Efficacy and Safety of Wound Catheter Infusion with Ropivacaine After Abdominal Surgery in Children Aged < 1 Year: A Randomized Controlled Trial

Abstract

Background and Objective

Wound catheter infusion (WCI) with local anesthetics provides effective postoperative analgesia in adults, without adverse effects on wound healing. Studies on WCI in infants are scarce. The aim of this study was to investigate the efficacy and safety of WCI with ropivacaine as treatment for postoperative pain in infants.

Methods

We conducted a prospective, randomized, double-blind, placebo-controlled trial including children aged < 1 year undergoing open abdominal surgery. Informed consent was obtained. All children received a wound catheter at the end of surgery and were randomized for treatment with either ropivacaine (bolus dose of 2 mg/kg and continuous infusion of 0.2 mg/kg/h) (R-group) or placebo (C-group), for 72 h postoperatively. The C-group received morphine 100 mcg/kg intravenously at the end of surgery, the R-group received placebo. Standard analgesia postoperatively was paracetamol intravenously and rescue morphine intravenously. Primary outcome was the cumulative amount of morphine (mcg/kg) administered in the first 48 hours postoperatively. Secondary outcomes were the number of patients needing morphine, area under the curve over 24 hours of COMFORT-B and Numeric Rating Scale pain scores, incidence of adverse events, and plasma concentrations of ropivacaine.

Results

After inclusion of 30 patients, the study was discontinued because of slow recruitment. In two cases, the wound catheter was accidentally displaced directly after surgery, therefore data of 28 children were analyzed (14 R-group, 14 C-group). Median [interquartile range] cumulative amount of morphine (mcg/kg) administered within 48 hours postoperatively was 0.0 [0.0–642.2] in the R-group, compared with 240.1 [15.1–759.0] in the C-group (P = 0.068). In the R-group, 6/14 children required morphine compared with 13/14 in the C-group (P = 0.013). Pain scores were not significantly different between groups. Plasma concentrations of ropivacaine stayed below toxic thresholds.

Conclusions

Cumulative morphine use postoperatively was not significantly different between infants receiving WCI with ropivacaine or placebo, although a lower number in the R-group required morphine. Wound catheter infusion provided adequate analgesia, with no signs of local anesthetic toxicity. The study may have been underpowered because of early discontinuation.

Clinical Trial Registration

The study was registered in EudraCT (2015-002209-12), and the Dutch Trial Registry NTR6130 on 23 November, 2016 (International Clinical Trials Registry Platform NL-OMON20504).

Key Points

In infants aged < 1 year receiving ropivacaine via wound catheter infusion after abdominal surgery, cumulative morphine requirements during the first 48 hours postoperatively were not significantly different compared with infants receiving placebo, although a significantly lower number of infants receiving ropivacaine needed any morphine.

Wound catheter infusion showed to be a feasible and safe technique, with plasma concentrations of ropivacaine remaining below toxic thresholds.

Introduction

The treatment of postoperative pain in children remains a challenge in pediatric healthcare. Analgesic medication such as opioids are used regularly after major surgical procedures in children; however, young children are vulnerable to the side effects of opioids, especially respiratory depression [1]. Morphine administration may even prolong the need for ventilator support in infants [1].

Regional anesthesia (RA) techniques for the treatment of postoperative pain have increased in popularity in pediatric anesthesia, especially since the introduction of ultrasound. Large cohort studies demonstrated that these techniques are safe to use in children, even when performed under general anesthesia [2–4]. The advantage of RA is the possibility of reducing morphine requirements postoperatively [5].

Subcutaneous wound catheter infusion (WCI) with local anesthetics (LA) is a relatively new RA technique that produces effective postoperative analgesia in adults [6–8]. The catheter is inserted by the surgeon under direct vision, which makes it an easy, safe, and straightforward technique. Wound catheter infusion was associated with low pain scores comparable to epidural analgesia, decreased morphine consumption, reduced length of stay, normal postoperative recovery, and was not associated with any adverse effects on wound healing [6, 7, 9].

In children, WCI has been described after iliac crest bone harvesting, abdominal surgery, sternotomy, thoracotomy, and orthopedic surgery [10–17]. Wound catheter infusion provided good postoperative analgesia after abdominal and extremity surgery and was not associated with any adverse events on wound healing. In one study, the lower requirement for morphine was associated with an earlier return of bowel function [15]. Most of these studies included children aged > 3 years. Few data are available on the efficacy and safety of WCI for the treatment of postoperative pain in neonates and infants, who would benefit especially from an opioid-sparing effect [16, 18].

