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Review Articles

Neuroanesthesiology Update

Pasternak, Jeffrey J. MD

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Journal of Neurosurgical Anesthesiology: April 2020 - Volume 32 - Issue 2 - p 97-119
doi: 10.1097/ANA.0000000000000676
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Education in Neuroanesthesiology

Simulation training is an effective way to teach crisis management skills,1 and checklists can be valuable to assure appropriate tasks are completed during crises.2 On behalf of the Society for Neuroscience in Anesthesiology and Critical Care (SNACC), Hoefnagel et al3 developed evidence-based checklists and cognitive aids for 10 major neurological crises. The authors provide evidence for management decisions and subscribers of the Journal of Neurosurgical Anesthesiology have access to download these cognitive aids and checklists for use in the clinical setting.

The American Council on Graduate Medical Education (ACGME) has introduced milestones as a means to achieve competency-based assessments in general anesthesiology training.4 SNACC recently organized and published neuroanesthesiology-specific milestones.5,6 These milestones address 4 major domains: patient care, medical knowledge, practice-based learning and improvement, and interpersonal and communication skills, and are adaptive to the level of training. The milestones can be used by training programs as a guide for training and as a means for trainee assessment.

SNACC has recently established the International Council on Perioperative Neuroscience Training (ICPNT), a body that will serve to accredit neuroanesthesiology training programs internationally. Ferrario and Kofke7 recently summarized the brief history of the ICPNT as well as its structure and future plans.

Global Burden of Neurological Diseases

Neurological diseases are a significant cause of disability and mortality. Data from The Global Burden of Diseases, Injuries, and Risk Factors Study was used to provide estimates of the morbidity, disability, and mortality related to neurological diseases during the years 1990-2016.8 In 2016, neurological disorders were the second leading cause of death, accounting for 16.5% of deaths, and the leading cause of disability-adjusted life years, accounting for 11.6% of all disability-adjusted life years, globally. Among neurological disorders, stroke was the leading contributor of disability-adjusted life years, accounting for 42% of neurologically related disability-adjusted life years. For readers with an interest in more detailed analyses of the global burden of specific neurological diseases, Lancet Neurology published analyses specific to traumatic brain injury (TBI),9 Alzheimer disease,10 multiple sclerosis,11 epilepsy,12 central nervous system cancers,12 and stroke.13

Venous Air Embolism

Adverse outcomes occur in up to 14% of patients with neurological disorders requiring surgery.14 One significant complication in neurosurgical patients is venous air embolism in those having surgery in the sitting position. Abcejo et al15 report on patients who required urgent repositioning due to severe venous air embolism. They identified 6 of 404 (1.5%), 2 of 324 (0.6%), and 0 of 875 cases that required urgent repositioning in patients having craniotomy, deep brain stimulator lead implantation, and cervical surgery, respectively. Decreases in end-expired CO2 tension preceded decreases in blood pressure. However, end-expired CO2 and blood pressure changes rapidly normalized with the placement of the patients in the supine position. Central venous catheter aspiration did not result in a meaningful change in outcome. No new postoperative neurological or cardiac events were attributed to venous air embolism or its impact on systemic physiology in this study. In the setting of significant venous air embolism, urgent placement of the patient in the supine position should be considered as it may mitigate adverse effects related to air entrainment.

Magnetic Resonance Imaging (MRI) Safety

Radiologic techniques are frequently used to guide neurosurgical procedures and pose unique challenges for anesthesiologists.16–20 Kamata et al21 report on adverse events in patients having intraprocedural MRI-guided craniotomy with an asleep-awake-sedated technique. Three hundred sixty-five patients underwent 579 MRI scans performed with a 0.3 T AIRIS-II (Hitachi Medical, Chiba, Japan) or 0.4 T APERTO Lucent (Hitachi Medical) MRI scanner. Adverse events occurred during imaging in 21 (5.8%) patients and 24 (4.1%) imaging sequences. Specific adverse events included seizures (6 sequences), respiratory arrest (2 sequences), nausea or vomiting (7 sequences), and agitation (9 sequences). Four imaging sequences had to be stopped due to seizures requiring administration of antiepileptic medication (n=2) or respiratory arrest requiring airway management (n=2). There were no cases of cardiac arrest or thermal injury during imaging. These findings may only be specific to patients having surgery with a low magnetic field magnet via the asleep-awake-sedated technique. Patients having procedures that utilize a different operating room/imaging design, a stronger magnet, or a different anesthetic technique for awake mapping with MRI guidance may have a different risk profile.

The Association of Anaesthetists of Great Britain and Ireland and the Neuroanaesthesia and Critical Care Society recently published guidelines for anesthetic management of patients having MRI.22 The authors review hazards, patient and staff safety, monitoring, and crisis management in addition to special circumstances such as pediatric, pregnant, and critically ill patients requiring MRI.

Acute Kidney Injury in Neurosurgical Patients

Acute kidney injury is common in patients having neurosurgical procedures.23–26 Oh et al27 retrospectively studied patients undergoing craniotomy for primary brain tumor resection to identify factors associated with postoperative acute kidney injury. Of the 726 patients included in the study, 39 (5.4%) developed new acute kidney injury during the first 3 postoperative days. Factors found to be independently associated with acute kidney injury were the use of nephrotoxic drugs, excessive balanced crystalloid solution administration, preoperative anemia, and increased serum chloride concentration. Increased perioperative chloride load has been shown to be associated with postoperative acute kidney injury, an effect that has been attributed to the development of hyperchloremic metabolic acidosis.28 However, there was no difference in the rates of metabolic acidosis (pH<7.35 and [HCO3]<24 mEq/dL) in the Oh et al27 investigation between those with (12.8%) and those without (12.2%; P=0.912) acute kidney injury, potentially suggesting an alternate mechanism.


Fever occurs in up to 70% of critically ill patients with neurological injury and can be a significant secondary cause of brain injury.29–32 Picetti et al33 performed a survey of members of the European Society of Intensive Care Medicine to explore differences in fever definitions and management. Among 231 respondents, there was substantial variability in fever definitions, triggers for treatment, and management strategies. The most common definition of fever was a core temperature >38.3°C. Temperature was most commonly measured with a bladder probe. The most common threshold to institute treatment was a core temperature >38.0°C, but lower thresholds were frequently used in patients with cerebral ischemia and intracranial hypertension. The most common first-line therapies included ice packs and acetaminophen, whereas common second-line therapies included an intravenous infusion of cold fluid and diclofenac. Only 43% and 28% of respondents stated that protocols were in place at their institution for the management of fever and shivering, respectively.

Airway Management

Acromegaly is a known risk factor for difficulty with both mask ventilation and tracheal intubation, and typical metrics used to identify patients at risk for airway difficulty have limited utility in this population.34–36 Lee et al37 retrospectively analyzed data from 90 patients with acromegaly who underwent transsphenoidal pituitary adenoma resection to identify factors associated with difficult direct laryngoscopy, with a specific focus on radiographic predictors. Twenty-one (23%) patients were identified as having difficult laryngoscopy based on a Cormack-Lehane grade view of ≥3. Two factors were found to be independently associated with difficult laryngoscopy—increased age and larger tongue surface area, the latter measured via computed tomography. The authors report the odds ratio (OR) but it is unclear how the data were stratified to calculate the ORs.

Critically ill patients with neurological diseases often require tracheostomy and blind landmark-based techniques carry greater risk compared with visually-guided techniques.38 Spina et al39 report on the use of translaryngeal tracheostomy, initially described by Fantoni and Ripamonti,40 in 199 patients in the neurological intensive care unit (ICU). Briefly, the endotracheal tube is substituted for a smaller caliber tube to prepare for tracheostomy. Once the tracheostomy is in place, the endotracheal tube is removed. Spina et al39 modified this procedure to incorporate suspension laryngoscopy and did not replace the endotracheal tube with a smaller caliber tube thus avoiding the stimulation and risk of tube exchange. All procedures were performed in the ICU by either intensivists (130, 65%) or otolaryngologists (69, 35%). There was a significant increase in median intracranial pressure (ICP) from 7 mm Hg (interquartile range [IQR]=4 to 10 mm Hg) to 12 mm Hg (IQR=7 to 18 mm Hg; P<0.0001) during the procedure with a significant increase in mean arterial pressure (MAP). A total of 181 (91%) procedures were performed without complication and there were no procedural related deaths. In 11 patients, ICP increased to ≥20 mmHg and a cerebral perfusion pressure of <60 mm Hg was recorded in 3 patients. Other procedural complications were minor bleeding (n=1), creation of a false airway passage (n=1), identification of tracheal ring lesions (n=2), malpositioned cannula (n=2), and lung atelectasis (n=1). One major advantage of bedside tracheostomy is avoiding the need to transfer the patient to the operating room for a surgical tracheostomy, as the transfer of critically ill patients is associated with a high rate of complications.41 In addition, many other percutaneous tracheostomy techniques that may have advantages or less risk than the technique described by Spina et al39 have been described.42


Sedative medication, especially those that increase affinity of the gamma-amino butyric acid (GABA) receptor for GABA, can exacerbate or unmask motor deficits in patients with brain tumors.43 Lin et al44 prospectively studied the effect of midazolam and flumazenil on motor function in patients with supratentorial peri-eloquent gliomas. Fifteen patients with gliomas and 17 normal healthy subjects received intravenous midazolam, titrated to an Observer Assessment of Alertness and Sedation Score of 4 (ie, sedated but alert and cooperative). Sedation was subsequently reversed with intravenous flumazenil. All subjects performed the Nine-Hole Peg Test45 to assess motor function with each hand before sedation, after sedation, and then after flumazenil. The time for subjects to complete with the Nine-Hole Peg Test are summarized in Table 1. In all cases, time to complete the test was significantly increased following midazolam sedation, but the delay to complete the test following midazolam was fully attenuated by subsequent administration of flumazenil. There was no difference in time to complete the test at any phase of testing between dominant and nondominant hands among patients without gliomas. In those with gliomas, midazolam significantly increased the duration to complete the test with the hand contralateral to the brain lesion compared with the duration of time required to complete the test with the ipsilateral hand. This delay to complete the Nine-Hole Peg test with the contralateral hand was completely attenuated by flumazenil. These findings indicate that subclinical gross neurological deficits can exist in patients with brain tumors that can be exacerbated by sedative drugs, such as midazolam, and that this effect can be reverse by sedative antagonists.

