Clinical Nutrition xxx (xxxx) xxx

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Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Randomized Control Trials

Application of enhanced recovery after surgery during the

perioperative period in infants with Hirschsprung's
disease e A multi-center randomized clinical trial
Jie Tang a, 1, Xiang Liu b, 1, Tongshen Ma c, 1, Xiaofeng Lv a, Weiwei Jiang a, Jie Zhang a,
Changgui Lu a, Huan Chen a, Wei Li a, Hongxing Li a, Hua Xie a, Chunxia Du a,
Qiming Geng a, Jiexiong Feng d, **, Weibing Tang a, *
a
Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing 210000, China
b
Department of Pediatric Surgery, Anhui Provincial Children's Hospital, Hefei 230000, China
c
Department of Pediatric Surgery, Xuzhou Children's Hospital of Xuzhou Medical University, Xuzhou 221000, China
d
Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China

a r t i c l e i n f o s u m m a r y

Article history:
Background & aims: Various enhanced recovery after surgery (ERAS) guidelines have been established
Received 16 June 2019
for several kinds of adult surgeries. While the guidelines for pediatric surgeries remained to be explored.
Accepted 2 October 2019
The aim of the study was to prospectively evaluate the safety and efficacy of an ERAS protocol for
Hirschsprung's disease (HSCR) infants undergoing pull-through procedures.
Keywords:
Methods: An infant-specific ERAS protocol was developed and implemented at multiple centers from
Enhanced recovery after surgery (ERAS)
Pediatric surgery June 1, 2016 to December 31, 2017. The study included 145 consecutive patients who underwent pull-
Infant through surgery for HSCR in three Children's hospitals. Patients were primarily divided into three
Hirschsprung's disease groups based on the clinical classification and surgical methods. Group I included patients with the short
Perioperative management segment type who received transanal endorectal pull-through (TEPT) surgery. Group II comprised of
patients with the classical type and long segment type who received laparoscopic-assisted pull-through
(LAPT) surgery. Group III involved patients with the long segment type (who had received ileostomy or
colostomy during the neonatal period) and total colonic aganglionosis who received open pull-through
(OPPT) surgery. Patients in the three groups mentioned above were randomly and equally assigned into
the ERAS group and traditional (TRAD) group with random number table row randomization. The pri-
mary outcome was the length of postoperative hospital stay (LOS). Secondary outcomes of interest
included white blood cell (WBC) and C-reactive protein (CRP) on postoperative day 1 (POD 1), the blood
glucose at the time of anesthesia and 24 h after surgery, time to first defecation, time to regular diet,
plasma markers of nutrition status on POD 5, plasma natrium on POD 5, the mean intraoperative fluid
volume, time to discontinuation of intravenous infusion, incidence of postoperative complications, re-
admission within 30 days, hospitalization costs, parental satisfaction, and growth from admission to 6
months after surgery.
Results: 73 and 75 patients were assigned to the TRAD and ERAS groups, respectively. There were no
significant differences in demographic data. The LOS decreased from 9.5 days in the TRAD group to 7.9
days (P < 0.001) in the ERAS group. WBC count on POD 1 showed no significant difference between the
two groups. CRP on POD 1 in the ERAS group was significantly lower (P < 0.001). In the ERAS group, the
blood glucose was higher at anesthesia compared to the TRAD group (P < 0.001). On the contrary, the
blood glucose at 24 h after surgery was significantly lower in the ERAS group (P < 0.001). Intraoperative
fluid volume was lower in the EARS group (P < 0.001). ERAS could also reduce the time to first defecation
(P < 0.001), discontinuation of intravenous infusion (P < 0.001) and regular diet (P < 0.001). In the ERAS
group, the concentrations of prealbumin and retinol conjugated protein on POD 5 were higher than those

* Corresponding author. Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210000, China.
** Corresponding author. Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan
430000, China.
E-mail addresses: [email protected] (W. Tang), [email protected] (J. Feng).
1
Contributed equality.

https://doi.org/10.1016/j.clnu.2019.10.001
0261-5614/© 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Please cite this article as: Tang J et al., Application of enhanced recovery after surgery during the perioperative period in infants with
Hirschsprung's disease e A multi-center randomized clinical trial, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.10.001
2 J. Tang et al. / Clinical Nutrition xxx (xxxx) xxx

in the TRAD group (P < 0.001, P < 0.001, respectively). The plasma natrium had no difference in the two
groups on POD 5 (P > 0.05). The rate of complications (P > 0.05) and 30-day re-admission (P > 0.05) were
not significantly different between the two groups. Hospitalization costs were also reduced (P < 0.001).
ERAS group has a higher parental satisfaction rate, although there was no statistical difference (96% vs
89%). There was no difference in growth between the ERAS and the TRAD groups from admission to 6
months after the surgery (weight for age z score: P > 0.05, weight for length z score: P > 0.05). We also
found that the shortening of LOS by the application of ERAS protocol was more obvious in the OPPT group
( 2.5 ± 1.0) than that in the TEPT ( 1.9 ± 1.3) and LAPT ( 1.3 ± 0.4) groups.
Conclusions: Implementation of the ERAS protocol in infants undergoing HSCR pull-through operations
is safe and efficient. The ERAS protocol is worthy of recommendation.
Trial registration: Clinical Trials.gov identifier: NCT02776176.
© 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

