August 2016 FAQs
August 2016 FAQs Heading link
What evidence supports the use of antibiotic-loaded bone cement to prevent infection in primary hip and knee arthroplasty?
What evidence supports the use of antibiotic-loaded bone cement to prevent infection in primary hip and knee arthroplasty?
Periprosthetic joint infection is a concern in total hip arthroplasty (THA) and total knee arthroplasty (TKA).1 Although the incidence of infection is approximately 1% to 2.5% in both procedures, it is the leading and third-leading cause of revision surgeries in THA and TKA, respectively, and is difficult to manage and heal.1-4 Bone cement, a viscous paste compounded from powder polymethylmethacrylate and a liquid methylmethacrylate, is used in orthopedic procedures to help fix prostheses to bone.1 Antibiotics can be added to the bone cement during its compounding to achieve high and prolonged local drug concentrations to prevent infection.2 Debate has existed over the use of antibiotic-loaded bone cement (ALBC) because of the risks for antibiotic resistance and reduction in structural integrity of the cement, as well as the efficacy of this practice. This review summarizes literature describing the efficacy of ALBC when used to prevent infection in primary THA and TKA.
Numerous studies have been conducted that evaluated the use of ALBC in both TKA and THA, which have been included in meta-analyses. A recent meta-analysis of high-quality studies of prophylactic ALBC in primary TKA evaluated the incidence of surgical site infection (SSI) that was either deep or superficial.5 Pooled data from 6637 patients in 5 studies found the risk of deep SSI was not significantly different with ALBC in analyses of prospective and retrospective studies (relative risk [RR], 0.75; 95% confidence interval [CI], 0.43 to 1.33), nor when analysis was restricted to only 3 randomized controlled trials (RCTs; RR, 0.28; 95% CI, 0.04 to 1.25). Prophylactic ALBC also provided no significant reduction in the incidence of superficial SSIs (RR, 0.28; 95% CI, 0.04 to 1.25). No adverse events were reported in any of the included studies. Additionally, data from registries of TKA-associated infection have reported conflicting findings for the use of ALBC in TKA.3 A Finnish registry found a higher risk of infection in patients who did not receive ALBC in primary TKA (RR, 1.35; 95% CI, 1.01 to 1.81), but data from an Australian registry found no difference in 1-, 5-, or 13-year infection or revision rates. Similarly, revision rates with ALBC were no different from non-ALBC among 36,000 patients in a Canadian registry of TKA.
In THA, results are less conflicting and overall demonstrate efficacy of prophylactic use of ALBC. The risk of infection in primary THA with ALBC was significantly reduced compared to control in a meta-analysis of 7 studies of approximately 7,000 patients (RR, 0.506; 95% CI, 0.341 to 0.751).6 This meta-analysis also found the risk of revision was significantly reduced with ALBC (RR, 0.721; 95% CI, 0.628 to 0.828).
Another meta-analysis of 8 RCTs combined results from settings of both THA and TKA, and again found no overall significant benefit with ALBC.7 Compared to control treatment with either plain bone cement or systemic antibiotics, ALBC did not significantly decrease the incidence of superficial infection, although it was associated with significant reductions in deep infection (RR, 0.41; 95% CI, 0.17 to 0.97). However, in subgroup comparisons to plain bone cement, neither outcome was significantly improved with ALBC; only comparisons to systemic antibiotics showed reduced deep infection with ALBC (RR, 0.37; 95% CI, 0.14 to 0.98). Conversely, compared to systemic antibiotics, ALBC significantly increased the risk of superficial infection (RR, 1.48; 95% CI, 1.1 to 2.0). In subgroup analyses of THA and TKA individually, results again showed significantly reduced deep infection rates with ALBC in THA (RR, 0.21; 95% CI, 0.08 to 0.50), but no effect in TKA. Another more recent meta-analysis reported consistent findings of no overall reduction in infection with ALBC when combining data from trials of THA, TKA, and total shoulder arthroplasties.8
While these meta-analyses indicate the benefit of ALBC may be limited to THA, several shortcomings leave questions on the true efficacy of ALBC. First, the methodologic quality of included studies was low, as the evidence rating systems scored few trials above 2 points on the maximum 5-point Jadad scale of trial quality.7 Secondly, the heterogeneity of interventions may lead to confounding. For example, because commercially available ALBC products were not available for all antibiotics, the type and amount of antibiotic included in ALBC was based on clinicians’ discretion and may vary within and between studies; this was not controlled for in meta-analyses. Likewise, the type of prosthesis was not controlled for, even though the nature of its material could differentially influence the production of biofilm.2 Comparisons of the type of antibiotic used were not consistently performed, and leave questions regarding the most efficacious product. Lastly, studies included in these meta-analyses have spanned continents and decades, leaving the potential for regional and temporal differences in microbiology and orthopedic procedures to influence outcomes.
