Adverse drug reactions and drug-drug interactions


  • 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.

  • 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.

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. 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.”

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%. Another study of 12 children’s hospitals found an average ADE rate of 11.1%, with 22% of those events classified as preventable. More specifically, the risk of ADRs and ADEs in the pediatric 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.

ADEs in the pediatric critical care setting can increase patient morbidity and mortality as well as hospital costs. 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). Nationally, pediatric ADRs have an estimated economic burden of approximately $252.9 million per year (2011 USD). 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. ,

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 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). 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. 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. 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. , 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.

Adverse drug reactions by organ system


Nephrotoxicity is the second most common adverse reaction at nearly 7% and is more common among infants and young children. , 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. 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, 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, β-blockers, and calcineurin inhibitors. 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. 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. 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.

TABLE 124.1

Drugs Associated With Nephrotoxicity

Tubular Necrosis Interstitial Nephritis Hemodynamic-Mediated Renal Failure
Methoxyflurane anesthesia
Radiologic contrast agents
Thiazide and loop diuretics
Valproic acid
Angiotensin-converting enzyme inhibitors
Radiologic contrast agents

NSAIDs, Nonsteroidal antiinflammatory drugs.

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. , 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.

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. , Antimicrobials and NSAIDs are the most common offending agents. The clinical presentation of AIN can appear between 2 and 44 days after initiation of therapy. , Clinical symptoms include fever, skin rash, arthralgias, and flank tenderness. Common laboratory findings include hematuria, sterile pyuria, and eosinophilia. , 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 7 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. , 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. 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.

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.

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. 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. 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. 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.

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.


The liver is a common target of drug toxicity owing to its major role of metabolism and elimination of foreign substances. Drug-induced 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. 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. , Many agents, including prescription medications, over-the-counter (OTC) drugs, and herbal and dietary supplements are associated with DILI.

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. , 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. 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. ,

Detecting DILI relies on a detailed history of medication exposure and careful examination of the onset and course of abnormal liver biochemistry tests. Measurements of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin are important measurements in assessment of DILI. Unfortunately, DILI is a diagnosis of exclusion; however, hepatobiliary imaging and liver biopsy may also aid in diagnosis.

DILI typically occurs within the first 6 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. , In general, children are less prone to drug-induced 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. They are also at risk for developing valproate-associated liver injury, which occurs more frequently in children younger than 2 years who have preexisting neurologic or physical defects. Box 124.1 lists common drugs associated with DILI.

• BOX 124.1

Drugs Associated With Drug-Induced Liver Injury


  • Acetaminophen

  • Nonsteroidal antiinflammatory drugs


  • Amoxicillin/clavulanate

  • Antiretrovirals

  • Ceftriaxone

  • Fluoroquinolones

  • Isoniazid

  • Macrolides

  • Minocycline

  • Nitrofurantoin

  • Rifampin

  • Sulfamethoxazole/Trimethoprim

  • Voriconazole


  • Carbamazepine

  • Felbamate

  • Lamotrigine

  • Phenobarbital

  • Phenytoin

  • Valproate

Immune modulators

  • Antitumor necrosis factor-α agents

  • Monoclonal antibodies (i.e., infliximab)

  • Tyrosine kinase inhibitors


  • 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

DILI can be characterized as hepatocellular, cholestatic, or mixed presentation depending on the pattern of liver damage. Several drugs have a signature presentation (phenotype) of liver injury. , For example, isoniazid and valproate typically exhibit a hepatocellular pattern, while chlorpromazine results in cholestatic liver damage. However, many drugs can lead to both hepatocellular and cholestatic injury, such as amoxicillin/clavulanate and trimethoprim/sulfamethoxazole. ,

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 ( ) 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. 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.


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 renin-angiotensin-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, 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. 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. 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. 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), α-agonists (clonidine, dexmedetomidine, atypical antipsychotics), histamine release (morphine, vancomycin), or direct vasodilation (prostacyclins, propofol). 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.

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. As mentioned, NSAIDs are also associated with fluid retention and may increase mean arterial pressure even with single doses via inhibition of prostaglandin production. Tacrolimus and cyclosporine, immunosuppressive agents, can significantly increase blood pressure, especially in cardiac transplant patients. 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 α-agonists, such as clonidine.

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. Additionally, with prolonged use and higher doses, clinicians should be aware of signs and symptoms of propofol infusion syndrome, which include fever, lipidemia, hyperkalemia, and hepatomegaly. Dexmedetomidine, another agent increasingly used for long-term sedation in the PICU, is an α-receptor agonist that may lead to bradycardia, especially at initiation.

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, β-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 β-blockers, it is recommended to use caution when combining dexmedetomidine and β-blockers in patients in the ICU. Phenylephrine and vasopressin are vasoactive medications used in the ICU to increase peripheral vascular resistance without affecting heart rate. , 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 α- and β-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. , Amiodarone, an antiarrhythmic often used to treat supraventricular tachycardia, is associated with bradycardia and hypotension, which may be both dose and infusion rate dependent. β-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. 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. 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 β-agonists. Stimulation of β 1 -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 β 1 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. Dobutamine and isoproterenol both cause direct stimulation of β-receptors. Therefore, patients should be closely observed for arrhythmias when these medications are required. In patients with higher risk of tachyarrhythmias, vasoactive agents with little or no β 1 effect—including norepinephrine, phenylephrine, and vasopressin—should be considered.

Other PICU medications associated with elevated heart rate include nonspecific β-receptor agonists and vasodilators. Albuterol, a nonselective β-agonist, is frequently used in PICU patients to improve respiratory function and treat underlying conditions. Bronchodilation is achieved via β 2 -receptor agonism in the lungs. However, it also stimulates β 1 -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 β 2 selective bronchodilator and active enantiomer of racemic albuterol, is superior to albuterol in patients predisposed to tachyarrhythmias. 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. ,

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 1 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 1 in 1000 live births. , 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. 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. , 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. , 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. Another concern when administering these medications is pharmacokinetic DDIs or pathophysiologic alterations in elimination. 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. The website 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.