Some studies measured plasma concentrations of LA in children, which remained within acceptable safety limits during continuous WCI [11, 15, 16, 18]. Ropivacaine appears to be the least toxic of the available long-acting LA, and should therefore preferably be used in children [19, 20]. Only one study measured plasma concentrations of ropivacaine during WCI in children (mean age 11 years), after reconstructive surgery of microtia [21]. During 48 h of WCI with ropivacaine 0.2% at 2–4 mL/h, plasma concentrations were maintained below the limits for central nervous and cardiovascular system toxicity.

The aim of this study was to determine if WCI with ropivacaine in infants aged < 1 year after abdominal surgery reduces postoperative pain and leads to a morphine-sparing effect of at least 30%. We also investigated whether WCI with ropivacaine is safe in this patient group, and results in non-toxic plasma concentrations of ropivacaine.

Methods

Study Design

This single-center, prospective, randomized, double-blind, placebo-controlled study was performed at Erasmus MC Sophia Children’s Hospital, Rotterdam, the Netherlands from January 2018 until May 2022. We investigated the hypotheses that WCI with ropivacaine leads to a morphine-sparing effect after abdominal surgery in infants aged < 1 year.

The Medical Ethics Committee of Erasmus MC approved this study on 21 June, 2017 (MEC-2017-074). This study was conducted in compliance with the current revision of the Declaration of Helsinki. Written informed consent was obtained from all parents or legal guardians of the children included in the study.

The study was registered in EudraCT (2015-002209-12) and the Dutch Trial Registry NTR6130 on 23 November, 2016 (International Clinical Trials Registry Platform NL-OMON20504). This manuscript adheres to the CONSORT guidelines.

Inclusion criteria were: children aged < 1 year, undergoing elective open abdominal surgery, post-conceptual age ≥ 35 weeks, and body weight ≥ 1500 g. Exclusion criteria were neurological disease, renal or hepatic dysfunction, receiving extra-corporeal membrane oxygenation therapy, long-term opioid or psychotropic drug (e.g., antiepileptic drugs, benzodiazepines, antidepressants) exposure pre- or postnatal, opioid exposure < 24 h before surgery, allergy to paracetamol, LA, or morphine, and contra-indications for RA (local or generalized infection).

Standard Anesthesia Protocol

Anesthesia was induced using propofol 1–4 mg/kg intravenously (IV) or by inhalation induction, using sevoflurane in a mixture of oxygen and air. Fentanyl 2 mcg/kg and rocuronium 0.6 mg/kg were administered IV before tracheal intubation. Anesthesia was maintained with sevoflurane at mean alveolar concentration (MAC) 0.7–1.0 in oxygen/air. Monitoring consisted of an electrocardiogram, non-invasive blood pressure, oxy-hemoglobin saturation, end-tidal CO₂, and temperature. Additional doses of fentanyl 2 mcg/kg IV were administered, based on a heart rate or blood pressure increase. If possible, patients were extubated directly postoperatively. Children aged < 3 months (or < 60 weeks post-conceptual age in the case of prematurity) were admitted to the pediatric intensive care unit (PICU) postoperatively according to the local protocol.

Investigational Treatment

All children received a multi-hole wound catheter with holes over a trajectory of either 2.5 or 6.5 cm, depending on the length of the incision (On Q^® Soaker Catheter; Halyard, Alpharetta, GA, USA). At the end of surgery, following closure of the muscle layers and fascia, the surgeon placed the wound catheter superficial to the muscle fascia under direct vision. The catheter was tunneled from a separate stab incision approximately 3 cm lateral to the wound. Thereafter, subcutaneous tissue and skin were sutured. The catheter was fixed to the skin using an adhesive plaster.

Included children were randomized for treatment with WCI with ropivacaine (R-group) or placebo (0.9% saline) [control or C-group], with 1:1 allocation. Hospital pharmacists performed randomization and prepared the blinded medication. A randomization schedule was made prior to the study, and codes were stored and kept solely by the pharmacist to ensure blinding until the end of the study. Surgical team, ward personnel, Acute Pain Service, and caregivers were all blinded to the treatment.

