- Email: [email protected]
The Effect of Antiemetics and Antihistamines on the QTc Interval in Emergent Dialysis Patients With Baseline QTc Prolongation
The Journal of Emergency Medicine, Vol. 51, No. 2, pp. 99–105, 2016 Ó 2016 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2016.04.027
Original Contribution
THE EFFECT OF ANTIEMETICS AND ANTIHISTAMINES ON THE QTC INTERVAL IN EMERGENT DIALYSIS PATIENTS WITH BASELINE QTC PROLONGATION Scott Burdette, MD, Lynn P. Roppolo, MD, Walter Green, MD, Nashid Shinthia, MD, Peter Ye, MD, and Linda S. Hynan, PHD Department of Emergency Medicine, University of Texas Southwestern, Dallas, Texas Corresponding Address: Lynn P. Roppolo, MD, Department of Emergency Medicine, University of Texas Southwestern, 5323 Harry Hines Blvd, Mail Code 8579, Dallas, TX 75390-8679
, Abstract—Background: Unfunded patients with end-stage renal disease (ESRD) who do not have routinely scheduled hemodialysis often receive medications known to prolong the QTc interval for their uremic symptoms even though they may have pre-existing QTc prolongation. Objectives: The purpose of this study was to determine the effects of these medications on the QTc interval in these patients. Methods: Unfunded patients with ESRD presenting to the emergency department (ED) for emergent hemodialysis (HD) with QTc prolongation on their initial electrocardiogram (ECG) were recruited. Approximately 2 hours after receiving an antihistamine or antiemetic, a second ECG was ordered and the QTc was measured. The patients were followed-up 1 week later. Results: Twenty-nine percent (44/152) of the unfunded patients with ESRD presenting for HD at a county hospital had QT prolongation and were included with 107 total ED visits during the 4-week study period. The mean QTc was 483.7 msec on presentation to the ED, and the mean QTc measured 2 hours after receiving an antihistamine or antiemetic was 483.8 msec. None of the patients were admitted for life-threatening dysrhythmias. Thirty-six percent (16/44) of the recruited patients had QTc intervals >500 msec with a combined total of 31 patient visits, of which only 25.8% (8/31) had an increase in the QTc interval after an antihistamine or antiemetic medication was given. None of these patients had adverse outcomes, such a dysrhythmia or death, at 1-week follow-up. Conclusion: This study shows that medications known to cause
QTc prolongation are safe to use in therapeutic doses in patients with ESRD who have pre-existing QT prolongation. Few patients in this cohort had significantly prolonged QTc intervals at baseline. Ó 2016 Elsevier Inc. All rights reserved. , Keywords—antiemetics; antihistamine; dialysis; ESRD; QTc
INTRODUCTION The QT interval is denoted as the time from ventricular depolarization to ventricular repolarization, with corrections (QTc) for heart rate typically being accounted for by the Bazett formula (QTc = QT/ORR). QTc prolongation is an established risk factor for sudden cardiac death caused by ventricular dysrhythmias, most frequently torsades de-pointes (1,2). In a prospective Rotterdam study by Straus et al., patients $55 years of age were deemed to have a 3 times greater incidence of sudden cardiac death regardless of pre-existing heart disease when they exhibited prolonged QT. In fact, they were able to show a direct correlation between sudden cardiac death risk and increasing QTc duration (1). Prolonged QT becomes a greater potential risk to patient viability when >1 coronary risk factor is present, because there is an increased incidence of sudden cardiac death to >4 times that of the general population (1).
Reprints are not available from the authors.
RECEIVED: 28 September 2015; FINAL SUBMISSION RECEIVED: 2 April 2016; ACCEPTED: 20 April 2016 99
100
The prevalence of congenital QT prolongation in the general population is approximately 1 in 2500 to 5000 people, and is typically the result of autosomal dominant mutations in cardiac ion channels that convey the ability of cardiac myocytes in the ventricles to repolarize (2–4). Polymorphisms in the KCNE1 gene predispose to druginduced prolonged QT, a pathology that is present in 2% to 3% of the population (5). Specific drugs, such as ondansetron, prolong QT by direct blockade of the human ether-a-go-go–related gene K channel. Common over the counter medications, such as diphenhydramine, an H1 antihistamine, have dose-dependent properties that block K channels and can increase QTc intervals at significantly high doses (6,7). In a case study by Husain et al., a 44year-old woman ingested 3 g of diphenhydramine and increased her QTc from 400 ms to 786 ms, which took 5 days to resolve (8). One group of patients who are well known to have prolonged QTc are those afflicted with end stage renal disease (ESRD). QTc prolongation has been found to be an independent predictor of mortality in patients with ESRD (9). Once dialysis is initiated, the mean survival of patients with ESRD is 5 to 6 years, with sudden cardiac death being 10 times more likely, accounting for #50% of deaths (10). Voiculesco et al. studied patients with ESRD and reported that 41.2% had prolonged QTc. Interestingly, there was no correlation with sudden cardiac death or angina at 3.8 months of follow-up in these patients, but the authors found that dysrhythmias were more common after volume reduction (11). There is a large group of patients with ESRD who reside in the United States without legal permission for residence, and they therefore lack medical funding. Many of these patients are unable to receive dialysis at outside dialysis centers and instead present to county hospitals to be dialyzed. Because of a limitation of resources and staff, these patients are dialyzed on a less frequent basis than their scheduled contemporaries in the community. These patients are dialyzed when their symptoms of overload, uremia, and electrolyte imbalances become overwhelming—or in some cases, dangerous to the patients’ well-being. Medications that predispose to prolongation of the QTc are typically avoided in patients with QTc prolongation. Because of the reduced frequency of hemodialysis in our unfunded hemodialysis patients, many of them are given medications that can cause QTc prolongation to alleviate their severe uremic symptoms because no other options are available. There is currently a paucity of evidence regarding administration of QTc-prolonging medications in patients with ESRD, especially those who are not routinely dialyzed or have pre-existing prolonged QTc. Therefore, the purpose of this study is to determine the effect of antihistamines and antiemetics (which are known to cause QTc prolon-
