Current Drug Targets - Volume 10, Issue 9, 2009

This is the second of a two-part series on New and Old Drugs in Perioperative Medicines. The editorial that was included in the volume 10 No. 8, written by the guest editor Franco Cavaliere, is reprinted here. We are very pleased to introduce this Current Drug Targets issue titled “New and old drugs in Perioperative Medicine”. When we first had the idea of this issue, we started from the consideration that Perioperative Medicine is characterized by a particularly high degree of innovation. In last years, many important novelties about drug therapy have been introduced. In particular, some relatively new drugs and many old drugs have gained new indications in the perioperative period in order to improve anesthesia and analgesia, or to prevent or treat perioperative complications. Colimicine is one example among many; this drug, which was indeed nearly obsolete few years ago, is now largely utilized to treat multi-drug resistant infections. Since its theme is perioperative medicine, the issue includes many topics, which go from anesthesia to postoperative intensive care. Some reviews, on anesthetic adjuvants for fast track surgery and on dexmedetomidine intraoperative utilization, deal with anesthesia. Others, on gabapentanoids, ketamine, magnesium sulphate perioperative utilization and on new drugs for epidural analgesia, mainly concern postoperative analgesia. Analgosedation and clonidine infusion are two recent developments in sedation techniques and are both the subject of a review. In last years many compounds have been utilized to prevent postoperative complications; they include statins, betablockers, levosimendan, alogenated inhalatory anesthetics, immunonutrients. Evidences on their effectiveness and current indications are examined in some of the reviews included in this issue. Finally, some topics on sepsis have also been included, such as the utilization of antioxidants and corticosteroids, or the choice among antipyretic drugs.

In last years opioids have been increasingly utilized to sedate patients during mechanical ventilation. First, in Hypnotic Based Sedation (HBS), they were added to hypnotics because of their analgesic properties. Successively, in Analgesic Based Sedation (ABS), both sedative and analgesic properties were utilized and opioids were given alone; hypnotics were added only if adequate sedation was not achieved at maximum dosage. Apart from their analgesic and sedative properties, opioid effects on respiratory function are of particular value in many mechanically-ventilated patients. Dose-dependent inhibition of respiratory drive may usefully prevent spontaneous breathing during controlled ventilation, particularly when permissive hypercapnia is applied, or decrease excessive respiratory rate during assisted or noninvasive ventilation. Even cough inhibition can be valuable in some conditions, for instance, during respiratory weaning and endotracheal tube removal in patients that should not cough because of a recent tracheal resection. On the other hand, excessive respiratory depression may cause hypoventilation and apnea during assisted or spontaneous ventilation and lengthens the weaning process. In order to take advantage from positive effects and to avoid negative ones, opioid dosage should be thoroughly titrated. On this basis remifentanil has become increasingly popular as the opioid agent most suitable for ABS because of its unique, favorable pharmacokinetics.

Acute severe asthma is characterized by a state of airway inflammation and increased bronchiolar smoothmuscle tone that leads to increased resistance to expiration and lung hyperinflation. Despite the better knowledge of its pathophysiology, the incidence and severity of asthma in the last twenty years is increased worldwide, although with significant age and geographic variation. As a result, the number of patients requiring more intensive medical therapy has also increased. In the most severe cases, often referred to as near-fatal asthma, the institution of mechanical ventilation may be required. Volatile anesthetics have bronchodilator effects on the bronchial smooth muscle. The use of inhalational anesthetic agents for treatment of severe status asthmaticus has been documented in case reports, case series and small uncontrolled studies. Their use may be considered in any mechanically ventilated patients whose severe bronchospasm failed to respond to maximal medical treatment. In the present review article, we aim to provide a brief description of the physio-pathological and clinical features of acute severe asthma, and of the principles of treatment, focusing our attention on the use of the inhalational anesthetics in severe patients requiring mechanical ventilation and not responding to conventional therapy.

Background: Myocardial ischemia remains a major cause of morbidity in patients undergoing noncardiac surgery. The purpose of the paper was to review the evidence of the use of perioperative β-blockers for the reduction of myocardial ischemia in patients having noncardiac surgery. Method: Pubmed was searched for articles that included β-blockers and perioperative myocardial ischemia. Randomized controlled trials that assessed the effect of β-blockers on myocardial ischemia in patients undergoing noncardiac surgery were included in this review and a meta-analysis was performed. Results: Sixteen randomized controlled trials including 2230 patients were included. The study methodologies and results were summarized and meta-analysis performed. Ten trials used β-blockers in the postoperative period; 954 patients received β-blockers and 924 patients were in the control group. Of the six trials that used β-blocker for premedication, there were 207 patients in the β-blocker and 145 patients in the control group. For the cohort when β-blockers were used postoperatively, myocardial ischemia was reduced significantly with the use of β-blockers (OR 0.42; 95% CI 0.27-0.65; P=0.0001; I2=0%). A similar beneficial effect was observed in trials that used β-blocker for premedication (OR 0.16; 95% CI 0.07-0.35; P<0.00001; I2=40%). Conclusion: The meta-analysis shows that the use of β-blockers, both as premedication and postoperatively, in noncardiac surgery is associated with a significant reduction in perioperative myocardial ischemia.