Before the end of anesthesia, the children received a bolus dose via the wound catheter of ropivacaine 2 mg/kg (= 1 mL/kg of ropivacaine 0.2%) (R-group) or the same amount of placebo (C-group). Thereafter, the wound catheter was connected to a syringe in a perfusor pump, administering a constant infusion of ropivacaine 0.1% at 0.2 mg/kg/h (R-group) or placebo (C-group).

At the end of the procedure, the C-group received a loading dose of morphine 100 mcg/kg IV to guarantee good analgesia at emergence of anesthesia in this group. The R-group received placebo IV.

Assessment and Treatment of Postoperative Pain

All patients received the first dose of paracetamol 20 mg/kg IV 30 minutes before the end of surgery. Intravenous paracetamol was continued postoperatively as a standard analgesic (60 mg/kg/day). In children aged 4 months and older, non-steroidal anti-inflammatory drugs, diclofenac or ibuprofen, were added to the standard analgesic regimen.

Postoperative pain was assessed every 2 h on the first day postoperatively, and after that on a regular basis, using the COMFORT Behavior Scale and Numeric Rating Scale (NRS) pain, as observed by the nurses [22]. Patients received rescue morphine doses, whenever the NRS was ≥ 4 and COMFORT ≥ 17, according to the local protocol, published by Ceelie et al. [23]. Doses of additional morphine 15 mcg/kg IV were administered every 10 min whenever needed, with a maximum of three times. Ten minutes after each extra dose of morphine, pain was reassessed. If there was no improvement, an additional dose of morphine 100 mcg/kg IV was administered and continuous morphine infusion was started. This could be increased, and other pain medication (esketamine, clonidine) or sedation could be added at the discretion of the attending physician. The infusion rate of WCI was kept constant until the removal of the wound catheter by the Acute Pain Service nurses at 72 h postoperatively.

Primary and Secondary Outcomes of the Study

The primary outcome of the study was the cumulative amount of morphine administered within the first 48 h postoperatively (mcg/kg) compared between both groups. Secondary outcomes were the number of patients needing extra morphine boluses within the first 48 h postoperatively, total amount of morphine administered postoperatively until removal of the wound catheter, area under the curve (AUC) over 24 h of COMFORT-B scores and NRS pain scores, percentage of high pain scores (NRS ≥ 4 and COMFORT ≥ 17), and the incidence of adverse events related to the wound catheter and the use of opioids and ropivacaine, including plasma concentrations of ropivacaine.

Adverse events related to the wound catheter and the administration of ropivacaine and opioids were recorded. Adverse events related to underlying disease and regular postoperative care were not recorded. Time until extubation, time until discharge from the PICU (if applicable), time to first feeding, and surgical stress score (SSS) were recorded [24]. An interim analysis of the primary outcome and safety (adverse events and plasma concentrations) was planned after the inclusion of 30 patients.

Plasma Concentrations of Ropivacaine

Samples for plasma concentrations of ropivacaine were collected until 72 h postoperatively, when venous blood sampling was needed for clinical purposes. Blood samples of 500 mcl were taken in CAT serum tubes and within 48 h these were centrifuged for 6 minutes at 20 °C with 3000 revolutions per minute. Plasma was stored in cryotubes at – 80 °C until shipment. The clinical pharmacology laboratory of the University Medical Centre Groningen, Groningen, the Netherlands analyzed total and unbound plasma concentrations of ropivacaine using liquid chromatography-mass spectrometry with a lower limit of quantification (LLQ) of 0.05 mg/L. If the total plasma concentration of ropivacaine was above the LLQ, free concentration of ropivacaine was analyzed further.

Sample Size Calculation

For the primary aim of the study, the calculation of the sample size was based on a previous study on the use of morphine postoperatively in children aged < 1 year after major surgery in our hospital [23]. We considered a 30% reduction in the cumulative morphine dose up to 48 h postoperatively in the R-group compared with controls to be clinically relevant. The number of patients required in each group was 26, as shown by a power analysis, in which the level of significance was 0.05 and the desired statistical power was 0.8. Considering a drop-out rate of 15%, the number of patients included in this trial was 60 (30 in each group). This sample size also provided sufficient power (> 80%) to detect a difference in the AUC of the COMFORT scores between groups with 0.8 standard deviations, using an independent samples t-test with a significance level of 0.05.

