Mortality and Management of Surgical Necrotizing Enterocolitis in Very Low Birth Weight Neonates: A Prospective Cohort Study Melissa A Hull, MD, Jeremy G Fisher, MD, Ivan M Gutierrez, MD, Brian A Jones, MD, Kuang Horng Kang, MD, Michael Kenny, MS, David Zurakowski, PhD, Biren P Modi, MD, Jeffrey D Horbar, MD, Tom Jaksic, MD, PhD, FACS Necrotizing enterocolitis (NEC) is a leading cause of death in very low birth weight (VLBW) neonates. The overall mortality of NEC is well documented. However, those requiring surgery appear to have increased mortality compared with those managed medically. The objective of this study was to establish national birth-weight-based benchmarks for the mortality of surgical NEC and describe the use and mortality of laparotomy vs peritoneal drainage. STUDY DESIGN: There were 655 US centers that prospectively evaluated 188,703 VLBW neonates (401 to 1,500 g) between 2006 and 2010. Survival was defined as living in-hospital at 1-year or hospital discharge. RESULTS: There were 17,159 (9%) patients who had NEC, with mortality of 28%; 8,224 patients did not receive operations (medical NEC, mortality 21%) and 8,935 were operated on (mortality 35%). On multivariable regression, lower birth weight, laparotomy, and peritoneal drainage were independent predictors of mortality (p < 0.0001). In surgical NEC, a plateau mortality of around 30% persisted despite birth weights >750 g; medical NEC mortality fell consistently with increasing birth weight. For example, in neonates weighing 1,251 to 1,500 g, mortality was 27% in surgical vs 6% in medical NEC (odds ratio [OR] 6.10, 95% CI 4.58 to 8.12). Of those treated surgically, 6,131 (69%) underwent laparotomy only (mortality 31%), 1,283 received peritoneal drainage and a laparotomy (mortality 34%), and 1,521 had peritoneal drainage alone (mortality 50%). CONCLUSIONS: Fifty-two percent of VLBW neonates with NEC underwent surgery, which was accompanied by a substantial increase in mortality. Regardless of birth weight, surgical NEC showed a plateau in mortality at approximately 30%. Laparotomy was the more frequent method of treatment (69%) and of those managed by drainage, 46% also had a laparotomy. The laparotomy alone and drainage with laparotomy groups had similar mortalities, while the drainage alone treatment cohort was associated with the highest mortality. (J Am Coll Surg 2013;-:1e8. 2013 by the American College of Surgeons)
BACKGROUND:
is inversely related to birth weight, with the great preponderance of affected patients having very low birth weight (VLBW).2,4-6 It may be inferred that VLBW patients with NEC receiving an operation (surgical NEC) harbor a more severe form of the disease than those treated without surgery (medical NEC).7 However, there are no large-scale cohort studies directly evaluating the mortality of surgical and medical NEC by birth weight categories. Such data are important to surgeons because they potentially afford a more accurate determination of prognosis and may be used as a basis for future quality improvement efforts. Various strategies are available to treat surgical NEC: laparotomy and primary peritoneal drainage (PPD). Primary peritoneal drainage was initially proposed as a
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of newborns1 and remains a major cause of mortality.2,3 The incidence of NEC Disclosure information: Nothing to disclose. Drs Hull and Fisher contributed equally to this work. Presented at the New England Surgical Society 94th Annual Meeting, Hartford, CT, September 2013. Received September 27, 2013; Revised November 14, 2013; Accepted November 18, 2013. From the Department of Surgery, Center for Advanced Intestinal Rehabilitation, Boston Children’s Hospital and Harvard Medical School, Boston, MA (Hull, Fisher, Gutierrez, Jones, Kang, Zurakowski, Modi, Jaksic) and the Vermont Oxford Network, Burlington, VT (Kenny, Horbar). Correspondence address: Tom Jaksic, MD, PhD, FACS, 300 Longwood Ave, Fegan 3, Boston, MA 02115. email: [email protected]
ª 2013 by the American College of Surgeons Published by Elsevier Inc.
