Current Drug Targets - Volume 10, Issue 8, 2009

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 the end, we would like to thank all the Authors that joined us in the preparation of this issue and devoted their time and efforts to produce exhaustive up-to-date contributions that, we sincerely hope, could be valuable for readers' clinical practice.

With the changes in health care dictated by economic pressure, there has been a realization that hospital stay could be shortened without compromising quality of care. Advances in surgical technology and anesthetic drugs have made an impact in the way perioperative care is delivered with some emphasis on multidisciplinary approach. From the expansion of ambulatory care, lessons were learnt how to apply same concepts to major surgery with the understanding that interventions to attenuate the surgical stress would facilitate the return to “baseline”. Beside minimal invasive approach to surgery, anesthesia interventions are arranged with the intent to decrease the negative effects of surgical stress and pain, to minimize the side effects of drugs and at the same time to facilitate the recuperation which follows after surgery. Fast-track or accelerated care encompasses many aspects of anesthesia care, not only preoperative preparation and prehabilitation, but intraoperative attenuation of surgical stress and postoperative rehabilitation. The anesthesiologist is part of this team with the specific mission to use medications and techniques which have the least side effects on organ functions, provide analgesia which in turn facilitates the intake of food and mobilization out of bed. This chapter has been conceived with the intention to direct the clinician towards procedure-specific protocols where the choice of medications and techniques is based on published evidence. The success of implementing fast-track depends more on dynamic harmony amongst the various participants (surgeons, anesthesiologists, nurses, nutrtionists, physiotherapists) than on reaching an optimum level of excellence at each separate organization level.

Dexmedetomidine is a potent and highly selective α2-adrenoreceptor agonist currently utilized for continuous infusion for sedation/analgesia in the intensive care unit (ICU). Dexmedetomidine offers remarkable pharmacological properties including sedation, anxiolysis, and analgesia with the unique characteristic to cause no respiratory depression. In addition it posses sympatholytic and antinociceptive effects that allow hemodynamic stability during surgical stimulation. Different from most of clinically used anesthetics, dexmedetomidine brings about not only a sedativehypnotic effect via an action on a single type of receptors, but also an analgesic effect and an autonomic blockade that is beneficial in cardiac risk situations. Several studies have demonstrated its safety, although bradycardia and hypotension are the most predictable and frequent side effects. Dexmedetomidine has shown to consistently reduce opioids, propofol, and benzodiazepines requirements. In the last years it has emerged as an affective therapeutic drug in a wide range of anesthetic management, promising large benefits in the perioperative use. In particular this review focuses on dexmedetomidine utilization in premedication, general surgery, neurosurgery, cardiac surgery, bariatric surgery, and for procedural sedation and awake fiberoptic intubation. In all these fields dexmedetomidine has demonstrated to be an efficacious and safe adjuvant to other sedative and anesthetic medications.

In recent years there has been a wide use of the epidural technique not only during surgery to provide anesthesia and analgesia, but also for obstetric and trauma as well as acute, chronic and cancer pain states. Nowadays there is an increase in the number of the epidural drugs. Local anesthetics and opioids are still the pharmacological agents more widely used epidurally, nevertheless other drugs from different pharmacological classes are administered as adjuvant to local anesthetics and opioids or are in various early stages of investigation. Regarding to local anesthetics, the most recent literature focuses on the new enantiomers, ropivacaine and levobupivacaine, the efficacy of which is similar to that of bupivacaine with a reduced risk of cardiotoxicity. About opioids, the other class of drugs mainly used, the debate, in the last years, concerned the physicochemical properties of morphine and of the more recent lipophilic agents, fentanyl and sufentanil, in order to explain the main differences in efficacy and safety. Other categories of agents have been investigated for epidural administration, such as α2-adrenergic agonists clonidine and dexmedetomidine. They are being used increasingly as adjuvants to local anesthetics and opioids. Ketamine and neostigmine, the more recent studied drugs for epidural use, are still under investigation and are not part of routine clinical practice.

Ketamine acts mainly as a N-methyl-D-aspartate receptor (NMDAr) antagonist. Originally developed as a general anesthetic, it is now seldom employed as such in richer countries due to the relatively high risk of psychotomimetic adverse effects. Recently, low-dose regimens in the range of 0.25-0.5 mg/kg as an initial bolus followed by 50-500 μg/kg/h have been proposed as an adjuvant for postoperative analgesia and for the reduction of exogenous opioid-induced hyperalgesia. In this review, we examine the evidence for clinical usefulness of perioperative ketamine infusion and its role in the context of general and/or regional anesthesia.

