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 Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label)
• Condition: Methemoglobinemia
• Interventions: Drug: 4% prilocaine plain; Drug: 2% Lidocaine with 1:100,000 epinephrine
• Enrollment: 91

Participant Flow

Recruitment Details	Patients that were greater than 3 years but less than 6 years of age that were scheduled to undergo comprehensive dental rehabilitation under general anesthesia at the Koppel Special Care Dentistry Center at Loma Linda University School of Dentistry were recruited for the study.
Pre-assignment Details	Enrolled participants were excluded prior to group assignment if they had a body mass index (BMI) less than the 5th percentile or greater than the 95th percentile for their age and gender.

Arm/Group Title	Prilocaine	Lidocaine	No Local Anesthetic
Arm/Group Description	5mg/kg of 4% prilocaine plain administered via infiltration into multiple sites of the buccal mucosa of the mouth 1 time prior to start of restorative dental treatment	2.5mg/kg of 2% lidocaine with 1:100,000 epinephrine administered via infiltration into multiple sites of the buccal mucosa of the mouth 1 time prior to start of restorative dental treatment	No local anesthetic was administered prior to restorative dental treatment-Negative control
Period Title: Overall Study
Started	30	30	31
Completed	30	30	30
Not Completed	0	0	1
Reason Not Completed
Required Tooth Extraction	0	0	1

Baseline Characteristics

Arm/Group Title		Prilocaine	Lidocaine	No Local Anesthetic	Total
Arm/Group Description		5mg/kg of 4% prilocaine plain administered via infiltration into multiple sites of the buccal mucosa of the mouth 1 time prior to start of restorative dental treatment	2.5mg/kg of 2% lidocaine with 1:100,000 epinephrine administered via infiltration into multiple sites of the buccal mucosa of the mouth 1 time prior to start of restorative dental treatment	No local anesthetic was administered prior to restorative dental treatment-Negative control	Total of all reporting groups
Overall Number of Baseline Participants		30	30	30	90
Baseline Analysis Population Description		1 subject was withdrawn from the no local anesthetic group as the subject required 1 or more dental tooth extractions and required local anesthetic
Age, Continuous; Mean (Standard Deviation); Unit of measure: Months
	Number Analyzed	30 participants	30 participants	30 participants	90 participants
		50.97 (9.84)	50.77 (10.19)	50.63 (8.43)	50.79 (9.41)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants	30 participants	30 participants	90 participants
	Female	19 63.3%	12 40.0%	14 46.7%	45 50.0%
	Male	11 36.7%	18 60.0%	16 53.3%	45 50.0%
Weight Continuous; Mean (Standard Deviation); Unit of measure: Kilograms
	Number Analyzed	30 participants	30 participants	30 participants	90 participants
		17.17 (2.94)	17.24 (2.78)	17.19 (2.96)	17.20 (2.86)
ASA Health Classification; Measure Type: Number; Unit of measure: Participants	Number Analyzed	30 participants	30 participants	30 participants	90 participants
I-Healthy patients; no systemic disease		26	25	24	75
II-Patients with mild, systemic disease		4	5	6	15
Body Mass Index Numerical Value; Mean (Standard Deviation); Unit of measure: Kg/m^2
	Number Analyzed	30 participants	30 participants	30 participants	90 participants
		15.62 (1.12)	15.69 (1.08)	15.60 (1.03)	15.64 (1.07)
Body Mass Index Percentile; Measure Type: Number; Unit of measure: Participants	Number Analyzed	30 participants	30 participants	30 participants	90 participants
>=5th and <=35th percentiles		11	6	6	23
>35th and <=65th percentiles		6	14	12	32
>65th and <=95th percentiles		13	10	12	35
Baseline Methemoglobin Blood Level [1]; Mean (Standard Deviation); Unit of measure: Percentage
	Number Analyzed	30 participants	30 participants	30 participants	90 participants
		0.82 (0.39)	0.85 (0.35)	0.84 (0.43)	0.83 (0.39)
		[1] Measure Description: Methemoglobin blood level recorded non-invasively by the Masimo Radical-7 Pulse Co-Oximeter prior to the administration of local anesthetic or start of restorative dental procedures.

