Current Drug Targets - Volume 6, Issue 7, 2005

It has been with great pleasure that we have accepted the task of editing the hot topic "Sedation and analgesia in Post-Anesthesia Intensive Care Units" in the current issue of Current Drug Targets. In comparison with the more general subject of sedation and analgesia in generic intensive care units (ICUs), this topic has relevant peculiarities and has been characterized in the previous years by many important changes. Achieving a good postoperative analgesia is a key point to assure patient's well-being and to attenuate nervous and hormonal changes following surgery. On the other hand, analgesic drugs may cause complications that negatively affect patient's clinical course and worsen his/her judgment on hospital staying. Increased bleeding caused by NSAIDs, occurrence of PONV syndrome and delayed recovery of intestinal peristalsis caused by opioids are typical examples of collateral effects related to analgesic therapy. In the previous years, new drugs like anti COX-2 agents, have become available that may cause less complications than older ones; ketamine, an old drug nearly abandoned in clinical practice, has been rediscovered at subanesthetic dosages in order to decrease opioid requirement in the postoperative period; and finally, new routes of administration have been introduced to make safer and easier selfadministration of opioids by the patient. Short-term sedation is used in Post-Anesthesia Care Units (PACUs), when patients are transferred from the operation theatre under general anesthesia and in mechanical ventilation, in order to achieve a more smooth awakening after correction of circulatory, respiratory, and thermal derangements. Delayed awakening from anesthesia may be useful in case of prolonged or highly invasive surgery, but also in compromised patients affected by severe respiratory or circulatory diseases. In these cases, short-acting drugs are preferred in order to facilitate patient awakening and weaning from mechanical ventilation; often, infusions of the drugs employed during general anesthesia may be continued, provided that dosages are decreased consistently with the absence of surgical stimuli. Interactions with drugs administered during anesthesia should be considered; for instance, residual muscle paralysis may initially prevent the application of sedation scores and abrupt interruption of high-dosage remifentanil infusion may cause dangerous hypertensive crisis. Long-term sedation may be required in case of persistent circulatory instability, failure of weaning from mechanical ventilation, sepsis, or severe abdominal hypertension. Postoperative agitation and delirium are frequently observed in PACUs, particularly in elderly patients and following certain kinds of surgery, like hip surgery. Although the incidence of delirium may be even higher during long term sedation in general ICUs, postoperative delirium is particularly harmful because it may negatively affect morbility, mortality, and functional recovery of patients that undergo elective surgery. New approaches on this topic include environmental interventions, pharmacological treatment aimed at preserving the sleep-awake cycle, and the use of new atypical antipsychotics. We sincerely thank each author for the time and effort spent to prepare their contribution to the manuscript and hope that this CDT hot topic on "Sedation and Analgesia in PostAnesthesia Care Units" may be useful to the readers dealing with the problems of perioperative period.

The aim of the present article is to review the indications, the monitoring and the complications of sedation in the post-anaesthesia care unit (PACU). In this setting, sedation is often an unwanted side effect of anaesthetic drugs that delay discharge, however it could be specifically indicated. Such indications include postoperative anxiety and agitation, airway management and mechanical ventilation, protection against myocardial ischaemia and intracranial hypertension control. Whenever sedation is used, an appropriate monitoring is useful to achieve an adequate level for the specific indication. Methods for sedation monitoring in PACU may be subjective (clinical scales) or objective (lower oesophageal sphincter contractility measurement, heart rate variability, evoked potentials and parameters derived from the electroencephalogram). The target score of the most common clinical scales has been reviewed according to the specific indication. An adequate monitoring is fundamental to avoid the complications of sedation including bradycardia, hypotension, prolonged mechanical ventilation and increased risk of respiratory tract infection as pointed out by many recent data. Therefore, sedation should be used carefully and with an adequate monitoring in post-operative patients not to affect negatively morbidity and mortality.

