Letters RESEARCH LETTER
Maternal Holding vs Oral Glucose Administration as Nonpharmacologic Analgesia in Newborns: A Functional Neuroimaging Study Nonpharmacologic analgesia is administered in newborns using, for example, sweet solutions, breastfeeding, or maternal holding.1,2 Nonpharmacologic analgesia can decrease pain during minor procedures, such as a heel prick for blood sampling. From a neurophysiological standpoint, a previous study1 has demonstrated that, during a heel prick, oral glucose administration is associated with no significant cortical activation and therefore may interfere with the pain-associated response at the cortical level. Conversely, breastfeeding analgesia is associated with generalized cortical activation and may act by multisensory stimulation, possibly overwhelming the perception of pain.1 We aimed to study the effect of 2 nonpharmacologic analgesic methods (administration of an oral glucose solution and maternal holding) on neonatal cortical activation during a heel prick. We tested the hypothesis that analgesia associated with maternal holding would differ from that associated with oral glucose administration and would be mediated by a difference in cortical activation. Methods | The independent committee for bioethics of the Institute for Maternal and Child Health, Trieste, Italy, approved the study. Written informed consent was obtained from the parents. We enrolled 40 healthy newborns undergoing a heel prick for metabolic screening on their third day of life. Data were collected from November 1, 2013, through March 31, 2014. Assessment of cortical activation during the heel prick procedure was performed by multichannel near-infrared spectroscopy (ETG-100; Hitachi Medical, Ltd), which continuously monitors concentration changes in cortical hemoglobin from 24 channels. Eighteen near-infrared light emitters and detectors were positioned bilaterally above the parietal, midtemporal, and posterior frontal cortex (Figure 1). Newborns were randomly assigned to receive different nonpharmacologic analgesia. Twenty newborns were given 2 mL of oral glucose solution at a concentration of 20% two minutes before the heel prick, and blood sampling was performed with the newborn lying supine on a changing table. Twenty newborns were held by their mothers, beginning 2 minutes before the heel prick and throughout the procedure. Specifically, the mothers sat comfortably on a chair, kept their dressed newborn in their arms, and were not allowed to talk to him or her. An increase in the oxyhemoglobin (Hb O 2 ) level during the heel prick was considered an estimation of cortical activation.3 After removing physiological or movement noise by filtering the signal,1 the near-infrared spectroscopy data were analyzed, channel by channel, using a 284
1-tailed paired t test to compare the baseline measurement (mean variation in the HbO2 level in the 10 seconds before disinfection) and a pain-associated hemodynamic response (mean variation in the HbO2 level in the 25 seconds after the heel prick).1 Statistical analysis was performed separately in the 2 groups. We used the false discovery rate to control for statistical multiple testing (q = 0.05). Results | Use of the oral glucose solution was associated with no significant cortical activity during the heel prick. Instead, maternal holding (Figure 2) was associated with a bilateral activation of the left (channel 5: t 17 = −3.837 [P < .001]; channel 7: t19 = −2.929 [P = .005]) and right (channel 18: t16 = −3.136 [P = .003]) somatosensory cortex and of the posteroinferior right frontal cortex (channel 22: t18 = −2.686 [P = .008]). We found no difference in clinical pain expression between the 2 groups, as measured by the Neonatal Infant Pain Scale.4 Discussion | As previously shown,1 no significant cortical activation was observed during a heel prick using oral glucose analgesia. Thus, the hypothesis that this compound may act by interfering with the cortical processing of pain is further supported. Conversely, maternal holding during the heel prick was associated with cortical activation, particularly in areas associated with the processing of somatic sensations and, in newborns, with affective responses (frontal cortex).5 We speculate that such analgesia may be mediated by multisensory
Figure 1. Schematic Representation of Placement of Near-Infrared Light Emitters and Detectors Near-infrared light emitter Near-infrared light detector
8 11 T3
F3
F4
3
17
6 9
12
1
10
Cz
4 7
2 5 P3
14
22 19
16 13
24 21
18 15 P4
T4 23
20
Channels are indicated by their numbers. Optodes were located according to the International 10-20 System for electroencephalography and can be identified by standard letters and numbers. Cz indicates central; F3 and F4, superior frontal; P3 and P4, parietal; and T3 and T4, midtemporal.
