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J Neurosurg 2008;108:37–41 transsphenoidal surgery for residual endocrine-inactive macroad- 41 order hyzaar 12.5mg free shipping hypertension food. Neurosurgery 2006;58:857–865 generic 12.5 mg hyzaar otc hypertension 16090, discussion 857–865 fects of hydrogen peroxide on brain and brain tumors cheap hyzaar 12.5mg on line heart attack and vine cover. The extended direct endonasal 2003;59:398–407 order hyzaar 50 mg mastercard heart attack grill calories, discussion 407 transsphenoidal approach for nonadenomatous suprasellar tumors. Graded repair of cra- J Neurosurg 2005;102:832–841 nial base defects and cerebrospinal fuid leaks in transsphenoidal 35. Neurosurgery 2007;60(4, Suppl 2):295–303, discussion scopic approach for pituitary adenomas and other parasellar tumors: 303–304 a 10-year experience. Clinical review: Early morning rebrospinal fuid leaks obviates tissue grafts and cerebrospinal fuid cortisol levels as a predictor of remission after transsphenoidal sur- diversion after pituitary surgery. Operative Neurosurgical Techniques: Indications, the adhesion and growth of cells. Development of a histological pseudo- 635–641 capsule and its use as a surgical capsule in the excision of pituitary 46. Are 1995;82:406–412 nonfunctioning pituitary adenomas extending into the cavernous 47. Recognition and of cavernous sinus invasion by pituitary macroadenoma using three- management of delayed hyponatremia following transsphenoidal dimensional anisotropy contrast periodically rotated overlapping pituitary surgery. The goal is to resolve symptoms and control tumor progression without causing additional neurologic defcit. Radical re- I Indications for Endoscopic Endonasal moval, if associated with signifcant postoperative defcits, is no longer acceptable. The advantages of an extradural ap- with the microscope, became the approach of choice. The endoscope im- nerves; the operation proceeds through surgical corridors proves the possibility of accessing, through an extracranial with no risk (medial and posterosuperior compartments) or route, the lateral extension of the tumor thanks to the pan- little risk (anteroinferior or lateral compartments) of cranial oramic and angled view and peripheral magnifcation. If there is an intradural growth, a transcra- anatomical study in 2001, Alferi and Jho4 demonstrated the nial approach, or a combined or multistaged craniotomy and feasibility and the advantages of the endoscope in the endo- endoscopic approach, is preferred. Another extreme lateral approach may be consid- a Xenon 300-W cold-light fountain source, an endoscopic ered, namely the trans-maxillo-pterygoid approach, which video camera, and a video recorder. Therefore, multiple endoscopic endonasal ap- cleaning system with pedal control is used to reduce the 212 212 21 Endoscopic Pituitary Surgery in the Cavernous Sinus 213 necessity of extracting the telescope from the nose every Stage I: Approach time vision becomes unclear. At the end of the approach The lateral dislocation of the middle and upper turbinate al- phase and during the tumor removal phase, we use a me- lows the localization of the sphenoethmoidal recess and the chanical holder for the endoscope to allow the surgeon to natural ostium of the sphenoid sinus. The camera zoom allows a better The opening of the sphenoid sinus starts with the en- defnition of the anatomical features, and positioning the largement of the natural ostium. The anterior sphenoidot- endoscope further away from the surgical feld reduces the omy should be wide, extending from the roof to the foor of possibility of contamination of the tip of the telescope by the sphenoid sinus vertically and exceeding the sphenoidal blood. To gain access to the surgical feld from both nostrils, 1 cm of the posterior end of the nasal septum has to be removed, using a back-biting forceps. We be- the paraclival carotid protuberance vertically and 1 cm lat- lieve that they should be adjuncts to, and not substitutes for, erally to the sella, exposing the main bulge of the parasellar the navigation system and the Doppler. The nose and face are cleaned with soap and aqueous (more rarely) making an incision into the medial wall in a solutions. The nasal mucous membranes are decongested safe area (normally located in the posterior two thirds of the with 5% Xylocaine. At the Midline Transsphenoidal Endoscopic Approach end of the removal stage, free-hand exploration into the sur- The surgical procedure can be divided into three stages: ap- gical feld using angled 30- and 45-degree optic scopes is proach, tumor removal, and closure. Tumor removal from the sella cavity and the anteroinferior com- docrine-inactive macroadenomas. Suboptimal sphenoid and sellar exposure: a consistent fnding in 21 Endoscopic Pituitary Surgery in the Cavernous Sinus 215 Fig. The procedure can be schemati- performed, taking into account the degree of pneumatization cally divided into three stages. After ligation of the sphenopalatine artery, the superior portion of the medial pterygoid process located between the opticocarotid recess and the paraclival is drilled out. A partial resection of the pterygoid process is on the foor of the sphenoidal sinus is a useful landmark Fig. Age ranged from 18 to 77 years (mean, 50; me- The overall results of the multimodal management of the dian, 51). There was at least a 6-month follow-up (range, 6 individual patients were classifed in the comprehensive to 102; mean, 30; median, 23). Pituitary adenomas were histologically and immunohis- Statistical analysis was performed using the Fisher’s ex- tochemically investigated. The None of 32 patients with preoperative hypopituitarism referral symptoms are shown in Table 21. In one case, visual worsening, due to overpacking of the sur- Surgical Results gical cavity, occurred, and it was only partially corrected by early surgical revision. The surgical results for individual procedures were evalu- All preoperative neurologic symptoms (Table 21. We did not fnd any association between the sex variable and each category of outcome data. The last column indicates the number of patients still presenting an uncontrolled disease despite a multimodal treatment. Based on a long-term follow-up, it seems that, in patients un- Patients with focal invasion had a better chance of disease der 40 years of age, there was less control of the disease. Histopathologic Findings: Proliferative Index Consistency The Ki-67 proliferative index was measured in every sur- gical specimen; in the majority of cases (72%), it was less We analyzed the consistency subdivided into two groups: soft than 3%, and in 25 (28%) cases it was between 3 and 10% tumors and hard tumors (intermediate and hard consistency, (Table 21. The two-sided p-value shows a signifcant cor- We found a proliferative index higher than 10% in nine relation (p =. Two out of these nine cases were both positive for p53 having hard tumors have a lower probability of total tumor and developed metastases (one after 3 months and one af- removal, but this did not afect control of the symptoms. In one, the disease has not been controllable even after craniotomy and radio- Type of Tumors therapy. Surgical and endocrinologic complications are summarized This is the reason why variations in the classic microscopic in Table 21. Lalwani et al14 accessed this route using a Lynch in- In one case, a worsening of a visual defcit was observed; cision and combined this with a medial maxillectomy when it was related to overpacking of the sella and was only par- necessary. Arita et al,15 using a slightly modifed speculum, tially corrected by early surgical revision. One delayed (18 days osteotomy or by fracturing the medial wall of the maxillary after surgery) epistaxis was observed, and it required in- sinus in the standard transsphenoidal approach with the use traoperative coagulation of the sphenopalatine artery after of a modifed speculum. Taneda19 suggested an extended microscopic transsphenoi- One patient died 3 months after surgery from tumor dal approach with a submucosal posterior ethmoidectomy. One patient, 6 years after surgery, developed rigid, with limited lateral visualization due to the use of the multiple brain metastases; he underwent a retrosigmoid ap- speculum and the optical features of the microscope.