Application to practice
Until further data or guidance becomes available, clinicians who choose to use ALBC should consider several important points to ensure optimal outcomes. First, when compounding ALBC, the selected antibiotic must possess a spectrum of activity against likely gram-positive and gram-negative pathogens.9 Aminoglycosides and vancomycin are commonly used, although use of penicillins, cephalosporins, macrolides, fluoroquinolones, and linezolid has been reported. The antibiotic also should be available in powder form because addition of liquid antibiotics significantly decreases the mechanical strength of the bone cement.2,9 Additionally, because the polymerization of the cement is an exothermic reaction reaching temperatures up to 80° C, the antibiotic should be chemically and thermally stable at these temperatures. The dose of the antibiotic must also be considered. Generally, recommendations are that the amount of antibiotic should range from 10% to 15% of the total weight of the cement (eg, 4 to 6 g per 40 g of cement).9 Some argue that in settings of infection treatment, antibiotic doses above 2 g per each 40 g of cement should be used. In contrast, in prophylactic settings where the primary function of the cement is for fixation, doses lower than 2 g per 40 g of cement have been recommended.2
Commercially available ALBC is also an option that could obviate the need for compounding. Commercial ALBC products are available with premixed tobramycin (eg, Simplex P with Tobramycin); gentamicin (eg, Cemex Genta; Cobalt G-HV; DePuy CMW 1, 2, and 3; Palacos LV+G; Palacos R+G; Refobacin LV; Refobacin Plus; Refobacin R; Smartset GHV; Smartset GMV); and gentamicin and clindamycin (eg, Refobacin Revision). Clinicians should be aware that these products are regulated by the Food and Drug Administration as devices via 510(k) or Premarket Authorization (PMA) pathways, and therefore may require less clinical study to achieve marketing approval compared to traditional drug approval. Such devices only need to demonstrate substantial equivalence to legally marketed predicate devices (for the brief 510k pathway approval, which does not usually require human data) or safety and efficacy (for the more rigorous PMA pathway approval, which requires data from human clinical studies).1012 Therefore, a review of published clinical literature for a particular product may be helpful in determining the most appropriate, safe, and effective commercial ALBC product for a particular use.
While meta-analyses support the ability of ALBC to reduce infection in THA, currently available data do not suggest benefit in TKA. Limitations in the design of studies included in meta-analyses leave questions on the true benefit of ALBC, as they were commonly uncontrolled or retrospective in design. Until definitive guidance is available on its use in primary THA and TKA, clinicians who choose to use ALBC in arthroplasty procedures should select an appropriate quantity of the mixed antibiotic if the ALBC is to be compounded or consider the use of commercially available ALBC products.
The information presented is current as of July 7, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.
1. Saleh KJ, El Othmani MM, Tzeng TH, Mihalko WM, Chambers MC, Grupp TM. Acrylic bone cement in total joint arthroplasty: A review. J Orthop Res. 2016;34(5):737-744.
2. Bistolfi A, Massazza G, Verne E, et al. Antibiotic-loaded cement in orthopedic surgery: a review. ISRN Orthop. 2011;2011:290851.
3. Hinarejos P, Guirro P, Puig-Verdie L, et al. Use of antibiotic-loaded cement in total knee arthroplasty. World J Orthop. 2015;6(11):877-885.
4. Lindeque B, Hartman Z, Noshchenko A, Cruse M. Infection after primary total hip arthroplasty. Orthopedics. 2014;37(4):257-265.
5. Zhou Y, Li L, Zhou Q, et al. Lack of efficacy of prophylactic application of antibiotic-loaded bone cement for prevention of infection in primary total knee arthroplasty: results of a meta-analysis. Surg Infect (Larchmt). 2015;16(2):183-187.
6. Parvizi J, Saleh KJ, Ragland PS, Pour AE, Mont MA. Efficacy of antibiotic-impregnated cement in total hip replacement. Acta Orthop. 2008;79:335-341.
