Current Drug Safety - Volume 5, Issue 1, 2010

Medication safety is critical and complex area of improvement for health-care systems. The patient population of the intensive care unit (ICU) presents a unique challenge of constantly changing laboratory values, procedures, and medications. In a complex environment, several key factors play roles which are critical to the success of medication safety. One factor is the error analysis after an event has occurred. Encompassing a structured, consistent, and thorough approach to medication error analysis is vital to the summary of recommendations an error analysis can provide. In addition, the utilization of technology is equally important in the prevention of medication errors which can occur in the ICU setting. Several categories of pharmacotherapy present significant challenges in the ICU include the following: sedation/analgesia, hyperglycemia management, chemotherapy, and parenteral nutrition. The following six articles in this Hot Topic series titled “A Focus on Medication Safety” address these areas of focus and provide recommendations for utilizing these medications safely in clinical practice. Medication safety is a multidisciplinary approach to improve patient outcome in the ICU and the implementation of these medication safety principles and strategies are critical in impacting patient survival.

Medication errors are a common unfortunate occurrence in hospitals. One population that is particularly vulnerable are patients admitted to the Intensive Care Unit (ICU). ICU patients have a combination of rapidly changing medical conditions, laboratory values, and medications, which present a particular challenge for clinicians in practice in every aspect of patient care. Medication errors can occur in different phases (prescribing, distribution, administration, and monitoring) of the medication process and have a significant impact on morbidity and mortality. Medication error analysis requires a structured approach including: detection, reporting, and analysis, in order to provide the most efficient and practical information to the ICU team. In addition, a particular focus is made on the implementation of medication error prevention strategies such as evidenced-based protocols, team education, and technology. In an effort to reduce medication error rates in the ICU requires a collaborative, multi-disciplinary approach in order to be effective and consistent through time. Further research efforts are currently taking place in this challenging aspect of patient care to further provide more strategies for medication error detection, analysis, and prevention.

Optimizing sustained use of ICU sedation in mechanically ventilated patients requires careful consideration of drug-specific characteristics (E.G. pharmacokinetics), consideration of potential adverse effects in susceptible patients, and utilization of sedationminimizing strategies. In the era of anxiolytic dosing protocols adjusted to specific patient behaviors as defined by sedation scales in conjunction with daily interruption, midazolam is a reasonable option for long-term sedation. Propofol is an appealing agent for ICU sedation due to it's pharmacokinetic profile and a reduced propensity to result in prolonged sedation. However, care should be taken to monitor for potential devastating adverse effects including hypertriglyceridemia and propofol-related infusion syndrome (PRIS). Dexmedetomidine unreliably provides adequate sedation at doses currently approved by the FDA, though upward titration of dexmedetomidine coupled with rescue benzodiazepines and/or fentanyl appears to be safe and comparable to benzodiazepines in the achievement of light to moderate Richmond Agitation Sedation Scale (RASS) goals. Clinicians should closely monitor patients receiving dexmedetomidine for hemodynamic-altering bradycardia. Strategies that promote frequent patient assessment with corresponding sedative dose minimization have demonstrated the benefits of limiting oversedation. Implementation of a sedation protocol requires careful consideration of ICU resources and staffing such that efforts made are sustainable and will be safe and effective for the patient population affected.

Medication errors have been increasingly recognized as a major cause of iatrogenic illness and system-wide improvements have been the focus of prevention efforts. Critically ill patients are particularly vulnerable to injury resulting from medication errors because of the severity of illness, need for high risk medications with a narrow therapeutic index and frequent use of intravenous infusions. Health information technology has been identified as a method to reduce medication errors as well as improve the efficiency and quality of care; however, few studies regarding the impact of health information technology have focused on patients in the intensive care unit. Computerized physician order entry and clinical decision support systems can play a crucial role in decreasing errors in the ordering stage of the medication use process through improving the completeness and legibility of orders, alerting physicians to medication allergies and drug interactions and providing a means for standardization of practice. Electronic surveillance, reminders and alerts identify patients susceptible to an adverse event, communicate critical changes in a patient's condition, and facilitate timely and appropriate treatment. Bar code technology, intravenous infusion safety systems, and electronic medication administration records can target prevention of errors in medication dispensing and administration where other technologies would not be able to intercept a preventable adverse event. Systems integration and compliance are vital components in the implementation of health information technology and achievement of a safe medication use process.