Statistical Analysis

Statistical analyses were performed using SPSS Statistics, version 28.0.1.0 (IBM Corporation, Armonk, NY, USA). The distribution of clinical characteristics was assessed using descriptive statistics. Primary outcome was compared between the randomization arms using the Mann–Whitney U test. Comparisons between randomization arms were performed using the Mann–Whitney U test for continuous variables and Fisher’s exact test for categorical variables. The AUC of the COMFORT and NRS scores during the first 24 h postoperatively were compared between randomization arms using the Mann–Whitney U test. A multivariable linear regression analysis was performed with the log-transformed values of cumulative morphine after 48 h as outcome and group allocation as predictors, and age, weight, gestational age at birth, and SSS as covariates.

Results

From January 2018 until May 2022, of the 177 children aged < 1 year undergoing elective abdominal surgery in the Erasmus MC Sophia Children’s Hospital, 30 were included in the trial (Fig. 1, CONSORT flow diagram). These children were randomized and all received a wound catheter. In two children (one R-group, one C-group), directly postoperatively, the wound catheter was accidentally displaced, therefore continuous administration of ropivacaine/placebo was not started. Data on morphine need and pain scores from these children were not used in the analysis. Of the remaining 28 children, 14 were allocated to the R-group and 14 to the C-group.

Fig. 1.

CONSORT 2010 flow diagram. SSRIs selective serotonin reuptake inhibitors

In two children (both C-group), morphine intravenous rescue medication was not administered according to the protocol, which was considered a protocol violation. In three cases, the wound catheter was removed before 72 h postoperatively because the child was ready to be discharged from the hospital (one R-group, two C-group). Additionally, in two children, the wound catheter was accidentally displaced postoperatively (one R-group after 34 h, one C-group after 41 h). Data from all these children were included in the analysis (intention to treat).

Because of slow inclusion, recruitment was stopped after 30 patients over a 4-year inclusion period, on the advice of the Data Safety Monitoring Board. This moment was chosen because an interim analysis was already planned after including 30 patients.

Patient characteristics are presented in Table 1. The groups were comparable in terms of age and weight on the day of surgery, male/female ratio, birth weight, and gestational age at birth. In the R-group, 33.3% of the children were born prematurely, compared with 20% in the C-group, which was also reflected in their medical history (necrotizing enterocolitis and respiratory problems in the neonatal period). Types of surgery are described in Table 1, with the R-group undergoing more ileostomy closures than controls. Children undergoing abdominal surgery had a horizontal laparotomy incision, and in the children undergoing renal surgery, this was performed via a lumbotomy. Duration of surgery was comparable between groups, as were the SSS and the need for perioperative analgesics (fentanyl). In both groups, an equal percentage of children were admitted to the PICU postoperatively, and an equal percentage was prescribed non-steroidal anti-inflammatory drugs as a standard analgesic in addition to the standard paracetamol postoperatively.

Table 1.

Patient and surgery characteristics

	Ropivacaine group (n = 15)	Control group (n = 15)
Gestational age at birth (weeks)	37.6 [34.4–40.2]	38.0 [36.5–39.5]
Birth weight (kg)	3.0 [2.5–3.4]	3.0 [2.4–3.4]
Male/female	11 (73.3)/4 (26.7)	9 (60)/6 (40)
Age at day of the operation (days)	105 [60–174]	111 [66–147]
Weight at day of the operation (kg)	5.4 [3.5–7.3]	5.9 [4.7–6.5]
Type of operation (n)
Closure ileostomy	9	5
Closure colostomy	1	4
Partial kidney resection	0	2
Pyeloplasty	3	3
Recurrent diaphragmatic hernia closure	0	1
Laparotomy for duodenal atresia/web	2	0
Duration of surgery (h:min)	1:41 [1:12–1:55]	1:51 [1:08–2:07]
Dose of fentanyl during the operation (mcg/kg)	5.6 [3.7–6.8]	6.2 [4.6–9.4]
Surgical Stress Score	7.0 [7.0–9.0]	9.0 [7.0–10.0]
Comorbidity
Prematurity (< 37 weeks at birth)	5 (33.3)	3 (20.0)
History of necrotizing enterocolitis	2 (13.3)	0
Respiratory problems in neonatal period (IRDS, BPD, needing mechanical ventilation)	5 (33.3)	4 (26.7)
ASA classification
ASA I	3 (20.0)	0
ASA II	7 (46.7)	9 (60.0)
ASA III	5 (33.3)	6 (40.0)
Admission to the PICU postoperatively	9 (60.0)	9 (60.0)

Data are presented as n (%) for categorical values and as median [interquartile range] for continuous values

