Methemoglobin Levels in Generally Anesthetized Pediatric Dental Patients Receiving Local Anesthetics

• ClinicalTrials.gov Identifier: NCT01402869
• Recruitment Status: Completed
• First Posted: July 26, 2011
• Results First Posted: April 25, 2014
• Last Update Posted: April 25, 2014
• Sponsor: Loma Linda University
• Information provided by (Responsible Party): Lauren GutenBerg, Loma Linda University

Study Description

Brief Summary:

To establish and compare maximum methemoglobin blood levels and times to maximum methemoglobin blood levels following the administration of the injectable local anesthetics prilocaine and lidocaine when used for dental treatment in pediatric patients under general anesthesia. Patients will be randomized into three equal study groups. Two of the study groups will receive local anesthetic and the third group will not. Methemoglobin blood levels will be non-invasively monitored and recorded throughout dental treatment for all groups using a Masimo Radical-7 Pulse Co-Oximeter device.

Condition or disease	Intervention/treatment	Phase
Methemoglobinemia	Drug: 4% prilocaine plain; Drug: 2% Lidocaine with 1:100,000 epinephrine	Not Applicable

Detailed Description:

Methemoglobin is an abnormal hemoglobin that is formed by the oxidation of one or more of the four heme groups of hemoglobin by oxygen and other exogenous oxidizing agents. The injectable local anesthetic prilocaine that is routinely used in the medical and dental professions is a well known inducer of methemoglobin. The injectable local anesthetic lidocaine has also been suggested to be associated with the development of methemoglobin; however, there is no direct evidence supporting these claims.

The concern with methemoglobin is that it is a dose-dependent toxin. The oxidation of one of the iron groups from a ferrous state to a ferric state alters the molecular structure of the hemoglobin molecule and impairs its ability to bind oxygen. This ultimately results in less oxygen being delivered to peripheral tissues and less carbon dioxide being removed which can cause tissue hypoxia. A small amount (0-2%) of methemoglobin is normally present in the blood as a result of the oxidation of hemoglobin by the prototypical oxidant oxygen. However, when an individual is exposed to an exogenous oxidizing agent of sufficient dosage and potency, methemoglobin levels can rise above 2% and a person can develop what is known as acquired methemoglobinemia. Signs of cyanosis as a result of acquired methemoglobinemia usually become present when methemoglobin blood levels rise above 15%.

Despite the injectable local anesthetic prilocaine being a well known inducer of methemoglobin and lidocaine being a speculated inducer, there are no documented studies or trials in the dental literature as to the extent of the amount of methemoglobin that is formed following the routine use of these injectable local anesthetics.

This investigation will examine the peak blood levels of methemoglobin and the time to the peak levels of methemoglobin following the use of injectable prilocaine and lidocaine when used for dental treatment in pediatric patients under general anesthesia.

This study population will consist of 90 patients, 3 to 6 years of age, scheduled to undergo comprehensive dental rehabilitation under general anesthesia at the Koppel Special Care Dentistry Center at Loma Linda University School of Dentistry. Following enrollment, subjects will be randomized into three equal study groups: 1) 4% prilocaine plain, 2) 2% lidocaine with 1:100,000 epinephrine, and 3) No local anesthetic. All subjects will have a Masimo Radical-7 pediatric, non-disposable, pulse co-oximeter sensor placed on the ring finger of the right hand following the induction of general anesthesia. The sensor will then be connected to a Radical-7 Pulse Co-Oximeter. The pulse co-oximeter will non-invasively monitor and record methemoglobin blood levels at 10 second intervals throughout dental treatment. Following a routine oral examination, radiographs, and prophylaxis, subjects assigned to Groups 1 and 2 will be administered local anesthetic for restorative dental treatment. Group 1 subjects will receive 5mg/kg of 4% prilocaine plain and Group 2 subjects will receive 2.5mg/kg of 2% lidocaine with 1:100,000 epinephrine. Group 3 subjects will not receive local anesthetic. The time of local anesthetic administration and baseline methemoglobin blood levels will be recorded. Methemoglobin blood levels will be monitored and recorded throughout the completion of the dental treatment and during recovery from general anesthesia until subject movement precludes any further monitoring.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 91 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Official Title: Methemoglobin Levels in Generally Anesthetized Pediatric Dental Patients Receiving Prilocaine Versus Lidocaine
• Study Start Date: August 2011
• Actual Primary Completion Date: July 2012
• Actual Study Completion Date: July 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: Prilocaine; 30 subjects will receive 5mg/kg of 4% prilocaine plain local anesthetic for restorative dental treatment under general anesthesia	Drug: 4% prilocaine plain; 5mg/kg via infiltration into multiple sites of the buccal mucosa of mouth 1 time prior to start of restorative dental treatment; Other Name: Citanest Plain
Experimental: Lidocaine; 30 subjects will receive 2.5mg/kg of 2% lidocaine with 1:100,000 epinephrine local anesthetic for restorative dental treatment under general anesthesia	Drug: 2% Lidocaine with 1:100,000 epinephrine; 2.5mg/kg via infiltration into multiple sites of buccal mucosa of mouth 1 time prior to restorative dental treatment; Other Name: Xylocaine
No Intervention: No local anesthetic; 30 subjects will not receive local anesthetic for dental treatment under general anesthesia-Negative control