7. Wang J, Zhu C, Cheng T, et al. A systematic review and meta-analysis of antibiotic-impregnated bone cement use in primary total hip or knee arthroplasty. PLoS One. 2013;8(12):e82745.
8. Yi Z, Bin S, Jing Y, Zongke Z, Pengde K, Fuxing P. No decreased infection rate when using antibiotic-impregnated cement in primary total joint arthroplasty. Orthopedics. 2014;37(12):839-845.
9. Soares D, Leite P, Barreira P, Aido R, Sousa R. Antibiotic-loaded bone cement in total joint arthroplasty. Acta Orthop Belg. 2015;81(2):184-190.
10. Premarket notification 510(k). US Food and Drug Administration website. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketNotification510k/default.htm. Updated September 16, 2015. Accessed July 11, 2016.
11. Premarket approval (PMA). US Food and Drug Administration website. http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissions/premarketapprovalpma/default.htm. Updated July 8, 2016. Accessed July 11, 2016.
12. Overview of device regulation. US Food and Drug Administration website. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/. Updated August 14, 2015. Accessed July 25, 2016.
What does the American Psychiatric Association recommend regarding the use of antipsychotics in patients with dementia?
What does the American Psychiatric Association recommend regarding the use of antipsychotics in patients with dementia?
Many patients with dementia suffer symptoms beyond cognitive impairment. Neuropsychiatric symptoms such as agitation, aggression, delusions, depression, and hallucinations are common. A recent survey determined that agitation or aggression occurred in over one-third of outpatients with dementia.1 Alarmingly, nearly three-quarters of patients with dementia suffer psychiatric symptoms during hospital admission.2 Despite the prevalence of neuropsychiatric symptoms in patients with dementia, appropriate management remains controversial. Antipsychotic medications are frequently prescribed, but there are numerous concerns with their use. This concern is not new; the Food and Drug Administration (FDA) called attention to this issue over a decade ago. A 2005 FDA statement warned of an increased risk of mortality with atypical antipsychotics in elderly patients with dementia-related psychosis.3 The majority of the deaths were cardiovascular or infection related. In 2008, the FDA expanded this warning to conventional antipsychotics. Unfortunately, there are few effective alternative treatments for agitation or psychosis, and providers often have to weigh the risk versus benefit of these agents for neuropsychiatric symptoms in patients with dementia.
In an attempt to improve the care of patients with dementia who have agitation or psychosis, the American Psychiatric Association (APA) recently provided guidance on the use of antipsychotic medications in these patients.4,5 The guidelines consist of 15 statements in 5 categories rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system (Table). All guideline statements are depicted with a strength of evidence ranking – high (A), moderate (B), or low (C). Many of the recommendations in the APA guidelines simply support what is being done in good clinical practice; however, some of the parameters may require adaptation to current practice.
Table. APA recommendations regarding the use of antipsychotics for agitation or psychosis in patients with dementia.4,5
Assessment of psychological or behavioral symptoms of dementia
- Assess the type, frequency, severity, pattern, and timing of symptoms
- Assess for pain or other symptom contributors as well as the subtype of dementia that may influence treatment
- Assess response to treatment with a quantitative measure
Development of a comprehensive treatment plan
- Develop a patient-specific treatment plan that includes pharmacologic and nonpharmacologic interventions
Assessment of benefits and risks of antipsychotic treatment for the patient
- Antipsychotics should only be used for agitation or psychosis in nonemergency situations in patients with dementia when symptoms are severe, dangerous, or cause significant distress to the patient
- Response to nonpharmacologic measures should be assessed prior to treating patients with antipsychotics in nonemergency situations
- The potential risks and benefits of antipsychotic medications should be assessed by the clinician and discussed with the patient (if possible), the patient’s surrogate decision maker, family, or others involved in care of the patient in nonemergency situations
Dosing, duration, and monitoring of antipsychotic treatment
- Initiate treatment at a low dose and titrate to the minimum effective dose as tolerated
- When a patient experiences a side effect, the risks and benefits of the medication should be reviewed to determine if tapering and discontinuing the medication is appropriate
- Taper and withdraw antipsychotics in patients who do not have a clinically significant response after 4 weeks of treatment
- In patients who respond to antipsychotic treatment, discuss possible tapering of antipsychotics with the patient (if possible), the patient’s surrogate decision maker, family, or others involved in the care of the patient to determine their preferences