Beta-blocker therapy is accepted to reduce perioperative cardiovascular complications. Moreover, betablockers have potentially beneficial effects other than prevention of cardiac events. In addition to reducing anesthetic and analgesic requirements during the perioperative period, beta-blockers have neuroprotective effects, possible effectiveness in the management of intraoperative awareness-induced post-traumatic stress disorder, and antinociceptive effects. Betablockers are also useful in stabilizing hemodynamics during electroconvulsive therapy, intubation and emergency periods. Physicians need to bear in mind the benefits of beta-blockers for purposes other than preventing cardiac events when applied in the perioperative period, and should be familiar with the pharmacodynamics and effective dosages of these agents.

Statins are widely prescribed cholesterol lowering agents that exert their effects by inhibiting 3-hydroxy- 3methylglutaryl co-enzyme A reductase. With their modulatory effects on the atherogenic lipid profile, the role of statin therapy is expanding amidst the growing obesity epidemic. The cholesterol lowering effects of statin therapy remain central in the long term management of coronary artery disease and cerebrovascular disease. While statin therapy is used commonly to target elevated LDL cholesterol, there is an emerging evidence supporting its role during acute coronary syndromes and stroke. Clinical research into plaque histology, vulnerable high risk plaques and plaque rupture has improved our insight into the pathophysiology of these acute vascular events. Non lipid lowering effects of statin, the so called pleitrophic effects, have become the focal point of investigation. This review discusses recent experimental and clinical evidence supporting the role of statin in perioperative medicine.

BACKGROUND: Until now no randomized trial can be considered powered enough to show a reduction on both perioperative myocardial infarction and mortality. METHODS: We performed an extensive research of the literature to identify dugs or technique that could have an effect on perioperative myocardial infarction in cardiac and non-cardiac surgery. RESULTS: Volatile agents reduce myocardial infarction (NNT=37) and mortality (NNT=83) in cardiac surgery when compared to total intravenous anesthesia. No data regarding the use of volatile agents in non-cardiac surgery exists. Levosimendan reduces myocardial infarction (NNT=21) and mortality (NNT=12) in cardiac surgery when compared to placebo or other inotropic agents. No data regarding its use in non-cardiac surgery exists. Epidural analgesia has promising beneficial effects in both cardiac and non-cardiac surgery. In non-cardiac surgery statins and calcium antagonists have minor beneficial effects while alpha(2) agonists could reduce perioperative myocardial infarction and are included in the American College of Cardiology/American Heart Association Guidelines. Beta blockers are also included in the international guidelines but benefits and hazards should be careful considered. CONCLUSIONS: Volatile agents and levosimendan consistently reduce perioperative myocardial infarction and mortality in cardiac surgery but they have not been properly studied in non-cardiac surgery. Minor (epidural analgesia, statins, calcium antagonists and alpha(2) agonists) or doubtful (beta-blockers) results were found in non-cardiac surgery.

Patients with heart failure undergoing non-cardiac surgery still have an unacceptably high morbidity and mortality. Compromised myocardial physiologic reserves in combination with extensive surgery and anesthesia appear to play a crucial role in determining high perioperative morbidity and mortality. Nevertheless, several other mechanisms and pathways such as metabolic factors, ischemia-reperfusion conditions, neurohormonal activation, inflammation and oxidative stress contribute to the adverse outcome. Several cardiovascular drugs have been investigated with the attempt to reduce the incidence of cardiovascular adverse events after major non-cardiac surgery. In the last years, increasing attention has been paid to the use of levosimendan in the perioperative period of patients undergoing cardiac surgery. As an inodilator, levosimendan - at low energy expenditure - may improve perioperative cardiac performance of heart failure patients by optimizing ventriculo-arterial coupling, rather than by increasing myocardial contractility itself. By its vasodilating properties, levosimendan may also improve systemic and regional blood flow. In addition to these hemodynamic properties, non hemodynamic effects of levosimendan may further improve microcirculation and organ function. At the cellular level in the heart, kidney, lung, liver as well as the gut, levosimendan exerts protective preconditioning effects secondary to activation of adenosine triphosphate (ATP)-sensitive potassium channels. Taking into account these multiple but complementary mechanisms, levosimendan appears to be a suitable agent for preoperative optimization of cardiac functions in heart failure patients undergoing major elective surgery. Nevertheless, large-scale trials are needed before final conclusions can be drawn on the use of levosimendan in this indication.