• BOX 124.2

All unmarked medications are considered low risk; however, they have a documented or theoretical association with QT prolongation. For a complete list, see .

Drugs Commonly Associated With QT Interval Prolongation


  • Amiodarone a

  • Flecainide

  • Procainamide a

  • Propafenone b

  • Quinidine a

  • Sotalol a


  • Amitriptyline b

  • Citalopram (doses >40 mg) a

  • Escitalopram

  • Fluoxetine

  • Sertraline

  • Venlafaxine


  • Ciprofloxacin

  • Clarithromycin b

  • Erythromycin b

  • Fluconazole

  • Levofloxacin

  • Moxifloxacin a

  • Pentamidine b

  • Quinidine b

  • Quinine b

  • Trimethoprim-sulfamethoxazole

  • Voriconazole


  • Aripiprazole

  • Haloperidol b

  • Quetiapine

  • Risperidone

  • Ziprasidone

Cardiovascular agents

  • Isradipine

  • Nicardipine

  • Verapamil

Gastrointestinal agents

  • Cisapride c

  • Droperidol b

  • Ondansetron a


  • Methadone

  • Tacrolimus

Medications highly associated with QT prolongation.

Medications moderately associated with QT prolongation.

Cisapride, though removed from the US market, has been approved for limited compassionate use in some pediatric disease states.

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 4 mEq/L and magnesium levels greater than 1.7 mEq/L. In fact, intravenous magnesium sulfate is the drug of choice to treat TdP. Magnesium stabilizes the myocyte and prevents early depolarization, which may disrupt an unstable rhythm. Owing to alterations in extracellular levels of potassium, the risk of medication-induced TdP increases with decreased heart rate. Known as reverse-use dependence , the inhibition of potassium ion channels is enhanced in the setting of both hypokalemia and bradycardia. For this indication, it has been suggested that the use of vasoactive medications to increase heart rate, such as isoproterenol, may potentially minimize the effects of drug-induced LQTS. ,

Medication-induced heart failure may be caused by a reduction in myocardial contractility, increase in preload, direct myocyte toxicity, or development of cardiovascular risk factors. Dexmedetomidine, non-DHP CCBs (nifedipine, verapamil, diltiazem), β-blockers, and some antiarrhythmics (dronedarone, flecainide, ivabradine, and sotalol) exert a negative inotropic effect, decreasing contractility, which may lead to acute heart failure. Medications that increase fluid and sodium retention, such as NSAIDs and corticosteroids, can slowly or dramatically increase preload precipitating heart failure with chronic use. NSAIDs are considered to be contraindicated in patients with or at risk of heart failure due to increased preload and decreased response to diuretics. If treatment with NSAIDs is necessary in patients with heart failure, lower doses and shorter durations are recommended.

Many medications used in pediatric patients have been affiliated with myocyte injury and subsequent cardiac damage leading to heart failure. Amphotericin B has been associated with cardiomyopathy in multiple case reports; however, patients generally recover within 6 months after stopping therapy. Rheumatologic agents—such as infliximab, etanercept, and adalimumab, used to treat rheumatoid arthritis and Crohn disease—have been associated with increased risk of heart failure. However, this has mostly been seen in adults, with limited case reports in pediatric patients.

Chemotherapeutic agents are commonly associated with cardiotoxicity. Anthracyclines—such as doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone—may lead to acute cardiotoxicity or cardiomyopathy, which is related to cumulative lifetime dose. The rate of heart failure related to anthracyclines in pediatric patients has been reported to be as high as 16%. However, it is important to note that the development of cardiotoxicity may not be seen for many years. There are reports in the literature of patients who received anthracycline therapy as children who developed cardiac symptoms between 4 and 20 years after exposure. Severe anthracycline toxicity is irreversible; therefore, it is associated with poor prognosis and increased risk of mortality. In adults, strategies to minimize anthracycline toxicity include limiting total lifetime dose (goal <550 mg/m ), use of liposomal anthracyclines, prolonged infusion times, initiation of ACE inhibitors in high-risk patients, and dexrazoxane. Dexrazoxane, a derivative of the chelating agent ethylenediaminetetraacetic acid, binds free radicals produced by anthracyclines, preventing oxidative damage to the myocyte. Its use is reserved for patients whose diagnoses typically require higher cumulative lifetime doses of anthracyclines.

More recent data suggest that pediatric patients treated with anthracyclines may be at greater lifetime risk of developing heart failure than patients first treated with anthracyclines as adults. In a study of pediatric anthracycline recipients, there was a higher rate of heart failure with increased time from first dose and cumulative lifetime dose greater than 300 mg/m , which is much lower than adult guidelines. , In addition, higher weekly doses (>45 mg/m ) appear to be independently associated with increased risk of acute heart failure. , Frequent, lifelong, and guideline-directed monitoring is required for pediatric patients after administration of anthracycline chemotherapy owing to the heightened risk of acute heart failure.

Cyclophosphamide, an alkylating agent used for induction prior to bone marrow transplantation, is also associated with myocarditis. Up to 50% of patients receiving higher-dose induction regimens may experience left ventricular dysfunction, with 15% to 30% developing acute heart failure. Though fatalities have been reported, cyclophosphamide-associated heart failure typically resolves within 3 to 4 weeks of therapy.

Other agents used to treat pediatric cancer have been implicated in the development of cardiotoxicity. These include monoclonal antibodies, tyrosine kinase inhibitors, high-dose interleukin-2, and mitomycin C. Often used as targeted therapy, these agents increase the risk of heart failure by direct myocyte damage that may be related to their underlying mechanisms of action.

Many medications increase cardiovascular risk through the development of associated comorbidities. Long-term use of older-generation protease inhibitors, such as indinavir and lopinavir/ritonavir and atypical antipsychotics, can cause hyperlipidemia, glucose abnormalities, and weight gain. This predisposes patients to long-term cardiovascular issues. The calcineurin inhibitors tacrolimus and cyclosporine are known to cause hypertension; they are also associated with left ventricular dysfunction and hyperlipidemia. Owing to their required use in transplant patients, long-term cardiac sequelae may be unavoidable. Cardiovascular death is one of the most common causes of death after organ transplantation. Gonadotropin-releasing hormone agents (goserelin, histrelin, and leuprolide) may also lead to weight gain and hypertriglyceridemia with continued use. It is important to recognize agents that may contribute to the development of cardiovascular disease and follow patients closely with guideline-directed care when chronic therapy is indicated.

