September 2014 FAQs
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What evidence supports the use of extended or continuous infusions for carbapenem administration?
What evidence supports the use of extended or continuous infusions for carbapenem administration?
Beta-lactam antibiotics are considered time dependent agents since their antimicrobial effects are higher with a longer duration of time above the infecting organism’s minimum inhibitory concentration (MIC).1,2 The time-dependent nature of beta-lactam efficacy has prompted research regarding the administration of some beta-lactams via extended-duration or continuous infusions, in order to maximize the time above the MIC. Some authors have suggested that the time above the MIC should be 90% to 100% of the dosing interval to minimize the development of antibiotic resistance, which is difficult to achieve with traditional intermittent dosing methods.1 Several studies have observed improved clinical outcomes with prolonged infusions of piperacillin-tazobactam, in addition to institutional cost savings.3-5 There is also clinical experience with prolonged infusions of several other antibiotics (eg, cefepime, ceftazidime, oxacillin, ceftriaxone) in both adults and children.6,7 These positive results with other beta-lactams and a growing reliance on carbapenems due to the increased prevalence of multidrug resistant organisms has garnered interest in administering agents in this antibiotic class as prolonged infusions. This article summarizes the available evidence regarding clinical outcomes with extended or continuous infusion carbapenem administration.
Currently, the carbapenem with the largest number of studies describing clinical outcomes with prolonged infusions is meropenem. These articles are summarized in the Table.8-15 The largest study to date observed a significant improvement in intensive care unit (ICU) length of stay with a meropenem continuous infusion compared to intermittent infusion, but there was no difference in clinical cure, hospital length of stay, or mortality. 11 Two other studies found a significant improvement in clinical cure/treatment success with prolonged infusions.8,14 Although outcomes were promising in the handful of available case reports, the remaining studies did not identify any compelling benefits of extended or continuous meropenem administration compared to standard bolus dosing.9,10,12,13,15 There is not enough information to determine the relative benefits of a specific dosing regimen or populations that are most likely to benefit from prolonged infusions of meropenem.
Table. Clinical outcomes with prolonged meropenem infusions.8-15
Reference Design and population Drug regimen(s) Outcomes and results Feher 20148 R, SC (Spain)
n=175 patients with FN following hematopoietic stem cell transplant or induction chemotherapy for AML
Meropenem 1 g every 8 hours (30-minute infusion)
Meropenem 1 g every 8 hours (4-hour infusion)
Monotherapy or in combination with an AG and/or glycopeptide
Treatment success was more common with the longer infusion (68.4% vs. 40.9%, p=0.001).
Time to defervescence and time to CRP <5 mg/dL or <50% of initial value were improved with the 4-hour infusion (p=0.021 and 0.037, respectively).
There were no differences in 100-day mortality (p=0.278) or LOS (p=0.053).
Zobell 20149 Case report (United States)
13 y.o. patient with CF and MDR Inquilinus limosus followed over multiple hospital admissions
Meropenem 0.5 to 6 g given over 23.5 hours (dose adjusted based on serum concentration)
Also received once-daily tobramycin
PFTs improved to near baseline values. There was no improvement in time between exacerbations. Dulhunty 201310 P, DB, DD, RCT, MC (Australia and Hong Kong)
n=60 adults with severe sepsis
Meropenem 24-hour infusion with placebo boluses every 8 hours
Placebo 24-hour infusion with meropenem boluses every 8 hours
Doses were chosen by clinicians (meropenem ranged from 3 to 3.8 g/day); other study arms were piperacillin-tazobactam and ticarcillin-clavulanate.
Meropenem plasma concentrations were higher with CI vs. bolus (p=0.001); no other meropenem-specific results were reported.
Antibiotic concentrations >MIC and clinical cure were greater for all 3 CI groups combined vs. bolus; no difference in other outcomes (eg, time to clinical resolution, LOS in ICU, survival) was observed.
Chytra 201211 P, OL, RCT, SC (Czech Republic)
n=240 adults with sepsis in the ICU
Meropenem 2 g loading dose followed by 4 g over 24 hours
Meropenem 2 g every 8 hours (30-minute infusion)
Concomitant antibiotics were allowed.
Clinical cure was similar between groups (p=0.18).
Meropenem-related ICU LOS (p=0.044), duration of meropenem therapy (p=0.041), and total meropenem dose (p<0.0001) were significantly lower with the 24-hour infusion. There was no difference in hospital LOS or mortality.
