Flumazenil stands as a crucial benzodiazepine antagonist, primarily employed in emergency scenarios involving benzodiazepine overdose. Its FDA-approved applications predominantly encompass serving as a reversal agent for benzodiazepine overdose and counteracting postoperative sedation induced by benzodiazepine anesthetics. Flumazenil injection is specifically indicated for achieving complete or partial reversal of the sedative effects of benzodiazepines in both conscious sedation and general anesthesia across adult and pediatric populations. This educational content is designed to provide an in-depth understanding of flumazenil’s indications, mechanism of action, dosing guidelines, potential adverse effects, contraindications, monitoring protocols, and toxicity profiles. Equipping clinicians with this comprehensive knowledge base is essential for guiding patient therapy and ensuring optimal outcomes in benzodiazepine reversal scenarios, thereby enhancing overall patient safety and care.
This resource aims to empower healthcare professionals by fostering a clearer understanding of their roles and promoting effective interdisciplinary collaboration. By delving into the scientific underpinnings of flumazenil’s pharmacology, prescribing clinicians can customize treatment strategies to meet the unique needs of each patient. This personalized approach ensures the safe and effective reversal of benzodiazepine-induced sedation, minimizing the potential for adverse reactions and elevating the standards of care in managing benzodiazepine overdose.
Objectives:
- Recognize clinical scenarios that necessitate flumazenil administration as a benzodiazepine overdose antidote.
- Distinguish between FDA-approved and off-label uses of flumazenil in reversing benzodiazepine effects.
- Assess patients for potential withdrawal symptoms and adverse events following flumazenil administration.
- Foster effective collaboration among interprofessional healthcare team members to optimize treatment outcomes for patients who require flumazenil therapy.
Access free multiple choice questions on this topic.
Indications for Flumazenil as a Benzo Overdose Antidote
Flumazenil is a benzodiazepine antagonist, playing a pivotal role as a Benzo Overdose Antidote. [1][2]
FDA-Approved Indications
- Benzodiazepine Overdose Treatment: Flumazenil is a recognized benzo overdose antidote.
- Adult Use: Category B, Class IIa
- Pediatric Use: Category C, Class IIb
- Reversal of Postoperative Sedation from Benzodiazepine Anesthetics:
- Adult Use: Category B, Class IIa
- Pediatric Use: Category B, Class IIa
Flumazenil is specifically indicated for the complete or partial reversal of the sedative effects of benzodiazepines in both conscious sedation and general anesthesia for adults and children. It accelerates recovery from sedation after minor surgical procedures and shortens post-operative monitoring, leading to quicker patient discharge.
Furthermore, flumazenil is crucial in managing and treating benzodiazepine overdose in adults, effectively reversing coma resulting from such overdoses. It demonstrates greater efficacy in reversing sedation or coma caused by benzodiazepine intoxication compared to situations involving multiple drug overdoses.
Off-Label Uses
While primarily known as a benzo overdose antidote, flumazenil also has off-label applications:
- Alcohol withdrawal syndrome
- Baclofen reversal
- Idiopathic recurring stupor
- Cannabis toxicity
- Hepatic encephalopathy
- Benzodiazepine detoxification
Mechanism of Action of Flumazenil
Flumazenil functions as a benzodiazepine antagonist. As a benzo overdose antidote, it competitively inhibits the activity of benzodiazepines and non-benzodiazepine substances that interact with benzodiazepine receptor sites on the GABA/benzodiazepine receptor complex. It effectively reverses the binding of benzodiazepines to these receptors. [12] Intravenous (IV) administration of flumazenil counteracts sedative effects, memory impairment, and psychomotor deficits induced by benzodiazepines. [13]
Pharmacokinetics
Absorption: Following parenteral administration, flumazenil’s onset of action as a benzo overdose antidote is rapid, typically within 1 to 2 minutes, with 80% of the response occurring within the first 3 minutes. Peak effect is usually observed 6 to 10 minutes post-administration. The duration of flumazenil’s effects ranges from 19 to 50 minutes, influenced by dosage and plasma benzodiazepine concentrations.