Time to Complete Nine-Hole Peg Test

Brain tumors, especially large tumors, can decrease propofol requirements.46,47 Kurita et al48 studied the effect of an acute mass lesion on isoflurane requirements in pigs. Anesthetic depth was estimated by spectral edge frequency-95, the frequency below which 95% of the spectral power of the electroencephalogram (EEG) is contained. Increasing hypnotic depth results in a decrease in high-frequency power and an increase in low-frequency power causing the spectral edge frequency-95 to decrease. An acute mass lesion was created by inflating an epidural balloon catheter with 3 mL of distilled water to increase ICP by ∼10 mm Hg. Balloon inflation resulted in a 9.8% to 17.9% decrease in isoflurane requirements in this swine model. The effect was completely reverse upon balloon deflation. Unfortunately, it was not possible to study the effect of long-term balloon inflation on isoflurane requirements; longer-term effects likely more closely represent the effect of the growth of a tumor.

Recently, dexmedetomidine has been shown to have a lower incidence of unmasking subclinical neurological deficits in patients with intracranial mass lesions compared with other sedative drugs.43 Dexmedetomidine has other advantageous effects in neurosurgical patients such as reducing postoperative opioid consumption and pain.49,50 Lin et al51 provide a narrative review that summarizes the advantages and disadvantages of dexmedetomidine in neurosurgical patients. The authors address the potential role of dexmedetomidine during specific neurosurgical procedures.

Gabapentin has been used to decrease postoperative pain for patients undergoing a diverse group of surgical procedures. In patients undergoing craniotomy, prior investigations report conflicting findings with regard to the effect of gabapentin on postcraniotomy pain.52,53 Zeng et al54 prospectively randomized 122 patients undergoing elective suboccipital or subtemporal craniotomy to receive either 600 mg gabapentin or placebo administered orally on the evening before surgery, and again at 2 hours before induction of anesthesia. Anesthesiologists and patients were blinded to group assignment. Intraoperative propofol was dosed to maintain bispectral index (BIS) between 40 and 50 and remifentanil was dosed to maintain MAP and heart rate within 20% of baseline. Requirements for propofol and remifentanil were both decreased in the gabapentin group. Gabapentin significantly decreased pain scores at rest and with the movement for up to 24 hours, but not at 48 hours, after surgery. Gabapentin was also associated with decreased rates of nausea and vomiting and the need for rescue medications to treat nausea and vomiting. Postoperative opioid requirements were not decreased by gabapentin. Unfortunately, gabapentin was associated with increased sedation in the few hours following surgery but not at 24 or 48 hours after surgery.

Although acetaminophen may improve patient satisfaction, it has not been associated with a decrease in opioid consumption following craniotomy.55,56 Sivakumar et al57 prospectively randomized 204 patients to receive either 1000 mg of acetaminophen intravenously or an equivalent volume of normal saline every 8 hours for 48 hours following supratentorial craniotomy. Postoperative opioid consumption was similar between groups but patients who received acetaminophen had significantly lower pain scores at 24 hours, but not at 48 hours, following surgery. Unfortunately, the authors did not report details about anesthetic technique or intraoperative or postoperative analgesic management. Specifically, it was unclear if the study dictated a specific protocol for the administration of opioid and nonopioid analgesics other than acetaminophen as this may have impacted the study findings.

Scalp blocks can significantly decrease postcraniotomy pain.58–61 Yang et al62 randomized 51patients undergoing supratentorial craniotomy for cerebral aneurysm clipping into 3 groups, those that received either: (1) scalp nerve blocks, (2) local infiltration before incision, or (3) only intravenous analgesia. Scalp blocks were performed bilaterally targeting the following nerves: supratrochlear, supraorbital, zygomaticotemporal, auriculotemporal, and both greater and lesser occipital nerves. In patients who received nerve blocks and local infiltration, a total dose of 15 mL of 0.75% ropivacaine was administered. Compared with the group that received only intravenous analgesics, those that received local infiltration had significantly reduced pain score up to 2 hours after surgery, whereas those who received scalp blocks had reduced pain scores up for to 48 hours following surgery. Only in the group that received scalp blocks was there a decrease in MAP throughout surgery, a decrease in postoperative opioid consumption, and a decrease in serum concentrations of inflammatory cytokines. One major limitation of this study was related to the technique used in the group that received local infiltration of ropivicaine. Specifically, the anesthesiologist performed the infiltration 10 minutes before incision. This is problematic as the surgeon may have not performed the incision at the site of local anesthetic infiltration. In addition, it was unclear if local infiltration was performed at the site of head frame pin placement. Had the technique assured incision at the site of infiltration and that the pin site were also infiltrated, the findings of this investigation may have been different.

Fluids, Electrolytes, and Osmotic Drugs

Routine administration of hypotonic fluids should be avoided in most patients undergoing intracranial procedures as cerebral edema may be exacerbated.63 Pediatric fluid administration guidelines also recommend avoiding the routine use of hypotonic fluids but offer no guidance on whether isotonic saline or other isotonic balanced electrolyte solutions should be chosen.64 Lima et al65 randomized 49 children undergoing brain tumor resection to receive either 0.9% sodium chloride solution or Plasma-Lyte A (Baxter Healthcare, Deerfield, IL) during and for 24 hours following surgery. Fluids were administration was standardized. Specifically, maintenance fluid rate was calculated based on each patients’ weight using the 4-2-1 rule, that is, 4 mL/kg/h for the first 10 kg weight, 2 mL/kg/h for 11 to 20 kg weight, and 1 mL/kg/h for each kg body weight >20 kg. For cases of hypotension or hypovolemia, a 10 mL/kg bolus of the study fluid could be administered as frequently as deemed necessary. Also, colloid and blood products were also allowed to be administered if the clinician deemed them necessary. The calculated maintenance rate was continued until 24 hours following surgery. There was no difference between groups in total crystalloid, total colloid, rate of blood transfusion, or urine output either intraoperatively or postoperatively. Sodium chloride 0.9% was associated with a greater increase in serum chloride concentration and a greater decrease in serum magnesium concentration and base excess compared with Plasma-Lyte A. Hyperchloremic acidosis was more common in the group that received 0.9% sodium chloride (24%) compared with the Plasma-Lyte A group (0%, P=0.022). There was no difference in the degree of brain relaxation between groups. Although the authors conclude that Plasma-Lyte A “was associated with a safer electrolyte and acid-base profile compared with the use of saline,” they did not study any outcome measure or the impact of these disturbances on any outcome measure other than the degree of brain relaxation, which was not different between groups. Readers may be interested in the editorial that accompanies this article.66

Dostalova et al67 studied the effect of liberal versus restrictive fluid loading on cortical cerebral microcirculation in rabbits using side-stream dark-field imaging.68 Animals were randomly allocated to receive either restrictive (<2 mL/kg/h) or liberal (30 mL/kg/h) administration of Plasma-Lyte (Baxter, Lessines, Belgium) during craniotomy. Animals that received liberal fluid administration had evidence of impaired cortical vessel perfusion and higher serum concentrations of syndecan-1, a marker of endothelial glycocalyx dysfunction. The authors attribute this finding to fluid overload and altered blood-brain barrier integrity that led to cerebral edema and impaired cerebral microperfusion. Animals in both groups then received 5 mL/kg of either 0.9% or 3.2% sodium chloride solution intravenously. There was no difference between groups in cortical vessel perfusion or syndecan-1. These latter findings contradict earlier data that showed an adverse effect of hypertonic sodium chloride solution on endothelial glycocalyx integrity.69,70 The authors attribute this discrepancy to an inadequate hypertonic load and insufficient study duration to appreciate the adverse effect on glycocalyx integrity in their current investigation.

In addition to hypertonic saline, other solutions that can be used to treat intracranial hypertension include those containing sodium lactate, sodium bicarbonate, and urea.71–73 However, mannitol is probably one of the most common osmotic drugs used to treat intracranial hypertension. Zhang et al74 provide a systematic review of data describing the uses, efficacy, and complications related to mannitol use. They summarize data related to the use of mannitol in specific settings such as TBI, craniotomy, critical care, and non-neurological applications such as during renal transplantation.


Perioperative seizures are common following craniotomy although the incidence varies with the indication for surgery.75,76 Of 1916 patients who underwent elective supratentorial craniotomy with motor evoked potential (MEP) monitoring, Kutteruf et al77 identified 45 (2.3%) who experienced an intraprocedural seizure. Temporally, there was an increase in the rate of seizures when levetiracetam replaced phenytoin and a decrease in the rate when fosphenytoin replaced levetiracetam in their practice. This is a unique finding that warrants further investigation as levetiracetam has been found to have similar efficacy to phenytoin and fosphenytoin in the prevention of postoperative seizures following craniotomy,78 and recently for the treatment of status epilepticus in children.79,80 Factors found to be independently associated with increased risk for intraoperative seizures were prior history of seizures, surgery for a brain tumor, and temporal craniotomy, whereas the use of any antiepileptic drug, especially phenytoin or fosphenytoin, reduced risk for intraoperative seizures.

Intraoperative functional mapping with motor cortex stimulation is used to identify eloquent cortex to avoid injury to, or resection of, critical cortical tissue during brain tumor resection. Motor cortex stimulation can cause intraoperative seizures. Dineen et al81 retrospectively identified 544 patients who received intraoperative motor cortex stimulation during either awake craniotomy (n=204, 38%) or craniotomy performed with general anesthesia without muscle relaxation during mapping (n=340, 62%). Of this cohort, 135 (25%) sustained an intraoperative seizure. Factors found to be independently associated with increased risk for intraoperative seizures were lack of well-circumscribed margins around the lesion and use of the Penfield stimulation technique (compared with the multipulse train technique).82 The only factor independently associated with a decrease in seizure risk was intraoperative loading with an antiepileptic drug. Anesthetic technique was not associated with risk for intraoperative seizures.

Stereoelectroencephalography (SEEG) involves the placement of electrodes via burr holes in the brain to map seizure foci. This technique avoids a craniotomy that would be required for traditional grid placement. Tandon et al83 retrospectively compared outcomes among patients who underwent traditional craniotomy with grid placement (n=139) versus SEEG (n=121) at a single center. Demographics and preoperative seizure severity were similar. In those who underwent SEEG, operative time, requirements for blood transfusions, narcotic requirements, and rate of major complications were significantly lower. Ten (7%) patients sustained severe complications following grid placement—7 intracranial hemorrhage (ICH) and 3 infections—whereas no significant complications were identified in those who underwent SEEG. A greater fraction of patients who underwent grid placement received subsequent resective surgery (127; 91%) compared with those who underwent SEEG (90, 74%; P<0.001). Favorable epilepsy outcome (ie, seizure-free or rare disabling seizures) at 1 year in those who underwent resective surgery was higher in those who underwent SEEG (76%) versus grid placement (55%; P=0.003). There was no difference in the rate of favorable epilepsy outcome in the entire cohort (ie, including those who did and did not receive subsequent resective surgery) between those who underwent grid placement (42%) versus SEEG (47%, P=0.45). Given the favorable outcomes and positive adverse outcome profile associated with SEEG, it should be considered in lieu of craniotomy with grid placement to map seizure foci in patients with severe epilepsy.