Ho 201112 Case report (United States)
58 y.o. patient with MDR Klebsiella pneumoniae in blood and urine
Meropenem 2 g every 8 hours, given as a CI over 8 hours After 6 weeks of meropenem, the infection cleared and the patient was discharged without antibiotics. The patient remained infection-free at 21 months of follow-up. Wang 200913 P, RCT, SC (China)
n=30 patients in the ICU with HAP due to Acinetobacter baumanii
Meropenem 1 g every 8 hours (1-hour infusion) Meropenem 500 mg every 6 hours (3-hour infusion) Eradication at 7 days and rates of relapse were similar between groups (both p>0.05).
Longer infusions were associated with significant medication cost savings (p<0.01).
Lorente 200614 R, SC (Spain)
n=89 adults in the ICU undergoing empiric treatment for VAP caused by gram negative bacilli
Meropenem 1 g every 6 hours (30-minute infusion)
Meropenem 1 g loading dose over 30 minutes followed by 1 g every 6 hours, given as a CI over 6 hours
All patients received once daily tobramycin.
Clinical cure was more common with CI vs. bolus administration (90.47% vs. 59.57%, p<0.001). No other clinical outcomes were reported. Domenig 200115 Case report
58 y.o. patient with pneumonia due to MDR Pseudomonas aeruginosa in a transplanted lung
Meropenem 2 g loading dose followed by 8 g daily CI
Vancomycin was added at day 10.
Clinical status improved, mechanical ventilation was stopped, and patient was discharged with no clinical signs of infection.
Abbreviations: AG, aminoglycoside; AML, acute myeloid leukemia; CI, continuous infusion; CRP, C-reactive protein; DB, double-blind; DD, double dummy; FN, febrile neutropenia; HAP, hospital-acquired pneumonia; ICU, intensive care unit; LOS, length of stay; MC, multicenter; MDR, multidrug resistant; MIC, minimum inhibitory concentration; OL, open label; P, prospective; PFTs, pulmonary function tests; R, retrospective; RCT, randomized controlled trial; SC, single center; VAP, ventilator-associated pneumonia.
Two studies have reported clinical outcomes with doripenem prolonged infusions.16,17 The first was a retrospective, single-center analysis of 200 critically ill adults who received at least 72 hours of doripenem therapy for gram-negative infections.16 All patients received doripenem 500 mg every 8 hours (or renally adjusted doses, if needed) administered as either 1-hour or 4-hour infusions. More critically ill patients achieved clinical success with the 4-hour infusion compared to the 1-hour infusion (72.2% vs. 47.6%, p=0.017); however, there was no difference in clinical success within the full study population (p=0.336). All other study outcomes (hospital length of stay, duration of bacteremia, inpatient mortality, and 90-day infection recurrence) were similar in both groups. . The authors concluded that extended infusion doripenem should be considered in critically ill patients.
In a case series, 3 pediatric patients with cystic fibrosis were switched from continuous meropenem infusions to doripenem due to meropenem drug shortages. 17 All patients received weight-based doripenem doses every 8 hours, given as extended infusions over 4 hours. Pulmonary function and overall clinical status were improved in all patients compared to baseline (prior to the start of carbapenem therapy). Transient doripenem-related adverse effects among the 3 patients included nausea, diarrhea, and mild increases in liver function tests.
Ertapenem and imipenem/cilastatin administration via extended or continuous infusion have only been investigated in pharmacokinetic/pharmacodynamics studies.18-20 Clinical outcomes with these agents are not available.
Infusion pump and formulation-related concerns need to be addressed prior to implementation of prolonged infusion of beta-lactams, including carbapenems. One article describes a 40% loss of antibiotic doses in the infusion line “dead space” if the line was not flushed after infusion of concentrated solutions (50 mL) via a volumetric pump.21 Clinicians should consider the potential for unadministered medication depending on the drug concentration and characteristics of the specific pump used.