Critically ill patients admitted to intensive care units (ICUs) often present with multiple medical or surgical problems requiring a high level of care. In addition to a patient's underlying illness, a number of known risk factors can predispose patients to episodes of hyperglycemia as well as hypoglycemia. The concept of glycemic control and its implication on morbidity and mortality has been welldescribed, along with the potential risks. Conflicting study results have complicated implementing universal methods for optimal glycemic control in the ICUs. There are many factors to consider when implementing intensive glycemic control, including reliability of point-of-care testing for glucose measurement, healthcare resources, types of protocols and appropriate target ranges. It is important that clinicians fully understand the risks and benefits of glucose management in the ICU setting to safely administer this potentially beneficial therapy.

Guidelines on how to treat cancer patients receiving cytotoxic chemotherapy in the intensive care unit (ICU) are very limited. Recognizing the severity of the patient, their disease may require the need for chemotherapy whether for localized, metastatic, or hematological malignancies. It may be given alone or in combination with other cancer treatments such as radiation, or hormonal therapies. Nevertheless, the toxicities associated with chemotherapy serve as the driving force for managing complications and safe handling in the ICU. Tumor lysis syndrome, nausea and vomiting, pain management, and adverse medication effects requiring antidotes are complications for patients receiving chemotherapy in the ICU. The administration and safe handling of chemotherapy by nursing is emphasized to provide additional safety precautions. A basic understanding of cytotoxic chemotherapy is reviewed for patients requiring therapy in an ICU.

The nutrition support clinician must understand and evaluate all components of parenteral nutrition (PN) to maximize benefits while avoiding unfavorable consequences for the patients in the intensive care unit. The various aspects in caring for the PN patient include appropriate patient selection, intravenous access choice and maintenance, and individualized PN prescription to meet each patient's unique macronutrient and micronutrient requirements. Once the PN prescription has been determined, the clinician should also be familiar with the compounding process to ensure the final solution is safe for infusion. PN is one of the most complex solutions prepared in the pharmacy with numerous ingredients. Due to the number of components in the PN solution, physicochemical incompatibilities are a common and serious problem, thus specific compounding sequence and guidelines must be followed to avoid precipitation of mixed products. Once the PN solution is ready for infusion, protocols should be in place to assure safe administration. Close monitoring for tolerance of electrolytes and macronutrients, as well as glucose control is necessary initially; whereas monitoring of specific micronutrients is crucial in long-term PN usage. A standardized process for ordering, preparing, administering and monitoring PN is recommended to assure patient safety.

This issue of Current Drug Safety includes a review of scientific and regulatory implications of QT interval prolongation by drugs and the mechanisms involved for several drug classes: like cardiovascular, metabolic, endocrine, anti-infectives, antineoplastic chemotherapy, antihistamines, prokinetic agents and drugs affecting the Central Nervous System. In normal healthy subjects, the normal range of the QTc interval is quite broad ranging from 0.38 to 0.45 seconds, with age and gender modifying the range. Furthermore, in any given subject, the QTc interval can be different from one day to the next, even when taken at the same time of the day and at the same heart rate. In addition, the formulae for correction of the QT interval for heart rate are problematic, especially at heart rates either low (<50 bpm.) or high (>90 bpm). Syncope associated with the initiation of quinidine therapy has been recognized since the 1920s.The electrocardiographic monitoring in the 1960s led to the identification of pause-dependent polymorphic ventricular tachycardia as the underlying mechanism. Basic and clinical investigations performed during the last decade have helped a better understanding of the mechanisms and risk factors of this serious public health problem. In their vast majority, QT interval prolonging drugs block the human ether-a-go-go-related gene (HERG) channel that contributes prominently to terminal (phase 3) repolarization in human ventricular myocytes, and thus lengthen the QT interval. At least ten separate genes, if mutated, can cause the congenital long-QT syndrome (cLQTS) [1]. Among them the HERG gene, which encodes a potassium-channel protein, is especially relevant for drug-associated torsades de pointes (TdP). HERG controls an important repolarizing current (IKr). Mutations in HERG reduce IKr causing the cLQTS [2]. In addition, virtually all drugs that prolong the QT interval and cause TdP also block IKr. Unfortunately, this finding is not specific, since many drugs that do not appear to cause TdP also block this current. Such mechanisms will be reviewed in depth by Ponte et al. in his article in this issue of Current Drug Safety. Although the risk of TdP for noncardiac medication is generally lower than for antiarrhythmic drugs, it is difficult to estimate the actual incidence of acquired LQTS. A number of noncardiovascular drugs have been recently withdrawn from the market because of unexpected postmarketing reports of sudden cardiac death associated with prolongation of QT interval and TdP. Most drug classes involved will be also reviewed in several articles of this issue.

