Future Advances in Neuroanesthesia

Numerous clinical situations remain as problematic issues which continue to vex neuroanesthesiologists and neurointensivists as they work to optimize outcomes for their patients. Nascent research ongoing at this time may provide a window to a future approach to these problems. In this chapter we review many of these new research areas and speculate as to how they may eventually translate to clinical care of neurosurgical patients in the operating room and neurointensive care unit. Areas to be reviewed include genomics, stem cells, neuroprotection, ICP management, technology, and pharmacology.

Genomics

Each cell has to produce proteins in order to function. The specific protein structure is determined by the sequence of base pairs on the organism’s DNA combined with post-translational modifications. One estimate is that there are some 35,000–40,000 genes with about 6,000 proteins active at any given time. However, actual protein composition varies according to the needs (and regulation) of the moment such that as many as 100,000 proteins are thought to be transcribed by a cell. Thus, the actual genetic structure of an individual has an important role in the development of and response to disease and the response to therapy.

The field of genomics is significantly complex. Notably the word “gene” has a multitude of definitions, reflecting the wide variety of approaches to the field. The field includes work with single nucleotide polymorphisms (SNPs), transcript mRNA studies, siRNA epigenetics and copy number variants. SNPs are naturally occurring variation in the specific DNA nucleotides that code for specific proteins resulting in naturally occurring variations in proteins with associated variations in function. After a gene has been transcribed into mRNA then further regulation with potential for variation arises such that there can be heritable changes in gene expression or translation without a change in DNA sequence, so-called epigenetics work. This concept is more recently and specifically described in siRNA (short interfering RNA) epigenetics studies wherein a transcribed mRNA is bound by a complementary siRNA, thus interfering (or regulating) the translation of the DNA nucleotide sequence into a protein. These observations have spawned an area of genetics research examining the possible uses of these interfering RNAs as future research or therapeutic tools.

To date, SNPs are the variant type of choice for association studies in common diseases and complex traits. This has resulted in many case control and association studies that have provided valuable information on age-related macular degeneration, diabetes, obesity, cardiovascular diseases, prostate cancer, and breast cancer. However, SNPs are not the only source of polymorphism of the human genome. Another abundant source of polymorphism, the so-called copy number variants, is one that involves deletions, insertions, duplications and complex rearrangements of genomic regions. Such polymorphisms can result in deletion of specific genes, as occurs with rhesus blood type, or with increased numbers of copies of genes, as has been demonstrated with alpha hemoglobin. Indeed, up to 10% of the variation in the human genome has been attributed to copy number variation (also called copy number polymorphism). Notably, the number of combinations and permutations of these causes of variation seem endless. Thus, biostatistical issues with sample size, repeated measures, sample independence, and association versus causation become essential considerations in experimental design and the ability to draw conclusions from the data. One practical result of these constraints with SNP and other studies is that the most robust conclusions can only be derived from variants which have a high enough frequency to reasonably allow for inferences to be drawn.

These and other current advances in causes of genomic variation foretell a day when an individual patient’s genome will be part of his/her history and physical examination. This information will be used to allow the anesthesiologist to optimize or individualize specific anesthetic effects, such as hyperemia or neuroexcitation in specific brain areas, define likely anesthetic tolerance and thus appropriate dosing, foretell susceptibility to ischemic and other types of brain damage, and adapt the application of general medical therapies to a person’s specific genomic signature. Moreover, this information will undoubtedly lead to efforts to alter an individual’s genotype, genomic regulation, or phenotype either with respect to the diseases anesthesiologists see in the operating room (OR) or with respect to specific responses to anesthetic interventions. A series of annual reviews have underscored these issues.

Specific Anesthetic Effects of Genetic Factors

Blood Flow and Metabolism

Probably the first report to detail a neurophysiologic effect of an anesthetic drug based on a single nucleotide polymorphism was published by Kofke et al. They determined the cerebral blood flow (CBF) response to increasing doses of remifentanil in human volunteers, determining an element of limbic system activation. However, subjects with an ApoE4 genotype had a different pattern of limbic system response from those who did not possess this SNP. If similar analogous effects of anesthetics are found with other SNPs we can expect an SNP-based selection of anesthetics based on the likelihood of producing some side effects such as cerebral hyperemia, ictal activation or suppression, and variable neuroprotection.

In a non-neurologic context early studies in rodents indicate that changes in chromosome composition affect cardiovascular responses to propofol. Countless other physiologic responses to anesthetics will also undoubtedly be determined with each patient’s genome studied for anticipated interactions between genome and reaction to an anesthetic or other perioperative drug.