- Taper and discontinue the antipsychotic within 4 months of initiation in patients with an adequate response unless the patient had recurrent symptoms with prior tapering attempts
- Assess patients at least monthly for 4 months while discontinuing antipsychotics
Use of specific antipsychotic medications, depending on clinical context
- In the absence of delirium, haloperidol should not be used first-line in nonemergency situations
- Long-acting injectable antipsychotics are not recommended for agitation or psychosis in patients with dementia unless they are needed for a comorbid disease state
The guidelines recommend use of a quantitative measure for treatment response.5 There are a number of scales available for agitation and/or psychosis, and the guidelines recommend using the same scale for a particular patient but do not recommend a particular scale overall. Examples of appropriate scales include the Neuropsychiatric Inventory Questionnaire (NPI-Q) and the Brief Psychiatric Rating Scale (BPRS) as well as the Cohen-Mansfield Agitation Inventory (CMAI) or Modified Overt Aggression Scale in patients who are agitated without other psychosis. In some patients an abbreviated approach such as rating specific symptoms on a Likert scale may be indicated. The patient must also be assessed for factors contributing to his or her symptoms. Pain is a frequent cause of agitation, but communication of pain may be impaired, and use of scales such as the Pain Assessment in Advanced Dementia (PAINAD) scale may be useful.5,6 Other factors such as new medical conditions (e.g., infection) or medication changes should be ruled out as causative factors prior to initiating treatment.5
The treatment plan
The treatment plan should consist of nonpharmacologic and pharmacologic interventions.5 Importantly, the guidelines remind providers that an effective intervention for one patient may be distressing to another. They also point out that while a behavior may be distressing to a caregiver, it may not distress the patient, and the treatment plan should appropriately include the needs of the caregiver. Regular reassessment of the treatment plan is also recommended.
The guidelines reinforce the need to weigh the risks and benefits of antipsychotic treatment prior to initiating therapy.5 The risk of adverse effects in older patients with concomitant disease states and medications may outweigh the benefits of treatment. Consideration should also be given to the type of dementia. Patients with Lewy body or Parkinson’s disease dementia may have greater risks associated with the extrapyramidal or cognitive effects of antipsychotic medications.
There are a number of considerations when selecting an initial antipsychotic therapy including insurance coverage, cost, concomitant medication or disease states, medication pharmacokinetics and adverse effects, as well as available dosage forms.5 The guidelines recommend that second-generation antipsychotics be considered first and haloperidol be avoided in non-emergent situations. In a review of the evidence, the APA found risperidone to be effective for psychosis and risperidone, olanzapine, or aripiprazole effective for agitation. They found insufficient evidence for quetiapine and no evidence for asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, paliperidone, or ziprasidone in patients with dementia. The guidelines do not recommend a particular agent as first-line therapy. Long-acting injectable formulations are not recommended as initial treatment but may be used in select patients who have difficulty with adherence.
Regardless of antipsychotic choice, elderly or frail patients require small doses ‒ the guidelines suggest one-half to one-third of the dose used in younger patients as an appropriate initial dose.5 The dose should be titrated. If there is an inadequate response after 4 weeks of treatment at an appropriate therapeutic dose, the antipsychotic should be tapered and discontinued. Careful monitoring of adverse effects and adherence is recommended. The guidelines recommend that an attempt to taper and discontinue the medication should be made within 4 months of initiation for patients that have been prescribed the antipsychotic solely for dementia-related agitation or psychosis. The APA does not provide rationale for the selection of the 4-month time frame but does recommend that specific patient factors are considered in the timing of a discontinuation attempt. They also recommend close monitoring for at least 4 months after discontinuation to assess symptom recurrence.
The APA released 2016 guidelines to improve the care of patients with agitation or psychosis related to dementia. The recommendations are specific to the use of antipsychotics in these patients, and alternative medications are not discussed. Key recommendations in these guidelines include careful patient selection for antipsychotic initiation, the use of quantitative measures for response to therapy, and an attempt at discontinuation as soon as reasonably possible. The guidelines do not recommend a particular antipsychotic but do recommend haloperidol and long-acting antipsychotic avoidance.
- Thyrian JR, Eichler T, Hertel J, et al. Burden of behavioral and psychiatric symptoms in people screened positive for dementia in primary care: results of the DelpHi-Study. J Alzheimers Dis. 2015;46(2):451-459.
