February 2013 FAQs

What are the updated guideline recommendations for management of pain, agitation, and delirium in critically ill adult patients?

Background

Pain, agitation, and delirium occur commonly in patients in the intensive care unit (ICU). A clinical practice guideline providing recommendations for management of these conditions was published in January 2013.1 The guideline, which is supported by the American Society of Critical Care Medicine, Society of Critical Care Medicine, and American Society of Health-System Pharmacists and endorsed by the American College of Chest Physicians and American Association for Respiratory Care, updates the prior guideline from 2002.2 In addition to considering current literature, the authors used a new recommendation grading system in the updated guideline.1 The grading system defines each recommendation as strong (1) or weak (2) and in favor (+) or against (-) the intervention. For some clinical questions no recommendation is provided due to lack of consensus or lack of evidence. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology was used to rate the quality of evidence.3 The medication-related recommendations from the updated guideline are summarized below.1

Recommendations for managing pain

Historically, opioids have been the primary medications used for ICU pain management.1 Available opioids include morphine, hydromorphone, fentanyl, methadone, and remifentanyl. Although not mentioned in the formal recommendations, the guideline comments that meperidine is usually avoided in ICU patients due to the risk of neurotoxicity. Several analgesics are available for adjunctive pain management, including anesthetics, ketamine, nonsteroidal anti-inflammatory drugs, intravenous (IV) acetaminophen, and anticonvulsants. The guideline provides the following recommendations for pain management:

• First-line treatment of non-neuropathic pain in ICU patients should include IV opioids, with no preference given for any particular opioid. (+1C)
• Oral gabapentin or carbamazepine may be considered in addition to IV opioids in patients with neuropathic pain and adequate enteral absorption. (+1A)
• Nonopioid analgesics may be considered to decrease total opioid requirements and decrease opioid-related adverse effects. (+2C)
• Thoracic epidural analgesia is recommended in patients undergoing abdominal aortic surgery (+1B) and those with traumatic rib fracture. (+1B)
• No specific recommendations are provided for postoperative pain control after other procedures due to lack of compelling evidence or lack of consensus regarding the optimal analgesic approach.

Recommendations for managing agitation

The guideline recommends that agitation and anxiety in ICU patients should be addressed using nonpharmacologic techniques such as treatment of pain, frequent reorientation, and ensuring normal sleep patterns.1 Pharmacologic therapy with sedatives should be provided if nonpharmacologic therapy is ineffective. Sedative options include benzodiazepines, propofol, and dexmedetomidine, with the choice of agent based on the patient’s sedation goal, cost, and medication properties such as onset, duration, and elimination. Dexmedetomidine, the newest agent, had just been approved at the time of the 2002 guideline and is discussed more fully in the 2013 guideline.1,2 Noteably, the authors comment on several literature reports that have documented safe and effective use of dexmedetomidine for higher doses (up to 1.5 mcg/kg/hr) and longer durations (up to 28 days) than the labeled dose and duration. 1 The guideline recommendations for sedative use include:

• Clinical outcomes may be improved with use of nonbenzodiazepine sedatives (propofol or dexmedetomidine) compared to sedation with benzodiazepines in mechanically ventilated patients (+2B). A meta-analysis of 6 studies performed by the guideline authors suggests that patients who receive nonbenzodiazepines have a decreased length of ICU stay by about 0.5 days and a shorter duration of mechanical ventilation. Based on their meta-analysis, the authors concluded that mortality was similar between the 2 pharmacologic strategies.
• Benzodiazepines play an important role in managing anxiety, seizures, and substance withdrawal, and can be used for deep sedation, amnesia, or in combination with other agents to reduce overall sedative requirements.

Recommendations for managing delirium

Delirium is an acute syndrome characterized by a disturbed level of consciousness with a reduced ability to focus, sustain, or shift attention, and either a change in cognition or development of a new perceptual disturbance.1 This syndrome is a significant public health problem that occurs in up to 80% of mechanically ventilated patients. However, despite substantial research on delirium since the release of the 2002 guidelines, many questions remain regarding its pathophysiology and management. Benzodiazepines may increase the risk for developing delirium, but there are insufficient or conflicting data regarding the risk of delirium with opioids and propofol. Dexmedetomidine may be associated with less delirium than benzodiazepines. Since drug withdrawal can cause delirium, opioids or sedatives that have been given for a prolonged period should be weaned over several days to prevent withdrawal symptoms. Although antipsychotics, particularly haloperidol, are often used to treat delirium in ICU patients, no robust data support this practice and further research is needed. The following statements summarize the guideline recommendations for delirium:

• No recommendation is provided for pharmacologic delirium prevention protocols (alone or in combination with nonpharmacologic interventions) due to lack of compelling data regarding the efficacy of these protocols.
• Neither haloperidol nor atypical antipsychotics should be given to prevent delirium in ICU patients. (-2C) No recommendation is provided regarding the prophylactic use of dexmedetomidine to prevent delirium.
• Atypical antipsychotics may reduce the duration of delirium in ICU patients, but there are no data that haloperidol reduces the duration of delirium in this population.
• Rivastigmine should not be used to reduce the duration of delirium. (-1B)
• Antipsychotics should not be used in patients with an increased risk for torsades de pointes, such as those with baseline QT prolongation or those receiving other medications that can prolong the QT interval. (-2C)
• In patients who require sedation, continuous IV infusions of dexmedetomidine are preferred over benzodiazepine infusions to reduce the duration of delirium. (+2B) Data regarding the duration of delirium with propofol are lacking.

