1464 124 Adverse Drug Reactions and Drug Drug Interactions JESSIE O’NEAL, LAUREN DARTOIS, ANNY CHAN, WADE W BENTON, AND CHRISTA JEFFERIS KIRK • Adverse drug events (ADEs) are defined as any injury res[.]
124 Adverse Drug Reactions and Drug-Drug Interactions JESSIE O’NEAL, LAUREN DARTOIS, ANNY CHAN, WADE W BENTON, AND CHRISTA JEFFERIS KIRK Adverse drug events (ADEs) are defined as any injury resulting from the use of a drug This includes both expected but harmful side effects resulting in dose reduction or discontinuation and unintended adverse drug reactions that occur with appropriately prescribed medications.1 Often, the terms adverse drug event and adverse drug reaction (ADR) are used interchangeably in the literature; however, an ADE is a broad term that refers to any harmful event associated with medication administration This includes inappropriate use or inadvertent side effects not associated with the pharmacology of the medication More specifically, an ADR is considered an ADE if it occurs with normal clinical use of a medication and has an established causal relationship to the drug For example, a medication error, defined as “any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient, or consumer” is considered an ADE, but not an ADR.”2 ADEs and ADRs are common in pediatric patients A large systematic review found that the frequency of pediatric ADRs in the inpatient hospital setting ranged from 0.6% to 16.8%.3 Another study of 12 children’s hospitals found an average ADE rate of 11.1%, with 22% of those events classified as preventable.4 More specifically, the risk of ADRs and ADEs in the pediatric 1464 • • Adverse drug events (ADEs) are defined as any injury resulting from both prescribed and unintended administration of drugs, including inappropriate use or inadvertent side effects not associated with the pharmacology of the medication ADEs are common in the pediatric intensive care unit (PICU), with a reported average rate of 4.9 events per 100 patient days Approximately 43% of those ADEs were considered preventable ADEs substantially increase the risk of morbidity and mortality in the PICU and have a significant economic impact Polypharmacy, critical illness, use of high-risk medications, and the need for nonstandard dosage forms increase the risk of ADEs in the PICU • • • • PEARLS ADEs affect all major organ systems, leading to nephrotoxicity, liver injury, cardiotoxicity, hemodynamic instability, neurotoxicity, hematologic abnormalities, endocrine disturbances, and dermatologic reactions Drug-drug interactions (DDIs) are precipitated by the pharmacokinetic and pharmacodynamic properties of medications in every drug class used in the PICU and may be impacted by alterations in absorption, clearance, distribution, and metabolism associated with critical illness The pediatric intensive care provider is confronted daily with DDIs In most cases, DDIs are predictable and preventable with appropriate dosage modifications or avoidance of combinations intensive care unit (PICU) is significant owing to the complexity and variety of patients and diagnoses A large multicenter, retrospective review of ADEs in the PICU found a mean rate of 4.9 ADEs per 100 patient days, with 2.1 per 100 patient days determined as preventable Additionally, the authors found a relationship between increasing age and risk of ADE For each additional year of age, the rate of ADEs increased by 4%, with the highest rate of ADEs noted in patients age 13 years and older.5 ADEs in the pediatric critical care setting can increase patient morbidity and mortality as well as hospital costs.6–9 Though often hard to calculate, the literature suggests that the annual economic impact from drug-related morbidity and mortality from ADRs is approximately $137 to $177 billion (2001 USD).9 Nationally, pediatric ADRs have an estimated economic burden of approximately $252.9 million per year (2011 USD).9 Epidemiologic studies of ADR data confirm that the risk of developing an ADR is as high or higher in pediatric patients as compared with adults.6–8,10–13 There are multiple factors that contribute to the increased risk of ADEs in the PICU First, most therapeutic agents used in pediatric critical care have not been studied or evaluated for safety and efficacy in pediatric patients This often leads references and providers to adapt dosing from adult data, which may be CHAPTER 124 Adverse Drug Reactions and Drug-Drug Interactions inaccurate based on developmental differences in drug disposition and clearance Second, many patients in the PICU may have multiorgan system failure or other comorbidities that can affect medication metabolism or clearance Owing to the