July 2012 FAQs
July 2012 FAQs
Does azithromycin increase the risk of cardiovascular death?
Does azithromycin increase the risk of cardiovascular death?
Macrolide antibiotics have been associated with cardiotoxic effects, specifically in terms of their proarrhythmic potential.1 QT prolongation has been observed, which increases the risk of torsades de pointes1-6 and sudden cardiac death.7-9 Azithromycin, unlike other macrolide antibiotics, has previously not been associated with the same cardiac concerns and has a lower risk of QT prolongation.10-11 Interestingly, azithromycin had even previously been tested for its potential for cardioprotective effects, although study results failed to reveal any benefits from its use.12-15
Newer concerns over the cardiac safety of azithromycin have risen, however, due to published case reports of arrhythmia-related adverse events 16-22 as well as multiple reports of torsades de pointes associated with azithromycin on the Food and Drug Administration (FDA) Adverse Event Reporting System.23 Based on this, a cohort study was recently conducted to assess the risk of cardiovascular death with azithromycin. 24
Theoretical cardioprotective effects
The role of azithromycin in cardioprotection stemmed from the concept that infections may trigger the inflammatory cascade, increasing atherosclerosis and thrombotic events.25 Chlamydia pneumoniae was strongly suspected as a cause of worsening coronary artery disease (CAD), so multiple studies were undertaken to determine if treatment with azithromycin for this infection would reduce cardiovascular mortality. The ACADEMIC study 12, the AZACS study13, the WIZARD study14, and the ACES study15 were all randomized controlled trials comparing azithromycin to placebo in patients with CAD, although the doses and treatment durations varied from 5 days to 1 year. In all studies, no benefit was found with the use of azithromycin for the primary endpoints, which were a composite of cardiovascular death, nonfatal myocardial infarction, recurrent ischemia, hospitalization for unstable angina, and/or coronary revascularization.
Macrolides and cardiotoxicity
Macrolides have been found to prolong the action potential duration, which is significant as QT prolongation is often used as a surrogate marker for cardiotoxicity. 1 The electrophysiologic effects of erythromycin, clarithromycin, and azithromycin have been studied, however, and were found to differ.10 While all 3 medications had similar increases in QT interval and monophasic action potential (MAP) duration, only erythromycin and clarithromycin led to cases of early after depolarizations and torsades de pointes.
Erythromycin was previously studied in relation to its effect on sudden cardiac death.26 A Tennessee Medicaid cohort was reviewed for confirmed sudden death from cardiac causes as well as use of concomitant cytochrome P450 (CYP) 3A inhibitors, as this would increase serum concentration of erythromycin and potentially increase the risk of cardiotoxicity. Amoxicillin use and sudden cardiac death was also evaluated. There were 1476 confirmed cases of sudden death from cardiac causes, and the multivariate adjusted rate in patients receiving erythromycin was twice as high as those who had not used any study antibiotics (incidence-rate ratio 2.01; 95% confidence interval [CI] 1.08-3.75, P=0.03). There were no significant differences among former users of erythromycin and no study antibiotic use, or between amoxicllin use and no use. The adjusted rate of sudden death from cardiac causes was significantly higher among patients taking erythromycin and concurrent CYP3A inhibitors compared to those not taking either medication (incidence-rate ratio 5.35; 95% CI 1.72-16.64, P=0.004).
Clarithromycin was studied in a randomized, placebo-controlled, multicenter trial to assess its effects on mortality and cardiovascular morbidity in patients with stable coronary heart disease.27 The primary outcome was a composite of all-cause mortality, myocardial infarction, and unstable angina during 3 years of follow-up. The intervention was 2 weeks of clarithromycin 500 mg/day or matching placebo. Randomization resulted in 2172 patients receiving clarithromycin and 2201 receiving placebo. There were no significant effects of clarithromycin in regards to the primary outcome (hazard ratio [HR] 1.15, 95% CI 0.99-1.34). All-cause mortality, however, was significantly higher in the clarithromycin group versus placebo (HR 1.27, 95% CI 1.03-1.54, P=0.03). This was likely due to higher cardiovascular mortality with erythromycin in comparison to placebo (HR 1.45, 95% CI 1.09-1.92).
