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CHAPTER 15: Long-Term Outcomes After Critical Illness 113

trials plus a wake up and breathe protocol that interrupts and reduces CAREGIVER AND FAMILY BURDEN IN CRITICAL ILLNESS
sedative exposure compared to spontaneous breathing trials alone.
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Neurocognitive impairments were less common in the group that received More recently, some researchers have begun to focus on the importance
the wake up and breathe intervention at 3 months but not at 12-month of caregiver outcomes and their interaction with those of ICU survivors
follow-up. There was no difference in symptoms of depression and post- to understand the effect of critical illness on the family unit. There is a
traumatic stress disorder or neurocognitive function between the two considerable body of work evaluating these interactions in other medi-
groups at 3 and 12 months. 210 cal conditions. As one example, there is a well-developed literature in
A number of medications routinely administered in the ICU have stroke and elderly care giving. These data show that caregivers who are
known effects on neurotransmitters including acetylcholine, dopamine, challenged in their care-giving role may contribute to poor rehabilita-
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serotonin, γ-aminobutyric acid (GABA) glutamate, and norepineph- tion outcomes for survivors or threaten the ability to sustain care at
rine. Medications such as tricyclic antidepressants, H blockers, opiates, home. 236,237
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furosemide, benzodiazepines, and others have central anticholinergic Recent work indicates that 57% of ICU survivors who received long-
properties. A relative excess of dopamine is a risk factor for delirium term mechanical ventilation required the assistance of a family caregiver
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and GABA abnormalities contribute to hepatic encephalopathy and 1 year after their critical illness. Existing evidence suggests that pro-
delirium. 213 viding such care may have a deleterious impact on caregivers, and may
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It may be that the effects of medications on cognition are mediated compromise HRQoL compared with age- and sex-matched persons.
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by genetic factors, with one of the probable genetic factors in drug sen- In addition, there have been reports of posttraumatic stress disorder,
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sitivity being the apolipoprotein E4 (APOE4) allele. The APOE4 allele emotional distress, 8,238-240 burden, depression, and anxiety. 241
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has been shown to be a significant risk factor for the development of In a review article, Johnson concluded that caregivers experience
certain forms of dementia, increased risk for greater hippocampal burden due to the patient’s physical and psychological dysfunction
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atrophy, worse recovery of neurological function following traumatic and the challenges of managing complex care in the home. Lifestyle
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brain injury, neurocognitive decline following cardiopulmonary disruption and provision of high levels of care also contribute to poor
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bypass surgery, and delirium. While more research is needed, caregiver outcome. 8,243 This area of research is limited by its predomi-
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certain anticholinergic agents may have particularly adverse effects nantly cross-sectional design and limited follow-up to 1 year after hospi-
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on cognition when used with patients possessing the APOE4 carriers. tal discharge. In addition, there is a deficiency in our knowledge about
For example, lorazepam—commonly used in ICU settings—increases how caregiver health outcomes change over time.
susceptibility to impaired verbal learning and related neurocognitive
deficits in patients with APOE4 when compared to those without this
polymorphism. 219 TREATMENT—EARLY MOBILITY AND REHABILITATION
Inflammation and Sepsis One important potential cause of neurocognitive A major limitation in constructing rehabilitation programs after critical
morbidity is cytokines and inflammation such as occurs during sepsis. For illness is our inability to risk stratify our patients. Risk stratification is
example, induced cytokine activation in healthy male volunteers by intra- a fundamental principle employed by other disciplines to devise robust
venous injection of Salmonella abortus equi endotoxin resulted in increased treatment approaches. The field of cardiology has a detailed understand-
anxiety, depressed mood, and impaired memory that correlated with cyto- ing of pathogenesis of the disease process and therefore has been able to
kine secretion. Inflammation and elevated cytokine levels are also related construct detailed critical pathways that vary depending on the nature
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to cognitive impairments associated with chronic fatigue. Neural lesions and risk of presenting signs and symptoms. They have devised tools
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in septic patients include necrosis of cerebral white matter, basal ganglia, for stratification that are inexpensive (eg, ECG), accessible, reliable,
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and cortical infarcts. Sepsis and inflammation can decrease blood flow, and which are correlated/validated with both clinical and biochemical
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resulting in reduced cerebral blood flow and hypoxia. 224 markers. Most importantly, they have interventions that are responsive
The brain is immunologically active and is influenced by systemic to level of risk and that change measureable outcome.
inflammatory reactions and responses, such as those that result ICUAW and the other sequelae of critical illness have none of these. We
from systemic illness and sepsis. These inflammatory responses fundamentally lack a detailed understanding of the pathophysiology and
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are mediated by cytokines that penetrate the blood-brain barrier long-term outcome of this lesion. We do not have robust critical pathways
and directly or indirectly modulate brain activity. Neurocognitive nor reliable tools to elucidate risk. We do not understand the spectrum of
dysfunction is associated with inflammation. Endotoxin-induced rehabilitative potential across our varied critically ill patient population.
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inflammation and cytokine activation in healthy volunteers result in This latter point is crucial because inherent to the process of surveillance
impaired learning and memory. Further animal models of sepsis is the assumption that identification and categorization of the disease will
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find elevated interleukin-1 (IL-1) and IL-6 in the hippocampus and lead to the application of an intervention that will improve outcome.
prefrontal cortex, and rodents with sepsis are impaired in tasks of The heterogeneity of critically ill populations is an important barrier
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learning and memory. In humans with sepsis, a long-term outcome that needs to be addressed to be able to understand differences in func-
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study found sepsis survivors had neurocognitive impairments several tional outcome across different patient groups and the various factors
years after hospital discharge. There is considerable evidence show- that appear to drive a broad spectrum of outcome. In reference to the
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ing that inflammation and oxidative damage directly or indirectly, earlier discussion about clinical phenotypes, there is clearly an enor-
due to free radical production and reactive oxygen species, can lead to mous difference in functional outcome between relatively young sur-
brain damage in humans following ischemia, traumatic brain injury, vivors of ARDS compared to older chronically critically ill patients
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and Alzheimer’s disease. Animal models have shown that a number despite the apparent similarities of severity of illness and a protracted
of antioxidants prevent brain injury through a variety of cellular ICU length of stay. The young, previously working, lung injured group
mechanisms. 229,230 had few comorbid disorders, very low mortality after ICU discharge, and
Other mechanisms of brain injury associated with sepsis include a significant, albeit less than predicted, improvement in functional status
nitric oxide, cytokines, and prostaglandins modulating brain neu- to 1 year and with virtually all returning to independent living. This is
rotransmitter systems. At the intracellular level immune activation in stark contrast to an older group of chronically critically ill patients
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inhibits mitochondrial respiration and releases cytotoxic agents such with a significant burden of comorbid disease, with a 44% mortality at
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as calcium and reactive oxygen species. Multiple factors associated 1-year after ICU discharge and only 11% achieving a good (alive with no
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with sepsis can trigger neuronal apoptosis including ischemia, anoxia, functional dependency) outcome.
glial activation, TNF-α, IL-1β, interferon, and nitric oxide. 222-225 For a Current interventional work has focused on early mobility, which has
review of sepsis associated brain injury, see Sharshar et al. 234 been shown to be safe and feasible and to alter short-term outcome in
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