heightened complexity of patients in the PICU, polypharmacy may be unavoidable However, this also increases the risk of ADRs as well as drug-drug interactions (DDIs).9 Finally, the variety of ages and developmental stages makes it challenging for institutions to ensure that weight-based dosing strategies and compounded dosage forms are safe for all patients In order to recognize and prevent ADRs, pediatric intensivists should be aware of complications associated with drug therapy and have a heightened awareness of risks related to the development of ADRs Isolation and identification of an ADR can be challenging owing to the ambiguous characteristics of the reaction, polypharmacy, and the inability to establish a causal relationship.14 Certain medications are high risk and more commonly associated with ADRs Chemotherapy agents, corticosteroids, vaccines, immunosuppressants, and nonsteroidal antiinflammatory drugs (NSAIDs) were found to be associated with an increase in ADR-related hospital admissions.15 Due to their narrow therapeutic index, medications such as insulin, anticoagulants, digoxin, certain antimicrobials, and older anticonvulsants may also lead to ADRs in pediatric patients The most common symptoms associated with ADRs are dermatologic reactions, mental status changes, gastrointestinal (GI) distress, and central nervous system (CNS) disturbances However, these are common symptoms found in PICU patients, which makes it difficult to definitively attribute their presence with an ADR Multiple scoring systems exist to assess the relationship between medications and adverse effects, which should be used in conjunction with a thorough clinical review.14,16–19 Prevention and management of ADRs should be a team approach focusing on both provider and system-based improvements PICU clinical teams should be vigilant in monitoring high-risk drugs, discontinuing unnecessary drugs, avoiding DDIs, adjusting doses based on developmental and clinical status, and evaluating any new symptoms in consideration of possible ADRs Examples of system-based tools for ADR prevention include computerized provider order entry, bar coding, and smart pump technology Additionally, as part of the PICU rounding team, a pharmacist is instrumental in reviewing and monitoring medications while also identifying and alerting the team to possible ADRs The presence of a pharmacist on rounds in the ICU significantly reduces the rate of ADEs.20 Adverse Drug Reactions by Organ System Renal Nephrotoxicity is the second most common adverse reaction at nearly 7% and is more common among infants and young children.21,22 Several factors place the renal system at risk for ADRs It is responsible for eliminating many drugs and metabolites, several of which are known nephrotoxins Because the renal vascular system receives approximately 20% to 25% of resting cardiac output, the kidneys are exposed to high concentrations of drugs and diagnostic agents Additionally, nephrotoxicity occurs more frequently in patients with intravascular depletion, heart failure, and sepsis.22 Although the renal system is highly vulnerable to nephrotoxicity, there are only a few mechanisms by which nephrotoxins can induce injury These mechanisms include hemodynamically mediated nephrotoxicity, tubular necrosis, 1465 interstitial nephritis, obstructive nephropathy, and vascular toxicity Many nephrotoxins can also injure the kidney through more than one mechanism Several drugs are implicated in the alteration of renal blood flow Some of the most common include angiotensin-converting enzyme (ACE) inhibitors, NSAIDs, b-blockers, and calcineurin inhibitors.23 ACE inhibitors can induce renal insufficiency in patients suffering from any process that decreases renal blood flow, including bilateral renal artery stenosis or unilateral stenosis with a single kidney or heart failure.24 The mechanism involves inhibiting the conversion of angiotensin I to angiotensin II, which results in dilation of the efferent arterioles, with resultant decreased glomerular capillary hydrostatic pressure and reduced glomerular filtration.24 NSAIDs inhibit prostaglandin synthesis, which leads to reduced renal blood flow and reduced glomerular filtration This renal insufficiency is dose related and most commonly develops in patients with concurrent conditions, such as heart failure, cirrhosis, hypovolemia, and concomitant nephrotoxic drugs NSAID-induced renal toxicity is not associated with structural damage and is reversible if the toxic agent is discontinued immediately Table 124.1 provides a more complete list of drugs associated with hemodynamic renal failure Acute tubular necrosis is one of the most common renal disorders