A study was published by Ray and colleagues regarding the issue of azithromycin and risk of cardiovascular death.24 This cohort study reviewed a group of Tennessee Medicaid patients, which included 347,795 prescriptions for azithromycin between 1992 and 2006.24 Patients with azithromycin prescriptions were compared to a control group of 1,391,672 patients with no prescriptions for antibiotics, a group of 1,348,672 patients with amoxicillin prescriptions, a group of 264,626 patients with ciprofloxacin prescriptions, and a group of 193,906 patients with prescriptions for levofloxacin. Patients were between the ages of 30 and 74 years and were excluded if they were considered at high risk for death from causes unrelated to a short-term exposure to a proarrhythmic medication. Additionally, patients could not have resided in a nursing home in the last year or been hospitalized in the last 30 days. The lower limit of 30 years of age was set by the authors as sudden death in children and young adults is rare.
The primary endpoints of the study were cardiovascular death and death from any cause.24 Cardiovascular deaths were identified by a computerized death certificate file and had to have an underlying cause of death consistent with a cardiovascular disease based on International Classification of Diseases (ICD-9) codes. An additional outcome included sudden cardiac death, which was defined as “a sudden pulseless condition that was fatal, consistent with aventricular tachyarrhythmia, and occurred in the absence of a known noncardiac condition as the proximate cause of the death.” Study comparisons were all adjusted for a large set of covariates that could have been associated with both the use of an antibiotic as well as the risk of death. Propensity scores were used for each matched comparison.
There were no major significant differences between groups.24 Among patients with prescriptions for azithromycin, there were 29 cardiovascular deaths during the 5-day treatment course or 85.2 per 1 million courses.24 Additionally, 22 of these deaths were considered sudden cardiac deaths (64.6 per 1 million courses). In comparison, patients with no antibiotics during a same 5-day period had 41 cardiovascular deaths (29.8 per 1 million courses) and 33 sudden cardiac deaths (24.0 per 1 million courses). During the first 5 days of treatment of amoxicillin, there were 42 cardiovascular deaths (31.5 per 1 million courses) and 29 sudden cardiac deaths (21.8 per 1 million courses). The risk for cardiovascular death for azithromycin compared to no antibiotic was increased (HR 2.88, 95% CI 1.79-4.63, P<0.001) during days 1 to 5. The risk of death from any cause was also increased with azithromycin (HR 1.85, 95% CI 1.25-2.75, P=0.002) for days 1 to 5, but this risk became non-significant when looking at the entire 10-day period after the prescription was filled (HR 1.27, 95% CI 0.92-1.75, P=0.20). In comparison, amoxicillin was not associated with an increased risk of death from cardiovascular or noncardiovascular causes at 5 or 10 days versus no antibiotics. Similar results were found when azithromycin was compared to amoxicillin. There were statistically significant increased risks of cardiovascular death at 5 and 10 days (HR 2.49, 95% CI 1.38-4.50, P=0.002 and HR 1.87, 95% CI 1.16-3.01, P=0.01, respectively) with azithromycin, but only a statistically significant risk of death from any cause at 5 days (HR 2.02, 95% CI 1.24-3.30, P=0.005). In comparison to ciprofloxacin, azithromycin was found to have an increased risk of cardiovascular death at 5 days (HR 3.49, 95% CI 1.32-9.26, P=0.01) but not for death from any cause. There was no statistically significant difference between azithromycin and levofloxacin for cardiovascular death or for death from any cause.
Azithromycin has historically been considered safer than other macrolides in regards to cardiotoxicity and proarrhythmic potential.10-11 It has even been studied previously for its potential for cardioprotection by eradicating C pneumoniae, which was thought to have atherogenic properties. 12-15,25 More recently, however, newer case reports and reporting by the FDA have prompted concern about azithromycin and its potential to cause arrhythmias, torsades de pointes, and sudden cardiac death.16-23 Based on this, a cohort study was performed to evaluate the association between azithromycin use and cardiovascular death.24 While this study did not compare azithromycin to other macrolides, it did compare azithromycin to patients with no antibiotics, amoxicillin, ciprofloxacin, and levofloxacin. There was a statistically significant increase in cardiovascular death as well as death from any cause when looking at azithromycin in comparison to no antibiotics as well as amoxicillin. Only cardiovascular death was significantly increased in comparison to ciprofloxacin, and there was no significant difference in comparison to levofloxacin.