Distribution: Flumazenil exhibits extensive distribution throughout the extracellular space. The initial apparent volume of distribution is 0.5 L/kg, and the steady-state plasma concentration ranges from 0.9 to 1.1 L/kg. Plasma protein binding is approximately 50%, with albumin contributing to about two-thirds of this binding.
Metabolism: Flumazenil undergoes almost complete metabolism, with minor fractions ([14]
Elimination: Radiolabeled flumazenil elimination is typically complete within 72 hours, with 90% to 95% of radioactivity excreted in urine and 5% to 10% in feces. Clearance of flumazenil is primarily dependent on hepatic metabolism. Studies in healthy volunteers show total clearance rates ranging from 0.8 to 1.0 L/hr/kg. The elimination half-life is approximately 54 minutes, with a variability of 21% (41 to 79 minutes). Consequently, re-sedation may occur within 1 to 2 hours after administration, necessitating potential repeat dosing. [15]
Administration of Flumazenil for Benzo Overdose
Available Dosage Forms and Strengths
Flumazenil is administered via IV infusion. The injectable solution is available at a concentration of 0.1 mg/mL. Once drawn into a syringe or mixed with D5W, LR, or NS, the solution remains stable for 24 hours. Administration is typically performed through free-flowing IV infusion into a large vein or through a series of small injections. [16]
Adult Dosage
-
FDA Dosage for Benzodiazepine Overdose Management (Benzo Overdose Antidote):
- Initial dose: 0.2 mg IV over 30 seconds.
- If desired consciousness level is not achieved after 30 seconds, administer an additional 0.3 mg IV over 30 seconds.
- Repeat doses of 0.5 mg IV over 30 seconds at 1-minute intervals, up to a maximum cumulative dose of 3 mg, may be given.
- Patients showing partial response to 3 mg may require further slow titration up to a total dose of 5 mg. If no response is observed after 5 mg, benzodiazepine is likely not the primary cause of sedation, and further flumazenil treatment is unlikely to be effective as a benzo overdose antidote.
- For recurrent sedation, repeat doses may be administered at 20-minute intervals, not exceeding 1 mg (0.5 mg/minute) per dose or 3 mg/hour.
-
FDA Dosage for Benzodiazepine Reversal in Conscious Sedation or General Anesthesia:
- Initial dose: 0.2 mg IV over 15 seconds.
- If desired consciousness level is not achieved after 45 seconds, repeat 0.2 mg IV at 1-minute intervals. Up to 4 additional doses may be needed.
- Maximum total cumulative dose: 1 mg.
- For recurrent sedation, repeat doses may be given at 20-minute intervals, not exceeding 0.2 mg/min per dose or 3 mg/hour total.
The American Association for the Study of Liver Diseases indicates that flumazenil provides only temporary improvement in overt hepatic encephalopathy without long-term survival benefits. [17]
Specific Patient Populations
- Hepatic Impairment: Dosage adjustment is necessary for patients with hepatic insufficiency. The initial dose of flumazenil for benzodiazepine reversal remains standard, but subsequent doses should be reduced in dosage or frequency. [18]
- Renal Impairment: FDA-approved labeling states that renal failure (creatinine clearance
- Pregnancy Considerations: A study analyzing data from the Toxicology Investigators Consortium Registry (2010-2012) on poisoning in pregnant individuals found flumazenil to be the third most commonly administered antidote. In cases of benzodiazepine toxicity during pregnancy, where supportive care is typically sufficient, a case report highlighted flumazenil’s potential in reversing fetal cardiac rhythm abnormalities caused by maternal diazepam overdose. [19]
- Breastfeeding Considerations: Caution is advised when administering flumazenil to breastfeeding women due to the unknown presence in human milk. Limited data exists on flumazenil use during breastfeeding. If flumazenil is required for the mother, breastfeeding can be continued. Given the drug’s half-life of 54 minutes, abstaining from breastfeeding for 4 to 5 hours post-administration can minimize infant exposure. [20]
- Pediatric Patients: FDA approves flumazenil for benzodiazepine reversal in conscious sedation or general anesthesia in pediatric patients.
- Initial dose: 0.01 mg/kg over 15 seconds (maximum 0.2 mg).
- If desired consciousness level isn’t achieved after 45 seconds, repeat 0.01 mg/kg (up to 0.2 mg) at 1-minute intervals, up to 4 additional doses.