JAMA Pediatrics March 2015 Volume 169, Number 3 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
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jamapediatrics.com
Letters
Figure 2. Mean Variations in Oxyhemoglobin and Deoxyhemoglobin Levels in the Maternal Holding Group Oxyhemoglobin level
Left hemisphere
Right hemisphere
Deoxyhemoglobin level 0.6
F3
Ch 8
0.6
0.0 0.6
0.6
0.6
0.6
0.0
0.6
0.6
Ch 2
0.6
–0.6
P3
Ch 13
T4
0.6
Ch 18a
0.6
0.6
–0.6
0.0
Ch 15
0.6 –0.6
0.0
0.0
–0.6
–0.6
Ch 23
–0.6
0.0
Ch 5a –0.6
0.0
–0.6 0.0
0.0
0.0
–0.6
0.6
Ch 21
–0.6
–0.6
0.0
Ch 24
0.0
Ch 16
0.0
0.6
0.6 –0.6
–0.6
Cz
–0.6
Ch 10
0.6
0.0
Ch 4
Ch 7a
–0.6
Ch 22a
Ch 19
–0.6
0.0
Ch 12
0.6
0.0
Ch 14
0.0
–0.6
0.0
0.6
0.6
0.0
–0.6
T3
Ch 1
–0.6
–0.6
–0.6
0.6
0.0
Ch 9
F4
Ch 17
0.0
Ch 6
–0.6
0.6
0.6
0.0
Ch 11
0.0
0.6
Ch 3
Ch 20 –0.6
0.0
P4
–0.6
Levels were measured in the 20 infants during the 25 seconds after the heel prick. Mean variation of the optical path length, reported in millimolar per millimeters of hemoglobin (SE, 0.5 mM/mm) is represented on the y-axes. Ch indicates channel; Cz, central; F3 and F4, superior frontal; P3 and P4, parietal; and T3 and T4, midtemporal. a
Indicates a channel that passed the threshold for the false discovery rate (q = 0.05).
stimulation in the context of an emotionally significant attachment relationship between the newborn and his or her mother.6
1. Bembich S, Davanzo R, Brovedani P, Clarici A, Massaccesi S, Demarini S. Functional neuroimaging of breastfeeding analgesia by multichannel near-infrared spectroscopy. Neonatology. 2013;104(4):255-259.
Stefano Bembich, PhD Gabriele Cont, MD Giulio Baldassi, BS Jenny Bua, MD Sergio Demarini, MD
2. Phillips RM, Chantry CJ, Gallagher MP. Analgesic effects of breast-feeding or pacifier use with maternal holding in term infants. Ambul Pediatr. 2005;5(6): 359-364.
Author Affiliations: Division of Neonatology, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy. Corresponding Author: Sergio Demarini, MD, Division of Neonatology, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Via dell’Istria, 65, I-34137 Trieste, Italy ([email protected]). Published Online: January 19, 2015. doi:10.1001/jamapediatrics.2014.3052. Author Contributions: Drs Bembich and Demarini had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Bembich, Bua, Demarini. Acquisition, analysis, or interpretation of data: Bembich, Cont, Baldassi. Drafting of the manuscript: Bembich, Bua, Demarini. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Bembich. Administrative, technical, or material support: Cont, Baldassi. Study supervision: Demarini. Conflict of Interest Disclosures: None reported. Funding/Support: This study was supported by grant NR.50/11 from the Institute for Maternal and Child Health, IRCCS Burlo Garofolo. jamapediatrics.com
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
3. Meek J. Basic principles of optical imaging and application to the study of infant development. Dev Sci. 2002;5(3):371-380. 4. Lawrence J, Alcock D, McGrath P, Kay J, MacMurray SB, Dulberg C. The development of a tool to assess neonatal pain. Neonatal Netw. 1993;12(6):59-66. 5. Saito Y, Aoyama S, Kondo T, et al. Frontal cerebral blood flow change associated with infant-directed speech. Arch Dis Child Fetal Neonatal Ed. 2007; 92(2):F113-F116. 6. Harlow HF. The nature of love. Am Psychol. 1958;13(12):673-685.
