Introduction

Perioperative neuroscience is a very dynamic field due to ongoing research, clinical innovations, and technological developments. In this chapter, we review some of the major recurring themes, innovative findings, and prevalent topics associated with advances in the field of neuroanesthesiology.

Endovascular Treatment of Stroke and Perioperative Stroke

Ischemic stroke is one of the leading causes of morbidity and mortality worldwide. Treatment of ischemic stroke may involve administration of intravenous thrombolytic drugs such as tissue plasminogen activator (tPA). Endovascular treatment can supplement intravenous thrombolytic treatment for acute ischemic stroke or provide an alternative therapy for thrombolysis. Initially, data from randomized controlled trials suggested that endovascular treatment was not superior to intravascular tPA administration for the treatment of ischemic stroke. However, subsequent large randomized trials have demonstrated improved rates of recanalization and outcomes with endovascular treatment without increased rates of complications.

The anesthetic care of patients undergoing endovascular treatment of stroke has been highly debated. Several anesthetic techniques have been described for patients undergoing endovascular treatment of stroke including general and local anesthesia with or without sedation. Data have suggested that clinical outcomes may be worse in patients who have received general anesthesia compared to those who underwent local anesthesia. This association may be due to effects of anesthetic drugs on the injured brain, a deeper anesthetic state with general anesthesia, greater risk for systemic hypotension with general anesthesia, or a selection bias on the part of general anesthesia. For the last of these, patients with greater stroke severity may require general anesthesia due to factors such an altered consciousness, severe neurologic deficits, respiratory dysfunction, or inability to protect their airway. Thus, greater stroke severity, and not specifically general anesthesia, may be a more important factor determining the outcome.

Perioperative stroke can be a devastating complication in surgical patients and is associated with an increased risk of death compared to patients who did not have a perioperative stroke. The Peri-Operative Ischemic Evaluation trial demonstrated an increased risk of stroke and death after noncardiac surgery with the use of perioperative metoprolol compared with placebo. In 57,218 patients having noncardiac surgery, Mashour et al. found the rate of perioperative stroke to be 0.09% and that preoperative metoprolol use was associated with a 4.2-fold increased odds for perioperative stroke [P < 0.001; 95% confidence interval (CI), 2.2–81]. Patients who were taking preoperative metoprolol had a significantly higher incidence of stroke compared to those taking atenolol (P = 0.016). Intraoperative metoprolol administration was associated with a 3.3-fold increase in perioperative stroke (P = 0.003; 95% CI, 1.4–7.8). This differential perioperative stroke risk associated with specific β-blockers was confirmed by other data. Further studies are necessary to determine the safety of β-blockers in the perioperative period.

Indications for Deep Brain Stimulation

Surgical procedures to treat functional neurological disorders such as Parkinson disease and essential tremor historically involved ablative procedures such as pallidotomy and thamotomy. These procedures often resulted in several permanent side effects. Originally approved for the treatment of essential tremor in 1997, deep brain stimulation (DBS) revolutionized the treatment for a variety of functional and psychiatric disorders. However, unlike earlier ablative procedures, side effects were minimal and treatment could be stopped if the patient did experience significant complications.

Due to the success of DBS for multiple indications, investigational and off-label use of DBS has widely expanded. Table 56.1 outlines the current and emerging indications for DBS as of 2016. DBS has been shown to be a very effective treatment in patients with Parkinson disease and efficacious for medically refractory essential tremor, dystonia (under a Humanitarian Device Exemption), and obsessive-compulsive disorder. DBS is successful in treatment by stimulating targeted nuclei in the brain specific to each disorder. Targets for approved indications are illustrated in Fig. 56.1 . Essential tremor is treated by targeting an area of the thalamus, the ventral intermedius nucleus. Parkinson disease and dystonia are treated by targeting the subthalamic nucleus and the internal part of the globus pallidum. Obsessive-compulsive disorder is treated by targeting the anterior limb of the internal capsule.

Targets for approved indications for deep brain stimulation. Parkinson disease and dystonia: subthalamic nucleus and internal part of globus pallidum; essential tremor: ventral intermedius nucleus of the thalamus; obsessive-compulsive disorder: anterior limb of the internal capsule.

With the growing number of indications for placement of DBS, anesthesiologists are likely to encounter a greater number of patients undergoing this procedure. Placement of DBS may have special considerations for the anesthesiologist. Patients should be appropriately selected and counseled on preoperative and postoperative expectations. Some DBS placement procedures may require that the patients be awake for either the entire procedure or a portion of the procedure and in the semisitting position. Patients often require magnetic resonance imaging while in a stereotactic head frame, something that may not be tolerable for some patients such as children, or those with claustrophobia or developmental delay. Some anesthetic drugs, especially those with γ-aminobutyric acid–ergic properties (i.e., benzodiazepines, propofol, inhaled halogenated ethers), can impair mapping of brain structures via microelectrode recordings. Thus sedation with dexmedetomidine and narcotics is preferred. Additionally, the anesthesiologist should be aware that there may be specific requirements for patients to discontinue or continue certain drug therapies to facilitate intraoperative mapping and testing. This may aggravate the patient’s symptoms and pose additional challenges in the perioperative period.

Anesthetic Neurotoxicity

Several in vitro and animal studies have demonstrated that exposure to general anesthetics can cause neuronal degeneration and apoptosis in immature and developing brains. In addition to impairing cellular functions such as signaling mechanisms, gene expression, and synapse formation, behavioral changes have been demonstrated in animals exposed to general anesthetics at a young age.

