Share this article on:

The Use of Neuraxial Catheters for Postoperative Analgesia in Neonates: A Multicenter Safety Analysis from the Pediatric Regional Anesthesia Network

Long, Justin B. MD, FAAP; Joselyn, Anita S. MD; Bhalla, Tarun MD, FAAP; Tobias, Joseph D. MD, FAAP; De Oliveira, Gildasio S. Jr. MD, MSCI; Suresh, Santhanam MD, FAAP

doi: 10.1213/ANE.0000000000001322
Pediatric Anesthesiology: Research Report

BACKGROUND: Currently, there is limited evidence to support the safety of neuraxial catheters in neonates. Safety concerns have been cited as a major barrier to performing large randomized trials in this population. The main objective of this study is to examine the safety of neuraxial catheters in neonates across multiple institutions. Specifically, we sought to determine the incidence of overall and individual complications encountered when neuraxial catheters were used for postoperative analgesia in neonates.

METHODS: This was an observational study that used the Pediatric Regional Anesthesia Network database. Complications and adverse events were defined by the presence of at least 1 of the following intraoperative and/or postoperative factors: catheter malfunction (dislodgment/occlusion), infection, block abandoned (unable to place), block failure (no evidence of block), vascular (blood aspiration/hematoma), local anesthetic systemic toxicity, excessive motor block, paresthesia, persistent neurologic deficit, and other (e.g., intra-abdominal misplacement, tremors). Additional analyses were performed to identify the use of potentially toxic doses of local anesthetics.

RESULTS: The study cohort included 307 neonates with a neuraxial catheter. There were 41 adverse events and complications recorded, resulting in an overall incidence of complications of 13.3% (95% confidence interval, 9.8%–17.4%). Among the complications, catheter malfunction, catheter contamination, and vascular puncture were common. None of the complications resulted in long-term complications and/or sequelae, resulting in an estimated incidence of any serious complications of 0.3% (95% confidence interval, 0.08%–1.8%). There were 120 of 307 patients who received intraoperative and/or postoperative infusions consistent with a potentially toxic local anesthetic dose in neonates. The incidence of potentially toxic local anesthetic infusion rates increased over time (P = 0.008).

CONCLUSIONS: Neuraxial catheter techniques for intraoperative and postoperative analgesia appear to be safe in neonates. Further studies to confirm our results and to establish the efficacy of these techniques across different surgical procedures are required. We suggest that each center that uses neuraxial anesthesia techniques in neonates closely evaluate the dose limits for local anesthetic agents and develop rigorous quality assurance methods to ensure potentially toxic doses are not used.

From the *Department of Pediatric Anesthesiology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, Chicago, Illinois; Department of Anesthesia, Christian Medical College and Hospital, Vellore, Tamil Nadu, India; Department of Pediatric Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, The Ohio State University, Columbus, Ohio; and §Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

See Appendix 1 for full list of PRAN investigators and affiliations.

Accepted for publication March 2, 2016.

Funding: This study was supported by the Department of Pediatric Anesthesiology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, Chicago, Illinois, and Department of Pediatric Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, The Ohio State University, Columbus, Ohio.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Gildasio S. De Oliveira Jr., MD, MSCI, Department of Anesthesiology, Northwestern University, 241 East Huron St. F5-704, Chicago, IL 60208. Address e-mail to g-jr@northwestern.edu.

Neonatal patients (<1 month old) present a unique challenge in postoperative pain management. Neonates are complex, given their immature metabolic pathways and physiologic response to analgesic medications. Furthermore, neonates are at risk for having undertreated pain.1 Undertreated pain in neonates has been linked to undesirable long-term effects on cognitive and motor development.2 Because of the complexity of these patients, there is no single solution that provides the safest, most effective, and least deleterious method of pain control.3