ASA American Society of Anesthesiologists, BPD bronchopulmonary dysplasia, h hours, IRDS infant respiratory distress syndrome, min minutes, PICU pediatric intensive care unit

Morphine Requirements Postoperatively

The cumulative amount of morphine administered to children in the R-group until 48 h postoperatively (median [interquartile range, IQR]) was 0.0 [0.0–642.2] mcg/kg versus 240.1 [15.1–759.0] mcg/kg in the C-group (P = 0.068) [Table 2]. The amount of morphine administered in the periods 0–24 h, 24–48 h, and 48–72 h postoperatively was low in the R-group: median 0.0 mcg/kg in all periods (Table 2, Fig. 2). However, this was also not statistically different compared to the C-group.

Table 2.

Primary and secondary outcomes

	Ropivacaine group (n = 14)	Control group (n = 14)	P value
Morphine administered until 48 h postop (mcg/kg)	0.0 [0.0–642.2]	240.1 [15.1–759.0]	0.068
Morphine administered 0–24 h postop (mcg/kg)	0.0 [0.0–375.0]	162.3 [15.0–405.5]	0.067
Morphine administered 24–48 h postop (mcg/kg)	0.0 [0.0–267.3]	80.5 [0.0–353.0]	0.404
Morphine administered 48–72 h postop (mcg/kg)	0.0 [0.0–215.2]	0.0 [0.0–252.0]	0.760
Duration of wound catheter infusion (hours)a	72.0 [69.0–73.0]	71.0 [47.0–73.0]	0.389
Number of pts needing morphine until 48 h postop	6 (42.9)	13 (92.9)	0.013*
Number of pts administered NSAIDs postoperatively (as standard analgesic)	3 (21.4)	3 (21.4)	1.00
Number of pts needing extra analgesics or sedatives	0	4 (28.6)b	0.098
Clonidine	0	2
Esketamine	0	1
Midazolam	0	2
Time until extubation postoperatively (min)a	22 [16–841]	20 [11–46]	0.806
Time until discharge from the PICU (h)	44.1c [21.9–73.6]	48.1d [35.9–84.3]	0.673
Time to first feeding (h)	57.7 [8.1–86.1]	58.3 [4.2–86.1]	0.890
AUC COMFORT-B scores, 0–24 h	12.1 [11.5–13.8]	13.3 [11.9–14.4]	0.329
Percentage of COMFORT-B ≥17, 0–24 h	13.4 [0.0–23.8]	14.4 [7.1–41.9]	0.306
AUC NRS pain, 0–24 h	1.0 [0.1–2.3]	1.5 [0.6–2.9]	0.454
Percentage of NRS pain ≥4, 0–24 h	12.4 [0.0–25.7]	7.4 [0.0–50.0]	0.734

Data are presented as n (%) for categorical values and as median [interquartile range] for continuous values

AUC area under the curve, h hours, min minutes, NRS numeric rating scale, NSAIDs non-steroidal anti-inflammatory drugs, PICU pediatric intensive care unit, postop postoperatively, *P < 0.05, statistically significant

^aTwo patients (n = 1 in ropivacaine group and n = 1 in control group) with accidental dislocation of the wound catheter directly postoperatively. Both patients were extubated at the time of catheter dislocation

^bOne patient needed both esketamine and clonidine postoperatively

^cn = 8 patients admitted to the PICU

^dn = 9 patients admitted to the PICU

Fig. 2.

Morphine requirements postoperatively (postop). a The total amount of morphine (mcg/kg) administered per day, on days 1, 2, and 3 postop, in both patients groups (ropivacaine and control groups)

Six out of 14 children in the R-group needed administration of rescue doses or continuous infusion of morphine in the first 48 hours postoperatively (Table 2), compared with 13 of 14 children in the C-group, a statistically significant difference (P = 0.013). The six children in the R-group requiring morphine all underwent an ileostomy closure. Children in the R-group undergoing closure of colostomy (n = 2), pyeloplasty (n = 3), or laparotomy (n = 2) did not need any rescue analgesia postoperatively, as did one child undergoing ileostomy closure. The only child in the C-group who did not require any morphine underwent a partial nephrectomy. In four children in the C-group, additive analgesia (esketamine and/or clonidine) or sedation was needed; this was not necessary in any child in the R-group; however, this difference was not significant.