1. Introduction through operations from June 1, 2016 to December 31, 2017. All
patients were followed up for more than 6 months. A total of 148
The concept of enhanced recovery after surgery (ERAS) was first consecutive HSCR patients who were treated at three pediatric
described by Prof. Henrik Kehlet which aimed at optimizing peri- surgery centers (Children's Hospital of Nanjing Medical Univer-
operative care through the use of fast-track elements to maintain sity, Anhui Provincial Children's Hospital, and Xuzhou Children's
physiological homeostasis, reducing surgical stress and facilitating Hospital of Xuzhou Medical University) were included in this
a quick return to baseline for patients who had underwent major study. Patients who were less than 1 year old and diagnosed with
surgical procedures [1]. The ERAS protocol has been successfully HSCR by barium enema, anorectal manometry, and preoperative
implemented in perioperative management, especially in man- pathological examination were included. Patients were excluded
agement of colorectal surgery [2e7]. with the following conditions: emergency operations, clinical
General ERAS protocol for colorectal surgery includes periop- relevant comorbidities (liver and/or kidney dysfunction, severe
erative counseling, nutritional assessment, supportive care, mini- cardiovascular diseases, immunodeficiency conditions), total in-
mized preoperative fasting, proper preoperative bowel preparation, testinal aganglionosis and refusal to sign the written informed
better anesthesia, minimally invasive techniques, multimodal consent. Patients were primarily divided into three groups based
opioid-sparing analgesia, early postoperative oral feeding and on clinical classification and surgical methods. Group I included
mobilization, limited intravenous fluids, and minimized surgical patients with the short segment type who received transanal
drains and tubes [4,8]. Mounting evidence showed that ERAS endorectal pull-through (TEPT) surgery. Group II comprised of
strategies can reduce perioperative stress and improve clinical patients with the classical type and long segment type who
outcomes, including shortening of length of stay (LOS) [7,9e13]. received laparoscopic-assisted pull-through (LAPT) surgery. Group
Studies of ERAS have been carried out earlier in adult surgery, III involved patients with the long segment type (who had
and have made contributions in promoting postoperative rehabil- received ileostomy or colostomy during the neonatal period) and
itation. While few ERAS protocols exist for infants who are total colonic aganglionosis who received open pull-through
vulnerable during perioperative period. The management of in- (OPPT) surgery. They were randomly assigned to the ERAS sub-
fantile surgery has physiological and sociological challenges that group or a traditional (TRAD) subgroup with random number
are totally different from those encountered in adult surgeries. The table row randomization (Fig. 1). The TRAD group was the control
infantile population is complex due to lower blood volume, tem- group. The primary outcome was the length of stay after surgery
perature instability, immature immune system, greater need for (LOS). Secondary outcomes were classified as inflammation and
nutritional support and the difficulty in communication. stress, recovery of gastrointestinal function, perioperative infu-
Therefore, optimizing perioperative management is important sion, postoperative nutrition status and growth, and other in-
and urgent for infants, and the successful experience that has been dicators. Inflammation and stress included white blood cell
achieved in adult surgery cannot be simply replicated in periop- (WBC) counts, C-reactive protein (CRP) on postoperative day 1
erative management of this vulnerable population. How to imple- (POD 1), and the blood glucose at the time of anesthesia and 24 h
ment ERAS in infants is imperative to explore and standardize. after surgery. The recovery of gastrointestinal function included
Hirschsprung's disease (HSCR) is a common digestive tract the time to first defecation and the time to regular diet. The
malformation. Most children require surgery during infancy perioperative infusion included the mean intraoperative fluid
[14e16]. Several ERAS pathways for pediatric surgery have been volume, and the time to discontinuation of intravenous infusion.
described recently [17e19], while there remains a paucity of evi- Postoperative nutrition status and growth included the concen-
dence regarding ERAS in HSCR patients with pull-through surgery, tration of plasma markers on POD 5 (prealbumin, albumin, retinol
particularly in terms of clinical outcomes. conjugated protein and hemoglobin) and the growth from
In the study, we developed and implemented a ERAS protocol admission to 6 months after surgery (weight for age z score:
for these patients based on previous research and our experience, WAZ, weight for length z score: WLZ). The other indicators
and we conducted a prospective multicenter randomized study to included concentration of plasma natrium on POD 5, incidence of
clarify whether the ERAS protocol was safe and effective in peri- postoperative complications, hospitalization costs, parental satis-
operative management. faction rate, and re-admission within 30 days. Complications were
defined as events that resulted in prolonged LOS or need for
2. Methods reoperation or re-admission, such as anastomotic leak, bleeding,
incisional infection, Hirschsprung-associated enterocolitis (HAEC)
2.1. Study design and respiratory infection. Approval for this study was obtained
from the Review Board of the Children's Hospital of Nanjing
The study was a prospective, multicenter trial of an ERAS Medical University (No. 201601005e1.1). This trial was registered
protocol adapted for infants with HSCR disease undergoing pull- at the Clinical Trials.gov as NCT02776176.

