Vibration-based mitigation of noxious-evoked responses to skin puncture in neonates and infants: a randomised controlled trial.

OBJECTIVE: To assess the effect of a non-noxious vibratory stimulus on noxious-evoked cortical responses to skin puncture and to determine whether the presence of certain behavioural components may be used to predict such cortical responses. DESIGN: Randomised controlled trial. SETTING: Level IV neonatal intensive care unit at a stand-alone children's hospital. PATIENTS: 134 hospitalised infants between 36 and 52 weeks' postmenstrual age and ordered to receive a clinically required laboratory draw. INTERVENTIONS: Infants randomised to receive the intervention, a vibratory stimulus at the site of skin puncture beginning 10 s prior to a heel stick, or the control, no vibration. MAIN OUTCOME MEASURES: Electroencephalography and video recording time-locked to the deployment of the lancet for the skin puncture. Noxious-evoked cortical responses were measured by the area under the curve in the somatosensory region contralateral to the skin puncture. Behavioural responses were coded through video analysis. RESULTS: Noxious-evoked cortical responses were significantly reduced in participants receiving the vibratory stimulus compared with the control (frontal, p<0.0001; central, p=0.0088; central-parietal, p=0.0111). There were no significant differences in behavioural responses between groups (all p>0.05). CONCLUSIONS: A non-noxious vibratory stimulus presented prior to and continuing simultaneously with skin puncture significantly mitigates nociception in hospitalised infants. The presence or absence of facial expression components is inadequate to reliably predict pain signalling in the brain. TRIAL REGISTRATION NUMBER: NCT04050384.

Behavioral and neural measures of infant responsivity increase with maternal multisensory input in non-irritable infants.

INTRODUCTION: Parents often use sensory stimulation during early-life interactions with infants. These interactions, including gazing, rocking, or singing, scaffold child development. Previous studies have examined infant neural processing during highly controlled sensory stimulus presentation paradigms. OBJECTIVE: In this study, we investigated infant behavioral and neural responsiveness during a mother-child social interaction during which the mother provided infant stimulation with a progressive increase in the number of sensory modalities. METHODS: We prospectively collected and analyzed video-coded behavioral interactions and electroencephalogram (EEG) frontal asymmetry (FAS) from infants (n = 60) at 2-4 months born at ≥ 34 weeks gestation. As the number of sensory modalities progressively increased during the interaction, infant behaviors of emotional connection in facial expressiveness, sensitivity to mother, and vocal communication increased significantly. Conversely, infant FAS for the entire cohort did not change significantly. However, when we accounted for infant irritability, both video-coded behaviors and EEG FAS markers of infant responsiveness increased across the interaction in the non-irritable infants. The non-irritable infants (49%) demonstrated positive FAS, indicating readiness to engage with, rather than to withdraw from, multisensory but not unisensory interactions with their mothers. RESULTS: These results suggest that multisensory input from mothers is associated with greater infant neural approach state and highlight the importance of infant behavioral state during neural measures of infant responsiveness.

Continuous epidural chloroprocaine after abdominal surgery is associated with lower postoperative opioid exposure in NICU infants.

BACKGROUND: Epidural anesthesia in infants undergoing open abdominal surgery has the potential to reduce opioid consumption, lower pain scores, and expedite tracheal extubation. We evaluated associations between use of continuous epidural chloroprocaine and improved intra- and post-operative outcomes. METHODS: This matched retrospective cohort study first identified 24 patients who between April 2018 through December 2019 were treated with a caudal catheter and epidural chloroprocaine infusion for a laparotomy at postnatal age of 6 months or less. A matched comparator group of 24 patients was derived based on age and type of surgery. Exclusion criteria were the presence of a preoperative opioid infusion, comorbidities that would preclude appropriate pain assessment, or a recent surgical procedure. Primary outcomes included opioid consumption and pain scores; we secondarily analyzed intraoperative anesthetic requirements, other systemic analgesic use, vital signs, tracheal extubation time, and procedural times. RESULTS: Treatment with epidural anesthesia was associated with lower 5-day total postoperative opioid consumption (3.2 mg/kg vs. 19.7 mg/kg in the respective epidural vs. systemic groups, p = 0.001) and time to tracheal extubation (1.3 days vs. 3.2 days, p = 0.005). Any statistically significant differences in pain scores were not clinically meaningful. There were no differences in mean arterial pressure or intraoperative inhaled anesthetic doses. CONCLUSION: Continuous infusion of epidural chloroprocaine in infants following open abdominal surgery may limit exposure to systemic opioid medications while providing adequate postoperative analgesia and shortening time to tracheal extubation.