Outcome Measures

1. Primary Outcome

Title	Peak Methemoglobin Blood Levels
Description	The maximum percentage of methemoglobin in blood
Time Frame	Measured at 10 second intervals during dental treatment for an average of 2 hours

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Prilocaine	Lidocaine	No Local Anesthetic
Arm/Group Description:	5mg/kg of 4% prilocaine plain administered via infiltration into multiple sites of the buccal mucosa of the mouth 1 time prior to start of restorative dental treatment	2.5mg/kg of 2% lidocaine with 1:100,000 epinephrine administered via infiltration into multiple sites of the buccal mucosa of the mouth 1 time prior to start of restorative dental treatment	No local anesthetic was administered prior to restorative dental treatment-Negative control
Overall Number of Participants Analyzed	30	30	30
Mean (Standard Deviation); Unit of Measure: percentage of methemoglobin in blood
	3.55 (1.22)	1.63 (0.52)	1.60 (0.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prilocaine, Lidocaine, No Local Anesthetic
	Comments	Null hypothesis: There is no statistically significant difference in peak methemoglobin blood levels following the administration of prilocaine, lidocaine, or no local anesthetic in pre-cooperative children undergoing comprehensive dental rehabilitation under general anesthesia.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power of 80
Statistical Test of Hypothesis	P-Value	<.001
	Comments	LSD post hoc test was used for multiple group comparisons. P<.05
	Method	ANOVA
	Comments	LSD post hoc test was used for multiple group comparisons.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Prilocaine, Lidocaine
	Comments	LSD post hoc pairwise comparison
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power of 80
Statistical Test of Hypothesis	P-Value	<.001
	Comments	P<.05
	Method	Least significant difference post hoc
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Prilocaine, No Local Anesthetic
	Comments	LSD post hoc pairwise comparison
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power of 80
Statistical Test of Hypothesis	P-Value	<.001
	Comments	P<.05
	Method	least significant difference post hoc
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Lidocaine, No Local Anesthetic
	Comments	LSD post hoc pairwise comparison
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power of 80
Statistical Test of Hypothesis	P-Value	=.89
	Comments	P<.05
	Method	Least significant difference post hoc
	Comments	[Not Specified]

2. Secondary Outcome

Title	Time to Peak Methemoglobin Blood Levels
Description	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.
Time Frame	Measured at 10 second intervals during dental treatment for an average of 2 hours

Outcome Measure Data

Analysis Population Description

per protocol

Arm/Group Title	Prilocaine	Lidocaine	No Local Anesthetic
Arm/Group Description:	5mg/kg of 4% prilocaine plain administered via infiltration into multiple sites of the buccal mucosa of the mouth 1 time prior to start of restorative dental treatment	2.5mg/kg of 2% lidocaine with 1:100,000 epinephrine administered via infiltration into multiple sites of the buccal mucosa of the mouth 1 time prior to start of restorative dental treatment	No local anesthetic was administered prior to restorative dental treatment-Negative control
Overall Number of Participants Analyzed	30	30	30
Mean (Standard Deviation); Unit of Measure: minutes
	62.73 (23.78)	57.50 (30.67)	29.50 (20.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prilocaine, Lidocaine, No Local Anesthetic
	Comments	Null hypothesis: There is no statistically significant difference in the time frame to peak methemoglobin levels following the administration of prilocaine, lidocaine, or no local anesthetic in pre-cooperative children undergoing comprehensive dental rehabilitation under general anesthesia.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power of 80
Statistical Test of Hypothesis	P-Value	<.001
	Comments	[Not Specified]
	Method	ANOVA
	Comments	LSD post hoc test was used for multiple group comparisons.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Prilocaine, Lidocaine
	Comments	LSD post hoc pairwise comparison
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power of 80
Statistical Test of Hypothesis	P-Value	=.43
	Comments	P<.05
	Method	Least significant difference post hoc
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Prilocaine, No Local Anesthetic
	Comments	LSD post hoc pairwise comparison
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power of 80
Statistical Test of Hypothesis	P-Value	<.001
	Comments	P<.05
	Method	Least significant difference post hoc
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Lidocaine, No Local Anesthetic
	Comments	LSD post hoc pairwise comparison
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power of 80
Statistical Test of Hypothesis	P-Value	<.001
	Comments	P<.05
	Method	Least significant difference post hoc
	Comments	[Not Specified]