Please cite this article as: Tang J et al., Application of enhanced recovery after surgery during the perioperative period in infants with
Hirschsprung's disease e A multi-center randomized clinical trial, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.10.001
 J. Tang et al. / Clinical Nutrition xxx (xxxx) xxx 3

Fig. 1. Flowchart of study participant. Patients were primarily divided into three groups based on the clinical classification types and surgical methods. Then they were randomly
and equally assigned into the ERAS group or traditional (TRAD) group, respectively.

2.2. Similarities and differences between the ERAS and traditional none of the other complications. Global perceived effect scale was
protocols captured from parents when the children were discharged
(Supplemental file 1) [24]. If the parents chose “correct” or “rather
The ERAS multidisciplinary team included surgeons, anesthe- correct”, we thought that they were satisfied with the treatment
siologists, pain specialists, surgical ward nurses, operating room during hospitalization. The ERAS program includes a number of
nurses and nutritionists. The ERAS protocol was developed to elements and the percentage of fulfilled elements was an indicator
include preoperative, intraoperative and postoperative elements of of successful implementation of the ERAS protocol. During the
care. Combined existing ERAS protocols with our experience, the perioperative period, some elements might not be applied due to
specific ERAS protocol was designed to address the distinct peri- the patient's condition.
operative needs of infants with HSCR who received pull-through Nurse would contact the parents and check for alarming
surgery. Prior to implementation, extensive education regarding symptoms at the first, third and seventh days after discharge. If
the protocol was provided to the ERAS multidisciplinary team there were any signs of complications, the patient would be sug-
members. Standardized instructional handouts regarding the ERAS gested to come back for examination.
protocol was distributed to each patient before operation.
Patients with HSCR undergoing pull-through surgeries were 2.3. Sample size, data collection and analysis
generally managed with the ERAS protocol or a TRAD protocol.
Regarding the traditional program, there is no guideline at present. We tested the hypothesis that there would be no difference in
We designed the TRAD protocol based on the perioperative man- the main clinical outcomes (the LOS was the primary outcome)
agement program of multiple children medical centers in recent between the two groups. 5% or less difference between the two
years. The main differences between the ERAS protocol and the groups was considered to be clinically equivalent. Assuming 5% loss
TRAD protocol are shown in Table 1. Some details are described of follow up, with power of 90%, type 1 error rate of 0.05, and 1 day
below. Every patient will receive the nutritional risk assessment in decrease of LOS attributed to ERAS protocol, the sample size esti-
outpatient department before surgery (STAMP score) [20,21]. On mated for testing the main outcome was 69 children in each group.
this basis, we used the weight for age z score (WAZ) to further Demographic and clinical characteristics were summarized for the
evaluate the nutrition status of the children (STAMP  4) and guide study population using counts/percentages for categorical variables
nutritional support. Normothermia was maintained by monitoring and medians/interquartile ranges or means/standard deviations for
body temperature using a nasopharyngeal temperature probe, and continuous variables. Characteristics were compared between the
a warm blanket was used in all cases. In addition, the disinfectant two groups using Student's t-test or the StudenteNewmaneKeuls
and the fluids administered were heated to reduce the low tem- (ANOVA) test for continuous variables and the chi-square test for
perature stimulus. In the ERAS group, nasogastric tubes and cath- categorical variables. When the expected counts were less than 5,
eters were placed after anesthesia to reduce discomfort if needed. Fisher's exact test was used. Univariate analysis of variance was
Regarding anesthesia, we chose caudal block combined with basal used to detect the factors of influencing the LOS. All tests were two-
anesthesia to reduce the administration of narcotic medication in tailed. P < 0.05 was considered to indicate a statistically significant
the ERAS group. Pain assessment was performed daily to guide difference.
appropriate analgesic treatment. Acetaminophen was used for oral
analgesia. In addition, all patients in the EARS group received a 3. Results
small amount of sucrose solution (concentration: 24%) by directly
administered onto the anterior surface of the tongue with a 1 ml 3.1. Demographics
sterile syringe to relieve anxiety, irritability and pain after surgery
[22,23]. Fluids were discontinued, and medications were transi- In total, 148 patients with HSCR were enrolled. 73 patients were
tioned to oral administration if patients could tolerate oral feeding. managed following traditional postoperative guidelines, and 75
The discharge criteria included no need for intravenous fluid, patients were managed according to our ERAS protocol. No losses
tolerance of oral diet, a well-healed surgical incision, no fever and or exclusions occurred after randomization. All patients were

Please cite this article as: Tang J et al., Application of enhanced recovery after surgery during the perioperative period in infants with
Hirschsprung's disease e A multi-center randomized clinical trial, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.10.001
4 J. Tang et al. / Clinical Nutrition xxx (xxxx) xxx

Table 1
Difference in perioperative care between the ERAS and TRAD groups.