Solution stability during extended or continuous infusions is also a concern. When prepared according to the manufacturer’s directions, doripenem is stable for 4 hours (in 5% dextrose) or 12 hours (in 0.9% sodium chloride) at room temperature, which is likely adequate for extended infusions.22 This is supported by one published stability study that reported 12-hour room temperature stability for doripenem 5 mg/mL solutions in 0.9% sodium chloride, which is a slightly different concentration than recommended by the manufacturer.23 The product labeling of brand meropenem (Merrem, AstraZeneca) provides only a 1-hour room temperature stability for 1 to 20 mg/mL solutions in 0.9% sodium chloride.24 On the other hand, generic manufacturers of meropenem solutions provide slightly longer stability requirements (eg, 4 hours at room temperature for 1 to 20 mg/mL solutions in 0.9% sodium chloride), which may also be sufficient for extended administration.25 Stability data for meropenem administration via continuous infusion are limited, but one study suggests that 5 mg/mL solutions in sterile water for injection can be changed after no more than 6 to 8 hours at room temperature.26 Another stability study suggests that solutions of meropenem for continuous infusion are stable at concentrations of no more than 4 g/100 mL and temperatures of no more than 25 degrees Celsius, but no specific comments about how to apply this data to clinical practice are provided. 27
A meta-analysis of 5 studies did not identify a mortality benefit of extended/continuous carbapenem infusions compared to standard administration (risk ratio [RR] 0.66, 95% confidence interval [CI] 0.34 to 1.30).28 There was also no difference in clinical cure between these strategies (RR 1.16, 95% CI 0.82 to 1.65). However, this analysis included articles with substantial heterogeneity (eg, dosing, populations studied) so the overall question of whether prolonged carbapenem infusions provide any substantial clinical benefit remains largely unanswered.29 Individual studies and case reports have noted improved clinical cure/improvement rates with extended and continuous carbapenem infusions, but mortality and length of stay were similar compared to standard infusion durations. Future research may provide additional information regarding these outcomes and other concerns such as stability of solutions for continuous infusion.
1. Roberts JA, Paratz J, Paratz E, Krueger WA, Lipman J. Continuous infusion of beta-lactam antibiotics in severe infections: a review of its role. Int J Antimicrob Agents. 2007;30(1):11-18.
2. Nicolau DP. Pharmacodynamic optimization of beta-lactams in the patient care setting. Crit Care. 2008;12(Suppl 4):S2.
3. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis. 2007;44(3):357-363.
4. Yost RJ, Cappelletty DM; RECEIPT Study group. The Retrospective Cohort of Extended-Infusion Piperacillin-Tazobactam (RECEIPT) study: a multicenter study. Pharmacotherapy. 2011;31(8):767-775.
5. Nichols KR, Knoderer CA, Cox EG, Kays MB. System-wide implementation of the use of an extended-infusion piperacillin/tazobactam dosing strategy: feasibility of utilization from a children's hospital perspective. Clin Ther. 2012;34(12):2297-2300.
6. Walker MC, Lam WM, Manasco KB. Continuous and extended infusions of β-lactam antibiotics in the pediatric population. Ann Pharmacother. 2012;46(11):1537-1546.
7. Teo J, Liew Y, Lee W, Kwa AL. Prolonged infusion versus intermittent boluses of β-lactam antibiotics for treatment of acute infections: a meta-analysis. Int J Antimicrob Agents. 2014;43(5):403-411.
8. Fehér C, Rovira M, Soriano A, et al. Effect of meropenem administration in extended infusion on the clinical outcome of febrile neutropenia: a retrospective observational study. J Antimicrob Chemother. 2014 May 22. pii: dku150. [Epub ahead of print]
9. Zobell JT, Ferdinand C, Young DC. Continuous infusion meropenem and ticarcillin-clavulanate in pediatric cystic fibrosis patients. Pediatr Pulmonol. 2014;49(3):302-306.
10. Dulhunty JM, Roberts JA, Davis JS, et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis. 2013;56(2):236-244.
11. Chytra I, Stepan M, Benes J, et al. Clinical and microbiological efficacy of continuous versus intermittent application of meropenem in critically ill patients: a randomized open-label controlled trial. Crit Care. 2012;16(3):R113.
12. Ho VP, Jenkins SG, Afaneh CI, Turbendian HK, Nicolau DP, Barie PS. Use of meropenem by continuous infusion to treat a patient with a Bla(kpc-2)-positive Klebsiella pneumoniae blood stream infection. Surg Infect (Larchmt). 2011;12(4):325-327.
13. Wang D. Experience with extended-infusion meropenem in the management of ventilator-associated pneumonia due to multidrug-resistant Acinetobacter baumannii. Int J Antimicrob Agents. 2009;33(3):290-291.
