Society for Pediatric Anesthesia

Section Editor: James DiNardo

The Use of Neuraxial Catheters for Postoperative

Analgesia in Neonates: A Multicenter Safety Analysis
from the Pediatric Regional Anesthesia Network
Justin B. Long, MD, FAAP,* Anita S. Joselyn, MD, Tarun Bhalla, MD, FAAP, Joseph D. Tobias, MD, FAAP,
Gildasio S. De Oliveira Jr., MD, MSCI, and Santhanam Suresh, MD, FAAP,* The PRAN Investigators
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. (Anesth Analg 2016;122:196570)

eonatal 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

From the *Department of Pediatric Anesthesiology, Ann & Robert H. Lurie

Childrens 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 Childrens 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 Childrens Hospital of Chicago,
Northwestern University, Chicago, Illinois, and Department of Pediatric
Anesthesiology and Pain Medicine, Nationwide Childrens 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.
Copyright 2016 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000001322

June 2016 Volume 122 Number 6

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
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Safety of Neuraxial Catheters in Neonates

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.

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 patients 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.

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,

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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).

RESULTS
Demographic and Catheter Characteristics

There were 307 neuraxial catheters placed in neonates.

Demographic and catheter characteristics of subjects are
presented in Table1. 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.
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.

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 Table2. There were no reports of persistent neurologic problems, deep infection, spinal cord injury,

anesthesia & analgesia

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Table 1.Patient Demographic and Catheter

Characteristics
Subjects
(n = 307)
Gender
Male
Female
Weight (kg)
ASA physical status
I
II
III
IV
Calendar year of block placement
2007
2008
2009
2010
2011
2012
2013
2014
Catheter location
Sacral caudal
Lumbar caudal
Thoracic caudal
Lumbar epidural
Sacral epidural
Thoracic epidural
Patient state during catheter placement
Awake
Sedated
General anesthesia without neuromuscular
blockade
General anesthesia with neuromuscular blockade
Intraoperative local anesthetic type
Bupivacaine
Ropivacaine
Lidocaine
Chlorprocaine
None
Technology used in block placement
None
Ultrasound
Nerve stimulator
Fluoroscopy contrast
Nerve stimulator and fluoroscopy contrast
Ultrasound and fluoroscopy contrast
Unknown
Postoperative local anesthetic type
Bupivacaine
Ropivacaine
Lidocaine
Chloroprocaine
None/unknown

179
128
3.03 (2.683.5)
12
77
169
49
8
13
14
43
52
71
75
31
34
35
99
40
4
95
4
1
145
157
102
131
8
40
26
149
35
8
70
14
5
26
14
166
1
91
35

Data are presented as median (interquartile range) and counts (n).

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, 0.421.62, P = 0.6). The
incidence of complication was also similar in thoracic catheters compared with sacral/lumbar catheters (OR, 1.29; 95%
CI, 0.642.62, P = 0.47). Combining abandoned and failed

June 2016 Volume 122 Number 6

Table 2.Incidence of Specific Adverse Events and

Complications
Complication type
Catheter malfunction (e.g.,
dislodgement, leaking)
Vascular puncture (e.g., blood
aspiration)
Abandoned block or block
failure
Catheter contamination
Rash/erythema
Dural puncture (e.g.,
aspiration of CSF)
Hypotension
Potential local anesthetic
toxicity (e.g., tremors)
Catheter in abdominal cavity

n
15

Incidence
(95% CI)
4.8% (2.87.7)

1.9% (0.83.9)

1.6% (0.63.5)

9
2
1

2.9% (1.45.2)
0.6% (0.12.0)
0.3% (0.031.5)

1
1

0.3% (0.031.5)
0.3% (0.031.5)

0.3% (0.031.5)

CI = confidence interval; CSF = cerebrospinal fluid.

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).
The median (interquartile range) time to remove catheters was 3 (23) days. The median time to catheter removal
was shorter in patients who developed a complication (1
[02] day compared with patients who did not develop
complications (3 [24] 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, 0.24.7,
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, 1.312.7, P = 0.01). The difference in risk of using
bupivacaine compared with ropivacaine occurred in postoperative infusions (OR, 4.8; 95% CI, 1.515.2, 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, 0.110, P = 0.87).
This CI is so wide that conclusions could not be made from
the data.
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 patients weight (P = 0.72), catheter type (caudal
catheter versus epidural, P = 0.13), or catheter location (thoracic versus caudal/lumbar, P = 0.79).

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Safety of Neuraxial Catheters in Neonates

Figure 1. Line plot demonstrating an upward trend toward greater

rates of potentially toxic local anesthetic doses across years when
neuraxial catheters were used for neonates, P = 0.06. Data were
analyzed with the Fisher exact test.

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.

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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

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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. E

Appendix 1
Contributing Centers and Principal Investigators
Seattle Childrens Hospital: Lynn Martin, Adrian Bosenberg,
Corrie Anderson, Sean Flack.
Childrens Hospital Colorado: David Polaner.
Childrens Hospital at Dartmouth: Andreas Taenzer.
Lurie Childrens Hospital, Northwestern University:
Santhanam Suresh, Amod Sawardekar, Justin Long.
Lucile Packard Childrens Hospital at Stanford: Elliot Krane,
R. J. Ramarmurthi.
Childrens Medical Center, Dallas: Peter Szmuk.
The Cleveland Clinic: Sarah Lozano.
Childrens 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 Childrens Hospital: Robert Power, Kim Nguyen,
Nancy Glass.
Doernbecher Childrens Hospital, Oregon Health Sciences
University: Jorge Pineda.
Nationwide Childrens Hospital, Ohio State University:
Tarun Bhalla.
Hospital Municipal Jesus, Rio De Janiero, Brazil: Pedro
Paulo Vanzillotta.*
American Family Childrens Hospital, University of
Wisconsin: Benjamin Walker.
Amplatz Childrens 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 Childrens Hospital, Emory University: Vidya
Yalamanchili.
Childrens of Mississippi, University of Mississippi:
Madhankumar Sathyamoorthy.

June 2016 Volume 122 Number 6

Columbia University: Susumu Ohkawa.*

University Hospital Rijeka, Croatia: Helga Usljebrka.*
Childrens Healthcare of Atlanta at Egleston: Vidya
Yalamanchili, Claudia Venable.**
Joe DiMaggio Childrens Hospital: Lisa Chan.**
Seluk 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.

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
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.
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