Traditional group ERAS group

Preoperative counseling Non-compulsory requirement Intensive (by both surgeons, anesthesiologists, and nurses)
Preoperative bowel preparation Mechanical bowel preparation (MBP) (colonic lavage) for 7 MBP for 4e5 days before surgery
e10 days before surgery
Nutritional assessment and treatment Yes (malnourished children would receive enteral Yes (same as traditional group)
(STAMP score, weight for age z score) nutritional support by adding high-calorie formula
(1.0 kcal/ml) to the original diet for 1e2 weeks by orally at
home. Total energy was about 140e150 kcal/kg/d (actual
weight) or 110e120 kcal/kg/d (ideal weight).)
Preoperative fasting (oral intake) Fasting from the previous midnight Fasting from breast milk for 4 h, formula for 6 h; Drinking
10% Glucose solution (10 ml/kg, 2 h prior to anesthesia)
Preoperative antibiotics Within 60 min prior to incision Within 60 min prior to incision
Anesthesia General anesthesia Combination of caudal anesthesia and basal anesthesia
Intraoperative fluid management No Yes (goal-direct fluid therapy, by monitoring the systolic
(avoidance of sodium/fluid overload) pressure variation (SPV))
Maintenance of normothermia No Always
Nasogastric tube Used, removed on POD 4e6 Not used or used but removed as soon as possible (TEPT: did
not place; LAPT: removed on POD 1; OPPT: removed on POD
2e3), Tubes were placed after anesthesia
Urethral catheters Removed on POD 5e7 Removed on POD 3
Abdominal drainage tubes Placed at the OPPT group, removed on POD 5e7 No drains left routinely, unless they had much exudation
during the surgery at the OPPT group, removed on POD 3e5
Postoperative fasting No oral intake for 5e6 days Early feeding
Routine postoperative mobilization No (immobilization) Mobilization (on POD 1)
care
Pain assessment and analgesia No Yes
Early removal of intravenous fluids No Yes

followed up for more than 6 months. Patient demographics are group, with no difference between the two groups. At admission,
presented in Table 2. Overall, the cohorts were well matched in we conducted a nutritional risk screening again (STAMP score), and
terms of gender, age distribution, weight, etc. (Table 2). The ERAS their scores were all less than 4. In addition, the WAZ scores of the
protocol included 15 elements in our study. Children in the ERAS two groups were similar. And, there was no difference in plasma
group received 12e15 elements (median: 14). nutritional markers, including prealbumin, albumin, retinol con-
jugated protein and hemoglobin (Table 3).
3.2. Nutrition assessment and support
3.3. Clinical outcomes
As shown in Table 3, there were 25 patients who had high risk of
malnutrition (STAMP score  4). A total of 25 malnourished pa- 3.3.1. Length of stay (LOS) after surgery
tients (TRAD group: 11 patients; ERAS group: 14 patients) received The LOS decreased from 9.5 days in the TRAD group to 7.9 days
1e2 weeks (median: 12 days) of nutritional support at home. Their in the ERAS group, and the difference was statistically significant
WAZ scores were 2.32 ± 0.31 in the TRAD group, and 2.36 ± 0.38 (P < 0.001) (Table 4). We further analyzed the impact of surgical
in the EARS group before nutritional support. After the nutritional methods (TEPT, LAPT, OPPT) and perioperative management
support, the WAZ scores increased to 1.38 ± 0.15 in the TRAD models (ERAS, TRAD) on the primary clinical outcome (LOS). The
group, and 1.35 ± 0.23 in the ERAS group. Their nutritional status results showed that the LOS was longer in the OPPT group than
had been improved through nutritional support. The WAZ scores those in the TEPT and LAPT groups. Interestingly, the results also
increased 0.94 ± 0.28 in the TRAD group, and 1.0 ± 0.26 in the ERAS showed that the shortening of LOS by the application of ERAS

Table 2
Demographics and patients characteristics.

TRAD group ERAS group P value

Number of patients 73 75 >0.05

Age (days) 130 ± 72 140 ± 68 >0.05
Sex
Males 57 64 >0.05
Females 16 11
Height (cm) 62.7 ± 5.7 62.1 ± 5.4 >0.05
Weight (kg) 6.9 ± 1.5 6.7 ± 1.3 >0.05
Clinical classification
Short segment type 6 7 >0.05
Typical type 42 46
Long segment type 23 20
Total colonic aganglionosis 2 2
Surgical procedures
Trans-anal endorectal pull-through operations 6 7 >0.05
Laparoscopic-assisted pull-through operations 56 57
Open pull-through operations 11 11

Please cite this article as: Tang J et al., Application of enhanced recovery after surgery during the perioperative period in infants with
Hirschsprung's disease e A multi-center randomized clinical trial, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.10.001
 J. Tang et al. / Clinical Nutrition xxx (xxxx) xxx 5

Table 3
Nutritional assessment and growth.

