathy in ■ PATIENT PRESENTATION AND DIAGNOSTIC APPROACH
Seventy percent of patients with severe sepsis develop septic
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ICU patients, associated with increased morbidity and mortality. The Patients can present in a myriad of ways with sepsis, and thus clinicians
symptoms vary from mild confusion, agitation, and delirium to stupor must have a high index of suspicion for infections that may cause sepsis
and coma. Originally septic encephalopathy was thought to be due as well as for the condition itself. The most systematic way to diagnose
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to the presence of microorganisms or toxins in the blood. However, sepsis is to determine the SIRS criteria on all patients. Many patients
microorganisms and toxins have not been isolated from many septic may have subtle findings and various combinations of the SIRS criteria,
patients. The exact mechanism in septic encephalopathy in humans is presenting with mild leukocytosis and tachypnea, or mild tachycardia
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unknown, although alterations in neurotransmitters and their receptors and fever or often overlooked hypothermia. During the initial evalua-
are being investigated. Chronic LPS exposure in hippocampal cells has tion of the patient, the patient should be evaluated for the SIRS criteria
been found to increase the hippocampus production of IL-1bβ, and and then clinically assessed for any evidence or suggestion of infection.
IL-1β-dependent IL-6 levels, which effects the neuronal and synaptic Patients can present in profound septic shock with an occult infec-
function that could contribute significantly to cognitive disturbances. tion. Severe sepsis can be easily missed on admission. Patients can be
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Altered iNOS expression disrupts glutamatergic neurotransmission, admitted to a general hospital floor and acutely decompensate, requiring
expression, and function leading to behavioral changes in rat models. emergent ICU transfer.
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Septic encephalopathy likely arises from brain injury from inflammatory The first step in both diagnosing and managing a patient with sepsis
mediators and the brain cells’ cytotoxic response to these mediators. 50 is a complete history and physical examination. The vital signs pro-
Tight junctions between endothelial cells make up the blood-brain vide important information on the systemic nature of the infection
barrier, which regulates the uptake and efflux of nutrients, toxins, and the overall condition of the patient. Clinicians are like detectives,

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