associated with drug therapy A variety of drugs are associated with acute tubular necrosis, including aminoglycosides, cisplatin, amphotericin B, radiocontrast media, and cyclosporine.22,25 Minimizing risk factors for nephrotoxicity with these agents is imperative For example, administration of a saline load and volume repletion have been shown to be beneficial in reducing toxicity Table 124.1 presents a more complete list of medications associated with tubular necrosis TABLE 124.1 Drugs Associated With Nephrotoxicity Tubular Necrosis Aminoglycosides Amphotericin Carboplatin Cephalosporins Cisplatin Cyclosporine Mannitol Methoxyflurane anesthesia NSAIDs Pentamidine Radiologic contrast agents Interstitial Nephritis HemodynamicMediated Renal Failure Allopurinol Aminoglycosides Aztreonam Captopril Carbamazepine Cephalosporins Cimetidine Ciprofloxacin Cyclosporine Erythromycin Interferon-a NSAIDs Penicillins Phenobarbital Phenytoin Ranitidine Rifampin Sulfonamides Tacrolimus Thiazide and loop diuretics Valproic acid Vancomycin Warfarin Angiotensin-converting enzyme inhibitors Cyclosporine Mannitol NSAIDs Propranolol Radiologic contrast agents Tacrolimus NSAIDs, Nonsteroidal antiinflammatory drugs 1466 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology Acute interstitial nephritis (AIN) is another common source of drug-induced nephrotoxicity It is reported to cause 15% to 27% of all cases of acute renal failure.26,27 Antimicrobials and NSAIDs are the most common offending agents The clinical presentation of AIN can appear between and 44 days after initiation of therapy.26,27 Clinical symptoms include fever, skin rash, arthralgias, and flank tenderness Common laboratory findings include hematuria, sterile pyuria, and eosinophilia.26,27 Histologic findings of AIN include interstitial infiltrate of lymphocytes, plasma cells, eosinophils, and neutrophils Prompt discontinuation of the offending drug is recommended; administration of corticosteroids within days of diagnosis may improve recovery and decrease risk of chronic renal impairment However, delayed steroid treatment has little benefit since interstitial fibrosis has already taken place in the kidney It is also important to document any occurrence of AIN, since it can occur with reexposure of the offending drug.26,27 Table 124.1 lists some medications associated with AIN Renal tubular obstruction is associated with precipitation of endogenous products, drugs, and their metabolites For example, uric acid precipitant or poorly soluble drugs in the urine can result in renal obstruction Hydration is critical for all patients, as hypovolemia is a predisposing factor for crystal formation When chemotherapy is given, modalities such as urinary alkalization and use of allopurinol or rasburicase can help prevent uric acid precipitation.28 Drugs associated with formation of crystals include acyclovir, sulfonamides, mannitol, pentobarbital, methotrexate, protease inhibitors, and high-dose vitamin C Rhabdomyolysis can also cause intratubular precipitation of myoglobin and lead to acute renal failure It is commonly caused by toxins, inflammatory processes, and muscle compression Many cases involve multiple factors, with antipsychotics, zidovudine, selective serotonin reuptake inhibitors (SSRIs), and lithium being the most common drug causes Mortality is often low from rhabdomyolysis; however, acute renal failure can be irreversible and associated with significant morbidity.29 Many of these drugs also cause vascular toxicity that can lead to renal damage Antiangiogenesis therapy, such as bevacizumab, has antibodies against vascular endothelial growth factor (VEGF), which can cause vascular injury within the kidney Glomerular endothelial VEGF receptors promote normal functioning of the glomerular basement membrane However, when those VEGF levels are inhibited by antiangiogenesis agents, it can cause microvascular injury in the kidney and lead to proteinuria and nephrotoxicity.30 An example of a well-documented class of drugs with multiple nephrotoxic properties is the aminoglycoside antibiotics All aminoglycosides have been shown to be toxic to the proximal renal tubules and can cause necrosis.31 Aminoglycoside nephrotoxicity is related to dose, high trough concentrations, and prolonged therapy Drug-induced nephrotoxicity normally manifests as nonoliguric renal failure with a slow rise in serum creatinine after several days of treatment.31 Several risk factors for developing aminoglycoside nephrotoxicity include the need for intensive care, decreased albumin, poor nutritional status, prolonged therapy, hypovolemia, pneumonia, shock, preexisting liver or kidney disease, and elevated