TRAD group ERAS group P value

Nutritional risk assessment (STAMP score)

Score 4 11 14 >0.05
Score <4 62 61
WAZ < 2 11 14 >0.05
WAZ before nutritional support (malnourished patients) 2.32 ± 0.31 2.36 ± 0.38 >0.05
WAZ after nutritional support (malnourished patients) 1.38 ± 0.15 1.35 ± 0.23 >0.05
The change of WAZ after nutritional support (malnourished patients) 0.94 ± 0.28 1.00 ± 0.26 >0.05
Plasma markers of nutritional status at admission (all patients)
Prealbumin (g/l) 0.20 ± 0.04 0.19 ± 0.04 >0.05
Albumin (g/l) 42.33 ± 3.73 43.01 ± 3.29 >0.05
Retinol conjugated protein (mg/l) 24.30 ± 7.90 25.30 ± 7.44 >0.05
Hemoglobin (g/l) 115.75 ± 13.90 116.52 ± 15.30 >0.05
WAZ at admission (all patients) 0.08 ± 1.19 0.12 ± 1.22 >0.05
WAZ at 6 months after surgery (all patients) 0.34 ± 0.93 0.36 ± 0.88 >0.05
WLZ at admission (all patients) 0.13 ± 1.14 0.14 ± 1.17 >0.05
WLZ at 6 months after surgery (all patients) 0.30 ± 0.95 0.36 ± 0.93
Growth (from admission to 6 months after surgery, all patients)
WAZ change 0.43 ± 0.36 0.47 ± 0.44 >0.05
WLZ change 0.43 ± 0.31 0.48 ± 0.38 >0.05

WAZ: weight for age z score; WLZ: weight for length z score.

protocols was better in the OPPT group ( 2.5 ± 1.0) than those in 3.3.4. The perioperative infusion
the TEPT ( 1.9 ± 1.3) and LAPT ( 1.3 ± 0.4) groups (Table 5). In the ERAS group, the patients received an average of 4.5 ml/kg/
h of fluid during the surgery, which was significantly lower than
3.3.2. Inflammation and stress that in the TRAD group (P < 0.001). Furthermore, the time to dis-
The WBC counts on POD 1 showed no significant difference continue intravenous infusion was shorter in the ERAS group
between the ERAS and TRAD groups. CRP on POD 1 was lower in compared with the TRAD group (P < 0.001) (Table 4).
the ERAS group than that in the TRAD group (P < 0.001). The
results showed that blood glucose was higher in the ERAS group 3.3.5. Post-operative nutritional status and growth
than that in the TRAD group at the time of anesthesia (P < 0.001). In the ERAS group, the concentration of prealbumin and retinol
However, the blood glucose level was higher in the TRAD group conjugated protein on POD 5 were higher than those in the TRAD
at 24 h after surgery (P < 0.001) than that in the ERAS group group (P < 0.001). There were no significant difference in albumin
(Table 4). and hemoglobin.
Growth is a very important factor in clinical research related to
3.3.3. The recovery time of gastrointestinal function children. We analyzed the data of WAZ (weight for age z scores) and
We also achieved positive results in terms of gastrointestinal WLZ (weight for length z scores) from admission to 6 months after
function recovery indicators. The results showed that the ERAS surgery.
protocol was successful in reducing the time to first defecation The WAZ at admission were 0.08 ± 1.19 in the TRAD group
after surgery (P < 0.001). In addition, the time to regular diet in and 0.12 ± 1.22 in the EARS group (P > 0.05). The WAZ at 6 months
the ERAS group was shorter than that in the TRAD group after surgery were 0.34 ± 0.93 and 0.36 ± 0.88 in the TRAD and
(P < 0.001) (Table 4). ERAS groups, respectively (P > 0.05). The changes of WAZ were

Table 4
Outcomes in the ERAS group compared to the TRAD group.

TRAD group ERAS group P value

Length of postoperative stay (LOS) (days) 9.5 ± 2.1 7.9 ± 2.7 <0.001
Intraoperative fluid infusion (ml/kg/h) 8.6 ± 2.7 4.5 ± 1.4 <0.001
Blood glucose level (mmol/l)
At the time of anesthesia 4.9 ± 0.8 6.1 ± 0.7 <0.001
At 24 h after surgery 7.2 ± 0.5 6.2 ± 0.6 <0.001
WBC count (POD 1) (109/l) 13.5 ± 3.6 12.8 ± 4.0 >0.05
CRP value (POD 1) (mg/l) 21.9 ± 14.5 13.9 ± 18.5 <0.001
Time to first defecation (h) 26.6 ± 7.2 22.0 ± 7.1 <0.001
Time to regular diet (days) 7.4 ± 1.0 5.0 ± 1.5 <0.001
Time to discontinuation of intravenous infusion (days) 7.0 ± 1.0 4.7 ± 1.4 <0.001
Concentration of plasma markers of nutritional status (POD 5)
Prealbumin (g/l) 0.14 ± 0.04 0.19 ± 0.05 <0.001
Albumin (g/l) 42.55 ± 4.01 42.25 ± 3.89 >0.05
Retinol conjugated protein (mg/l) 19.91 ± 6.86 26.08 ± 7.28 <0.001
Hemoglobin (g/l) 115.74 ± 12.41 116.08 ± 11.44 >0.05
Concentration of plasma natrium (POD 5) (mmol/l) 137.9 ± 2.3 138.0 ± 2.8 >0.05
In-hospital costs (yuan) 33,954.0 ± 4229.7 31,044.5 ± 5280.1 <0.001
Complications, n (%) 5 (6.8%) 3 (4%) >0.05
30-day readmissions, n (%) 0 0 >0.05
Parental satisfaction rate (%) 89% 96% >0.05