1
ISSN 1072-7515/13/$36.00 http://dx.doi.org/10.1016/j.jamcollsurg.2013.11.015
2
Hull et al
Surgical Necrotizing Enterocolitis Mortality
Abbreviations and Acronyms
NEC NICU PPD SIP VLBW VON
¼ ¼ ¼ ¼ ¼ ¼
necrotizing enterocolitis neonatal ICU primary peritoneal drainage spontaneous intestinal perforation very low birth weight Vermont Oxford Network
bridge to laparotomy in 19758 and subsequently has gained popularity as a potentially definitive therapy.9-11 Two randomized controlled trials comparing laparotomy to PPD for NEC demonstrated no significant difference with respect to mortality.12,13 Unfortunately, due to the small size of these trials, a Cochrane Review determined that alone or in combination, these investigations cannot be used to guide therapy.14 A third randomized control trial is currently enrolling patients, with a specific emphasis on evaluating neurologic outcomes.15 Given this incomplete evidence base, it is of interest to determine with what frequency surgeons choose PPD and laparotomy in the treatment of surgical NEC. This study used a large, prospectively collected cohort of VLBW neonates to establish birth weight-based mortality benchmarks for surgical NEC. These mortality rates are compared with those from a contemporaneous group of patients with rigorously defined medical NEC. The frequency of PPD and laparotomy use and the mortalities associated with these therapies, are also reported.
METHODS The Vermont Oxford Network (VON) is a nonprofit voluntary collaboration of health care professionals dedicated to improving the quality and safety of medical and surgical care for newborn infants and their families. The VON prospectively collects data on infants of birth weight 401 to 1,500 g, who are born at participating institutions or who are transferred to such an institution within 28 days of birth. These data are accrued until neonates are discharged from the hospital, die, or reach 1 year of age in the hospital. Death after transfer to a non-VON center is or readmission is tracked and included. Discharge home without readmission is considered survival. Data are collected by local staff using uniform definitions and then submitted electronically or on paper forms to the VON central office. Records are subjected to automated checks for quality and completeness and returned for correction if needed. This study was performed as part of an ongoing collaboration between VON and a group of pediatric surgeons. Compilation and quality review of data were performed
J Am Coll Surg
with surgical input, ensuring that data fields were completed and that any ambiguities in the entries were clarified. For example, surgeons evaluated any unclear surgical coding by hand. No protected health care information was collected. The VON is approved by the University of Vermont Institutional Review Board (#04-370) and exempted from review at Boston Children’s Hospital. Among the 655 United States VON centers, survey data indicate that 37% of centers were classified as having a type A NICU (restriction on assisted ventilation or only perform minor surgery). Forty-seven percent had a type B NICU (no restriction on assisted ventilation and perform major surgery, ie, repair of tracheoesophageal fistula/ esophageal atresia, or meningomyelocoele). The remaining 16% of centers had a type C NICU (no restriction on ventilation and perform cardiac surgery requiring bypass for neonates). For this cohort study, data were prospectively collected in the VON database from United States centers between January 2006 and December 2010 on newborns weighing between 401 and 1,500 g. Neonates with major birth defects, as listed in the VON Manual of Operations16 (anencephaly, holoprosencephaly, and major cardiac defects), and those with a length of stay of 3 or fewer days were excluded. Per VON Manual definition, NEC was diagnosed either by direct observation of intestine at operation or pathologic examination or by using a set of strict clinical criteria. A clinical diagnosis of NEC was made based on at least 1 physical finding (bilious gastric aspirate or emesis, abdominal distention, or occult/gross blood in the stool in the absence of anal fissures) and at least 1 radiographic finding (pneumatosis intestinalis, hepatobiliary gas, or pneumoperitoneum). Severity of NEC was not specifically coded in the dataset and the diagnosis of NEC can be coded only once. The VON Manual definition also distinguishes spontaneous intestinal perforation (SIP) from NEC if laparotomy is performed. Spontaneous intestinal perforation is defined as a single focal defect without other significant bowel pathology seen at laparotomy. Because SIP and NEC cannot be incontrovertibly differentiated without a laparotomy, the PPD group necessarily contains patients with both diagnoses. So for veracity of comparison, SIP and operative NEC are grouped together and referred to as “surgical NEC” in this article. Primary peritoneal drainage and laparotomy were identified by specific procedure codes. Patients with codes entered for PPD and laparotomy were considered to have undergone both procedures. Because the dates of procedures were not included, the order could not be specified.
Vol.
-,
No.
-, -
2013
Statistical analyses were conducted using SAS version 9.3 (SAS Institute). The primary outcome was death before 1 year of age or hospital discharge. Multivariable logistic regression modeling was performed. Multivariate logistic regression modeling was performed with adjustments for clustering of infants within hospitals (generalized estimating equations were used to account for correlation between infants at a given hospital). Model covariates included gestational age, small for gestational age, maternal race, sex, multiple births, Apgar score at 1 minute, birth location, and vaginal delivery (because these are independent predictors of mortality on multivariable analysis). Additional multivariable analysis was performed to assess factors associated with treatment by PPD vs laparotomy. Values of p < 0.05 were considered significant. Categorical measures were compared using z-tests and continuous measures were assessed by unpaired t-test.