MAC, Analgesia, and Other Anesthetic Side Effects

Redheads are known to require more anesthesia than the rest of the population. As such this represents probably the first observation of a heritable condition’s effect on MAC, although the specific SNP or set of SNPs or other causes of genetic variation producing red hair and linking this to anesthesia are not known. Early studies in nematodes have isolated specific genes which impact on sensitivity to anesthetics. ^, Moreover, specific genetic alterations in mice are reported to affect anesthetic sensitivity to disparate anesthetics pentobarbital, ketamine, and nitrous oxide. A clinical correlate of these observations can be found in Mullholland et al.’s report of the effect of various SNPs on several of the EEG responses to desflurane anesthesia in humans, though one might suggest that this is not that important as future management paradigms will most likely entail individual titration. Nonetheless this type of information will likely also relate to pain tolerance, anticipated needs for postoperative pain control regimens and, possibly, susceptibility to addiction. Such studies in humans have been published describing specific SNPs affecting pain tolerance and need for postoperative analgesia. In addition, neuropathic pain and more focused pain therapy is suggested in some preclinical studies evaluating effects of siRNA treatment on pain. Moreover, SNPs are now being described in humans regarding genetic predisposition to postoperative nausea and vomiting, ^, malignant hyperthermia, and cognitive dysfunction.

Pharmacokinetics

Genetic influences on pharmacokinetics have become reasonably well known for a handful of antihypertensive drugs as they relate to genetic effects on metabolism (e.g., hydralazine) and perioperative drugs. Certainly, genetic factors are known for such entities as pseudocholinesterase deficiency, the interaction of thiopental with porphyria, or the genetics of malignant hyperthermia. ^, Cytochrome P450 is important in the metabolism of many drugs including anesthetics. These genomic variations in cytochrome P450 have been reported to impact on the metabolism of midazolam and opioids, ^, with clinical relevance made manifest in a report of genomic differences with cytochrome contributing to mortality from non-medical fentanyl ingestion. Multiple other effects of genetic variation on anesthetic metabolism and side effects have been reviewed. It is clear that increased information will become available with respect to SNPs, arrays of SNPs, and other causes of genetic variation and their impact on anesthetic metabolism.

Ischemic Tolerance

One group reports that up to 10% or more of genes undergo alteration in expression after brain ischemia. ^, In humans, alterations in the expression of genes responsible for the inflammatory response have similarly been reported after stroke. ^, Many others report increased risk of stroke associated with different genotypes. Thus, the effect of one’s genomic inheritance on one’s predisposition to stroke and susceptibility to its sequelae may be an important piece of information. However, the preponderance of such research in humans deals with genomic contribution to risk of stroke and not with direct genomic contribution to tolerance of, or vulnerability to, brain ischemia, factors which, arguably, are of greater interest to the neuroanesthesiologist.

These risk-oriented studies are nonetheless important areas of research. However, they are confounded by the natural heterogeneity of clinical stroke and provide no information on the possible genomic contributors in humans to congenitally determined ischemic tolerance or vulnerability. Three lines of genetic research have introduced the notion of gene-based ischemic tolerance which may be a therapeutic target. In the first, altering the genetic makeup of animals subsequent to cerebral ischemia can alter the animal’s ischemic tolerance. In the second line of work, researchers have demonstrated that environmental factors introduced in advance of a severe ischemic insult can induce genes to produce proteins that provide tolerance to subsequent ischemia. The prototypical paradigm is one of ischemia or other insult inducing upregulation of heat shock proteins, which are important contributors to subsequent tolerance to a greater ischemic stress. Other genes have also been suggested as contributing to ischemic preconditioning. ^, Indeed, some authors are now suggesting induction of ischemic tolerance as the basis for recovery in an ischemic penumbra. And, thirdly, Kofke et al. have observed genomic factors apparently contributing to a greater release of biomarkers of brain damage during cardiac surgery.

Cerebral ischemia clearly has a significant effect on transcription and translation of important genes, perhaps related to organismal survival and evolution. ^, ^, ^, The phenomenon of ischemic tolerance has been known for many years. Although incompletely understood, a basis in altered genetic regulation seems likely ^, ^, with the most attractive corollary that such information will lead to gene-based therapeutics. ^, Gidday et al. observed that the extent of cerebral infarction in a neonatal rat model was substantially attenuated if animals were pretreated with small doses of hypoxia first. This work was further developed and supported with similar observations in other ischemic models. Recent work has suggested convincingly that elaboration of heat shock proteins has an important role in ischemic tolerance. Other candidate contributing genes have also been suggested. HIF-1 (hypoxia inducible factor) is one such alternate inducible protective protein. Also described in this context are erythropoietin, glial cell-line-derived neurotrophic factor, and TGF beta-1. One report provides convincing evidence that a significant component of HIF is, in fact, induced expression of erythropoietin.