S. Burdette et al.
gation) on the QT interval in patients with ESRD and pre-existing prolonged QTc prolongation. We hypothesize that the administration of antiemetics and antihistamines in therapeutic doses does not cause significant increases in the QTc interval in patients with chronic renal failure with pre-existing QTc prolongation. METHODS Study Design This study was a prospective observational study of unfunded dialysis patients who presented to a large, publicly funded county hospital for emergent hemodialysis. The study and all protocols were reviewed and approved by the institutional review board before implementation. Study Setting and Population This study was conducted in the emergency department (ED) of a large county hospital with an annual ED volume of >200,000 patients. Approximately 150 unfunded hemodialysis patients present every week to this county hospital ED requesting emergent hemodialysis because their financial status does not allow them to be seen in a regular dialysis center. Only unfunded hemodialysis patients were included in this study because these were the patients who routinely presented to our ED for dialysis, were able to be consented, and were easy to follow-up because their medical care and dialysis occurred only at Parkland. Patients who have the financial resources to receive scheduled dialysis rarely present to the ED for dialysis and were not included in this study. Depending on the severity of their ESRD, there is wide variation with regard to the frequency of presentation—from as often as every 3 days to as long as twice a month. The vast majority of these patients are foreign nationals who do not qualify for financial assistance under Medicare. Their most common presenting complaints are related to volume overload and uremia, such as dyspnea, nausea, and pruritus. The ED maintains a standard procedure for patients presenting for emergent dialysis. A complete blood cell count, electrolytes (e.g., sodium, potassium, calcium, magnesium, and phosphorus), blood urea nitrogen, creatinine, and an electrocardiogram (ECG) are obtained when the patient is brought into the treatment area. A paper copy of the ECG is delivered by hand to the senior ED resident or attending physician for immediate analysis. The hospital uses an electronic medical record (EMR) system that facilitates the recording of all laboratory orders and results, medications, ECGs, and pharmaceutical interventions. All physician orders and entries are digitally recorded and time-stamped.
Effect of Antiemetics and Antihistamines on QTc Interval
Study Protocol Between June 1, 2013 and July 4, 2013, all patients $18 years of age who presented to this county hospital ED were screened by research assistants to identify patients who met inclusion criteria. All research assistants were medical students employed in a summer research program, and at least 1 was present in the ED 24 hours a day to continually screen presenting patients for emergent dialysis and inclusion. The research assistants used the EMR to identify all dialysis patients presenting to the ED. The QTc interval was taken from the automated analysis printed on each ECG that was uploaded onto the EMR. All ECG machines in the ED were the same model (MAC 5500 HD Resting ECG System; GE Healthcare, New York, NY) and used the Bazett formula (described above) to automatically calculate the QTc intervals that could be found on a printed copy of the ECG results. All automated ECG interpretations were subsequently reviewed by a staff cardiologist who documented their verification or any changes to the automated ECG interpretation to the version of the ECG that was uploaded to the EMR. The QTc intervals obtained by the research assistants on each patient were obtained from this final version of the ECG recorded on the electronic chart. The ECGs were repeated if there was any significant artifact that could potentially affect ECG interpretation. The following parameters were used to identify QTc prolongation in this study: >450 msec in men and >470 msec in women. The prolonged QTc interval was confirmed with the ED resident or attending physician providing care to the patient in the ED. Written informed consent was obtained from all patients who did not meet exclusion criteria to participate in the study. Patients were excluded if: 1) their QTc was <450 msec in men and <470 msec in women; 2) they were not given an antihistamine or antiemetic for their uremic symptoms; 3) they would not give consent; or 4) they were <18 years of age. As per the current practice in this county hospital ED, dialysis patients were given symptomatic treatment for uremic symptoms with oral or parenteral medications at the discretion of the attending physician or resident assigned to their care. Medications used for dialysis patients at this county hospital included promethazine, ondansetron, diphenhydramine, hydroxyzine, and prochlorperazine. The treating physicians were not blinded to the study. The research assistant continually tracked all dialysis patients with prolonged QTc intervals and identified patients who received any of the above medications by reviewing the patient’s EMR and speaking with the physician providers. Once identified, the research assistants notified the treating physician that a repeat ECG needed to be obtained 2 hours after the medications were given. The research assistants collected study data from the
101
EMR, through direct contact with the patient while in the ED, and communication with the physician providers caring for the patient. Patients were asked about the last time they had received dialysis. None of them were dialyzed at other hospitals. All patients presented with some complaint related to uremic symptoms or volume overload that would prompt them to come to the ED for dialysis. Information that was verbalized by the patient was confirmed in the EMR. The following data were collected by the research assistants on all recruited patients: medical record number, age, race, date and time of presentation, initial vital signs, symptomatic complaints (e.g., nausea or vomiting, pruritus, headache, edema, dyspnea, chest pain, or abdominal pain), comorbidities, frequency of ED presentation for dialysis, duration the patient has been on hemodialysis, QTc interval at ED presentation and 2 hours after an antiemetic or antipruritic was given in the ED, type and dosing of the agents given for uremic symptoms, vital signs, laboratory study results, disposition, and follow-up information. Each patient’s chart was reviewed 1 week later to determine if the patient had a repeat visit to this county hospital ED for dialysis, to review the QTc interval on the ECG performed on the return visit, and to identify if the patient had had any admissions to the hospital since discharge. Outcome Measures The primary outcome was any worsening QTc prolongation 2 hours after medications known to prolong the QT interval were given. A secondary outcome of the study was the presence of any dysrhythmias or sudden cardiac death. All charts were reviewed within 1 week to evaluate if any patient was admitted for any dysrhythmia, syncope, or had died. Primary Data Analysis Data were collected using a standard electronic collection template (Excel; Microsoft, Redmond, WA). Results are described using basic descriptive statistics, including the mean, standard deviation, minimum, and maximum values. RESULTS A total of 44 of 152 patients with ESRD (29%) presenting to this county hospital ED for hemodialysis over a 4-week period had QTc prolongation. All 44 patients consented to participate, accounting for 107 ED visits during the study period. All patients were Hispanic; 77% were men and 23% were women. The mean frequency of dialysis was 3.8 days, and the mean number of years on
