|
| A) | Vision only | ||
| B) | Executive function | ||
| C) | Autonomic stability only | ||
| D) | Peripheral motor reflexes only |
Before studying any process seen as "abnormal," it is important to understand what "normal" looks like and how a state of normalcy is measured. This is particularly important in POCD, when the area affected is neither anatomic nor pathophysiologic, but an acute and/or chronic degradation of what is referred to as executive function. In order to understand the devastation that may accompany POCD, it is important to understand the concept of executive function. Each day, individuals go about usual activities of daily living in the midst of a conscious state using what is referred to as executive function [1,2,3]. As we are insensitive to the air that surrounds us, so we are insensitive to executive functioning each day. Both air and executive function have another thing in common: if either one goes bad or missing, it instantly becomes a priority. Baddeley noted this first in 1983 through a term he referred to as "working memory" [1]. He described this as a "temporary storage of information" that was transactional in nature (i.e., used to get things done).
| A) | Basic brainstem reflexes (e.g., pupillary light reflex) | ||
| B) | Cerebral blood flow autoregulation over a specified blood pressure range | ||
| C) | Physiologic stability (e.g., heart rate and blood pressure) during anesthesia | ||
| D) | Instrumental activities of daily living (IADLs) and other goal-directed activities |
Since Baddeley's description in 1983, other researchers have sought to further hone this concept. Their research reflects the fact that executive function is inextricably linked to brain physiology, and the determination of the specific neuroanatomic sites in which these physiologic interactions take place, thus allowing executive function to occur. Executive function is defined as functions necessary to successfully complete instrumental activities of daily living (IADLs) (e.g., grocery shopping, public transportation use, work- or school-related tasks) and are essential for completion of goal-directed behavior [3]. Okutemo and Nakamura have a useful description of executive function [4]:
Experts identify three main areas: working memory, inhibitory control and cognitive flexibility. Indeed, when we want to do something, whether it is solving a math exercise, making a declaration of love, learning to play the piano or learning a dance step; we need three so-called executive skills: we need a good working memory, which allows us to keep information in memory and organize it; a good inhibitory control, which allows us to inhibit distractions to stay focused, to control our impulses, our emotions, or inappropriate actions; and finally, we need cognitive flexibility, to be creative and adjust our strategies in case of mistakes.
| A) | Attention, orientation, and recognition | ||
| B) | Sedation, hypnosis, and autonomic stability | ||
| C) | Working memory, inhibitory control, and cognitive flexibility | ||
| D) | Complement activation, cytokine release, and microtubule formation |
Executive function therefore hinges on these three linchpins: good working memory, good inhibitory control, and cognitive flexibility [4]. POCD's primary manifestation is impaired executive function in the postoperative patient. One can easily see the problems arising in patients with POCD secondary to the degradation of any or all these three crucial faculties.
| A) | Wechsler Memory Test (WMT) | ||
| B) | Mini-Mental State Exam (MMSE) | ||
| C) | Computed tomography (CT) | ||
| D) | Electroencephalography (EEG) |
It is clear that the concept of executive function is both real and measurable. For various reasons, executive function may be degraded, temporarily or permanently, in large groups of patients, some unrelated to surgery. Therefore, clinicians require techniques and tools to measure the degree of degradation of this function. A review of all available neuropsychologic tests is beyond the purview of this course; however, the most common is the Mini-Mental State Exam (MMSE). The MMSE is a bedside evaluation tool that can be used to help evaluate patients with suspected executive function degradation [10]. It was invented in 1975 to provide a quick indication of cognitive function, with the authors noting that it can be administered in as little as 5 to 10 minutes [10]. Since its release in the 1970s, the tool has been used across populations and cultures, as well as in the presence of many types of organic and injury-induced central nervous system trauma [11]. The maximum score one can receive on the test is 30 points, and any score greater than 24 is considered "normal" [11]. In the original study, researchers reported scores of 20 or less only in patients with dementia, delirium, schizophrenia, or affective disorder—not in healthy older adults or in patients with a primary diagnosis of neurosis and personality disorder [10]. As this course progresses, please keep these numbers in mind as indicators of the degree of executive functioning, with a score of 20 or less seen as indicative of diminished function.