The branched-chain amino acids (BCAA) leucine, isoleucine, and valine easily cross the blood-brain barrier and can serve as substrates in the biosynthesis of the excitatory neurotransmitter glutamate.84 BCAAs can also decrease amounts of glutamate in the brain by inhibiting glutamate oxaloacetate dehydrogenase, a source of glutamate synthesis,85 and by serving as a source for branched-chain ketoacid production where degradation of branched-chain ketoacids require glutamate for degradation.86 BCAAs have acute antiepileptic effects although the long-term effects of BCAAs on the brain are unknown.87 To determine the short-term and long-term effects of BCAA consumption on seizure activity in rats, Gruenbaum et al88 allowed rats unlimited access to pure water or water supplemented with 4% BCAAs for 33 days. After 10 days, a microcatheter was stereotactically implanted in the right hippocampal dentate gyrus to deliver methionine sulfoximine to produce a rodent model of mesial temporal lobe epilepsy.89 EEG screw electrodes were also implanted and the rats were monitored via EEG and video for evidence of seizure activity for 21 days. There were no differences in the rates of both EEG-based seizures and convulsive seizures during the study period. However, the fraction of all seizure activity that resulted in frank convulsive seizures was lower during the first week in the group that received BCAA supplementation but increased significantly over the remainder of the study period compared with the control group. Rats were killed at the end of the study period and histologic analysis revealed significantly fewer neurons in the hippocampal dentate gyri in rats that received BCAA supplementation. These data suggest that BCAA supplementation did not decrease seizure frequency but, instead, facilitated seizure propagation out of the hippocampus and enhanced neuronal loss. These findings would need to be confirmed in other epilepsy models.

Spine Surgery

Spine procedures are increasing in frequency and complexity leading to increased prevalence of complications.90–92 Pulmonary complications occur in up to 10% of patients having spine surgery.93,94 With increasing surgical complexity, the need for blood transfusion also increases the risk for transfusion-related acute lung injury after spine surgery. Xu et al95 compared pulmonary function and markers of inflammation in 60 patients who received cell salvaged autologous blood during spine surgery either with or without leukocyte filtration. Patients above 65 years old having major spine surgery received intraoperative salvaged autologous blood either with or without a Pall Leurkoguard-6 leukocyte filter. The volume of crystalloid and autologous blood administered were similar between groups. Leukocyte filtration was associated with improved pulmonary compliance and oxygenation, reduced serum concentration of white blood cells, neutrophils, surfactant protein-A (a biomarker for pulmonary epithelial injury), and the inflammatory biomarkers interleukin-6, interleukin-8, and tumor necrosis factor. Pulmonary complications occurred in 0 of 30 patients who received leukocyte filtered blood and 3 of 30 (10%; P=0.1) patients who did not receive filtered blood, although the study was not powered to detect a difference in the rates of pulmonary complications. This investigation should be replicated in a larger study population.

Avoiding general anesthesia, intubation, and mechanical ventilation in patients having spine surgery may reduce the risk of complications. Spinal anesthesia has been described as a valid anesthetic technique for patients having lumbar spine surgery.96 Using the American College of Surgeons National Surgical Quality Improvement Program database, Wahood et al97 propensity matched 342 patients who had lumbar decompression with neuraxial anesthesia with 1000 who had surgery with general anesthesia. Anesthesia type was not independently associated with readmission rate, hospital length of stay, or risk of complications. In 42 and 126 matched patients who underwent a lumbar fusion with regional or general anesthesia, respectively, the anesthetic technique was also not associated with readmission rate, hospital length of stay, or risk of complications.

Intrathecal opioids can minimize pain and systemic side effects from opioids. Dhaliwal et al98 randomly assigned 150 healthy patients having lumbar fusion to receive either 0.2 mg morphine or saline via intrathecal injection before starting wound closure. Intrathecal morphine was associated with a significant decrease in pain, both at rest and with movement, and decreased parenteral opioid requirements during only the first 24 hours after surgery. There was no difference in the incidence of respiratory depression (defined as a respiratory rate of <10 breaths per minute), rate of other complications, or hospital length of stay between groups, suggesting that intrathecal opioids can safely reduce postoperative pain following lumbar fusion.

Visual Loss

Postoperative visual loss is most commonly described following spine surgery but has also been described following other types of nonocular procedures.99 In 2012, the American Society of Anesthesiologists (ASA) developed a practice advisory on perioperative visual loss following spine surgery.100 In 2019, the ASA updated this practice advisory and received an endorsement from both the North American Neuro-Ophthalmology Society and SNACC.101 Recommendations from the updated practice advisory are summarized in Table 2.

Summary of Recommendations in the American Society of Anesthesiologists Practice Advisory for Perioperative Visual Loss Associated With Spine Surgery

Hofer et al102 retrospectively identified 20,128 patients who underwent spine surgery of whom 39 (0.19%) sustained an ocular injury. The 3 most common ocular complications were the blurry vision of unknown etiology (n=13), ischemic optic neuropathy (n=9), and corneal abrasion (n=7). Of those with ocular injury, the surgical position was either prone (n=29) or lateral (n=5). Patients with ischemic optic neuropathy were significantly older, had a longer surgical procedure, received a more crystalloid solution, had greater estimated blood loss, and had a higher rate of blood transfusions. Unfortunately, due to the low rate of ocular complications, multivariate regression analysis was not performed.

Goyal et al103 retrospectively identified 12 patients at their institution who experienced ischemic optic neuropathy (of whom 10 suffered from posterior ischemic optic neuropathy) and matched these 1:4 with 48 similar patients without ischemic optic neuropathy. Factors found to be associated with the development of ischemic optic neuropathy were spinal fusion (vs. decompression only), large number of operative levels, increased blood loss, lower hemoglobin, and administration of a larger volume of crystalloids. Of this cohort, 75% had a bilateral visual loss and only 30% had any improvement in vision at their last follow-up appointment.

Visual evoked potential monitoring has recently been described as a means to screen for intraoperative visual loss.104 Visual stimulation was conducted with red light-emitting diodes imbedded in silicon disks placed on the cornea and signals were recorded via electrodes placed over the occipital region of the scalp. Anesthesia was maintained with a propofol infusion titrated to a BIS of 40 to 60. The authors reported successful visual evoked potential monitoring in 72 of 73 patients. Eight patients had decreased visual function postoperative of whom 6 had a >50% decrease in signal amplitude.


Ischemic Stroke

Worldwide, 15 million people will suffer from a stroke annually with 1 in 6 suffering from a stroke in their lifetime.105 In 2019, the American Heart Association and American Stroke Association updated previous guidelines that address the management of acute ischemic stroke for health care professionals.106 The guidelines provide evidence-based recommendations for all aspects of stroke management, and the authors specifically identify new or updated recommendations compared with past guidelines.

Recently, prospective trials showed improved outcomes in selected patients who underwent mechanical thrombectomy.107 General anesthesia, sedation, and even local anesthesia have been employed to facilitate mechanical thrombectomy.108–110 In earlier nonrandomized studies, general anesthesia was associated with poorer outcomes, including in a recent post hoc analysis of patient data from the Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke (DEFUSE-3) Trial.111,112 A recent meta-analysis of 3 single-center prospective trials showed significantly lower odds of disability at 3 months in those who received general anesthesia,113 and a recent post hoc analysis of the General or Local Anesthesia in Intra-arterial Therapy Trial114 showed that safety and the quality of revascularization were similar between patients who received general anesthesia and those who received conscious sedation.115

Peng et al116 performed a prospective multicenter, but nonrandomized, trial to assess outcome after thrombectomy stratified by whether patients received general anesthesia or sedation. Patients above 17 years old presenting to 17 centers in China were included. The selection of anesthetic drugs and techniques was at the discretion of the anesthesiologists. Patients intubated before entering the radiology suite were not included in the study. The primary outcome was the rate of functional independence, defined as a modified Rankin Scale score of 0 to 2, at 90 days after the intervention. Of 149 patients, 105 (70.5%) received sedation and the remainder received general anesthesia. Rates of functional independence at 90 days were similar between those who received sedation (56/105; 53%) and those who received general anesthesia (27/44; 61%; P=0.368) and remained similar after correcting for imbalances in factors that could potentially influence outcome. Median National Institutes of Health Stroke Scale score was less favorable among those who received general anesthesia at 24 hours, but the difference was no longer significant at 7 days. There were no differences between groups in any other outcome metrics including rates of symptomatic ICH, medical or procedural complications, mortality, ICU or hospital length of stay, or total cost. Unfortunately, all but 1 patient who received general anesthesia in the Peng et al’s116 study was administered propofol, with or without inhaled anesthetics, for maintenance of general anesthesia. Given that patients randomized to receive general anesthesia in the 3 earlier randomized controlled trials114,117,118 did not receive inhaled anesthetics, it is unclear if general anesthesia maintained with inhaled anesthetic would also result in outcomes similar to anesthesia maintained with predominantly intravenous drugs.

Hypertension and hypotension are common in patients having thrombectomy procedures with either general anesthesia or conscious sedation, and alterations in intraprocedural blood pressure may influence neurological outcome.116,119,120 Petersen et al121 retrospectively analyzed intraprocedural blood pressure profiles from 390 patients who underwent mechanical thrombectomy at 2 stroke centers. Of these, 140 (35%) received general anesthesia. For each patient, the investigators calculated the greatest decrease in MAP compared with admission mean MAP (ΔMAP) and the area over the MAP versus time profile for MAP<admission MAP (aMAP) before revascularization. Poor outcome was defined as a modified Rankin Scale score >2 at 90 days. After correcting for covariates, greater values of ΔMAP (OR per 10 mm Hg=1.22, 95% confidence interval [CI]=1.07-1.38, P=0.003) and aMAP (OR per 300 mm Hg×min=1.15, 95% CI=1.06-1.24, P=0.001) were associated higher odds of poor outcome. Infarct size at 24 hours after revascularization was available for 154 patients. Increases in both ΔMAP and aMAP were independently associated with infarct growth (P=0.036 and 0.035, respectively; ORs not provided). Unfortunately, based on the way that the authors analyzed their data, they do not provide useful information to guide intraprocedural blood pressure other than suggesting decreases in MAP compared with admission MAP should be minimized. Maier et al122 compared 9 studies that evaluated the association between blood pressure during thrombectomy and outcome. In 5 investigations, decreases in blood pressure, measured as both a decrease in MAP from baseline and the lowest MAP, were associated with poor functional outcome at 3 months. The remaining 4 studies did not demonstrate an association between intraprocedural hypotension and outcome.