102
S. Burdette et al.
Table 1. Comparisons of Antiemetic Dosing in Patients with End Stage Renal Disease and Prolonged QTc Intervals Drug
N
Mean (mg)
Minimum (mg)
Maximum (mg)
Promethazine Ondansetron Diphenhydramine Hydroxyzine Prochlorperazine
31 22 23 5 6
24.7 4.94 31.3 22 9.17
20 4 25 10 5
25 8 50 25 25
hemodialysis (HD) was 3.8. More than half (56.8%; n = 19) of the patients studied had diabetes and 100% possessed preexisting hypertension (HTN) (n = 44). Presenting symptoms of the study patients included pruritus (33/44; 75%), headache (11/44; 25%), edema (33/44; 75%), nausea and vomiting (37/44; 84.1%), chest pain (17/44; 38.6%), abdominal pain (30/44; 68.2%), and shortness of breath (34/44; 77%) being the most common symptom. All of the above data were obtained by interviewing the patient, when appropriate, and confirmed by reviewing the EMR. Some of this information was exclusively obtained from the patient’s electronic chart because the patient either did not know the information, was not available to answer the question by the research assistant, or was part of the patient’s care provided in the ED. A wide variety of treatment dosing of antiemetics/antihistamines were given for uremic symptoms. The mean dose of medications given per patient during each ED visit is listed in Table 1. Mean electrolyte levels are listed in Table 2. The mean QTc was 483.7 msec on presentation to the ED. The mean QTc interval was 483.8 msec 2 hours after these medications were given and 485.4 msec on 1-week follow up. There were no significant differences in QTc posttreatment with antiemetics or antihistamines. All patients were followed-up 1 week later. No patients were admitted for any dysrhythmias or suffered sudden cardiac death.
Of the 108 encounters, there were 28 encounters in 13 patients where the QTc was >500 msec. After the QTc prolonging medication was given, only 9 of these patients had an increase in the QTc interval on ECG 2 hours after a QTc prolonging medication was given. The average QTc increase was 11.8 msec (standard deviation [SD] 6.7 msec). The average overall change in the QTc interval for these 28 patients (with a baseline QTc of >500 msec) was 1.4 msec, with the highest being 14 and the lowest being 22 msec. There were 8 patients with QTc intervals <500 msec who had QTc intervals >500 msec after the QTc-prolonging medication was given. The average QTc increase was 15.5 msec (SD 14.4). Refer to Table 3 for a comparison of the QTc interval before and after the QTc prolonging medication was given and on 1-week follow-up. None of these patients had adverse outcomes on 1-week follow-up. All patients recruited in this study were followed-up 1 week later. DISCUSSION The objective of this study was to show the safety of these specific medications, which are known to increase the QTc interval, in patients with ESRD with pre-existing QTc prolongation. In this investigation, it was shown that the use of these specific antiemetics and antihistamines had no adverse outcomes in terms of significant changes in the QTc interval, both 2 hours posttreatment and on subsequent presentation to the ED within a 1-week period, in patients with ESRD with pre-existing QTc prolongation. Likewise, none of these patients developed dysrhythmias requiring hospitalization or sudden cardiac death. This was of great importance to the health care providers in this hospital setting because these are often the only medications available to provide relief of symptoms for these uremic patients, and it is imperative that their safety is demonstrated. In addition, none of the patients who presented with significantly prolonged QTc intervals (>500 msec) in the
Table 2. Comparison of Serum Electrolytes and QTc Changes Pre/Post-treatment with Antiemetic Drugs in Patients with End Stage Renal Disease and Prolonged QTc Intervals Percentiles Measure
N
Mean
SD
Minimum
Maximum
25%
50%
75%
K Ca Mg Pho Days since last dialysis QTc on presentation (msec) QTc after medications (msec) QTc on 1-week follow-up (msec)
43 44 41 41 44 44 44 43
5.55 8.46 2.69 7.2 4.44 483.7 483.8 485.4
0.55 0.95 0.44 1.82 1.98 18.4 20.0 22.6
4.2 5.92 1.7 4.7 0 454.8 448 442
6.6 10.5 3.78 13.1 8.5 532.5 537.5 537
5.2 7.81 2.42 5.88 3 468.9 466.8 467
5.6 8.62 2.67 6.8 4 480 484.8 483.4
6 9.09 3 8.06 5.75 496.6 493.4 499.3
Unit Measurement for K, mEq/L; Ca, mg/dL; Mg, mEq/L; Pho, mg/dL.
Effect of Antiemetics and Antihistamines on QTc Interval
103
Table 3. Comparison of QTc Intervals at Presentation, 2 Hours After QTc Medication was Given, and on 1-week Follow-up Descriptive Statistics
95% CI
Measurement
N
Mean
SD
Lower Limit
Upper Limit
QTc on presentation (msec) QTc after medications (msec) QTc on 1-week follow-up (msec)
43 43 43
483.24 483.74 485.40
18.36 20.19 22.58
477.59 477.53 478.45
488.90 489.95 492.35
CI, confidence interval; SD, standard deviation.
present study had any adverse outcome after receiving any of the medications known to cause QTc prolongation. Nausea and pruritus are 2 of the most common uremic symptoms in our unfunded patients with ESRD and are often treated with antiemetics and antihistamines, respectively. These uremic symptoms are magnified in the absence of routinely scheduled hemodialysis. The most commonly used medications for symptomatic relief in this study were promethazine, odansetron, and diphenhydramine at doses recommended for patients without renal disease (12). All of these medications are known to prolong the QTc interval, which causes great concern when using these medications in patients with pre-existing prolongation of the QTc interval. QT prolongation is common in patients with chronic renal failure. There are several proposed mechanisms for QTc prolongation in patients with ESRD, including autonomic neuropathy, iron body stores, electrolyte abnormalities, and comorbidities, such as congestive heart failure, left ventricular hypertrophy, diabetes, and ischemic heart disease (13–15). Several medications are known to cause QT prolongation and are intuitively avoided in patients with preexisting QT prolongation because of the fear of inducing life-threatening dysrhythmias, such as torsades de pointes. Promethazine is an antiemetic that is known to cause QT prolongation, but the risk of causing torsades de pointes is low (16). Diphenhydramine may cause prolonged QT prolongation but is rare and reported when excessive dosages of this drug are ingested (8). The toxicity of diphenhydramine is dose-dependent, with a critical dose limit of 1.0 g (8). Odansetron, a commonly used antiemetic, can also cause QT prolongation. One study on patients with heart disease found that although these patients had a significant prolongation in the QTc interval after a single 4-mg dose of odansetron, none of the patients developed concerning dysrhythmias, such as torsades de pointes. The authors recommend that high-risk patients receiving odansetron should be closely monitored with telemetry (17). The authors of the present study conclude that promethazine, diphenhydramine, and odansetron can be safely administered in therapeutic doses for symptomatic relief of pruritus and nausea for patients with ESRD with QT prolongation. However, these medications should be used with caution in patients with significantly prolonged
QT intervals; although no adverse events were seen in the study, the sample size was small. There are not enough data to support the safe use of these medications in these patients. Limitations There were many limitations to this study, including its lack of external validity; the sample size here was exclusively an unfunded group of Hispanic patients with no access to dialysis other than emergent dialysis. This study lacked power because of the small sample size (n = 44). However, given the proximity in the QTc measurement both before and after treatment, we assume that a larger sample size would have also shown no difference with treatment. The Bazett formula used to calculate the QTc measurement has its own limitations. It is also not known what method was used by the staff cardiologist to verify this interpretation. There were also not enough patients in this study with significantly prolonged QTc intervals (>500 msec) to look for adverse effects, and therefore conclusions cannot be made regarding the effect of these specific medications on this group of patients who would seemingly be at greater risk for prolonged QTcrelated dysrhythmias. There was only 1 ECG measurement performed 2 hours after the medication was given. The QTc prolonging effect may have extended beyond these 1 hours in patients with ESRD. All patients were followed-up 1 week later, so we can confidently say that there were no episodes of dysrhythmias requiring hospitalization or sudden death in these patients. Future research should focus on patients who have more prolonged QT prolongation and more frequent evaluation of the QTc after the administration of medications known to prolong the QTc interval. Finally, this study does not make allowances for acquired vs. genetic differences (e.g., both channel deficiencies and drug susceptibility) in QTc. It is possible that some of our patients had other reasons for QTc outside of their ESRD that require HD. CONCLUSION Patients with ESRD with preexisting prolonged QTc intervals in this study had no adverse cardiac dysrhythmias requiring admission or sudden cardiac death after the