- Sampson EL, White N, Lord K, et al. Pain, agitation, and behavioural problem in people with dementia admitted to general hospital wards: a longitudinal cohort study. Pain. 2015;156(4):675-683.
- Information for healthcare professionals: conventional antipyschotics. Food and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124830.htm. Published June 16, 2008. Accessed June 24, 2016.
- Reus VI, Fochtmann LJ, Eyler E, et al. The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. Am J Psychiatry. 2016;173(5):543-546.
- Practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. Psychiatry Online website. http://psychiatryonline.org/doi/book/10.1176/appi.books.9780890426807. Accessed June 24, 2016.
- Warden V, Hurley AC, Volicer L. Development and psychometric evaluation of the Pain Assessment in Advanced Dementia (PAINAD) scale. J Am Med Dir Assoc. 2003;4(1):9-15.
The information presented is current as of July 1, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.
Can a simplified 2-bag acetylcysteine approach improve tolerability in acetaminophen overdoses?
Can a simplified 2-bag acetylcysteine approach improve tolerability in acetaminophen overdoses?
N-acetylcysteine (NAC) is an important antidote for acetaminophen overdoses and when administered early it can prevent acetaminophen-induced hepatotoxicity.1 N-acetylcysteine is indicated in patients at risk for hepatotoxicity which is determined by use of the Rumack-Matthew nomogram. For acute overdoses, NAC is initiated if the initial acetaminophen serum concentration is above the treatment line of the nomogram. While NAC has been utilized since the 1970s and many different dosing and administration regimens have been studied, the current Food and Drug Administration-approved regimen for intravenous NAC involves a 3-bag regimen (150 mg/kg over 1 hour, followed by 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours).1,2
Rationale for simplified regimen
The current intravenous NAC regimen is complex and has been associated with a high rate of medical errors.1 A 2008 retrospective evaluation of intravenous NAC cases in a regional poison center revealed that medical errors occurred in 33% of patients.3 Furthermore, a prospective analysis of NAC infusion bags prepared for acetaminophen overdoses revealed a large variation between the anticipated dose and the actual dose given.4 The authors reported a systematic calculation error in 5% of cases and inadequate preparation of the NAC infusion bag in 12% of cases.
Additionally, NAC is associated with adverse reactions including nausea, vomiting, and systemic hypersensitivity reactions.5 Hypersensitivity reactions are mediated through a non-immunoglobulin-E pathway leading to an anaphylactic reaction characterized by rash, flushing, tachycardia, bronchospasm, hypotension, and angioedema. The majority of adverse reactions occurs within the first hour of NAC administration and appears to correspond to peak NAC concentrations. Therefore, many investigators have hypothesized that a lower dose or a slower initial infusion rate could reduce adverse reactions associated with NAC.
Three recent studies have evaluated whether adverse reactions associated with NAC administration can be reduced with a simplified, 2-bag dosing approach.6-8 All 3 studies evaluated the incidence of NAC-related adverse reactions in patients who were admitted to the emergency department with an acetaminophen overdose and received an abbreviated NAC dosing regimen. Each of the regimens utilizes a slower initial infusion rate. The Table summarizes the study design characteristics and NAC regimens used in these studies.
Table. Design characteristics of studies evaluating an abbreviated NAC dosing regimen.6-8
Abbreviated NAC protocol
All patients presenting to 2 EDs who ingested >4 g of APAP initiated prior to receiving APAP serum concentration levels
First infusion: 200 mg/kg in 500 mL D5W over a variable durationa
Second infusion: 100 mg/kg in 1000 mL D5W over 16 h
All patients presenting to 3 EDs with an APAP overdose requiring treatment with NAC as determined by the treating physician
First infusion: 200 mg/kg in 500 mL NS over 4 h
Second infusion: 100 mg/kg in 1000 mL NS over 16 h
First infusion: 150 mg/kg in 200 mL NS over 1 h
Second infusion: 50 mg/kg in 500 mL NS over 4 h
Third infusion: 100 mg/kg in 1000 mL NS over 16 h
All patients presenting to 2 EDs with an APAP overdose requiring NAC on the basis of their APAP serum concentration
First infusion: 100 mg/kg in 200 mL D5W over 2 h
Second infusion: 200 mg/kg in 1000 mL D5W over 10 h
Third infusionb: 500 mL of D5W continued until 20-25 h after initiation of the protocol
Prospective, parallel control:
First infusion: 150 mg/kg in 200 mL D5W over 15 min
Second infusion: 50 mg/kg in 500 mL D5W over 4 h
Third infusion: 100 mg/kg in 1000 mL D5W over 16 h
aDuration of the first infusion was determined based on time of overdose: 11 hours minus time since ingestion (eg, a patient presenting at 3 h post-ingestion would receive a 8 h infusion). Exceptions included: all patients presenting within 2 hours of ingestion received a 9 hour infusion; all patients presenting after 7 hours of ingestion, those who had poisoning associated with staggered, repeated supratherapeutic ingestions, or those who had an unknown ingestion time received a 4 hour infusion.