As the majority of children underwent an ostomy (either ileostomy or colostomy) closure (n = 9 R-group and n = 8 C-group), we analyzed the morphine requirements of this group separately. The cumulative amount of morphine administered until 48 h postoperatively (median [IQR]) was 158.8 [0.0–831.0] mcg/kg in the R-group versus 677.3 [202.4–898.0] mcg/kg in the C-group, which was not statistically significantly different (P = 0.177). A multivariable linear regression analysis revealed no significant effect of age, weight, gestational age at birth, or SSS on morphine requirements postoperatively.

Pain Assessment

In the 28 children included in the analysis, 403 COMFORT-B scores were assessed in the first 24 h postoperatively (mean 14 scores per child; range 7–23). The median [IQR] AUC of COMFORT-B scores in the first 24 hours was 12.1 [11.5–13.8] in the R-group, which was not significantly different from the C-group: 13.3 [11.9–14.4] (Table 2). This was also the case for the median [IQR] AUC of the NRS pain scores: 1.0 [0.1–2.3] for the R-group, compared with 1.5 [0.6–2.9] in the C-group. Furthermore, the percentage of high pain scores (COMFORT ≥ 17 or NRS ≥ 4) was not significantly different between the groups.

Adverse Events

Adverse events in all 30 children were analyzed. Of these children, 26 experienced one or more adverse events (range 0–6). No severe adverse events were reported. Sixteen children experienced adverse events related to WCI (n = 8 R-group, n = 8 C-group), mostly fluid leakage from the wound (n = 6 R-group, n = 7 C-group), which was usually mild. In one case (R-group), a wound infection occurred, which was treated with antibiotics and wound drainage. No wound-healing problems were observed. No children experienced signs of local anesthetic systemic toxicity (LAST) during ropivacaine infusion. Fever or signs of intestinal obstruction were recorded frequently (fever in 40% in both groups; signs of intestinal obstruction in 40% in both groups) and were not considered to be related to WCI or the medication administered.

Plasma Concentration of Ropivacaine

A total of 42 blood samples were collected from 21 patients (range 0–4 samples per patient). Thirty-nine blood samples could be analyzed for plasma concentrations of ropivacaine. Seventeen samples were collected from patients in the R-group and 22 from controls. Sixteen R-group samples were taken during continuous administration of ropivacaine; the plasma concentrations (total and unbound) are presented in Fig. 3. One of the blood samples was collected 190 minutes after discontinuation of continuous WCI: total ropivacaine concentration was 1.43 mg/L and the unbound concentration was < 0.05 mg/L.

Fig. 3.

Plasma concentrations of ropivacaine. a Total plasma concentrations of ropivacaine. x-axis: time in minutes, after start of ropivacaine administration. y-axis: concentration ropivacaine in mg/L. Lower limit of quantification 0.05 mg/L. Toxic threshold: 2.3 mg/L (red line) [26]. Each dot represents the concentration of ropivacaine in a separate plasma sample. Each color represents a single patient; in five patients more than one sample was analyzed, these dots are connected. b Free plasma concentrations ropivacaine. x-axis: time in minutes, after start of ropivacaine administration. y-axis: concentration ropivacaine in mg/L. Lower limit of quantification: 0.05 mg/L. Toxic threshold: 0.16 mg/L [25]. Each dot represents the concentration of ropivacaine in a separate plasma sample, of the four out of 16 samples where the concentration of free ropivacaine was above the lower limit of quantification. Each sample represents a single patient (color same as in a)

In all samples from the C-group, total plasma concentrations of ropivacaine were < 0.05 mg/L. The toxic threshold for total plasma concentration of ropivacaine is 2.3 mg/L, all measured concentrations were below this level [25]. The highest level was a total plasma concentration of 2.17 mg/L after 66 h of ropivacaine infusion.

The toxic threshold for the unbound fraction of ropivacaine is 0.16 mg/L [26]. In 13 patients, the unbound plasma concentration of ropivacaine was < 0.05 mg/L, the LLQ. In the four plasma samples where unbound plasma concentration was above the LLQ, the highest concentration was 0.10 mg/L at 1 h and 39 min after bolus ropivacaine and the start of continuous WCI. The concentrations in these four plasma samples are presented in Fig. 3b. The fractions of the unbound plasma concentrations were between 3.2% and 8.8% of the total plasma concentration ropivacaine, where the 8.8% unbound plasma ropivacaine concentrations was also measured after 1 h and 39 min.

