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Assessing pain and analgesia with a lidocaine-prilocaine emulsion in infants and toddlers during venipuncture
Clinical and laboratory observations Assessing pain and analgesia with a lidocaine-prilocaine emulsion in infants and toddlers during venipuncture Isabelle Robieux, MD, Ram Kumar, BSc. Shyam Radhakrishnan, BSc, a n d G i d e o n Koren, MD* From the Divisionof Clinical Pharmacology, Department of Pediatrics and Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
For many years it was assumed that young children have less pain than adults; painful procedures were sometimes performed on infants without any or with minimal analgesia.1 Recently an increasing number of clinicians and scientists have voiced their concerns about this practice, which has not been based on scientific evidence.2 Venipunctures are frightening and painful experiences for children.3 The pain of venipuncture has been shown in older children and adults to be alleviated by the application of the anesthetic cream EMLA (Eutectic Mixture of Local Anesthetics) .4-6 We compared pain response in infants and toddlers undergoing venipuncture in a placebo-controlled, double-blind, crossover, randomized study. Our objective was to determine whether EMLA would decrease the pain response in infants and toddlers as in older children and adults. In addition, we wanted to assess the safety of EMLA in this age group.
they all had a normal level of consciousness, and none had received sedation or opioid analgesics during the previous weeks. The EMLA preparation is a water emulsion of lidocaine and prilocaine; 1 gm of cream contains 25 mg of both local anesthetics. The placebo cream had the same odor, appearance, and packaging. The double-blind order of administration was randomized. A standardized amount of cream (2 gm) was applied on the intended site of venipuncture at least 45 minutes before the procedure, and the cream was covered by a plastic adhesive film. Subsequently the cream was wiped off, and the venipuncture was carried out according to the usual procedure. Because local anesthetics have been reported to cause methemoglobinemia in infants,7, 8 methemoglobin levels were measured when sufficient blood, obtained for routine tests, was available. One investigator (I.R.) observed the child's behavior before and during the puncture. Pain was scored according to a behavioral pain scale adapted from the Children's Hospital of
METHODS Thisprotocol was approved by the hospital's committee of human experimentation, and consent was obtained from all parents. Forty-one chronically ill infants and toddlers between 3 and 36 months of age were studied during hospitalization (32 patients) or when attending an outpatient clinic (nine). All of them had had previous venipunctures, Supported by Astra Pharmaceuticals, Etobicoke, Ontario, and the Foundation for Medical Research, Paris, France (Dr. Robieux). Submitted for publication Dec. 5, 1990; accepted Jan. 18, 1991. Reprint requests: G. Koren, MD, Divisionof Clinical Pharmacology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. *Career Scientist of Ontario Ministry of Health. 9/26/28092
BPS HR VAS
Behavioralpain scale Heart ra[e Visualanalogue scale
Eastern Ontario Pain Scale9 (Table). In addition, the investigator scored on a 10 cm visual analogue scale the degree of pain she thought the child had been having. The nurse performing the puncture and the mother, when present, were also asked to score the pain on a similar VAS, which ranged from 0 (no pain) to 100 (maximal possible pain). Blood pressure and heart rate were recorded with a Dinamap 8100 monitor, (Critikon Inc., Tampa, Fla.) 1 minute before and then during the puncture. The difficulty of the puncture was recorded on a 4-point scale: 1 = insertion
971
972
Clinical and laboratory observations
The Journal of Pediatrics June 1991
Parenti
"1
Nurse
t
I
Investigato~r '
0
[] II
.- B i
10
"
I
20
"
I
'
30
I
40
"
Placebo EMLA
[ I
50
"
I
60
'
|
*
70"
i
!
!
80
90
100
Figure. VAS for pain (mean and SD) as scored by different observers.