Immune Function following Major Spinal Surgery and General Anesthesia.

There are reported differences in the effects that general anesthetics may have on immune function after minor surgery. To date, there are no prospective trials comparing total intravenous anesthesia (TIVA) with a volatile agent-based technique and its effects on immune function after major spinal surgery in adolescents. Twenty-six adolescents undergoing spinal fusion were randomized to receive TIVA with propofol-remifentanil or a volatile agent-based technique with desflurane-remifentanil. Immune function measures were based on the antigen-presenting and cytokine production capacity, and relative proportions of cell populations. Overall characteristics of the two groups did not differ in terms of perioperative times, hemodynamics, or fluid shifts, but those treated with propofol had lower bispectral index values. Experimental groups had relatively high baseline interleukin-10 values, but both showed a significant inflammatory response with similar changes in their respective immune functions. This included a shift toward a granulocytic predominance; a transient reduction in monocyte markers with significant decrease in antigen-presenting capacity and cytokine production capacity. Anesthetic choice does not appear to differentially impact immune function, but exposure to anesthetics and surgical trauma results in reproducibly measurable suppression of both innate and adaptive immunity in adolescents undergoing posterior spinal fusion. The magnitude of this suppression was modest when compared with pediatric and adult patients with critical illnesses. This study highlighted the need to evaluate immune function in a broader population of surgical patients with higher severity of illness.

Regional anesthesia in neonates and infants outside the immediate perioperative period: A systematic review of studies with efficacy and safety considerations.

This review examines the quality and quantity of literature regarding methods that measure efficacy in the context of reported safety of regional anesthesia techniques in preterm and term infants <1 year of age. Because the role of anesthesiologists continues to expand outside the operating room, we focused on all relevant settings with assessments that extend beyond 24 hours from the intraoperative period. All study designs were included from a search of MEDLINE, EMBASE, CINAHL, Scopus, and Cochrane databases from 1946 to the end of 2019. A total of 31 studies were included (n = 1038 participants), consisting of five randomized controlled trials and 26 observational studies. Twenty-three studies examined neuraxial procedures, seven studies examined peripheral procedures, and one study examined both. Efficacy measures included pain assessment tools, analgesic use, and factors pertaining to the recovery of patients. Safety was assessed in multiple systems (neurological, cardiovascular, respiratory, pathological) and with vital signs and/or measures of systemic toxicity. Evidence in this review establishes that neuraxial and peripheral anesthesia treatments may be applied to neonates and infants with a high degree of safety. However, large gaps in the consistency of methods used to assess pain in these studies underline the need for rigorous prospective efficacy studies of these techniques in this population. This systematic review was registered on PROSPERO (CRD42018114466).

Regional Anesthesia Facilitates the Early Recognition of Local Anesthetic Toxicity.

Rising concerns regarding the potential long-term neurocognitive effects of general anesthetic agents have renewed an interest in using regional anesthesia instead of general anesthesia in infants. Although generally safe and effective, the primary risk associated with regional anesthesia relates to the use of large doses of local anesthetic agents and the potential for local anesthetic systemic toxicity (LAST). We present three infants who suffered LAST after receiving regional anesthesia instead of general anesthesia. The early signs and symptoms were quickly identified in the awake state thereby allowing for cessation of continuous drug administration and a rapid response to treat LAST before progression to severe sequelae.

Behavioral and Physiological Signs for Pain Assessment in Preterm and Term Neonates During a Nociception-Specific Response: A Systematic Review.

BACKGROUND/GOAL: Assessment and treatment of neonatal pain is difficult because current scales are rarely validated against brain-based evidence. We sought to systematically evaluate published evidence to extract validation of the most promising markers of neonatal pain. METHODS: We searched four databases using germane MeSH terms. We focused on assessments of pain and/or nociception that had at least two measures among behavioral, physiological, or cortical components in preterm and/or term neonates. We evaluated studies for quality of evidence and strength of recommendations using standardized tools. RESULTS: Fifteen articles met our inclusion criteria. Among the behavioral components uncovered in this review, the withdrawal reflex and changes in facial expression are the most strongly associated with nociception-specific brain activity. These associations may be influenced by gestational age and change over time. Physiological signs, such heart rate and oxygen saturation, have little to no association with this type of response. CONCLUSIONS: Current assessments of neonatal pain include behavioral components that are associated with nociceptive processing, but also other less valid components, while omitting newer measures based on neuroscientific research.