bThird infusion was utilized to protect the blind in the experiment, but is not considered part of the abbreviated protocol.
Abbreviations: APAP=acetaminophen; D5W=5% dextrose in water; ED=emergency department; NAC=N-acetylcysteine; NS=normal saline.
Isbister and colleagues conducted a prospective, observational study to measure the proportion of patients who developed gastrointestinal symptoms or systemic hypersensitivity reactions with the introduction of their abbreviated protocol.6 The protocol for this study differed substantially from current clinical practice as NAC was initiated immediately on presentation and terminated if it was later determined that the patient had a low-risk acetaminophen serum concentration (<150 mg/mL at 4 h). All patients received the same abbreviated NAC protocol (Table) and were prospectively monitored to measure adverse reactions. There were 654 patients treated with their abbreviated protocol over the study period; however, only 231 patients received the entire infusion course. The majority of the patients had their NAC infusion terminated early due to low-risk acetaminophen serum concentrations. Adverse reactions were reported in 35% of all patients receiving NAC. Gastrointestinal symptoms were identified in 26.5% of patients; while, skin-only hypersensitivity reactions and severe anaphylaxis occurred in 8% and 0.5% of patients, respectively. However, in patients who received the full course of NAC, 48% developed a NAC-related adverse reaction compared to 28% in those who had their NAC infusion stopped. Hepatotoxicity (alanine transaminase [ALT] >1000 Unit/L) was observed in 16 patients; all of those patients presented ≥11 hours after ingestion. Based on the time course and rates of adverse reactions, the authors concluded that an initial dose of 200 mg/kg over 4 hours followed by 100 mg/kg over 16 hours in patients with established toxic acetaminophen concentrations would be a preferred regimen over the variable duration approach utilized in the trial.
Wong and colleagues conducted a quasi-experimental study which evaluated the rate of non-allergic anaphylactic reactions (systemic hypersensitivity reactions) and gastrointestinal symptoms with an abbreviated, 2-bag NAC protocol compared to an historical cohort receiving a traditional 3-bag regimen (Table).7 Adverse reactions for both groups were collected retrospectively through a chart review. During the 2-bag regimen treatment period, 470 patients presented with an acetaminophen overdose and 44.7% received the NAC regimen. This was similar to the historical control period where there were 920 presentations and 42.3% received NAC. There were no significant differences observed between the 2 groups for gastrointestinal symptoms (41% for 2-bag vs 39% for 3-bag; odds ratio [OR], 1.17; 95% confidence interval [CI], 0.83 to 1.65; p=0.38). However, the 2-bag regimen was associated with fewer non-allergic anaphylactic reactions compared to the 3-bag regimen (4.3% vs 10%; OR, 2.5; 95% CI, 1.1 to 5.8; p=0.02). The study also reported no significant differences in the rate of hepatotoxicity (ALT >1000 Unit/L) between groups (5.2% for 2-bag vs 4.3% for 3-bag; OR, 1.2; 95% CI, 0.55 to 2.63; p=0.68).