initial steady-state drug concentrations.31 Additionally, vancomycin, piperacillin, furosemide, amphotericin B, and cephalosporins, when administered concomitantly with aminoglycosides, are associated with an increased risk for developing nephrotoxicity Fortunately, aminoglycoside nephrotoxicity is typically reversible upon discontinuation of the offending agent.31 Drug-induced nephrotoxicity is a serious ADR that can lead to morbidity and lengthened hospital stay It is important to recognize potential nephrotoxins before initiating therapy and to evaluate therapeutic options It is also important to monitor therapy appropriately for signs of toxicity and modify therapy as needed Hepatic The liver is a common target of drug toxicity owing to its major role of metabolism and elimination of foreign substances Druginduced liver injury (DILI), also known as drug-induced hepatotoxicity, is a frequent cause of acute liver injury, has a broad spectrum of clinical manifestations, and can lead to significant morbidity and mortality.32 It is also the most common cause of acute liver failure in the United States, a leading cause of investigational drugs not reaching the market, and for approved drugs being restricted or withdrawn.33,34 Many agents, including prescription medications, over-the-counter (OTC) drugs, and herbal and dietary supplements are associated with DILI.35 The two main types of DILI are intrinsic and idiosyncratic Intrinsic DILI is dose dependent with predictable adverse effects (e.g., acetaminophen) Idiosyncratic drug-induced liver injury (IDILI) is unpredictable, less dose dependent, and more variable in latency, presentation, and course IDILI is also less common and affects only a small proportion of susceptible individuals.32,36 The pathogenesis of DILI is mediated through either direct cell damage or by activating the immune system, which largely depends on the causative drug or toxin Ultimately, liver injury from drug hepatotoxicity leads to hepatocyte inflammation and cell death via apoptosis or necrosis.32 There are a variety of mechanisms by which liver injury can occur, including direct hepatocyte damage from the accumulation of drugs and/or their reactive metabolites; organelle stress (i.e., endoplasmic reticulum and mitochondrial stress); or by triggering the innate and adaptive immune system.32,35 Detecting DILI relies on a detailed history of medication exposure and careful examination of the onset and course of abnormal liver biochemistry tests.36 Measurements of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin are important measurements in assessment of DILI.34 Unfortunately, DILI is a diagnosis of exclusion; however, hepatobiliary imaging and liver biopsy may also aid in diagnosis.36 DILI typically occurs within the first months after starting a new medication, but some drugs are known to exhibit a longer latency—such as nitrofurantoin, minocycline, and isoniazid Overall, both prospective and retrospective studies have shown antibiotics and antiepileptic agents as the most common cause of DILI in children.36,37 In general, children are less prone to druginduced liver disease than adults but appear susceptible to specific hepatotoxins For example, children have an increased risk of developing Reye syndrome, a hepatocellular disease caused by aspirin.36 They are also at risk for developing valproate-associated liver injury, which occurs more frequently in children younger than years who have preexisting neurologic or physical defects.36 Box 124.1 lists common drugs associated with DILI DILI can be characterized as hepatocellular, cholestatic, or mixed presentation depending on the pattern of liver damage.36 Several drugs have a signature presentation (phenotype) of liver injury.36,37 For example, isoniazid and valproate typically exhibit a hepatocellular pattern, while chlorpromazine results in cholestatic CHAPTER 124 Adverse Drug Reactions and Drug-Drug Interactions • BOX 124.1 Drugs Associated With Drug-Induced Liver Injury Analgesics Immune Modulators Acetaminophen Nonsteroidal antiinflammatory drugs Antitumor necrosis factor-a agents Monoclonal antibodies (i.e., infliximab) Tyrosine kinase inhibitors Antimicrobials Amoxicillin/clavulanate Antiretrovirals Ceftriaxone Fluoroquinolones Isoniazid Macrolides Minocycline Nitrofurantoin Rifampin Sulfamethoxazole/Trimethoprim Voriconazole Antiepileptics Carbamazepine Felbamate Lamotrigine Phenobarbital Phenytoin Valproate Miscellaneous Allopurinol Amiodarone (oral) Anabolic steroids Azathioprine/6-Mercaptopurine Dantrolene Direct oral anticoagulants: rivaroxaban, apixaban, dabigatran Green tea extract (catechin) Methotrexate (oral) Selective serotonin