Summary

In addition to providing the specific recommendations above for analgesia, sedation, and delirium, the 2013 guideline also makes some general recommendations that have been shown to improve outcomes in ICU patients. These include daily sedation interruption or use of a light target sedation level (+1B), use of analgesia-first sedation (+2B), promoting sleep (+1C), and using interdisciplinary ICU team approaches that include effective protocols and order sets (+1B). To assist with successful implementation, the guideline provides a pocket card and a care bundle template that can be used in clinical practice.

References

1. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306.
2. Jacobi J, Fraser GL, Coursin DB, et al; Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), American Society of Health-System Pharmacists (ASHP), American College of Chest Physicians. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30(1):119-141.
3. GRADE working group Web site. http://gradeworkinggroup.org/. Accessed January 25, 2013.

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Drug-induced QT prolongation (Part 2): a focus on select medications

Introduction

In part I of this 2-part FAQ, a thorough overview of drug-induced QT prolongation was presented, including pathophysiology, risk factors, and prevention.1 Part 2 of this FAQ provides more detailed evidence to facilitate the assessment and management of patients for whom drug-induced QT prolongation and torsades de pointes (TdP) are of concern. Specifically, it is a practical and systematic guide for addressing circumstances commonly encountered by the hospital pharmacist.

The following flowchart illustrates a suggested systematic approach for the management of this common adverse drug reaction.

What risk factors for drug-induced QT prolongation and TdP are present in the patient? Are any risk factors modifiable?

As mentioned in Part I and in a scientific statement by the American College of Cardiology (ACC) and American Heart Association (AHA), there are numerous known risk factors for drug-induced TdP including:1,2

• A QTc interval >500 msec or an increase in QTc interval by >60 msec compared to baseline
• Genetic predisposition – ion channel mutations leading to congenital QT prolongation
• Heart disease including heart failure and myocardial infarction
• Bradycardia
• Female gender
• Advanced age
• Concomitant administration of >1 drug known to cause QT prolongation or TdP*
• Hypokalemia or hypomagnesemia*
• Rapid intravenous (IV) infusion of a drug known to cause QT prolongation or TdP*
• Drug interactions or organ dysfunction (hepatic, renal) that cause elevated plasma drug levels*
• History of drug-induced TdP

*Modifiable risk factors

One study found that at least 1 concomitant risk factor was present in almost all patients who experienced TdP associated with a non-cardiac drug. 3 At least 2 concomitant risk factors were present in 71% of patients. As such, when drug-induced QT prolongation is of concern, identification of these risk factors is crucial to initial patient assessment. Few risk factors are truly modifiable, but it is important to understand how these risk factors can impact a patient’s clinical condition and take steps to minimize these risks.

Hypokalemia and hypomagnesemia

Hypokalemia is a well-documented risk factor for QT prolongation.2 Low extracellular potassium results in a paradoxical inhibition of the delayed rectifier potassium current (IKr), thus prolonging the QT interval; similarly, IKr blockade is a common mechanism for drug-induced QT prolongation. As such, in the setting of QT prolongation due to factors such as drugs, it is especially important that extracellular potassium be maintained at a normal or even high-normal range to shorten the QT interval and prevent associated cardiac abnormalities.4

The arrhythmogenicity of hypomagnesemia has not been well-established, possibly because hypomagnesemia nearly always occurs concomitantly with hypokalemia, a condition more strongly implicated in arrhythmias as stated above.5 Administration of IV magnesium sulfate has demonstrated clinical benefits in the treatment of TdP, suggesting that it may more appropriate to list severe hypomagnesemia as a risk factor for drug-induced TdP.6

Close monitoring for hypokalemia and hypomagnesemia is one of the easiest means of reducing risk of drug-induced TdP. Potassium and magnesium should be supplemented as needed, with the IV route being most efficient for normalization. Clinicians should also be aware of changes in any underlying medical conditions or medications that may alter these electrolyte values, such as use of diuretics, renal and metabolic disturbances, or diarrhea.