Neuraxial anesthesia has been recognized as an important strategy to minimize pain in neonates.4 In addition, the benefits of using neuraxial anesthesia in this patient population also may include decreased mechanical ventilation time and reduction of the adverse neuroendocrine stress response to surgery.5,6 Nonetheless, safety concerns of using neuraxial catheters in neonates remain one of the primary barriers to research and clinical use of this technique. Studies examining the use of neuraxial anesthesia in neonates have been limited to a single-center analysis; therefore, the external validity (generalizability) of such an analysis is limited.7

The main objective of this study was to examine the safety of neuraxial catheters in neonates across multiple institutions. Specifically, we sought to determine the incidence of overall and individual complications occurring when neuraxial catheters were used for postoperative analgesia in neonates. In addition, we describe studies found in the Pediatric Regional Anesthesia Network (PRAN) database reporting the clinical and technical characteristics of neonatal epidural (neuraxial) catheters placed for postoperative analgesia.

Back to Top | Article Outline

METHODS

The PRAN is a multicenter project to prospectively collect information about pediatric regional anesthetic techniques and complications. Currently, the PRAN database has 20 participating sites, with >91,000 blocks recorded, and is audited regularly for accuracy and completeness. PRAN centers and local primary investigators are listed in Appendix 1. Details of the PRAN database, audits, and methodology have been reported.8

In brief, the PRAN database is a nonrandomized, prospective, observational repository of the details and adverse events associated with every pediatric regional anesthetic placed by an anesthesiologist at each participating center. Data on every neuraxial catheter in patients younger than 1 month postpartum, placed from April 1, 2007, to August 31, 2014, were examined as a subset of the PRAN protocol. Approval for data collection was obtained from the local IRB of each individual site participating in the PRAN. All centers were granted waivers of informed consent by their IRBs because the data had no identifiers and were collected during the course of routine patient care. The study protocol also was approved by the PRAN publication committee.

Data collected included (1) demographic and anthropometrics (age, gender, and weight), (2) the patient’s state of consciousness at the time of the block (awake, sedated, or anesthetized with or without neuromuscular blockade), (3) technology used to place the block, (4) whether a test dose was given, (5) the type and dose of local anesthetic administered, (6) the time of catheter removal and reason for removal, and (7) complications and adverse events defined by the presence of at least 1 of the following intraoperative and/or postoperative factors: catheter malfunction (dislodgment/occlusion), infection, block abandoned (unable to place), block failure (no evidence of block), vascular (blood aspiration/hematoma), local anesthetic systemic toxicity, excessive motor block, persistent neurologic deficit, and other (e.g., intra-abdominal misplacement, tremors). Any identified complication or adverse event was followed up until the complication resolved. Every complication and adverse event, rather than a selected sample, is audited at each site before its entry to the database.

Back to Top | Article Outline

Statistical Analyses

The data are maintained in the PRAN database by Axio Research, LLC (Seattle, WA) and queried by Christie Wolf, the project manager at Axio Research, for the purposes of analysis. All neonatal blocks performed between April 1, 2007, and August 31, 2014 (all available audited data) were analyzed. This data set was further narrowed to include only neuraxial catheters in children younger than 1 month and coded for statistical analysis with the use of software designed by the primary author in Perl and spreadsheet tools in Microsoft Excel 2008 for Mac (Microsoft Corporation, Redmond, WA). Any neonate whose weight was more than the 95th percentile for an infant aged 1 month was resubmitted to the original site for an additional audit before further analysis was performed.

Nonnormally distributed interval and ordinal data are reported as median, range, or interquartile range and were analyzed with the Mann-Whitney U test.9,10 Categorical variables are presented as counts and were evaluated using Fisher exact test. The 95% binomial confidence interval (CI) for the incidence of neuraxial catheter complications was calculated with the Jeffreys method. The coverage properties of that method are similar to others, but it has the advantage of being equal tailed (e.g., for a 95% CI, the probabilities of the interval lying above or below the true value are both close to 2.5%).11 The Clopper-Pearson exact method was used in binomial interval estimations when zero events were observed.