14. Lorente L, Lorenzo L, Martín MM, Jiménez A, Mora ML. Meropenem by continuous versus intermittent infusion in ventilator-associated pneumonia due to gram-negative bacilli. Ann Pharmacother. 2006;40(2):219-223.
15. Domenig C, Traunmüller F, Kozek S, et al. Continuous beta-lactam antibiotic therapy in a double-lung transplanted patient with a multidrug-resistant Pseudomonas aeruginosa infection. Transplantation. 2001;71(6):744-745.
16. Hsaiky L, Murray KP, Kokoska L, Desai N, Cha R. Standard versus prolonged doripenem infusion for treatment of gram-negative infections. Ann Pharmacother. 2013;47(7-8):999-1006.
17. Zobell JT, Kemper AL, Young DC. The use of doripenem in pediatric cystic fibrosis patients in case of meropenem shortages. Pediatr Pulmonol. 2014;49(3):E48-E51.
18. Breilh D, Fleureau C, Gordien JB, et al. Pharmacokinetics of free ertapenem in critically ill septic patients: intermittent versus continuous infusion. Minerva Anestesiol. 2011;77(11):1058-1062.
19. Sakka SG, Glauner AK, Bulitta JB, et al. Population pharmacokinetics and pharmacodynamics of continuous versus short-term infusion of imipenem-cilastatin in critically ill patients in a randomized, controlled trial. Antimicrob Agents Chemother. 2007;51(9):3304-3310.
20. Courter JD, Kuti JL, Girotto JE, Nicolau DP. Optimizing bactericidal exposure for beta-lactams using prolonged and continuous infusions in the pediatric population. Pediatr Blood Cancer. 2009;53(3):379-385.
21. Claus B, Buyle F, Robays H, Vogelaers D. Importance of infusion volume and pump characteristics in extended administration of ß-lactam antibiotics. Antimicrob Agents Chemother. 2010;54(11):4950.
22. Doribax [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2007.
23. Psathas PA, Kuzmission A, Ikeda K, Yasuo S. Stability of doripenem in vitro in representative infusion solutions and infusion bags. Clin Ther. 2008;30(11):2075-2087.
24. Merrem I.V. [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2013.
25. Meropenem [package insert]. Lake Forest, IL: Hospira, Inc.; 2013.
26. Franceschi L, Cojutti P, Baraldo M, Pea F. Stability of generic meropenem solutions for administration by continuous infusion at normal and elevated temperatures. Ther Drug Monit. 2014 Mar 14. [Epub ahead of print]
27. Berthoin K, Le Duff CS, Marchand-Brynaert J, Carryn S, Tulkens PM. Stability of meropenem and doripenem solutions for administration by continuous infusion. J Antimicrob Chemother. 2010;65(5):1073-1075.
28. Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infect Dis. 2013;56(2):272-282.
29. Frippiat F, Vercheval C, Lambermont B, Damas P. Is extended or continuous infusion of carbapenems the obvious solution to improve clinical outcomes and reduce mortality? Clin Infect Dis. 2013;57(2);324-325.
What evidence describes the effect of inhaled morphine for dyspnea or pain?
What evidence describes the effect of inhaled morphine for dyspnea or pain?
Dyspnea is a common stressful symptom experienced by a large proportion of patients with various lung conditions, including chronic obstructive pulmonary disease (COPD), lung cancer, and interstitial lung disease.1,2 Because the underlying pathology of these diseases is often irreversible, symptomatic treatment of dyspnea may be required. Specifically, guidelines for the treatment of dyspnea in patients receiving palliative care all recommend use of systemic opioids to alleviate dyspnea; however, systemic administration carries concerns of respiratory depression, addiction, and ileus. 3-8
Human lung tissue in the bronchi and alveoli has been shown to contain opioid receptors.2 Activation of pulmonary opioid receptors inhibits acetylcholine release, decreasing smooth muscle contraction and mucus secretion. Pulmonary opioid receptors are largely comprised of kappa receptor subtypes, for which morphine has a greater affinity compared with other opioids.8,9 Therefore, inhaled administration of morphine has been explored as a way to provide rapid local action without systemic adverse effects.10 Anecdotal and retrospective evidence has reported some success with this strategy.11,12 This article will discuss findings of prospective trials evaluating the efficacy and safety of inhaled morphine for various indications.