reuptake inhibitors/ Serotonin-norepinephrine reuptake inhibitors (duloxetine in particular) Sulfasalazine liver damage.37 However, many drugs can lead to both hepatocellular and cholestatic injury, such as amoxicillin/clavulanate and trimethoprim/sulfamethoxazole.36,38 It is useful to have a general knowledge of common agents associated with hepatotoxicity However, it would be challenging to maintain an exhaustive list, especially in the setting of multiple new agents coming to market on a consistent basis Resources are available to help the clinician evaluate for DILI LiverTox (https:// livertox.nih.gov) is a clinical and research database developed by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Library of Medicine (NLM) to provide up-to-date, easily accessible information on DILI.39 The DILIrank dataset is a useful reference that contains information on over 1000 US Food and Drug Administration (FDA)approved drugs that ranks them according to their potential for causing DILI.40 Cardiovascular Owing to the underlying hemodynamic instability of patients in the PICU, unintended alterations in cardiovascular function can dramatically impact morbidity and mortality Many clinically necessary medications may lead to cardiovascular ADRs, necessitating close monitoring and minimization of any identified risk factors Hemodynamic stability is dependent on multiple factors that may be affected by the physiochemical properties of medications used in the PICU The most common ADRs affecting the cardiovascular system are fluid and electrolyte imbalances, hemodynamic instability, arrhythmias, and direct cardiotoxicity Medications can affect electrolyte and volume status by direct action on electrolyte receptors or indirect effects on the reninangiotensin-aldosterone system (RAAS) Dramatic shifts in fluid and electrolytes can lead to severe changes in blood pressure, heart rate, or cardiac rhythms NSAIDs, corticosteroids, diuretics, 1467 erythropoiesis-stimulating agents, estrogen-containing oral contraceptives, mannitol, ACE inhibitors, angiotensin II receptor blockers (ARBs), and certain immunosuppressive agents, such as cyclosporine and tacrolimus, are all medications that can alter fluid and electrolyte balance.41 Combinations of these medications, often required in critical care, may exacerbate fluid and electrolyte shifts NSAIDs, for example, increase fluid and sodium retention while vasoconstricting blood vessels in the kidney.42 This decreases the bioavailability of diuretics in the kidney, diminishing their effect, necessitating higher doses Owing to this counterproductive cycle, NSAIDs should be used with caution in patients requiring diuretics Achieving and maintaining hemodynamic stability in PICU patients can be challenging Therefore, it is necessary to recognize that certain medications may create unwanted alterations in blood pressure Additionally, the PICU team should be aware that medications used to achieve hemodynamic goals may cause an ADR if clearance or metabolism is affected by other comorbidities For example, milrinone can be used for afterload reduction to balance the effects of other vasoactive medications However, in the setting of renal dysfunction, milrinone can accumulate, leading to hypotension.43 Similarly, other necessary PICU medications may lead to hypotension through a variety of mechanisms This is due to the direct or indirect hemodynamic effects of those medications and may be secondary to hypovolemia (diuretics), a-agonists (clonidine, dexmedetomidine, atypical antipsychotics), histamine release (morphine, vancomycin), or direct vasodilation (prostacyclins, propofol).44–48 Interestingly, some intravenous formulations of medications—such as amiodarone, lorazepam, and phenytoin—are diluted in propylene glycol, which can lead to hypotension if given too quickly or in cumulatively larger amounts via continuous infusion.49 Medication-induced hypertension is rare in the PICU However, early recognition of possible adverse reactions related to medications or their management is important Corticosteroids may increase blood pressure via fluid and sodium retention, which is dependent on mineralocorticoid activity Comparatively, fludrocortisone has the highest amount of mineralocorticoid activity, followed by hydrocortisone and prednisone.48 As mentioned, NSAIDs are also associated with fluid retention and may increase mean arterial pressure even with single doses via inhibition of prostaglandin production.48 Tacrolimus and cyclosporine, immunosuppressive agents, can significantly increase blood pressure, especially in cardiac transplant patients.50 Many transplant patients on these medications require