Rapid infusion of a QT-prolonging drug

The QT-prolonging potential of drugs is believed to be enhanced when administered rapidly by the IV route due to cardiac exposure of initially higher drug concentrations.2 This concern explains why manufacturers recommend electrocardiogram (ECG) monitoring during IV administration of haloperidol. 7 Similar concerns have recently led to label changes for IV ondansetron, which is discussed further below.8 Evidence for infusion-related risks arose from early antiarrhythmic drug studies in animal models, whereas recent dosing precautions have primarily evolved from surveillance data.2,9

Potentially arrhythmogenic drugs should be infused over the recommended administration time. For high-risk patients, it would be prudent to give infusions over a longer period of time when it is therapeutically appropriate.

Drug interactions or organ dysfunction (hepatic, renal)

QT prolongation and TdP, when associated with a medication, are generally considered to be dose-dependent. With the exception of quinidine, the risk increases with increased plasma drug concentrations.2 As such, it is crucial for clinicians to address factors that increase plasma levels of these drugs.

Numerous drugs with QT-prolonging potential are metabolized by the liver or excreted by the kidneys.2 Hepatic dysfunction leads to slower breakdown of drugs such as methadone, while renal dysfunction may lead to accumulation of medications such as fluoroquinolones. Drug-drug interactions, particularly those involving the hepatic cytochrome (CYP) P450 enzymes, are also commonly implicated. Macrolides such as erythromycin and clarithromycin inhibit CYP enzymes, thus inhibiting metabolism of medications that are CYP substrates. Examples of significant CYP substrates include methadone and some antidepressants.

Hepatic and renal dose adjustments should be made to medications that are administered in patients with these organ dysfunctions. Additionally, a drug-drug interaction check is always warranted for at-risk patients.

What is the overall risk of QT prolongation and TdP with the drug? Which of the patient's other medications are of concern?

While numerous medications have demonstrated QT-prolonging potential, some are prescribed more frequently than others. Part I of this FAQ summarizes the various drug classes associated with this adverse effect. Below is a detailed summary of select agents that, due to widespread use in current medical practice, are most likely to trigger warnings for drug-induced TdP.

Antiarrhythmics

Due to their mechanism of action of delaying repolarization, class I and III antiarrhythmic agents are particularly potent in their ability to prolong the QT interval, with the risk of TdP highest within a few days of initiation.10 The most commonly used antiarrhythmic, amiodarone, carries the lowest risk of TdP due to its unique mechanism of action.11 These medications are typically administered and monitored closely by specialists in cardiology and/or electrophysiology; as such, they will not be covered in detail in this FAQ.

It is worth recognizing that use of a class I or III antiarrhythmic may itself be considered a significant risk factor for drug-induced TdP.Monitoring should be closely performed when these medications are administered concomitantly with any other QT-prolonging medication .12

Antidepressants – Citalopram

In August 2011, the maximum daily dose of citalopram was lowered to 40 mg, following a Food and Drug Administration (FDA) warning regarding dose-dependent increases in QTc prolongation.13 This recommendation was based on data showing that patients receiving citalopram 20 mg daily and 60 mg daily experienced a mean QTc increase of 8.5 msec and 18.5 msec, respectively, with an extrapolated estimate of 12.6 msec with 40 mg daily. The advisory was updated in March 2012 with additional recommendations that 20 mg should be the maximum for patients older than 60 years of age, those with known poor CYP 2C19 function, or those taking concomitant CYP 2C19 inhibitors that could decrease citalopram metabolism and lead to toxicity. Its use is discouraged in patients with congenital long QT syndrome or other risk factors, and it is recommended to monitor ECG and electrolytes if citalopram must be used in this patient population. In addition, the FDA recommended that citalopram be discontinued if the QTc persists above 500 msec. The concerns with citalopram led to further investigation of escitalopram, its S-isomer. The QTc-prolonging effect with therapeutically equivalent doses of escitalopram was approximately half of that of citalopram, and did not warrant a change in dosing recommendations.

It is worth noting, however, that although QT prolongation has been noted with citalopram, its association with TdP is not well-established. Citalopram overdose cases have not been associated TdP in otherwise healthy individuals.14,15 Cases of citalopram-associated TdP were associated with additional risk factors such as hypokalemia, concomitant QT-prolonging medications, advanced age, and other medical illnesses.15

Fluoroquinolone antibiotics

All fluoroquinolones antagonize IKr and have the potential to prolong the QT interval. However, based on in-vitro data, IKr-blocking and QT-prolonging potencies vary among the specific agents (moxifloxacin > levofloxacin > gatifloxacin > ciprofloxacin).16,17 Those deemed unsafe after postmarketing case reports of cardiac adverse effects (eg, sparfloxacin and grepafloxacin) have been voluntarily withdrawn from the market. Various trials have investigated the effect of moxifloxacin, levofloxacin, and ciprofloxacin, the 3 agents commonly used systemically. Of these, moxifloxacin has the most evidence for QT prolongation. Following a standard 7-day treatment course, it prolonged the QTc interval by 6 to 11 msec in healthy volunteers. 18 In the same study, standard therapeutic courses of levofloxacin and ciprofloxacin did not result in prolongation of the QTc interval.