The long QT syndrome (LQTS) is characterized by a prolonged QT interval, as well as a propensity to develop syncope and sudden cardiac death caused by the malignant polymorphic ventricular arrhythmia called torsades de pointes (TdP). The QT interval is measured from the onset of the QRS complex to the end of the T wave and can be affected by both ventricular conduction velocities as well as by the velocity of repolarization. In most cases, QT prolongation is caused by factors that prolong the duration of the action potential, mainly by delaying the repolarization phase 3. The molecular mechanism is partially known. There are two well described mechanisms: blocking of the ion channel cavity of HERG; or causing an abnormal protein trafficking required for the location of HERG subunits in cell membrane. Both of them impair the IKr current. However the blockade of ion channels is not the only condition to generate TdP. Other factors may play an important role, e.g. myocardium heterogeneity, drug-drug interaction, genetic polymorphism, and electrolyte disturbances. Several drugs had been subject of withdrawal because QT-prolongation and arrhythmia. Understanding of processes involved in drug-induced QT prolongation is needed for the study and prevention of life-threatening arrhythmias.

The assessment about the proarrhythmic risk associated with a particular drug is a major requirement for drugs under development, since many drugs have been withdrawn from market or got under strict pharmacological vigilance because of such a risk. Predicting the development of a life-threatening arrhythmia is a hard task but, in the case of TdP (“Torsades de Pointes”), there are some useful markers. Among them, the prolongation of the QT interval and its heart rate correction (QTc) are the most remarkable. Actually, QT prolongation is considered the surrogate marker of TdP from the clinical and regulatory standpoint. ICH E14 provides recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization. The regulatory information about preclinical safety evaluation is contained in ICH S7B. Both guidelines have been a matter of intense debate. False negative and false positive results have been found within the preclinical and clinical field. There still are grey areas in which further research would be necessary. Improvement of tools that may contribute to complement the data from the human ether-a-go-go-related gene HERG channel and QT/QTc studies, such as concentration-QT relationship (CQT) studies and other innovative techniques, will be more than welcome.

Antihistamines are drugs frequently used. Several drugs in this family had to be withdrawn from the market or limited in their marketing due to potentially fatal adverse events. These events were related to the ability of some antihistamines to affect cardiac potassium channels and prolong the QT interval with an excessive risk of serious arrhythmias such as Torsades de Pointes (TdP). The presence of arrhythmias in the course of a treatment with antihistamines is essentially dependent on the presence of two factors related to the drugs and other factors related to the patient individual risk. First, the drugs ability to affect potassium channels either at therapeutic or higher doses. Secondly the possibility of interactions with other drugs or natural products resulting in increased plasma concentrations obtained following usual dosage. The drugs mainly involved in interactions are the family of macrolide antibiotics and azole antifungal agents. Among patient-related factor, predisposing genes and co morbid conditions are paramount. This article reviews the characteristics and mechanisms of these interactions and the ability of antihistamines to block different potassium channels. Special consideration is prompted to the existence of genetic polymorphism that affects the kinetics of antihistamines as well as its arrhythmogenic potential. However, the tests for their detection are not widely available and the costs significantly limit their use.