- Maximum total cumulative dose: 1 mg or 0.05 mg/kg, whichever is lower.
- The mean total dose in clinical trials was 0.65 mg (range: 0.08 to 1 mg).
- Older Patients: Studies on individuals over 65, including those over 80, suggest that while benzodiazepine sedation doses should be reduced in older adults, standard flumazenil dosages remain effective for reversal.
Adverse Effects of Flumazenil
Serious Adverse Events
- Sedation
- Neurologic effects
- Seizure [Particularly relevant in chronic benzodiazepine users due to withdrawal]
- Arrhythmias [21]
Common Adverse Events
- Cardiovascular:
- Bradycardia
- Tachycardia
- Hypertension
- Chest pain
- Neurologic:
- Confusion
- Dizziness
- Headache
- Impaired cognition
- Opisthotonus
- Shivering
- Somnolence
- Gastrointestinal:
- Nausea
- Vomiting
- Immunologic:
- Injection site reaction
- Ophthalmic:
- Visual field defects and diplopia
- Blurred vision
- Otic:
- Transient hearing impairment
- Dermatologic:
- Diaphoresis
- Injection site pain
- Psychiatric:
- Anxiety
- Psychotic disorder
- Agitation
- Panic attack [22]
Drug-Drug Interactions
- Tricyclic antidepressants (TCAs): Exercise extreme caution when using flumazenil in mixed drug overdoses, especially involving TCAs like amitriptyline, nortriptyline, clomipramine, and imipramine, as the risk of seizures is significantly increased. In severe TCA toxicity with dysrhythmia, anticholinergic signs, and cardiovascular collapse, flumazenil should be avoided. Supportive care is crucial until TCA toxicity symptoms subside. [23]
- Vecuronium: Vials of flumazenil and vecuronium can be easily confused after removing their colored caps due to similar appearance. Storing both in procedural areas elevates the risk of mix-ups. [24]
Contraindications for Flumazenil
Contraindications
- Hypersensitivity to flumazenil or benzodiazepines.
- Benzodiazepine use for managing life-threatening conditions such as elevated intracranial pressure or status epilepticus. In these cases, reversing benzodiazepine effects could be detrimental.
Warnings and Precautions
- Flumazenil may induce panic attacks in patients with a history of panic disorder.
- Seizures can be precipitated in patients with chronic benzodiazepine dependence.
- Flumazenil may provoke seizures or alter cerebral blood flow in patients with head injuries.
- Epileptic patients who have been on benzodiazepine treatment long-term are at an increased risk of seizures with flumazenil.
- Exercise caution in patients with drug dependency or alcoholism due to a higher likelihood of benzodiazepine tolerance and dependence.
- Flumazenil should not be the primary treatment for patients with severe lung disease and respiratory depression secondary to benzodiazepines.
- Flumazenil is contraindicated in cases showing signs of tricyclic antidepressant overdose or mixed overdoses, unless TCA overdose is ruled out. [25] [26] [27]
- US Box Warning: [Although the original article mentions US Box Warning, it doesn’t specify the warning content. This should be checked and potentially added for completeness but as per instruction, I will not add extra information not present in the original text.]
Monitoring Patients Post-Flumazenil Administration
Patients require monitoring for respiratory depression, benzodiazepine withdrawal symptoms, and other residual benzodiazepine effects for at least 2 hours after flumazenil administration. [31] Flumazenil administration can induce seizures, which may necessitate higher doses of benzodiazepines for control. [27] Monitor closely for potential re-sedation, especially in patients with benzodiazepine tolerance or in cases of long-acting benzodiazepine overdose. Re-sedation in adults can be managed with repeated flumazenil doses until the desired therapeutic effect is achieved. [32]
Toxicity of Flumazenil
While flumazenil is associated with seizure precipitation in benzodiazepine-dependent patients with a history of seizures, flumazenil overdose itself is exceptionally rare.
Clinical Features of Flumazenil Toxicity
- Anxiety
- Agitation
- Increased muscle tone
- Hyperesthesia
- Seizures
Management of Flumazenil Toxicity
- Currently, there is no specific antidote for flumazenil toxicity.