Central nervous system

CNS adverse effects include cerebrovascular events, delirium, seizures, movement disorders, serotonin syndrome, neuroleptic malignant syndrome, and ototoxicity . Cerebrovascular and cerebellar consequences can present as loss of coordination and balance. Drugs causing these effects include phenytoin, lithium, carbamazepine, cytarabine, and aminoglycosides. Most cases are reversible with discontinuation of the offending agent; higher doses and extended duration increase risk of irreversibility.

Delirium in critically ill patients is a common occurrence, which presents as fluctuations in cognition, mood, attention, and arousal. Both the hypoactive and agitation/hyperactive types of delirium are associated with negative outcomes, longer ICU stays, and increased costs. , The risk factors for ICU delirium are multifactorial and include sleep deprivation, chronic neurologic illnesses, psychiatric disease, mechanical ventilation, and analgesics and sedative administration. Evidence suggests that sedative practices may influence and contribute to the development of delirium, especially the use of benzodiazepines. Lorazepam has been shown to be an independent risk factor for transition to delirium. Antipsychotic medications are used off-label for delirium, but no clinical trial has shown significant reduction in delirium or ICU stay. Nonpharmacologic interventions and increasing awareness among pediatric intensivists should help to prevent or attenuate ICU delirium.

Seizure disorders affect millions of patients. It can be difficult to distinguish between a seizure disorder and a drug-induced seizure. Prescription medications are the most common cause of iatrogenic seizures. Drug-related factors that may contribute to seizures include the intrinsic epileptogenicity of the agent, serum levels (dose, schedule, and route dependent), and permeability into the CNS (lipid solubility, molecular weight, ionization of the drug, protein binding, transport by endogenous systems). Patient-related factors may influence the risk for drug-induced seizures, such as preexisting epilepsy, neurologic abnormality, decreased drug elimination capacity (renal, hepatic), and conditions that disrupt the blood-brain barrier.

Several medications used within the ICU have been associated with seizures ( Table 124.2 ). Meperidine may induce seizures, especially in patients with renal insufficiency, owing to accumulation of its metabolites. This is why its use in ICU patients is often restricted to specific clinical indications. Multiple antiinfective and immunosuppressive medications—including β-lactam antibiotics, high-dose metronidazole, isoniazid, and cyclosporine—induce seizures. Many of the antiepileptic drugs can be implicated in worsening seizure activity, which usually occurs when higher than normal concentrations are used. Seizures also may be precipitated by medication withdrawal. Withdrawal of antiepileptic agents may cause seizures due to either subtherapeutic levels or excessively rapid removal of the agent. Owing to the complexity of care needed for intensive care patients, increasing awareness of these medications and their mechanisms of action should allow practitioners to recognize and diagnose drug-induced seizures more effectively.

TABLE 124.2

Medications That Can Induce Seizures

Medication Potential Mechanism of Action Comments
Acyclovir Neurotoxicity Renal impairment and parenteral administration increase the incidence
Antipsychotics Decrease seizure threshold Increased incidence with high doses and rapid dose adjustments
Carbapenems Potentiate seizure activity through the inhibition of GABA receptor Use caution in patients with CNS disorders and renal dysfunction
Imipenem has higher incidence compared with meropenem, ertapenem, doripenem
Cephalosporins Inhibition of GABA receptor Ceftazidime > ceftriaxone > cefuroxime and cefotaxime
Cyclosporine Unknown but may involve the release of the potent vasoconstrictor endothelin from endothelial cells that induce microvascular damage and/or changes in permeability of the blood-brain barrier More common with high doses
Increased incidence with hypercholesterolemia and hypomagnesemia
Cytarabine Cerebral dysfunction Increased incidence with intrathecal administration
Fluoroquinolones Unknown but may involve inhibition of GABA receptor History of seizures and use of NSAIDs associated with increased risk of seizures
Flumazenil May precipitate benzodiazepine withdrawal; inhibition with seizure medications Use caution in patients with underlying seizure disorder
Meperidine CNS excitation from toxic metabolite (normeperidine); blockade of serotonin Common reaction with renal impairment and high doses
Metronidazole Penetrates the blood-brain barrier Occurs with cumulative high dose and prolonged use
Penicillins Irritation of nervous system Use in caution with infants, rapid IV infusions, and renal impairment
Tacrolimus Neurotoxicity May be secondary to local vasoconstriction mediated by endothelin; elevated levels and hepatic impairment may increase the risk of neurotoxicity
Theophylline CNS toxicity Serum concentrations >25 µg/mL have been noted to induce seizures

CNS, Central nervous system; GABA, γ-aminobutyric acid; IV, intravenous; NSAIDs, nonsteroidal antiinflammatory drugs.

Drug-induced movement disorders often present in patients taking a variety of drugs concurrently. These movement disorders impose challenges for patients in resuming their activities of daily life after critical illness. First-generation antipsychotics (e.g., haloperidol) and GI agents (e.g., metoclopramide) are frequently used in the ICU and may induce extrapyramidal side effects (EPSs). Second-generation antipsychotics, such as risperidone, are thought to induce less EPSs; however, they are still possible. EPSs, particularly tardive dyskinesia, can be permanent; therefore, it is important to identify symptoms early and treat them appropriately.

Another movement disorder commonly seen in the ICU is critical illness myopathy (CIM). It is associated with inability to wean from ventilatory support and is the most common cause of neuromuscular weakness in the ICU. Risk factors include vasopressor administration, renal replacement therapy, aminoglycosides, steroids, and neuromuscular blockade. Combinations of these medications may further exacerbate CIM. CIM is often underdiagnosed but has a mortality rate of up to 55%. Pediatric intensivists should consider the need for these medications carefully in patients at risk for CIM. If unavoidable, every attempt should be made to limit combinations of offending agents and duration of therapy.