Please cite this article as: Tang J et al., Application of enhanced recovery after surgery during the perioperative period in infants with
Hirschsprung's disease e A multi-center randomized clinical trial, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.10.001
6 J. Tang et al. / Clinical Nutrition xxx (xxxx) xxx

Table 5 of the perioperative care and criteria for discharge. These parents
The impact of surgical methods (TEPT, LAPT, OPPT) and perioperative management were motivated to participate in the perioperative care and were
models (ERAS, TRAD) on the primary clinical outcome (the length of postoperative
hospital day, LOS).
more compliant with the patient-driven elements of the protocol,
such as early mobilization and oral feeding. The satisfaction rate
LOS (days) D-value ± SE P value was 96% in the EARS group which was higher than that in the TRAD
All cases TEPT vs LAPT 1.5 ± 0.7 >0.05 group (89%), although there was no statistical difference. It's worth
TEPT vs OPPT 2.7 ± 0.8 <0.01 noting that children's irritability was highly likely to cause dissat-
LAPT vs OPPT 1.2 ± 0.5 >0.05
isfaction in parents with treatment and care, which may affect ac-
ERAS vs TRAD 1.6 ± 0.6 <0.001
ERAS group TEPT vs LAPT 1.7 ± 0.9 >0.05 curacy of the results. Furthermore, the limited sample size might
TEPT vs OPPT 2.4 ± 1.1 >0.05 affect the results. The ERAS protocols could not be successfully
LAPT vs OPPT 0.5 ± 0.7 >0.05 implemented and promoted without the understanding and sup-
TRAD group TEPT vs LAPT 1.2 ± 1.0 >0.05
port from parents. Optimization is required to strengthen care and
TEPT vs OPPT 3.0 ± 1.2 <0.05
LAPT vs OPPT 1.8 ± 0.8 >0.05
comfort in order to improve hospitalization experience for both
TEPT group ERAS vs TRAD 1.9 ± 1.3 <0.001 children and parents.
LAPT group ERAS vs TRAD 1.3 ± 0.4 <0.01 Studies have shown that preoperative nutritional support can
OPPT group ERAS vs TRAD 2.5 ± 1.0 <0.001 improve the prognosis of patients [31,32]. For children with ostomy,
regular nutrition assessment is more important because they are
more likely to suffer from malnutrition due to intestinal dysfunc-
0.43 ± 0.36 and 0.47 ± 0.44 in the TRAD and ERAS groups, tion. In our study, every patient received nutrition assessment by
respectively (P > 0.05). STAMP. Children with STAMP score greater than 4 would receive
The WLZ at admission were 0.13 ± 1.14 in the TRAD group enteral nutritional support (11 patients in the TRAD group, 14 in the
and 0.14 ± 1.17 in the EARS group (P > 0.05). They increased to ERAS group). The nutritional status was reinforced after enteral
0.30 ± 0.95 and 0.36 ± 0.93 in the TRAD and ERAS groups, nutrition support.
respectively at 6 months after surgery (P > 0.05). The changes of It is widely known that enhanced catabolism and declined
WLZ were 0.43 ± 0.31 and 0.48 ± 0.38 in the TRAD and ERAS anabolism occur under stress such as surgery, leading to malnu-
groups, respectively (P > 0.05). There were no difference in growth trition. As a result, reducing the perioperative stress is critical for
between the two groups from admission to 6 months after the the maintenance of nutritional status during the perioperative
surgery (WAZ: P > 0.05, WLZ: P > 0.05) (Table 4). period. In addition, early postoperative enteral nutrition can help
reduce the high catabolism rate and insulin resistance, and pro-
3.3.6. Other indicators mote anabolism, which is helpful to improve the nutritional status
The plasma natrium had no significant difference between the of patients after surgery [33,34]. By monitoring the nutritional in-
two groups (P > 0.05). The ERAS protocol could decrease the cost of dicators, we found that Retinol conjugated protein and prealbumin
hospitalization (P < 0.001). The complication rates and 30-day on POD 5 were higher in the ERAS group. In addition, the plasma