| A) | 5–10 | ||
| B) | Less than or equal to 20 | ||
| C) | Greater than 24 | ||
| D) | Greater than 90 |
It is clear that the concept of executive function is both real and measurable. For various reasons, executive function may be degraded, temporarily or permanently, in large groups of patients, some unrelated to surgery. Therefore, clinicians require techniques and tools to measure the degree of degradation of this function. A review of all available neuropsychologic tests is beyond the purview of this course; however, the most common is the Mini-Mental State Exam (MMSE). The MMSE is a bedside evaluation tool that can be used to help evaluate patients with suspected executive function degradation [10]. It was invented in 1975 to provide a quick indication of cognitive function, with the authors noting that it can be administered in as little as 5 to 10 minutes [10]. Since its release in the 1970s, the tool has been used across populations and cultures, as well as in the presence of many types of organic and injury-induced central nervous system trauma [11]. The maximum score one can receive on the test is 30 points, and any score greater than 24 is considered "normal" [11]. In the original study, researchers reported scores of 20 or less only in patients with dementia, delirium, schizophrenia, or affective disorder—not in healthy older adults or in patients with a primary diagnosis of neurosis and personality disorder [10]. As this course progresses, please keep these numbers in mind as indicators of the degree of executive functioning, with a score of 20 or less seen as indicative of diminished function.
| A) | By increasing neuronal sodium entry to promote action potentials | ||
| B) | By lowering neuronal membrane potential so more input is required for neurons to fire | ||
| C) | By causing permanent focal lesions that stop synaptic neurotransmitter release | ||
| D) | By increasing neuronal resting voltage so fewer impulses are needed to fire |
The purpose of anesthetics is to render the patient unresponsive to surgical stimulus and induce a hypnotic state of unconsciousness, while also maintaining autonomic stability during the conduct of the surgical or diagnostic procedure. The primary way in which this occurs is through the lowering of the electrical membrane potential (or voltage) of the neuron. In the classical view of neurophysiology, neurons communicate by passing neurotransmitters across a synapse [12]. This release is caused by an electrical stimulation to the neuron, called an action potential. These action potentials occur when the millivolts inside the neuron reach the threshold, resulting in the entry of cations into the neuron and the establishment and propagation of an electric "spark" down the axon of the neuron [12]. Anesthetics lower voltage inside the neuron, so more and more impulses are required to cause the neuron to fire. With enough anesthesia, the neuron can be completely inhibited from firing or it can be inhibited enough to prevent consciousness [12,13,14,15,16,17].
| A) | Inhibiting sodium channels as its primary mechanism | ||
| B) | Blocking NMDA receptors to prevent excitatory cation entry | ||
| C) | Acting primarily as an agonist at potassium channels to drive potassium efflux | ||
| D) | Enhancing GABAA receptor activity to increase chloride influx and reduce neuronal firing |
Propofol is nearly universally used for both the induction and maintenance of general anesthesia [13,17]. Induction is the process whereby an intravenous bolus dose of propofol quickly renders the patient unconscious. A period of less than 30 seconds from injection to unresponsiveness is not uncommon. Propofol acts on a specific binding site on gamma-amino butyric acid proteins (i.e., type A or GABAA) on the surface of neurons in the brain [18]. These proteins act as channels that allow the passage of chloride ions from the plasma into the interior of the neuron. As chloride ions are negatively charged (anions), they lower the membrane potential inside the cell. This makes the cell less likely to generate an action potential, and less likely to send impulses to other brain cells. When enough neuronal transmissions are inhibited, classical brain theory states that unconsciousness occurs [16]. Note that this inhibition occurs along a continuum, where smaller doses of the agent lead not to unconsciousness, but sedation (response to a voice while feeling unconcerned). This continuous spectrum of effects impacts executive function. In small doses, executive function is diminished, but still in effect. For example, a patient may receive a local anesthetic technique resulting in the numbing of an arm or leg. In order to diminish the anxiety associated with such a technique, patients may receive a continuous intravenous infusion of a low dose of propofol [17]. They will still respond to questions, take deep breaths when requested, and move other unblocked extremities in response to a verbal command. Propofol wears off in a fashion that inversely mirrors its onset; patients awaken extremely rapidly when the agent is discontinued [13]. Further, they have no hangover effect, such as that seen with barbiturate agents; indeed, they seem to have a feeling of well-being upon awakening, and some have reported feelings of euphoria [19].