An industry-sponsored study also looked at the effect of these antibiotics when administered at 2 to 3 times the typical therapeutic dose. Compared to placebo, 1 dose of moxifloxacin 800 mg prolonged the QT interval by 16.34 to 17.83 msec, levofloxacin 1000 mg prolonged the QT interval by 3.53 to 4.88 msec, and ciprofloxacin 1500 mg prolonged the QT interval by 2.27 to 4.93 msec.19 It is worth noting that the QT-prolonging effects of fluoroquinolones are not consistent across the body of literature; for each of these agents, there has been at least 1 study that detected no significant change in the QT interval. Moreover, the majority of case reports of fluoroquinolone-associated TdP involved other risk factors such as concomitant QT-prolonging medications, making it difficult to identify the fluoroquinolone as the sole contributor to the event.

Overall, fluoroquinolones carry a low risk for TdP. Studies have demonstrated the QT-prolonging potential of these agents, but the association with clinical TdP has not been strongly established. ECG monitoring during fluoroquinolone administration is not necessary unless the patient has other significant risk factors for drug-induced QT prolongation and TdP. 12 Of the fluoroquinolones currently used, moxifloxacin is associated with the highest risk and its use should be closely monitored in the presence of concomitant risk factors. Ciprofloxacin is generally considered the fluoroquinolone with the least risk of QT prolongation. In patients with renal impairment, proper fluoroquinolone dose-adjustment will minimize excessive serum levels and thus arrhythmogenic risk.

Haloperidol

There are a substantial number of case reports of sudden death, QT prolongation, and TdP following administration of IV haloperidol, making the association fairly well-established.7 Manufacturers state in their package labeling that haloperidol injection is not approved for the IV route of administration, and recommend continuous ECG monitoring if it is to be administered in this fashion. Use of IV haloperidol has led to significant increases in QTc.20,21 Patients who developed TdP were found to have experienced a QTc increase from 501 to 606 msec, whereas patients who did not develop TdP experienced a significant but lower magnitude increase from 466 to 507 msec.20 The odds ratio of developing haloperidol-induced TdP was 12.1 in patients whose QTc interval surpassed 521 msec. In another study, 8 hours after concomitant administration of IV haloperidol and flunitrazepam resulted in a statistically significant increase of 9.1 msec in mean QTc, compared to a decrease of 15 msec with flunitrazepam alone.21 However, no ventricular tachyarrhythmias were detected in over 300 patients over a 1-year period at this institution, and the QTc difference between groups was insignificant in the moments immediately following administration. The QTc change was also found to be proportional to the dose of haloperidol given. Data on TdP-specific risk with IV haloperidol are more limited, although the overall incidence of TdP from IV haloperidol is estimated to be 3.6%.22 One observational study of patients in the intensive care unit found an 11% incidence rate of TdP following high-dose IV haloperidol; 8 out of 286 patients developed TdP following IV haloperidol, and 7 of them had received more than 35 mg in a 24-hour period.23

Intramuscular (IM) haloperidol prolongs the QT to a lesser extent and carries a lower risk of drug-induced TdP. The administration of IM haloperidol 7.5 mg led to a mean 6.0 msec increase in QTc, and administration of a second 10 mg dose 4 hours later resulted in a mean 14.7 msec increase from baseline. 24 Mean QTc values remained under 450 msec, and no changes greater than 60 msec were observed. This was consistent with findings of a prior study that showed that a single dose of IM haloperidol 7.5 mg increased QTc by 5 msec, as calculated by the commonly used Bazzett’s correction equation. 25

As with IM haloperidol, administration of the oral formulation is also associated with lower risk of QT prolongation compared with IV administration. A single dose of oral haloperidol 10 mg resulted in an increased mean QTc of 421.6 msec versus 408.4 msec with placebo when ECG was measured 10 hours post-dose.26 One large cohort study found that 4.3% of patients receiving a mean total dose of 15.9 mg experienced a pathological QTc interval, defined as being greater than 470 and 480 msec in male and female patients, respectively.27

All formulations of haloperidol have been associated, in a dose-dependent manner, with QT prolongation. Intravenous haloperidol, having been associated with numerous case reports of TdP, requires continuous ECG monitoring during and after administration. The IV route should be avoided if possible, particularly in patients with other risk factors for drug-induced TdP.

Macrolide antibiotics

Macrolides, particularly erythromycin and clarithromycin, have been associated with QT prolongation and TdP especially because of their strong inhibition of CYP 3A4 metabolism, which leads to higher serum levels of other drugs that may promote QT prolongation.11 Azithromycin, purportedly because of its weaker inhibition of CYP 3A4, has the least association with QT prolongation.