A potentially life-threatening drug-induced adverse event is serotonin syndrome. Serotonin syndrome often presents as mental status changes, autonomic hyperactivity, hyperthermia, and neuromuscular abnormalities, specifically myoclonus. Although it is a relatively rare disease, use of multiple combinations of serotoninergic drugs greatly increases the risk. Some of the drugs associated with serotonin syndrome and often used in the ICU include SSRIs, monoamine oxidase inhibitors (MAOIs), fentanyl, ondansetron, linezolid (partial MAOI), and valproate. The disease will persist as long as precipitating agents continue to be administered or the drug’s activity is present. Fluoxetine, an SSRI, has a half-life of approximately 1 week, which could cause prolonged duration of serotonin syndrome. Early diagnosis is critical; treatment involves supportive care. There have been reports of effective use of cyproheptadine, a serotonin antagonist, to treat serotonin syndrome; however, this remains controversial.

Similar to serotonin syndrome, neuroleptic malignant syndrome (NMS) is also life-threatening and presents as mental status changes, autonomic hyperactivity, hyperthermia, and neuromuscular abnormalities, specifically muscle rigidity. The clinical characteristics of NMS also include abnormal laboratory findings, including elevated creatine kinase, liver function tests, and inflammatory markers. Medications associated with NMS include first- and second-generation antipsychotics and the antiemetic metoclopramide. NMS is considered an emergency; therefore, treatment includes vigilant monitoring and significant supportive care as well as administration of higher doses of the intravenous skeletal muscle relaxant dantrolene to decrease associated muscle rigidity. The dopamine agonists bromocriptine and amantadine may also be considered to help reverse symptoms of NMS.

Several medications are associated with ototoxicity, which is usually iatrogenic. The main sites of action of ototoxic drugs are the cochlea, vestibulum, and stria vascularis. Salicylates and aminoglycosides are the most common agents associated with hearing loss. , Other agents include cisplatin, loop diuretics, erythromycin, and vancomyin. , The effect is usually dose and administration dependent, as with loop diuretics. , , High-dose and long-term therapy are common risk factors for aminoglycoside-induced ototoxicity, which is irreversible. , Cisplatin is the most ototoxic of the antineoplastic agents, whereas ethacrynic acid is the loop diuretic with the greatest potential for causing ototoxicity. Appropriate dosing and monitoring of agents associated with ototoxicity are important for prevention and early detection.


Chemotherapy with cytotoxic agents is the most common cause of drug-induced bone marrow suppression and can lead to secondary morbidities. For example, neutropenia predisposes a patient to opportunistic infections and sepsis. Chemotherapy-induced thrombocytopenia may render a patient vulnerable to hemorrhage in the CNS or GI tract. Severe anemia may lead to dizziness, fatigue, hypotension, and myocardial infarction. In addition to bone marrow suppression, some antineoplastics may produce thrombotic and hemorrhagic coagulation toxicities. For example, l -asparaginase has been reported to induce changes in the von Willebrand factor multimer in children and, thereby, promote platelet aggregation.

Drug-induced hematologic side effects have also been observed with several classes of antiinfectives, such as β-lactam antibiotics, linezolid, trimethoprim-sulfamethoxazole (TMP-SMX), dapsone, chloramphenicol, and antiviral agents. β-Lactam antibiotics have been reported to be associated with autoimmune hemolytic anemia, leukopenia, and thrombocytopenia. , Linezolid-induced thrombocytopenia and anemia are most commonly seen when therapy continues for more than 2 weeks. , However, these effects are reversible upon discontinuation of therapy. The manufacturer recommends weekly monitoring of complete blood counts, especially for patients who require treatment beyond 2 weeks. Neutropenia and thrombocytopenia are common side effects of TMP-SMX. , Dapsone use has been associated with hemolytic anemia and methemoglobinemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Therefore, patients should be screened for G6PD deficiency before initiating therapy and dapsone should be avoided in patients with this deficiency. Ganciclovir and valganciclovir may cause neutropenia and are commonly used in immunosuppressed patients who are often on concurrent marrow suppressive agents. Close monitoring of neutrophil counts in these patients is prudent to prevent neutropenia-associated complications. These antiviral medications should be renally adjusted as appropriate to prevent neutropenia. However, it is important to note that dose adjustments should not be made based on neutrophil counts, as it may lead to subtherapeutic drug levels and the potential for drug resistance.

Clozapine is an antipsychotic drug that has a risk of causing severe neutropenia in 3% of treated patients. , The highest incidence occurs 4 to 12 weeks after initiating therapy. In the United States, dispensing of clozapine requires the prescriber, pharmacy, and patient to enroll in the Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program and comply with neutrophil monitoring and reporting requirements. Carbamazepine and valproic acid are anticonvulsants that have been associated with neutropenia, with reported incidences of 2.1% and 0.4%, respectively. , Antithyroid medications, such as methimazole and propylthiouracil, are also commonly cited as causes for agranulocytosis. ,

Heparin-induced thrombocytopenia (HIT) is an immune-mediated ADR that develops when antibodies bind to heparin and platelet factor 4. This reaction results in a complex formation that leads to platelet activation and consumption, with platelets falling below 150 × 10 9 /L or a 50% or greater reduction in platelet counts. The incidence of HIT ranges from 0.1% to 5.0%; thrombosis develops in 25% to 50% of those affected. Risk factors for HIT include the type of heparin (unfractionated heparin > low-molecular-weight heparin) and the duration of exposure (>5 days). Untreated HIT can progress to life-threatening thrombosis. A scoring system such as the 4 Ts can help predict the likelihood of HIT. , It evaluates four criteria: (1) degree of thrombocytopenia; (2) timing of platelet count fall, (3) presence of thrombosis or other HIT complications, (4) and other causes of thrombocytopenia. An immunologic assay, such as enzyme-linked immunosorbent assay, and platelet activation assay are useful in ruling out HIT. Owing to the potential severe sequelae of HIT, all forms of heparin should be discontinued promptly upon any suspicion of HIT; anticoagulation with a nonheparin product, such as argatroban or bivalirudin, should be initiated to prevent thrombosis. Once platelet count has recovered, warfarin therapy can begin, with a minimum 5-day overlap with the nonheparin agent. Treatment of HIT requires anticoagulation for a minimum of 4 weeks and should be prolonged to a minimum of 3 months if thrombosis is involved. Heparin should be avoided in the future for most patients diagnosed with HIT.