Efficacy of inhaled morphine for dyspnea
A 2005 review summarized results of trials of nebulized morphine in patients with chronic lung diseases, primarily COPD.2 Five double-blind randomized controlled trials (RCTs) in patients with COPD found no benefit overall, including trials over a wide dose range (1 to 40 mg), with no evidence of a dose-response relationship.13-17 Only one small trial reported positive findings.13 The randomized, placebo-controlled crossover of 11 adults found a single dose of inhaled morphine 5 mg improved endurance time in an exercise test (mean improvement of 35% with morphine vs 0.8% with saline placebo; p<0.01). A double-blind RCT not included in the review compared inhaled morphine 5 mg vs placebo in patients with chronic lung disease (9 with COPD and 1 with interstitial lung disease).18 The authors found no difference between treatments in an exercise test in maximum power output achieved, minute ventilation, or degree of breathlessness.
Further evaluations of morphine for treatment of dyspnea continued to be performed after these findings, though they provided little support. A double-dummy crossover compared inhaled morphine with subcutaneous morphine in cancer patients with dyspnea.19 Despite a finding of significant improvement in dyspnea visual analog scale (VAS) scores from baseline with both interventions, the between-group difference was not significant. Another double-blind crossover trial in 12 adults with lung cancer and dyspnea found no difference in VAS scores between placebo and inhaled morphine.20 Positive findings were reported by one trial including 40 patients exposed to sulfur mustard during chemical warfare.21 Compared with placebo, patients who received inhaled morphine 1 mg once daily for 5 days reported significantly lower VAS scores for dyspnea, cough, and quality of life, with approximately a 1.5-point improvement on each 10-point scale with morphine.
Overall, there appears to be little evidence supporting the use of inhaled morphine for treatment of dyspnea, as concluded by various reviews. 1,9,10,22-26 As such, guidelines for COPD and for treatment of dyspnea in patients receiving palliative care or who have advanced lung or heart disease do not encourage the use of nebulized opioids.3-5,27
Efficacy of inhaled morphine for pain
Inhaled morphine has also been studied for its analgesic effects, again with little evidence of benefit. One double-dummy randomized controlled trial compared nebulized morphine every 4 hours (mean dose 11.96 mg) with morphine administered via patient-controlled analgesia (PCA) in patients with posttraumatic thoracic pain.6 No significant differences were found between groups in mean VAS pain scores (3.38 with inhaled vs 3.84 with PCA morphine; p=0.2), although patients receiving inhaled morphine had a lower mean heart rate (79 vs 92 beats per minute; p<0.001) and sedation score (0.33 vs 0.9; p=0.03). Another trial in patients with chest trauma compared inhaled morphine with epidural analgesia with 0.125% bupivacaine and 0.115% fentanyl. 28 While both interventions were effective in achieving the primary outcome of VAS pain score <4, there was no between-group difference. Additionally, one trial compared morphine as 1 inhalation (2.2 mg), morphine as 3 inhalations (6.6 mg), intravenous morphine 4 mg, and placebo in patients undergoing bunionectomy.29 The authors found 3 inhalations of morphine and intravenous morphine were both more effective than 1 inhalation of morphine and placebo in time to pain relief. There was no difference between 1 inhalation of morphine and placebo. Another prospective cohort of adult patients with pain in an emergency setting evaluated the effect of inhaled morphine 0.2 mg/kg on pain 10 minutes after administration.30 No patients experienced either pain relief (score of 30/100 on a numerical rating scale) or the authors’ predefined threshold of a minimum clinically significant improvement in pain severity (≥14 points).
A study by Krajnik and colleagues evaluated the effect of the technique of morphine nebulization on various pharmacokinetic parameters.31 A nebulization method delivering particles of larger size (2 to 5 µm) preferentially to the bronchial tree and trachea was compared with a device delivering smaller particles (0.5 to 2 µm) to the alveoli in 10 cancer patients. The area under the curve for morphine levels was several times higher with delivery of larger particles, leading the authors to conclude this nebulization technique may be preferred for inhaled morphine. However, this rationale has not been cited as an influential factor on clinical outcomes in trials, and trials that reported using nebulizers delivering larger particles as categorized by Krajnik have nonetheless reported negative results.14,16,32
Safety of inhaled morphine
Prospective trials of inhaled morphine reported no serious adverse events. The most common adverse events included dizziness, emesis, nausea, xerostomia, and bitter taste.31 However, many trials were of limited duration and in small sample sizes, which may limit the ability to detect rare but serious adverse events. Acute respiratory depression was described in a case report of a 74-year-old woman with lung cancer who was previously treated with oral morphine and experienced breathlessness.33 The patient was treated via inhalation with morphine 4 mg and dexamethasone 4 mg in saline, after which she experienced hypotension, bradypnea, and altered mental status requiring emergent intubation. The risk of such adverse events and limitations of trials to detect them must be considered in light of the limited efficacy demonstrated with inhaled morphine.