Spinal anesthesia instead of general anesthesia for infants undergoing tendon Achilles lengthening.

Spinal anesthesia (SA) has been used relatively sparingly in the pediatric population, as it is typically reserved for patients in whom the perceived risk of general anesthesia is high due to comorbid conditions. Recently, concern has been expressed regarding the potential long-term neurocognitive effects of general anesthesia during the early stages of life. In view of this, our center has developed a program in which SA may be used as the sole agent for applicable surgical procedures. While this approach in children is commonly used for urologic or abdominal surgical procedures, there have been a limited number of reports of its use for orthopedic procedures in this population. We present the use of SA for 6 infants undergoing tendon Achilles lengthening, review the use of SA in orthopedic surgery, describe our protocols and dosing regimens, and discuss the potential adverse effects related to this technique.

Ultrasound-guided rectus sheath block, caudal analgesia, or surgical site infiltration for pediatric umbilical herniorrhaphy: a prospective, double-blinded, randomized comparison of three regional anesthetic techniques.

BACKGROUND: Umbilical hernia repair is a common pediatric surgical procedure. While opioid analgesics are a feasible option and have long been a mainstay in the pharmacological intervention for pain, the effort to improve care and limit opioid-related adverse effects has led to the use of alternative techniques, including regional anesthesia. The current study prospectively compares the analgesic efficacy of three techniques, including caudal epidural blockade, peripheral nerve blockade, and local wound infiltration, in a double-blinded study. PATIENTS AND METHODS: A total of 39 patients undergoing umbilical hernia repair were randomized to receive a caudal epidural block (CDL), ultrasound-guided bilateral rectus sheath blocks (RSB), or surgical site infiltration (SSI) with local anesthetic. Intraoperative anesthetic care was standardized, and treatment groups were otherwise blinded from the intraoperative anesthesiology team and recovery nurses. Postoperatively, the efficacy was evaluated using Hannallah pain scores, Aldrete recovery scores, the need for intravenous fentanyl, and the time to discharge. RESULTS: Each cohort was similar in terms of age, weight, premedication dosing, length of case, intraoperative and postoperative fentanyl requirements, and time to tracheal extubation. Among the three cohorts, there were no significant differences noted in terms of pain scores or time to recovery. CONCLUSION: All the three techniques provided effective analgesia following umbilical hernia repair. Our findings offer effective and safe analgesic options as alternatives to the neuraxial (caudal) approach.

The TCR repertoires of regulatory and conventional T cells specific for the same foreign antigen are distinct.

The relationship between the TCR repertoires of natural regulatory T cells (nTregs) and conventional CD4(+) T cells (Tconv) capable of responding to the same antigenic epitope is unknown. In this study, we used TCRß-chain transgenic mice to generate polyclonal nTreg and Tconv populations specific for a foreign Ag. CD4(+) T cells from immunized 3.L2ß(+/-) TCRα(+/-) Foxp3(EGFP) mice were restimulated in culture to yield nTregs (EGFP(+)) and Tconv (EGFP(-)) defined by their antigenic reactivity. Relative to Tconv, nTreg expansion was delayed, although a higher proportion of viable nTregs had divided after 72 h. Spectratype analysis revealed that both the nTreg and Tconv responses were different and characterized by skewed distributions of CDR3 lengths. CDR3 sequences from nTregs displayed a divergent pattern of Jα usage, minimal CDR3 overlap (3.4%), and less diversity than did CDR3 sequences derived from Tconv. These data indicate that foreign Ag-specific nTregs and Tconv are clonally distinct and that foreign Ag-specific nTreg populations are constrained by a limited TCR repertoire.

A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity.

Although both natural and induced regulatory T (nTreg and iTreg) cells can enforce tolerance, the mechanisms underlying their synergistic actions have not been established. We examined the functions of nTreg and iTreg cells by adoptive transfer immunotherapy of newborn Foxp3-deficient mice. As monotherapy, only nTreg cells prevented disease lethality, but did not suppress chronic inflammation and autoimmunity. Provision of Foxp3-sufficient conventional T cells with nTreg cells reconstituted the iTreg pool and established tolerance. In turn, acute depletion of iTreg cells in rescued mice resulted in weight loss and inflammation. Whereas the transcriptional signatures of nTreg and in vivo-derived iTreg cells were closely matched, there was minimal overlap in their T cell receptor (TCR) repertoires. Thus, iTreg cells are an essential nonredundant regulatory subset that supplements nTreg cells, in part by expanding TCR diversity within regulatory responses.