The preischemic stress does not necessarily have to be an hypoxic/ischemic stress, as fever and acidosis (among others) also induce subsequent ischemic tolerance mediated by induction of a protective protein. Similarly, ischemic tolerance can be pharmacologically induced by pretreatment with estrogen (Bcl-2), cobalt chloride (HIF-1), desferrioxamine (HIF-1), or isoflurane. In contrast, ischemia, despite the induction of a plethora of putative protective genes, also induces the BRCA-1 associated protein BARD-1 that mediates apoptosis, which is thought to be deleterious. Genetic manipulation of mice has also been used and also demonstrates how genetic factors can alter endogenous vulnerability to an ischemic insult. ^, ^, ^, Bernaudin et al. identified several genes that appear to be regulated by hypoxia, leading them to suggest that these could have a role in a genetic predisposition to ischemic tolerance. Genetic makeup and gene expression clearly contribute to one’s vulnerability to brain ischemia.

Nonetheless the notion of ischemic preconditioning is an increasingly attractive one. Recent research underscores the complexity of this phenomenon with numerous reports on only some of the factors thought to play a role. One important practical consideration in translating these findings to clinical management will be defining whether a given preconditioning therapy has, indeed, introduced increased ischemic tolerance. This consideration underlies work which is endeavoring to identify biomarkers, indicating, before ischemia, that tolerance has been enhanced.

Hundreds of nucleotide polymorphisms are under active investigation of their contribution to stroke and other cardiovascular diseases. Such studies in humans generally deal with the role of a gene in risk of stroke. Many genes have been suggested, based on animal work such as that described above, to have important roles in determination of tolerance to ischemia. However, of the apparent myriad of potentially important genes only a relative handful of genes have been studied. Nonetheless, one can surmise, based on knowledge about the pathophysiology of cerebral ischemia, that evaluation of pathogenetically grouped genes would be a rational approach to screening for SNPs and other causes of genetic variation with potential therapeutic value. From such an approach one could develop “ischemic axes” with corresponding variant structure and regulation of genes, gene number, transcription, and translation, as depicted in Fig. 29.1 . This knowledge could be used to develop new neuroprotective therapies or, if known for an individual patient, be used to tailor optimal neuroprotective therapy. Finding such clinically relevant effects for a given patient’s or patient group’s genetic variables will then lead to more intense scrutiny of the protein eventually translated that is transcribed by a given gene. Such information will then lead to rational selection of genes for possible gene delivery or perhaps development of drugs which mimic the effect of favorable proteins or inhibit the effects of unfavorable proteins. Examples of the validity of this approach are now appearing.

Fig. 29.1, Proposed pathophysiologic axes of cerebral ischemia that can be used as a basis for single nucleotide polymorphism selection in the proposed research. 81

Several years of work from many investigators has shown the relevance of ApoE polymorphisms to neurologic outcomes. Thus, it should be clear that unlike most gene association studies used to predict a given patient’s risk based on his/her genomic profile, knowledge of SNP associations with ischemic tolerance will likely result in new genome-based gene, proteomic, or other categories of neuroprotective therapies. This is simply one example of potential translational outcomes from such genomic association studies. In the case of ApoE, work has followed on the neuroprotective potential of so-called apo-mimetic peptides. Preclinical reports indicate neuroprotective efficacy in hypoxia-ischemia, subarachnoid hemorrhage, peripheral nerve injury, traumatic brain injury, intracerebral hemorrhage, autoimmune encephalitis, and spinal cord injury. It thus seems likely that identified genomic contributors to tolerance or vulnerability to acute brain insults will lead to gene-based therapies and also associated proteomic-based therapies.

Risk of Comorbidities

Gene association studies with stroke are just one example of the role of genomics in defining a given medical risk. Such studies are burgeoning regarding a host of medical conditions. There have been some studies showing statistical associations between specific SNPs and postoperative complications. Specific examples include renal failure, ^, post-transplant kidney infection, total hip arthroplasty failure, ^, allograft dysfunction, pain intensity and analgesic requirements, vasopressor requirements, myocardial infarction, inflammatory response, thromboembolism, ^, stroke, and vascular graft patency. ^, These studies will undoubtedly contribute to risk assessment in individual patients and lead to new therapeutic strategies designed to minimize perioperative complications.