Positioning for intubation is based on the known differences in the neonatal airway order 50mg hyzaar overnight delivery blood pressure patch. No changes in position are usually needed hyzaar 50mg without a prescription arteria bulbi urethrae, although additional extension of the head may be accomplished by a shoulder roll cheap hyzaar 50mg sinus arrhythmia icd 10. Sliding the blade down the right side of the mouth allows the blade to be seated with minimal overlap by the tongue (Fig purchase hyzaar 50mg line heart attack ekg. The tip of the blade is advanced to lift the epiglottis directly instead of placing it in the vallecula, as is commonly done with older patients. Every patient’s anatomy is different, but if the laryngoscope is advanced in the direction parallel to the handle, one will get the best visualization. If the 2971 glottis is not easily seen, cricoid pressure can be applied with the little finger of the hand holding the handle or by an assistant, often improving the view (Fig. Uncuffed tubes have traditionally been used in newborns to minimize cuff pressure on the subglottic larynx, especially at the level of the cricoid cartilage. Modern cuffed endotracheal tubes make minimal sacrifice in tube diameter to allow for the presence of a cuff, which has renewed interest in cuffed endotracheal tubes. Although various formulas have been proposed for how far to advance an uncuffed tube, it is prudent to use the depth markers at the end of the tube to ensure under direct vision that the tip is advanced 2 or 3 cm past the vocal cords. Once inserted, the presence of a positive capnograph tracing, bilateral expansion of the thorax, and bilateral breath sounds are used to ensure proper placement. Although some anesthesiologists prefer to advance the endotracheal tube past the carina and then withdraw until bilateral breath sounds are heard, there are two major disadvantages to the technique: trauma to the airway and lack of a guarantee that the tip of the tube is not sitting right at the carina, increasing the chance of migration into a bronchus with head movement. Finally, listen for an air leak at an airway pressure of about 20 cm H O to2 ensure that the tube is not too large for the airway, increasing the chances of subglottic edema and damage. Fiberoptic laryngoscopy, the most flexible of intubating tools routinely used in older children and adults, can also be used in the newborn. After establishing a baseline of acceptable ventilation, it is important to continuously monitor the peak airway pressures, chest expansion, return volume, pulse oximetry, and capnograph tracings for changes. Initial tidal volumes of 6 to 7 mL/kg and rates of 20 to 25 breaths per minute are a reasonable starting point for most patients. With this rate 2973 and volume setting, it would be expected that peak airway pressures be approximately 20 cm H O. Of course, this strategy must be modified for some patients with severe coexisting disease. Mechanical ventilation of the neonate can be challenging for the anesthesiologist. Modern anesthetic systems make ventilation much easier than in the past, even in the smallest patients. Although the standard has been to use pressure control ventilation in this population, all modes of ventilation are now readily available on modern anesthesia machines. Table 42-4 shows the modes of ventilation and breath synchronization most commonly used in neonates. Use of high frequency ventilation in the operative setting will require use of a specialized ventilator and close consultation with a critical care physician and respiratory therapist. Table 42- 5 lists some of the advantages and disadvantages to use of pressure control, volume targeted, and high frequency ventilation. Table 42-4 Common Ventilator Strategies in Neonates Impact of Surgical Requirements on Anesthetic Technique Every procedure has its own unique challenges. With any surgery, issues related to presurgical resuscitation, perioperative fluid and blood loss, 2974 heat loss from the surgical field, likely perioperative complications, and the likely need for postoperative intubation and ventilation should be anticipated, both on the basis of experience and communication about the unique needs of the upcoming procedure. There is a dramatic increase in the use of laparoscopic and thoracoscopic approaches to lesions, even in the smallest neonates. There may be less blood, fluid, and heat loss, but there are additional issues related to positioning, insufflation pressures in the chest and abdomen, and prolonged surgical time. As new techniques evolve, close communication between the anesthesiologist and the surgeon is necessary to ensure adequate preparation, monitoring, and resolution of problems or complications. One not well-recognized factor that may result in higher concentrations of volatile anesthetics being administered to infants has to do with the use of nonrebreathing systems such as the Bain or a Mapleson “D” circuit. When an adult circle system is used with infant tubes and bag, the clinician experienced with this equipment is used to reading the