Loss of IQ in the ICU brain injury without the insult
Introduction
Increasingly, the quality of one’s life has become the coin of trade compared to survival alone [1]. Recent evidence suggests that critical illness may pose a significant risk for long-term declines in cognitive functioning and has the potential to severely impact the quality and independence of one’s life. Accumulating data has linked critical illness to significant losses in cognitive ability (including loss of IQ), which unfortunately appear in many cases to be permanent [2], [3], [4], [5], [6], [7], [8], [9], [10]. Although the total number of hospital beds has been reduced in the United States over the last 15 years, the number of critical care beds has increased by 26% with the majority of this increase accounted for by the elderly [11]. With the burgeoning number of older individuals in the current population, and the high percentage of elderly admitted to the ICU, this public health issue has become of vital importance. Unfortunately, it is only in the last decade that researchers and clinicians have begun to document the neurocognitive decline associated with this vulnerable population, despite neurologic dysfunction having been studied extensively for other conditions such as coronary artery bypass grafting (CABG) [12]. Other lines of evidence suggest that CNS degradation is not only linked to cognitive loss and declines in quality of life, but is also an independent predictor of mortality in the ICU [13].
Although the exact mechanism or mechanisms by which ICU-related neurological degradation occur remain under investigation, it appears likely that the development of delirium, i.e. an acute cerebral dysfunction, is a major precursor to post-ICU cognitive decline. Recent advances in the study of Alzheimer’s disease (AD) offer a potential new lens from which to conceptualize ICU-related cognitive deficits. In a series of studies, Buckner and colleagues employed multi-modal neuroimaging techniques to examine neuro-molecular (amyloid protean plaque formation) signatures of Alzheimer’s disease [14]. They then observed that plaque formation overlapped with metabolic changes (hypoactivation) and grey matter atrophy in the medial temporal/hippocampal region (MTL), posterior parietal cortex (PPC) and dorsal prefrontal cortex (PFC). Not surprisingly, grey matter degradation in these regions was also observed to correlate with functional blood oxygen level dependent (BOLD) declines in activation for these known mnemonic regions, while engaged in memory tasks. These regions are anatomically and functionally connected [15], [16] and are hypothesized to be critical for maintaining a normal and clear sensorium [16], [17], [18], [19].
Other evidence suggests that the brain’s primary arousal mechanism, the ascending reticular activating system (ARAS) may also play an important role in the modulation of delirium [20]. Excitatory projections originating in the myelencephalon innervate the midbrain and cortex directly and are hypothesized to be critically involved in general attention [20], [21]. As many anesthetic and sedative agents are believed to act on the brainstem, it is possible that perturbation of the ARAS may lead to fluctuating arousal, sensorium, attention and executive functioning ability [9]. Excitatory myelencephalic afferents may therefore be involved in maintaining an equilibrium between top down regulation via cortical structures and bottom up arousal levels originating in the brainstem (see Fig. 1). For older individuals, transient interference in either or both areas could have the potential for major neurocognitive disruption. Gross longitudinal changes in brain physiology are known to impact metabolic cellular mechanisms [14], [22], [23]. If such changes persist for a sufficient length of time, either hyper or hypo metabolic modifications could lead to apoptosis and neuronal degradation. Once again, patients with prior CNS deterioration or insults may be particularly at risk for the hypothesized mechanism depicted in Fig. 1.
Section snippets
Hypothesis
In healthy individuals there is normal and consistent connectivity between the PPC, MTL and PFC [16], [17], [18], [19] (see Fig. 1). This circuit is innervated, activated and maintained by the ARAS arising from the brainstem via the thalamus [14], [20]. As elderly individuals begin to show signs of grey matter atrophy in these regions, functional connectivity remains intact [20]; however, the strength of the connections is no longer as robust as it once was in the healthy CNS [16], [17], [18],
Evaluation of the hypothesis
This hypothesis could be tested using fMRI to examine functional connectivity between the MTL, PPC and PFC in elderly individuals with and without the APOE-ε4 genotype [32]. If this hypothesis is correct, those possessing the genetic risk of the APOE-ε4 should show a relative lower strength of functional connectivity between the three regions of interest compared to controls without the APOE-ε4 genotype. For this design, investigators would also need to document that other anatomically
Consequences of the hypothesis
If these hypotheses are true it would suggest several alternative modes of practice in ICU settings. For example, pharmacologic regimes could be optimized to minimize the perturbation of the ARAS for individuals at risk for the development of ICU delirium (e.g. avoiding the administration of benzodiazepines). If time permitted, individuals could also be screened to determine whether or not they possess the genetic risk of APOE-ε4 and could be administered alternative agents in order to help
References (35)
Neurocognitive dysfunction after coronary artery bypass surgery: a systematic review
J Thorac Cardiov Sur
(2000)- et al.