Mistry et al123 prospectively collected postthrombectomy blood pressure data from 485 patients from 12 stroke centers in the United States. The peak systolic blood pressure during the first 24 hours following thrombectomy was determined for each patient. A peak systolic blood pressure of 158 mm Hg was found to have the best discrimination for the dichotomized outcome of the modified Rankin Scale score of 0 to 2 (ie, good outcome) versus 3 to 6 (ie, poor outcome). Patients with a peak systolic blood pressure of ≥158 mm Hg had increased odds of poor outcome (OR=2.24, 95% CI=1.52-3.29, P<0.01) but this association was no longer significant following correction for factors thought to influence outcome (OR=1.29, 95% CI=0.81-2.06, P=0.28).

Cernik et al124 retrospectively collected blood pressure data from 690 patients with acute ischemic stroke at 2 centers to determine the association between outcome and postprocedural blood pressure during the first 24 hours following revascularization. Patients in whom median systolic blood pressure was <140 mm Hg had a higher rate of functional independence (54% vs. 41%; P=0.001) and lower mortality (23% vs. 32%; P=0.01) at 90 days. Rates of symptomatic ICH at 24 hours were 5.1% in both groups. Patients with symptomatic ICH at 24 hours had a higher maximal systolic blood pressure (175 mm Hg [range=135 to 230 mm Hg]) compared with those without symptomatic hemorrhage (165 mm Hg [range=130 to 250 mm Hg]; P=0.029); maximal diastolic blood pressures were similar between groups. After correction for covariates thought to influence outcome, only median diastolic blood pressure was independently associated with increased odds for favorable outcome (OR=0.977, 95% CI=0.957-0.997; P=0.024). Unfortunately, the authors did not describe the comparison groups in this calculation or whether higher or lower median diastolic blood pressure was associated with a better outcome.

Anadani et al125 retrospectively collected data from 1245 patients from 10 comprehensive stroke centers to assess the relationship between postthrombectomy blood pressure and outcome. In the first 24 hours after revascularization, lower mean systolic blood pressure, maximum systolic blood pressure, and systolic blood pressure range were all independently associated with higher odds of good functional outcome, lower odds of symptomatic ICH, and lower rates of need for hemicraniectomy.

Anderson et al126 reported on an international trial where 2227 patients with acute ischemic stroke were randomized to receive either intensive (target systolic blood pressure 130 to 140 mm Hg) or guideline (target systolic blood pressure <180 mm Hg) guided blood pressure management for 72 hours after intravenous alteplase; only 1.9% of patients in this study underwent mechanical thrombectomy. Although fewer patients in the intensive group had symptomatic ICH at 7 days (14.8% vs. 18.7%; P=0.014) there was no difference in the rates of good functional outcomes (66.4% vs. 66.5%; P=0.909) or mortality (9.5% vs. 7.9%) at 90 days in those who received intensive versus guideline-guided blood pressure management. It is unfortunate that the authors did not report revascularization rates and that they conducted this study in a population in whom very few patients received mechanical thrombectomy.

Hyperglycemia in the setting of neuronal injury and ischemia is associated with adverse outcomes.127 In the Glucose Insulin in Stroke Trial (GIST), patients with ischemic and hemorrhagic stroke were randomized to receive either intensive or liberal serum glucose management.128 GIST failed to show a difference in outcome between the 2 glucose management regimes; however, the difference in mean serum glucose concentrations between groups was only 10 mg/dL. Currently, the American Heart Association/American Stroke Association recommend maintaining serum glucose between 140 and 180 mg/dL following an acute ischemic stroke but acknowledge limited data to support this recommendation that is specific to patients with ischemic stroke.106,129 In the Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial, adults with acute ischemic stroke were randomized to receive either intensive or liberal glucose management for 72 hours within 12 hours of ictus. In the intensive group, patients were managed with an intravenous insulin infusion to maintain a target serum glucose of 80 to 130 mg/dL, whereas the liberal group was managed with subcutaneous insulin to maintain serum glucose of 80 to 179 mg/dL. Overall, 1118 (97%) patients completed the trial and 63% and 13% received intravenous thrombolytics and mechanical thrombectomy, respectively. Mean serum glucose throughout the study period was 118 mg/dL (95% CI=115-121 mg/dL) and 179 mg/dL (95% CI=175-182 mg/dL) in the intensive and liberal groups, respectively. The primary outcome was the rate of functional independence at 90 days corrected for admission National Institutes of Health Stroke Scale score and was similar between groups (20.5% vs. 21.6% in the intensive vs. liberal groups, respectively; adjusted P=0.55). There were no differences in other metrics of outcome including the National Institutes of Health Stroke Scale score, Barthel Index, Quality of Life Index, or morality rate at 90 days. Hypoglycemia, defined as any serum glucose <80 mg/dL occurred in 11.2% and 3.2% of patients in the intensive and liberal groups, respectively; severe hypoglycemia occurred only in patients randomized to intensive management with a rate of 2.6%.

Readers interested in acute ischemic stroke management are referred to 2 narrative reviews in the April 2019 issue of Anesthesia & Analgesia.130,131 These reviews address the details of mechanical thrombectomy, the association between both blood pressure and anesthetic technique on outcome, and guide clinicians in decision making when caring for patients with acute ischemic stroke.

Symptomatic perioperative stroke is not uncommon following surgery and anesthesia, occurring at a rate of ∼0.1% in those having noncardiac and non-neurological surgery.132 Unlike symptomatic strokes, “silent” or covert strokes represent infarcts that did not overtly manifest with signs and symptoms. NeuroVISION133 was a prospective cohort study involving 1114 patients 65 years of age or older who underwent noncardiac surgery at 12 academic centers in 9 countries. Patients with postoperative overt stroke were excluded. All remaining patients underwent MRI between 2 and 9 days following surgery. Covert stroke was diagnosed in those with positive findings on either axial fluid-attenuated inversion recovery, gradient-recalled echo, susceptibility-weighted imaging, T2 sequences, or diffusion-weighted imaging. Overall, 78 (7%) of patients were diagnosed with covert stroke—the anatomical locations of the infarcts were not reported. The primary outcome, cognitive decline at 1 year based on the Montreal Cognitive Assessment Evaluation, was significantly higher in those with covert stroke (42%) compared with those without covert stroke (29%, P=0.006). Delirium in the first 3 days after surgery was higher in the covert stroke group (10% vs. 5%; P=0.03). One-year mortality rates were similar between groups. Further research is needed to identify risk factors and preventative strategies for covert stroke.

Hemorrhagic Stroke

Current guidelines for the management of aneurysmal subarachnoid hemorrhage (SAH) do not provide recommendations for intraprocedural management of blood pressure or arterial carbon dioxide tension (PaCO2).134,135 Akkermans et al136 performed a retrospective observational study that included 1099 patients with aneurysmal SAH undergoing general anesthesia for aneurysm clipping (521; 47%) or coiling (578; 53%) to determine if specific thresholds of MAP or end-tidal CO2 are modulators of outcome. The mean values of MAP and end-tidal CO2 during the entire procedure were calculated. Also, time-weighted average areas under the curves were calculated for the following parameters: end-tidal CO2 of <30 mm Hg, <35 mm Hg, <40 mm Hg, and <45 mm Hg, MAP<60 mm Hg, <70 mm Hg, <80 mm Hg, >90 mm Hg, and >100 mm Hg, and decrease in MAP versus baseline of <50%, <60%, and <70%. Baseline MAP was calculated as the sum of all preinduction MAPs obtained in the procedure room. The primary and secondary outcome were rates of a good outcome, defined as a Glasgow Outcome Score (GOS) of 4 (ie, disabled but independent) or 5 (ie, good recovery with minimal deficits) at discharge or at 3 months, respectively. There was no difference in primary or secondary outcome rates among any strata of MAP or end-tidal CO2 even after correction for multiple comparisons and for covariates thought to influence outcome including treatment modality and timing of treatment after ictus. There are a few limitations of this investigation worth addressing. First, GOS is a crude outcome metric that may not be sensitive enough to detect more subtle differences in outcome. Second, hemodynamic and ventilatory targets necessary to optimize outcomes may be different during different parts of the procedure and this was not considered in this investigation. Finally, the analysis included end-expired CO2 and not PaCO2.

External ventricular drains (EVDs) can be used following SAH to monitor ICP and remove cerebrospinal fluid (CSF). Infection of EVDs can lead to ventriculitis, meningitis, or abscess. Lenski et al137 retrospectively compared potential serum and CSF biomarkers for ventriculitis in 63 patients with SAH who required EVD placement. At the authors’ institution, in those with EVDs, the following potential biomarkers were measured daily: serum values of white blood cell count, C-reactive protein, and glucose and CSF values of glucose, total protein, and leukocyte count. Serum procalcitonin and serum neutrophil percentage were determined twice per week or more frequently if infection was suspected. Ventriculitis was diagnosed based on Center for Disease Control Criteria.138 Overall, 17 (27%) of patients developed ventriculitis within a mean of 8±2 days following EVD insertion. Markers that were strongly predictive of ventriculitis were high serum neutrophil percentage and high CSF total leukocyte count. A serum neutrophil percentage ≥70% and CSF total leukocyte count of ≥635/µL were strongly predictive of ventriculitis, whereas either a serum neutrophil percentage <70% or a CSF total leukocyte count of <635/µL made the diagnosis unlikely.

Cerebral vasospasm is a significant contributor to poor outcome following SAH. Dexmedetomidine is a an alpha-2 receptor antagonist that has protective effects against cerebral ischemia.139 To determine if dexmedetomidine can attenuate cerebral vasospasm and minimize ischemic brain injury, Song et al140 produced SAH in rats that either did or did not receive an intraperitoneal injection of 10 µg/kg dexmedetomidine; they also included a sham group for comparison. SAH was produced by injection of 0.3 mL of autologous blood into the cisterna magna. Significant motor deficits were present in animals with SAH but this was significantly attenuated by dexmedetomidine despite no difference in the severity of SAH determined after sacrifice at 48 hours. Basilar artery cross-sectional area was determined at similar rostral levels and was smaller in animals with SAH (20,445±3873 µm2) than animals in the sham group (44,678±12,556 µm2; P<0.001), but the decrease in area was attenuated by dexmedetomidine (32,239±6999 µm2; P=0.011 vs. SAH without dexmedetomidine). Serum interleukin-6 and C-reactive protein, both inflammatory biomarkers, were increased in the SAH group compared with concentrations found in the sham group. These increases were attenuated by dexmedetomidine.