The evidence is limited with regard to optimal dosage of local anesthetics in neuraxial infusions in neonates; an exploratory analysis also was performed to identify patterns of local anesthetic dose and patient demographic characteristics. When the block was dosed with ropivacaine, equipotent doses of ropivacaine were converted to bupivacaine (0.7 mg bupivacaine = 1 mg ropivacaine).12,13 Potentially toxic doses were defined following previously published values (Appendix 2: cutoffs). A 2-tailed P < 0.05 was used to reject the null hypothesis. Data were analyzed with STATA, version 13 (Stata Corp, College Station, TX).

Back to Top | Article Outline

RESULTS

Demographic and Catheter Characteristics

There were 307 neuraxial catheters placed in neonates. Demographic and catheter characteristics of subjects are presented in Table 1. The majority of catheters were placed while the patient was under general anesthesia, 302 of 307 (98%). When the placement technology was documented, 149 of the 281 (53%) catheters were placed without the use of any technology assistance (ultrasound, other radiologic imaging, or nerve stimulation). For thoracic epidural catheters, 87 of 178 (49%) were placed with imaging assistance compared with 37 of 103 (36%) lumbar or sacral catheters, P = 0.046. There was no difference in the use of technology when thoracic/lumbar epidural catheters were compared with caudal epidural catheters, P = 0.16. In addition, the incidence of complications in the catheters using the caudally threaded technique was 18 of 134 (13%) compared with 17 of 135 (13%) for direct puncture, P = 0.86.

Table 1

Table 1

A test dose was used in 196 of 307 (63%) patients having a neuraxial catheter. There was no difference regarding the use of a test dose in caudal catheters, 112 of 168 (66%) compared with lumbar or thoracic epidural catheters 84 of 139 (60%), P = 0.28.

Back to Top | Article Outline

Adverse Events and Complications

There were 41 adverse events and complications recorded, resulting in an overall incidence of complications of 13.3% (95% CI, 9.8%–17.4%). The incidence of specific complications is presented in Table 2. There were no reports of persistent neurologic problems, deep infection, spinal cord injury, or epidural hematoma, resulting in an estimated incidence of any serious complications of 0.3% (95% CI, 0.08%–1.8%). Among the complications, catheter malfunction, catheter contamination, and vascular aspiration during catheter placement were common. The incidence of catheter complications was not different between caudal and epidural catheters (odds ratio [OR], 0.83; 95% CI, 0.42–1.62, P = 0.6). The incidence of complication was also similar in thoracic catheters compared with sacral/lumbar catheters (OR, 1.29; 95% CI, 0.64–2.62, P = 0.47). Combining abandoned and failed blocks, the overall incidence of catheter failure rate was 1.3% (95% CI, 0.8%–1.7%). Catheters were removed because of a complication in 34 of 307 cases (11%; 95% CI, 8%–15%). The incidence of complications was not associated with the weight of patients (P = 0.38) or the use of technology to assist the placement of catheters (P = 0.35). In addition, the incidence of specific complications, such as catheter malfunction and vascular puncture, were not associated with the use of technology (all P > 0.5).

Table 2

Table 2

The median (interquartile range) time to remove catheters was 3 (2–3) days. The median time to catheter removal was shorter in patients who developed a complication (1 [0–2] day compared with patients who did not develop complications (3 [2–4] days, P < 0.001). We calculated the CI for the risk of contamination of catheter insertion by the location of insertion. The OR was 1.1 (95% CI, 0.2–4.7, P = 0.82). This CI is so wide that conclusions could not be made from the data.

A potentially toxic dose of local anesthesia was administered to 17 of 272 (6%) patients intraoperatively, 59 of 272 (20%) postoperatively, and 9 of 272 (3%) both intraoperatively and postoperatively. Thus, 85 of 272 (31%) individual patients received intraoperative and/or postoperative infusions consistent with a potentially toxic local anesthetic dose in neonates. There was a difference in the risk of potentially toxic doses based on the type of local anesthetic used (bupivacaine versus ropivacaine; (OR, 4.0; 95% CI, 1.3–12.7, P = 0.01). The difference in risk of using bupivacaine compared with ropivacaine occurred in postoperative infusions (OR, 4.8; 95% CI, 1.5–15.2, P = 0.007). We calculated the CI for the risk of using potentially toxic intraoperative infusions for bupivacaine compared with ropivacaine. The OR was 1.2 (95% CI, 0.1–10, P = 0.87). This CI is so wide that conclusions could not be made from the data.