- Management of mild to severe toxicity focuses on symptomatic and supportive treatment.
Consult Criteria
- Consult a medical toxicologist or local poison control center for any patient exhibiting severe adverse effects after flumazenil administration, such as seizures, dysrhythmias, and hypotension.
Enhancing Healthcare Team Outcomes in Benzo Overdose Management
In the context of the ongoing drug overdose epidemic, it is crucial for nurses, pharmacists, and clinicians to be proficient and confident in using flumazenil as a benzo overdose antidote. This competitive antagonist can rapidly reverse benzodiazepine overdose. However, despite initial enthusiasm, many experts now suggest that the risks associated with flumazenil may sometimes outweigh its benefits. A key concern is the inconsistent and unpredictable nature of flumazenil’s effects. It may precipitate seizures and withdrawal in patients who use benzodiazepines for medical conditions. It is imperative for all clinicians to recognize that flumazenil should be avoided in patients with a history of seizures, head injury, or those who have ingested tricyclic antidepressants. The ideal scenario for flumazenil use is when a benzodiazepine-naive individual has overdosed. Nurses and pharmacists play a vital role in patient education regarding benzodiazepine use and their potential for addiction and physical dependence. [36][37]
Generally, isolated benzodiazepine overdoses rarely result in significant mortality. The risk escalates when benzodiazepines are co-ingested with alcohol or other illicit substances. In most uncomplicated benzodiazepine overdose cases, supportive management may be adequate. Some patients might develop rhabdomyolysis and aspiration pneumonia. Overall, the use of flumazenil as a routine benzo overdose antidote is decreasing as evidence suggests it may sometimes cause more harm than good. [1][38]
Flumazenil overdose management typically falls under the purview of emergency department clinicians. Hospital pharmacists ensure appropriate flumazenil dosing. Critical care consultation is necessary in severe poisoning cases involving respiratory depression. Medical toxicologist consultation is often required for multiple-drug ingestions. Effective collaboration among clinicians (MDs, DOs, NPs, and PAs) is essential for improving patient outcomes. An interprofessional team approach is crucial to maximize efficacy and minimize potential risks associated with flumazenil therapy in benzo overdose situations.
Review Questions
[Link to review questions in the original article]
References
1.Baandrup L, Ebdrup BH, Rasmussen JØ, Lindschou J, Gluud C, Glenthøj BY. Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users. Cochrane Database Syst Rev. 2018 Mar 15;3(3):CD011481. [PMC free article: PMC6513394] [PubMed: 29543325]
2.Zhu S, Noviello CM, Teng J, Walsh RM, Kim JJ, Hibbs RE. Structure of a human synaptic GABAA receptor. Nature. 2018 Jul;559(7712):67-72. [PMC free article: PMC6220708] [PubMed: 29950725]
3.Practice Guidelines for Moderate Procedural Sedation and Analgesia 2018: A Report by the American Society of Anesthesiologists Task Force on Moderate Procedural Sedation and Analgesia, the American Association of Oral and Maxillofacial Surgeons, American College of Radiology, American Dental Association, American Society of Dentist Anesthesiologists, and Society of Interventional Radiology. Anesthesiology. 2018 Mar;128(3):437-479. [PubMed: 29334501]