Critical illness and particularly sepsis are associated with a significant redox imbalance resulting from an increased production of oxidant species and a decrease in endogenous antioxidant defences. In critical patients sources of oxidative stress include the mitochondrial respiratory electron transport chain, xanthine oxidase activation, the respiratory burst associated with neutrophil activation, and arachidonic acid metabolism. Several endogenous antioxidants have been identified including enzymes, like superoxide dismutases and glutathione peroxidase, vitamins and other molecules such as uric acid and bilirubin. Recent studies pointed out the correlations between oxidative stress, systemic inflammatory response and apoptosis. Prospective randomized clinical trials regarding antioxidant therapy in critical illness provide increasing evidence in support of selenium, glutamine and omega-3 fatty acids. In particular selenium seems to improve clinical outcome in terms of infections and organ failure, glutamine has been associated with a significant reduction in infectious complications and omega-3 fatty acids could be particularly efficacious in sepsis. Melatonin is a promising molecule that deserves the attention of future research, as well as vitamin C. Further studies should also try to establish the more beneficial combination of antioxidants, as well as the doses, and the timing of administration. When such problems will be resolved hopefully results about antioxidant therapy in critical illness will be more univocal and promising.

It has been estimated that nosocomial fever occurs in approximately one-third of hospitalized patients. The incidence is even higher in critically-ill patients in whom both infectious and noninfectious etiologies of fever are common. Polypeptide cytokines (endogenous pyrogens) such as interleukin-1b (IL-1b), tumor necrosis factor (TNF) and interleukin-6 (IL-6) act directly on the hypothalamus to affect a fever response by promoting an increase in heat generation and a decrease in heat loss. There is widespread acceptance that in most if not all critically ill neurologic patients fever should be treated but still it is not clear if fever per se in nonneurologic critically ill patients should be treated too. We review physical and pharmacological methods presently utilized to treat fever in critically ill patients.

Adrenal insufficiency has been reported with increased frequency in critical ill patients with sepsis and other inflammatory states. Its incidence varies widely depending on the criteria used to define it and the patient population studied. Increased glucocorticoid action is essential in the stress response to acute injury and even minor degrees of adrenal insufficiency can be fatal. Recently the so-called relative or functional adrenal insufficiency (CIRCI) has been described: in this syndrome cortisol levels may be low or high but nonetheless inadequate to meet the elevated metabolic demand. Since laboratory diagnosis of adrenal insufficiency is still controversial, the diagnosis of ICU associated adrenal insufficiency is essentially a clinical diagnosis. Whether exogenous corticosteroid support may be beneficial in critical illness is still a matter of debate: most international guidelines recommend that the decision to treat patients with corticosteroids should be based on clinical criteria (low blood pressure poorly responsive to vasopressor despite adequate fluid resuscitation) rather than on tests of the hypothalamic-pituitary-adrenal axis alone. As regards specifically the role of steroids in the treatment of sepsis and septic shock, at present there are no strong evidence-based recommendations. More studies are needed to reach consensus about several issues: which is the best target population, whether a cosyntropin test should be used to guide treatment, whether fludrocortisones should be given along with hydrocortisone, and how long treatment should continue.

Multidrug resistant bacteria infections are associated with an increase in attributable mortality and morbidity in ICU patients. Unfortunately, an emerging resistance to novel antibiotics used in the therapy of gram negative and gram positive bacteria infections is often reported in literature. Old antibiotics have been reintroduced in clinical practice. In this review we report the efficacy and safety use of older antimicrobial agents in critically ill patients. Polymyxins are used for nosocomial infection caused by Pseudomonas aeruginosa and Acinetobacter baumannii resistant strains. Patients with polymyxin-only susceptible gram-negative Nosocomial pneumonia are reported to be successfully treated with inhaled colistin. Isepamicin can probably be used in intensive care units that harbor Gram-negative bacteria resistant to other aminoglycosides. Fosfomycin may be a useful alternative to linezolid and quinupristin-dalfopristin in the treatment of Vancomycin Resistant Enterococci (VRE) infections in certain clinical situations, e.g. uncomplicated urinary tract infections. Chloramphenicol has a wide antimicrobial spectrum and excellent tissue penetration; though it is sometimes used empirically in the hospital setting for the treatment of patients with unknown source of fever, its role is still a matter of controversy. The colistin/rifampicin combination might have a synergistic effect in Acinetobacter baumannii and Pseudomonas aeruginosa infections. Fusidic acid is active against staphylococcal strains.