RESULTS There were 215,057 very low birth weight neonates identified from 655 VON centers in the United States (Fig. 1). A total of 26,354 were excluded: 10,821 with a major congenital malformation or unknown congenital
Hull et al
Surgical Necrotizing Enterocolitis Mortality
3
malformation status, 15,493 with length of stay 3 or fewer days or unknown, and 40 with unknown NEC status. Of the remaining 188,703 patients, 17,159 were diagnosed with NEC (incidence 9%). Demographic characteristics are listed in Table 1. There were small but significant differences between the medical and surgical NEC groups. Infants with surgical NEC had lower birth weights, younger gestational age, and lower Apgar scores. The overall mortality for all patients with NEC was 28%. Mortality declined with birth weight. There were 8,221 patients with medical NEC and 8,935 with surgical NEC. Medical NEC mortality was 21% overall, with significantly lower mortality in neonates of larger birth weight. Surgical NEC mortality was 35% overall (higher than medical NEC, p < 0.0001) and, unlike that of medical NEC, it did not consistently improve with larger birth weight (Fig. 2). The surgical group was subdivided into those undergoing laparotomy (n ¼ 6,126, 69%) and those receiving PPD (n ¼ 2,804, 31%). The PPD group was also divided into those with PPD alone (n ¼ 1,521) and those who underwent PPD and laparotomy (n ¼ 1,283). In other words, 46% of the PPD group also had a laparotomy. Mortality in the laparotomy only group was 31% overall
Figure 1. Study design schema. LOS, length of stay; NEC, necrotizing enterocolitis; PPD, primary peritoneal drain; VLBW, very low birth weight.
4
Hull et al
Table 1.
Demographic and Obstetric Characteristics
J Am Coll Surg
Surgical Necrotizing Enterocolitis Mortality
Characteristic
Male sex, n (%) Vaginal delivery Multiple birth Small for gestational age Birth location (inborn) Antenatal steroids Birth weight, g, mean SD Gestational age, wk, mean SD Apgar 1 min, mean SD Apgar 5 min, mean SD
Medical NEC (n ¼ 8,221)
Surgical NEC (n ¼ 8,935)
p Value
4,508 (54.8) 2,500 (30.4) 1,967 (23.9) 1,117 (13.6) 6,518 (79.3) 6,360 (79.0) 938 273 26.9 2.4 5.0 2.5 7.1 1.9
5,220 (58.4) 2,955 (33.1) 2,237 (25.0) 952 (10.7) 5,802 (64.9) 6,741 (76.3) 841 248 25.9 2.3 4.5 2.4 6.7 2.0
BACKGROUND:
is inversely related to birth weight, with the great preponderance of affected patients having very low birth weight (VLBW).2,4-6 It may be inferred that VLBW patients with NEC receiving an operation (surgical NEC) harbor a more severe form of the disease than those treated without surgery (medical NEC).7 However, there are no large-scale cohort studies directly evaluating the mortality of surgical and medical NEC by birth weight categories. Such data are important to surgeons because they potentially afford a more accurate determination of prognosis and may be used as a basis for future quality improvement efforts. Various strategies are available to treat surgical NEC: laparotomy and primary peritoneal drainage (PPD). Primary peritoneal drainage was initially proposed as a
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of newborns1 and remains a major cause of mortality.2,3 The incidence of NEC Disclosure information: Nothing to disclose. Drs Hull and Fisher contributed equally to this work. Presented at the New England Surgical Society 94th Annual Meeting, Hartford, CT, September 2013. Received September 27, 2013; Revised November 14, 2013; Accepted November 18, 2013. From the Department of Surgery, Center for Advanced Intestinal Rehabilitation, Boston Children’s Hospital and Harvard Medical School, Boston, MA (Hull, Fisher, Gutierrez, Jones, Kang, Zurakowski, Modi, Jaksic) and the Vermont Oxford Network, Burlington, VT (Kenny, Horbar). Correspondence address: Tom Jaksic, MD, PhD, FACS, 300 Longwood Ave, Fegan 3, Boston, MA 02115. email: [email protected]
ª 2013 by the American College of Surgeons Published by Elsevier Inc.