104
S. Burdette et al.
administration of specific medications known to cause QT prolongation. While this is limited in external validity because of the small study size and narrow population demographics, the implications are potentially important, allowing for ongoing treatment with these agents in those with prolonged QTc. In addition, this study has great importance in this county hospital ED because it revealed that emergency physicians are not doing more harm to patients with ESRD with existing QTc prolongation while treating their uremic symptoms with specific antiemetics and antihistamines; this is reassuring given the frequent use of these medications in these patients. These medications should be used with caution in patients with significantly prolonged QT intervals, because although no adverse events were observed the sample size was small. Acknowledgments—We thank the University of Texas Summer Research Program for making this data collection possible and all of the unfunded dialysis patients at Parkland Hospital for their willingness to participate in this investigation.
REFERENCES 1. Straus SM, Kors JA, De Bruin ML, et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am College Cardiol 2006;47:362–7. 2. Roden DM. Clinical practice. Long-QT syndrome. N Engl J Med 2008;358:169–76. 3. Quaglini S, Rognoni C, Spazzolini C, Priori S, Mannarino S, Schwartz PJ. Cost-effectiveness of neonatal ECG screening for the long QT syndrome. Eur Heart J 2006;27:1824–32. 4. Kies SJ, Pabelick CM, Hurley HA, White RD, Ackerman MJ. Anesthesia for patients with congenital long QT syndrome. Anesthesiology 2005;102:204–10.
5. George AL Jr., Roden DM. Method for screening for susceptibility to drug-induced cardiac arrhythmia. U.S. Patent 6,458,242, B1, 2002. 6. Kuryshev Y, Brown AM, Wang L, Benedict CR, Rampe D. Interactions of the 5-hydroxytryptamine 3 antagonist class of antiemetic drugs with human cardiac ion channels. J Pharmacol Exp Ther 2000;295:614–20. 7. Zareba W, Moss AJ, Rosero SZ, et al. Electrocardiographic findings in patients with diphenhydramine overdose. Am J Cardiol 1997;80: 1168–73. 8. Husain Z, Hussain K, Nair R, Steinman R. Diphenhydramine induced QT prolongation and torsade de pointes: an uncommon effect of a common drug. Cardiol J 2010;17:509–11. 9. Hage FG, de Mattos AM, Khamash H, et al. QT prolongation is an independent predictor of mortality in end-stage renal disease. Clin Cardiol 2010;33:361–6. 10. Agodoa LU, Jones CA, Held PJ. End-stage renal disease in USA: data from United States Renal Data System. Am J Nephrol 1996; 16:7–16. 11. Voiculescu M, Ionescu C, Ismail G. Frequency and prognostic significance of QT prolongation in chronic renal failure patients. Rom J Intern Med 2006;44:407–17. 12. Monthly Prescribing Reference website. Antiemetic treatments. Available at: http://www.empr.com/clinical-charts/antiemetictreatments/article/125873/ [registration required]. Accessed February 3, 2016. 13. Wu VC, Lin LY, Wu KD. QT interval dispersion in haemodialysis patients. Nephrology 2005;10:109–12. 14. Nappi SE, Virtanen VK, Saha HHT, et al. QTc dispersion increases during haemodialysis with low-calcium dialysate. Kidney Int 2000; 57:2117–22. 15. Wu V, Huang J, Wu M, et al. The effect of iron stores on corrected QT dispersion in patients undergoing peritoneal dialysis. Am J Kidney Dis 2004;44:720–8. 16. Owczuk R, Tswardowski P, Dylczyk SA, et al. Influence of promethazine on cardiac repolarization: a double-blind, midazolamcontrolled study. Anesthesia 2009;64:609–14. 17. Hafermann MJ, Namdar R, Gretchen ES, Page RL. Effect of intravenous odansatron 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: 53–8.
Effect of Antiemetics and Antihistamines on QTc Interval
ARTICLE SUMMARY 1. Why is this topic important? There are many patients on dialysis with pre-existing QTc prolongation with severe uremic symptoms and necessitate the administration of QTc-prolonging drugs. 2. What does this study attempt to show? This study attempts to show that patients with end stage renal disease, severe uremic symptoms, and pre-existing QTc prolongation do not worsen with the administration of therapeutic doses of medications known to cause QTc prolongation. 3. What are the key findings? Dialysis patients with severe uremia and pre-existing QTc prolongation do not have lengthened QTc intervals after the administration of medications used to treat their uremic symptoms that are known to cause QTc prolongation. The chronic dialysis patients investigated in this study those at patients at highest risk because they do not receive routinely scheduled dialysis. 4. How is patient care impacted? These QTc-prolonging medications may be withheld from severely uremic patients because of pre-existing QTc prolongation. This study shows that the administration of these medications at therapeutic doses is safe. Patients with significant pre-existing QTc prolongation did not experience any adverse outcomes from receiving these medications, such as an dysrhythmia or sudden death.