This study suggests that there are evidence-based concerns for cardiotoxicity with azithromycin and that the idea that azithromycin is essentially safe in regards to cardiac events is no longer valid. As this study did not compare azithromycin to other agents in its class and previous studies have shown reduced cardiotoxicity in comparison to erythromycin and clarithromycin, it is still appropriate to use this agent for accepted indications. The incidence of cardiovascular death was still relatively small with azithromycin (85.2 per 1 million treatment courses), thus routine use of cardiac monitoring during treatment with azithromycin in the general population is not warranted at this time. Based on the available evidence, consideration for the use of azithromycin with other agents that may have proarrhythmic effects or in patients with underlying cardiovascular diseases should be part of the clinical discussion when determining an appropriate treatment plan, and appropriate monitoring should be considered in high-risk patients.
Written By : Deborah Raithel, PharmD,
University of Illinois at Chicago
1. Ohtani H, Taninaka C, Hanada E, et al. Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin and azithromycin in rats. Antimicrob Agents Chemother. 2000;44(10):2630–2637.
2. Vogt AW, Zollo RA. Long Q-T syndrome associated with oral erythromycin used in preoperative bowel preparation. Anesth Analg. 1997;85(5):1011-1013.
3. Tschida SJ, Guay DRP, Straka RJ, et al. 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.
4. De Ponti F, Poluzzi E, Montanaro N. QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience. Eur J Clin Pharmacol. 2000;56(1):1-18.
5. Shaffer D, Singer S, Korvick J, et al. Concomitant risk factors in reports of torsades de pointes associated with macrolide use: review of the United States Food and Drug Administration Adverse Event Reporting System. Clin Infect Dis. 2002;35(2):197-200.
6. Koh TW. Risk of torsades de pointes from oral erythromycin with concomitant carbimazole (methimazole) administration. Pacing Clin Electrophysiol. 2001;24(10):1575-1576.
7. Ray WA, Murray KT, Meredith S, et al. Oral erythromycin use and the risk of sudden cardiac death. N Engl J Med. 2004;351(11):1089-96.
8. Straus SMJM, Sturkenboom MCJM, Bleumink GS, et al. Non-cardiac QTc prolonging drugs and the risk of sudden cardiac death. Eur Heart J. 2005;26(19):2007-2012.
9. Zambon A, Friz HP, Contiero P, et al. Effect of macrolide and fluoroquinolone antibacterials on the risk of ventricular arrhythmia and cardiac arrest. Drug Saf. 2009;32(2):159-167.
10. Milberg P, Eckardt L, Bruns HJ, et al. Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsades de pointes. J Pharmacol Exp Ther. 2002;303(1):218-225.
11. Owens RC Jr, Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis. 2006;43(12):1603-1611.
12. Anderson JL, Muhlestein JB. The ACADEMIC study in perspective (Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia). J Clin Infect Dis. 2000;181(Suppl 3):S569-571.
13. Cerzek B, Shah PK, Noc M, et al. Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromcyin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet. 2003;361(9360):809-813.
14. O’Connor CM, Dunne MW, Pfeffer MA, et al. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA. 2003;290(11):1459-1466.
15. Grayston JT, Kronmal RA, Jackson LA, et al. Azithromycin for the secondary prevention of coronary events. N Eng J Med. 2005;352(16):1637-1645.
16. Matsunaga N, Oki Y, Prigollini A. A case of QT-interval prolongation precipitated by azithromycin. N Z Med J. 2003; 116(1185):U666.
17. Samarendra P, Kumari S, Evans SJ, et al. QT prolongation associated with azithromycin/amiodarone combination. Pacing Clin Electrophysiol. 2001;24(10):1572-1574.
18. Russo V, Puzio G, Siniscalchi N. Azithromycin-induced QT prolongation in elderly patient. Acta Biomed. 2006;77(1):30-32.
19. Arellano-Rodrigo E, García A, Mont L, et al. Torsade de pointes and cardiorespiratory arrest induced by azithromycin in a patient with congenital long QT syndrome. Med Clin (Barc). 2001;117(3): 118-119.
20. Kezerashvili A, Khattak H, Barsky A, et al. Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors. J Interv Card Electrophysiol. 2007;18(3):243-246.