inspired, end-tidal, and dialed concentrations of the volatile anesthetic. In the circle system, the inspired concentration is a result of the combination of the end-tidal concentration that is rebreathed through the soda lime absorber and the dialed concentration. The inspired concentration is always lower than the dialed concentration, unless the flow rates are so high that a nonrebreathing system has been created. In the nonrebreathing system, the dialed concentration is the inspired concentration. However, if the clinician switches back and forth between the circle system and a nonrebreathing circuit, but does so infrequently, there is a danger of not recognizing the possibility of excessive overpressure of volatile anesthetics with the nonrebreathing systems. The newborn infant has elevated progesterone levels, similar to those of the mother. Elevated levels of β-endorphin and β-lipotropin have been demonstrated in infants in the first few days of postnatal life. Regional Anesthesia 2976 There has been a tremendous increase in the use of regional anesthesia in infants and children. In general, regional techniques are combined with general anesthesia to permit early extubation and provide postoperative pain relief. Useful regional anesthesia techniques include spinal anesthesia, caudal anesthesia, epidural analgesia, penile block, and other peripheral nerve blocks (Table 42-6). Regional anesthesia may even have other applications outside surgery, including management of neonatal limb ischemia. The use of ultrasonography has revolutionized the use of regional anesthesia as vascular structures can be easily avoided while still providing a regional blockade. The use of sole regional anesthesia in neonates and infants is for avoidance of general anesthetics, for either theoretical decreased risk of apnea or decreased risk of neurotoxicity. Although neurotoxicity trials are still ongoing, it has been shown that spinal anesthesia decreases early apnea following surgery in premature neonates, but does not decrease the risk of overall apnea following surgery in premature neonates. Some patients may benefit from providing a caudal block in addition to the spinal anesthetic. Total spinal anesthesia, produced either with a primary spinal technique or secondary to an attempted epidural puncture, will present as apnea, rather than as hypotension, because of the lack of sympathetic tone in infants. The exact mechanism for the lack of cardiovascular change with spinal anesthesia in infants and young children is not clear. Consequently, the first indication of a high spinal is falling oxygen saturation rather than a falling blood pressure. Sedation can be added to regional anesthesia but may cause problems with apnea in ex-premature infants.

Variations in diag- nostic accuracies of tests are due to differences in cutoff values discount 50 mg hyzaar blood pressure medication insomnia, testing platform used order hyzaar 12.5 mg without a prescription low pressure pulse jet bag filter, and study designs [16] buy hyzaar 50mg with mastercard blood pressure medication helps acne. The intensity of the color is read against a reference card effective 12.5mg hyzaar hypertension teaching plan, and concentrations are reported as <0. However, interpretation of this test can be difficult, given that the test results are somewhat subjective in nature [26]. Although turnaround times vary from laboratory to laboratory based on testing platform and staffing, the aver- age turnaround time is approximately 3 h for quantitative tests performed in the clinical laboratory [11]. Sepsis is currently defined as a systemic inflammatory response to bacterial, fungal, or viral infections [45]. It is an innate physiologic response by the immune system to infection, involving complex pathophysiologic processes with many different disease mechanisms, including 128 A. Schuetz coagulation, inflammation, complement activation, and apoptosis in many different organ systems in the body [46]. The septic response to infection is a complex chain of events involving many different arms of the immune and circulatory systems [ 43]. Early in the disease course, a massive release of inflammatory mediators is in part responsible for organ hypoperfusion and dysfunction [47 ]. The innate immune response directly or indirectly results in the release of thousands of endogenous mediators of inflammation and coagulation [48 ]. Treatment of sepsis focuses on administration of broad-spectrum antimicrobials, with stabilization of the circulatory system. The traditional diagnosis of sepsis based on physical findings and conventional laboratory methods is complicated by the nonspecific signs and symptoms and high variability of presentation from patient to patient [49]. Methods of diagnosis include culture, but diagnosis by culture is prolonged due to length of time to grow the microorganism. In addition, cultures may be insensitive, as some organisms may not grow under certain circumstances, and others may only be present in very low concentrations below the threshold of sensitivity for the blood culture system