Endocrine and metabolic

Owing to the complexity of the biochemical processes that influence the endocrine and metabolic balance of the body, several medications have the potential to alter neuroendocrine hormonal production, binding, transport, and signaling. In addition, exogenous drug administration may change hormonal counter-regulatory efforts. The most common types of medication-induced endocrine disorders include alterations in carbohydrate metabolism (i.e., changes in blood glucose), electrolyte abnormalities, thyroid changes, and variations in acid-base status.

Hypoglycemia most commonly occurs due to overtreatment with insulin or diabetic medications, while drug-induced hyperglycemia commonly occurs due to decreased insulin secretion, alterations in liver glucose metabolism and production, or increased insulin resistance. Table 124.3 lists common medications associated with hypoglycemia and hyperglycemia subdivided by neuroendocrine effect.

TABLE 124.3

Drugs That Cause Endocrine/Metabolic Changes

Hyperglycemia Hypoglycemia Hyponatremia Hypernatremia
Insulin Secretion
Thiazide diuretics
Alterations in Liver Glucose Metabolism
Oral contraceptives
Insulin Resistance
Protease inhibitors
Thiazide diuretics
Amphotericin B (liposomal)
Loop diuretics
Insulin Secretion
Loss of Sodium
Loop diuretics
Thiazide diuretics
SIADH Effect
Antidepressants (SSRIs, TCAs)
Antiepileptics (carbamazepine, oxcarbazepine)
Vinca alkaloids (vinblastine, vincristine)
NSAIDs (fluid retention)
Amphotericin B
Hypokalemia Hyperkalemia Calcium or Magnesium Thyroid
Influx (Intracellular)
β-Agonists (albuterol, terbutaline)
Amphotericin B
Azole antifungals
Echinocandins (caspofungin, micafungin)
Exogenous Administration
Penicillin G potassium
Potassium supplements
Stored packed red blood cells
Efflux (Extracellular)
β-Blockers (nonselective > selective)
Digoxin toxicity
Intravenous amino acids (arginine, lysine, aminocaproic acid)
Mannitol (via hyperosmolality)
Propofol (via PRIS)
Aldosterone Deficiency/Resistance
ACE inhibitors
Calcineurin inhibitors (cyclosporine, tacrolimus)
Trimethoprim (TMP-SMX)
Amphotericin B
Calcineurin inhibitors (cyclosporine, tacrolimus)
Loop diuretics
Amphotericin B
Chelation therapy
Chemotherapy (cisplatin, carboplatin, 5-FU, cyclophosphamide, ifosfamide)
Ethylene glycol poisoning
Loop diuretics
Thiazide diuretics
Vitamin D toxicity

ACE , Angiotensin converting enzyme; ADH, antidiuretic hormone; ARB , angiotensin II receptor blockers; NSAIDs , nonsteroidal antiinflammatory drugs; PRIS, propofol-related infusion syndrome; SGA, second-generation antipsychotics; SIADH, syndrome of inappropriate antidiuretic hormone secretion; TMP-SMX, sulfamethoxazole-trimethoprim; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; TKIs, tyrosine kinase inhibitors; 5-FU, 5-fluorouracil.

Glucocorticoids are perhaps the most well-known medications to cause hyperglycemia, which occurs by impairing insulin sensitivity and promoting hepatic gluconeogenesis. This ADR appears to be dose dependent and is usually reversible upon discontinuing therapy. However, long-term glucocorticoid therapy inhibits the function of the hypothalamic-pituitary-adrenal (HPA) axis, which can cause adrenal insufficiency if corticosteroids are stopped abruptly. Adrenal insufficiency is a serious and potentially life-threatening side effect of corticosteroid use. As a result, glucocorticoid replacement therapy in the setting of stress—such as acute illness, trauma, or surgery—should be considered when patients with a history of chronic corticosteroid use present to the ICU. Such patients may also require physiologic glucocorticoid replacement dosing.

Electrolyte abnormalities are frequently seen in critically ill patients and can lead to significant morbidity and mortality. Although this can occur for many different reasons, several medications are known to cause electrolyte derangements. The most common ADRs include alterations in serum sodium, potassium, magnesium, and calcium (see Table 124.3 ). ,

Hyponatremia is often secondary to a dilutional effect (excess water retention) or a depletional effect (excessive loss of sodium with or without water). Diuretics are a common class of medications that cause depletional hyponatremia by promoting urinary loss of sodium. Dilutional hyponatremia is often secondary to effects on antidiuretic hormone (ADH), such as the syndrome of inappropriate ADH secretion (SIADH), or drugs that stimulate ADH release or enhance its effects.

Critically ill patients are also at significant risk for developing hypernatremia. The etiology is often multifactorial, but drugs can increase serum sodium concentration via free water loss or administration of hypertonic sodium solutions (e.g., sodium bicarbonate and sodium chloride infusions). Free water loss can occur by drug-induced renal losses, such as medications that induce nephrogenic or central diabetes insipidus. Hypernatremia can also occur in response to GI losses (e.g., vomiting, diarrhea, fistulas) if the losses are not adequately replaced. Additionally, some medications, such as TMP-SMX, can cause renal salt wasting.