Erythromycin itself carries some arrhythmogenic risk, and the effect is typically associated with IV administration.28,29 Even slow IV infusions have led to mean QTc values of 555 msec in critically ill patients, although TdP associated with erythromycin use is rare and case reports are usually associated with other risk factors.30 There is less evidence for clarithromycin’s arrhythmogenicity, possibly due to the fact that it is less frequently used than other macrolides. No trials have investigated its QT-prolonging or TdP effects, although there are case reports suggesting that this association is directly due to the drug itself rather than its effects on pharmacokinetic drug interactions.31,32

Use of erythromycin or clarithromycin should always involve a drug-drug interaction check.

ECG monitoring during erythromycin IV infusion is generally not recommended, although may be warranted if the patient has multiple risk factors for drug-induced QT prolongation and TdP.

Methadone

Methadone’s inhibition of the IKr and QT-prolonging potential have been well-established.33 QT prolongation is more pronounced with IV administration, with a mean hourly dose of 17.8 mg resulting in a mean QTc increase of approximately 42 msec.34 This effect may be enhanced by the presence of the chlorobutanol preservative in the injectable formulation. Furthermore, methadone’s negative chronotropic effect results in bradycardia, an established risk factor for drug-induced TdP.33,35

Oral methadone is also associated with QT prolongation and TdP risk. A review of reports to the FDA MedWatch program has shown that the risk is especially high with methadone doses greater than 40 mg daily, as only 1 of 59 reported cases of QT prolongation or TdP involved the use of a lesser dose. 33 This is reflected in the findings of a retrospective case review of former IV drug abusers managed with oral methadone in which TdP following QTc intervals greater than 500 msec were associated with doses of 40 to 200 mg daily, and less commonly with daily doses less than 70 mg.36 Typical therapeutic doses of oral methadone, both for pain management and opioid detoxification, may easily surpass 40 mg daily.

Due to its well-documented arrhythmogenic risks, guidelines recommend specific monitoring for patients taking methadone.37 An ECG should be obtained at baseline, 30 days following initiation of therapy, and annually thereafter. More frequent monitoring is warranted with doses of greater than 100 mg daily, QTc intervals of 450 msec to 499 msec, or if unexplained symptoms of syncope or seizure occur. A dose decrease or discontinuation of methadone treatment is recommended if the QTc interval is greater than 500 msec. Finally, because methadone is metabolized by the liver, accumulation and increased risk of cardiac toxicity likely occurs with hepatic impairment.

ECG monitoring guidelines are recommended with methadone use as above. Particularly high-risk patients are those with hepatic dysfunction, and those taking doses of more than 100 mg daily.

Ondansetron

Ondansetron is one of the newest medications for which FDA labeling has been affected by QT-prolonging potential. In the fall of 2012, the 32 mg injectable vial was removed from the market over concerns of drug-induced TdP; at that same time, the product labeling was revised to limit single IV doses to no more than 16 mg.8 This labeling change was prompted by results of manufacturer-sponsored safety studies mandated by the FDA.38 A 2011 study found that, in healthy adults, ondansetron 32 mg infused IV over 15 minutes resulted in a QTc prolongation of 19.6 msec. This prolongation was significantly higher than that from an 8 mg dose, which resulted in a clinically insignificant QTc prolongation of 5.8 msec. Investigators extrapolated these results to predict a QTc prolongation of 9.1 msec from IV ondansetron 16 mg. There was no observed QTc greater than 480 msec, no increase in QTc of greater than 60 msec, or case of TdP or any other serious adverse effect.

The FDA has reminded healthcare providers of the potential for more pronounced QT prolongation with ondansetron in the setting of the aforementioned risk factors.8 This is consistent with the fact that patients receiving IV ondansetron 4 mg following heart failure exacerbation or acute coronary syndrome experienced a mean QTc increase of 18 to 20 msec, a value comparable to the prolongation seen in healthy patients receiving IV ondansetron 32 mg. 39 The FDA also recommends optimization of electrolyte abnormalities prior to the administration of IV ondansetron. There have been no changes in standard oral ondansetron dosing regimens.

drug-induced TdP is an uncommon occurrence with IV ondansetron, and its QT-prolonging effect is less significant with therapeutic doses than with some other higher-risk medications. Due to FDA and manufacturer investigation and review, the ondansetron package labeling has been changed to recommend no more than 16 mg per IV dose. The 32 mg injectable vial will no longer be marketed. Electrolyte abnormalities should be normalized prior to administration of IV ondansetron. If the patient has other risk factors, cautious use and ECG monitoring may be warranted.

Conclusion

A thorough assessment of risk versus benefit is key to making an appropriate decision on use of a drug with known QT-prolonging effects. Authors of the 2010 ACC/AHA scientific statement on prevention of TdP in the hospital setting state that prolonged QT potential should not be a reason to exclude use of a drug when the benefit of its use clearly outweighs the associated risks.2 In other words, it would be appropriate to use the medication if there is no alternative agent with comparable therapeutic efficacy and lower arrhythmogenic potential. Additionally, with the exception of antiarrhythmic medications, the ACC/AHA statement also emphasizes that QT prolongation does not equate to arrhythmogenicity, which is the ultimate concern for the medications discussed.