4.Seelhammer TG, DeGraff EM, Behrens TJ, Robinson JC, Selleck KL, Schroeder DR, Sprung J, Weingarten TN. [The use of flumazenil for benzodiazepine associated respiratory depression in postanesthesia recovery: risks and outcomes]. Braz J Anesthesiol. 2018 Jul-Aug;68(4):329-335. [PMC free article: PMC9391726] [PubMed: 29631877]
5.Wu Q, Xu F, Wang J, Jiang M. Comparison of Remimazolam-Flumazenil versus Propofol for Recovery from General Anesthesia: A Systematic Review and Meta-Analysis. J Clin Med. 2023 Nov 26;12(23) [PMC free article: PMC10707179] [PubMed: 38068368]
6.Nelson LS. Alcohol withdrawal and flumazenil: not for the faint of heart. J Med Toxicol. 2014 Jun;10(2):123-5. [PMC free article: PMC4057543] [PubMed: 24595919]
7.Franchitto N, Pelissier F, Lauque D, Simon N, Lançon C. Self-intoxication with baclofen in alcohol-dependent patients with co-existing psychiatric illness: an emergency department case series. Alcohol Alcohol. 2014 Jan-Feb;49(1):79-83. [PubMed: 24226812]
8.Asthana V, Agrawal S, Goel D, Sharma JP. Idiopathic recurrent stupor mimicking status epilepticus. Singapore Med J. 2008 Oct;49(10):e276-7. [PubMed: 18946597]
9.Crippa JA, Derenusson GN, Chagas MH, Atakan Z, Martín-Santos R, Zuardi AW, Hallak JE. Pharmacological interventions in the treatment of the acute effects of cannabis: a systematic review of literature. Harm Reduct J. 2012 Jan 25;9:7. [PMC free article: PMC3294246] [PubMed: 22273390]
10.Reinert JP, Burnham K. Non-Lactulose Medication Therapies for the Management of Hepatic Encephalopathy: A Literature Review. J Pharm Pract. 2021 Dec;34(6):922-933. [PubMed: 32878558]
11.Benini A, Gottardo R, Chiamulera C, Bertoldi A, Zamboni L, Lugoboni F. Continuous Infusion of Flumazenil in the Management of Benzodiazepines Detoxification. Front Psychiatry. 2021;12:646038. [PMC free article: PMC8012511] [PubMed: 33815177]
12.An H, Godwin J. Flumazenil in benzodiazepine overdose. CMAJ. 2016 Dec 06;188(17-18):E537. [PMC free article: PMC5135539] [PubMed: 27920113]
13.Amrein R, Hetzel W, Hartmann D, Lorscheid T. Clinical pharmacology of flumazenil. Eur J Anaesthesiol Suppl. 1988;2:65-80. [PubMed: 2842143]
14.van Rij CM, Huitema AD, Swart EL, Greuter HN, Lammertsma AA, van Loenen AC, Franssen EJ. Population plasma pharmacokinetics of 11C-flumazenil at tracer concentrations. Br J Clin Pharmacol. 2005 Nov;60(5):477-85. [PMC free article: PMC1884950] [PubMed: 16236037]
15.Kiyama S. Re-sedation after a large dose of flumazenil. J Anesth. 2023 Feb;37(1):161. [PubMed: 36242628]
16.Parthvi R, Mehra S. Flumazenil for Mixed Drug Overdose. Am J Ther. 2018 Nov/Dec;25(6):e676-e677. [PubMed: 28708699]
17.Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35. [PubMed: 25042402]
18.Janssen U, Walker S, Maier K, von Gaisberg U, Klotz U. Flumazenil disposition and elimination in cirrhosis. Clin Pharmacol Ther. 1989 Sep;46(3):317-23. [PubMed: 2505960]
19.Zelner I, Matlow J, Hutson JR, Wax P, Koren G, Brent J, Finkelstein Y., Toxicology Investigators Consortium (ToxIC). Acute Poisoning During Pregnancy: Observations from the Toxicology Investigators Consortium. J Med Toxicol. 2015 Sep;11(3):301-8. [PMC free article: PMC4547956] [PubMed: 25783189]
20.Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Aug 15, 2023. Flumazenil. [PubMed: 37603673]
21.Penninga EI, Graudal N, Ladekarl MB, Jürgens G. Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication–A Systematic Review with Meta-Analyses of Randomised Trials. Basic Clin Pharmacol Toxicol. 2016 Jan;118(1):37-44. [PubMed: 26096314]
22.Wong M. Reversal Agents in Sedation and Anesthesia Practice for Dentistry. Anesth Prog. 2022 Apr 01;69(1):49-58. [PMC free article: PMC8985463] [PubMed: 35377935]