Several studies have sought to determine the effect of general anesthetics on the developing human brain. Some studies have shown an association between multiple exposures to general anesthetics in young children and learning and behavioral disorders later in life. However, these and other retrospective studies do not indicate a cause-and-effect relationship in humans and may be biased as “sicker” children are more likely to require anesthesia to facilitate tests and procedures. There are currently at least four trials in progress to assess the nature of the association between general anesthesia in childhood and impaired learning and behavioral disorders: (1) General Anesthesia Compared to Spinal Anesthesia (GAS) trial, (2) Pediatric Anesthesia and Neurodevelopment Assessment trial, (3) Mayo Anesthesia Study in Kids, and (4) University of California San Francisco Human Trial. These trials consist of either prospective or retrospective exposure but prospective assessment of neuropsychometric function.

At the time of writing of this chapter, only preliminary results for the GAS Trial were available. The GAS Trial is an international, multicenter, randomized controlled investigation aimed to assess whether general anesthesia in infancy has an effect on neurodevelopmental outcome. Infants younger than 60 weeks postmenstrual age born at greater than 26 weeks’ gestation with no existing risk factors for neurologic injury undergoing inguinal hernia repair were included. Patients were randomized to receive awake regional anesthesia or sevoflurane-based general anesthesia. Although the primary outcome is performance on the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, assessed at 5 years of age, the authors report a secondary outcome—performance on the Bayley Scales of Infant and Toddler Development III, assessed at 2 years of age. The investigators found no evidence that 1 h or less of exposure to sevoflurane general anesthesia during infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared to awake regional anesthesia.

Anesthetic neurotoxicity is not only an issue in children and infants but also a concern in mature adults. Older patients undergoing anesthesia and surgery are at risk for the development of postoperative delirium and cognitive dysfunction. Delirium is an acute, fluctuating condition in which the patient has a decreased ability to focus and sustain attention. Delirium can develop in the postoperative period and is one of the most common postoperative complications as it can occur in up to 70% of patients older than 60 years. Characteristics associated with the risk of developing delirium in the recovery period include prolonged procedures and preexisting neurological comorbidities. The impact of postoperative delirium remains undetermined. Several studies have demonstrated postoperative delirium to be associated with increased morbidity and mortality. However, others have not demonstrated an increased risk of death in patients with postoperative delirium.

Although postoperative cognitive dysfunction (POCD) does not have a formal definition, it is generally considered to be a cognitive decline following exposure to anesthesia and surgery that is detected by neuropsychological tests with a potential for slow improvement. At 3 months following surgery, approximately 10% of elderly patients will demonstrate signs of cognitive deficits. Interestingly, regular exercise and cognitive stimulation are associated with reduced odds of cognitive impairment in the elderly population. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability showed that patients who underwent lifestyle modifications (improved diet, regular exercise, cognitive training, and vascular risk factor modifications) had better postintervention executive functioning skills and processing speed than those who received only general health advice. Animal studies have demonstrated this principle to be effective as a way to attenuate the neurotoxic effect of general anesthesia. A reduced rate of apoptosis and improved cognitive function were demonstrated through environmental enrichment.

The mechanisms precipitating POCD are not well understood. However, inflammatory mechanisms may play a contributory role in the development of POCD but are not the sole cause of POCD as patients who have received corticosteroids have an increased risk of developing POCD. Other contributory factors may include increased sensitivity of the aged brain to general anesthetics and possibly anesthesia-induced increased permeability of the blood–brain barrier. Research in this area is likely to be ongoing to determine the causes and elucidate the possible preventative measures.

Pre- and Postconditioning

Perioperative cerebral ischemia is unfortunately a risk for patients who undergo surgery and anesthesia with some procedures such as intracranial and cardiac surgery posing greatest risk. Neuroprotective strategies can minimize the extent of injury. This can include various drugs and techniques in addition to maintaining adequate oxygen and substrate delivery to the brain and appropriate perfusion pressure. One such set of techniques involves conditioning of the brain in the setting of ischemic injury. Pre conditioning involves administration of a neuroprotective strategy before a potential ischemic episode. Per conditioning is a method by which a neuroprotective strategy is employed during an ischemic event. Post conditioning occurs only after an ischemic event has occurred.

Ischemic preconditioning involves inducing a state of subinjurious brain or spinal cord hypoxia prior to an expected ischemic event. The premise is that the brain will develop tolerance toward ischemic injury. Interestingly, ischemic preconditioning can also be accomplished by inducing ischemia in other regions of the body, a technique referred to as remote ischemic preconditioning. Generally performed by inflating a blood pressure cuff on the arm, remote ischemic preconditioning has been shown to reduce the levels of biomarkers of brain injury and improve neurologic function. As preconditioning involves anticipation of ischemic brain injury, induction of intermittent and mild hypoxic events following injury, a technique called ischemic postconditioning can also attenuate ischemic brain injury. Anesthetic drugs, especially the inhaled halogenated ethers, can also attenuate ischemic brain injury in animals if administered prior to (i.e., anesthetic preconditioning), during (anesthetic perconditioning), or following (i.e., anesthetic postconditioning) an ischemic event. Anesthetic preconditioning is thought to involve a variety of protective mechanisms in the brain including inducing the opening of ATP-sensitive potassium channels, altering nitric oxide metabolism, and activating the Akt pathway. Anesthetic perconditioning is often attributed to drug-induced decreases in cerebral metabolism, glutamate receptor antagonism, augmentation of cerebral blood flow, activation of ATP-dependent potassium channels, and upregulation of antiapoptotic protein expression in the brain. Anesthetic postconditioning is not as well studied but sevoflurane exposure following ischemic injury has been shown to attenuate ischemic brain injury.