Current Pharmaceutical Design - Volume 18, Issue 38, 2012

Underlying cardiovascular disease is a potentially modifiable risk factor that contributes significantly to perioperative morbidity and mortality. Reducing perioperative and long-term morbidity and mortality requires risk modifying perioperative management. This, in turn, requires preoperative identification of patients with, or at risk of having cardiovascular disease. Preoperative cardiac evaluation includes, (i) recognition and treatment of active cardiac conditions, (ii) assessment of surgical risk, functional capacity, and clinical risk factors, (iii) identification of candidates for non-invasive cardiac testing, coronary angiography and preoperative coronary revascularization, and (iv) pharmacologic management. A cardiac risk assessment algorithm is useful in guiding systematic evaluation. Although preoperative cardiac evaluation has improved during the past decades, we are not yet in the situation where we can accurately predict individual perioperative risk because the individual stress response to a given stressor, and the individual interactions between pharmacological intervention and intra- and postoperative risk factors are highly variable. Furthermore, preoperative cardiac evaluation is only one aspect of overall perioperative care. There are numerous intra- and postoperative factors which have been shown to affect overall outcome. Not all of them can reliably be predicted or modified in a way which improves outcome. However, recognition of such factors and aggressive attempts at appropriate intervention may reduce overall risk more than preoperative evaluation in isolation. Without defining and subsequently targeting intra- and postoperative risk factors, the benefit of preoperative cardiac evaluation will be limited.

Hyperglycemia is associated with increased mortality and morbidity in critically ill patients. Surgical patients commonly develop hyperglycemia related to the hypermetabolic stress response, which increases glucose production and causes insulin resistance. Although hyperglycemia is associated with worse outcomes, the treatment of hyperglycemia with insulin infusions has not provided consistent benefits. Despite early results, which suggested decreased mortality and other advantages of “tight” glucose control, later investigations found either no benefit or increased mortality when hyperglycemia was aggressively treated with insulin. Because of these conflicting data, the optimal glucose concentration to improve outcomes in critically ill patients is unknown. There is agreement, however, that hypoglycemia is an undesirable complication of intensive insulin therapy and should be avoided. In addition, the risk of increased glucose variability should be recognized, because of the associated increased risk for worse outcomes. Patients with diabetes mellitus experience chronic hyperglycemia and often require more intensive perioperative glucose management. When diabetic patients are evaluated before surgery, appropriate management of oral hypoglycemic agents is necessary as several of these agents warrant special consideration. Current recommendations for perioperative glucose management from national societies are varied, but, most suggest that tight glucose control may not be beneficial, while mild hyperglycemia appears to be well-tolerated.

Increasingly more Americans are being diagnosed with diabetes mellitus, and the number of those using the continuous subcutaneous insulin infusion pump (CSII), commonly known as the insulin pump, is on the rise. Although evidence is lacking on how best to manage insulin pump patients perioperatively, several individual or institutional approaches have been developed. Here we propose a comprehensive algorithm for perioperative glycemic management in insulin pump patients undergoing noncardiac surgery. Where applicable, we discuss the rationale behind the algorithm.

The cornerstone of treating patients with shock remains as it has for decades, intravenous fluids. Surprisingly, dosing intravenous fluid during resuscitation of shock remains largely empirical. Recent data suggests that early aggressive resuscitation of critically ill patients may limit and/or reverse tissue hypoxia, progression to organ failure and improve outcome. However, overzealous fluid resuscitation has been associated with increased complications, increased length of intensive care unit (ICU) and hospital stay and increased mortality. This review focuses on methods to assess fluid responsiveness and the application of these methods for goal directed fluid therapy in critically ill and peri-operative patients.

Normal cognitive development depends on the timely formation of meaningful neuronal circuitries. These, in turn, depend on the proper formation and functioning of neuronal synapses, which control the flow of information between neurons. The time period when synapse formation is most intense is referred to as synaptogenesis, coinciding with the peak of brain development. The latest animal and human research suggests that general anesthetics, which act by modulating the fine balance in neurotransmission, may disturb the fine homeostasis necessary for neuronal signaling, resulting in morphometric and functional disturbances of developing synapses in synaptogenesis. Anesthesia-induced impairment of synaptogenesis is strongly age-dependant. At a younger stage, neurons respond by decreasing synaptic densities. But in later development, they respond by overly upregulating synapse formation. Although a direct causal link between disturbed synaptogenesis and behavioral development is not yet established, several animal studies have confirmed that cognitive development of rodents and non-human primates could be permanently impaired after a single exposure to clinically-relevant general anesthetics. Clinical evidence is now beginning to emerge suggesting that very young children may be susceptible to anesthesiainduced impairment of behavioral development, cognitive in particular. This review will summarize some of the presently available evidence regarding anesthesia-induced effects on developmental synaptogenesis and intellectual functioning.