References

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2. Drew BJ, Ackerman MJ, Funk M, et al; American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology; Council on Cardiovascular Nursing; American College of Cardiology Foundation. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2010;55(9):934-947.

3. Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine. 2003;82(4):282-290.

4. Choy AM, Lang CC, Chomsky DM, Rayos GH, Wilson JR, Roden DM. Normalization of acquired QT prolongation in humans by intravenous potassium. Circulation. 1997;96(7):2149-2154.

5. Millane TA, Ward DE, Camm AJ. Is hypomagnesemia arrhythmogenic? Clin Cardiol. 1992;15(2):103-108.

6. Roden DM. drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10):1013-1022.

7. Haloperidol (Haldol) injection [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2005.

8. FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran). U.S. Food and Drug Administration Web site. http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm . Accessed January 21, 2013.

9. Carlsson L, Abrahamsson C, Andersson B, Duker G, Schiller-Linhardt G. Proarrhythmic effects of the class III agent almokalant: importance of infusion rate, QT dispersion, and early afterdepolarisations. Cardiovasc Res. 1993;27(12):2186-2193.

10. Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA. 2003;289(16):2120-2127.

11. Nelson S, Leung J. QTc prolongation in the intensive care unit: a review of offending agents. AACN Adv Crit Care. 2011;22(4):289-295.

12. Briasoulis A, Agarwal V, Pierce WJ. QT prolongation and torsade de pointes induced by fluoroquinolones: infrequent side effects from commonly used medications. Cardiology. 2011;120(2):103-110.

13. FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses. U.S. Food and Drug Administration Web site. http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm . Accessed January 21, 2013.

14. Catalano G, Catalano MC, Epstein MA, Tsambiras PE. QTc interval prolongation associated with citalopram overdose: a case report and literature review. Clin Neuropharmacol. 2001;24(3):158-162.

15. Vieweg WV, Hasnain M, Howland RH, et al. Citalopram, QTc interval prolongation, and torsade de pointes. How should we apply the recent FDA ruling? Am J Med. 2012;125(9):859-868.

16. Iannini PB, Circiumaru I. Gatifloxacin-induced QTc prolongation and ventricular tachycardia. Pharmacotherapy. 2001;21(3):361-362.

17. Owens RC Jr. Risk assessment for antimicrobial agent-induced QTc interval prolongation and torsades de pointes. Pharmacotherapy. 2001;21(3):301-319.

18. Tsikouris JP, Peeters MJ, Cox CD, Meyerrose GE, Seifert CF. Effects of three fluoroquinolones on QT analysis after standard treatment courses . Ann Noninvasive Electrocardiol. 2006;11(1):52-56.

19. Noel GJ, Natarajan J, Chien S, Hunt TL, Goodman DB, Abels R. Effects of three fluoroquinolones on QT interval in healthy adults after single doses. Clin Pharmacol Ther. 2003;73(4):292-303.

20. Tisdale JE, Rasty S, Padhi ID, Sharma ND, Rosman H. The effect of intravenous haloperidol on QT interval dispersion in critically ill patients: comparison with QT interval prolongation for assessment of risk of Torsades de Pointes. J Clin Pharmacol. 2001;41(12):1310-1318.

21. Hatta K, Takahashi T, Nakamura H, et al. The association between intravenous haloperidol and prolonged QT interval. J Clin Psychopharmacol . 2001;21(3):257-261.

22. Tisdale JE. Ventricular arrhythmias. In: Tisdale JE, Miller DA, eds. Drug Induced Diseases: Prevention, Detection, and Management. 2nd ed. Bethesda, MD: American Society of Health-System Pharmacists; 2010:405-515.

23. Sharma ND, Rosman HS, Padhi ID, Tisdale JE. Torsades de Pointes associated with intravenous haloperidol in critically ill patients. Am J Cardiol. 1998;81(2):238-240.

24. Miceli JJ, Tensfeldt TG, Shiovitz T, et al. Effects of high-dose ziprasidone and haloperidol on the QTc interval after intramuscular administration: a randomized, single-blind, parallel-group study in patients with schizophrenia or schizoaffective disorder. Clin Ther. 2010;32(3):472-491.

25. Harvey AT, Flockhart D, Gorski JC, et al. Intramuscular haloperidol or lorazepam and QT intervals in schizophrenia. J Clin Pharmacol. 2004;44(10):1173-1184.

26. Desai M, Tanus-Santos JE, Li L, et al. Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6. Pharmacogenomics J. 2003;3(2):105-113.

27. Ozeki Y, Fujii K, Kurimoto N, et al. QTc prolongation and antipsychotic medications in a sample of 1017 patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(2):401-405.