used [ 50]. Hence, a definitive microbiological diagnosis can only be made in two-thirds of patients with clinical sepsis [51]. Leukocytosis and band counts of peripheral blood also have low diagnostic accuracy for sepsis [52]. Rapid diagnosis of sepsis is important in order to start appropriate antimicrobial and other therapy, because even a 1-h delay in beginning antibiotic therapy increases mortality of infection and sepsis by 5–10% [41]. Alternative diagnostic methods, such as molecular-based testing, increase sensitivity and specificity and decrease time to results. Biomarkers can also decrease the time to results, as the assays are more typically rapid than conventional cultures. The role of biomarkers in determining the severity of sepsis for prognostic purposes has been assessed, in addition to the differentiation of bacterial from viral or other causes of infection [20, 53]. Biomarkers have also been used to guide antibiotic therapy, to differentiate gram-negative from gram-positive microorganisms as the cause of sepsis, and to evaluate response to therapy [20, 54 ]. Investigators have studied hundreds of biomarkers in an effort to identify sensitive, specific, and rapid markers of sepsis, more so than in many other disease processes [ 55]. C-reactive protein has been utilized as a biomarker for many years, but its specificity is relatively low [ 57–59]. In their review of 3,370 studies on biomarkers of sepsis, Pierrakos and Vincent found that 178 different biomarkers were evaluated amongst the studies [55 ] 7 Infectious Disease Biomarkers: Non-Antibody-Based Host Responses 129 Some of these biomarkers were evaluated only in experimental studies, and some were evaluated in clinical studies. An overview of the most commonly reported biomarkers will be presented, as will some novel biomarkers which appear promising for future use in clinical diagnostic laboratories. However, most studies have been somewhat small in number with fewer than 200 patients. In a large prospective multicenter observational study, blood was collected within 24 h of onset of sepsis in 1,156 hospitalized patients [62]. Since it rises relatively slowly, it may not be a highly sensitive marker of infection during initial assessment. Sequential measurement has been utilized to evaluate response to therapy in septic patients [58]. The wide range of diagnostic accuracy reported in the literature is mainly due to the wide range of cutoff values reported in different studies [16]. The Roles of Miscellaneous and Novel Biomarkers in Infectious States Other biomarkers have been examined for a variety of roles in the diagnosis and/or management of infectious diseases. Angiopoietins Angiopoietins (Angs) comprise a family of vascular growth factors which act on endothelial cells. Ang-1 stabilizes the endothelium, preventing vascular leakage, inflammation, and the recruitment and transmigration of leukocytes [112 ]. Ang-1 exerts its action by binding to the Tie2 receptor (tyrosine kinase recep- tor with immunoglobulin and epidermal growth factor domains). Ang-2 is stored with von Willebrand factor in platelets and is released from monocytes and endothe- lial cells in septic shock [113]. The actions of Ang-1 and Ang-2 antagonize each other, and Ang-2 competes with Ang-1 for binding to the Tie2 receptor [114 ]. In animals, infusion of lipopolysaccharide stimulates the expression of Ang-2 and attenuates gene expression of Ang-1 [115 ]. Schuetz Numerous studies have shown that Ang-2 expression is increased in sepsis [116, 117]. Some studies have demonstrated increased Ang-2/Ang-1 ratios in patients who did not survive sepsis [118, 119]. Ricciuto and colleagues assessed the ability of a panel of biomarkers including Angs to predict outcome in sepsis [120]. The panel included Ang-1, Ang-2, von Willebrand factor, soluble intercellular adhesion molecule-1, and E-selectin. Ang-1 has itself been an independent factor related to unfavorable outcome in infection [ 113]. Activated protein C, which is used in the treatment of sepsis, increases the level of Ang-1 and decreases the level of Ang-2 in vitro [121]. One study of Angs in patients with invasive streptococcal infections demonstrated greater dysregulation of Angs in patients with shock than in those without shock [122]. Neopterin Neopterin is a mediator of cell immunity against intracellular pathogens. It has been used to discriminate between bacterial and viral origins of lower respiratory tract infections [ 123, 124]. It is constitutively expressed in low levels in all cells but most abundantly in the lung [135]. A study has shown that presepsin increased propor- tionally to the severity of sepsis [149]. Cytokines The cytokines comprise a group of compounds which are currently well studied as potential biomarkers of sepsis. As important mediators in the complex pathway of sepsis, they are produced early after the onset of sepsis [55 ]. However, blood cytokine measurements can be erratic, which render interpretation difficult [150]. Circulating cytokines have short half-lives, which can result in false negative results [ 18, 106].