Intravenous and intra-arterial administration of the arterial dilator milrinone has been used to treat cerebral vasospasm and can be administered by guided intra-arterial injection, intravenously, or both.141–143 Crespy et al144 retrospectively identified patients who received milrinone at a single institution via 2 different protocols. During the interval between November 2004 and November 2007, 24 patients received both intra-arterial and intravenous milrinone, whereas between November 2011 and February 2015, 77 patients received only intravenous milrinone. There were no differences between groups in rates of resolution of vasospasm, rates of need for rescue angioplasty, neurological outcome at 1 year, and rates of complications attributed to milrinone, with the latter being rare in both groups. A prospective and randomized trial would be necessary to confirm these findings as these data were retrospectively acquired and the protocols were not employed simultaneously. Thus, advances in SAH management during the study interval may have played a role in modulating the findings of this study.

ICH can be a source of secondary brain injury following TBI.145 In the CRASH-2 trial, tranexamic acid was associated with a decrease in mortality in trauma patients with extracranial bleeding.146 Data from 2 small studies showed that the administration of tranexamic acid to patients with TBI decreases mortality but the effect on rates of disability were not assessed.147,148 CRASH-3149 prospectively allocated 12,737 patients with TBI at 175 hospitals in 29 countries to receive either placebo or tranexamic acid (1 g over 10 min followed by 1 g over 8 h). Adults with an admission Glasgow Coma Score of ≤12, within 3 hours of injury, and with evidence of intracranial bleeding on computed tomography scan but without extracranial sources of bleeding, were eligible for inclusion. In the entire cohort, death within 28 days was not different among those who did (18.5%) and did not (19.8%; P>0.05) receive tranexamic acid. Among those with mild-to-moderate TBI (ie, Glasgow Coma Score on admission of 9 to 15), the relative risk (RR) of death was lower in subjects who received tranexamic acid (RR=0.78, 95% CI=0.64-0.95), an effect not observed in the cohort with severe TBI (RR=0.99, 95% CI=0.91-1.07). Earlier treatment with tranexamic acid significantly decreased risk for death but only in the cohort with mild-to-moderate TBI. Tranexamic acid was not associated with increased rates of stroke, seizures, or other adverse events.

Patients with acute ICH can have cardiovascular aberrations. Lele et al150 performed a systematic review of the literature to summarize cardiovascular abnormalities that occur following acute ICH. They grouped manifestations into electrocardiographic, biomarker, echocardiographic, and hemodynamic changes. Electrocardiographic changes occur in 56% to 81% of patients with the most prevalent being prolongation of the QT interval and ST and T wave changes; the significance of changes is related to hemorrhage volume and location. Elevated serum troponin I and beta-natriuretic peptide are also common and associated with poor outcomes. Although wall motion abnormalities are not common, occurring in 14% of patients, echocardiography can be helpful to guide treatment of hemodynamic instability as it provides information about volume status, myocardial performance, and other structural and functional parameters that could guide management decisions. Acute hypertension is common after ICH. Current evidence supports maintaining systolic blood pressure 140 to 179 mm Hg during the first 24 hours.


Intraoperative Evoked Potential Monitoring

MEP monitoring can be used to monitor the integrity of the motor pathways during surgery. Although the amplitude of MEP waveforms can be impacted by preoperative motor deficits,151 MEP amplitudes also tend to decrease during anesthesia despite no change in anesthetic doses, a phenomenon known as “anesthetic fade.”152 Tanaka et al153 compared anesthetic fade between 2 MEP stimulation paradigms. One hundred seventeen patients undergoing spine surgery with MEP monitoring received a standard anesthetic consisting of propofol, fentanyl, and remifentanil. MEP stimulation was conducted at either a constant voltage of 500 V with an SEN-4100 stimulator (Nihon Koden, Tokyo, Japan) or a constant current of 200 mA with an MS-120B stimulator (Nihon Koden). With both techniques, stimulation occurred with a train of 5 pulses at 500 Hz with a 2 ms interstimulus interval. Compound muscle action potentials were recorded. The rate of anesthetic fade was greater when measured in the muscles of the lower extremities compared with the upper extremities for both stimulation techniques. The rate of anesthetic fade was greater in those having constant current stimulation compared with constant voltage stimulation. Since constant-voltage stimulation may have greater resistance to anesthetic fade, it may have an advantage over constant current stimulation for very long procedures requiring MEP monitoring.

Yoshida et al154 reported on the rate of non-neurological adverse events in patients having MEP monitoring. Outcome data from 2643 patients having MEP monitoring during spine surgery at 11 hospitals were prospectively acquired. Seventeen (0.64%) patients suffered from non-neurological complications related to MEP monitoring that included tongue laceration (n=11), lip laceration (n=2), tooth breakage (n=2), scalp hair loss near electrode placement site (n=1), and nasal bleeding after placement of a nasal electrode (n=1). The authors warn of the need for correct tongue and lip positioning and placement of a soft bite block in cases when MEP monitoring is employed.

Evoked potential monitoring can be used to indicte neurological trespass either due to the surgical procedure itself or due to positioning. Chui et al155,156 prospectively studied the utility of using an automated somatosensory evoked potential (SSEP) monitor in 21 patients having total shoulder arthroplasty to assess for intraoperative peripheral nerve injury. SSEPs were monitored with the EPAD device (SafeOp Surgical, Carlsbad, CA), an automated device that provides alert notification if there is a >50% reduction in amplitude or >10% prolongation of latency of signals. The median, radial, and ulnar nerves were stimulated on the operative arm and only the median nerve was stimulated on the nonoperative arm; nerve stimulation occurred at the wrists. SSEP alerts that responded to the repositioning of the extremity occurred in 5 patients, including 1 alert in the nonoperative arm that responded to repositioning. Interestingly, loss of SSEP signals occurred in 19 of 21 patients upon instillation of the local anesthetic solution via a brachial plexus nerve catheter at the end of the procedure. The remaining 2 patients emerged from anesthesia with severe pain and required replacement of the brachial plexus nerve catheter due to block failure. SSEP monitoring could potentially be used to assess the adequacy of regional anesthetic techniques.

The International Society of Intraoperative Neurophysiology recently published recommendations regarding the intraprocedural use of SSEP monitoring.157 The authors review relevant anatomy, summaries technical aspects of SSEP, discuss warning criteria, and discuss specific indications for intraprocedural use of SSEP monitoring.

Cerebral Autoregulation

The state of cerebral autoregulation can be estimated by calculating the moving Pearson correlation coefficient between MAP and ICP. This pressure reactivity index, or PRx, can vary between −1 and 1 with higher values indicating greater impairment of cerebral autoregulation as changes in ICP occur in parallel with changes in MAP.158 The relationship between PRx and MAP can be used to determine a MAP where cerebral autoregulatory status is maximized, and an increasing duration of time with a MAP below the optimal pressure is associated with poor outcome.159 Unfortunately, the calculation of PRx can only be accomplished in patients in whom ICP is monitored. Calculation of a reactivity index based on noninvasively determined surrogates for ICP have been described, such as middle cerebral artery blood flow velocity or regional cerebral oxygen saturation (rSO2), measured by transcranial Doppler sonography or near-infrared spectroscopy, respectively.160–165 The use of these surrogates may not reflect more global changes in autoregulation. Petkus et al166 compared PRx measurements to a noninvasively determined volumetric reactivity index (VRx) in 61 patients with severe TBI. Time-of-flight of ultrasound through the cranium was used as a surrogate for ICP. Specifically, ultrasound waves are generated and detected on opposite sides of the cranium. Since sound travels faster in blood compared with other intracranial contents,167 the duration of time required for a sound wave to traverse the cranium (ie, time-of-flight) is inversely proportional to intracranial blood volume along the path of the wave. VRx is then calculated as the moving Pearson correlation coefficient between estimated intracranial blood volume, calculated by time-of-flight ultrasound, and MAP. The linear regression between PRx and VRx, based on 1201 simultaneous paired data points, showed a significant correlation (r=0.843, 95% CI=0.751-0.903, P<0.001) and the standard deviation of the difference between simultaneous values of VRx and PRx was 0.192 with a bias of −0.065. Transcranial time-of-flight ultrasonography may represent a unique tool to estimate intracranial blood volume and may be useful to study other factors that affect cerebral blood volume, such as anesthetic drugs. Also, the authors hypothesize that time-of-flight ultrasound may better reflect a more global state of the brain compared with middle cerebral artery blood flow velocity or rSO2 when correlating to MAP.

Cerebral Hypoxia and Hypoperfusion Monitoring

The beach chair position is frequently used during shoulder surgery. Significant adverse cerebral ischemic events have been reported in patients who underwent surgery in the beach chair position and were attributed to inadequate cerebral perfusion pressure.168,169 Aguirre et al170 prospectively measured rSO2 with near-infrared spectroscopy in 40 patients undergoing shoulder surgery in the beach chair position via a standard anesthetic technique titrated to a BIS of 40 to 60. Patients underwent a battery of neurocognitive tests the day before surgery and then again 24 hours following surgery. Overall, 10 (25%) patients exhibited cerebral desaturation events defined as a ≥20% decrease in rSO2 from baseline for >15 seconds. Blood pressure decreased upon placement of patients into the beach chair position with a significantly greater decrease among those who exhibited cerebral desaturation events. Also, performance on neurocognitive testing was significantly worse among those who suffered a cerebral desaturation event compared with those with more stable rSO2 values. An interesting follow-up to this investigation would be to determine if a higher rate of postoperative diffusion-weighted imaging defects on MRI (ie, covert strokes) occurred in those with cerebral desaturation events.

