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Methemoglobin Levels in Generally Anesthetized Pediatric Dental Patients Receiving Local Anesthetics

Sponsor
Loma Linda University (Other)
Overall Status
Completed
CT.gov ID
NCT01402869
Collaborator
(none)
91
Enrollment
1
Location
3
Arms
11
Duration (Months)
8.3
Patients Per Site Per Month

Study Details

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
  • Drug: 4% prilocaine plain
  • Drug: 2% Lidocaine with 1:100,000 epinephrine
 N/A

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
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 :
Aug 1, 2011
Actual Primary Completion Date :
Jul 1, 2012
Actual Study Completion Date :
Jul 1, 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 Names:
  • 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 Names:
  • 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 [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 [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 [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

    Criteria

    Ages Eligible for Study:
    3 Years to 5 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    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

    Site City State Country Postal Code
    1 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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Lauren GutenBerg, Pediatric Dental Resident, Loma Linda University
    ClinicalTrials.gov Identifier:
    NCT01402869
    Other Study ID Numbers:
    • 5110172
    First Posted:
    Jul 26, 2011
    Last Update Posted:
    Apr 25, 2014
    Last Verified:
    Mar 1, 2014
    Keywords provided by Lauren GutenBerg, Pediatric Dental Resident, Loma Linda University
    Methemoglobin
    Methemoglobinemia
    Prilocaine
    Lidocaine
    Additional relevant MeSH terms:
    Methemoglobinemia
    Lidocaine
    Epinephrine
    Prilocaine

    Study Results

    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 Detail 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

    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 Participants 30 30 30 90
    Age (months) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [months]
    50.97
    (9.84)
    50.77
    (10.19)
    50.63
    (8.43)
    50.79
    (9.41)
    Sex: Female, Male (Count of Participants)
    Female
    19
    63.3%
    12
    40%
    14
    46.7%
    45
    50%
    Male
    11
    36.7%
    18
    60%
    16
    53.3%
    45
    50%
    Weight Continuous (kilograms) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kilograms]
    17.17
    (2.94)
    17.24
    (2.78)
    17.19
    (2.96)
    17.20
    (2.86)
    ASA Health Classification (participants) [Number]
    I-Healthy patients; no systemic disease
    26
    86.7%
    25
    83.3%
    24
    80%
    75
    83.3%
    II-Patients with mild, systemic disease
    4
    13.3%
    5
    16.7%
    6
    20%
    15
    16.7%
    Body Mass Index Numerical Value (kg/m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg/m^2]
    15.62
    (1.12)
    15.69
    (1.08)
    15.60
    (1.03)
    15.64
    (1.07)
    Body Mass Index Percentile (participants) [Number]
    >=5th and <=35th percentiles
    11
    36.7%
    6
    20%
    6
    20%
    23
    25.6%
    >35th and <=65th percentiles
    6
    20%
    14
    46.7%
    12
    40%
    32
    35.6%
    >65th and <=95th percentiles
    13
    43.3%
    10
    33.3%
    12
    40%
    35
    38.9%
    Baseline Methemoglobin Blood Level (percentage) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [percentage]
    0.82
    (0.39)
    0.85
    (0.35)
    0.84
    (0.43)
    0.83
    (0.39)

    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
    Measure Participants 30 30 30
    Mean (Standard Deviation) [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
    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
    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
    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
    Measure Participants 30 30 30
    Mean (Standard Deviation) [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
    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
    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
    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
    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
    Measure Participants 30 30 30
    Mean (Standard Deviation) [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
    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
    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

    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
    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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Prilocaine Lidocaine No Local Anesthetic
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/30 (0%) 0/30 (0%) 0/30 (0%)
    Other (Not Including Serious) Adverse Events
    Prilocaine Lidocaine No Local Anesthetic
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/30 (0%) 0/30 (0%) 0/30 (0%)

    Limitations/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.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Lauren Gutenberg
    Organization Loma Linda University
    Phone 909-558-4690
    Email lgutenberg@llu.edu
    Responsible Party:
    Lauren GutenBerg, Pediatric Dental Resident, Loma Linda University
    ClinicalTrials.gov Identifier:
    NCT01402869
    Other Study ID Numbers:
    • 5110172
    First Posted:
    Jul 26, 2011
    Last Update Posted:
    Apr 25, 2014
    Last Verified:
    Mar 1, 2014