3. Secondary Outcome

Title	Delta Methemoglobin Blood Level
Description	Change in percentage of methemoglobin in blood from baseline level to peak 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

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Prilocaine	Lidocaine	No Local Anesthetic
Arm/Group Description:	5mg/kg of 4% prilocaine plain administered via infiltration into multiple sites of the buccal mucosa of the mouth 1 time prior to start of restorative dental treatment	2.5mg/kg of 2% lidocaine with 1:100,000 epinephrine administered via infiltration into multiple sites of the buccal mucosa of the mouth 1 time prior to start of restorative dental treatment	No local anesthetic was administered prior to restorative dental treatment-Negative control
Overall Number of Participants Analyzed	30	30	30
Mean (Standard Deviation); Unit of Measure: percentage of methemoglobin in blood
	2.73 (1.23)	0.78 (0.44)	0.76 (0.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prilocaine, Lidocaine, No Local Anesthetic
	Comments	Null hypothesis: There is no statistically significant difference in delta methemoglobin blood levels following the administration prilocaine, lidocaine, or no local anesthetic in pre-cooperative children undergoing comprehensive dental rehabilitation under general anesthesia.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power of 80
Statistical Test of Hypothesis	P-Value	<.001
	Comments	P<.05
	Method	ANOVA
	Comments	LSD post hoc test was used for multiple group comparisons.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Prilocaine, Lidocaine
	Comments	LSD post hoc pairwise comparison
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power of 80
Statistical Test of Hypothesis	P-Value	<.001
	Comments	P<.05
	Method	Least significant difference post hoc
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Prilocaine, No Local Anesthetic
	Comments	LSD post hoc pairwise comparison
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power of 80
Statistical Test of Hypothesis	P-Value	<.001
	Comments	P<.05
	Method	Least significant difference post hoc
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Lidocaine, No Local Anesthetic
	Comments	LSD post hoc pairwise comparison
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Power of 80
Statistical Test of Hypothesis	P-Value	=.92
	Comments	P<.05
	Method	Least significant difference post hoc
	Comments	[Not Specified]

Adverse Events

Time Frame	Reported adverse events include those that occurred at or after the administration of local anesthetic in the Prilocaine and Lidocaine Groups or the start of restorative dental procedures in the No Local Anesthetic Group.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Prilocaine	Lidocaine	No Local Anesthetic
Arm/Group Description	5mg/kg of 4% prilocaine plain administered via infiltration into multiple sites of the buccal mucosa of the mouth 1 time prior to start of restorative dental treatment	2.5mg/kg of 2% lidocaine with 1:100,000 epinephrine administered via infiltration into multiple sites of the buccal mucosa of the mouth 1 time prior to start of restorative dental treatment	No local anesthetic was administered prior to restorative dental treatment-Negative control
All-Cause Mortality
	Prilocaine	Lidocaine	No Local Anesthetic
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Prilocaine	Lidocaine	No Local Anesthetic
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/30 (0.00%)	0/30 (0.00%)	0/30 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Prilocaine	Lidocaine	No Local Anesthetic
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/30 (0.00%)	0/30 (0.00%)	0/30 (0.00%)

Limitations and Caveats

Did not compare locals anesthetics with equivalent concentrations of epinephrine; unable to control length of time methemoglobin blood levels were monitored as all subjects varied in extent of restorative dental procedures needed.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Dr. Lauren Gutenberg
• Organization: Loma Linda University
• Phone: 909-558-4690
• EMail: lgutenberg@llu.edu

Publications:

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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

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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. 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.

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

• Responsible Party: Lauren GutenBerg, Loma Linda University
• ClinicalTrials.gov Identifier: NCT01402869
• Other Study ID Numbers: 5110172
• First Submitted: July 25, 2011
• First Posted: July 26, 2011
• Results First Submitted: October 15, 2013
• Results First Posted: April 25, 2014
• Last Update Posted: April 25, 2014