The majority of prospective trials of inhaled morphine have found nonsignificant changes from baseline or significant changes that were indistinguishable from placebo effects. While the safety profile of inhaled morphine has been overall positive, the ability of trials to detect serious adverse events has been limited, and respiratory depression has been described in a case report. Considering the scarcity of evidence for benefit of inhaled morphine, clinicians should carefully consider other treatment modalities for patients with dyspnea associated with chronic lung conditions or terminal illness.
1. Viola R, Kiteley C, Lloyd NS, Mackay JA, Wilson J, Wong RK. The management of dyspnea in cancer patients: a systematic review. Support Care Cancer. 2008;16(4):329-337.
2. Brown SJ, Eichner SF, Jones JR. Nebulized morphine for relief of dyspnea due to chronic lung disease. Ann Pharmacother. 2005;39(6):1088-1092.
3. Lanken PN, Terry PB, Delisser HM, et al. An official American Thoracic Society clinical policy statement: palliative care for patients with respiratory diseases and critical illnesses. Am J Respir Crit Care Med. 2008;177(8):912-927.
4. Mahler DA, Selecky PA, Harrod CG, et al. American College of Chest Physicians consensus statement on the management of dyspnea in patients with advanced lung or heart disease. Chest. 2010;137(3):674-691.
5. Qaseem A, Snow V, Shekelle P, et al. Evidence-based interventions to improve the palliative care of pain, dyspnea, and depression at the end of life: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;148(2):141-146.
6. Fulda GJ, Giberson F, Fagraeus L. A prospective randomized trial of nebulized morphine compared with patient-controlled analgesia morphine in the management of acute thoracic pain. J Trauma. 2005;59(2):383-388.
7. Barnes PJ. Pulmonary pharmacology. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: The McGraw-Hill Companies; 2011. http://accesspharmacy.mhmedical.com/content.aspx?bookid=374&Sectionid=41266244. Accessed August 13, 2014.
8. Yaksh TL, Wallace MS. Opioids, Analgesia, and Pain Management. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. ed. New York, NY: The McGraw-Hill Companies; 2011. http://accesspharmacy.mhmedical.com/content.aspx?bookid=374&Sectionid=41266224. Accessed August 13, 2014.
9. Bausewein C, Simon ST. Inhaled nebulized and intranasal opioids for the relief of breathlessness. Curr Opin Support Palliat Care. 2014 ; 8(3):208-212.
10. Shirk MB, Donahue KR, Shirvani J. Unlabeled uses of nebulized medications. Am J Health Syst Pharm. 2006;63(18):1704-1716.
11. Ballas SK, Viscusi ER, Epstein KR. Management of acute chest wall sickle cell pain with nebulized morphine. Am J Hematol. 2004;76(2):190-191.
12. Farncombe M, Chater S, Gillin A. The use of nebulized opioids for breathlessness: a chart review. Palliat Med. 1994;8(4):306-312.
13. Young IH, Daviskas E, Keena VA. Effect of low dose nebulised morphine on exercise endurance in patients with chronic lung disease. Thorax. 1989;44(5):387-390.
14. Masood AR, Reed JW, Thomas SH. Lack of effect of inhaled morphine on exercise-induced breathlessness in chronic obstructive pulmonary disease. Thorax. 1995;50(6):629-634.
15. Beauford W, Saylor TT, Stansbury DW, Avalos K, Light RW. Effects of nebulized morphine sulfate on the exercise tolerance of the ventilatory limited COPD patient. Chest. 1993;104(1):175-178.
16. Jankelson D, Hosseini K, Mather LE, Seale JP, Young IH. Lack of effect of high doses of inhaled morphine on exercise endurance in chronic obstructive pulmonary disease. Eur Respir J. 1997;10(10):2270-2274.