In critically ill patients, adequate sedation increases comfort, minimizes stress response and facilitates diagnostic and therapeutic procedures. Propofol (2-, 6-diisopropylphenol) is an intravenous sedative-hypnotic agent popular for sedation in the Intensive Care Unit. The favorable propofol pharmacokinetic, characterized by a three compartment linear model, allows rapid onset and short duration of action. The emergence time from sedation with propofol varies with the depth and the duration of sedation and the patient's bodyweight. Propofol causes hypotension, particularly in volume depleted patients, decreases cerebral oxygen consumption, reduces intracranial pressure and has potent anti-convulsant properties. It is a potent antioxidant, has anti-inflammatory properties and is a bronchodilator. As a consequence of these properties, propofol is being increasingly used in the management of traumatic head injury, status epilepticus, delirium tremens, status asthmaticus and in septic patients. Prolonged use (>48h) of high doses of propofol (>66mcg/Kg/min) has been associated with lactic acidosis, bradycardia, and lipidemia in pediatric patients. A rare complication firstly reported in pediatrics patients and also observed in adults is known as "propofol syndrome" characterized by myocardial failure, metabolic acidosis and rhabdomiolysis. Hyperkalemia and renal failure have also been associated with this syndrome. Hypertriglyceridemia and pancreatitis are uncommon complications. A large number of trials have compared the use of propofol with midazolam. Sedation with propofol is associated with adequate sedation in ICU patients, shorter weaning time and earlier tracheal extubation compared to midazolam, but not before ICU discharge.

Many patients in the ICU receive mechanical ventilation and require sedative medications. Anxiolysis, hypnosis, and amnesia can be considered the primary objects of sedative therapy. Intravenous benzodiazepines are the drugs most commonly used for sedation in ICU. Proper choice and use of benzodiazepines is based on knowledge of the pharmacology and is an essential component of caring for patients in the intensive care unit. Three benzodiazepines -- Diazepam, Lorazepam and Midazolam -- are currently available for parenteral use in the ICU. Onset and duration of action are determined by their lipid solubility. Respiratory depression and hypotension are dose-dependent. Midazolam is generally preferred to other benzodiazepines in most ICU. It has the shortest half-life of the benzodiazepines, does not have active metabolites, is water soluble and can be administered by continuous infusion. Despite the relatively short half-life of Midazolam, extensive distribution can cause prolonged sedation. Recovery time is proportional to the infusion's duration. Lorazepam is lipid soluble and dissolved in a propylene glycol carrier, produces a delayed onset and prolonged duration of effect and is preferred for long-term sedation (>48 hours). Propylene glycol toxicity is possible with high-dose or prolonged infusions. Diazepam has become less used with the introduction of the shorter-acting and less irritating benzodiazepine. The recent literature focuses on the differences between Midazolam and Propofol, the most used sedatives in ICU, their sequential use and combination. Relevant studies have been performed about propylene glycol toxicity.

While most patients recover uneventfully from the effects of anesthesia and surgery, for a small percentage of patients the immediate postoperative period can be a period of significant physiological stress. Hence the goal for a Post Anesthesia Care Unit (PACU) is to provide a safe environment for a patient to recover, while avoiding the undesirable side effects of pain, nausea, vomiting and shivering, and to monitor for potentially life threatening hemodynamic and respiratory complications that may require admission into the intensive care unit (ICU). Anesthetic techniques in the operating room are extremely important as these may have significant bearing on the post-operative course. The type of surgery, the patients' co morbid conditions, anticipated extubation and recovery of the patient, as well as the sophistication of the PACU and the expertise of its staff, all influence the choice of anesthetic technique. These agents, however, may themselves contribute to some of the complications and unpleasant events encountered in the PACU. Therefore, evaluation of newer and safer agents, which promote a smoother PACU transition, are warranted. Alpha 2 agonists are increasingly being used as adjuvant therapeutic agents in the perioperative period because of their ability to block the sympathetic stress response, complete with their anesthetic and analgesic sparing properties, lack of respiratory depression and low and predictable side effect profile.