Table. Behavioral pain score
Behavior observed Facial expression Positive (smiling) Neutral Negative (grimace) Cry Laughing or giggling Not crying Moaning FulMunged cry or sobbing Movements Usual activities (i.e., playing) Neutral, not moving Attempt to withdraw limb Complex agitation involving head, other limbs
Score (total 0-8) 0 1 2 0 1 2 3 0 1 2 3
Modified from McGrath P J, Johnson G, Goodman JT, et al. The Children of Eastern Ontario Pain Scale (CHEOPS): a behavioral scale for rating postoperative pain in children. In: Fields HL, Dubner R, Cervero F. Advances in pain research and therapy; vol 9. New York: Raven Press, 1985:395-402.
at first attempt, 2 = minor adjustments needed, 3 = second insertion required, and 4 = failure of two or more attempts. The procedure was recorded with a video camera by another investigator, standing 1 m away from the bed. After completion of the study, a research nurse and the investigator, both unaware of the assigned treatment, scored the child's behavior independently. Results are expressed as means + 1 SD. Scores were compared with the Wilcoxon signed rank test. Reliability of the VAS and BPS scores was tested by a K test. 1~ Methemoglobin levels, blood pressure, and H R were compared by
the Student t test for paired data. Stepwise regression was used with VAS as a dependent variable to detect potential predictive value of age, gender, difficulty of the procedure, and baseline BPS score. RESULTS The duration skin exposure to E M L A and placebo was similar (48 + 12 and 51 +_ 11 minutes, respectively), as was the difficulty of puncture ( E M L A 1.9 _+ 1.2 vs placebo 1.6 _+ 1.0). Local reactions were minor (blanching or redness) and transient in both groups. Methemoglobin levels were similar during placebo and E M L A studies (1.44 +_ 1.76 g m / L and 1.06 + 0.44 g i n / L , respectively). The BPS score was high (7 or 8) in 25% of patients (10 E M L A - t r e a t e d and 10 placebo-treated). In these cases a lack of increase in BPS score during the venipuncture cannot be interpreted as effective analgesia. For 25 infants the BPS score before puncture was --<6 in both E M L A and placebo studies. In this group the venipuncture elicited an increase in the BPS score in both E M L A and placebo trials. However, changes in behavioral scores were smaller in the E M L A group than in the placebo group (mean change 1.2 _+ 1.5 and 1.8 _+ 1.5, respectively; p <0.01). Agreement beyond chance was good or excellent among the different observers scoring the VAS (K test). We calculated the mean value of the VAS score obtained from the different observers after the puncture. The difficulty of the venipuncture had a significant predictive value (r = 0.3; p <0.01) for the VAS, whereas age, gender, and baseline BPS score did not significantly correlate with the VAS score. Subsequently we analyzed the VAS scores for the 26 children for whom the puncture was of comparable level'of dif-
Volume 118 Number 6
ficulty during both studies. The mean VAS score was significantly lower with E M L A cream (33 --- 26) than with placebo (42 ___ 26) (p -- 0.01 in a Student t test for paired data). The Figure illustrates the mean VAS score for the different observers. The increase in H R was not significantly different in the E M L A group versus the placebo group (6.5 _+ 9% vs 13.2 _+ 22%). Changes in systolic and diastolic blood pressure were highly variable and not statistically different in the E M L A group versus the placebo group. DISCUSSION Both the BPS and VAS scores showed the superiority of E M L A over placebo in alleviating pain associated with venipuncture in young children. However, our results are not as clear cut as those obtained with older children and adults. 46 During both trials ( E M L A and placebo) the BPS score increased, but the behavioral changes evoked by the venipuncture were statistically lower in the E M L A group, suggesting that the puncture was less distressing than with the placebo. A limitation of this score is that in one fourth of the cases the behavior indicated obvious distress before the puncture. This probably reflects the high state of anxiety of these infants and toddlers, who were familiar with venipuncture from previous experience. 11 The VAS has been validated as an appropriate tool for pain assessment when used by patients having pain themselves. 