21. Huang BH, Wu CH, Hsia CP, et al. Azithromycin-induced torsade de pointes. Pacing Clin Electrophysiol. 2007;30(12):1579-1582.
22. Kim MH, Berkowitz C, Trohman RG. Polymorphic ventricular tachycardia with a normal QT interval following azithromycin. Pacing Clin Electrophysiol. 2005; 28(11):1221-1222.
23. Poluzzi E, Raschke R, Moretti U, et al. Drug-induced torsades de pointes: data mining of the public version of the FDA Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf. 2009;18(6):512-518.
24. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20):1881-1889.
25. Libby P, Egan D, Skarlatos S. Roles of infectious agents in atherosclerosis and restenosis. Circulation. 1997;96(11):4095- 4103.
26. Ray WA, Murray KT, Meredith S, et al. Oral erythromycin and the risk of sudden death from cardiac cases. New Engl J Med. 2004;351(11):1089-1096.
27. Jespersen CM, Als-Nielsen B, Damgaard M, et al. Randomised placebo controlled multicentre trial to assess short term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. BMJ. 2006;332(7532):22-27.
What are the most recent guidelines for the treatment of diabetic foot infections?
What are the most recent guidelines for the treatment of diabetic foot infections?
Infection of the lower extremities, primarily as infections of the foot, is a serious complication of diabetes.1,2 Lavery and colleagues reported that in one cohort of patients with diabetes, 53% of patients with foot ulcers were treated for infections.1 In addition, 15% of diabetic patients with foot ulcers have been reported to develop osteomyelitis.2 There are a number of factors that contribute to the development of foot ulcers and infection in diabetic patients, including alterations in immune defenses, diabetic neuropathy, and diabetic angiopathy. 3 In addition to these patient-related factors, the density of bacteria, pathogen resistance or virulence, and the formation of biofilms are important in the development of diabetic foot infections.
Infectious Diseases Society of America Practice Guideline for Diabetic Foot Infections
Early recognition and effective treatment of diabetic foot ulcers is essential to avoid or minimize the risk of hospitalization and limb amputation. Diagnosis is generally based on the clinical features of the ulcer, with treatment based on its severity.4 Because of the seriousness of this complication of diabetes, the Infectious Diseases Society of America (IDSA) has developed a clinical practice guideline for the diagnosis and treatment of diabetic foot infections.5 This article will provide a summary of the most recent IDSA recommendations.
Published in June 2012, the IDSA guidelines provide evidence-based recommendations for the management of diabetic foot infections.5
Initial evaluation of diabetic foot infections
One of the initial steps in the treatment of diabetic foot infections is classifying the wound present.5 A number of wound classification systems are available; the IDSA guideline provides a comparison of 2 “user-friendly” systems—the PEDIS (perfusion, extent/size, depth/tissue loss, infection, sensation/neuropathy) and IDSA systems. Grading for the 2 systems is described in Table 1.
Table 1. Classification systems for diabetic foot infections.5
PEDIS grade IDSA grade
Grade 1 Uninfected No signs/symptoms of infection Grade 2 Mild Local infectiona with involvement of skin/subcutaneous tissue Erythema around the ulcer between 0.5 and 2 cm No systemic evidence of infectionb Grade 3 Moderate Local infection with >2 cm erythema or involvement of deeper tissues No system evidence of infection Grade 4 Severe Local infection with systemic evidence of infection
a Infection is defined by at least 2 symptoms/signs: local swelling/induration; erythema; local tenderness/pain; local warmth; purulent discharge.
b Systemic evidence of infection includes temperature >38°C or <36°C; heart rate > 90 beats/min; respiratory rate >20 breaths/min or PaCO 2<32 mmHg; white blood cell count > 12,000 or < 4000 cells/µL or ≥ 10% immature forms.
Abbreviations: IDSA, Infectious Diseases Society of America; PEDIS, perfusion/extent/depth/infection/sensation.