Cerebral venous thrombosis can lead to impairment of cerebral venous drainage, cerebral edema, and intracranial hypertension. Severe intracranial hypertension can impair cerebral perfusion and may require a decompressive craniectomy. Venkateswaran et al171 prospectively studied bilateral rSO2 in 17 patients before and following decompressive craniectomy for severe intracranial hypertension associated with cerebral venous thrombosis. There was a significant increase in rSO2 on the side ipsilateral, but not contralateral, to the site of decompressive craniectomy in the postanesthesia recovery unit (PACU) compared with preoperative values, with the persistence of increased rSO2 over the following 2 postoperative days. The increase in rSO2 was not found to be correlated to changes in blood pressure, arterial oxygen partial pressure, PaCO2, or hemoglobin concentration. Although unlikely, other physiological parameters, such as ventilator settings, may also impact the accuracy of rSO2 data.172 rSO2 did not correlate with preoperative or postoperative Glasgow Coma Score or modified Rankin Scale score at 18 months postprocedure, although this investigation was likely not powered to assess for changes in outcome.

Busch et al173 report on the utility of diffuse correlation spectroscopy to detect cerebral ischemic events in comatose patients. Diffuse correlation spectroscopy employs a laser light source in the near-infrared region of the electromagnetic spectrum that estimates microvascular blood flow based on the scattering of light from moving red blood cells.174 Microvascular changes in blood flow were correlated with global cerebral blood flow by measuring indocyanine green wash-in with near-infrared spectroscopy.175 Patients also had brain tissue oxygen partial pressure (PbtO2) monitoring and monitoring of rSO2 with near-infrared spectroscopy. Decreases in MAP and cerebral blood flow, estimated by diffuse correlation spectroscopy, were both significantly correlated with decreases in PbtO2. However, rSO2 was poorly correlated with PbtO2. This latter finding is in line with earlier data and a recent review that suggests that rSO2 may have limitations as a monitor for cerebral ischemia.176,177 The investigators then compared the ability of changes in cerebral blood flow, estimated by diffuse correlation spectroscopy, to discriminate between normal (PbtO2>21 mm Hg) and low (PbtO2<19 mm Hg) PbtO2. Receiver operating characteristic curve analysis revealed that decreases in cerebral blood flow could discriminate between normal and low PbtO2 with an area under the curve of 0.762 but the strength of discrimination can be increased if decreases in both cerebral blood flow and decreases in MAP were considered (area under the curve=0.876).


Increased sympathetic nervous system activity can indicate inadequate analgesia. Various techniques that assess sympathetic nervous system activity, such as measurement of skin vasomotor activity or heart rate variability,178,179 can be used to estimate the degree of nociception. Sabourdin et al180 prospectively studied the utility of the pupillary pain index (PPi) in response to alfentanil in children receiving general anesthesia. Briefly, PPi utilizes pupillometry to measure the rate of pupillary dilation in response to painful electrical stimulation of the skin. The PPi is then based on the intensity of electrical stimulation and degree of pupillary constriction with a range of 1 to 9, with lower numbers indicating a greater degree of analgesia. Twenty children above 2 years old having elective surgery requiring orotracheal intubation were recruited. Following induction and intubation, anesthesia was maintained with 2% end-expired sevoflurane. PPi was measured before and 2 minutes following a 10 µg/kg intravenous dose of alfentanil. There was no difference in static pupillary diameter before (2.2±0.2 mm) versus the following (2.2±0.3 mm; P=0.86) alfentanil. Median PPi values decreased from 6 (95% CI=4-7) to 2 (95% CI=2-3) after the administration of alfentanil (P<0.001). Unfortunately, the authors did not compare pupillary pain indices with other quantitative nociceptive metrics such as heart rate variability or skin vasomotor reactivity.

Vinclair et al181 studied PPi in 40 sedated and intubated patients of whom 20 had moderate to severe brain injury (admission Glasgow Coma Score of 3 to 13) and 20 were without brain injury. Causes of brain injury were trauma (n=11), stroke (n=7), and SAH (n=2). During endotracheal tube suctioning, physical responsiveness to suctioning was positively correlated with PPi in those with and without brain injury. Collectively, a PPi of ≤4 had a sensitivity and specificity of 88% and 79%, respectively, for predicting no-to-mild response to endotracheal tube suctioning, respectively. Tetanic electrical stimulation used to ascertain the PPi did not adversely affect ICP in those with brain injury.

Natzeder et al182 retrospectively determined the relationships between neurological pupil index (NPi) and SAH severity and outcome in 18 patients. NPi was determined using the NeurOptics Pupillometer-200 (NeurOptics Inc., Irvine, CA) that measures parameters including pupil size, constriction velocity, and constriction latency and calculates the NPi based on a proprietary algorithm. NPi values range from 0 to 5 where increasing values indicate a more “normal” pupil reactivity. The average number of NPi values per patient was 248±37. Severe versus nonsevere SAH was based on a World Federation of Neurological Surgeons Scale score of 4 to 5 versus 1 to 3, respectively. NPi values <3 were more frequently measured in those with severe SAH (16%±9%) versus nonsevere SAH (0%±0%; P=0.002). Those with delayed cerebral ischemia had significantly lower mean NPi values (3.9±2.0) compared with those without delayed cerebral ischemia (4.2±0.4; P=0.011). Outcome was quantified by the GOS as favorable (GOS=4 to 5) or unfavorable (GOS 1 to 3). NPi values <3 were more frequently measured in those with unfavorable (19%±11%) versus favorable outcomes (1%±1%; P=0.017). The authors also showed that, even during the first 3 days following ictus, those with severe SAH, unfavorable outcomes, or in-hospital mortality were more likely to have NPi values <3. NPi values of <3 had a sensitivity and specificity of 36% and 96%, respectively, for detecting an ICP of >15 mm Hg. Ong et al183 showed that NPi values significantly increased in 72 patients with intracranial hypertension following administration of either mannitol or hypertonic saline (median NPi before treatment=4.1, IQR=3.4 to 4.6 and NPi following treatment=4.2, IQR=3.5 to 4.6; P=0.003). Although these findings were statistically significant, the NPi values before and following treatment of intracranial hypertension did not differ by a significant magnitude that would likely allow for discrimination of effectiveness of treatment of elevated ICP.


Anesthetic Neurotoxicity in Children

Exposure of young animals to common anesthetic drugs is associated with both adverse changes in the brain and functional neurological manifestations.184,185 Most animal investigations have focused on the effect of anesthetics on neuronal development and synapse integrity. Li et al186 exposed mouse pups on postnatal day 7 to either isoflurane (1.5% for 4 h) or air. On postnatal days 21 to 35, cohorts of mice received either rapamycin (an inhibitor of the mammalian target of the rapamycin signaling pathway, important for oligodendrocyte development and subsequent myelin formation), clemastine (a promyelination drugs), or neither rapamycin nor clemastine. A cohort of mice was killed on a postnatal day 35 for brain immunohistochemistry and western blot while the remainder underwent behavioral testing on postnatal days 56 to 63 after which they were killed for electron microscopic studies. Animals exposed to isoflurane exhibited impaired learning, an effect that was attenuated by both rapamycin and clemastine. Isoflurane exposure was also associated with both reduced proliferation and differentiation of cells destined to become oligodendrocytes and decreased thickness of myelin sheaths in the central nervous system. These effects were also attenuated by rapamycin. Collectively, these findings suggest that isoflurane has deleterious effects on myelination by impairing oligodendrocyte differentiation and proliferation.

Offspring of animals exposed to sevoflurane at an early age can also exhibit manifestations of anesthetic neurotoxicity, an effect that may be due in part to the differential expression of ionic transporters by neurons.187 Ju et al188 tested whether exposure of young adult rats to sevoflurane can also lead to neurobehavioral deficits in offspring. Rats of both sexes were exposed to 30% oxygen in the air with or without 2.1% sevoflurane for 3 hours on postnatal days 56, 58, and 60. Some rats were sacrificed 1 hour after the last exposure. Sevoflurane exposure was associated with higher serum cortisol concentrations in both sexes but a greater increase in males. Male, but not female, rats that received sevoflurane had lower expression of the potassium-chloride cotransporter Kcc2 in the hippocampus and hypothalamus. Kcc2 was also hypermethylated in the testis and ovaries of sevoflurane-exposed rats. The remaining rats underwent testing with the elevated plus-maze and startle reflex on postnatal days 125 and 135, respectively. Male but not female rats exposed to sevoflurane exhibited impaired performance on the elevated plus-maze and in response to startle testing. Rats were also mated with nonlittermates on postnatal day 85. Male, but not female, progeny, where either 1 or both parents were exposed to sevoflurane, had impaired performance on the elevated plus-maze and startle reflex compared with progeny from parents where neither parent was exposed to sevoflurane. Male, but not female, progeny of sevoflurane-exposed parents (where either 1 or both were exposed) had significantly increased methylation and reduced expression of Kcc2 in the hypothalamus. During development, intraneuronal chloride ion concentration is maintained high due to low expression of Kcc2 and high expression of the sodium-potassium-chloride cotransporter, NKCCl, such that activation of GABA receptors can lead to neuronal depolarization and not hyperpolarization.189 In normal adult neurons, Kcc2 is upregulated and NKCCl is downregulated resulting in low intraneuronal chloride ion concentrations and neuronal hyperpolarization from GABA receptor activation. Sevoflurane exposure is associated with reduced expression of Kcc2 in adult rats and this can possibly attenuate the inhibitory effect of GABA in the adult brain. Sevoflurane is also associated with epigenetic reprogramming of parental germ cells that results in reduced expression of Kcc2 and cognitive deficits in unexposed male but not female adult offspring. Further research will be required to better understand how sevoflurane exposure differentially affects male but not female rat Kcc2 expression, and the role of Kcc2 expression on cognitive function.

Studies in human children have failed to consistently demonstrate an adverse clinical effect on cognitive performance by early exposure to anesthesia.190 The General Anesthesia or Awake Regional Anesthesia in Infancy (GAS) Trial191 was a multicenter prospective study involving 722 infants below 60 weeks postconceptual age undergoing inguinal herniorrhaphy. Infants were randomized to receive either general or awake regional anesthesia. The initial analysis reported when study participants were 2 years of age and did not show a difference in cognitive performance between those who received general versus regional anesthesia based on multiple metrics. McCann et al192 now report on outcome 5 years after randomization. There was no difference in the primary outcome, the full-scale intelligence quotient based on the Wechsler Preschool and Primary Scale of Intelligence third edition. There was also no difference in any other secondary outcome metrics between groups independent of whether data were corrected for covariates or whether analyzed based on a per-protocol or intention to treat basis. It is important to note that for 70% of enrolled children, the anesthetic for the study procedure was the only anesthetic that they received before the 5-year assessment. Further, only sevoflurane was allowed for the maintenance of general anesthesia and the mean duration of general anesthesia was relatively short only 54 minutes. Therefore, these findings may not be generalized to a sicker cohort of children undergoing multiple or more complex procedures involving drugs other than sevoflurane.