The correct treatment of postoperative pain, in the early period immediately following surgery, is founded on the following four principles: 1- correct diagnosis of the source and magnitude of nociception; 2- understanding of the relationship of ongoing nociception and other components of pain including anxiety, ethnocultural components, meaning, prior experience; 3- treatment by establishment and maintenance of drug level at active sites to achieve and maintain analgesia and anxiolysis as appropriate; 4- continued re-evaluation of the therapy and refinement of the approach. The PACU standard of cure requires a strict accordance between intra and postoperative analgesia. It requires "proactive preoperative plan" that includes: - preoperative patient evaluation; - discussion with a single patient on different treatment options; - patient and family education; - pre-emptive measures as indicated; - intra-operative multimodal analgesia; - a correct triage of analgesia, just after initial evaluation of vital parameters in PACU; - re-evaluation of analgesia plan, if analgesia is inadequate; - a new titration, intravenous or epidural way, in order to achieve a stable VAS < 3; - plan a new analgesia scheme or confirm a preoperative plan; - control of adverse events, related to analgesia plan (gastric bleeding and/or bleeding of the surgical wound site, NSAIDs-induced renal damage, respiratory depression, delayed canalisation, nausea, vomiting, excessive sedation, difficulty in bladder emptying, itchiness); - a transmission of analgesia plan to ward nurses; - a control quality for verify at prefixed times patients satisfaction level, analgesia performed, adverse effects percent, analgesia related, plan variations percent.

Critically ill patients, particularly those under mechanical ventilation, require analgo-sedation to control noxious stimuli and enhance comfort. Despite their harmful side effects, such as respiratory depression, physical dependance and difficult arousal, opioids are effective in providing a good level of analgesia and comfort. Traditional opioids (morphine and fentanyl) have been shown effective in providing analgesia; however, the respiratory adverse effects and their pharmacokinetics, with an high risk of accumulation, limits their use, especially for a long-term sedation. In the last decade, new synthetic opioids with limited side effects and favourable pharmacokinetics profile, such as Sufentanil and Remifentanil, have been investigated to evaluate their efficacy in mitigating pain and enhancing comfort in critically ill patients.

Opioids remain the main pharmacological tools for pain control in the postoperative patient. Recent concerns about chronic use of non-steroidal anti-inflammatory drugs have put extra pressure on health care workers to device and develop new medications and delivery methods to provide patients with appropriate pain relief after surgery. New technologies and better understanding of the pharmacology of the opioids administered by non-traditional ways will be reviewed in this manuscript. Understanding the anatomy of the nose cavity is important to use the inhaled way to deliver fentanyl, sufentanyl or butorphanol in surgical patients. High concentration and small volume are keys to good absorption and effect by nasal administration. Transdermal delivery of fentanyl has been used in chronic pain for some years. A new fentanyl self-administration method is in advanced trials for clinical use. It has a huge potential in giving good pain relief with lower side effects and more patient independence because of its reduced size and lack of tubing attached to it. Day surgery patients could be great candidates for this therapeutic alternative. Finally, oral transmucosal fentanyl is also in the market. Better suited to be used in controlling breakthrough pain in chronic settings, it has been so far marketed in the perioperative period. Side effects are a concern in its use for preoperative sedation in children. Large studies are now required for drugs approval and for new indications at regulatory agencies level. Good clinical judgment is more relevant now than ever before to avoid complications and new withdraw of old good medications inappropriately prescribed from the market place.

Control and abolition of pain during and after surgical procedures is crucial point in the practice of anaesthesiology. In the last years the concept of multimodal analgesia (the use of different analgesic and techniques to relieve pain), has developed and non-steroidal anti-inflammatory drugs (NSAIDs) have a major role in it, because they have an opioid sparing effect. Moreover, they are very effective on somatic and breakthrough pain. NSAIDs can be divided functionally in four classes: salicylates, acetaminophen, non-specific inhibitors (i.e. ibuprofen, ketorolac, etc.) and cyclooxygenase2-inhibitors (coxibs). The target of action of these drugs is the different isozymes of the Prostaglandin G/H synthase, called Cyclooxygenases (COX). At least three different types of COX have been identified, which are probably organ specific. These isozymes play a crucial role in the developing of the inflammatory cascade, and in the genesis of various pain mediators released from tissue injury. Their most important side effects affect mainly gastrointestinal system, the kidney and the coagulation system. Less important are the effects on the liver and the immunologic system (asthma). The analgesic nephropathy and the coagulopathy must be taken into account in the surgical patient, for the possibility of increase perioperative morbidity. Very recently the newest class of coxibs, although they reduce g.i. bleeding and coagulopathy, have proved to increase the risk of cardiovascular accidents both in long term therapy than postoperatively in cardiac surgical patients. Many data are needed, but in patients at high risk of cardiac disease other NSAIDs should be considered.