More complex grading systems, such as the Diabetic Foot Infection (DFI) wound score, can also be used. The DFI wound score assesses both wound parameters and wound measurements using a 10-item score. Wound parameters include purulent discharge, scored as absent or present, and signs/symptoms of inflammation (nonpurulent discharge, erythema, induration, tenderness, and warmth), each scored as absent, mild, moderate, or severe. Items included for wound measurements are wound size and depth (each scored on a scale of 0 to 10) and undermining (scored on a scale of 3 to 8). The DFI scale has a total score range of 3 to 49 points. Both the IDSA system and the DFI wound score have been validated in clinical trials as predictive of clinical outcomes. However, the DFI wound score may be more difficult to use for initial evaluation due to its complexity. In addition to grading the wound, patients should be assessed for other contributors to foot ulcers, such as limb/foot arterial ischemia, venous insufficiency, and loss of protective sensation (neuropathy).
Once diagnosed and the severity of infection is determined, hospitalization should be considered for some patients.5 Per the IDSA guidelines, all patients with a severe infection, those with moderate infections and complications (eg, peripheral artery disease), or those who cannot or would not comply with an outpatient treatment regimen should be hospitalized for initial treatment of the infection. If possible, cultures of the infected wound should be taken before treatment is initiated, except for mild infections where antibiotic therapy has not been previously administered.
Treatment of diabetic foot infection
Antibiotic therapy is not recommended for clinically uninfected wounds.5 All infected wounds should be treated with antibiotics in addition to appropriate wound care. Selection of antibiotic therapy is guided by both the severity of infection and the likely infecting organisms.
- Mild to moderate infections with no recent antibiotic treatment should be treated with empiric therapy to target gram-positive cocci.
- If there is recent use of antibiotics, gram-negative coverage should be included.
- For severe infections, broad-spectrum antibiotics (gram-positive/gram-negative/anaerobic) should be used until culture and sensitivity testing results are available.
- Empiric coverage for Pseudomonas aeruginosa is usually not needed unless there are specific risk factors present (eg, areas where P aeruginosa is a frequent isolate, failure of nonpseudomonal therapy, severe infections).
- Empiric coverage for methicillin-resistant Staphylococcus aureus (MRSA) is suggested for patients with a history of MRSA, if MRSA infection/colonization is locally prevalent, or if the infection is severe.
- Parenteral administration is recommended for severe infections and some moderate infections; a switch to oral agents can be done once culture results are known and the patient is systemically well.
- Oral agents with high bioavailability can most likely be used for mild infections and some moderate infections.
- Topical therapy may be appropriate for mild superficial infections.
- Duration of an initial course of therapy should be about 1 to 2 weeks for mild and 2 to 3 weeks for moderate/severe infections (until resolution of signs of infection but not necessarily through complete ulcer healing).
Based on available clinical trials, no one agent or combination of agents has been shown to be superior to another.5 The IDSA guideline provides suggested antibiotic therapy regimens based on severity of the infection (see Table 2).
Table 2.Suggested empiric antibiotic therapy for diabetic foot infections.5
Infection severity (route) Likely pathogen Antibiotic regimena Mild (oral) MSSA; Streptococcus sp. Dicloxacillin
Moderate (oral or initially parenteral) or severe (usually parenteral) MSSA; Enterobacteriaceae; obligate anaerobes Levofloxacin
Levofloxacin or ciprofloxacin combined with clindamycin
Pseudomonas aeruginosa Piperacillin-tazobactam MRSA,
Pseudomonas, and obligate anaerobes
Vancomycin, ceftazidimeb, cefepimeb, piperacillin-tazobactam, aztreonamb, or a carbapenem
a Agents with a narrow spectrum (eg, vancomycin, linezolid, daptomycin) should be used in combination with other antibiotics (eg, a fluoroquinolone) if a polymicrobial infection is suspected.
b An agent for obligate anaerobes should be added.
Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus.
Agents in italics are Food and Drug Administration approved for diabetic foot infections.
Evaluation for osteomyelitis
Osteomyelitis is a serious and not uncommon complication of diabetic foot infections, occurring in up to 20% of mild/moderate infections and in up to 60% of severe infections.5 It should be suspected in any infected, deep or large foot ulcers, especially when the ulcer is over a bony prominence of the foot. Lack of healing of an ulcer with adequate blood flow after 6 weeks of appropriate care should also prompt evaluation for osteomyelitis. Magnetic resonance imaging (MRI) is recommended for the diagnosis of osteomyelitis, but other methods (eg, bone scan combined with leukocyte/antigranulocyte scan) may be used if MRI is not available, along with bone culture and histology findings.