Hypokalemia is directly affected by medications that increase potassium excretion or increase sodium-potassium adenosine triphosphatase (Na-K-ATPase) activity causing potassium influx into the cells. In contrast, drug-induced hyperkalemia can develop when medications lead to decreased Na-K-ATPase activity or block sodium channels in principal cells of the distal nephron, leading to potassium efflux from cells. , , Hyperkalemia can also result from excessive potassium intake or impaired renal excretion of potassium via decreased aldosterone synthesis or resistance. , Succinylcholine, a depolarizing neuromuscular blocker, may cause hyperkalemia as well by directly affecting ion-channel depolarization. Typically, this is clinically insignificant, but the change in serum potassium level is more pronounced in patients with burns, muscle trauma, neuromuscular disease, severe infection, and/or renal insufficiency. , , Overall, drug-induced hyperkalemia is most common in patients with renal insufficiency or other disturbances in potassium homeostasis (e.g., hypoaldosteronism, nephropathy, renal transplantation). See Table 124.3 for drug-induced causes of hypokalemia and hyperkalemia divided by mechanism of action. , , , ,

Lastly, medications can also alter serum magnesium and calcium concentrations. Primary mechanisms of drug-induced hypomagnesemia include agents that affect kidney resorption or influence transcellular shifts. Nephrotoxic drugs—such as amphotericin B, cisplatin, and cyclosporine—are thought to cause magnesium loss by drug-induced injury. Diuretics cause hypomagnesemia through urinary excretion of magnesium, with loop diuretics causing a more pronounced effect than thiazides. This is due to their site of action on the loop of Henle, where most of the magnesium is resorbed. In addition, hypomagnesemia is often closely associated with hypocalcemia and hypokalemia; correcting serum magnesium may be required to normalize potassium and calcium levels.

Hypocalcemia is another common abnormality in critically ill patients. Calcium is critical for cell function, neural transmission, membrane stability, bone health, and intracellular signaling. Calcium homeostasis is maintained through regulatory mechanisms via parathyroid hormone (PTH) and vitamin D but disruptions can cause calcium to shift from the extracellular fluid in greater quantities than it can be replaced. Overall, hypocalcemia typically occurs as a result of PTH deficiency, vitamin D deficiency, calcium chelation, or bone resorption dysfunction. For example, some antiepileptic agents (e.g., phenytoin, phenobarbital, carbamazepine) cause vitamin D deficiency/resistance, whereas several chemotherapeutic agents and bisphosphonates inhibit bone resorption (see Table 124.3 ). , ,

Drug-induced hypercalcemia is also secondary to disruptions in calcium homeostasis that involve PTH and vitamin D. Overall, the rate of calcium influx extracellularly exceeds the kidney’s ability to eliminate it. The most common drugs associated with hypercalcemia include vitamin D toxicity, thiazide diuretics, lithium, and calcium supplementation (e.g., calcium carbonate). ,

In summary, electrolyte abnormalities are a common ADR that can complicate therapy. The cause is often multifactorial; however, medications are a known cause of electrolyte disorders. As a result, critically ill patients may require frequent electrolyte monitoring, especially if on multiple-drug therapy.

Electrolyte abnormalities have been noted with the use of amiodarone; however, it is most commonly known for its adverse effects on the thyroid gland. Due to the large amount of iodine in amiodarone (3 mg iodine/100 mg drug is released into circulation), it has a counter-regulatory effect on the production of thyroid hormones. In patients in more developed countries, where iodine deficiency is rare, use of amiodarone is associated with hypothyroidism. In contrast, in countries where iodine deficiency is more common, amiodarone can cause hyperthyroidism. Therefore, it is recommended to obtain baseline thyroid studies prior to starting therapy and to periodically monitor them throughout treatment. Other drugs associated with thyroid dysfunction can be found in Table 124.3 . ,

Sodium nitroprusside (SNP), a potent vasodilator, has been used to control blood pressure in the ICU for many years. However, SNP is metabolized to cyanide and thiocyanate; thus, cyanide toxicity should be considered when SNP is given at higher doses and with prolonged use. , Overall, SNP is considered safe to use in pediatric patients at lower doses and for short durations. The pediatric literature has demonstrated that cyanide toxicity is uncommon. Risk factors for developing toxicity include renal or liver dysfunction, prolonged infusion duration (≥24 hours), and/or higher doses (>2 μg/kg per minute). ,

Propofol is widely used for procedural sedation in the ICU, although its use as a continuous infusion is limited owing to the possibility of developing propofol-related infusion syndrome (PRIS). Although rare, the hallmark signs of PRIS include severe metabolic acidosis, acute refractory bradycardia, rhabdomyolysis, and hyperlipidemia that can lead to cardiovascular collapse and death. In 2001, the FDA issued a warning against off-label use of propofol for sedation in the PICU after reviewing data from a randomized controlled trial. The trial evaluated the safety and efficacy of propofol versus standard sedation in pediatric patients. Approximately 10% of patients treated with propofol died compared with 4% of children receiving standard treatment. In general, PRIS appears to be dose dependent and is associated with propofol infusion rates greater than 4 mg/kg per hour for at least 48 hours, although there are reports of PRIS occurring at shorter durations and lower infusion rates. , Other risk factors for developing PRIS include younger age, severe critical illness, exogenous catecholamine or glucocorticoid administration, low carbohydrate supplies (especially in children), and subclinical mitochondrial disease (such as defects in lipid metabolism). , , Overall, the use of propofol infusions in the PICU remains controversial. If used, appropriate monitoring of arterial blood gases (pH), serum lactate, creatinine kinase, electrolytes, and liver and renal function is warranted. PRIS can also be prevented by ensuring that patients maintain an adequate carbohydrate load, which will help avoid an increase in fatty acids. Although the safe use of propofol without adverse effects has been reported, high-dose, prolonged propofol infusions are not recommended in the pediatric ICU setting given the risk of death with PRIS.