Ketamine is a non-competitive antagonist to the phencyclidine site of N-methyl-d-aspartate (NMDA) receptor for glutamate, though its effects are mediated by interaction with many others receptors. It has been introduced in clinical use since 1960's but today it is not largely employed as a general anaesthetic for its undesired psychic effects (emergence reactions) occurring in approximately 12% of patients. In the last decade, there has been a renewed interest in the use of subanaesthetic doses of ketamine for the treatment of acute and chronic pain. In the late 1990's, multiple prospective, randomised, controlled study has shown the efficacy of low dose of ketamine for postoperative pain relief, for analgesia during regional or local anaesthesia, and for opioid-sparing effect. At present, non-definitive conclusion can be drawn. More data are needed to define the possible long term effects and the clinical goal of ketamine use.

Epidural analgesia is widely used for postoperative pain in a variety of surgical operations and it is recognised to provide superior quality of analgesia when compared with systemic opioids. The combination of low doses of local anaesthetics and opioids appears to provide optimal analgesia with minimal motor blockade. However, side effects have been reported with epidural analgesia such as postoperative nausea and vomiting (PONV), respiratory depression and arterial hypotension. Although the incidence of these side effects is lower than those reported with the use of systemic opioids, they can contribute to a delay in discharging patients from PACU. Epidural analgesia is also associated with perioperative hypothermia. The incidence of cognitive dysfunction is not decreased by using postoperative epidural analgesia. Assessment of the quality of analgesia by using pain visual analogue score (VAS) at rest and with movements or on coughing remains the most preferred in PACU, although there are limitations with this measurement. Epidural failure due to technical failure or malposition of the catheter represents potential problems having direct consequence on the quality of analgesia provided. All epidural catheters have to be checked and the quality of analgesia assessed before patients are discharging from PACU to the surgical wards. With advances in pain pharmacology, multimodal interventions and adjuvants can be used safely with the intent of providing better analgesia and decreasing the side effects associated with one technique.

Delirium is a global impairment of upper brain functions caused by an organic substrate. It is frequently observed in the postoperative period, particularly in elderly people. Vascular and orthopedic surgery and long-duration surgery are associated with a higher incidence of postoperative delirium. When it occurs, postoperative delirium makes patient management much more difficult, increases costs, and, above all, causes severe discomfort to the patient. Delirium is also associated with higher postoperative mortality and morbidity, and with delayed functional recovery, but it is still unclear whether worse prognosis is directly caused by delirium or results from the neurological damage of which delirium is simply a symptom. Drug therapy should be part of a complex approach to prevent and treat this complication. Neuroleptics like haloperidol and droperidol, and benzodiazepines are usually employed in order to control symptoms like agitation, restlessness, and altered perceptions. Atypical neuroleptics, like risperidone, have not yet been studied in postoperative delirium, although some case reports in which they were successfully used have been published. Physiostigmine is effective in delirium caused by anticholinergic syndrome; vitamins may be useful in alcoholics; melatonin use has been suggested in order to prevent and treat delirium by normalizing sleep-wake cycle alterations. Environmental interventions are often costless and may be very useful to prevent and treat postoperative delirium in patients at risk.