Acquired QT syndrome is mainly caused by the administration of drugs that prolong ventricular repolarization. On the other hand, the risk of drug-induced torsades de pointes is increased by numerous predisposing factors, such as genetic predisposition, female sex, hypokalemia and cardiac dysfunction. This adverse reaction is induced by different chemical compounds used for the treatment of a variety of pathologies, including arrhythmias. As it is known, antiarrhythmic agents and other cardiovascular drugs can prolong the QT interval, causing this adverse reaction. Of the 20 most commonly reported drugs, 10 were cardiovascular agents and these appeared in 348 of the reports (46%). Class Ia antiarrhythmic agents have frequently been linked to inducing arrhythmia, including torsades de pointes. Sotalol and amiodarone, class III antiarrhythmics, are known to prolong the QT interval by blocking IKr. Due to the severity of events caused by the therapeutic use of these drugs, in this work of revision the cardiovascular drugs that present this property and the factors and evidence will be mentioned.

Prokinetic agents are a very large family of drugs with different mechanisms of action. Only QT prolongation by cisapride has made notable impact and deserved its partial restriction and/or withdrawal from the market. Postmarketing surveillance initially showed that cisapride was generally safe and well tolerated, but in the past decade, more recent data have shown some risk in the patient populations. QT prolongation by prokinetic agents can raised from different mechanisms: some involve increased plasma concentrations of cisapride due to increased bioavailability by inhibiting P glycoprotein, and inhibition of metabolism or deficit in the elimination. On the other hand, pharmacodynamic interactions can also enhance the arrhythmogenic effect of cisapride. The present article presents the mechanisms and reviews the main interactions studied so far, and the role of pharmacovigilance in the detection of rare clinical events. We emphasize the need for physicians to look for conditions (either clinical or not) prone to increase the risk of QT interval prolongation.

QT interval represents the period between the initiation of depolarization and the end of repolarization of the ventricular myocardium. Excessive prolongation of this interval may drive to a potentially fatal ventricular tachyarrhythmia known as “torsades de pointes”. Agents used to manage many endocrine disorders have been linked with QTc alterations. Among them, oral antidiabetic agents, lipid lowering and anti-obesity drugs, somatostatin analogues, thyroid and anti-thyroid agents, and adrenal steroids should be considered. Nevertheless, it is very well known that some endocrine diseases are associated with constraints in the repolarization reserve, and, as a consequence, with QTc prolongation. Besides, some disturbances in the clearance of certain drugs are more frequent in patients affected by selected endocrine entities. Taking these into account, the purpose of this article is to review the behavior of the most widely used drugs in endocrinology with regards to their potential QTc prolongation effect in human beings.

QT interval prolongation is one of the most important causes of withdrawal of drugs from the market, due to its association with Torsades de Pointes (TdP), a potentially fatal arrhythmia. Although many antimicrobial drugs are capable of inducing this type of arrhythmia, the importance of this effect is usually underestimated. Macrolides, quinolones, azoles, pentamidine, protease inhibitors, antimalarial drugs and cotrimoxazole are the anti-infective agents more frequently associated with this adverse effect. Despite the fact that the risk of QT prolongation and TdP under single antimicrobial therapy is low, these drugs are so extensively used that sporadic cases of this arrhythmia are reported. Moreover, antimicrobial drugs are susceptible to pharmacokinetic and pharmacodynamic interactions with other drugs, which may increase the risk of this arrhythmia. Therefore, physicians must be familiar with not only the antimicrobial drugs capable of producing QT interval prolongation, but also their potential interactions. In addition, patient’s specific risk factors of prolonging QT interval or producing TdP must be taken into account. This article reviews the role of anti-infective drugs in QT prolongation, focusing on QT prolongation mechanisms, potential drug interactions, and patients’ predisposing factors to this arrhythmia.