| A) | Analgesia without impairment of executive function | ||
| B) | A prolonged "hangover" effect similar to barbiturates | ||
| C) | Sedation with response to voice and a feeling of unconcern | ||
| D) | Permanent inhibition of neuronal firing due to structural brain injury |
Propofol is nearly universally used for both the induction and maintenance of general anesthesia [13,17]. Induction is the process whereby an intravenous bolus dose of propofol quickly renders the patient unconscious. A period of less than 30 seconds from injection to unresponsiveness is not uncommon. Propofol acts on a specific binding site on gamma-amino butyric acid proteins (i.e., type A or GABAA) on the surface of neurons in the brain [18]. These proteins act as channels that allow the passage of chloride ions from the plasma into the interior of the neuron. As chloride ions are negatively charged (anions), they lower the membrane potential inside the cell. This makes the cell less likely to generate an action potential, and less likely to send impulses to other brain cells. When enough neuronal transmissions are inhibited, classical brain theory states that unconsciousness occurs [16]. Note that this inhibition occurs along a continuum, where smaller doses of the agent lead not to unconsciousness, but sedation (response to a voice while feeling unconcerned). This continuous spectrum of effects impacts executive function. In small doses, executive function is diminished, but still in effect. For example, a patient may receive a local anesthetic technique resulting in the numbing of an arm or leg. In order to diminish the anxiety associated with such a technique, patients may receive a continuous intravenous infusion of a low dose of propofol [17]. They will still respond to questions, take deep breaths when requested, and move other unblocked extremities in response to a verbal command. Propofol wears off in a fashion that inversely mirrors its onset; patients awaken extremely rapidly when the agent is discontinued [13]. Further, they have no hangover effect, such as that seen with barbiturate agents; indeed, they seem to have a feeling of well-being upon awakening, and some have reported feelings of euphoria [19].
| A) | GABAA receptor | ||
| B) | Glycine receptor | ||
| C) | N-methyl-D-aspartate (NMDA) receptor | ||
| D) | Nicotinic acetylcholine receptor (nAChR) |
Ketamine is a dissociative anesthetic with a different mechanism of action than propofol. While binding with numerous receptors in the brain, its primary effect derives from binding with and blocking the N-methyl d-aspartate (NMDA) receptor [17]. When activated, these receptors excite the brain by allowing the entry of positive ions (or cations) into neurons, thus moving the resting membrane potential of the neurons closer to threshold, making it easier for the brain to become excited and aroused. Ketamine affects neurons in both the brain and the spinal cord, making both an anesthetic as well as a potent analgesic. Sufficient doses of the agent completely abolish executive function, and even small doses result in altering inhibition and cognitive ability. Indeed, patients receiving ketamine demonstrate markedly reduced executive function, which may continue after emergence from anesthesia. Calvey and Williams have described ketamine's emergence phenomena as such [13]:
During recovery from ketamine anesthesia there is a significant possibility of emergence phenomena, ranging from vivid dreams and visual images to hallucinations and delirium, which occur in about 30% of patients and may continue for 24 hours after administration. These psychotomimetic sequelae may be extremely unpleasant, and it has been suggested that they are related to the misperception or misinterpretation of sensory information, particularly visual or auditory stimuli. Emergence phenomena may be considerably modified by the use of appropriate premedication with opiates or benzodiazepines.