12 In our study we asked observers to quantify the pain on a VAS. When the insertion was successful at first attempt, the effectiveness of E M L A was easily demonstrated. When the puncture was more difficult, the efficacy of E M L A was less certain. It is possible that E M L A provides good superficial anesthesia but is less effective when the needle is inserted and moved into deeper tissues. However, even if E M L A is effective only in punctures successful at the first attempt, pain associated with 60% of the punctures can be relieved with the use of this drug. We report that E M L A can be used safely in infants older than 3 months of age; it produced no local or systemic adverse effects when applied on a limited skin area for <90 minutes. Severe methemoglobinemia was reported in a 5-year-old child during the application of E M L A on a large area for 5 hours; the methemoglobin concentration was maximal during the time of application. 8 Methemoglobin
Clinical and laboratory observations
973
reduction pathways mature in early infancy and reach adult levels at around 3 months of a g e ] In our patients, even in the youngest, E M L A did not increase methemoglobin levels above normal values. W e believe that infants and toddlers should be offered analgesia in situations where older children and adults would receive such treatment, once the safety of the analgesic modality has been proved in early childhood. We express our gratitude to Sheelagh Martin, RN, and to the phlebotomy nurses and the nurses of the hematology clinic at the Hospital for Sick Children for their cooperation in this study. REFERENCES
1. Schechter NL. The undertreatment of pain in children: an overview. Pediatr Clin North Am 1989;36:781-94. 2. Anand KJS, Phil D, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med 1987;317:1321-9. 3. Eland J, Anderson J. The experience of pain in children. In: Jacox A. A source book for nurses and other health professionals. Boston: Little, Brown, 1977:453-76. 4. Hallen B, Carlsson P, Uppfeldt A. Clinical study of a lidocaine-prilocaine cream to relieve the pain of venipuncture. Br J Anaesth 1985;57:326-8. 5. Maunuskela EL, Korpela R. Double-blind evaluation of lignocaine-prilocaine cream (EMLA) in children. Br J Anaesth 1986;58:1242-5. 6. Halperin DL, Koren G, Attias D, Pellegrini E, Greenberg M, Wyss M. Topical skin anesthesia for venous, subcutaneous drug reservoir and lumbar punctures in children. Pediatrics 1989;84:281-4. 7. Gosselin RE, Hodge HC, Smith RP. In: Clinical toxicology of commercial products. Baltimore: Williams & Wilkins, 1984: 31-5, 314-9. 8. Jakobson B, Nilson A. Methemoglobinemia associated with a prilocaine-lidocaine cream and trimethoprim-sulfamethoxazole: a case report. Acta Anesthesiol Scand 1985;29:453-5. 9. McGrath P J, Johnson G, Goodman .IT, et al. The Children of Eastern Ontario Pain Scale (CHEOPS): a behavioral scale for rating postoperative pain in children. In: Fields HL, Dubner R, Cervero F. Advances in pain research and therapy; vol 9. New York: Raven Press, 1985:395-402. 10. Fleiss JL, ed. Statistical methods for rates and proportions. New York: John Wiley & Sons, 1981:213-35. 11. Booth JC, McGrath PA, Brigham M, Frewen TC, Whitthall S. Pain in infants: distress response to painful stimuli [Abstract]. Toronto: Canadian and American Pain Societies, 1988. 12. Scott J, Huskinsson EC. Graphic representation of pain. Pain 1976;2:175-84.
For many years it was assumed that young children have less pain than adults; painful procedures were sometimes performed on infants without any or with minimal analgesia.1 Recently an increasing number of clinicians and scientists have voiced their concerns about this practice, which has not been based on scientific evidence.2 Venipunctures are frightening and painful experiences for children.3 The pain of venipuncture has been shown in older children and adults to be alleviated by the application of the anesthetic cream EMLA (Eutectic Mixture of Local Anesthetics) .4-6 We compared pain response in infants and toddlers undergoing venipuncture in a placebo-controlled, double-blind, crossover, randomized study. Our objective was to determine whether EMLA would decrease the pain response in infants and toddlers as in older children and adults. In addition, we wanted to assess the safety of EMLA in this age group.