Anticancer drugs are sometimes associated with QT prolongation. Classical, new and candidate agents to treat cancer may affect ventricular repolarization through a set of different mechanisms. Interference on human ether-a-go-go-related gene potassium ion channels (HERG K+) seems to be a common mechanism for many of these drugs. Anthracycline chemotherapy is associated with electrocardiographic alterations including prolongation of QT interval, development of ventricular late potentials and various arrhythmias. The effects of the interaction of anthracyclines with the monoclonal antibody against HER2/neu (Erb-2) trastuzumab could potentiate the cardiotoxic effects. Electrocardiographic changes have been also reported with the use of 5-fluorouracil. QTc alterations have also been reported with some platinum compounds. Taxanes (paclitaxel and docetaxel) have also been associated with cardiotoxicity, promoting both bradi- and tachyarrhythmias and other cardiac disturbances. Among the newest compounds, symptomatic or asymptomatic QTc aberrations were reported with multitargeted tyrosine-kinase inhibitors, anti HERG2, anti-VEGF, vascular disruption agents and histone deacetylase inhibitors. Patients with cancer are at increased risk of sudden death due to severe cardiac arrhythmias because of the high prevalence of predisposing risk factors such as electrolytic abnormalities, starvation and concomitant medications. The use of specific anticancer drug that may prolong the QT interval needs to be properly evaluated in each case to reduce this risk.

Psychotropics are among the most common causes of drug induced acquired long QT syndrome. Blockage of Human ether-ago- go-related gene (HERG) potassium channel by psychoactive drugs appears to be related to this adverse effect. Antipsychotics such as haloperidol, thioridazine, sertindole, pimozide, risperidone, ziprasidone, quetiapine, olanzapine and antidepressants such as amitriptyline, imipramine, doxepin, trazadone, fluoxetine depress the delayed rectifier potassium current (Ikr) in a dose dependent manner in experimental models. The frequency of QTc prolongation (more than 456ms) in psychiatric patients is estimated to be 8%. Age over 65 years, tricyclic antidepressants (TCA), thioridazine, droperidol, olanzapine, and higher antipsychotic doses were predictors of significant QTc prolongation. In large epidemiological controlled studies a dose dependent increased risk of sudden death has been identified in current users of antipsychotics (conventional and atypical) and of TCA. Thioridazine and haloperidol shared a similar relative risk of SCD. Lower doses of risperidone had a higher relative risk than haloperidol for cardiac arrest and ventricular arrhythmia. No increased risk was identified in current users of selective serotonin reuptake inhibitors (SSRI). Cases of TdP have been reported with thioridazine, haloperidol, ziprazidone, olanzapine and TCA. Evidence of QTc prolongation with sertindole is significant and this drug has not been approved by the Food and Drugs Administration (FDA). A large trial is ongoing to evaluate the cardiac risk profile of ziprazidone and olanzapine. Selective serotonin reuptake inhibitors have been associated with QTc prolongation but no cases of TdP have been reported with the use of these agents. There are no reported cases of lithium induced TdP. Risk factors for drug induced LQT syndrome and TdP include: female gender, concomitant cardiovascular disease, substance abuse, drug interactions, bradychardia, electrolyte disorders, anorexia nervosa, and congenital Long QT syndrome. Careful selection of the psychotropic and identification of patient´s risk factors for QTc prolongation is applicable in current clinical practice.

Several drugs acting on the nervous system have been implicated in the prolongation of the QT interval. Leaving aside the antidepressant and antipsychotic drugs, some have shown to prolong the QT interval in vivo. These include opioids, particularly methadone, inhalational anesthetics, and some preparations used for treatment of cough. These drugs have a narrow therapeutic interval or possible drug interactions that lead to clinical toxicity manifested by arrhythmias. They share the ability to block potassium channels (HERG), prolong the action potential and QT interval, and generate arrhythmias and Torsades de Pointes like other typicality recognized like antiarrhythmics, antihistamines, prokinetics, psychotropics and anti-infectives agents. Muscle relaxants like alcuronium, pancuronium and atracurium associated with or without atropine prolong significantly the QT interval. Methadone is the opiod most tightly associated with QTc prolongation; with much lesser potency buprenorphine and oxycodone can block HERG channels and depress the IKr current in vitro. Antineoplastic chemotherapy like anthracyclines, alkylating drugs, alkilants and cisplatin are associated with electrocardiographic alterations including prolongation of QT and emesis of different grades. It's very important take in account the synergic effects over the QT prolongation when effective antiemetics like 5-HT3 receptor antagonist (granisetron, ondansetron, and dolasetron) are administered. The Knowledge of their pharmacological properties is of vital importance to avoid exposing particularly vulnerable individuals as those with congenital long QT syndrome, and even the general public to unnecessary risk of potentially fatal arrhythmias.