Discussion

This study showed that in infants receiving WCI with ropivacaine after abdominal surgery, the cumulative amount of morphine administered in the first 48 h postoperatively was not significantly different compared to controls. However, a significantly lower number of infants who received ropivacaine required morphine postoperatively. Plasma concentrations of ropivacaine were never above toxic thresholds during continuous WCI, and no severe adverse events occurred.

Several studies have been published on WCI with LA in children of different age categories and after different surgical procedures, with various results [10, 12, 27–29]. Hermansson et al. published a randomized controlled trial on the efficacy of WCI with bupivacaine after minor abdominal surgery in 33 children with a mean age of 3.4 years and 2.8 years in controls (receiving 0.9% saline) [12]. On postoperative day 1, patients in the bupivacaine group needed significantly less morphine rescue doses compared with controls.

A study by Popat et al. randomized 30 neonates undergoing laparotomy for WCI with bupivacaine or no wound catheter [29]. Median age [IQR] was 2.5 days [2–4.5] (catheter) and 4 days [2–6] (no catheter). All children received morphine or fentanyl IV continuously postoperatively, and the infusion rate was adjusted based on pain assessments. The median [IQR] cumulative amount of opioid (morphine equivalent) in the first 72 h postoperatively did not significantly differ between groups: 432 [241–1174] mcg/kg in the catheter group versus 771 [406–1010] mcg/kg in controls. This trial also had to be discontinued early because of slow recruitment: 30 of the expected sample size of 70 infants were enrolled. No adverse events were observed. The amount of opioids administered was higher than in our study, which might be partly explained by the type of surgical procedures; half of the patients underwent closure of a congenital diaphragmatic hernia. The duration of postoperative mechanical ventilation was longer (> 48 h), which probably reflects the higher number of patients undergoing major surgical procedures (SSS was not provided) or disease level. Continuous opioid infusion was started immediately after surgery, whereas in our study, morphine was titrated to effect.

Our study is the first to determine ropivacaine plasma concentrations in children aged < 1 year during WCI. In studies in preterm infants and neonates receiving levobupivacaine via WCI after major thoracic or abdominal surgery, plasma concentrations also did not exceed toxic thresholds [16, 18].

Amide LA (such as [levo]bupivacaine and ropivacaine) bind to serum alpha-1-acid glycoprotein [19]. The alpha-1-acid glycoprotein level is very low at birth and progressively increases during the first year of life. Therefore, neonates and young infants have a much higher unbound fraction of LA than adults. Additionally, cytochrome P450 1A2 activity, which metabolizes ropivacaine, is immature before the age of 4–7 years [30]. Therefore, infants are more prone to develop LAST [20], and the toxic threshold for LA may be even lower in neonates. In our study, in only four out of 16 plasma samples, the unbound plasma concentration was above the LLQ, and in these four samples, all concentrations were below the toxic threshold, so apparently administration of ropivacaine via WCI in this dose regimen seems to be safe. However, the number of blood samples in our study was small, which involves a risk of high concentrations to be missed. None of the children in this study developed symptoms of LAST, such as seizures or arrhythmia. Because of their young age, mild signs of toxicity (altered taste or tinnitus) can go unnoticed. We can only conclude that more serious signs of LAST were not detected. We would recommend safety protocols on the pediatric ward when administering LA continuously, via regional or neuraxial catheters, such as the immediate availability of intravenous lipid emulsion in the case of LAST.

In our study, one child developed an incisional hernia and one child developed a wound infection, which are known complications after stoma formation or closure operations in children [31]. An interesting aspect of WCI and postoperative wound healing is that LA seem to have an antimicrobial effect, inhibit local inflammatory responses to injury, and reduce the release of inflammatory mediators [19]. The current study was however underpowered to detect a difference in the incidence of wound infections.

The most important limitation of this study was the discontinuation at 30 inclusions, which may have underpowered the results. If the study could have included a larger sample size, ideally 60 patients as planned, the study might have presented more significant results. Many of the eligible children had a complex history of congenital malformations and hospital and/or intensive care unit admissions. We experienced that this made parents reluctant to participate in a study on postoperative pain. In addition, many children had exclusion criteria; children who had been undergoing a laparotomy as a neonate or were premature in many cases received total parenteral nutrition, sometimes causing increased liver enzymes and/or low albumin levels (n = 23), which is a contra-indication for receiving continuous LA [20, 32]. These factors made the recruitment process slow, and after 4 years, the Data Safety Monitoring Board advised to discontinue the study.