Identification of such genetic contributions not only to disease causation and susceptibility but also to the individual patient’s responses to disease and drug therapy generic hyzaar 50mg without a prescription blood pressure norms, and incorporation of genetic risk information in clinical decision-making generic 12.5mg hyzaar mastercard heart attack in the style of demi lovato ameritz top tracks, may lead to improved health outcomes and reduced costs discount hyzaar 12.5 mg mastercard heart attack or heartburn. However order hyzaar 50 mg with mastercard hypertension 2013, some individuals are more sensitive than others to any given exposure to perioperative stressors, making them more susceptible to develop adverse events. Heterogeneity in response at the individual level tends to 403 “stretch out” the population-level dose–response curve for any perioperative stress 8 exposure. The occurrence of perioperative adverse events is further determined by the effectiveness of adaptive (hormetic) responses to perioperative stressors, which can mitigate injurious systemic host responses. In addition to the nuclear genome, the mitochondrial genome encodes for 37 genes essential to mitochondrial function. As it will be shown later, haplotype analysis is a useful way of applying genotype information in disease gene discovery. Glossary: locus, the location of a gene/genetic marker in the genome; alleles, alternative forms of a gene/genetic marker; genotype, the 405 observed alleles for an individual at a genetic locus; heterozygous, two different alleles are present at a locus; homozygous, two identical alleles are present at a locus. Furthermore, although the human genome contains only about 26,000 genes, functional variability at the protein level is far more diverse, resulting from extensive posttranscriptional and posttranslational modifications. Such dynamic genomic markers can be incorporated in genomic classifiers and used clinically to improve perioperative risk stratification or monitor postoperative recovery. An14 example of using the interplay between static genomic and dynamic genomic information for perioperative risk prediction in the case of thoracic aortic disease follows. Although surgical repair of thoracic aortic aneurysms is typically recommended when the aortic diameter reaches 5. Thus functional variability at the protein level, ultimately responsible for biologic effects, is the cumulative result of genetic variability as well as extensive transcriptional, posttranscriptional, translational, and posttranslational modifications. We illustrate such applications with several examples from the perioperative period. Rather than being the primary source of serum cytokines as previously believed, peripheral blood leukocytes only assume a primed phenotype upon contact with the extracorporeal circuit which facilitate their trapping and subsequent tissue-associated inflammatory response. Similar whole blood transcriptomic analyses in cardiac surgical patients have identified convergent regulatory mechanisms triggered by ischemia- reperfusion (e. Using28 27 circulating blood cells as a sentinel or reporter tissue is complemented by a large number of reports describing gene expression changes directly in myocardial tissue in response to acute ischemia, such as alterations in immediate-early genes (c-fos, junB), genes coding for calcium-handling proteins (calsequestrin, phospholamban), extracellular matrix, and cytoskeletal proteins in ischemic myocardium, as well as upregulation of17 transcripts involved in cytoprotection (heat shock proteins), resistance to apoptosis, and cell growth in areas of stunned myocardium. Whole-genome expression analysis has also been20 utilized to study molecular changes associated with myocardial preconditioning. The main functional categories of genes identified as potentially involved in cardioprotective pathways include a host of transcription factors, heat shock proteins, antioxidant genes (heme-oxygenase, glutathione peroxidase), and growth factors, but different gene programs were found to be activated in ischemic versus anesthetic preconditioning, resulting in two distinct molecular cardioprotective phenotypes. Deregulation of these conserved survival23 pathways thus appears to generalize across tissues, making them important targets for cardioprotection, but further studies are needed to correlate perioperative gene expression response patterns in end organs such as the myocardium to those in readily available surrogate tissues such as peripheral blood leukocytes. Alternative splicing, a wide variety of posttranslational modifications, and protein–protein interactions responsible for biologic function, would therefore remain undetected by gene expression profiling (Fig. This has led to the emergence of proteomics, a field seeking to study the sequence, abundance, modification, localization, and function of proteins in a biologic system at a given time and in response to a disease state, trauma, stress, or therapeutic intervention. Thus, proteomics37 offers a more global and integrated view of biology, complementing other functional genomic approaches. Several preclinical proteomic studies relevant to perioperative medicine have characterized the temporal changes in brain protein expression in response to various inhaled anesthetics,38,39 or following cardiac surgery with hypothermic circulatory arrest. This may focus further40 studies aimed to identify new anesthetic binding sites, and the development of neuroprotective strategies. The natural cardioprotective adaptations invoked by mammalian hibernators to