COMMENT & RESPONSE
Don't Forget Palliative Patients To the Editor We appreciate the Viewpoint by Dr Schechter recently published in JAMA Pediatrics on the hazards of indiscriminate use of opioids in children.1 He has made major contributions to pain management for children and his words deserve great respect. We accept that pediatricians have insufficient data about the effectiveness of opioids for chronic (Reprinted) JAMA Pediatrics March 2015 Volume 169, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Michigan User on 05/19/2015
285
Maternal Holding vs Oral Glucose Administration as Nonpharmacologic Analgesia in Newborns: A Functional Neuroimaging Study Nonpharmacologic analgesia is administered in newborns using, for example, sweet solutions, breastfeeding, or maternal holding.1,2 Nonpharmacologic analgesia can decrease pain during minor procedures, such as a heel prick for blood sampling. From a neurophysiological standpoint, a previous study1 has demonstrated that, during a heel prick, oral glucose administration is associated with no significant cortical activation and therefore may interfere with the pain-associated response at the cortical level. Conversely, breastfeeding analgesia is associated with generalized cortical activation and may act by multisensory stimulation, possibly overwhelming the perception of pain.1 We aimed to study the effect of 2 nonpharmacologic analgesic methods (administration of an oral glucose solution and maternal holding) on neonatal cortical activation during a heel prick. We tested the hypothesis that analgesia associated with maternal holding would differ from that associated with oral glucose administration and would be mediated by a difference in cortical activation. Methods | The independent committee for bioethics of the Institute for Maternal and Child Health, Trieste, Italy, approved the study. Written informed consent was obtained from the parents. We enrolled 40 healthy newborns undergoing a heel prick for metabolic screening on their third day of life. Data were collected from November 1, 2013, through March 31, 2014. Assessment of cortical activation during the heel prick procedure was performed by multichannel near-infrared spectroscopy (ETG-100; Hitachi Medical, Ltd), which continuously monitors concentration changes in cortical hemoglobin from 24 channels. Eighteen near-infrared light emitters and detectors were positioned bilaterally above the parietal, midtemporal, and posterior frontal cortex (Figure 1). Newborns were randomly assigned to receive different nonpharmacologic analgesia. Twenty newborns were given 2 mL of oral glucose solution at a concentration of 20% two minutes before the heel prick, and blood sampling was performed with the newborn lying supine on a changing table. Twenty newborns were held by their mothers, beginning 2 minutes before the heel prick and throughout the procedure. Specifically, the mothers sat comfortably on a chair, kept their dressed newborn in their arms, and were not allowed to talk to him or her. An increase in the oxyhemoglobin (Hb O 2 ) level during the heel prick was considered an estimation of cortical activation.3 After removing physiological or movement noise by filtering the signal,1 the near-infrared spectroscopy data were analyzed, channel by channel, using a 284
1-tailed paired t test to compare the baseline measurement (mean variation in the HbO2 level in the 10 seconds before disinfection) and a pain-associated hemodynamic response (mean variation in the HbO2 level in the 25 seconds after the heel prick).1 Statistical analysis was performed separately in the 2 groups. We used the false discovery rate to control for statistical multiple testing (q = 0.05). Results | Use of the oral glucose solution was associated with no significant cortical activity during the heel prick. Instead, maternal holding (Figure 2) was associated with a bilateral activation of the left (channel 5: t 17 = −3.837 [P < .001]; channel 7: t19 = −2.929 [P = .005]) and right (channel 18: t16 = −3.136 [P = .003]) somatosensory cortex and of the posteroinferior right frontal cortex (channel 22: t18 = −2.686 [P = .008]). We found no difference in clinical pain expression between the 2 groups, as measured by the Neonatal Infant Pain Scale.4 Discussion | As previously shown,1 no significant cortical activation was observed during a heel prick using oral glucose analgesia. Thus, the hypothesis that this compound may act by interfering with the cortical processing of pain is further supported. Conversely, maternal holding during the heel prick was associated with cortical activation, particularly in areas associated with the processing of somatic sensations and, in newborns, with affective responses (frontal cortex).5 We speculate that such analgesia may be mediated by multisensory
Figure 1. Schematic Representation of Placement of Near-Infrared Light Emitters and Detectors Near-infrared light emitter Near-infrared light detector
8 11 T3
F3
F4
3
17
6 9
12
1
10
Cz
4 7
2 5 P3
14
22 19
16 13
24 21
18 15 P4
T4 23
20
Channels are indicated by their numbers. Optodes were located according to the International 10-20 System for electroencephalography and can be identified by standard letters and numbers. Cz indicates central; F3 and F4, superior frontal; P3 and P4, parietal; and T3 and T4, midtemporal.