Treatment of diabetic foot osteomyelitis
Treatment for osteomyelitis must be individualized and may include surgical or nonsurgical therapies.5 Surgical interventions may range from drainage and excision of infected tissues to revascularization or limb amputation. Prolonged antibiotic therapy along with appropriate wound care has also been reported to be effective.
Similar to diabetic foot infections, no data are available to support one antibiotic regimen over another for treatment of diabetic foot osteomyelitis. 5 This is also true for the route and duration of therapy. Improved outcomes have been seen with antibiotic regimens based on bone culture results as compared to empiric therapy. The recommended duration and route of antibiotic therapy are given in Table 3.
Table 3. Suggested duration and route of administration of antibiotics for diabetic foot osteomyelitis.5
Extent of infection Route Duration No residual infected tissue (eg, postamputation) Parenteral or oral 2 to 5 days Residual infected tissue Parenteral or oral 1 to 3 weeks Residual infected viable bone Parenteral initially then oral 4 to 6 weeks No surgery or residual dead bone postoperatively Parenteral initially then oral ≥3 months
Diabetic foot infections are a common and severe complication of diabetes. Both patient- and bacteria-related factors can contribute to the development of ulcers and infection. Early diagnosis and appropriate treatment of diabetic foot infections is essential to avoid hospitalization, progression to osteomyelitis, or need for limb amputation.
1. Lavery LA, Armstrong DG, Wunderlich RP, Tredwell J, Boulton AJ. Evaluating the prevalence and incidence of foot pathology in Mexican-Americans and non-Hispanic whites from a diabetes disease management cohort. Diabetes Care. 2003;26(5):1435-1438.
2. Butalia S, Palda VA, Sargeant RJ, Detsky AS, Mourad O. Does this patient with diabetes have osteomyelitis of the lower extremity? JAMA. 2008;299(7):806-813.
3. Richard J, Lavigne J, Sotto A. Diabetes and foot infection: more than double trouble. Diabetes Metab Res Rev. 2012;28(suppl 1):146-53.
4. Lipsky BA, Peters EJG, Senneville E, et al. Expert opinion on the management of infections in the diabetic foot. Diabetes Metab Res Rev. 2012;28(suppl 1):163-178.
5. Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012;54(12):132-173.
What information is available on intravenous acetaminophen overdose in children?
What information is available on intravenous acetaminophen overdose in children?
Although available in other countries since 2002, intravenous (IV) acetaminophen (Ofirmev) has only recently become available in the United States. 1 It is indicated for use in adults and children over the age of 2 years for pain management and reduction of fever.2 Recommended doses of IV acetaminophen are outlined in Table 1. The calculated dose (mg) should be converted to the appropriate volume (mL) for administration. Intravenous acetaminophen is supplied in a 100-mL vial at a concentration of 10 mg/mL. When administering a 1000 mg dose, the entire volume (100 mL) of the vial can be given using a vented IV set. Lower doses require withdrawal of the appropriate volume from the vial and placement into a sterile container for IV administration. A syringe pump can be used for volumes up to 60 mL. Dilution of the drug is not necessary. The appropriate dose of IV acetaminophen should be infused over 15 minutes.
Table 1. Recommended dosing of intravenous acetaminophen.1,2
Children 2 to 12 years old and adults and adolescents < 50 kg Adults and adolescents ≥ 50 kg Dose 15 mg/kg every 6 hours OR 12.5 mg/kg every 4 hours 1 g every 6 hours OR 650 mg every 4 hours Maximum single dose 15 mg/kg up to 750 mg 1 g Maximum daily dose 75 mg/kg/day up to 3750 mg 4 g/day
A recent publication from the Rocky Mountain Poison and Drug Center in Denver, Colorado highlighted the risk of potential dosing errors with IV acetaminophen (also known as paracetamol) in children.1 According to a European regulatory agency, over 200 cases of IV acetaminophen overdose have been reported, with 23 of these cases occurring in pediatric patients under the age of 1 year; 1 case has resulted in death. A search of the literature found 4 published case reports of IV acetaminophen overdose in children due to dosing errors. A brief description of these cases is provided below.