Figure 1

Figure 1

The incidence of potentially toxic local anesthetic infusion rates across time is presented in Figure 1. The use of potentially toxic local anesthetic doses was not associated with the patient’s weight (P = 0.72), catheter type (caudal catheter versus epidural, P = 0.13), or catheter location (thoracic versus caudal/lumbar, P = 0.79).

Back to Top | Article Outline

DISCUSSION

The most important finding of the current investigation was the low risk of major complications when neuraxial postoperative analgesic techniques were evaluated across multiple institutions in the United States and abroad. No patients in this cohort were reported to have had any sequelae or complications that were long term, and no complications resulted in prolongation of the hospitalization. Virtually every complication in this cohort was managed by adjusting the catheter infusion or removing the catheter (in the cases of contamination or disconnection). The results of this study suggest that neuraxial catheter techniques are probably safe in neonates undergoing surgery.

Our results are clinically important because postsurgical pain commonly is undertreated in neonates.14 Nonetheless, neuraxial anesthesia was not recommended as a major strategy to mitigate pain in this population in the American Academy of Pediatrics’ policy statement on neonatal pain.15 Moreover, local anesthetics are a very effective tool in the management of pain without deleterious side effects when used appropriately. Neuraxial catheters seem to be a viable technique to minimize postsurgical pain in neonates with local anesthetic infusions, demonstrating safety across a range of institutions and applications.

Another important finding of this study was the high incidence of cases that used a potentially toxic dose of local anesthetic. In addition, the use of toxic doses was more common when bupivacaine was used as a postoperative infusion. Because each institution is deidentified in the database query process, it is not possible to identify whether certain institutions contributed more to this propensity than others. Also, we cannot account for the effect of the addition of new PRAN sites during this time. Nevertheless, the high risk of administering potentially toxic doses of local anesthetics to neonates identified in this study suggests the need for local quality improvement programs to minimize variability in the dosage of local anesthetic administration through neuraxial catheters.

Concern continues to grow in the scientific community and popular media regarding early childhood exposure to anesthetic agents. Recently, there has been a general recommendation to consider delay of nonurgent surgery in children younger than 3 years made by the Food and Drug Administration/International Anesthesia Research Society public/private partnership, SmartTots.16 One potential answer to this concern that presently is being considered is the use of neuraxial anesthesia to limit exposure to anesthetic agents. The General Anesthesia compared to Spinal anesthesia consortium seeks to determine whether neurodevelopment is measurably affected by early childhood exposure to general anesthesia versus spinal anesthesia for necessary surgical procedures.17 Preliminary data from that trial already show some benefits in neonates and infants in terms of reduction in early postoperative apnea rates for patients undergoing a spinal anesthesia versus general anesthesia.18 Data from this consortium should eventually provide answers as to whether regional anesthesia is less deleterious in terms of neurotoxicity versus general anesthesia in children undergoing surgery.

To the best of our knowledge, this is the largest study to date on the safety of neuraxial catheters specific to neonates. Previous studies investigating the use of neuraxial catheters in neonates were limited by examination of a single center or by the inclusion of a wider age range.7,19,20 PRAN investigators recently have published an article on the safety of single-shot caudal techniques in children, but did not specifically evaluate neonates or catheter techniques.21 Our current results on epidural/caudal catheters in neonates, and our previous findings on single-shot caudal blocks support the overall safety of neuraxial anesthesia/analgesia techniques in children.

A 2014 publication from the PRAN database revealed that performance of regional anesthesia under general anesthesia is as safe as performance of regional anesthesia in awake pediatric patients.22 Neonates reported in the PRAN database lack the same comparative cohort of awake patients to consider. Therefore, it is presently unknown whether awake neuraxial catheter placement in neonates would be as safe as placement of these catheters under general anesthesia and warrants additional study.