17. Noseda A, Carpiaux JP, Markstein C, Meyvaert A, de Maertelaer V. Disabling dyspnoea in patients with advanced disease: lack of effect of nebulized morphine. Eur Respir J. 1997;10(5):1079-1083.
18. Leung R, Hill P, Burdon J. Effect of inhaled morphine on the development of breathlessness during exercise in patients with chronic lung disease. Thorax. 1996;51(6):596-600.
19. Bruera E, Sala R, Spruyt O, Palmer JL, Zhang T, Willey J. Nebulized versus subcutaneous morphine for patients with cancer dyspnea: a preliminary study. J Pain Symptom Manage. 2005;29(6):613-618.
20. Grimbert D, Lubin O, de Monte M, et al. [Dyspnea and morphine aerosols in the palliative care of lung cancer]. Rev Mal Respir. 2004;21(6 Pt 1):1091-1097.
21. Shohrati M, Ghanei M, Harandi AA, Foroghi S. Effect of nebulized morphine on dyspnea of mustard gas-exposed patients: a double-blind randomized clinical trial study. Pulm Med. 2012;2012:610921.
22. Jennings AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE. A systematic review of the use of opioids in the management of dyspnoea. Thorax. 2002;57(11):939-944.
23. DiSalvo WM, Joyce MM, Tyson LB, Culkin AE, Mackay K. Putting evidence into practice: evidence-based interventions for cancer-related dyspnea. Clin J Oncol Nurs. 2008;12(2):341-352.
24. Ben-Aharon I, Gafter-Gvili A, Paul M, Leibovici L, Stemmer SM. Interventions for alleviating cancer-related dyspnea: a systematic review. J Clin Oncol. 2008;26(14):2396-2404.
25. Foral PA, Malesker MA, Huerta G, Hilleman DE. Nebulized opioids use in COPD. Chest. 2004;125(2):691-694.
26. Polosa R, Simidchiev A, Walters EH. Nebulised morphine for severe interstitial lung disease. Cochrane Database Syst Rev. 2002(3):CD002872.
27. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease website. http://www.goldcopd.org/uploads/users/files/GOLD_Report_2014_Jan23.pdf. Accessed August 8, 2014.
28. Nejmi H, Fath K, Anaflous R, Sourour S, Samkaoui MA. A prospective randomized comparison of nebulized morphine versus thoracic epidural analgesia in the management of thoracic trauma. Ann Fr Anesth Reanim. 2010;29(6):415-418.
29. Thipphawong JB, Babul N, Morishige RJ, et al. Analgesic efficacy of inhaled morphine in patients after bunionectomy surgery. Anesthesiology. 2003;99(3):693-700; discussion 696A.
30. Bounes V, Ducasse JL, Bona AM, Battefort F, Houze-Cerfon CH, Lauque D. Nebulized morphine for analgesia in an emergency setting. J Opioid Manag. 2009;5(1):23-26.
31. Krajnik M, Podolec Z, Siekierka M, et al. Morphine inhalation by cancer patients: a comparison of different nebulization techniques using pharmacokinetic, spirometric, and gasometric parameters. J Pain Symptom Manage. 2009;38(5):747-757.
32. Harris-Eze AO, Sridhar G, Clemens RE, Zintel TA, Gallagher CG, Marciniuk DD. Low-dose nebulized morphine does not improve exercise in interstitial lung disease. Am J Respir Crit Care Med. 1995;152(6 Pt 1):1940-1945.
33. Lang E, Jedeikin R. Acute respiratory depression as a complication of nebulised morphine. Can J Anaesth. 1998;45(1):60-62.
What is the new guidance regarding palivizumab (Synagis®) administration for respiratory syncytial virus?
What is the new guidance regarding palivizumab (Synagis®) administration for respiratory syncytial virus?
Palivizumab (Synagis®) is a monoclonal antibody indicated for the prevention of serious lower respiratory tract infection caused by respiratory syncytial virus (RSV) in children at high risk of disease.1 Palivizumab was Food and Drug Administration (FDA)-approved in June 1998. 2 Since its introduction, the American Academy of Pediatrics (AAP) has developed guidance on the appropriate use of palivizumab on 4 separate occasions. The most recent guidance document was published in August 2014. Input on the final document was received from various committees, councils, and advisory groups within AAP as well as from external organizations such as the American College of Chest Physicians, American Thoracic Society, National Association of Neonatal Nurses, and Society of Hospital Medicine, among others.