Background: Gabapentin and pregabalin inhibit Ca2+ currents via high-voltage-activated channels containing the α2δ-1 subunit, reducing neurotransmitter release and attenuating the postsynaptic excitability. They are antiepileptic drugs successfully used also for the chronic pain treatment. A large number of clinical trials indicate that gabapentin and pregabalin could be effective as postoperative analgesics. This systematic-narrative review aims to analyse the most recent evidences regarding the effect of gabapentinoids on postoperative pain treatment. Methods: Medline, The Cochrane Library, EMBASE and CINHAL were searched for recent (2006-2009) randomized clinical trials (RCTs) of gabapentin-pregabalin for postoperative pain relief in adults. Quality of RCTs was evaluated according to Jadad method. Visual analogue scale (VAS), opioid consumption and side-effects (nausea, vomiting, dizziness and sedation) were considered the most important outcomes. Results: An overall of 22 gabapentin (1640 patients), 8 pregabalin (707 patients) RCTs and seven meta-analysis were involved in this review. Gabapentin provided better post-operative analgesia and rescue analgesics sparing than placebo in 6 of the 10 RCTs that administered only pre-emptive analgesia. Fourteen RCTs suggested that gabapentin did not reduce PONV when compared with placebo, clonidine or lornoxicam. Pregabalin provided better post-operative analgesia and rescue analgesics sparing than placebo in two of the three RCTs that evaluated the effects of pregabalin alone vs placebo. Four studies reported no pregabalin effects on preventing the PONV. Conclusion: Gabapentin and pregabalin reduce pain and opioid consumption after surgery in confront with placebo, but comparisons with other standard post-operative regimens are not sufficient. Gabapentin and pregabalin seem not to have any influence on the prevention of PONV.

Purpose : to review current knowledge concerning the use of magnesium in anesthesiology, the role of hypomagnesemia and hypermagnesemia in perioperative period, analizing the cardiologic problems related to blood serum concentration changes of magnesium that can interesting in primis the anaesthesist in perioperative period. Methods: References were obtained from Pubmed (1995 to 2009). All categories of articles were selected, such as reviews, meta-analyses, abstracts, clinical trials etc). Principal findings: Magnesium is a bivalent ion, like calcium, the fourth most common cation in the body, and the second most common intracellular cation after potassium. Magnesium deficiency has been demonstrated in 7-11% of the hospitalized patients and it has been found to coexist with other electrolyte disorders, particulary hypokalaemia or hypophosphatemia and, to a less extent, hyponatraemia and hypocalcaemia, in more than 40% of patients. Hypomagnesemia needs to be detected and corrected to prevent increased morbidity and mortality. Historically, magnesium sulphate has been proposed as a general anaesthetic. Magnesium reduces the catecholamine release during the stressful manouvres like intubation. Magnesium has also anti-nociceptive effects in animal and human models of pain by blocking the N- methyl-D-aspartate receptor and the associated ion channels and thus preventing central sensitization caused by peripheral nociceptive stimulation. So for some authors it reduces the need for intraoperative anesthetics and relaxant drugs and reduces the amount of morphine for the treatment of pospoperative pain. The use of magnesium is extended not only to general anaesthesia but also in loco-regional anaesthesia. The role of magnesium has been extensively studied in cardiology especially during myocardial infarction, arrhythmia and cardiac surgery. Recent studies show the important of magnesium to prevent the postoperative neurocognitive impairment during carotid endoarterectomy and its utility in treatment of severe asthma. Conclusions Magnesium has many known indications. In peioperative period blood serum concentration changes of magnesium are frequent so anesthesiologists need to know the role of this important cation.

Recombinant activated factor VII (rFVIIa), developed and effective in managing inhibitors in haemophilia patients, is being widely used off-label as a “panhaemostatic agent” with ongoing controversy as to its benefits and risks in terms of controlling critical haemorrhage and improving patient outcomes. Current insights into haemostatic mechanisms have resulted in a better understanding of the central role of FVII/FVIIa and tissue factor in the localization and initiation of haemostasis. There is a plethora of case reports and series published on the use of rFVIIa in critical lifethreatening haemorrhage and in perioperative settings associated with significant blood loss or the potential for catastrophic haemorrhage. Additionally, the literature is replete with reviews for the use of rFVIIa in various clinical settings, but there is a dearth of good evidence from randomized controlled trials for efficacy. Safety, especially from the thrombogenicity perspective, has been a major issue, but turns out to be less of a concern with thrombotic potential needing to be weighed against the anticipated benefits. Although there is some clinical trial and observational data supporting efficacy it has been difficult to recommend clear clinical practice guidelines, especially as clinical outcome data in terms of morbidity and mortality is limited. Some of the best evidence relates to reduction in allogeneic blood transfusion requirements. This in itself is important and probably clinically relevant in view of the accumulating evidence that allogeneic blood transfusion is an independent risk factor for poorer clinical outcome. It is unlikely that there will be adequate randomized clinical trials to better answer the question of efficacy, thus making data from registries of greater importance. Indeed, the process of establishing efficacy, safety and regulation of a therapeutic that is increasingly used off-label is not without significant difficulties.