105
http://dx.doi.org/10.1016/j.jemermed.2016.04.027
Original Contribution
THE EFFECT OF ANTIEMETICS AND ANTIHISTAMINES ON THE QTC INTERVAL IN EMERGENT DIALYSIS PATIENTS WITH BASELINE QTC PROLONGATION Scott Burdette, MD, Lynn P. Roppolo, MD, Walter Green, MD, Nashid Shinthia, MD, Peter Ye, MD, and Linda S. Hynan, PHD Department of Emergency Medicine, University of Texas Southwestern, Dallas, Texas Corresponding Address: Lynn P. Roppolo, MD, Department of Emergency Medicine, University of Texas Southwestern, 5323 Harry Hines Blvd, Mail Code 8579, Dallas, TX 75390-8679
, Abstract—Background: Unfunded patients with end-stage renal disease (ESRD) who do not have routinely scheduled hemodialysis often receive medications known to prolong the QTc interval for their uremic symptoms even though they may have pre-existing QTc prolongation. Objectives: The purpose of this study was to determine the effects of these medications on the QTc interval in these patients. Methods: Unfunded patients with ESRD presenting to the emergency department (ED) for emergent hemodialysis (HD) with QTc prolongation on their initial electrocardiogram (ECG) were recruited. Approximately 2 hours after receiving an antihistamine or antiemetic, a second ECG was ordered and the QTc was measured. The patients were followed-up 1 week later. Results: Twenty-nine percent (44/152) of the unfunded patients with ESRD presenting for HD at a county hospital had QT prolongation and were included with 107 total ED visits during the 4-week study period. The mean QTc was 483.7 msec on presentation to the ED, and the mean QTc measured 2 hours after receiving an antihistamine or antiemetic was 483.8 msec. None of the patients were admitted for life-threatening dysrhythmias. Thirty-six percent (16/44) of the recruited patients had QTc intervals >500 msec with a combined total of 31 patient visits, of which only 25.8% (8/31) had an increase in the QTc interval after an antihistamine or antiemetic medication was given. None of these patients had adverse outcomes, such a dysrhythmia or death, at 1-week follow-up. Conclusion: This study shows that medications known to cause
QTc prolongation are safe to use in therapeutic doses in patients with ESRD who have pre-existing QT prolongation. Few patients in this cohort had significantly prolonged QTc intervals at baseline. Ó 2016 Elsevier Inc. All rights reserved. , Keywords—antiemetics; antihistamine; dialysis; ESRD; QTc
INTRODUCTION The QT interval is denoted as the time from ventricular depolarization to ventricular repolarization, with corrections (QTc) for heart rate typically being accounted for by the Bazett formula (QTc = QT/ORR). QTc prolongation is an established risk factor for sudden cardiac death caused by ventricular dysrhythmias, most frequently torsades de-pointes (1,2). In a prospective Rotterdam study by Straus et al., patients $55 years of age were deemed to have a 3 times greater incidence of sudden cardiac death regardless of pre-existing heart disease when they exhibited prolonged QT. In fact, they were able to show a direct correlation between sudden cardiac death risk and increasing QTc duration (1). Prolonged QT becomes a greater potential risk to patient viability when >1 coronary risk factor is present, because there is an increased incidence of sudden cardiac death to >4 times that of the general population (1).
Reprints are not available from the authors.
RECEIVED: 28 September 2015; FINAL SUBMISSION RECEIVED: 2 April 2016; ACCEPTED: 20 April 2016 99
100
The prevalence of congenital QT prolongation in the general population is approximately 1 in 2500 to 5000 people, and is typically the result of autosomal dominant mutations in cardiac ion channels that convey the ability of cardiac myocytes in the ventricles to repolarize (2–4). Polymorphisms in the KCNE1 gene predispose to druginduced prolonged QT, a pathology that is present in 2% to 3% of the population (5). Specific drugs, such as ondansetron, prolong QT by direct blockade of the human ether-a-go-go–related gene K channel. Common over the counter medications, such as diphenhydramine, an H1 antihistamine, have dose-dependent properties that block K channels and can increase QTc intervals at significantly high doses (6,7). In a case study by Husain et al., a 44year-old woman ingested 3 g of diphenhydramine and increased her QTc from 400 ms to 786 ms, which took 5 days to resolve (8). One group of patients who are well known to have prolonged QTc are those afflicted with end stage renal disease (ESRD). QTc prolongation has been found to be an independent predictor of mortality in patients with ESRD (9). Once dialysis is initiated, the mean survival of patients with ESRD is 5 to 6 years, with sudden cardiac death being 10 times more likely, accounting for #50% of deaths (10). Voiculesco et al. studied patients with ESRD and reported that 41.2% had prolonged QTc. Interestingly, there was no correlation with sudden cardiac death or angina at 3.8 months of follow-up in these patients, but the authors found that dysrhythmias were more common after volume reduction (11). There is a large group of patients with ESRD who reside in the United States without legal permission for residence, and they therefore lack medical funding. Many of these patients are unable to receive dialysis at outside dialysis centers and instead present to county hospitals to be dialyzed. Because of a limitation of resources and staff, these patients are dialyzed on a less frequent basis than their scheduled contemporaries in the community. These patients are dialyzed when their symptoms of overload, uremia, and electrolyte imbalances become overwhelming—or in some cases, dangerous to the patients’ well-being. Medications that predispose to prolongation of the QTc are typically avoided in patients with QTc prolongation. Because of the reduced frequency of hemodialysis in our unfunded hemodialysis patients, many of them are given medications that can cause QTc prolongation to alleviate their severe uremic symptoms because no other options are available. There is currently a paucity of evidence regarding administration of QTc-prolonging medications in patients with ESRD, especially those who are not routinely dialyzed or have pre-existing prolonged QTc. Therefore, the purpose of this study is to determine the effect of antihistamines and antiemetics (which are known to cause QTc prolon-