| A) | About 5% and may continue for 72 hours | ||
| B) | About 10% and may continue for one year | ||
| C) | About 30% and may continue for up to 24 hours | ||
| D) | About 52% and may continue for five months |
Ketamine is a dissociative anesthetic with a different mechanism of action than propofol. While binding with numerous receptors in the brain, its primary effect derives from binding with and blocking the N-methyl d-aspartate (NMDA) receptor [17]. When activated, these receptors excite the brain by allowing the entry of positive ions (or cations) into neurons, thus moving the resting membrane potential of the neurons closer to threshold, making it easier for the brain to become excited and aroused. Ketamine affects neurons in both the brain and the spinal cord, making both an anesthetic as well as a potent analgesic. Sufficient doses of the agent completely abolish executive function, and even small doses result in altering inhibition and cognitive ability. Indeed, patients receiving ketamine demonstrate markedly reduced executive function, which may continue after emergence from anesthesia. Calvey and Williams have described ketamine's emergence phenomena as such [13]:
During recovery from ketamine anesthesia there is a significant possibility of emergence phenomena, ranging from vivid dreams and visual images to hallucinations and delirium, which occur in about 30% of patients and may continue for 24 hours after administration. These psychotomimetic sequelae may be extremely unpleasant, and it has been suggested that they are related to the misperception or misinterpretation of sensory information, particularly visual or auditory stimuli. Emergence phenomena may be considerably modified by the use of appropriate premedication with opiates or benzodiazepines.
| A) | Swallowed orally and activated primarily by renal metabolism | ||
| B) | Applied topically and diffusing directly through the skull to the cortex | ||
| C) | Injected intravenously and transported as polar compounds across the blood–brain barrier | ||
| D) | Inhaled as vapor, absorbed from pulmonary capillaries into blood, then delivered via the circulation to the brain |
Since the first public reported use of ether in 1846 by Morton, those using inhaled anesthetic vapors have always known that they work. However, they simply have not been able to figure out how they work [22]. Many theories have been put forth, only to find that some agent does not follow the rules, requiring researchers to rethink their postulations. Broadly speaking, inhaled agents lower the resting membrane potential of neurons, in a fashion similar to the intravenous agents. The halogenated anesthetics are delivered as an inhaled vapor, absorbed into the bloodstream from the pulmonary capillaries, and delivered via the vascular system to the brain [13,23]. Being lipid soluble in nature, they cross the blood brain barrier and come into contact with the neurons. It is at this point that their mechanism of action becomes less clear.
| A) | Opening potassium channels to promote potassium efflux and lower resting membrane potential | ||
| B) | Opening sodium channels to promote sodium influx and raise resting membrane potential | ||
| C) | Blocking chloride entry and moving membrane potential toward threshold | ||
| D) | Destroying synapses to prevent neurotransmitter release |
A channel is simply a large protein that extends through the cell membrane. Once stimulated, specific ions flow through the channel created in the protein—for example, potassium. There are many types of potassium channels throughout the body. The loss of these cations from the interior of the neuron lowers the cell's resting membrane potential. The inhaled agents act to stimulate the TREK-1 and TASK-1 channels, both of which are critical to the efflux of potassium ions. With these two proteins, anesthetics act as agonists: they activate the protein, causing the channels to open.
| A) | A chronic, pre-existing organic condition of cognitive impairment present before surgery | ||
| B) | A brief, normal stage of emergence that lasts 2 to 4 minutes and resolves as the patient fully awakens | ||
| C) | A postoperative decline caused by a single anatomic brain lesion with universally accepted diagnostic criteria | ||
| D) | An acute brain injury in which the patient's mental functions are profoundly degraded and executive function nearly completely absent |
Delirium is a state in which the patient's mental functions are profoundly degraded and executive function nearly completely absent. One of the earliest studies of postoperative delirium characterized the condition as, "an acute brain syndrome characterized by impairment of orientation, memory, intellectual function, and judgment with lability of affect" [31]. This study matched 57 patients not experiencing delirium with 60 who had. The researchers found the principle pathologic states associated with delirium included metabolic imbalance, excessive surgical stress, cardiac failure, infection, intoxication, pre-existing brain disease, and anemia [31]. In the more than 50 years that followed, knowledge about delirium has grown, though not as exponentially as might be imagined.