Though general anesthetics have now been used clinically for well over a century, both their mechanisms of action as well as the nature of any potentially neurotoxic side effects remain elusive. With roughly 234 million people undergoing surgery each year worldwide, it remains imperative that any potentially deleterious effects of anesthetics be investigated and addressed. The issue of anesthetic- induced neurotoxicity in certain subsets of patients has continued to garner attention over the past decade, as more pre-clinical and clinical studies released are suggesting that inhalational and intravenous anesthetics may both cause and mitigate existing significant neuropathology. Pre-clinically, both cell-culture and animal studies suggest that anesthetics may cause neuroapoptosis, caspase activation, neurodegeneration, β-amyloid protein (Aβ) accumulation and oligomerization, and ultimately, deficits in neurocognition. Interestingly, however, newer data suggest that certain volatile anesthetics, such as desflurane, may have a less harmful neurotoxic profile compared to others in the pre-clinical and clinical settings. Continued pre-clinical investigation may have significant impact on clinical practice in the near future. Clinically, recent studies have raised awareness that exposure to general anesthetics during childhood may be associated with an increased risk for subsequent deficits in learning, memory, and cognition. Furthermore, retrospective studies continue to allude to the potential effects of surgery and anesthesia on cognitive trajectory, and more specifically, post-operative cognitive dysfunction (POCD) in the elderly. Studies to date regarding both of these clinical topics, however, are fraught with confounders, and many are underpowered statistically. The aim of this review is to examine the current data (both pre-clinical and clinical) on anesthetic-induced neurotoxicity and argue that further data are needed to either support or refute the potential connection between anesthetics and neurotoxicity.

Fospropofol is an intravenous sedative-anesthetic agent that is FDA-approved for monitored anesthesia care (MAC) sedation in adult patients undergoing diagnostic or therapeutic procedures. As a prodrug of propofol, fospropofol's pharmacologic activity results from its breakdown by alkaline phosphatase and release of propofol, which is the active molecule. It exhibits a longer time to peak clinical effect and a more prolonged action compared to propofol. Thus patients may exhibit smoother hemodynamic and respiratory depression compared to propofol lipid emulsion bolus. Another advantage over propofol is that it does not induce a burning sensation on IV administration. Side effects include perineal paresthesia and itching, respiratory depression, hypoxemia, hypotension, loss of consciousness, and apnea with higher IV boluses. Therefore, current recommendations call for it to be administered only by clinicians trained in general anesthesia, who are thus skilled in advanced airway management. Fospropofol has a unique dosing regimen, with a standard dose for adults 18-65 years of age, and a modified dose (75% of the standard dose) for patients > 65 years of age and for sicker adult patients whose American Society of Anesthesiologists physical status score is ≥ 3. Also, the minimum and maximun IV bolus doses are body-weight adjusted to 60 and 90 kg respectively. Available evidence demonstrates that fospropofol in MAC sedation is successful in patients undergoing esophagogastroscopy, colonoscopy and flexible bronchoscopy. The use of fospropofol is also now being explored in many other perioperative settings. In light of current shortages of many anesthetic drugs, whether forspropofol can take the place of propofol in ICUs and operating rooms remains to be determined.

Etomidate is a well established intravenous anaesthetic agent which has been widely used. Recognised limitations of the agent include adrenocortical suppression, myoclonus and post-operative nausea and vomiting, PONV. MOC-etomidate, carboetomidate and MOC-carboetomidate are novel etomidate derivatives. Their preclinical data and their potential for human administration are critically reviewed. ‘Soft’ pharmacology (rapid ester hydrolysis) limits the duration of action of MOC-etomidate and MOC-carboetomidate giving them rapid offset after administration is discontinued. Adrenocortical depression is minimised either by ester hydrolysis or by structural change to the etomidate molecule. Potential limitations include the yet to be determined incidence of myoclonus and PONV if these new agents are administered to humans.

The alpha-2 agonist dexmedetomidine is being increasingly used for sedation and as an adjunctive agent during general and regional anesthesia. It is used in a number of procedures and clinical settings including neuroanesthesia, vascular surgery, gastrointestinal endoscopy, fiberoptic intubation, and pediatric anesthesia. The drug is also considered a nearly ideal sedative agent in the intensive care setting. However, the drug frequently produces hypotension and bradycardia, and also decreases cerebral blood flow without concomitantly decreasing the cerebral metabolic rate for oxygen. This review discusses recent advances in the use of dexmedetomidine in anesthesia and intensive care settings, as well as discuss potential problems with its use.