Application of Therapies to a Specific Genomic Signature

At the time of writing, characterization of the entire genomes of many humans has been accomplished. This, combined with the abovementioned material, indicates a future that will encompass patients arriving for surgery with their entire genomes on record. One expectation is personal genome sequencing in many healthy people who later present for neurosurgery. This will likely also include other personal “omics” profiling. Applied across a population, including neurosurgical patients, this suggests characterization of the genome, epigenome, transcriptome, proteome, cytokine-ome, metabolome, auto antibody-ome, and microbiome (gut, urine, nose, tongue, skin) for possibly billions of individuals. With this we will have a large amount of impressively big data (e.g., a million genes and other -omic information in millions to billions of people). One hoped for consequence of this will be an ability to predict and monitor diseases, resulting in personalized therapies identified from big data analyses that will increase tolerance to various brain insults in individual patients. In addition, -omic profiling may allow us to tailor anesthetics to individuals or at least predict the consequences of anesthesia and surgery. For example, metabolomic profiling using proton magnetic resonance spectroscopy in children under anesthesia has demonstrated that sevoflurane anesthesia results in higher brain lactate and glucose levels in children compared with propofol. Analysis showed a positive correlation between lactate and glucose levels with agitation and delirium.

Stem cells

Stem cells seem certain to be an important future therapeutic tool. ^, In fact, recent work has shown that transplantation of mesenchymal stem cells into patients following ischemic stroke not only is safe, but also may improve survival and functional outcome. In addition, recent work has shown that injection of mesenchymal stem cells into the intervertebral disc in patients with discogenic back pain may improve pain and function for up to 2 years post-procedure. Larger trials to investigate the utility of this therapy are currently underway.

This will have important implications for neuroanesthesiologists who may encounter patients who are having neural stem cells placed as part of an operative procedure or who have had them placed earlier with a variable extent of post-implantation differentiation. Given the recent data suggesting specific neurotoxicity of some anesthetics in developing brain, it becomes reasonable to suggest that anesthetics used in the context of stem cell placement could significantly affect the success of the graft. Moreover, the physiologic milieu of the implantation may also be important. One well-known example of this is the effect of hyperoxia on immature retinal cells. Blood pressure, pCO2, temperature, and other aspects of anesthetic administration may have a similarly important impact. Future research will be needed to resolve these issues.

Neuroprotection

Neuroprotection has long been and should continue to be a central focus of neuroanesthesia and neurocritical care. At the time of writing, notwithstanding ample promising preclinical work, there are very few neuroprotectant strategies that have sustained scrutiny in clinical trials. There is significant laboratory work which forms much of the basis of neuroanesthesia practice. Much of this is based on the notion that a physiologic or anesthetic decision needs to be made and in the absence of satisfactory human data, the preclinical laboratory data are used to justify a decision. This current situation should eventually be rectified. Some encouraging approaches are currently being evaluated. These probably represent only a small fraction of what will eventually become a part of an evidence-based approach to neuroprotection during neurosurgical procedures.

Hypothermia

Definition of Subsets Suitable for Hypothermia

Hypothermia presently has evidence-based support for its use after global brain ischemia. ^, Clifton et al.’s multi-institutional study in TBI indicates that a TBI patient arriving hypothermic should not be rewarmed, although a protective effect of de novo induction of hypothermia could not be demonstrated. The authors postulated that earlier induction of hypothermia may improve outcome; however, a second trial did not demonstrate any benefit. Meanwhile, others have shown that induction of long-term (5 days) vs. short-term (2 days) mild hypothermia may be associated with decreased incidence of rebound intracranial hypertension on rewarming and improved functional outcome. The IHAST study in over 1000 patients undergoing aneurysm surgery showed no efficacy from the global practice of inducing moderate hypothermia in all patients undergoing cerebral aneurysm surgery. It still leaves open the question of the potential efficacy for a patient with active severe intraoperative focal temporary brain ischemia, without dealing statistically with all of the patients who did not need the hypothermia. The overwhelming evidence of efficacy in animal studies and humans with deep hypothermic circulatory arrest suggest a need to better focus the clinical studies to better identify the clinical subsets in which it will be found efficacious.

New Methods to Induce Hypothermia

As with most neuroprotective therapies, the efficiency and efficacy of induction of hypothermia seems an important factor. Thus some research is ongoing that suggests important advances in the means by which hypothermia will be induced and maintained.

Ice Crystals

Cold fluids have long been used to decrease temperature. This may have problems with the volume of fluid needed to affect the desired endpoints. Reports on using an ice slurry given intravenously may result in an improved method to induce hypothermia quickly, safely, and in a controlled manner. Work is needed to ensure that the infused ice crystals have no sharp edges and thus pose no risk potential for endothelial trauma.

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