1,25-Dihydroxyvitamin D3 acts directly on the T lymphocyte vitamin D receptor to inhibit experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an incurable autoimmune neurodegenerative disease. Environmental factors may be key to MS prevention and treatment. MS prevalence and severity decrease with increasing sunlight exposure and vitamin D(3) supplies, supporting our hypothesis that the sunlight-dependent hormone, 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2) D(3) ), inhibits autoimmune T-cell responses in MS. Moreover, 1,25-(OH)(2) D(3) inhibits and reverses experimental autoimmune encephalomyelitis (EAE), an MS model. Here, we investigated whether 1,25-(OH)(2) D(3) inhibits EAE via the vitamin D receptor (VDR) in T lymphocytes. Using bone marrow chimeric mice with a disrupted VDR only in radio-sensitive hematopoietic cells or radio-resistant non-hematopoietic cells, we found that hematopoietic cell VDR function was necessary for 1,25-(OH)(2) D(3) to inhibit EAE. Furthermore, conditional targeting experiments showed that VDR function in T cells was necessary. Neither 1,25-(OH)(2) D(3) nor T-cell-specific VDR targeting influenced CD4(+) Foxp3(+) T-cell proportions in the periphery or the CNS in these studies. These data support a model wherein 1,25-(OH)(2) D(3) acts directly on pathogenic CD4(+) T cells to inhibit EAE.

Affinity-based selection of regulatory T cells occurs independent of agonist-mediated induction of Foxp3 expression.

Natural regulatory T (nT(reg)) cells recognize self-peptides with high affinity, yet the understanding of how affinity influences their selection in the thymus is incomplete. We use altered peptide ligands in transgenic mice and in organ culture to create thymic environments spanning a broad range of ligand affinity. We demonstrate that the nT(reg) TCR repertoire is shaped by affinity-based selection, similar to conventional T cells. The effect of each ligand on the two populations is distinct, consistent with early nT(reg) cell lineage specification. Foxp3 expression is an independent process that does not rely on "high affinity" binding per se, but requires a high-potency agonistic interaction for its induction. The timing of ligand exposure, TGFbeta signaling, and the organization of the thymic architecture are also important. The development of nT(reg) cells is therefore a multistep process in which ligand affinity, potency, and timing of presentation all play a role in determining cell fate.

Regulatory T cell development in the absence of functional Foxp3.

Although the development of regulatory T cells (T(reg) cells) in the thymus is defined by expression of the lineage marker Foxp3, the precise function of Foxp3 in T(reg) cell lineage commitment is unknown. Here we examined T(reg) cell development and function in mice with a Foxp3 allele that directs expression of a nonfunctional fusion protein of Foxp3 and enhanced green fluorescent protein (Foxp3DeltaEGFP). Thymocyte development in Foxp3DeltaEGFP male mice and Foxp3DeltaEGFP/+ female mice recapitulated that of wild-type mice. Although mature EGFP(+) CD4(+) T cells from Foxp3DeltaEGFP mice lacked suppressor function, they maintained the characteristic T(reg) cell 'genetic signature' and failed to develop from EGFP(-) CD4(+) T cells when transferred into lymphopenic hosts, indicative of their common ontogeny with T(reg) cells. Our results indicate that T(reg) cell effector function but not lineage commitment requires the expression of functional Foxp3 protein.

Regulatory T cells dynamically control the primary immune response to foreign antigen.

The population dynamics that enable a small number of regulatory T (T(R)) cells to control the immune responses to foreign Ags by the much larger conventional T cell subset were investigated. During the primary immune response, the expansion and contraction of conventional and T(R) cells occurred in synchrony. Importantly, the relative accumulation of T(R) cells at peak response significantly exceeded that of conventional T cells, reflecting extensive cell division within the T(R) cell pool. Transfer of a polyclonal T(R) cell population before immunization antagonized both polyclonal and TCR transgenic responses, whereas blocking T(R) cell function enhanced those responses. These results define an inverse quantitative relationship between T(R) and conventional T cells that controls the magnitude of the primary immune response. The high frequency of dividing T(R) cells suggests degenerate TCR specificity enabling activation by a broad spectrum of Ags.