The primary outcome measure of the Mayo Anesthesia Safety in Kids (MASK) Trial, intelligence quotient, did not differ among children not exposed, singly exposed, or exposed to multiple general anesthetics before the age of 3 years, although secondary outcome metrics suggested neurocognitive impairment in multiply, not singly, exposed children.193 Zaccariello et al194 reanalyzed the data from the MASK trial using both factor and cluster analysis to determine if the findings in secondary metrics persisted. Factor analysis is a data analytical method that can be useful when making multiple comparisons of correlated variables. Factor analysis demonstrated that multiply, but not singly, exposed children had greater impairment of motor skills, visual-motor integration, and processing speed. Cluster analysis potentially increases sensitivity to detect differences by grouping subjects according to similar characteristics. Subjects were grouped based on test performances into 3 clusters, those with lowest, intermediate, and highest performance on most tests. Multiply exposed children had 2.83 increased odds (95% CI=1.49-5.35, P=0.001) of belonging to the cluster of children with the lowest versus intermediate performance. There were no other significant associations based on exposure or cluster.

Readers with an interest in anesthesia and neurodevelopment in children are encouraged to view a report of the 2018 Pediatric Anesthesia Neurodevelopment Assessment (PANDA) Symposium published in the January 2019 issue of the Journal of Neurosurgical Anesthesiology.195–208 The collection of articles also includes a summary of preclinical and clinical-based posters presented at the PANDA symposium.

Postoperative Delirium

Delirium is an acute and fluctuating disturbance in attention and cognition. Delirium can occur in the postanesthetic period and in the critically ill, with older patients at the highest risk. Susano et al209 retrospectively reviewed the records of 716 patients 65 years of age or older who underwent spine surgery for factors associated with increased risk for delirium during hospitalization. Overall, 127 patients (18%) were diagnosed with delirium. As summarized in Table 3, 7 factors were found to be independently associated with increased risk for delirium. Delirium was independently associated with increased odds of developing other in-hospital complications (OR=3.52, 95% CI=2.08-5.91, P<0.001) and increased odds of discharge to a site other than home (OR=4.51, 95% CI=2.35-8.92, P<0.001). Delirium increased duration of hospitalization by 60% and was associated with increased rates of readmission (14.7% vs. 6.0%, P=0.001) and mortality (5.5% vs. 0.8%, P=0.002) at 30 days versus in those without delirium.

Perioperative Factors Independently Associated With Increased Risk for Delirium in Elderly Patients Who Underwent Spine Surgery

Harris et al210 identified 1261 patients 65 years of age or older who underwent hip fracture repair via either general anesthesia only (n=720, 57%), combined general and regional anesthesia (n=54, 4%), or regional anesthesia alone (n=487, 39%) in the American College of Surgeons National Surgical Quality Improvement Program Geriatric Surgery Pilot Program database. Postoperatively, 526 (42%) were diagnosed with delirium. Factors found to be independently associated with increased risk of delirium were increasing age, smoking history, longer hospitalization before surgery, shorter operative time, and preoperative history of dementia. Anesthesia type (ie, general vs. regional anesthesia) was not associated with risk for delirium.

While postoperative delirium contributes to short-term complications, the long-term consequences of postoperative delirium are not well described. Daiello et al211 utilized data from 560 patients enrolled in the Successful Aging After Elective Surgery Study,212,213 an observational cohort of adults 70 years or older who underwent elective surgery. Assessment for postoperative cognitive dysfunction (POCD) was conducted at 1, 2, and 6 months following surgery based on methods adapted from the International Study on POCD.214 Overall, 134 (24%) patients developed delirium during hospitalization. In-hospital delirium was associated with increased risk of POCD at 1 month (RR=1.34, 95% CI=1.07-1.67), but not at 2 months (RR=1.08, 95% CI=0.72-1.64) or 6 months (RR=1.21, 95% CI=0.71-2.09) following surgery.

Shi et al215 prospectively enrolled 130 adults 65 years of age or older having hip surgery at a single hospital in China. Those with preoperative delirium, cognitive impairment, or psychiatric disorders were excluded. Overall, 34 (26%) developed delirium within 4 days after surgery. There were no significant differences in demographics, anesthetic techniques, or other perioperative factors between those who did and did not develop delirium. Mortality rate and ability to perform activities of daily living among survivors were assessed between 24 and 36 months after surgery. Patients who developed delirium had a significantly greater reduction in their abilities to perform activities of daily living following surgery. Moreover, the mortality rate was significantly greater in the cohort who developed delirium (29%) compared with those who did not develop delirium (9%, P=0.009). Collectively, the findings of the studies by Shi et al215 and Daiello et al211 suggest that delirium following surgery does contribute to poor long-term outcomes despite no long-term effect on cognitive function.

Alterations in cerebral autoregulation can predispose the brain to inadequate or excessive blood flow. Caldas et al216 estimated cerebral autoregulatory status in 67 patients before and at 24 hours and 7 days following cardiac surgery with cardiopulmonary bypass. The autoregulation index (ARI) was calculated based on a correlation between systemic blood pressure and blood flow velocity in the middle cerebral artery determined by transcranial Doppler sonography.217,218 The ARI ranges from values of 0 (indicating complete autoregulatory failure) to 9 (indicating that autoregulation is maximally intact). Autoregulatory insufficiency was defined as ARI<4. Of the 67 patients, 17 (25%) developed delirium during hospitalization. Preoperatively, ARI was significantly lower in those who developed delirium (4.8±1.9 vs. 5.9±1.5 in those with and without delirium, respectively; P=0.021) but rates of autoregulatory insufficiency were similar (35% vs. 14% in those with and without delirium, respectively; P=0.077). At 24 hours, lower mean ARI and higher rates of autoregulatory insufficiency were found in those with delirium (3.1±1.8 and 77% vs. 4.3±1.5 and 48% in those without delirium; P=0.010 and P=0.041 for mean ARI and rate of autoregulatory insufficiency, respectively). At 7 days after surgery, lower mean ARI and higher rates of autoregulatory insufficiency were found in those who developed delirium (4.5±2.4 and 53% vs. 5.9±1.5 and 10% in those without delirium; P=0.031 and 0.001 for mean ARI and rate of autoregulatory insufficiency, respectively). Even the following correction for differences between groups based on the presence or absence of delirium, impaired autoregulatory function, preoperatively and at 24 hours, were both significant predictors for delirium. These data need further confirmation but may suggest that impaired preoperative cerebral autoregulatory function may be a predictor for postoperative delirium.

Hesse et al219 prospectively compared intraoperative EEG patterns in 626 adult patients receiving general anesthesia and the development of delirium in the PACU. Delirium occurred in 125 (20%) patients while in the PACU. The odds of developing delirium in the PACU was significantly greater in patients who had at least 1 episode of burst suppression intraoperatively (adjusted OR=1.86, 95% CI=1.13-3.05). In addition, the lack of EEG sleep spindles during emergence from anesthesia was also associated with increased odds of delirium, especially in cases where either nitrous oxide or ketamine were administered (adjusted OR=6.51, 95% CI=3.00-14.12). Since sleep spindles are a part of normal sleep, the authors hypothesize that the greater spindle density in patients at lower risk for delirium may be related to an emergence from anesthesia that is more similar to a normal sleep-to-wake transition where the brain is more impervious to external stimuli.220

Numan et al221 recorded EEGs from 2 channels (ie, Fp2-Pz and T8-Pz) for 5 minutes in 159 patients 60 years of age or older before and daily for 3 days following general anesthesia for surgery. Patients were also assessed for delirium at the time of EEG acquisition. Overall, 29 (18%) had delirium at ≥1 postoperative assessment point. Increased delta power and increased power in the 1 to 6 Hz band were both increased in those with simultaneous postoperative delirium. Relatively delta band and power in the 1 to 6 Hz band preoperative were similar between those that did and did not subsequently develop delirium.

Wildes et al222 report on the results of the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Symptoms (ENGAGES) Trial, in which patients 60 years of age or older receiving general anesthesia were randomized to have either EEG-guided anesthesia (n=614) or usual care without EEG guidance (n=618). Clinicians were encouraged to avoid nitrous oxide and intravenous hypnotic drugs in both groups during the maintenance phase of general anesthesia. In those having EEG guidance, clinicians were encouraged to minimize periods of EEG suppression and periods where BIS<40. Patients were screened for delirium daily for the first 5 days postoperatively. Although mean minimum alveolar concentration-equivalent volatile anesthetic dose and duration of time with BIS<40 were both lower in the EEG-guided group, rates of any episode of delirium were similar between groups (26.0% vs. 23.0% in the EEG-guided and usual care groups, respectively, P=0.22). Although undesirable intraprocedural movement was more common in the EEG-guided group (22.3% vs. 15.4%, P=0.002) and 30-day mortality rates were lower in the EEG-guided group (0.7% vs. 3.1%, P=0.004), rates of other adverse events were similar. The authors attribute the negative findings of this study, which is different from that of a recent meta-analysis,223 to methodological differences including increased rigor in delirium diagnosis, reporting of missing data, and better compliance to the study protocol in ENGAGES. Also, the authors did not hypothesize on the etiology for lower mortality in those who received an EEG-guided anesthetic.

The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) Trial224 was a multicenter prospective trial that failed to show an effect of intraoperative ketamine on rates of postoperative delirium. Vlisides et al225 performed a post hoc analysis of data from the PODCAST Trial to determine if epidural use affected the rates of postoperative delirium. The authors only included patients who underwent gastrointestinal, gynecologic, hepatobiliary, and urologic procedures of whom 120 and 143 did or did not receive an epidural. Patients who received an epidural were 64% less likely to experience an episode of delirium in the PACU or during the first 3 days postoperatively (adjusted OR=0.36, 95% CI=0.17-0.78, P=0.009). Patients who received an epidural also had lower postoperative pain scores and opioid requirements, an effect that may have contributed to the decrease in rates of delirium in those who received an epidural.

Postoperative delirium is associated with increased inflammatory biomarkers.226 Li et al227 performed a meta-analysis of trials that evaluated the effect of the anti-inflammatory drug, dexamethasone, on rates of delirium and POCD. The authors included 5 studies that consisted of 1270 and 961 patients who did and did not receive dexamethasone, respectively. Risk of delirium (RR=0.96, 95% CI=0.68-1.35, P=0.80) and risk of POCD (RR=1.00, 95% CI=0.51-1.96, P=1.0) were similar between groups. The authors note significant differences in dexamethasone dosing, potentially low evidence quality, and that 4 of the 5 studies were conducted in patients having cardiac surgery, which may have contributed to the lack of a positive finding in this analysis.