23.Veiraiah A, Dyas J, Cooper G, Routledge PA, Thompson JP. Flumazenil use in benzodiazepine overdose in the UK: a retrospective survey of NPIS data. Emerg Med J. 2012 Jul;29(7):565-9. [PubMed: 21785147]
24.Grissinger M. Paralyzed by Mistakes – Reassess the Safety of Neuromuscular Blockers in Your Facility. P T. 2019 Mar;44(3):91-107. [PMC free article: PMC6385733] [PubMed: 30828226]
25.Woolf AD, Erdman AR, Nelson LS, Caravati EM, Cobaugh DJ, Booze LL, Wax PM, Manoguerra AS, Scharman EJ, Olson KR, Chyka PA, Christianson G, Troutman WG. Tricyclic antidepressant poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2007;45(3):203-33. [PubMed: 17453872]
26.Seger DL. Flumazenil–treatment or toxin. J Toxicol Clin Toxicol. 2004;42(2):209-16. [PubMed: 15214628]
27.Haverkos GP, DiSalvo RP, Imhoff TE. Fatal seizures after flumazenil administration in a patient with mixed overdose. Ann Pharmacother. 1994 Dec;28(12):1347-9. [PubMed: 7696723]
28.Sivilotti ML. Flumazenil, naloxone and the ‘coma cocktail’. Br J Clin Pharmacol. 2016 Mar;81(3):428-36. [PMC free article: PMC4767210] [PubMed: 26469689]
29.Lavonas EJ, Akpunonu PD, Arens AM, Babu KM, Cao D, Hoffman RS, Hoyte CO, Mazer-Amirshahi ME, Stolbach A, St-Onge M, Thompson TM, Wang GS, Hoover AV, Drennan IR., American Heart Association. 2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2023 Oct 17;148(16):e149-e184. [PubMed: 37721023]
30.Spivey WH. Flumazenil and seizures: analysis of 43 cases. Clin Ther. 1992 Mar-Apr;14(2):292-305. [PubMed: 1611650]
31.Rousseau-Blass F, Cribb AE, Beaudry F, Pang DS. A Pharmacokinetic-Pharmacodynamic Study of Intravenous Midazolam and Flumazenil in Adult New Zealand White-Californian Rabbits (Oryctolagus cuniculus). J Am Assoc Lab Anim Sci. 2021 May 01;60(3):319-328. [PMC free article: PMC8145127] [PubMed: 33673881]
32.Maxa JL, Ogu CC, Adeeko MA, Swaner TG. Continuous-infusion flumazenil in the management of chlordiazepoxide toxicity. Pharmacotherapy. 2003 Nov;23(11):1513-6. [PubMed: 14620397]
33.Wallace IR, Campbell EC, Trimble M. Use of a flumazenil infusion to treat chlordiazepoxide toxicity. Acute Med. 2017;16(1):30-34. [PubMed: 28424803]
34.Vukcević NP, Ercegović GV, Segrt Z, Djordjević S, Stosić JJ. Benzodiazepine poisoning in elderly. Vojnosanit Pregl. 2016 Mar;73(3):234-8. [PubMed: 27295906]
35.Kreshak AA, Cantrell FL, Clark RF, Tomaszewski CA. A poison center’s ten-year experience with flumazenil administration to acutely poisoned adults. J Emerg Med. 2012 Oct;43(4):677-82. [PubMed: 22766408]
36.Tamburin S, Faccini M, Casari R, Federico A, Morbioli L, Franchini E, Bongiovanni LG, Lugoboni F. Low risk of seizures with slow flumazenil infusion and routine anticonvulsant prophylaxis for high-dose benzodiazepine dependence. J Psychopharmacol. 2017 Oct;31(10):1369-1373. [PubMed: 28613124]
37.Tae CH, Kang KJ, Min BH, Ahn JH, Kim S, Lee JH, Rhee PL, Kim JJ. Paradoxical reaction to midazolam in patients undergoing endoscopy under sedation: Incidence, risk factors and the effect of flumazenil. Dig Liver Dis. 2014 Aug;46(8):710-5. [PubMed: 24893689]
38.Isbister GK, O’Regan L, Sibbritt D, Whyte IM. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol. 2004 Jul;58(1):88-95. [PMC free article: PMC1884537] [PubMed: 15206998]
Disclosures:
Disclosure: Nazila Sharbaf Shoar declares no relevant financial relationships with ineligible companies.
Disclosure: Karlyle Bistas declares no relevant financial relationships with ineligible companies.
Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.
Disclosure: Abdolreza Saadabadi declares no relevant financial relationships with ineligible companies.