The operating room offers a unique setting where anesthetics, preoperative medications, patient comorbidities, and surgery all merge. Anesthesiologists are responsible for combining these concerns into a dependable and safe approach. From formulation to administration, enhancements in nearly every aspect of a given drug have improved the ability of anesthesiologists to accomplish this. Some of these methodologies, including novel anesthetics and analgesics, drug delivery and administration including infusion pumps, antithrombotics, and a reappraisal of previous medications are highlighted in this review. While these advancements are significant, patients and healthcare systems globally are rightfully demanding safer application of drugs at every level. On May 1, 2012, a report issued by the Institute of Medicine advised the United States Food and Drug Administration to undertake a much more rigorous patient-centered effort to evaluate a drug's safety over its entire life-cycle. This recommendation is in agreement with the objectives of the Anesthesia Patient Safety Foundation. With these mutual goals shared by many stakeholders and their continued efforts, the future of the estimated 200 million global surgeries to be undertaken this year hopefully provides a safer experience while under anesthesia.

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are primarily used to treat dyslipidemia. Yet, these medications have a number of additional important pleiotropic properties that confer patient benefit in terms of reduced cardiovascular morbidity. Investigators have reported that statins may be underutilized in patients undergoing cardiac surgical procedures. Periprocedural benefits have been reported both in the short-term as well as with long – term post discharge follow-up period for both surgical and percutaneous coronary interventions. Mechanisms for statin's demonstrated benefit include improved endothelial function, antiinflammatory properties and stabilization of atherosclerotic plaque. While there are well-recognized side effects to statin therapy, its beneficial impact on patient cardiovascular outcomes is clear. Further research is necessary to determine specific patients who would best benefit from preoperative statin therapy, the dose and duration of therapy prior to surgical interventions and the influence of administration following surgery.

This update aims to provide an evidence based review of natural and synthetic colloids with a special emphasis on the various generations of the synthetic colloid hydroxyethyl starch. The effect of 1st, 2nd and 3rd generation hetastarches on bleeding, coagulopathy, acute kidney injury and mortality will be discussed. The results of randomised controlled trials addressing morbidity and mortality outcomes of colloid versus crystalloid resuscitation in critically ill patients will be described. In addition, the rationale and evidence behind early goal directed fluid therapy (EGDFT) including a practical approach to assessment of dynamic measures of fluid responsiveness will be presented.

Septic shock during the perioperative period imparts significant challenges for anesthetic management. There is increasing support for standardization of care using evidence-based, international consensus guidelines, such as the Surviving Sepsis Campaign. This review will highlight practices in the supportive management relevant to the perioperative care of patients with severe sepsis or septic shock and their effect on clinical outcomes. It will address the epidemiological data of sepsis, the diagnostic criteria, and the role of routine, goal-directed hemodynamic resuscitation. Furthermore, it will review other options for support, including antibiotics, intensive insulin therapy, and intensive care sedation in this high risk patient population.

The vasoconstrictive and antidiuretic physiologic properties of vasopressin (antidiuretic hormone) have long been known. Until recently however, vasopressin was mostly used for diabetes insipidus and noctournal enuresis. This review summarizes the growing body of evidence regarding the perioperative use of vasopressin and its analogues in the management of certain forms of cardiovascular collapse. Physiologically, vasopressin is involved in regulating osmotic, volemic, and cardiovascular homeostasis. It acts via several specific vasopressin receptors that are variably distributed in the heart, kidneys and vasculature etc. Under normal conditions, its antidiuretic effect predominates and vasopressin only induces vasoconstriction at high concentrations. Regarding catecholamine-resistant vasodilatory shock, current evidence suggests that with adequate volume resuscitation, exogenous vasopressin in low “physiologic” doses (0.01- 0.04 units/min) safely supports mean arterial pressure without adversely affecting myocardial function and splanchnic circulation. One possible explanation is that metabolic acidosis impairs the function of alpha-adrenergic (but not vasopressin) receptors, thus diminishing the response to catecholamines. Although there is yet no clear cut mortality benefit, vasopressin is now recommended as a second-line agent in septic shock for its catecholamine-sparing effect and as an alternative to epinephrine in cardiopulmonary resuscitation. It has also demonstrated efficacy in ameliorating vasoplegia after cardiopulmonary bypass as well as perioperative hypotension in patients on reninangiotensin system antagionists preoperatively. In summary, accumulating clinical experience and formal studies indicate that vasopressin has a role in restoring vascular tone in refractory vasodilatory shock states with minimal adverse effects provided that euvolemia is assured.