JAMA Pediatrics March 2015 Volume 169, Number 3 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Michigan User on 05/19/2015
jamapediatrics.com
Letters
Figure 2. Mean Variations in Oxyhemoglobin and Deoxyhemoglobin Levels in the Maternal Holding Group Oxyhemoglobin level
Left hemisphere
Right hemisphere
Deoxyhemoglobin level 0.6
F3
Ch 8
0.6
0.0 0.6
0.6
0.6
0.6
0.0
0.6
0.6
Ch 2
0.6
–0.6
P3
Ch 13
T4
0.6
Ch 18a
0.6
0.6
–0.6
0.0
Ch 15
0.6 –0.6
0.0
0.0
–0.6
–0.6
Ch 23
–0.6
0.0
Ch 5a –0.6
0.0
–0.6 0.0
0.0
0.0
–0.6
0.6
Ch 21
–0.6
–0.6
0.0
Ch 24
0.0
Ch 16
0.0
0.6
0.6 –0.6
–0.6
Cz
–0.6
Ch 10
0.6
0.0
Ch 4
Ch 7a
–0.6
Ch 22a
Ch 19
–0.6
0.0
Ch 12
0.6
0.0
Ch 14
0.0
–0.6
0.0
0.6
0.6
0.0
–0.6
T3
Ch 1
–0.6
–0.6
–0.6
0.6
0.0
Ch 9
F4
Ch 17
0.0
Ch 6
–0.6
0.6
0.6
0.0
Ch 11
0.0
0.6
Ch 3
Ch 20 –0.6
0.0
P4
–0.6
Levels were measured in the 20 infants during the 25 seconds after the heel prick. Mean variation of the optical path length, reported in millimolar per millimeters of hemoglobin (SE, 0.5 mM/mm) is represented on the y-axes. Ch indicates channel; Cz, central; F3 and F4, superior frontal; P3 and P4, parietal; and T3 and T4, midtemporal. a
Indicates a channel that passed the threshold for the false discovery rate (q = 0.05).
stimulation in the context of an emotionally significant attachment relationship between the newborn and his or her mother.6
1. Bembich S, Davanzo R, Brovedani P, Clarici A, Massaccesi S, Demarini S. Functional neuroimaging of breastfeeding analgesia by multichannel near-infrared spectroscopy. Neonatology. 2013;104(4):255-259.
Stefano Bembich, PhD Gabriele Cont, MD Giulio Baldassi, BS Jenny Bua, MD Sergio Demarini, MD
2. Phillips RM, Chantry CJ, Gallagher MP. Analgesic effects of breast-feeding or pacifier use with maternal holding in term infants. Ambul Pediatr. 2005;5(6): 359-364.
Author Affiliations: Division of Neonatology, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy. Corresponding Author: Sergio Demarini, MD, Division of Neonatology, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Via dell’Istria, 65, I-34137 Trieste, Italy ([email protected]). Published Online: January 19, 2015. doi:10.1001/jamapediatrics.2014.3052. Author Contributions: Drs Bembich and Demarini had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Bembich, Bua, Demarini. Acquisition, analysis, or interpretation of data: Bembich, Cont, Baldassi. Drafting of the manuscript: Bembich, Bua, Demarini. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Bembich. Administrative, technical, or material support: Cont, Baldassi. Study supervision: Demarini. Conflict of Interest Disclosures: None reported. Funding/Support: This study was supported by grant NR.50/11 from the Institute for Maternal and Child Health, IRCCS Burlo Garofolo. jamapediatrics.com
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
3. Meek J. Basic principles of optical imaging and application to the study of infant development. Dev Sci. 2002;5(3):371-380. 4. Lawrence J, Alcock D, McGrath P, Kay J, MacMurray SB, Dulberg C. The development of a tool to assess neonatal pain. Neonatal Netw. 1993;12(6):59-66. 5. Saito Y, Aoyama S, Kondo T, et al. Frontal cerebral blood flow change associated with infant-directed speech. Arch Dis Child Fetal Neonatal Ed. 2007; 92(2):F113-F116. 6. Harlow HF. The nature of love. Am Psychol. 1958;13(12):673-685.
COMMENT & RESPONSE
Don't Forget Palliative Patients To the Editor We appreciate the Viewpoint by Dr Schechter recently published in JAMA Pediatrics on the hazards of indiscriminate use of opioids in children.1 He has made major contributions to pain management for children and his words deserve great respect. We accept that pediatricians have insufficient data about the effectiveness of opioids for chronic (Reprinted) JAMA Pediatrics March 2015 Volume 169, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Michigan User on 05/19/2015
285