Outcome Measures

Primary Outcome Measures :

1. Peak Methemoglobin Blood Levels [ Time Frame: Measured at 10 second intervals during dental treatment for an average of 2 hours ]
   The maximum percentage of methemoglobin in blood

Secondary Outcome Measures :

1. Time to Peak Methemoglobin Blood Levels [ Time Frame: Measured at 10 second intervals during dental treatment for an average of 2 hours ]
   The length of time between the administration of local anesthetic (Prilocaine and Lidocaine Groups) or start of restorative dental procedures (No local anesthetic Group) and the time at which the maximum methemoglobin blood level is observed.
2. Delta Methemoglobin Blood Level [ Time Frame: From administration of local anesthetic or start of restorative procedures to time at which maximum methemoglobin blood level was documented during dental treatment for an average of 2 hours ]
   Change in percentage of methemoglobin in blood from baseline level to peak level

Eligibility Criteria

• Ages Eligible for Study: 3 Years to 5 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Patient scheduled to undergo comprehensive dental treatment under general anesthesia at the Koppel Special Care Dentistry Center at Loma Linda University School of Dentistry
• ASA I or II health status
• Age greater than 3 years but less than 6 years
• Weigh between 10kg and 25kg

Exclusion Criteria:

• Patient not requiring restorative dental treatment
• Have a BMI less than the 5th percentile or greater than the 95th percentile for their age and gender

Contacts and Locations

Locations

United States, California

Loma Linda University School of Dentistry Koppel Special Care Dentistry Center

Loma Linda, California, United States, 92350

Sponsors and Collaborators

Loma Linda University

Investigators

• Study Director: Lauren L Gutenberg, DDS; Loma Linda University Department of Pediatric Dentistry
• Principal Investigator: Jung-Wei Chen, DDS, MS, PhD; Loma Linda University Department of Pediatric Dentistry

More Information

Publications:

Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med. 1999 Nov;34(5):646-56. doi: 10.1016/s0196-0644(99)70167-8.

Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore). 2004 Sep;83(5):265-273. doi: 10.1097/01.md.0000141096.00377.3f.

Umbreit J. Methemoglobin--it's not just blue: a concise review. Am J Hematol. 2007 Feb;82(2):134-44. doi: 10.1002/ajh.20738.

Trapp L, Will J. Acquired methemoglobinemia revisited. Dent Clin North Am. 2010 Oct;54(4):665-75. doi: 10.1016/j.cden.2010.06.007. Epub 2010 Aug 7.

Malamed SF. Local anesthetics: dentistry's most important drugs, clinical update 2006. J Calif Dent Assoc. 2006 Dec;34(12):971-6.

Budenz AW. Local anesthetics in dentistry: then and now. J Calif Dent Assoc. 2003 May;31(5):388-96.

Moore PA, Hersh EV. Local anesthetics: pharmacology and toxicity. Dent Clin North Am. 2010 Oct;54(4):587-99. doi: 10.1016/j.cden.2010.06.015.

Bader AM, Concepcion M, Hurley RJ, Arthur GR. Comparison of lidocaine and prilocaine for intravenous regional anesthesia. Anesthesiology. 1988 Sep;69(3):409-12. doi: 10.1097/00000542-198809000-00022. No abstract available.