Using a portable infusion pump, intravenous opioid patient-controlled analgesia (PCA) permits a patient to selfdeliver a small bolus of opioid to achieve prompt relief without over sedation. Use of PCA for pain management is increasing in hospitals, largely because it can provide equivalent or better analgesia than conventional nurse-administered opioid analgesia, and patients are more satisfied with its use. There is no decisive pharmacological or clinical argument for the choice of one opioid rather than another. Thus, morphine remains the most frequently used opioid in PCA. The adjunction of non-opioid drugs to morphine in the PCA reservoir is still very controversial. A new investigational PCA transdermal system using iontophoresis to deliver fentanyl seems to provide an adequate pain control with the advantages of needle-free, preprogrammed, self-contained device. Whatever drug or device used, the overall success of the PCA technique relies mainly on the expert supervision of nurses or anesthesiologists in an Acute Pain Service. Indeed, PCA is effective and significant only on the condition that there is careful preoperative patient education and strict postoperative monitoring. In addition, preoperative patient selection allows to exclude patients with evidence of cognitive dysfunction or physical disabilities, making the use of the patientcontrolled device impossible. Caution is required among patients with respiratory or renal insufficiency. In the future, the indispensable improvement in the management of postoperative pain should lead to a greater expansion of PCA. However, more pharmaco-economic evaluations will be needed on the cost-effectiveness issue.

Parkinson' disease (PD) is a most common and debilitating degenerative disease resulted from massive loss of dopamine neurons in the substantia nigra pars compacta, which is characterized by severe motor symptoms of tremor, bradykinesia, rigidity and postural instability. Protection of nigral dopamine neurons from progressive degenerative death and cell replacement of novel dopamine neurons are hopeful strategies against PD in humans. The reactive astrocytes or functional activation of astrocytes abundantly occurred in brain insults including trauma, ischemia, and 6-OHDA or MPTP-treated PD animal models. Although they were traditionally assumed to impede neuronal regeneration by forming glial scars, growing evidence has indicated that reactive astrocytes do offer crucial benefits in functional recovery of brain injuries. The reactive astrocytes can produce various neurotrophic factors for neuron survival, synthesize extracellular substrates for axonal outgrowth and synaptogenesis, act as scavengers for free radical and excess glutamate, and promote neurogenesis of neural progenitor cells in the adult brains. We thereafter hypothesize that reactive astrocytes may also play important roles in the protection of nigral dopamine neurons or transplanted dopamine cells through their neurotrophic functions and active interaction with dopamine neurons or neural progenitor cells. Future approaches deserve to target on neurotrophic functions of reactive astrocytes in the basal ganglia and interventions to facilitate survival and axonal regeneration of dopamine neurons or differentiation of dopamine progenitor cells. Novel pharmaceutical and cell replacement strategies will hopefully be developed by potential manipulation of reactive astrocytes in the basal ganglia in prevention and treatment of Parkinson's disease.

Renal cell carcinoma (RCC) is a highly treatment-resistant tumor type; however, advances in elucidating the molecular pathophysiology underlying RCC has led to the identification of promising targets for therapeutic intervention. In clear-cell RCC, mutations to the von Hippel-Lindau (VHL) gene results in the up regulation of many proteins necessary for tumor growth and survival, - such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and platelet derived growth factor (PDGF), which are involved in tumor-initiated angiogenesis. Carbonic anhydrase IX and signaling via the epidermal growth factor receptor (EGFR) are involved in tumor cell proliferation and are also up regulated by mutation in the VHL gene. The intracellular messenger pathways phosphoinositide 3-kinase (PI3K) and Raf/MEK/ERK act as convergence points for positive growth signaling; the Raf/MEK/ERK pathway is also implicated in apoptosis. Several agents in development target VEGF (bevacizumab), the VEGF receptor (PTK787, SU11248, VEGF-trap, and BAY 43-9006), the PDGF receptor (SU11248 and BAY 43-9006), or the EGF receptor (gefitinib, cetuximab, ABX-EGF, and erlotinib). The intracellular Raf/MEK/ERK signaling cascade has been targeted at either the level of Raf (BAY 43-9006, ISIS 5132) or MEK (CI-1040, PD184352 and ARRY-142886), and PI3K signaling is disrupted by CCI-779. WX-G250 targets the G250 antigen, and PS-341 disrupts the 26S proteasome mediating the degradation of intracellular proteins. Given that multiple pathways contribute to tumor growth, anti-tumor activity may be increased by agents targeting multiple pathways, or by combining agents to allow horizontal or vertical inhibition of multiple pathways.