Bronchoscopic procedures are at times intricate and the patients often very ill. These factors and an airway shared with the pulmonologist present a clear challenge to anesthesiologists. The key to success lies in the understanding of both the underlying pathology and procedure being performed combined with frequent two-way communication between the anesthesiologist and the pulmonologist. Above all, vigilance and preparedness are paramount. Topics discussed in this review include anesthesia for advanced diagnostic procedures as well as for interventional/ therapeutic procedures. The latter includes bronchoscopic tracheal balloon dilation, tracheobronchial stenting, endobronchial electrocautery, bronchoscopic cryotherapy and other techniques. Special situations, such as tracheoesophageal fistula and mediastinal masses, are also considered.

An array of clinical events may lead to perioperative neurological injury. We first review the general cellular mechanisms leading to brain tissue injury and death. The genesis and mechanisms of injury after cerebral aneurysm surgery, traumatic brain injury, postoperative vascular insult in patients with severe cerebrovascular disease are discussed, as are strategies for prevention and treatment. More has become known about the epidemiology, risk factors and potential preventive strategies in postoperative delirium, and, to a lesser extent, postoperative cognitive dysfunction. Finally, emerging concepts in clinical brain protection are discussed, including preconditioning, gene therapy and stem cells.

Objective. Stimuli activating vascular smooth muscle cell death can constrain the neointimal response to arterial damage and prevent vascular thickening. Conversely, endothelial cell death increases endothelial dysfunction and thrombosis risk. We investigated the combined effect of atorvastatin and TNF-α on vascular cell death. Methods and Results. Cell death was investigated in cultures of human aortic smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs). Atorvastatin downregulated NF-κB and enhanced JNK activity and cell death in VSMC cultured with TNF- α. In the absence of TNF-α, percentages (mean and StDev) of annexin V positive cells were 17.4± 6.6%, 19.3± 5.9%, 22.9± 9.4% and 35.0± 20.0 % with 0, 1, 3 and 10 μM atorvastatin, respectively. The cytotoxic effect of statin was significant at the highest dose of 10 μM (p=0.001). In the presence of TNF-α, percentages of annexin V positive cells were 27.1±10.6%, 34.2±8.5%, 37.4±14.6, and 54.1±20.0% with 0, 1, 3 and 10 ±M atorvastatin, respectively. The cytotoxic effect of statin was significant at each dose used (p± 0.02), in the presence of TNF-α. The cell death sensitising effect of atorvastatin was apparently mediated by down modulation of PKCβ activity, because it was reproduced by the specific PKCβ inhibitor LY317615 and prevented by the PKC activator phorbol-12-myristate-13-acetate (PMA). This effect was cell context dependent because it was not observed in HUVECs. PKCβ was found to be constitutively active in VSMCs but not in HUVECs, thereby explaining the differential effect among the two cell types. Measurement of phosphoPKCβ protein levels in arterial specimens confirmed increased activation of this kinase in the smooth muscle layer, in comparison with endothelium. We show that PKCβ provides survival signals to vascular smooth muscle cells and not the endothelium. Conclusion. Our study suggests that atorvastatin enhances TNF-α-induced cell death in vascular smooth muscle- but not endothelial – cells; by a cell-context-dependent mechanism, involving PKCβ inhibition.

Reactive oxygen species (ROS) have been implicated in a variety of inflammatory diseases including cardiovascular disease (CVD), cancer, diabetes, Alzheimer's disease, autism, cataracts and aging. When endogenous mechanisms for the maintenance of redox homeostasis are overwhelmed, dietary intake of antioxidants contributes substantially to balancing the body's oxidant/antioxidant status. Ginsenosides are thought to be primarily responsible for the pharmacological effect of P. ginseng root extracts on oxidative stress and inflammation. However, little is known about the underlying antioxidant mechanisms of individual ginsenoside; specifically, the reactivity of ginsenoside Rb1 with ROS has not been well studied. We found that Rb1 can significantly and selectively reduce hydroxyl radical (·OH) and hypochlorous acid (HOCl), two of the strongest ROS, with unique molecular mechanisms in a cell-free system. Rb1 directly scavenges the ·OH and protects plasmid DNA from damage induced by ·OH. ·OH likely attacks the double bond on the side chain of Rb1 as well as hydrogen atoms adjacent to the –OH groups, including those of sugar moieties. Rb1 also shows a high reactivity to HOCl and effectively inhibits HOCl-induced tyrosine chlorination in a cell free system. HOCl is added to the double bond of Rb1; the -Cl group and –OH group of HOCl possibly bond at C-24 and C-25 of Rb1 based on the regioselectivity of Markovnikov's Rule. To our knowledge, this is the first demonstration that ginsenoside Rb1 scavenges HOCl and protects tyrosine from HOCl-induced chlorination. Thus, this study reveals unique antioxidant mechanisms of individual ginsenoside Rb1, which may contribute to the pharmacological effect of P. ginseng and to the development of effective strategies for clinical applications of ginsenosides.