they all had a normal level of consciousness, and none had received sedation or opioid analgesics during the previous weeks. The EMLA preparation is a water emulsion of lidocaine and prilocaine; 1 gm of cream contains 25 mg of both local anesthetics. The placebo cream had the same odor, appearance, and packaging. The double-blind order of administration was randomized. A standardized amount of cream (2 gm) was applied on the intended site of venipuncture at least 45 minutes before the procedure, and the cream was covered by a plastic adhesive film. Subsequently the cream was wiped off, and the venipuncture was carried out according to the usual procedure. Because local anesthetics have been reported to cause methemoglobinemia in infants,7, 8 methemoglobin levels were measured when sufficient blood, obtained for routine tests, was available. One investigator (I.R.) observed the child's behavior before and during the puncture. Pain was scored according to a behavioral pain scale adapted from the Children's Hospital of
METHODS Thisprotocol was approved by the hospital's committee of human experimentation, and consent was obtained from all parents. Forty-one chronically ill infants and toddlers between 3 and 36 months of age were studied during hospitalization (32 patients) or when attending an outpatient clinic (nine). All of them had had previous venipunctures, Supported by Astra Pharmaceuticals, Etobicoke, Ontario, and the Foundation for Medical Research, Paris, France (Dr. Robieux). Submitted for publication Dec. 5, 1990; accepted Jan. 18, 1991. Reprint requests: G. Koren, MD, Divisionof Clinical Pharmacology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. *Career Scientist of Ontario Ministry of Health. 9/26/28092
BPS HR VAS
Behavioralpain scale Heart ra[e Visualanalogue scale
Eastern Ontario Pain Scale9 (Table). In addition, the investigator scored on a 10 cm visual analogue scale the degree of pain she thought the child had been having. The nurse performing the puncture and the mother, when present, were also asked to score the pain on a similar VAS, which ranged from 0 (no pain) to 100 (maximal possible pain). Blood pressure and heart rate were recorded with a Dinamap 8100 monitor, (Critikon Inc., Tampa, Fla.) 1 minute before and then during the puncture. The difficulty of the puncture was recorded on a 4-point scale: 1 = insertion
971
972
Clinical and laboratory observations
The Journal of Pediatrics June 1991
Parenti
"1
Nurse
t
I
Investigato~r '
0
[] II
.- B i
10
"
I
20
"
I
'
30
I
40
"
Placebo EMLA
[ I
50
"
I
60
'
|
*
70"
i
!
!
80
90
100
Figure. VAS for pain (mean and SD) as scored by different observers.
Table. Behavioral pain score
Behavior observed Facial expression Positive (smiling) Neutral Negative (grimace) Cry Laughing or giggling Not crying Moaning FulMunged cry or sobbing Movements Usual activities (i.e., playing) Neutral, not moving Attempt to withdraw limb Complex agitation involving head, other limbs
Score (total 0-8) 0 1 2 0 1 2 3 0 1 2 3
Modified from McGrath P J, Johnson G, Goodman JT, et al. The Children of Eastern Ontario Pain Scale (CHEOPS): a behavioral scale for rating postoperative pain in children. In: Fields HL, Dubner R, Cervero F. Advances in pain research and therapy; vol 9. New York: Raven Press, 1985:395-402.
at first attempt, 2 = minor adjustments needed, 3 = second insertion required, and 4 = failure of two or more attempts. The procedure was recorded with a video camera by another investigator, standing 1 m away from the bed. After completion of the study, a research nurse and the investigator, both unaware of the assigned treatment, scored the child's behavior independently. Results are expressed as means + 1 SD. Scores were compared with the Wilcoxon signed rank test. Reliability of the VAS and BPS scores was tested by a K test. 1~ Methemoglobin levels, blood pressure, and H R were compared by
the Student t test for paired data. Stepwise regression was used with VAS as a dependent variable to detect potential predictive value of age, gender, difficulty of the procedure, and baseline BPS score. RESULTS The duration skin exposure to E M L A and placebo was similar (48 + 12 and 51 +_ 11 minutes, respectively), as was the difficulty of puncture ( E M L A 1.9 _+ 1.2 vs placebo 1.6 _+ 1.0). Local reactions were minor (blanching or redness) and transient in both groups. Methemoglobin levels were similar during placebo and E M L A studies (1.44 +_ 1.76 g m / L and 1.06 + 0.44 g i n / L , respectively). The BPS score was high (7 or 8) in 25% of patients (10 E M L A - t r e a t e d and 10 placebo-treated). In these cases a lack of increase in BPS score during the venipuncture cannot be interpreted as effective analgesia. For 25 infants the BPS score before puncture was --<6 in both E M L A and placebo studies. In this group the venipuncture elicited an increase in the BPS score in both E M L A and placebo trials. However, changes in behavioral scores were smaller in the E M L A group than in the placebo group (mean change 1.2 _+ 1.5 and 1.8 _+ 1.5, respectively; p <0.01). Agreement beyond chance was good or excellent among the different observers scoring the VAS (K test). We calculated the mean value of the VAS score obtained from the different observers after the puncture. The difficulty of the venipuncture had a significant predictive value (r = 0.3; p <0.01) for the VAS, whereas age, gender, and baseline BPS score did not significantly correlate with the VAS score. Subsequently we analyzed the VAS scores for the 26 children for whom the puncture was of comparable level'of dif-