Vasters FG, Eberhart LH, Koch T, Kranke P, Wulf H, Morin AM. Risk factors for prilocaine-induced methaemoglobinaemia following peripheral regional anaesthesia. Eur J Anaesthesiol. 2006 Sep;23(9):760-5. doi: 10.1017/S0265021506000913. Epub 2006 May 24.

Soeding P, Deppe M, Gehring H. Pulse-oximetric measurement of prilocaine-induced methemoglobinemia in regional anesthesia. Anesth Analg. 2010 Oct;111(4):1065-8. doi: 10.1213/ANE.0b013e3181eb6239. Epub 2010 Aug 12.

Wilburn-Goo D, Lloyd LM. When patients become cyanotic: acquired methemoglobinemia. J Am Dent Assoc. 1999 Jun;130(6):826-31. doi: 10.14219/jada.archive.1999.0306.

Guay J. Methemoglobinemia related to local anesthetics: a summary of 242 episodes. Anesth Analg. 2009 Mar;108(3):837-45. doi: 10.1213/ane.0b013e318187c4b1.

Adams V, Marley J, McCarroll C. Prilocaine induced methaemoglobinaemia in a medically compromised patient. Was this an inevitable consequence of the dose administered? Br Dent J. 2007 Nov 24;203(10):585-7. doi: 10.1038/bdj.2007.1045.

American Academy of Pediatric Dentistry. American Academy of Pediatric Dentistry 2010-2011 Definitions, Oral Health Policies, and Clinical Guidelines: Guidelines on use of local anesthetic for pediatric dental patients. Pediatr Dent 2010;32(6):156-61

Yagiela, J. Injectable and topical local anesthetics. In: ADA/PDR guide to dental therapeutics. 5th Edition. Chicago: American Dental Association Publishing Co; 2009 p. 11-2

Herdevall BM, Klinge B, Persson L, Huledal G, Abdel-Rehim M. Plasma levels of lidocaine, o-toluidine, and prilocaine after application of 8.5 g Oraqix in patients with generalized periodontitis: effect on blood methemoglobin and tolerability. Acta Odontol Scand. 2003 Aug;61(4):230-4. doi: 10.1080/00016350310004106.

Barker SJ, Curry J, Redford D, Morgan S. Measurement of carboxyhemoglobin and methemoglobin by pulse oximetry: a human volunteer study. Anesthesiology. 2006 Nov;105(5):892-7. doi: 10.1097/00000542-200611000-00008. Erratum In: Anesthesiology. 2007 Nov;107(5):863.

Feiner JR, Bickler PE. Improved accuracy of methemoglobin detection by pulse CO-oximetry during hypoxia. Anesth Analg. 2010 Nov;111(5):1160-7. doi: 10.1213/ANE.0b013e3181f46da8. Epub 2010 Sep 14.

Feiner JR, Bickler PE, Mannheimer PD. Accuracy of methemoglobin detection by pulse CO-oximetry during hypoxia. Anesth Analg. 2010 Jul;111(1):143-8. doi: 10.1213/ANE.0b013e3181c91bb6. Epub 2009 Dec 10.

Ash-Bernal R, Brophy GM, Kily D. Acquired methemoglobinemia in the clinical setting: an important health issue revealed. CME Zone Special Report 2006 Nov.

Dentsply Pharmaceutical. 4% Citanest Plain Package Insert. York, PA.

• Responsible Party: Lauren GutenBerg, Pediatric Dental Resident, Loma Linda University
• ClinicalTrials.gov Identifier: NCT01402869
• Other Study ID Numbers: 5110172
• First Posted: July 26, 2011
• Results First Posted: April 25, 2014
• Last Update Posted: April 25, 2014
• Last Verified: March 2014

Keywords provided by Lauren GutenBerg, Loma Linda University:

Methemoglobin; Methemoglobinemia; Prilocaine; Lidocaine

Additional relevant MeSH terms:

Methemoglobinemia; Hematologic Diseases; Lidocaine; Epinephrine; Prilocaine; Anesthetics, Local; Anesthetics; Central Nervous System Depressants; Physiological Effects of Drugs; Sensory System Agents; Peripheral Nervous System Agents; Anti-Arrhythmia Agents; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Adrenergic beta-Agonists; Bronchodilator Agents; Autonomic Agents; Anti-Asthmatic Agents; Respiratory System Agents; Mydriatics; Sympathomimetics; Vasoconstrictor Agents