readmission rates had no statistic differences between the two natrium at that time was within the normal range and had no
cohorts. In the TRAD group, there were 5 complications compared significant difference between the two groups, which could elimi-
with 3 complications in the ERAS group. There were no read- nate the dilution factor caused by the higher amount of infusion in
missions or deaths in the two groups. ERAS group had a higher the TRAD group. These indicated that ERAS could improve the
parental satisfaction rate, although there was no statistical differ- nutritional status of patients in the early postoperative period.
ence (96% vs 89%) (Table 4). We obtained consistent results in the Traditional bowel preparation is replaced by rapid bowel prep-
TEPT, LAPT and OPPT groups, respectively (Supplemental file 2: aration represented by oral polyhexylene glycol (PEG) in the adult
Supplemental Table 1, 2, and 3). elective colorectal surgery [4,35]. However, there is currently no
evidence that PEG can be used in infants. Intestine with HSCR is
4. Discussion deprived of ganglion cells, leading to stool accumulation in the
dilated and hypertrophic proximal bowel. Colonic lavage is indis-
Prof. Henrik Kehlet has long maintained that all the patients, pensable to relieve the accumulated feces. Since infants are mainly
regardless of age and comorbidity, should be managed by ERAS fed with breast milk or formula, the stool is mostly liquid or paste
protocols [25]. However, high quality clinical studies are lacked to with few fecal stones residue. Therefore, bowel preparation time
confirm the safety and effectiveness of ERAS protocols in the was shortened from 7e10 days to 4e5 days in the ERAS group.
vulnerable population, namely neonates and infants. The mental Cutting off the unnecessary colonic lavage is beneficial for the re-
and physiological state are far from mature, and it is easy to cause covery of postoperative gastrointestinal function. The intestinal
stress in perioperative period due to fear, pain, hunger, and various cleanliness was similar between the two groups. Moreover, it did
catheters, affecting recovery after operation. Numerous studies not increase the risk of complications, such as anastomotic leakage
have clarified the safety and value of individual elements and incision infection.
[18,26e28]. The current study demonstrated that a specific Surgery and related stress induces a metabolic and immune
comprehensive ERAS protocol in neonates/infants with HSCR un- response that damages metabolism and impairs insulin resistance,
dergoing pull-through surgeries was safe and effective. We showed which are associated with increased morbidity [36]. Additionally,
a statistically significant decrease in the mean LOS by 1.6 days in the mental state of children is not mature, and they cannot tolerate
patients who were managed with our ERAS protocols, with no in- physical discomfort, which leads to crying and irritability and
crease in complications or readmissions. We obtained consistent further increases the stress response. In our previous report, we
results in TERT, LAPT and OPPT groups. showed that preoperative oral carbohydrate administration (10 ml/
Most patients with HSCR are diagnosed and treated during kg, 10% glucose solution, 2 h before the anesthesia) was well
neonatal period and infancy [29]. Preoperative consultation with tolerated and not associated with increased risks of vomiting/
parents or guardians is important [30]. The ERAS protocol was well aspiration during surgery. In addition, the treatment could increase
accepted by families in our research. We found that parents whose blood glucose before surgery and reduce crying, leading to
children were managed with the protocol had better understanding improved recovery after surgery [28]. Carbohydrate administration