1. A 5-month-old infant weighing 6.9 kg was prescribed 15 mg/kg IV acetaminophen and morphine after abdominal surgery. 3 A dose of 520 mg (approximately 75 mg/kg) was administered in error and detected 6 hours later. The serum acetaminophen concentration was 38 mg/mL and use of N-acetylcysteine (NAC) was not deemed necessary. Twenty-four hours after the overdose, an increase in the international normalized ratio (INR) to 2.9 and alanine aminotransferase (ALT) levels to 437 IU/L was observed and treatment with NAC and vitamin K was initiated. Liver enzyme levels continued to rise for the next 24 hours and slowly declined over several days. The patient was eventually discharged without complication.
2. A 6-month-old premature infant weighing 3.96 kg was administered 30 mL (300 mg) of IV acetaminophen instead of 3 mL during an elective inguinal hernia repair procedure.3 The patient received 75.8 mg/kg instead of 7.5 mg/kg. The error was detected immediately and NAC was administered. Acetaminophen concentrations were 72 mg/L at 1 hour after administration and 35 mg/L after 4 hours. The patient was asymptomatic with no change observed in liver function tests.
3. Similar to the second case, a premature, 7-week-old, 2.6-kg infant received an overdose of 380 mg (146 mg/kg) of IV acetaminophen instead of 19.5 mg (7.5 mg/kg) after an inguinal hernia repair surgery.4 Treatment with NAC was initiated at 150 mg/kg given over 15 minutes followed by 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours. At 4 and 8 hours after administration, serum acetaminophen concentrations were 117 mg/L and 72 mg/L, respectively. The serum concentrations fell to less than 1 mg/L after 36 hours. Liver function was not affected; however, INR and partial thromboplastin time (PTT) were slightly elevated at 1.26 and 41.8 seconds, respectively. Vitamin K (0.8 mg) was administered for 5 days. Clinically, the patient was stable and discharged after 5 days.
4. A malnourished , 3-year-old, 10-kg child with gastric dysmotility syndrome presented with fever and vomiting.5 The patient was given150 mg/kg of IV acetaminophen instead of 15 mg/kg. Forty-two hours after the overdose, ALT and aspartate aminotransferase (AST) levels were elevated (529 IU/L and 652 IU/L, respectively) and NAC was administered. Liver enzymes continued to increase for 48 hours and slowly returned to normal levels over 2 weeks. Coagulation tests were normal 72 hours after the dose was given. The patient was stable and discharged after 1 week.
With usual doses of acetaminophen , a majority of the drug is metabolized via sulfation and glucuronidation to nontoxic metabolites.6 A small portion of the drug undergoes metabolism through the cytochrome P450 system that leads to formation of a hepatotoxic metabolite, n-acetyl-p-benzoquinoneimine (NAPQI), which is further conjugated by glutathione to benign compounds. With an overdose of acetaminophen, the major route of metabolism becomes saturated, glutathione stores are depleted, and the amount of NAPQI accumulates, leading to hepatic damage. Malnourishment, comorbid illness, fasting, and use of hepatic enzyme-inducing drugs are risk factors for development of hepatotoxicity.7 However, the risk of hepatotoxicity appears to be less in children under the age of 6 years compared to adults in an acute overdose. Factors that lead to this lower risk may include increased metabolism through conjugation, rapid regeneration of glutathione, and greater frequency of vomiting.
Oral acetaminophen overdoses can be effectively managed with NAC or activated charcoal in children.8 Gastrointestinal decontamination with activated charcoal can be used in children who present within 4 hours of an acute overdose of greater than 7.5 g or 150 mg/kg. The decision of whether to initiate NAC can be made using the Rumack-Matthew nomogram. This nomogram plots the plasma acetaminophen concentration against the time since ingestion to estimate the severity and risk of hepatotoxicity. Patients with acetaminophen plasma concentrations that fall at or above the 25% risk of hepatotoxicity-line of the nomogram should receive treatment with NAC. According to the nomogram, a 4-hour post ingestion acetaminophen concentration greater than 150 mg/L is considered toxic and would necessitate administration of NAC. The nomogram proves useful in acute and chronic overdoses since the exact amount ingested is typically unknown. Other indications for use of NAC in children include a single oral ingestion of greater than 150 mg/kg, an acetaminophen concentration > 10 mg/L at 24 hours post-ingestion, and increased liver enzymes greater than 24 hours after ingestion in patients with a history of excessive acetaminophen use. Whether these criteria can be applied to IV overdose situations is unknown.