Ayob et al228 performed a review of the literature to ascertain if there are data to support the utility of preoperative biomarkers as a tool to predict postoperative delirium. Of all potential biomarkers reviewed, only increased serum concentrations of C-reactive protein had the promise to predict increased risk for delirium. The authors state that preoperative serum concentrations >3 mg/L is predictive for delirium, but do not supply sensitivity or specificity data to support this conclusion.

Pan et al229 performed a meta-analysis that consisted of 11 prospective randomized trials involving patients above 60 years old assessing the role of dexmedetomide to decrease rates of postoperative delirium. Studies involving patients having cardiac surgery were excluded. There was significant heterogeneity in dexmedetomidine dosing among the studies. Overall, perioperative use of dexmedetomidine significantly decreased risk for postoperative delirium (RR=0.47, 95% CI=0.38-0.58, P<0.001). Intraoperative use only (RR=0.44, 95% CI=0.34-0.58; P<0.001) and postoperative use only (RR=0.42, 95% CI=0.32-0.54; P<0.001) of dexmedetomide both significantly reduced risk for subsequent delirium.

Ng et al230 performed a meta-analysis of 25 prospective trials where patients were randomized to receive dexmedetomidine or placebo and assessed rates of delirium in the ICU. On the basis of moderate to high quality of evidence, dexmedetomidine use in the ICU reduced the odds of delirium (OR=0.36, 95% CI=0.26-0.51, P<0.001) and agitation (OR=0.34, 95% CI=0.20-0.59, P<0.001) but not mortality (OR=0.86, 95% CI=0.66-1.10, P=0.23).

Cheng et al231 randomized 535 patients 65 years of age or older having abdominal laparotomy to receive either dexmedetomidine (0.5 µg/kg bolus followed by an 0.4 µg/kg/h via infusion) or placebo intraoperatively with a standardized anesthetic and analgesic plan. Patients underwent a battery of cognitive tests preoperatively and then again at 3 days, 7 days, 1 month, 3 months, and 6 months following surgery. Dexmedetomidine was associated with a reduced rate of PACU delirium (5% vs. 10%, P=0.03), and cognitive impairment on postoperative day 3 (15% vs. 24%, P=0.006), day 7 (12% vs. 18%, P=0.03) and at 1 month (16% vs. 25%, P=0.04) but not at 3 and 6 months following surgery. The serum concentration of brain-derived neurotrophic factor, a neuronal growth factor, was decreased by general anesthesia but this effect was attenuated in those who received dexmedetomidine. The authors report a threshold change from the preoperative concentration of serum brain-derived neurotropic factor of 1.43 and 0.63 ng/mL on days 3 and 7, respectively, as having optimal sensitivity and specificity to predict cognitive dysfunction on those days with a sensitivity and specificity of 0.9 and 0.3, respectively, on both days.

POCD in Adults

Unlike postoperative delirium, a temporary state, POCD represents a prolonged decrease in cognitive function following anesthesia and surgery. Mahanna-Gabrielli et al232 report on the proceedings of the ASA’s Brain Health Initiative Summit. The authors summarize epidemiology, risk factors, pathophysiology, and the potential role for biomarkers for POCD. In addition, they address the role for presurgical cognitive screening, provide recommendations to minimize risk, and summarize diagnostic techniques, treatment options, prognosis, and outcome in those with POCD.

Preoperative predictors of postoperative delirium and cognitive decline include frailty, reduced cognitive function, and lower formal education.214,233 Preoperative screening for frailty and reduced cognitive function can help stratify risk, prepare the patient and their family, and offer some prognostic information regarding risk for POCD.234–236 Amini et al237 report on the feasibility of establishing a preoperative screening program to detect frailty and cognitive deficits in a high-risk population of patients 65 years of age or older having surgery at a tertiary medical center. A patient was described as frail if they exhibited ≥4 of the following: (1) unintended weight loss, (2) exhaustion, (3) slow walking speed, (4) decreased grip strength, or (5) low physical activity. Cognitive function was assessed by asking patients to both draw a clock and copy a drawing of a clock and results were scored using Mini-Cog criteria.238 Memory was assessed by asking patients to recall 3 words after 2 to 3 minutes. The authors implemented this screening protocol by first instituting a pilot phase of 276 patients followed by an implementation phase of 694 patients. Using data from the 694 patients enrolled in the implementation phase of the study, increasing age and frailty and lower number of years of education were all associated with impaired cognitive abilities and memory. Cardiovascular surgery was associated with the highest frailty and number of comorbidities, whereas gastrointestinal surgery was associated with the lowest rate of frailty and the least number of comorbidities. However, the surgical type was not associated with differences in preoperative cognitive abilities. The investigators estimated that 19% of patients had a >90% chance of suffering from postoperative cognitive disorders, although they did not measure rates of postoperative delirium or POCD. Increased length of hospital stay was significantly associated with poorer performance on the clock copy test but not with 3-word recall, degree of frailty, nor the ability to draw a clock on command. These findings were supported by retrospective data derived from 1132 patients above 60 years old that showed that preoperative Mini-Cog test scores did not predict the length of ICU stay, rate of discharge to home with self-care, and rate of readmission.239

Cognitive training has been shown to have a durable positive effect on cognitive function in the elderly.240 Vlisides et al241 randomized 61 patients above 60 years of age to either no preoperative cognitive training or to perform computer-based cognitive exercises daily for the 7 days before surgery, for 20 minutes each day. Rates of postoperative delirium, short-term POCD, hospital length of stay, and physical therapy participation rates were all similar between groups. In the cognitive training group, 48% did not complete any of the training exercises with only 17% completing all of the assigned training. Reasons for not completing training included computer limitations, time commitment, and feeling overwhelmed before surgery. As the goal of this investigation was to assess feasibility, it was likely underpowered to detect differences in outcome. Also, differences in outcome may exist if rates of compliance with cognitive training can be improved.

Recently, the International Perioperative Neurotoxicity Working Group proposed that the diagnosis of a perioperative neurocognitive disorder will require both objective evidence and subjective complaints of cognitive decline.242,243 Deiner et al244 compared rates of subjectively reported cognitive complaints with objective assessments of cognitive function both before and 3 months following surgery in a cohort of 120 patients above 65 years of age. Subjective complaints were assessed based on a positive response to the question, “do you feel that surgery negatively impacted your quality of thought?” Cognitive function was assessed with the Uniform Data Set Battery.245 At 3 months following surgery and anesthesia, 13% reported a subjective cognitive decline, whereas 34% had objective evidence of cognitive decline. Subjective complaints have a 24% and 92% sensitivity and specificity, respectively, to predict objective cognitive decline. Monsch et al246 describe a user-friendly neurocognitive screening tool that can be self-administered by patients and used by clinicians to screen for cognitive decline.

Neuroinflammation is believed to play a role in the pathophysiology of POCD.247 Although multiple inflammatory mechanisms have been described, infiltration of the central nervous system by peripheral mononuclear cells is associated with postoperative cognitive deficits in animals.248 Berger et al249 performed lumbar punctures to obtained CSF samples before and again 24 hours and 6 weeks following surgery on 10 patients 60 years of age or older having noncardiac and non-neurological surgery lasting >2 hours. CSF samples were analyzed by flow cytometry that included immunophenotyping. Cognitive function was assessed at 6 weeks following surgery and 5 (50%) patients were identified as having POCD. Patients who developed POCD had increased ratios of monocytes to lymphocytes in CSF at 6 weeks after surgery. Monocyte chemoattractant protein 1 receptor was significantly downregulated at 24 hours in those who had POCD at 6 weeks, but the expression was not changed in those that did not develop POCD. The authors hypothesize that increased monocyte chemoattractant 1 signaling could enhance monocyte entry in the central nervous system which would subsequently cause downregulation of monocyte chemoattractant 1 receptor expression. These data do further support that inflammation may at least in part play a role in POCD.

Maresins are a group of compounds produced by macrophages that decrease inflammation.250 Yang et al251 performed orthopedic surgery in mice that either did or did not receive 100 ng maresin-1 intraperitoneally before skin incision closure. There was an attenuation of the postoperative increase in serum biomarkers after surgery in mice that received maresin-1. Morphologic changes in brain astrocytes and microglia after surgery were also attenuated by maresin-1. Mice that received maresin-1 had freezing behavior rates similar to a nonsurgical cohort with improved rates of freezing compared with that observed in the surgical group that did not receive maresin-1.

Han et al252 measured morning (AM) and evening (PM) salivary cortisol concentrations in 120 patients above 60 years old on the day before noncardiac surgery with general anesthesia. POCD occurred in 17% of participants at 1 week after surgery. The median AM-to-PM ratio of salivary cortisol was significantly higher in those that developed POCD (5.16, IQR=2.31 to 8.27) than those that tested negative for POCD (2.60, IQR=1.68 to 4.39; P=0.006). This difference was significant even after correcting for preoperative performance on the Mini-Mental State Exam. The optimal cutoff ratio of AM-to-PM salivary cortisol concentration was ≥5.69 resulting in an area under the receiver operating characteristic curve of 0.72 and a sensitivity and specificity for predicting POCD of 50% and 91%, respectively.

For readers interested in the relationship between inflammation and postoperative cognitive decline, Subramaniyan and Terrando253 provide a narrative review that summarizes the pathophysiological relationship between inflammation on cognitive decline and addresses the role of biomarkers and imaging as potential ways to identify patients at increased risk for POCD.

Exposure to anesthesia for noncardiac surgery has not been found to be associated with increased risk for subsequent dementia.254,255 Using data from the Mayo Clinic Study of Aging,256 Sprung et al257 identified 1410 participants above 70 years of age with a recent MRI of the head of whom 1,097 had at least 1 exposure to anesthesia after age 40 years and 932 had at least 1 exposure to anesthesia within 20 years of MRI. Participants who had at least 1 anesthetic exposure after the age of 40 years or in the 20 years before MRI had significantly decreased cortical thickness in the entorhinal, inferior temporal, middle temporal, and fusiform regions. However, anesthesia exposure was not associated with the number of white matter hyperintensities or infarctions as detected with fluid-attenuated inversion recovery imaging. These findings need further confirmation but suggest that anesthesia exposure in elderly patients may be associated with structural changes in the brain consistent with neurodegeneration.


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neuroanesthesiology; perioperative neuroscience; neurocritical care; craniotomy; spine surgery; stroke; monitoring; anesthetic neurotoxicity; delirium; postoperative cognitive dysfunction

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