28. Gitler B, Berger LS, Buffa SD. Torsades de pointes induced by erythromycin. Chest. 1994;105(2):368-372.

29. Brandriss MW, Richardson WS, Barold SS. Erythromycin-induced QT prolongation and polymorphic ventricular tachycardia (torsades de pointes): case report and review. Clin Infect Dis. 1994;18(6):995-998.

30. Tschida SJ, Guay DR, Straka RJ, Hoey LL, Johanning R, Vance-Bryan K. QTc-interval prolongation associated with slow intravenous erythromycin lactobionate infusions in critically ill patients: a prospective evaluation and review of the literature. Pharmacotherapy. 1996;16(4):663-674.

31. Hensey C, Keane D. Clarithromycin induced torsade de pointes. Ir J Med Sci. 2008;177(1):67-68.

32. Cetin M, Yıldırımer M, Ozen S, Tahriverdi S, Coskum S. Clarithromycin-induced long QT syndrome: A case report. Case Report Med. 2012;2012:634652.

33. Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf. 2005;14(11):747-753.

34. Kornick CA, Kilborn MJ, Santiago-Palma J, et al. QTc interval prolongation associated with intravenous methadone. Pain. 2003;105(3):499-506.

35. Ashwath ML, Ajjan M, Culclasure T. Methadone-induced bradycardia. J Emerg Med. 2005;29(1):73-75.

36. Ehret GB, Voide C, Gex-Fabry M, et al. drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors. Arch Intern Med. 2006;166(12):1280-1287.

37. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150(6):387-395.

38. Clinical Study Register. GlaxoSmithKline Web site. http://download.gsk-clinicalstudyregister.com/files/e294be4a-862c-418e-b4cc-23e5a905c199 . Accessed January 21, 2013.

39. Hafermann MJ, Namdar R, Seibold GE, Page RL 2nd. Effect of intravenous ondansetron on QT interval prolongation in patients with cardiovascular disease and additional risk factors for torsades: a prospective, observational study. Drug Healthc Patient Saf. 2011;3:53-58.

Written by: Aileen Chu, PharmD
PGY1 Pharmacy Resident

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What are the new clinical guidelines for the management of gastroparesis?

Introduction

Gastroparesis occurs when there is a delay in the movement of gastric contents, also known as delayed gastric emptying.1 This delay can be a result of impaired contractility of smooth muscle in the gastrointestinal (GI) tract, alterations in the autonomic and/or enteric nervous system, and reduction in action of GI hormones, such as motilin. A variety of causes can lead to gastroparesis including GI conditions such as reflux and peptic ulcer disease, neuromuscular diseases such as muscular dystrophy, systemic conditions including diabetes and scleroderma, surgical procedures, medications, and trauma.2 Idiopathic gastroparesis has been reported to account for close to 40% of gastroparesis cases. Symptoms of gastroparesis include early satiety, bloating, nausea, vomiting, GI discomfort or pain, and constipation or diarrhea.

A recent guideline published in the American Journal of Gastroenterology provides recommendations on the diagnosis and management of gastroparesis.3 Interventions are rated by the strength of recommendation and level of evidence. These categories are defined in the table below.

Table. Strength of recommendation and levels of evidence.3

*Actual definition not provided in guideline

This summary will focus on recommendations that involve pharmacologic agents. For additional information related to diagnosis, testing, and surgical options, the full guideline should be consulted.3

Medication-induced gastroparesis

As part of the differential diagnosis of gastroparesis, a comprehensive review of patients’ medication profiles is recommended to determine use of medications such as opioids, drugs with anticholinergic effects, glucagon-like peptide-1 (GLP-1) agonists, and cyclosporine that can delay gastric emptying (strong recommendation, high level of evidence).3 If possible, patients should be given a trial off these medications and/or switched to alternate agents that have little or no impact on gastric motility. Prior to administering a gastric emptying test, discontinuation of drugs that slow (e.g. opioids, anticholinergic agents) or accelerate (e.g. metoclopramide, erythromycin) gastric motility is recommended. These medications should be discontinued at least 48 to 72 hours before the diagnostic test depending on the pharmacokinetics of the particular agent.

Management of gastroparesis

Once a diagnosis of gastroparesis is established, patients should receive adequate fluid, electrolyte, and nutrition support (strong recommendation, moderate level of evidence).3 Control of blood sugar in patients with diabetes is also strongly recommended for management of gastroparesis. Acute hyperglycemia has been demonstrated to slow gastric emptying; however, it is unknown if there is a correlation to symptom improvement once hyperglycemia is corrected. Since GLP-1 agonists, such as exenatide, and amylin analogs, such as pramlintide, are known to delay gastric motility, these agents should not be used for blood sugar control in patients with diabetes and gastroparesis (conditional recommendation, low level of evidence).