Please cite this article as: Tang J et al., Application of enhanced recovery after surgery during the perioperative period in infants with
Hirschsprung's disease e A multi-center randomized clinical trial, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.10.001
 J. Tang et al. / Clinical Nutrition xxx (xxxx) xxx 7

decreased catabolism and improved postoperative insulin sensi- incidence of complications associated with hospitalization, such as
tivity, thus reducing LOS and elevate patient satisfaction [28]. In our respiratory tract infection and catheter associated infection. While
study, we found that the ERAS protocol could appropriately in- no relevant evidence was obtained in the present study, probably
crease the blood glucose level at the time of anesthesia by shorter due to the limited sample size. It is easy to understand that
fasting time and oral administration of 10% glucose solution. In shortened LOS might contribute to an increase in post-discharge
addition, it could reduce the postoperative stress-induced blood readmissions for complications occurred at home. In our study,
glucose instability. It is well known that hyperglycemia after sur- nurse gave phone calls to every patient and checked them for
gery may induce several negative consequences, including alarming symptoms at the first, third and seventh days after
increased risk of infection, prolonged wound healing, increased discharge. If there were any risk of complications, the patient would
LOS, and organ dysfunction, which may ultimately cause increased be suggested to come back for further examination. The results
mortality. showed that neither the rate of developing complication nor re-
The surgery requires relaxation of pelvic floor and perineum admission was increased in the ERAS cohort. This finding in-
muscles. Taking into account of the requirement, we combined dicates that our protocol could be implemented safely. It is believed
caudal block with basal anesthesia. As a result, the amount of that the trauma of OPPT is greater than those in TEPT and LAPT.
anesthetic drugs was reduced, which was beneficial for post- Consistent with the trauma of surgery, LOS is longer in the OPPT
operative rehabilitation in children, especially infants [37,38]. There group compared with the TEPT and LAPT groups. We also found
is evidence that a lower fluid load is beneficial for the recovery of that the ERAS protocol made more contributions in shortening LOS
postoperative intestinal function [39]. In our study, patients in the in the OPPT group than in the TEPT and LAPT groups. Finally, we
ERAS group received less fluid during surgery according to the goal- came to the conclusion that the greater the trauma, the higher
directed fluid therapy, which was achieved by monitoring the value of the ERAS protocol.
systolic pressure variation (SPV) [40,41]. We believe that optimized Despite the positive results in our study, further investigations
anesthesia and monitoring methods would emerge, contributing to are warranted. The integration of elements is in desperate need of
recovery of children. further research. Optimization of anesthesia is also required.
Pain has been considered as the fifth vital sign [42]. Numerous Methods to promote recovery of gastrointestinal function after
studies have shown that pain has fundamental effects on post- surgery also await for exploration. There are limitations in our
operative recovery [17,43]. Considering the side-effects of opioid research and the first is the limited sample size. Another limitation
analgesics, non-steroid anti-inflammatory drugs were recom- is that the fasting was started from midnight in the TRAD group
mended in various guidelines for post-operative analgesia. In our despite the recommended shortening of fasting time in guidelines,
research, acetaminophen was taken orally for analgesia. In addition, due to local restrictions. In the ERAS group, we confirmed that the
we used a small amount of sucrose solution to relieve anxiety, ir- shorter fasting time (breast milk for 4 h, formula for 6 h prior to
ritability and pain. Since analgesic drugs are limited and post- anesthesia) before surgery was safe and might facilitate in pro-
operative pain assessment are difficult to conduct for infants and motion of the anesthesia guidelines. As mentioned above, the ERAS
neonates, more studies are needed in the future. protocol included 15 elements while it could not be fully imple-
Previous studies have demonstrated that nasogastric tubes are mented in all patients. For example, if the child was suffering from
not necessary in patients undergoing elective colorectal surgery vomiting and abdominal bloating after surgery, remove of gastro-
[44e46]. In addition, Meta-analysis have shown that early remove intestinal decompression tube would be delayed. Similarly, if the
or no application of nasogastric tubes reduced the time to normal abdominal drainage tube draws more fluid than usual, extubation
gastrointestinal function and did not increase risk of pulmonary would be postponed. The perioperative condition of patient is
complications [47e50]. In our study, we placed nasogastric tubes changing all the time, requiring specific decisions in certain
after anesthesia to minimize discomfort and reduce irritation and context. The number of applied elements was an important indi-
damage. In the EARS group, we removed the nasogastric tubes as cator of successful implementation of the ERAS protocol. In our
soon as possible to reduce discomfort and began oral feeding earlier study, the children received 12e15 elements (median: 14).
to promote recovery of gastrointestine. In addition, caudal block In conclusion, we believe that our ERAS protocol has the po-
combined with basal anesthesia was used in the ERAS group to cut tential in promoting postoperative rehabilitation in infants.
down the use of opioid anesthetic drugs which would prolong the
recovery of gastrointestine. We found that the time to first defe- Conflict of interest
cation was shorter in the ERAS group compared to the TRAD group.
Additionally, the time to tolerance with a regulate diet was 5.0 ± 1.5 The authors declare no conflicts of interest.
days in the EARS group, which was shorter than that in the TRAD
group. Furthermore, in terms of the time to discontinuation of Founding source
intravenous infusion, the ERAS group was also shorter than the
TRAD group. The indicators of time to regular diet and IV infusion This work was supported by the National Natural Science
discontinuation are mainly related to the recovery of gastrointes- Foundation of China (81570467), the Key Research and Develop-
tinal function. During the perioperative period, numerous factors ment (Social development) Program of Jiangsu Province of China
could affect the recovery of postoperative gastrointestinal function, (BE2017609) and the Nanjing Medical Science and Technique
including the preoperative mechanical bowel preparation, fasting Development Foundation (ZKX17039).
time before surgery, the anesthesia and the use of opioids, surgical
trauma, perioperative fluid management, and the time to start Statement of authorship
enteral nutrition, and so on. For abdominal surgery, especially
gastrointestinal surgery, the recovery of gastrointestinal function is All the authors contributed to the work and approved the final
one of the most important indicators for postoperative rehabilita- version of the manuscript. Particularly, contributions were: Study
tion. The EARS protocol is to optimize the above factors and inte- design: WT, JF, JT, XL, TM; Data collection: JT, XL, TM, JZ, CL; Data
grate them to maximize the postoperative recovery of patients. analysis and interpretation: JT, HC, WL, HL, HX, CD; Manuscript
The primary goal of ERAS is to reduce physiologic stress and to drafting: JT, WT; Critical revision of the manuscript for important
promote recovery in shorter time. Shorter LOS might reduce the intellectual content: XL, WJ, QG, JF.

Please cite this article as: Tang J et al., Application of enhanced recovery after surgery during the perioperative period in infants with
Hirschsprung's disease e A multi-center randomized clinical trial, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.10.001
8 J. Tang et al. / Clinical Nutrition xxx (xxxx) xxx

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Please cite this article as: Tang J et al., Application of enhanced recovery after surgery during the perioperative period in infants with
Hirschsprung's disease e A multi-center randomized clinical trial, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.10.001