| A) | Outpatient recovery setting | ||
| B) | Lower baseline cognitive score | ||
| C) | Use of cardiopulmonary bypass pump | ||
| D) | Higher intraoperative cerebral oxygen levels |
Unfortunately, the preponderance of evidence related to POCD after cardiac surgery is still evolving. Two studies show the divergence of opinion on both the cause and the extent of POCD. In the first study. researchers sought to determine the extent to which cerebral hypoxia resulted in POCD [47]. These authors found that cerebral oxygen levels were not predictive of POCD, and their reported rate of POCD was 23%. In a second study, researchers looked at 1,156 patients who had open heart surgery and compared the rates of POCD between the two groups [48]. This was a large, multisite study, in which participants received an extensive neurocognitive evaluation after open heart surgery. In this sample, 581 of the participants had surgery using cardiopulmonary bypass pump, while 575 had off-pump surgery. The neurocognitive scores were measured approximately two days before surgery (baseline) and one year after surgery. In this large sample, the only predictors of POCD were lower baseline cognitive score, older age, lower level of education, and non-White ethnicity [48]. Use of the bypass pump had no effect on score differences. Further, the researchers reported that at one year, the rate of POCD was less than 14% in both sub-samples [48]. This is markedly different from some studies showing levels higher than 30%.
| A) | Both groups had persistently lower MMSE scores at postoperative day 5 compared with baseline. | ||
| B) | General anesthesia produced higher MMSE scores than regional anesthesia on postoperative day 1. | ||
| C) | Regional anesthesia produced lower MMSE scores than general anesthesia on postoperative day 5 only. | ||
| D) | General anesthesia produced significantly lower MMSE scores on postoperative day 1, with no significant differences by postoperative day 5. |
Other researchers sought to determine the extent to which the administration of a general anesthetic would lead to the development of POCD when compared to regional anesthesia [55]. A problem with studies like this is that patients receiving regional anesthesia frequently are moderately to heavily sedated; this study ameliorated that confounding variable by not administering any sedatives before or after the application of the regional anesthetic or during hip replacement surgery. Researchers found that patients receiving general anesthesia had significantly lower MMSE scores on postoperative day one than both the scores on their own baseline, as well as when compared to the scores of the regional anesthesia group [55]. By the fifth postoperative day, neither of the groups had neurocognitive scores that differed significantly from their preoperative scores. However, the researchers also ran a univariate regression on amyloid beta proteins (Ab), which have been found to be biomarkers for Alzheimer disease [55,56]. They found a strong inverse correlation between the presence of Ab and MMSE score. In short, 74% of the variance in neurocognitive scores was predicted by Ab levels in the blood [55]. This is interesting evidence that POCD may have the same pathogenic model as Alzheimer disease.
| A) | In-hospital 3.5%; home 9.8% | ||
| B) | In-hospital 9.8%; home 3.5% | ||
| C) | In-hospital 12.7%; home 5.7% | ||
| D) | In-hospital 41.4%; home 36.6% |
Other cases with high postoperative rates of POCD have also been reported. It is important that such cases are studied, as other procedures may be more frequently performed than cardiovascular surgeries. One consideration is that the complexity and invasiveness of the surgery may not be correlated to the development of POCD. One of the first attempts to describe the incidence of POCD in patients after minor surgery enrolled 372 patients older than 60 years of age, of whom 199 remained in the hospital for one night and 173 were discharged home after surgery [57]. Neurocognitive tests were performed preoperatively and then repeated seven days and three months after surgery. Of this group, researchers noticed a significant difference between those recovering at home compared with those recovering in the hospital. The one-week POCD rate for those recovering in the hospital was 9.8%, while those recovering at home had a rate of 3.5%, a significant difference [57]. When the cognitive tests were repeated at the three-month mark, there was no statistically significant difference between inpatients (8.8%) and out-patients (4.5%) [57]. The authors did believe that the decreased stress of home recovery probably accounted for the one-week difference in scores, which mirrors the previously discussed studies using cortisol and other stress biomarkers. The lack of difference after three months was not explained, though the incidence was lower than that found in other studies of more complex surgeries.