In eight of 14 children receiving WCI with ropivacaine, this technique provided adequate analgesia, with no need for any additional morphine postoperatively. The six children who did require morphine IV all underwent an ileostomy closure. The R-group included more children with a history of prematurity and related problems such as necrotizing enterocolitis, which may reflect on a more complicated abdominal history, and with more intra-abdominal adhesions, which could have influenced the need for opioids postoperatively. Because of the low number of included patients, it is difficult to draw firm conclusions regarding the reasons for the higher morphine demand in patients after an ostomy closure, although our data suggest that providing regional analgesia of the wound by WCI with LA is not sufficient as treatment of postoperative pain in these patients, and a multimodal analgesia approach is required.

Pediatric RA is a safe technique, with a low incidence of complications. Although the risks are considered small in experienced hands, a peripheral regional technique is still considered safer than neuraxial analgesia (such as epidural techniques), especially in children aged < 6 months [2, 33, 34]. Wound catheter infusion could be of benefit in the case of contra-indications for neuraxial analgesia, such as anatomical malformations of the spine, or where there is as risk of epidural hemorrhage [17]. Peripheral blocks of the abdominal wall provide analgesia with a good safety record, especially when performed under ultrasound guidance [34, 35]. However, because these blocks are single-shot blocks, the analgesic effect is short-lived. Wound catheter infusion is a feasible, simple, and safe option for continuous postoperative analgesia. Still, further research comparing the efficacy of WCI with pediatric epidural analgesia is warranted.

Conclusions

This study shows that WCI with ropivacaine after abdominal surgery in infants did not significantly decrease the cumulative amount of morphine required in the first 48 h postoperatively, although the number of children needing morphine postoperatively was reduced. Wound catheter infusion has been shown to be a feasible and safe RA technique, with plasma concentrations of ropivacaine remaining below toxic thresholds.

Declarations

Funding

This work was financially supported by Stichting Coolsingel, Rotterdam, the Netherlands and Stichting Erasmus Fonds Pijngeneeskunde, Rotterdam, the Netherlands.

Conflicts of interest/competing interests

Lonneke M. Staals, Jaap Dogger, Claudia Keyzer-Dekker, Anneke A. Boerlage, Eric F. Bokhorst, Jan J. van Wijk, Jeroen R. Scheepe, Monique van Dijk, Joost van Rosmalen, and Saskia N. de Wildt have no conflicts of interest that are directly relevant to the content of this article. Saskia N. de Wildt is an Editorial Board member of Pediatric Drugs. Sakia N. De Wildt was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Ethics approval

The Medical Ethics Committee of Erasmus MC (Chairperson Prof.dr. H.W. Tilanus) approved this study on 21 June, 2017 (MEC-2017-074). This study was conducted in compliance with the current revision of the Declaration of Helsinki.

Consent to participate

Written informed consent was obtained from all parents or legal guardians of the children included in the study.

Consent for publication

Not applicable.

Availability of data and material

Data are available on reasonable request to the corresponding author.

Code availability

Not applicable.

Authors’ contributions

LMS: contributed to the design of the study, to the acquisition, analysis, and interpretation of the data, drafted the manuscript, revised it critically, and approved the final version for publication. JD: contributed to the acquisition and interpretation of the data, revised the work critically, and approved the final version for publication. CK-D: contributed to the acquisition and interpretation of the data, revised the work critically, and approved the final version for publication. AAB: contributed to the acquisition and interpretation of the data, revised the work critically, and approved the final version of the manuscript. EFB: contributed to the design of the study, the acquisition and interpretation of the data, revised the work critically, and approved the final version of the manuscript. JJvW: contributed to the acquisition and interpretation of the data, revised the work critically, and approved the final version of the manuscript. JRS: contributed to the acquisition and interpretation of the data, revised the work critically, and approved the final version of the manuscript. MvD: contributed to the design of the study and the interpretation of the data, revised the work critically, and approved the final version of the manuscript. JvR: this author contributed to the design of the study, to the analysis and interpretation of the data, revised the work critically, and approved the final version of the manuscript. SNdW: contributed to the design of the study, to the analysis and interpretation of the data, revised the work critically, and approved the final version of the manuscript. All authors agree to be accountable for all aspects of the work and ensure that questions related to the accuracy and integrity of any part of the work are appropriately investigated and resolved.