We noticed that a variety of imaging techniques were used in block placement. This is likely attributable to the heterogeneity of the PRAN centers. Although it would seem intuitive that imaging assistance would increase the safety of these blocks, it did not. Furthermore, the 1 case of a misplaced catheter appearing in the abdominal cavity was placed with ultrasound guidance. Nonetheless, it is important to note that the PRAN database does not have enough granularity to discriminate between real-time guidance versus the simple use of ultrasound prescan. Further studies to determine the value of using imaging techniques to insert neuraxial catheters in neonates are warranted.

Our study should be evaluated within the context of its limitations. Multicenter databases rely on self-reporting, and underreporting of certain elements is always a possibility.23 However, reporting serious complications of neuraxial anesthesia in this database is expected to be reliable, and the rigorous auditing process in the PRAN database should be expected to partially offset this risk. Because the centers are deidentified in the PRAN database, we cannot account for variability among centers. Furthermore, the efficacy of neuraxial catheters cannot be validated because the PRAN database does not collect information on postoperative pain scores or opioid use. Finally, data regarding the use of chloroprocaine in neonates are lacking, but safety limits are suggested by the drug manufacturer and are used in our analysis.

In summary, we have demonstrated that neuraxial catheter techniques for intraoperative and postoperative analgesia appear to be safe in neonates. Further studies to confirm our current results and to establish the efficacy of these techniques across varied surgical procedures are required. Repeated ongoing analysis of the PRAN data in the neonatal will be useful, given the sample size presently available for analysis. We suggest that each center using neuraxial anesthesia techniques in neonates closely evaluate the dose limits for local anesthetic and develop rigorous quality assurance methods to ensure potentially toxic doses are not used. Additional studies on safe dose limits of local anesthetics in neonates are required. Overall, safety concerns should not be considered a barrier to further study of these techniques in neonates.

Back to Top | Article Outline

APPENDIX 1

Contributing Centers and Principal Investigators

  • Seattle Children’s Hospital: Lynn Martin, Adrian Bosenberg, Corrie Anderson, Sean Flack.
  • Children’s Hospital Colorado: David Polaner.
  • Children’s Hospital at Dartmouth: Andreas Taenzer.
  • Lurie Children’s Hospital, Northwestern University: Santhanam Suresh, Amod Sawardekar, Justin Long.
  • Lucile Packard Children’s Hospital at Stanford: Elliot Krane, R. J. Ramarmurthi.
  • Children’s Medical Center, Dallas: Peter Szmuk.
  • The Cleveland Clinic: Sarah Lozano.
  • Children’s Hospital Boston: Karen Boretsky, Navil Sethna.
  • University of Texas, Houston: Ranu Jain, Maria Matuszczak.
  • University of New Mexico: Nicholas Lam, Tim Peterson, Jennifer Dillow.
  • Texas Children’s Hospital: Robert Power, Kim Nguyen, Nancy Glass.
  • Doernbecher Children’s Hospital, Oregon Health Sciences University: Jorge Pineda.
  • Nationwide Children’s Hospital, Ohio State University: Tarun Bhalla.
  • Hospital Municipal Jesus, Rio De Janiero, Brazil: Pedro Paulo Vanzillotta.*
  • American Family Children’s Hospital, University of Wisconsin: Benjamin Walker.
  • Amplatz Children’s Hospital/University of Minnesota: Chandra Castro.
  • Riley Hospital for Children at IU Health: Kristen Spisak, Aali Shah.
  • Hospital for Special Surgery, New York: Kathryn DelPizzo, Naomi Dong.**
  • Egleston Children’s Hospital, Emory University: Vidya Yalamanchili.
  • Children’s of Mississippi, University of Mississippi: Madhankumar Sathyamoorthy.
  • Columbia University: Susumu Ohkawa.*
  • University Hospital Rijeka, Croatia: Helga Usljebrka.*
  • Children’s Healthcare of Atlanta at Egleston: Vidya Yalamanchili, Claudia Venable.**
  • Joe DiMaggio Children’s Hospital: Lisa Chan.**
  • Selçuk University, Konya, Turkey: Seza Apiliogullari.**

*No longer a Pediatric Regional Anesthesia Network member, but data included in this analysis.