S. Burdette et al.
gation) on the QT interval in patients with ESRD and pre-existing prolonged QTc prolongation. We hypothesize that the administration of antiemetics and antihistamines in therapeutic doses does not cause significant increases in the QTc interval in patients with chronic renal failure with pre-existing QTc prolongation. METHODS Study Design This study was a prospective observational study of unfunded dialysis patients who presented to a large, publicly funded county hospital for emergent hemodialysis. The study and all protocols were reviewed and approved by the institutional review board before implementation. Study Setting and Population This study was conducted in the emergency department (ED) of a large county hospital with an annual ED volume of >200,000 patients. Approximately 150 unfunded hemodialysis patients present every week to this county hospital ED requesting emergent hemodialysis because their financial status does not allow them to be seen in a regular dialysis center. Only unfunded hemodialysis patients were included in this study because these were the patients who routinely presented to our ED for dialysis, were able to be consented, and were easy to follow-up because their medical care and dialysis occurred only at Parkland. Patients who have the financial resources to receive scheduled dialysis rarely present to the ED for dialysis and were not included in this study. Depending on the severity of their ESRD, there is wide variation with regard to the frequency of presentation—from as often as every 3 days to as long as twice a month. The vast majority of these patients are foreign nationals who do not qualify for financial assistance under Medicare. Their most common presenting complaints are related to volume overload and uremia, such as dyspnea, nausea, and pruritus. The ED maintains a standard procedure for patients presenting for emergent dialysis. A complete blood cell count, electrolytes (e.g., sodium, potassium, calcium, magnesium, and phosphorus), blood urea nitrogen, creatinine, and an electrocardiogram (ECG) are obtained when the patient is brought into the treatment area. A paper copy of the ECG is delivered by hand to the senior ED resident or attending physician for immediate analysis. The hospital uses an electronic medical record (EMR) system that facilitates the recording of all laboratory orders and results, medications, ECGs, and pharmaceutical interventions. All physician orders and entries are digitally recorded and time-stamped.
Effect of Antiemetics and Antihistamines on QTc Interval
Study Protocol Between June 1, 2013 and July 4, 2013, all patients $18 years of age who presented to this county hospital ED were screened by research assistants to identify patients who met inclusion criteria. All research assistants were medical students employed in a summer research program, and at least 1 was present in the ED 24 hours a day to continually screen presenting patients for emergent dialysis and inclusion. The research assistants used the EMR to identify all dialysis patients presenting to the ED. The QTc interval was taken from the automated analysis printed on each ECG that was uploaded onto the EMR. All ECG machines in the ED were the same model (MAC 5500 HD Resting ECG System; GE Healthcare, New York, NY) and used the Bazett formula (described above) to automatically calculate the QTc intervals that could be found on a printed copy of the ECG results. All automated ECG interpretations were subsequently reviewed by a staff cardiologist who documented their verification or any changes to the automated ECG interpretation to the version of the ECG that was uploaded to the EMR. The QTc intervals obtained by the research assistants on each patient were obtained from this final version of the ECG recorded on the electronic chart. The ECGs were repeated if there was any significant artifact that could potentially affect ECG interpretation. The following parameters were used to identify QTc prolongation in this study: >450 msec in men and >470 msec in women. The prolonged QTc interval was confirmed with the ED resident or attending physician providing care to the patient in the ED. Written informed consent was obtained from all patients who did not meet exclusion criteria to participate in the study. Patients were excluded if: 1) their QTc was <450 msec in men and <470 msec in women; 2) they were not given an antihistamine or antiemetic for their uremic symptoms; 3) they would not give consent; or 4) they were <18 years of age. As per the current practice in this county hospital ED, dialysis patients were given symptomatic treatment for uremic symptoms with oral or parenteral medications at the discretion of the attending physician or resident assigned to their care. Medications used for dialysis patients at this county hospital included promethazine, ondansetron, diphenhydramine, hydroxyzine, and prochlorperazine. The treating physicians were not blinded to the study. The research assistant continually tracked all dialysis patients with prolonged QTc intervals and identified patients who received any of the above medications by reviewing the patient’s EMR and speaking with the physician providers. Once identified, the research assistants notified the treating physician that a repeat ECG needed to be obtained 2 hours after the medications were given. The research assistants collected study data from the
101
EMR, through direct contact with the patient while in the ED, and communication with the physician providers caring for the patient. Patients were asked about the last time they had received dialysis. None of them were dialyzed at other hospitals. All patients presented with some complaint related to uremic symptoms or volume overload that would prompt them to come to the ED for dialysis. Information that was verbalized by the patient was confirmed in the EMR. The following data were collected by the research assistants on all recruited patients: medical record number, age, race, date and time of presentation, initial vital signs, symptomatic complaints (e.g., nausea or vomiting, pruritus, headache, edema, dyspnea, chest pain, or abdominal pain), comorbidities, frequency of ED presentation for dialysis, duration the patient has been on hemodialysis, QTc interval at ED presentation and 2 hours after an antiemetic or antipruritic was given in the ED, type and dosing of the agents given for uremic symptoms, vital signs, laboratory study results, disposition, and follow-up information. Each patient’s chart was reviewed 1 week later to determine if the patient had a repeat visit to this county hospital ED for dialysis, to review the QTc interval on the ECG performed on the return visit, and to identify if the patient had had any admissions to the hospital since discharge. Outcome Measures The primary outcome was any worsening QTc prolongation 2 hours after medications known to prolong the QT interval were given. A secondary outcome of the study was the presence of any dysrhythmias or sudden cardiac death. All charts were reviewed within 1 week to evaluate if any patient was admitted for any dysrhythmia, syncope, or had died. Primary Data Analysis Data were collected using a standard electronic collection template (Excel; Microsoft, Redmond, WA). Results are described using basic descriptive statistics, including the mean, standard deviation, minimum, and maximum values. RESULTS A total of 44 of 152 patients with ESRD (29%) presenting to this county hospital ED for hemodialysis over a 4-week period had QTc prolongation. All 44 patients consented to participate, accounting for 107 ED visits during the study period. All patients were Hispanic; 77% were men and 23% were women. The mean frequency of dialysis was 3.8 days, and the mean number of years on