the addition of a calcium channel blocker (CCB) to control hypertension Finally, it is important to note that the fast wean or abrupt discontinuation of certain medications may lead to acute hypertension These include narcotics, benzodiazepines, and long-acting a-agonists, such as clonidine.51 Arrhythmias are more common in PICU patients than in other hospitalized pediatric patients owing to underlying hemodynamic instability, electrolyte abnormalities, and the use of vasoactive medications Though not always considered alarming in adults, even mild bradycardia can have serious consequences for pediatric patients, especially in infants and children who rely more on heart rate to maintain cardiac output than adults Many medications can induce bradycardia by decreasing atrioventricular (AV) node activity, stimulating reflex bradycardia, or directly inhibiting myocyte function The use of propofol is associated with the risk of bradycardia thought to be related to decreased AV node activity and myocyte activity depression.48 Additionally, with 1468 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology prolonged use and higher doses, clinicians should be aware of signs and symptoms of propofol infusion syndrome, which include fever, lipidemia, hyperkalemia, and hepatomegaly.52 Dexmedetomidine, another agent increasingly used for long-term sedation in the PICU, is an a-receptor agonist that may lead to bradycardia, especially at initiation.48 It is also important to note that bradycardic ADRs may occur with medications intended to treat elevated heart rates or blood pressure when their clearance or metabolism is affected by organ dysfunction or drug interactions For example, unwanted hypotension may present in the setting of kidney dysfunction with cardiovascular agents that are renally cleared, such as atenolol and sotalol Cardiovascular medications known to have significant drug interactions (amiodarone, b-blockers, and non-dihydropyridine CCBs [non-DHP CCBs]) may increase the risk of hypotension in the setting of polypharmacy In fact, owing to the risk of treatment-resistant bradycardia associated with the use of clonidine and b-blockers, it is recommended to use caution when combining dexmedetomidine and b-blockers in patients in the ICU.48 Phenylephrine and vasopressin are vasoactive medications used in the ICU to increase peripheral vascular resistance without affecting heart rate.53,54 However, use of these peripherally acting medications may lead to reflex bradycardia and a reduction in cardiac output, necessitating the use of alternative vasopressors that provide both a- and b-receptor stimulation Antiarrhythmic medications used to treat abnormal heart rhythms in the PICU require close monitoring, as they have mechanisms of action that manipulate cardiac action potential.55,56 Amiodarone, an antiarrhythmic often used to treat supraventricular tachycardia, is associated with bradycardia and hypotension, which may be both dose and infusion rate dependent.57 b-Blockers can be used as antiarrhythmic medications as well and increase the risk of life-threatening bradycardia at higher doses Therefore, it is recommended to start with lower doses and titrate slowly to the lowest effective dose.58 Owing to its narrow therapeutic index, digoxin—a direct-acting cardiac glycoside used in patients with heart failure—is often associated with a variety of arrhythmias, including bradycardia at supratherapeutic levels.57 Close monitoring of digoxin levels, renal function, and electrolytes, especially potassium and magnesium, help to prevent ADRs associated with digoxin Tachycardia is a common occurrence in PICU patients due to the use of vasopressors, vasodilators, and b-agonists Stimulation of b1-receptors in cardiac tissue increases heart rate, which may lead to tachyarrhythmias Vasoactive agents used in the ICU to maintain cardiac output have varying effects on b1 stimulation Dopamine, epinephrine, and norepinephrine stimulate beta receptors at lower doses; however, risk of tachycardia is increased with higher cumulative doses and longer duration of therapy.59 Dobutamine and isoproterenol both cause direct stimulation of b-receptors Therefore, patients should be closely observed for arrhythmias when these medications are required.60 In patients with higher risk of tachyarrhythmias, vasoactive agents with little or no b1 effect—including norepinephrine, phenylephrine, and vasopressin—should be considered.60 Other PICU medications associated with elevated heart rate include nonspecific b-receptor agonists and vasodilators Al buterol, a nonselective b-agonist, is frequently used in PICU patients to improve respiratory function and treat