Overall, the AAP Committee on Infectious Diseases and Bronchiolitis concluded that the benefits of palivizumab administration are “limited”.2 After a review of efficacy and safety data, the AAP stated that palivizumab is associated with no measurable mortality effect, a limited effect on RSV hospitalizations on a population basis, and a minimal effect on wheezing. As such, the AAP Committee recommends restriction of palivizumab use to certain populations as summarized in Table 1.
Table 1. AAP Recommendations for palivizumab use.2
- Prophylactic administration of palivizumab is recommended during the first year of life for infants born before 29 weeks, 0 days’ gestation and not recommended for otherwise healthy infants born at or after 29 weeks, 0 days’ gestation.
- For preterm infants with chronic lung disease of prematurity (i.e., birth at < 32 weeks, 0 days’ gestation and requiring > 21% oxygen for a minimum of 28 days after birth), prophylactic administration of palivizumab is recommended during the first year of life.
- Palivizumab administration may be considered for certain infants with hemodynamically significant heart disease during the first year of life.
- For infants who qualify for palivizumab prophylaxis during the first year of life, healthcare providers may administer up to 5 monthly doses (15 mg/kg/dose) during RSV season; qualifying infants born during RSV season, which typically commences in November and lasts through April, may be administered fewer doses.
- For children in the second year of life, prophylactic administration of palivizumab is not recommended unless the child required at least 28 days of supplemental oxygen after birth and continues to require medical intervention such as supplemental oxygen, corticosteroids, or diuretics.
- For children who experience a breakthrough RSV hospitalization, monthly prophylactic palivizumab should be discontinued.
- For those children with conditions that negatively impact the body’s ability to clear secretions from the upper airways (i.e., pulmonary abnormalities or neuromuscular disease), prophylactic palivizumab may be considered during the first year of life.
- Prophylactic administration of palivizumab may be considered in children < 24 months of age who are severely immunocompromised during RSV season.
- There are insufficient data to recommend the prophylactic administration of palivizumab to children with Down syndrome or cystic fibrosis.
- Broader administration of palivizumab may be acceptable in Alaska Native and select American Indian populations due to RSV disease burden and transport costs.
- Prophylactic administration of palivizumab is not recommended for prevention of healthcare-associated RSV disease.
Abbreviations: RSV, respiratory syncytial virus.
Response to Guidance
Clinicians who follow the recommendations within the new AAP guidance should experience a reduction in palivizumab prescribing, as fewer neonatal patients are deemed to benefit from therapy. Historically, the AAP has recommended less usage of palivizumab with publication of each new guidance document, which has led to a significant reduction in palivizumab sales. The current recommendations have resulted in AstraZeneca, the manufacturer of palivizumab, responding with a newspaper advertising campaign which states that the new guidance “will leave approximately 140,000 babies unprotected” from the effects of RSV.3,4 In addition, AstraZeneca has developed a website (www.rsvfacts.com) that provides an overview of palivizumab data, costs of severe RSV disease, and purported issues with the 2014 guidance document.5
Palivizumab is FDA-approved for the prevention of serious respiratory infections associated with RSV in high-risk children. Since approval, the AAP Committee on Infectious Diseases and Bronchiolitis has intermittently reviewed the efficacy and safety data regarding palivizumab and published recommendations for use. The most recently published AAP guidance concluded that there are limited benefits associated with palivizumab administration and recommended further scaling back usage.
1. Synagis [package insert]. Gaithersburg, MD: MedImmune, LLC; 2014.
2. Committee on Infectious Diseases and Bronchiolitis Guidelines Committee. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics. 2014;134(2):415-420.
3. AstraZeneca battles pediatrician group over preemie drug guidelines. Wall Street Journal Pharmalot. http://blogs.wsj.com/pharmalot/2014/07/28/astrazeneca-battles-pediatrician-group-over-preemie-drug-guidelines/ . Accessed August 7, 2014.
4. Why put these babies at risk? MedImmune. Specialty care division of AstraZeneca. http://freepdfhosting.com/1e5068819c.pdf. Accessed August 7, 2014.
5. The RSV facts. MedImmune. Specialty care division of AstraZeneca. http://www.rsvfacts.com/. Accessed August 7, 2014.