102
S. Burdette et al.
Table 1. Comparisons of Antiemetic Dosing in Patients with End Stage Renal Disease and Prolonged QTc Intervals Drug
N
Mean (mg)
Minimum (mg)
Maximum (mg)
Promethazine Ondansetron Diphenhydramine Hydroxyzine Prochlorperazine
31 22 23 5 6
24.7 4.94 31.3 22 9.17
20 4 25 10 5
25 8 50 25 25
hemodialysis (HD) was 3.8. More than half (56.8%; n = 19) of the patients studied had diabetes and 100% possessed preexisting hypertension (HTN) (n = 44). Presenting symptoms of the study patients included pruritus (33/44; 75%), headache (11/44; 25%), edema (33/44; 75%), nausea and vomiting (37/44; 84.1%), chest pain (17/44; 38.6%), abdominal pain (30/44; 68.2%), and shortness of breath (34/44; 77%) being the most common symptom. All of the above data were obtained by interviewing the patient, when appropriate, and confirmed by reviewing the EMR. Some of this information was exclusively obtained from the patient’s electronic chart because the patient either did not know the information, was not available to answer the question by the research assistant, or was part of the patient’s care provided in the ED. A wide variety of treatment dosing of antiemetics/antihistamines were given for uremic symptoms. The mean dose of medications given per patient during each ED visit is listed in Table 1. Mean electrolyte levels are listed in Table 2. The mean QTc was 483.7 msec on presentation to the ED. The mean QTc interval was 483.8 msec 2 hours after these medications were given and 485.4 msec on 1-week follow up. There were no significant differences in QTc posttreatment with antiemetics or antihistamines. All patients were followed-up 1 week later. No patients were admitted for any dysrhythmias or suffered sudden cardiac death.
Of the 108 encounters, there were 28 encounters in 13 patients where the QTc was >500 msec. After the QTc prolonging medication was given, only 9 of these patients had an increase in the QTc interval on ECG 2 hours after a QTc prolonging medication was given. The average QTc increase was 11.8 msec (standard deviation [SD] 6.7 msec). The average overall change in the QTc interval for these 28 patients (with a baseline QTc of >500 msec) was 1.4 msec, with the highest being 14 and the lowest being 22 msec. There were 8 patients with QTc intervals <500 msec who had QTc intervals >500 msec after the QTc-prolonging medication was given. The average QTc increase was 15.5 msec (SD 14.4). Refer to Table 3 for a comparison of the QTc interval before and after the QTc prolonging medication was given and on 1-week follow-up. None of these patients had adverse outcomes on 1-week follow-up. All patients recruited in this study were followed-up 1 week later. DISCUSSION The objective of this study was to show the safety of these specific medications, which are known to increase the QTc interval, in patients with ESRD with pre-existing QTc prolongation. In this investigation, it was shown that the use of these specific antiemetics and antihistamines had no adverse outcomes in terms of significant changes in the QTc interval, both 2 hours posttreatment and on subsequent presentation to the ED within a 1-week period, in patients with ESRD with pre-existing QTc prolongation. Likewise, none of these patients developed dysrhythmias requiring hospitalization or sudden cardiac death. This was of great importance to the health care providers in this hospital setting because these are often the only medications available to provide relief of symptoms for these uremic patients, and it is imperative that their safety is demonstrated. In addition, none of the patients who presented with significantly prolonged QTc intervals (>500 msec) in the
Table 2. Comparison of Serum Electrolytes and QTc Changes Pre/Post-treatment with Antiemetic Drugs in Patients with End Stage Renal Disease and Prolonged QTc Intervals Percentiles Measure
N
Mean
SD
Minimum
Maximum
25%
50%
75%
K Ca Mg Pho Days since last dialysis QTc on presentation (msec) QTc after medications (msec) QTc on 1-week follow-up (msec)
43 44 41 41 44 44 44 43
5.55 8.46 2.69 7.2 4.44 483.7 483.8 485.4
0.55 0.95 0.44 1.82 1.98 18.4 20.0 22.6
4.2 5.92 1.7 4.7 0 454.8 448 442
6.6 10.5 3.78 13.1 8.5 532.5 537.5 537
5.2 7.81 2.42 5.88 3 468.9 466.8 467
5.6 8.62 2.67 6.8 4 480 484.8 483.4
6 9.09 3 8.06 5.75 496.6 493.4 499.3
Unit Measurement for K, mEq/L; Ca, mg/dL; Mg, mEq/L; Pho, mg/dL.
Effect of Antiemetics and Antihistamines on QTc Interval
103
Table 3. Comparison of QTc Intervals at Presentation, 2 Hours After QTc Medication was Given, and on 1-week Follow-up Descriptive Statistics
95% CI
Measurement
N
Mean
SD
Lower Limit
Upper Limit
QTc on presentation (msec) QTc after medications (msec) QTc on 1-week follow-up (msec)
43 43 43
483.24 483.74 485.40
18.36 20.19 22.58
477.59 477.53 478.45
488.90 489.95 492.35
CI, confidence interval; SD, standard deviation.
present study had any adverse outcome after receiving any of the medications known to cause QTc prolongation. Nausea and pruritus are 2 of the most common uremic symptoms in our unfunded patients with ESRD and are often treated with antiemetics and antihistamines, respectively. These uremic symptoms are magnified in the absence of routinely scheduled hemodialysis. The most commonly used medications for symptomatic relief in this study were promethazine, odansetron, and diphenhydramine at doses recommended for patients without renal disease (12). All of these medications are known to prolong the QTc interval, which causes great concern when using these medications in patients with pre-existing prolongation of the QTc interval. QT prolongation is common in patients with chronic renal failure. There are several proposed mechanisms for QTc prolongation in patients with ESRD, including autonomic neuropathy, iron body stores, electrolyte abnormalities, and comorbidities, such as congestive heart failure, left ventricular hypertrophy, diabetes, and ischemic heart disease (13–15). Several medications are known to cause QT prolongation and are intuitively avoided in patients with preexisting QT prolongation because of the fear of inducing life-threatening dysrhythmias, such as torsades de pointes. Promethazine is an antiemetic that is known to cause QT prolongation, but the risk of causing torsades de pointes is low (16). Diphenhydramine may cause prolonged QT prolongation but is rare and reported when excessive dosages of this drug are ingested (8). The toxicity of diphenhydramine is dose-dependent, with a critical dose limit of 1.0 g (8). Odansetron, a commonly used antiemetic, can also cause QT prolongation. One study on patients with heart disease found that although these patients had a significant prolongation in the QTc interval after a single 4-mg dose of odansetron, none of the patients developed concerning dysrhythmias, such as torsades de pointes. The authors recommend that high-risk patients receiving odansetron should be closely monitored with telemetry (17). The authors of the present study conclude that promethazine, diphenhydramine, and odansetron can be safely administered in therapeutic doses for symptomatic relief of pruritus and nausea for patients with ESRD with QT prolongation. However, these medications should be used with caution in patients with significantly prolonged
QT intervals; although no adverse events were seen in the study, the sample size was small. There are not enough data to support the safe use of these medications in these patients. Limitations There were many limitations to this study, including its lack of external validity; the sample size here was exclusively an unfunded group of Hispanic patients with no access to dialysis other than emergent dialysis. This study lacked power because of the small sample size (n = 44). However, given the proximity in the QTc measurement both before and after treatment, we assume that a larger sample size would have also shown no difference with treatment. The Bazett formula used to calculate the QTc measurement has its own limitations. It is also not known what method was used by the staff cardiologist to verify this interpretation. There were also not enough patients in this study with significantly prolonged QTc intervals (>500 msec) to look for adverse effects, and therefore conclusions cannot be made regarding the effect of these specific medications on this group of patients who would seemingly be at greater risk for prolonged QTcrelated dysrhythmias. There was only 1 ECG measurement performed 2 hours after the medication was given. The QTc prolonging effect may have extended beyond these 1 hours in patients with ESRD. All patients were followed-up 1 week later, so we can confidently say that there were no episodes of dysrhythmias requiring hospitalization or sudden death in these patients. Future research should focus on patients who have more prolonged QT prolongation and more frequent evaluation of the QTc after the administration of medications known to prolong the QTc interval. Finally, this study does not make allowances for acquired vs. genetic differences (e.g., both channel deficiencies and drug susceptibility) in QTc. It is possible that some of our patients had other reasons for QTc outside of their ESRD that require HD. CONCLUSION Patients with ESRD with preexisting prolonged QTc intervals in this study had no adverse cardiac dysrhythmias requiring admission or sudden cardiac death after the