Purpose of the review: To outline recent findings concerning the efficacy of immunonutrients in patients undergoing surgery. Recent findings: Surgery induces an inflammatory response that can become excessive and damaging in some patients. The major risk factors are pre-existing nutritional status and increasing levels of surgical stress. A range of nutrients, including several amino acids, antioxidant vitamins and minerals, ω-3 fatty acids, and nucleotides, are able to modulate inflammation and the associated oxidative stress, and maintain or improve immune function. Considering the overall treatment effect of immune-modulating nutrients, parenteral glutamine is recommended in patients receiving parenteral nutrition, while enteral glutamine should be considered for burn and trauma patients. Antioxidants, particularly selenium, should be considered for critically ill patients, and enteral formulas enriched with fish oils are recommended for patients with acute respiratory distress syndrome. Arginine-supplemented diets are not recommended. In summary, malnourished patients should receive preoperative artificial nutrition for at least 10 days prior to major surgery and for 7 days postoperatively. Enteral nutrition is the best support for these patients. The benefit of immuneenhancing diets in severely malnourished patients remains to be proven. Preoperative oral immunonutrition (arginine, omega-3 fatty acids, and nucleotides) is indicated for non-malnourished patients. Although patients with cancer exhibit some special metabolic features, preoperative immunonutrition is also indicated. Summary: Immunonutrition is effective in improving outcome in a wide range of patients, particularly in malnourished individuals. However, further research using larger, better-designed trials is needed to assess whether immune function is benefited, with an improved clinical outcome in vulnerable patients.

The nonthyroidal illness syndrome (NTIS) is a clinical condition of abnormal thyroid function tests observed in patients with acute or chronic systemic illnesses. The laboratory parameters of NTIS usually include low serum levels of triiodothyronine, with normal or low levels of thyroxine and normal or low levels of thyroid-stimulating hormone. It is still a matter of controversy whether the NTIS represents a protective adaptation of the organism to a stressful event or a maladaptive response to illness that needs correction. Multiple studies have investigated the effect of thyroid hormone replacement therapy in certain clinical situations, such as caloric restriction, cardiac disease, acute renal failure, braindead potential donors, and burn patients. Treating patients with NTIS seems not to be harmful, but there is no persuasive evidence that it is beneficial. The administration of hypothalamic releasing factors in patients with NTIS appears to be safe and effective in improving metabolism and restoring the anterior pituitary pulsatile secretion in the chronic phase of critical illness. However, also this promising strategy needs to be explored further. Anyhow, an extremely prudent approach is needed if treatment is given. Much of the data appearing in the literature on the treatment of NTIS encourage further randomized controlled trials on large number of patients. At present, however, we believe that there is no indication for treating thyroid hormone abnormalities in critically ill patients until convincing proof of efficacy and safety is provided.

Arterial hypertension is a very common condition. Cerebral, coronary and renal vessels are mainly affected by the deleterious effect of this condition, and both acute and chronic organ failure may ensue. Exacerbation of underlying pathophysiologic conditions or new precipitating factors can lead to hypertensive crisis, either urgencies or emergencies. During hypertensive emergencies, a quick raise in arterial pressure may lead to acute and significant organ dysfunction, such as aortic dissection, acute myocardial infarction, intracranial bleeding or acute renal failure. Perioperative hypertension often takes the shape of a crisis and it can be related to hypothermia, pain, neuro-hormonal response to surgical trauma or antihypertensive drugs withdrawal. Treatment for hypertensive crisis should achieve a progressive control of blood pressure, avoiding any abrupt decrease in organ blood supply. Therapeutic options are many and different in terms of pharmacokinetics and pharmacodynamic profiles. The best option should be based upon the characteristics of the patient and the pathophysiology of the hypertensive crisis . Of particular interest, some agents are metabolized by blood esterase and have a very short half life (e.g., clevidipine). This allows tight titration of their effect, which is advisable when carefully lowering blood pressure. This is of particular importance when treating hypertensive crisis in surgical patients both intra-operatively or in critical care.

Clonidine is classified as an imidazoline and it is the prototypical alpha-2 receptor agonists. It has been used for several years to treat hypertension. It has also been used, “off label”, for a variety of purposes, including opioid and anesthetic sparing effects, anxiolysis and sedation, drug withdrawal as well as stabilizing blood pressure and reducing stress response to surgery. Particularly in the case of patients with overt or underlying cardiac disease and in those at risk of perioperative ischemia the action of clonidine can be expected to reduce the risk of procedure-related cardiac events. In addition, clonidine used as a premedication drug before surgery or surgical procedure, has been shown to substantially reduce anaesthetic, benzodiazepine and opioids requirements. However, its “off label” use, the absence of an intravenous form of in the United States, possible inadvertent hypotension, bradycardia or post-operative sedation, and the variability of the haemodynamic response to different doses or rates of administration, have limited its use in clinical practice. This review discusses the potential role of clonidine and the supporting evidence for the use of this drug beyond its antihypertensive use in perioperative medicine and critical care in adults patients.