**Current Pediatric Regional Anesthesia Network member, no data included in this analysis.

Back to Top | Article Outline

APPENDIX 2

Toxic Dose Thresholds for Local Anesthetic in Neonates24,25

  • Infusion dose
    • Lidocaine 0.8 mg/kg/h
    • Ropivacaine 0.3 mg/kg/h
    • Bupivacaine 0.2 mg/kg/h
    • Chloroprocaine 12 mg/kg/h
  • Bolus dose
    • Lidocaine 4 mg/kg
    • Lidocaine with epinephrine 7 mg/kg
    • Bupivacaine 2.5 mg/kg
    • Ropivacaine 3 mg/kg
    • Chloroprocaine 12 mg/kg
Back to Top | Article Outline

DISCLOSURES

Name: Justin B. Long, MD, FAAP.

Contribution: This author helped design the study, conduct the study, analyze the data, and prepare the manuscript.

Attestation: Justin B. Long approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Anita S. Joselyn, MD.

Contribution: This author helped design the study, conduct the study, and prepare the manuscript.

Attestation: Anita S. Joselyn approved the final manuscript.

Name: Tarun Bhalla, MD, FAAP.

Contribution: This author helped design the study, conduct the study, and prepare the manuscript.

Attestation: Tarun Bhalla approved the final manuscript.

Name: Joseph D. Tobias, MD, FAAP.

Contribution: This author helped design the study, conduct the study, and prepare the manuscript.

Attestation: Joseph D. Tobias approved the final manuscript.

Name: Gildasio S. De Oliveira Jr., MD, MSCI.

Contribution: This author helped design the study, conduct the study, analyze the data, and prepare the manuscript.

Attestation: Gildasio S. De Oliveira approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, and is the archival author for data.

Name: Santhanam Suresh, MD, FAAP.

Contribution: This author helped design the study, conduct the study, and prepare the manuscript.

Attestation: Santhanam Suresh approved the final manuscript.

This manuscript was handled by: James A. DiNardo, MD.