Drug-induced dermatologic reactions are the most common reported adverse events, affecting 2% to 3% of all hospitalized patients. They include hypersensitivities, cutaneous eruptions or exacerbations, and severe cutaneous adverse reactions (SCARs). Drug-induced hypersensitivities describe both immunoglobulin (Ig)-mediated allergic reactions and pseudoallergies. Urticaria, pruritus, angioedema, and facial flushing can occur with both types of hypersensitivity. Though their clinical presentation is similar, true allergic reactions require a sensitization period (5–21 days after the first dose) due to the activation of antibodies. Allergic reactions are often associated with antimicrobials, antivirals, and aromatic anticonvulsants, such as phenobarbital and phenytoin. Coexisting conditions may also contribute to the development of allergic reactions. For example, active infection with Epstein-Barr virus may increase the potential for a reaction to aminopenicillins. Though commonly described as true allergies, dermatologic reactions to vancomycin, radiocontrast, aspirin, and ACE inhibitors are usually pseudoallergic. Pseudoallergies include infusion-related reactions, skin flushing, and anaphylactoid reactions, which usually occur within minutes of administration. “Red man syndrome,” facial and neck flushing associated with vancomycin, is an example of a pseudoallergy. As with other pseudoallergies, reducing the infusion rate and premedicating with antihistamines are strategies to reduce the development of this adverse effect. Many medications are associated with hypersensitivities and pseudoallergy. Therefore, it is important to assess patients carefully when these types of reactions occur, as a falsely labeled “allergy” may limit future treatment options.

Maculopapular rashes are the most common types of drug-induced skin eruptions. Like hypersensitivity reactions, the rash usually develops 4 to 14 days after initiation of the causative medication. However, unlike urticaria, which is associated with IgE-mediated allergic reactions, maculopapular rashes are self-limiting and do not typically lead to more severe symptoms, such as angioedema and anaphylaxis. It is important to note that lesions located in the mucous membranes, palms, or soles of the feet are evident in approximately 90% of SCARs and may be a prelude to a more serious reaction. After discontinuation of the suspected medication, most erythematous reactions can be treated with antihistamines and a low-dose steroid taper (if rash is diffuse).

SCARs include drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and warfarin-induced necrosis. Drug rash with eosinophilia and systemic symptoms (DRESS) is defined by a constellation of symptoms, including high fever, symmetric maculopapular rash, and internal organ involvement. Often associated with anticonvulsants, specifically phenytoin and phenobarbital, allopurinol, and dapsone, symptoms may take 3 to 8 weeks to develop after the initiation of the causative medication. Organ dysfunction may be severe and can lead to liver or kidney failure. Treatment includes supportive care and high-dose steroids. In patients receiving allopurinol, it is beneficial to adjust for renal dysfunction and avoid concurrent use of thiazide diuretics or ACE inhibitors. SJS and TEN are similar SCARs that are considered dermatologic emergencies. Often preceded by a viral-appearing prodrome, both conditions are associated with high fever and maculopapular skin eruptions that blister, leading to epidermal necrosis and detachment. These symptoms often appear within 7 to 14 days of drug exposure. Though their presentations are similar, TEN is often considered a more severe presentation of SJS since patients with TEN develop epidermal detachment on greater than 30% of their body surface area (BSA) versus less than 10% of BSA in SJS. Additionally, TEN is associated with acute renal failure, respiratory failure, and sepsis. Medications commonly known to cause SJS and TEN include allopurinol, lamotrigine, penicillin, TMP-SMX, and voriconazole. Patients with SJS and TEN require admission to the ICU for supportive care, including extensive wound care and surgical debridement. In smaller studies, higher doses of intravenous immunoglobulin (IVIG) have been shown to decrease disease progression and improve outcomes.

Warfarin-induced skin necrosis (WISN) is a severe cutaneous reaction that typically occurs within the first 10 days after the initiation of warfarin therapy. A dramatic drop in protein C, compared with other coagulation factors, creates a hypercoagulable state in which areas with higher amounts of adipose tissue can develop blistering plaques eventually leading to necrosis. Treatment includes discontinuation of warfarin, anticoagulation with heparin to prevent further microthrombi from developing, fresh-frozen plasma or protein C concentrate to restore protein C levels, and surgical debridement with or without skin grafting. Strategies to prevent WISN include initiation with lower doses of warfarin and bridging with heparin or low-molecular-weight heparin for at least 5 days when starting warfarin therapy.

Drug-drug interactions

The pediatric intensive care physician is confronted daily with potentially hazardous DDIs in the critical care setting. A DDI has been defined as “the possibility that one drug may alter the intensity or pharmacological effects of another drug given concurrently. The net result may be enhanced or diminished effects of one or both of the drugs or the appearance of a new effect that is not seen with either drug alone.” Given the extent of polypharmacy in the PICU, the risk may be significant. However, of the thousands of documented DDIs, only a small fraction is clinically significant. The ability to differentiate between clinically significant and insignificant interactions requires an understanding of their mechanisms of action. In most cases, DDIs are predictable and preventable with appropriate dose modifications or avoidance of combinations.

Medications with narrow therapeutic indices are especially susceptible to DDIs, as small alterations in exposure can lead to large changes in response. Typically, drugs with large therapeutic indices are at minimal risk for clinically significant DDIs.

DDIs can occur by three different mechanisms: pharmacokinetic, pharmacodynamic, and pharmaceutical. Pharmacokinetic DDIs have been defined as “interactions which affect a target drug through alterations in their absorption, distribution, metabolism, or excretion; the result may be an increase or decrease in the concentration of drug at the site of action.” Pharmacodynamic interactions are defined as interactions at a common receptor site or that have additive or inhibitory effects as a result of actions at different sites. Pharmaceutical interactions or incompatibilities “occur when drugs interact in vitro so that one or both are inactivated.”

Pharmacokinetic drug-drug interactions

The most common and well-studied etiology of DDIs is through pharmacokinetic interactions. Pharmacokinetic interactions can occur throughout the entire pharmacologic spectrum and can affect the absorption, distribution, metabolism, or elimination of the compound of interest. However, DDIs are important only when they impact the resulting drug exposure to such an extent that the patient experiences an alteration in the expected drug effect, either through diminution of drug effect (when drug exposure is decreased) or through predisposition to adverse effects (when drug exposure is increased).