underlying conditions Bronchodilation is achieved via b2-receptor agonism in the lungs However, it also stimulates b1-receptors in cardiac tissue PICU patients requiring albuterol will often have an increased heart rate during respiratory treatments, which may lead to arrhythmias There is no clear evidence that levalbuterol, a b2 selective bronchodilator and active enantiomer of racemic albuterol, is superior to albuterol in patients predisposed to tachyarrhythmias.61 Peripheral vasodilators can also increase heart rate and potentiate arrhythmias via indirect effects on cardiac function Nicardipine, nitroglycerin, hydralazine, and isradipine are vasodilatory agents that cause reflex tachycardia in a dose-dependent manner This effect may not be seen until the agents reach steady state; however, tachycardia should resolve upon discontinuation.48,60 Torsades de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia that is associated with QT interval prolongation related to congenital abnormalities or acquired secondary to medications or electrolyte disturbances Congenital long QT syndrome (LQTS) is characterized by a disorder in ventricular myocardial repolarization leading to a prolonged QT, which increases the risk of TdP and sudden cardiac death Related to approximately 20 genetic mutations, the prevalence of congenital LQTS is thought to be in 2000 live births However, as an estimated 15% to 20% of patients may have clinical evidence of LQTS with a negative genotype, the true prevalence may be closer to in 1000 live births.62,63 Tachyarrhythmias in patients with congenital LQTS may be further exacerbated by certain drugs and electrolyte imbalances, such as hypokalemia and hypomagnesemia, also associated with acquired QT interval prolongation Almost all medications that cause QT prolongation work by blocking the outward flow of potassium via inhibition of the rapid delayed rectifier potassium current (Ikr) This leads to prolonged repolarization and lengthening of the QT interval.64 Risk factors for drug-induced TdP include dose and types of medications used, underlying structural heart disease, electrocardiogram (ECG) changes, such as a prolonged QT interval at baseline or bradycardia, presence of hypokalemia or hypomagnesemia, and female sex.57,65 Many drugs are associated with QT prolongation, and the risk of TdP increases with higher doses and concomitant use of QT-prolonging agents Antiarrhythmics, antipsychotics, antidepressants, azole antifungals, and fluoroquinolones are general classes of agents that demonstrate the potential to prolong the QT interval.66,67 Box 124.2 provides a more complete list of medications used in the PICU that may prolong the QT interval Current practice guidelines recommend avoiding high-risk medications if the patient has a baseline QTc greater than 450 ms and to discontinue or reduce the dose of the medication if the QTc increases by 60 ms or more from baseline after initial medication administration.68 Another concern when administering these medications is pharmacokinetic DDIs or pathophysiologic alterations in elimination.69 All efforts should be made to avoid DDIs and combinations of medications that can be known to precipitate TdP Algorithms are available to guide management when QT-prolonging medications are necessary and can be particularly helpful in the setting of polypharmacy and altered medication clearance.70 The website www.crediblemeds.org is an excellent resource for providers to help with identifying and assessing the risk of QT prolongation with certain drugs or combinations of drugs as well as evaluating possible therapeutic options.71 It is important to note that underlying clinical factors may increase the risk of acquired TdP Hypokalemia and hypomagnesemia have a profound effect on myocyte action potential and can lengthen the QT interval by prolonging repolarization Electrolytes should be closely monitored for those at risk of TdP; it is strongly recommended to keep potassium levels above mEq/L and magnesium levels greater than 1.7 mEq/L.70 In fact, intravenous ... vasoconstricting blood vessels in the kidney.42 This decreases the bioavailability of diuretics in the kidney, diminishing their effect, necessitating higher doses Owing to this counterproductive cycle, NSAIDs... prostaglandin synthesis, which leads to reduced renal blood flow and reduced glomerular filtration This renal insufficiency is dose related and most commonly develops in patients with concurrent... Interferon-a NSAIDs Penicillins Phenobarbital Phenytoin Ranitidine Rifampin Sulfonamides Tacrolimus Thiazide and loop diuretics Valproic acid Vancomycin Warfarin Angiotensin-converting enzyme inhibitors