Metoclopramide is recommended as the first-line agent for treatment of gastroparesis (moderate recommendation, moderate level of evidence).3 It is approved by the Food and Drug Administration (FDA) for this indication for 12 weeks unless the benefit of a longer duration of use outweighs the risk of adverse events. According to the guideline, a liquid formulation of metoclopramide should be used to aid in absorption and for ease of dose titration. The recommended starting dose is 5 mg three times daily before meals titrated to response up to a maximum of 40 mg daily. Due to its dopaminergic antagonistic actions, tardive dyskinesia is the main adverse effect of concern. Early recognition of symptoms and subsequent cessation of metoclopramide may reverse this adverse effect. Close monitoring of symptoms, use of the lowest effective dose, and dose reductions when possible are measures that are recommended to help minimize the development of tardive dyskinesia. The drug is also associated with QT interval prolongation. Concomitant administration of medications that influence the cytochrome P450 (CYP) 2D6 enzyme can affect metoclopramide plasma concentrations.

Domperidone, also a dopamine antagonist, is recommended as an alternative to metoclopramide (moderate recommendation, moderate level of evidence). 3 It is available for use as an investigational drug. Initially, domperidone 10 mg three times daily should be administered and increased to 20 mg three times daily and at bedtime. Although similar in mechanism and efficacy to metoclopramide, the incidence of central nervous system effects is lower with domperidone. Its effect on QT prolongation; however, requires baseline and regular electrocardiograms during treatment. Cessation of domperidone is recommended if the QT interval exceeds 470 ms in males and 450 ms in females. Similar to metoclopramide, drug-drug interactions with agents that affect CYP2D6 can occur.

Erythromycin, a motilin agonist, has been shown to be effective in increasing gastric motility and improving symptoms when used orally or intravenously (IV) (strong recommendation, moderate level of evidence).3 Intravenous use of erythromycin lactobionate 3 mg/kg every 8 hours is recommended for hospitalized patients that require IV therapy. The dose should be infused slowly over 45 minutes to avoid pain at the injection site. Although effective short-term (up to 4 weeks), oral erythromycin use may be limited due to development of tolerance with prolonged use. This agent may be useful for exacerbations or for intermittent use in patients unable to tolerate or are unresponsive to metoclopramide.2 Erythromycin is associated with numerous CYP3A4 drug interactions as well as QT prolongation.3

Patients with nausea and vomiting should receive symptomatic treatment with antiemetics; however, these agents will not aid in improving gastric emptying (conditional recommendation, moderate level of evidence).3 Prochlorperazine and promethazine are the most commonly used agents. Although comparative studies are lacking, serotonin 5-HT3 antagonists (e.g. ondansetron) are considered second-line agents. Aprepitant, dronabinol, and transdermal scopolamine have also been used. The use of tricyclic antidepressants (TCAs) should be reserved for patients with refractory nausea and vomiting (conditional recommendation, low level of evidence). Many issues, including safety concerns and lack of evidence, surround the use of these agents. Sedation, cardiac toxicity, peripheral vein damage, and lack of availability limit the use of promethazine. Dronabinol can lead to increased vomiting when treatment is withdrawn and the appropriate use of this agent is not well defined. Evidence for use of transdermal scopolamine is anecdotal. Amitriptyline is associated with anticholinergic activity and should be avoided in patients with gastroparesis.

Due to effects on gastric emptying, it is recommended that patients with gastroparesis, if possible, not receive opioids for pain management.3 The guideline suggests use of tramadol, gabapentin, pregabalin, and nortriptyline for pain management as alternatives to opioids. Compared to other TCAs, nortriptyline demonstrates less anticholinergic activity and would, theoretically, have less effect on gastric emptying. Tramadol demonstrated no effect on gastric emptying when studied in healthy patients. However, evidence on the use of any of these agents, specifically in patients with gastroparesis, is lacking and therefore patients receiving these medications should be evaluated regularly.

Conclusion

Recommendations for pharmacologic management of gastroparesis are based on a moderate level of evidence due to the fact that many of the studies evaluating these agents were conducted over 20 years ago and do not meet the current standards of randomized controlled trials.3 Additionally, the agents currently recommended for treatment can cause serious adverse reactions including tardive dyskinesia (metoclopramide), QT prolongation, and numerous drug-drug interactions. Until stronger recommendations become available, providers can rely on this guideline as well as clinical judgment to individualize management of patients with gastroparesis.

References

1. Mills JC, Stappenbeck TS, Bunnett N. Gastrointestinal disease. In: McPhee SJ, Hammer GD, eds. Pathophysiology of Disease. 6th ed. New York: McGraw-Hill; 2010. http://www.accessmedicine.com/content.aspx?aID=5369402. Accessed January 24, 2013.

2. Chan WW, Burakoff R. Disorders of gastric and small bowel motility. In: Greenberger NJ, Blumberg RS, Burakoff R, eds. Current Diagnosis & Treatment: Gastroenterology, Hepatology, & Endoscopy. 2nd ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=55957320. Accessed January 24, 2013.

3. Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013;108(1):18-37.

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