104
S. Burdette et al.
administration of specific medications known to cause QT prolongation. While this is limited in external validity because of the small study size and narrow population demographics, the implications are potentially important, allowing for ongoing treatment with these agents in those with prolonged QTc. In addition, this study has great importance in this county hospital ED because it revealed that emergency physicians are not doing more harm to patients with ESRD with existing QTc prolongation while treating their uremic symptoms with specific antiemetics and antihistamines; this is reassuring given the frequent use of these medications in these patients. These medications should be used with caution in patients with significantly prolonged QT intervals, because although no adverse events were observed the sample size was small. Acknowledgments—We thank the University of Texas Summer Research Program for making this data collection possible and all of the unfunded dialysis patients at Parkland Hospital for their willingness to participate in this investigation.
REFERENCES 1. Straus SM, Kors JA, De Bruin ML, et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am College Cardiol 2006;47:362–7. 2. Roden DM. Clinical practice. Long-QT syndrome. N Engl J Med 2008;358:169–76. 3. Quaglini S, Rognoni C, Spazzolini C, Priori S, Mannarino S, Schwartz PJ. Cost-effectiveness of neonatal ECG screening for the long QT syndrome. Eur Heart J 2006;27:1824–32. 4. Kies SJ, Pabelick CM, Hurley HA, White RD, Ackerman MJ. Anesthesia for patients with congenital long QT syndrome. Anesthesiology 2005;102:204–10.
5. George AL Jr., Roden DM. Method for screening for susceptibility to drug-induced cardiac arrhythmia. U.S. Patent 6,458,242, B1, 2002. 6. Kuryshev Y, Brown AM, Wang L, Benedict CR, Rampe D. Interactions of the 5-hydroxytryptamine 3 antagonist class of antiemetic drugs with human cardiac ion channels. J Pharmacol Exp Ther 2000;295:614–20. 7. Zareba W, Moss AJ, Rosero SZ, et al. Electrocardiographic findings in patients with diphenhydramine overdose. Am J Cardiol 1997;80: 1168–73. 8. Husain Z, Hussain K, Nair R, Steinman R. Diphenhydramine induced QT prolongation and torsade de pointes: an uncommon effect of a common drug. Cardiol J 2010;17:509–11. 9. Hage FG, de Mattos AM, Khamash H, et al. QT prolongation is an independent predictor of mortality in end-stage renal disease. Clin Cardiol 2010;33:361–6. 10. Agodoa LU, Jones CA, Held PJ. End-stage renal disease in USA: data from United States Renal Data System. Am J Nephrol 1996; 16:7–16. 11. Voiculescu M, Ionescu C, Ismail G. Frequency and prognostic significance of QT prolongation in chronic renal failure patients. Rom J Intern Med 2006;44:407–17. 12. Monthly Prescribing Reference website. Antiemetic treatments. Available at: http://www.empr.com/clinical-charts/antiemetictreatments/article/125873/ [registration required]. Accessed February 3, 2016. 13. Wu VC, Lin LY, Wu KD. QT interval dispersion in haemodialysis patients. Nephrology 2005;10:109–12. 14. Nappi SE, Virtanen VK, Saha HHT, et al. QTc dispersion increases during haemodialysis with low-calcium dialysate. Kidney Int 2000; 57:2117–22. 15. Wu V, Huang J, Wu M, et al. The effect of iron stores on corrected QT dispersion in patients undergoing peritoneal dialysis. Am J Kidney Dis 2004;44:720–8. 16. Owczuk R, Tswardowski P, Dylczyk SA, et al. Influence of promethazine on cardiac repolarization: a double-blind, midazolamcontrolled study. Anesthesia 2009;64:609–14. 17. Hafermann MJ, Namdar R, Gretchen ES, Page RL. Effect of intravenous odansatron 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: 53–8.
Effect of Antiemetics and Antihistamines on QTc Interval
ARTICLE SUMMARY 1. Why is this topic important? There are many patients on dialysis with pre-existing QTc prolongation with severe uremic symptoms and necessitate the administration of QTc-prolonging drugs. 2. What does this study attempt to show? This study attempts to show that patients with end stage renal disease, severe uremic symptoms, and pre-existing QTc prolongation do not worsen with the administration of therapeutic doses of medications known to cause QTc prolongation. 3. What are the key findings? Dialysis patients with severe uremia and pre-existing QTc prolongation do not have lengthened QTc intervals after the administration of medications used to treat their uremic symptoms that are known to cause QTc prolongation. The chronic dialysis patients investigated in this study those at patients at highest risk because they do not receive routinely scheduled dialysis. 4. How is patient care impacted? These QTc-prolonging medications may be withheld from severely uremic patients because of pre-existing QTc prolongation. This study shows that the administration of these medications at therapeutic doses is safe. Patients with significant pre-existing QTc prolongation did not experience any adverse outcomes from receiving these medications, such as an dysrhythmia or sudden death.
105