Bateman and colleagues conducted a double-blind, randomized, factorial trial assessing the effect of shortening the NAC regimen and antiemetic pretreatment on the rate of nausea and vomiting.8 Patients presenting with toxic acetaminophen serum concentrations were randomized to 4 treatment groups: shortened NAC regimen with ondansetron pretreatment (ondansetron-modified), shortened NAC regimen with placebo (placebo-modified), standard NAC with ondansetron pretreatment (ondansetron-standard), or standard NAC with placebo (placebo-standard) (Table). A total of 222 patients were randomized in the trial in a 1:1:1:1 ratio. The incidence of nausea or vomiting within 2 hours of initiation was significantly less with the modified NAC regimens compared to the standard NAC regimen (adjusted OR, 0.26; 97.5% CI, 0.13 to 0.52; p<0.0001) and with ondansetron pretreatment compared to placebo (adjusted OR, 0.41; 97.5% CI, 0.20 to 0.80; p=0.003). The superiority of the abbreviated NAC regimen and ondansetron pretreatment was maintained at 12 hours after initiation. Anaphylactoid or systemic hypersensitivity reactions were absent in 46% of patients receiving abbreviated NAC compared to 25% receiving the standard NAC regimen. Ondansetron pretreatment had no effect on the incidence of these reactions. At the end of the NAC infusion, 5 patients in all groups had an ALT >1000 Unit/L (2 ondansetron-modified, 1 ondansetron-standard, and 2 placebo-standard). Further, a post-hoc analysis demonstrated that patients receiving ondansetron had a higher risk of ALT doubling than those receiving placebo. Therefore, the authors concluded that an abbreviated NAC regimen can reduce vomiting and serious anaphylactoid reactions, but the addition of ondansetron pretreatment is not clinically warranted due to its effect on ALT.
A key limitation to all of these trials includes their inability to establish non-inferiority between traditional NAC regimens and new, abbreviated regimens from a hepatotoxicity perspective. Since each of these trials was designed to assess rate of adverse reactions, they cannot inform a full clinical decision on whether these simplified approaches can replace traditional dosing schemes. Furthermore it is difficult to compare the adverse reaction rates reported in each trial due to differences in the data collected. The Isbister and Bateman trials collected data prospectively while the Wong trial identified adverse reactions retrospectively through documentation in the medical record. Rates of adverse reactions may be underrepresented in retrospective data collection as very mild reactions may not be recorded. Lastly, the Bateman trial compared their abbreviated protocol to a traditional protocol that administered the first infusion over 15 minutes. The majority of organizations recommend a 60 minute initial infusion duration based on a previous study which investigated whether a 60 minute regimen can reduce the rate of adverse reactions compared to the original 15 minute regimen.1,9 Therefore, the control group may represent an overinflation in the expected rate of adverse reactions with traditional regimens commonly used in current clinical practice.
A simplified, 2-bag NAC regimen has promise as a future treatment option based on evidence supporting its ability to reduce adverse reactions associated with NAC including both nausea and vomiting and systemic hypersensitivity reactions. Further investigation is needed, however, before these regimens can be fully accepted into clinical practice as their efficacy in preventing hepatotoxicity has not yet been adequately studied.
1. Howland MA, Hendrickson RG. Antidotes in depth: N-acetylcysteine. In: Nelson LS, Lewin NA, Howland M, Hoffman RS, Goldfrank LR, eds. Goldfrank's Toxicologic Emergencies. 9th ed. New York, NY: McGraw-Hill; 2011. http://accesspharmacy.mhmedical.com/Content.aspx?bookid=454&Sectionid=40199409. Accessed June 27, 2016.
2. Acetadote [package insert]. Nashville, TN: Cumberland Pharmaceuticals Inc; 2013.
3. Hayes BD, Klein-Schwartz W, Doyon S. Frequency of medication errors with intravenous acetylcysteine for acetaminophen overdose. Ann Pharmacother. 2008;42(6):766-770.
4. Ferner RE, Langford NJ, Anton C, Hutchings A, Bateman DN, Routledge PA. Random and systematic medication errors in routine clinical practice: a multicentre study of infusions, using acetylcysteine as an example. Br J Clin Pharmacol. 2001;52(5):573-577.
5. Chiew AL, Isbister GK, Duffull SB, Buckley NA. Evidence for the changing regimens of acetylcysteine. Br J Clin Pharmacol. 2016;81(3):471-481.
6. Isbister GK, Downes MA, McNamara K, Berling I, Whyte IM, Page CB. A prospective observational study of a novel 2-phase infusion protocol for the administration of acetylcysteine in paracetamol poisoning. Clin Toxicol (Phila). 2016;54(2):120-126.
7. Wong A, Graudins A. Simplification of the standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning results in a lower incidence of adverse drug reactions. Clin Toxicol (Phila). 2016;54(2):115-119.
8. Bateman DN, Dear JW, Thanacoody HK, et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. Lancet. 2014;383(9918):697-704.
9. Kerr F, Dawson A, Whyte IM, et al. The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine. Ann Emerg Med. 2005;45(4):402-408.
The information presented is current as July 18, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.