cope with ischemia-reperfusion injury have been recently characterized using comparative proteomic approaches, and involve extensive metabolic remodeling with increased expression of fatty acid metabolic proteins and reduced levels of toxic lipid metabolites, offering insights into novel strategies for metabolic optimization as a transformative approach for perioperative organ protection. Furthermore,41 detailed knowledge of the plasma proteome has profound implications in perioperative transfusion medicine, in particular, related to peptide and42 protein changes that occur during storage of blood products. Innate and adaptive immune host responses to surgery play key roles in the pathogenesis of perioperative organ injury and dysfunction, prompting the use of comprehensive immune monitoring via flow cytometry (exact quantification of surface marker expression on blood immune cells) and cytokine determination for outcome prediction. Coronary sinus sampling distinguished cardiac-derived from peripheral metabolic changes. We applied a similar approach to cardiac45 surgical patients undergoing planned global myocardial ischemia/reperfusion, and identified clear differences in metabolic fuel uptake based on the pre- existing ventricular state (left ventricular dysfunction, coronary artery disease, or neither) as well as altered metabolic signatures predictive of postoperative hemodynamic course and perioperative myocardial infarction. Evidence from animal and human studies suggests that epigenetic mechanisms can explain susceptibility to acute and chronic pain, making them potential therapeutic targets. Specific epigenetic mechanisms relevant to perioperative analgesia involve the developmental expression of opioid receptors and opioid-induced hyperalgesia. This local anesthetic effect may have potential in the development of chronic pain and perioperative cancer medicine. Overview of Genetic Epidemiology and Functional Genomic Methodology Most ongoing research on complex disorders focuses on identifying genetic variants that modify susceptibility to given conditions or drug responses. Often the design of such studies is complicated by the presence of multiple risk factors, gene–environment interactions and a lack of even rough estimates of the number of genes underlying such complex traits. Genetic association studies examine the frequency of specific genetic or epigenetic variants in a population-based sample of unrelated diseased individuals and appropriately matched unaffected controls. The nature of most complex diseases in general, and perioperative adverse outcomes in particular (surgical patients are typically elderly), makes the study of extended multigenerational family pedigrees impractical (with few exceptions, e. Even a detailed family history, the first tool in the genomic toolbox, is seldom available for most categories of adverse perioperative events. Feasibility without requiring family-based sample collections, and the increased statistical power to uncover small clinical effects of multiple genes constitute the main advantages of the genetic association approach over 412 traditional linkage analysis methodology. Two broad strategies have been employed to identify complex trait loci through association analysis. The candidate gene approach is motivated by what is known about the trait biologically, with genes selected because of a priori hypotheses about their potential etiologic role in disease based on current understanding of the disease pathophysiology, and can be49 characterized as a hypothesis-testing approach, but is intrinsically biased. Until recently however, most significant results were gathered from candidate gene association studies. As it will be presented in more detail later, this includes most published reports on specific genotypes associated with a variety of organ-specific perioperative adverse outcomes, including myocardial infarction,50,51 neurocognitive dysfunction,52–54 renal compromise,55–57 vein graft restenosis,58,59 postoperative thrombosis,60 vascular reactivity, severe sepsis,61 62,63 transplant rejection, and death (for64 reviews, see references 1 and 4). The second strategy is the genome-wide scan, in which thousands of markers uniformly distributed throughout the genome or epigenome are used to locate regions that may harbor genes or regulatory regions influencing phenotypic variability. These are unbiased approaches, in the sense that no prior assumptions are being made about the biologic processes involved and no weight is given to known genes, thus allowing the detection of previously unknown trait loci. Although the73 74 75 76 ability to predict disease remains limited, the newly discovered genetic associations have provided insight into unsuspected mechanisms for disease, many of them located in known drug targets. Most genes however lack a common functional coding variant with a detectable functional effect, yet they typically contain several rare variants. A counter-hypothesis has emerged stating that there are additional novel genes harboring such low frequency variants (possibly with larger effects) that may be the primary drivers of common disease. Currently these variants are poorly detected by genotyping microarrays, but with the advent of next- generation sequencing technologies the potential exists to revolutionize complex traits genetics by identifying and typing rare variants and thus rendering virtually every gene susceptible for genetic analysis. Secondly, more than two-thirds of the variants identified so far are located either in intergenic regions or in genes of unknown function.