Back to Top | Article Outline

REFERENCES

1. Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med 1987;317:1321–9.
2. Grunau RE, Whitfield MF, Petrie-Thomas J, Synnes AR, Cepeda IL, Keidar A, Rogers M, Mackay M, Hubber-Richard P, Johannesen D. Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants. Pain 2009;143:138–46.
3. McPherson C, Grunau RE. Neonatal pain control and neurologic effects of anesthetics and sedatives in preterm infants. Clin Perinatol 2014;41:209–27.
4. Lönnqvist PA. Regional anaesthesia and analgesia in the neonate. Best Pract Res Clin Anaesthesiol 2010;24:309–21.
5. Bösenberg A, Hadley GP, Wiersma R. Oesophageal atresia: caudo-thoracic epidural anaesthesia reduces the need for post-operative ventilatory support. Pediatr Surg Int 1992;7:289–91.
6. Wolf AR, Hughes D. Pain relief for infants undergoing abdominal surgery: comparison of infusions of i.v. morphine and extradural bupivacaine. Br J Anaesth 1993;70:10–6.
7. Bösenberg AT. Epidural analgesia for major neonatal surgery. Paediatr Anaesth 1998;8:479–83.
8. Polaner DM, Taenzer AH, Walker BJ, Bosenberg A, Krane EJ, Suresh S, Wolf C, Martin LD. Pediatric Regional Anesthesia Network (PRAN): a multi-institutional study of the use and incidence of complications of pediatric regional anesthesia. Anesth Analg 2012;115:1353–64.
9. Divine G, Norton HJ, Hunt R, Dienemann J. Statistical grand rounds: a review of analysis and sample size calculation considerations for Wilcoxon tests. Anesth Analg 2013;117:699–710.
10. Dexter F. Wilcoxon-Mann-Whitney test used for data that are not normally distributed. Anesth Analg 2013;117:537–8.
11. Dann RS, Koch GG. Review and evaluation of methods for computing confidence intervals for the ratio of two proportions and considerations for non-inferiority clinical trials. J Biopharm Stat 2005;15:85–107.
12. Lee YY, Ngan Kee WD, Fong SY, Liu JT, Gin T. The median effective dose of bupivacaine, levobupivacaine, and ropivacaine after intrathecal injection in lower limb surgery. Anesth Analg 2009;109:1331–4.
13. Cox B, Durieux ME, Marcus MA. Toxicity of local anaesthetics. Best Pract Res Clin Anaesthesiol 2003;17:111–36.
14. Hall RW. Anesthesia and analgesia in the NICU. Clin Perinatol 2012;39:239–54.
15. American Academy of Pediatrics, Committee on Fetus and Newborn, Section on Surgery, and Section on Anesthesiology and Pain Medicine, Canadian Paediatric Society, Fetus and Newborn Committee. Prevention and management of pain in the neonate: an update. Pediatrics 2006;118:2231–41.
16. Rappaport BA, Suresh S, Hertz S, Evers AS, Orser BA. Anesthetic neurotoxicity—clinical implications of animal models. N Engl J Med 2015;372:796–7.
17. Davidson AJ, McCann ME, Morton N. Protocol 09PRT/9078: a multi-site randomised controlled trial to compare regional and general anaesthesia for effects on neurodevelopmental outcome and apnoea in infants: the GAS study (ACTRN12606000441516, NCT00756600). Lancet. Available at: http://www.thelancet.com/protocol-reviews/09PRt-9078. Accessed November 13, 2015
18. Davidson AJ, Morton NS, Arnup SJ, de Graaff JC, Disma N, Withington DE, Frawley G, Hunt RW, Hardy P, Khotcholava M, von Ungern Sternberg BS, Wilton N, Tuo P, Salvo I, Ormond G, Stargatt R, Locatelli BG, McCann MEGeneral Anesthesia compared to Spinal anesthesia (GAS) Consortium. General Anesthesia compared to Spinal anesthesia (GAS) ConsortiumApnea after awake regional and general anesthesia in infants: the general anesthesia compared to spinal anesthesia study—comparing apnea and neurodevelopmental outcomes, a randomized controlled trial. Anesthesiology 2015;123:38–54.
19. Llewellyn N, Moriarty A. The national pediatric epidural audit. Paediatr Anaesth 2007;17:520–33.
20. Wolf AR, Eyres RL, Laussen PC, Edwards J, Stanley IJ, Rowe P, Simon L. Effect of extradural analgesia on stress responses to abdominal surgery in infants. Br J Anaesth 1993;70:654–60.
21. Suresh S, Long J, Birmingham PK, De Oliveira GS Jr. Are caudal blocks for pain control safe in children? An analysis of 18,650 caudal blocks from the Pediatric Regional Anesthesia Network (PRAN) database. Anesth Analg 2015;120:151–6.
22. Taenzer AH, Walker BJ, Bosenberg AT, Martin L, Suresh S, Polaner DM, Wolf C, Krane EJ. Asleep versus awake: does it matter?: pediatric regional block complications by patient state: a report from the Pediatric Regional Anesthesia Network. Reg Anesth Pain Med 2014;39:279–83.
23. Auroy Y, Benhamou D, Amaberti R. Risk assessment and control require analysis of both outcomes and process of care. Anesthesiology 2004;101:815–7.
24. Berde CB. Convulsions associated with pediatric regional anesthesia. Anesth Analg 1992;75:164–6.
25. Ross AK, Bryskin RB. Davis PJ, Cladis FP, Motoyama EK, Regional anesthesia. In: Smith’s Anesthesia for Infants and Children. 2011:8 ed. Philadelphia, PA: Mosby, 452–510.
© 2016 International Anesthesia Research Society