Long-term neurocognitive function after critical illness
Chest
(2006) - et al.
Cytology and functionally correlated circuits of human posterior cingulate areas
Neuroimage
(2006) A longitudinal study of brain morphometrics using quantitative magnetic resonance imaging and difference image analysis
Neuroimage
(2003)Normal human aging: factors contributing to cerebral atrophy
J Neurol Sci
(1997)- et al.
Sedative and analgesic medications: risk factors for delirium and sleep disturbances in the critically ill
Crit Care Clin
(2006) Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory
Cell
(2006)- et al.
Assessing neurocognitive outcomes after critical illness: are delirium and long-term cognitive impairments related?
Curr Opin Crit Care
(2006) Delirium-O-Meter: a nurses’ rating scale for monitoring delirium severity in geriatric patients
Int J Geriatr Psych
(2005)- et al.
Delirium: acute cognitive dysfunction in the critically ill
Curr Opin Crit Care
(2005)
Delirium in an intensive care unit: a study of risk factors
Intens Care Med
Evaluation of delirium in critically ill patients: validation of the confusion assessment method for the intensive care unit (CAM-ICU)
Crit Care Med
Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS)
JAMA
Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients
Anesthesiology
The incidence of cognitive dysfunction after ARDS
Am J Resp Crit Care Med
Critical care medicine in the United States 1985–2000: an analysis of bed numbers, use, and costs
Crit Care Med
Cognitive deficits following coronary artery bypass grafting: prevalence, prognosis, and therapeutic strategies
CNS Spectrums
Cited by (31)
Delirium in the Intensive Care Unit
2021, Encyclopedia of Respiratory Medicine, Second EditionDesign and rationale of the “Sedation strategy and cognitive outcome after critical illness in early childhood” study
2018, Contemporary Clinical TrialsThe role of predictive coding in the pathogenesis of delirium
2017, Medical HypothesesDelirium: An emerging frontier in the management of critically ill children
2011, Anesthesiology ClinicsCitation Excerpt :Gamma aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system (CNS).79 Global and persistent inhibition of CNS arousal through GABAergic stimulation may cause disruption in cerebral functional connectivity and lead to unpredictable neurotransmission causing a constellation of acute brain dysfunction and LTCI.25,89,90 Many common sedatives used in the ICU setting, like benzodiazepines and propofol, have high affinity for the GABAergic receptors and contribute to delirium through interference in sleep patterns and production of a central-mediated acetylcholine deficient state.79,83,85
Delirium in the Intensive Care Unit: A Review
2011, Neurologic ClinicsCitation Excerpt :Studies of pathophysiology to date have involved brain modifications via neuroimaging, inflammation and sepsis, genetics, and the role of biomarkers and neurotransmitters. Little work has been done on the neuroimaging of delirium, though early evidence suggests that delirium may be caused by diffused brain dysfunction rather than localized disruption.34,35 Two studies have demonstrated decreased cerebral blood flow in multiple areas of the brain in studies of delirious patients.36,37
Hypothesis for the pathophysiology of delirium: Role of baseline brain network connectivity and changes in inhibitory tone
2011, Medical HypothesesCitation Excerpt :In delirium both the quantity and quality of experience is disturbed and the hypothesis suggests that this disturbance results from altered connectivity within cortical and corticothalamic networks. An important role for the breakdown in functional connectivity has already been proposed for delirium [8], however in this paper the role of inhibitory tone is highlighted as the mechanistic lever that breaks down effective connectivity to produce the disturbed state of consciousness that occurs in delirium. Indeed increased GABA release has already been hypothesized to play an important role in loss of consciousness occurring during non-rapid eye movement sleep (by reducing network connectivity) [9].