Interactions affecting drug absorption (enteral absorption)

Several factors determine the rate and extent of oral absorption of drug products. DDIs affecting enteral absorption occur through several mechanisms with a common result: alteration of availability of the drug at its primary site of absorption. The most common mechanisms include adsorption or complexation of the target drug by other drugs or food; alterations in the ionization of the drug through pH changes; and perturbation of normal GI function (e.g., motility, bacterial colonization, and mesenteric blood flow). In the critical care setting, adsorption and complex formation are the most likely causes of decreased enteral drug absorption. Commonly prescribed medications, such as sucralfate, are implicated in causing decreased absorption of other drugs by adsorbing target drugs and rendering them unavailable for absorption across the GI barrier. Food, especially enteral formula, is capable of causing adsorption of drugs. Phenytoin, levothyroxine, flecainide, and warfarin all have known interactions with enteral formulations. Although less commonly prescribed in the pediatric setting, tetracycline and quinolone antibiotics have long been known to cause drug complexes with metallic cations such as iron and calcium, resulting in a decreased effect of both the supplement and the antibiotic. ,

Interactions affecting drug distribution (protein or tissue binding)

Since the majority of drugs are bound to plasma proteins or tissue-binding sites, the most commonly cited mechanisms for DDIs affecting distribution are those that involve protein or tissue binding. Many factors affect protein or tissue binding, including pH, temperature, renal function, and low serum albumin. Several examples exist in which one drug displaces an object drug through competitive inhibition at a protein- or tissue-binding site. However, in most cases, the impact of the DDI is minimal. The amount of free (active) drug may increase temporarily, but the free level falls back to its previous equilibrium as the clearance of drug subsequently increases. Most cases of increased free drug concentrations secondary to protein-binding displacement occur when the displacing drug also inhibits the metabolism or excretion of the displaced drug.

Alterations in total body water

An important mechanism for DDIs affecting drug distribution that often is overlooked is alteration of body fluid composition. Severe dehydration can be caused iatrogenically, either through fluid restriction or overzealous diuretic use. In these cases, drug concentrations can be increased severalfold, resulting in adverse effects. Conversely, the volume of distribution of drugs can be increased significantly by increasing total body water. This can have the effect of decreasing drug concentrations to subtherapeutic levels. Drugs that distribute primarily in total body water, such as aminoglycosides, are particularly susceptible to these types of effects.

Interactions affecting drug metabolism

Most clinically relevant DDIs can be linked to an alteration in drug metabolism. The two major pathways for drug metabolism in humans are the phase I oxidative pathway and the phase II conjugation reactions. Inhibition or induction of the phase I pathway is the most studied mechanism of DDIs, especially in relation to the cytochrome P450 system of enzymes. Table 124.4 lists the drugs that affect cytochrome P450 enzymes and those metabolized by the various clinically relevant isoforms. The relative lack of formal pediatric studies makes predicting the impact of a particular interaction difficult in a given child. Factors that must be considered include the state of maturation of the isoform and the presence of compensatory pathways. In general, it is reasonable to assume that a reaction that occurs in adults will also occur in children; therefore, proper adjustments should be made if necessary.

One important consideration is the timing of DDIs secondary to P450 enzyme inhibition and/or induction. In general, enzyme inhibition results from competitive inhibition at the enzyme binding site and therefore becomes clinically relevant as soon as the offending drug reaches sufficient concentrations in the liver. Consequently, upon discontinuation of the offending drug, enzyme inhibition abates as the drug concentration falls. In contrast, enzyme induction results from an increase in the amount of enzyme synthesized by hepatic cells. Thus, there is a lag between the time that an inducer is introduced and the onset of induction effect. As expected, the offset of effect also is somewhat prolonged. Phase II reactions are rarely rate limiting, which makes their potential to be the cause of clinically significant DDIs low.

Interactions affecting drug excretion

The primary means for elimination of drugs or their metabolites is through renal excretion. The process of renal excretion involves three mechanisms: glomerular filtration rate (GFR), active tubular secretion, and tubular reabsorption. All three mechanisms can be affected by DDIs.

Alterations in GFR secondary to DDIs most often result from fluctuation in renal blood flow. Drugs that act to reduce renal blood flow, such as cyclosporine or NSAIDs, can reduce GFR and increase the blood concentration of drugs eliminated by this route. Conversely, drugs that improve renal blood flow could increase GFR and decrease plasma concentrations of drugs eliminated through the kidneys. As its name implies, active tubular secretion is a process during which drugs bind to receptors and are transported across the tubular cells to be excreted. Drugs that compete for these binding sites may inhibit the secretion of other drugs and increase concentrations. The two most commonly cited inhibitors of active tubular secretion are probenecid and cimetidine. These reactions are rarely of clinical significance.

Tubular reabsorption is a passive process in which drugs are reabsorbed into the systemic circulation from the lumen of the distal tubules. As with enteral absorption, only un-ionized molecules are available for reabsorption. Therefore, drugs that alter the pH of the urine have the potential to alter tubular reabsorption of other drugs. A common example is phenobarbital, which is a weakly acidic drug. In overdose situations, sodium bicarbonate is administered to alkalinize the urine in the hopes that phenobarbital will become more ionized in urine, resulting in reduced tubular reabsorption and more rapid excretion.

Interactions affecting P-glycoprotein receptors

Research in the oncology field has led to the identification of an important drug transporter that is ubiquitous throughout the human body: PgP. PgP can be found in renal tubule cells; hepatic cells; in the blood-brain barrier; and in mucosal cells of the intestines, pancreas, and adrenal glands. Table 124.4 lists drugs that are inhibitors and/or substrates for PgP. In general, PgP is believed to serve a protective function by transporting molecules out of the body or, in the case of the blood-brain barrier, out of the CNS. Drugs that inhibit PgP are expected to increase the concentrations of substrates (either in plasma or the CNS). Clinicians should be cautious when coadministering PgP substrates or inhibitors and should consider dose adjustments or alternative treatments when administering drugs with narrow therapeutic windows.

Jun 26, 2021 | Posted by in CRITICAL CARE | Comments Off on Adverse drug reactions and drug-drug interactions
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