In contrast to oral acetaminophen, the peak concentration of IV acetaminophen is higher and occurs soon after administration.2,9,10 When administered intravenously, first-pass metabolism of acetaminophen is avoided, which results in a lower concentration of the drug in the liver compared to oral administration; up to 50% lower according to one pharmacokinetic study. With a lower acetaminophen concentration present in the liver through IV administration, a lower concentration of NAPQI would be expected. Therefore, an overdose through this route may cause less toxicity compared to the oral route. On the other hand, patients that receive the drug IV (eg, surgical patients) can be considered at high risk for toxicity due to prolonged fasting, glutathione depletion, and higher peak concentrations. Whether these pharmacokinetic differences and patient factors require changes to the management of acetaminophen overdose that occurs through the IV route is unclear.
Based on the occurrence of hepatic injury in the first case described above and the presence of risk factors in patients receiving IV acetaminophen, the National Poisons Information Service in the United Kingdom suggests use of NAC when IV doses of greater than 60 mg/kg are administered.1,3 When the dose administered is unknown, the use of NAC is recommended if the 4-hour acetaminophen serum concentration is greater than 50 mg/L. However, Dart and colleagues from the Rocky Mountain Poison Center state that the absence of first-pass metabolism with IV acetaminophen and the possibility of other causes of hepatic injury in case 1 suggest that the risk of hepatotoxicity is not heightened with IV acetaminophen compared to oral overdose.1,8 Therefore, measurement of a serum acetaminophen concentration 4 hours after an IV overdose of greater than 150 mg/kg is recommended and the nomogram described above should be used to determine whether treatment with NAC is indicated. Treatment with NAC, however, may be appropriate immediately after an overdose of greater than 150 mg/kg since this dose would be expected to cause a toxic concentration earlier than 4 hours with IV administration. 1 The data on neonatal acetaminophen overdose are limited; therefore, overdose cases in this population would require consultation with a specialist.
Overdoses of IV acetaminophen in children reported in the literature have been either due to calculation errors or confusion between milligrams of drug and milliliters to be administered.1,10 Other reported causes include errors in the programming of infusion pumps, duplication in treatment, and IV administration of the oral suspension. In order to minimize the chance of errors, the European regulatory agency has required labeling of IV acetaminophen to state that only a 50-mL vial of acetaminophen should be used for patients weighing less than 33 kg. Other preventive measures include limiting the use of IV acetaminophen to pain specialists only, indicating the maximum daily dose, checking the dose, volume, and syringe pump set-up by 2 staff members, placement of IV acetaminophen in high-use areas only, and placement of “not for IV use” labels on oral suspension containers.
1. Dart RC, Rumack BH. Intravenous acetaminophen in the United States: iatrogenic dosing errors. Pediatrics. 2012;129(2):349-353.
2. Ofirmev [package insert]. San Diego, CA: Cadence Pharmaceuticals; 2010.
3. Beringer RM, Thompson JP, Parry S, Stoddart PA. Intravenous paracetamol overdose: two case reports and a change to national treatment guidelines. Arch Dis Child. 2011;96(3):307–308.
4. Nevin DG, Shung J. Intravenous paracetamol overdose in a preterm infant during anesthesia. Paediatr Anaesth. 2010;20(1):105-107.
6. Burns MJ, Friedman SL, Larson AM. Acetaminophen (paracetamol) poisoning in adults: pathophysiology, presentation, and diagnosis. In: Basow, DS, ed. UpToDate. Waltham, MA: UpToDate; 2012.
7. Heard K, Dart R. Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents. In: Basow, DS, ed. UpToDate. Waltham, MA: UpToDate; 2012.
8. Heard K, Dart R. Management of acetaminophen (paracetamol) poisoning in children and adolescents. In: Basow, DS, ed. UpToDate. Waltham, MA: UpToDate; 2012.
9. Jahr JS, Lee VK. Intravenous acetaminophen. Anesthesiology Clin. 2010;28(4) 619–645.
10. Gray T, Hoffman RS, Bateman DN. Intravenous paracetamol: an international perspective of toxicity. Clin Toxicol (Phila). 2011;49(3):150-152.