| A) | TREK-1 channel | ||
| B) | TASK-1 channel | ||
| C) | Glycine receptor | ||
| D) | Nicotinic acetylcholine receptor (nAChR) |
Acetylcholine (ACh) is one of the key neurotransmitters in the brain. The primary receptor responsible for this neurotransmission is the nicotinic acetylcholine receptor (nAChR), which is expressed ubiquitously in numerous subtypes throughout the body [60]. Anticholinergic drug use has been related to both POC and post-operative delirium [61]. The normal role of ACh in the brain is primarily one of exciting neurons and causing their discharge. The neurons most affected by ACh are ones that send projections throughout the cortex and striatum, areas responsible for wakefulness, learning, attention, and motivation [62]. Degradation of these neurons, or interruptions in their discharge, would lead to signs and symptoms associated with POCD [63]. Inhaled and intravenous anesthetic agents inhibit the nAChR [64]. This in turn blocks the entry of sodium ions into the cell as well as the entry of calcium ions. The former moves the electric potential within the cell closer to threshold, while the latter functions as a second messenger for numerous intracellular effects. One of the other effects of anesthetics is the desensitization of these receptors, such that even if ACh can bind, the receptor will not respond [64]. This desensitization may last after the anesthetic is no longer in the vicinity of the receptor and may account for prolonged POCD effects.
| A) | Disruption of the blood–brain barrier | ||
| B) | Complete closure of pulmonary capillaries | ||
| C) | Permanent opening of the spinal epidural space | ||
| D) | Increased exhalation of intravenous agents unchanged |
The one area in which there was common agreement was that of inflammation after surgery. In one study, the authors found POCD in patients three-months post-procedure in such disparate surgical interventions as open heart surgery (16%), total hip replacement (16%) and coronary angiography (21%), despite the fact that the last procedure was minimally invasive [65]. After nearly any procedure or injury, the natural inflammatory response of the body is activated, and numerous mediators are released into the bloodstream. When inflammation occurs, the blood brain barrier undergoes a breakdown, allowing these circulating mediators to enter the brain [66]. Numerous mediators may result in neuronal damage (Table 1).
| A) | Biomarker indicating the presence of neuronal damage | ||
| B) | Increasing secretion of corticotropin-releasing hormone | ||
| C) | Providing structural support for neuronal microtubules | ||
| D) | Activating the complement system to help clear damaged or dead cells |
COMMONLY RELEASED MEDIATORS, CYTOKINES, AND BIOMARKERS DURING INFLAMMATION
| Mediator, Cytokine or Biomarker | Abbreviation | Function |
|---|---|---|
| C-reactive Protein | CRP | Activate the complement system to destroy damaged or dead cells |
| Interleukins | Il-1, Il-6, Il-8 | Second messengers that activate numerous aspects of the immune system |
| Tumor necrosis factor-a | TNF-a | Increase the secretion of corticotropin releasing hormone |
| Beta amyloids | Aβ | Help create brain plaques, associated with Alzheimer disease |
| Tau proteins | Tau | Protein essential to form microtubules and structure in neurons |
| Neuron-specific enolase | NSE | Biomarker indicating the presence of neuronal damage |
| Cortisol | Cortisol | Glucocorticoid secreted during times of stress, including inflammatory processes |
| A) | Advanced age | ||
| B) | No comorbidities | ||
| C) | Higher level of education | ||
| D) | Lower levels of inflammation |
While we continue to search for a reliable biomarker with a high predictive rate for POCD, we do know that some patients are more likely to develop this disorder than others. Common traits in patients with POCD include [36,49,50,57,58,63,69]:
Pre-existing neurocognitive dysfunction
Multiple comorbidities
Lower level of education
Increased level of inflammation
Sleep deprivation
Advanced age