Volume 118 Number 6
ficulty during both studies. The mean VAS score was significantly lower with E M L A cream (33 --- 26) than with placebo (42 ___ 26) (p -- 0.01 in a Student t test for paired data). The Figure illustrates the mean VAS score for the different observers. The increase in H R was not significantly different in the E M L A group versus the placebo group (6.5 _+ 9% vs 13.2 _+ 22%). Changes in systolic and diastolic blood pressure were highly variable and not statistically different in the E M L A group versus the placebo group. DISCUSSION Both the BPS and VAS scores showed the superiority of E M L A over placebo in alleviating pain associated with venipuncture in young children. However, our results are not as clear cut as those obtained with older children and adults. 46 During both trials ( E M L A and placebo) the BPS score increased, but the behavioral changes evoked by the venipuncture were statistically lower in the E M L A group, suggesting that the puncture was less distressing than with the placebo. A limitation of this score is that in one fourth of the cases the behavior indicated obvious distress before the puncture. This probably reflects the high state of anxiety of these infants and toddlers, who were familiar with venipuncture from previous experience. 11 The VAS has been validated as an appropriate tool for pain assessment when used by patients having pain themselves. 12 In our study we asked observers to quantify the pain on a VAS. When the insertion was successful at first attempt, the effectiveness of E M L A was easily demonstrated. When the puncture was more difficult, the efficacy of E M L A was less certain. It is possible that E M L A provides good superficial anesthesia but is less effective when the needle is inserted and moved into deeper tissues. However, even if E M L A is effective only in punctures successful at the first attempt, pain associated with 60% of the punctures can be relieved with the use of this drug. We report that E M L A can be used safely in infants older than 3 months of age; it produced no local or systemic adverse effects when applied on a limited skin area for <90 minutes. Severe methemoglobinemia was reported in a 5-year-old child during the application of E M L A on a large area for 5 hours; the methemoglobin concentration was maximal during the time of application. 8 Methemoglobin
Clinical and laboratory observations
973
reduction pathways mature in early infancy and reach adult levels at around 3 months of a g e ] In our patients, even in the youngest, E M L A did not increase methemoglobin levels above normal values. W e believe that infants and toddlers should be offered analgesia in situations where older children and adults would receive such treatment, once the safety of the analgesic modality has been proved in early childhood. We express our gratitude to Sheelagh Martin, RN, and to the phlebotomy nurses and the nurses of the hematology clinic at the Hospital for Sick Children for their cooperation in this study. REFERENCES
1. Schechter NL. The undertreatment of pain in children: an overview. Pediatr Clin North Am 1989;36:781-94. 2. Anand KJS, Phil D, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med 1987;317:1321-9. 3. Eland J, Anderson J. The experience of pain in children. In: Jacox A. A source book for nurses and other health professionals. Boston: Little, Brown, 1977:453-76. 4. Hallen B, Carlsson P, Uppfeldt A. Clinical study of a lidocaine-prilocaine cream to relieve the pain of venipuncture. Br J Anaesth 1985;57:326-8. 5. Maunuskela EL, Korpela R. Double-blind evaluation of lignocaine-prilocaine cream (EMLA) in children. Br J Anaesth 1986;58:1242-5. 6. Halperin DL, Koren G, Attias D, Pellegrini E, Greenberg M, Wyss M. Topical skin anesthesia for venous, subcutaneous drug reservoir and lumbar punctures in children. Pediatrics 1989;84:281-4. 7. Gosselin RE, Hodge HC, Smith RP. In: Clinical toxicology of commercial products. Baltimore: Williams & Wilkins, 1984: 31-5, 314-9. 8. Jakobson B, Nilson A. Methemoglobinemia associated with a prilocaine-lidocaine cream and trimethoprim-sulfamethoxazole: a case report. Acta Anesthesiol Scand 1985;29:453-5. 9. McGrath P J, Johnson G, Goodman .IT, et al. The Children of Eastern Ontario Pain Scale (CHEOPS): a behavioral scale for rating postoperative pain in children. In: Fields HL, Dubner R, Cervero F. Advances in pain research and therapy; vol 9. New York: Raven Press, 1985:395-402. 10. Fleiss JL, ed. Statistical methods for rates and proportions. New York: John Wiley & Sons, 1981:213-35. 11. Booth JC, McGrath PA, Brigham M, Frewen TC, Whitthall S. Pain in infants: distress response to painful stimuli [Abstract]. Toronto: Canadian and American Pain Societies, 1988. 12. Scott J, Huskinsson EC. Graphic representation of pain. Pain 1976;2:175-84.