1
ISSN 1072-7515/13/$36.00 http://dx.doi.org/10.1016/j.jamcollsurg.2013.11.015
2
Hull et al
Surgical Necrotizing Enterocolitis Mortality
Abbreviations and Acronyms
NEC NICU PPD SIP VLBW VON
¼ ¼ ¼ ¼ ¼ ¼
necrotizing enterocolitis neonatal ICU primary peritoneal drainage spontaneous intestinal perforation very low birth weight Vermont Oxford Network
bridge to laparotomy in 19758 and subsequently has gained popularity as a potentially definitive therapy.9-11 Two randomized controlled trials comparing laparotomy to PPD for NEC demonstrated no significant difference with respect to mortality.12,13 Unfortunately, due to the small size of these trials, a Cochrane Review determined that alone or in combination, these investigations cannot be used to guide therapy.14 A third randomized control trial is currently enrolling patients, with a specific emphasis on evaluating neurologic outcomes.15 Given this incomplete evidence base, it is of interest to determine with what frequency surgeons choose PPD and laparotomy in the treatment of surgical NEC. This study used a large, prospectively collected cohort of VLBW neonates to establish birth weight-based mortality benchmarks for surgical NEC. These mortality rates are compared with those from a contemporaneous group of patients with rigorously defined medical NEC. The frequency of PPD and laparotomy use and the mortalities associated with these therapies, are also reported.
METHODS The Vermont Oxford Network (VON) is a nonprofit voluntary collaboration of health care professionals dedicated to improving the quality and safety of medical and surgical care for newborn infants and their families. The VON prospectively collects data on infants of birth weight 401 to 1,500 g, who are born at participating institutions or who are transferred to such an institution within 28 days of birth. These data are accrued until neonates are discharged from the hospital, die, or reach 1 year of age in the hospital. Death after transfer to a non-VON center is or readmission is tracked and included. Discharge home without readmission is considered survival. Data are collected by local staff using uniform definitions and then submitted electronically or on paper forms to the VON central office. Records are subjected to automated checks for quality and completeness and returned for correction if needed. This study was performed as part of an ongoing collaboration between VON and a group of pediatric surgeons. Compilation and quality review of data were performed
J Am Coll Surg
with surgical input, ensuring that data fields were completed and that any ambiguities in the entries were clarified. For example, surgeons evaluated any unclear surgical coding by hand. No protected health care information was collected. The VON is approved by the University of Vermont Institutional Review Board (#04-370) and exempted from review at Boston Children’s Hospital. Among the 655 United States VON centers, survey data indicate that 37% of centers were classified as having a type A NICU (restriction on assisted ventilation or only perform minor surgery). Forty-seven percent had a type B NICU (no restriction on assisted ventilation and perform major surgery, ie, repair of tracheoesophageal fistula/ esophageal atresia, or meningomyelocoele). The remaining 16% of centers had a type C NICU (no restriction on ventilation and perform cardiac surgery requiring bypass for neonates). For this cohort study, data were prospectively collected in the VON database from United States centers between January 2006 and December 2010 on newborns weighing between 401 and 1,500 g. Neonates with major birth defects, as listed in the VON Manual of Operations16 (anencephaly, holoprosencephaly, and major cardiac defects), and those with a length of stay of 3 or fewer days were excluded. Per VON Manual definition, NEC was diagnosed either by direct observation of intestine at operation or pathologic examination or by using a set of strict clinical criteria. A clinical diagnosis of NEC was made based on at least 1 physical finding (bilious gastric aspirate or emesis, abdominal distention, or occult/gross blood in the stool in the absence of anal fissures) and at least 1 radiographic finding (pneumatosis intestinalis, hepatobiliary gas, or pneumoperitoneum). Severity of NEC was not specifically coded in the dataset and the diagnosis of NEC can be coded only once. The VON Manual definition also distinguishes spontaneous intestinal perforation (SIP) from NEC if laparotomy is performed. Spontaneous intestinal perforation is defined as a single focal defect without other significant bowel pathology seen at laparotomy. Because SIP and NEC cannot be incontrovertibly differentiated without a laparotomy, the PPD group necessarily contains patients with both diagnoses. So for veracity of comparison, SIP and operative NEC are grouped together and referred to as “surgical NEC” in this article. Primary peritoneal drainage and laparotomy were identified by specific procedure codes. Patients with codes entered for PPD and laparotomy were considered to have undergone both procedures. Because the dates of procedures were not included, the order could not be specified.
Vol.
-,
No.
-, -
2013
Statistical analyses were conducted using SAS version 9.3 (SAS Institute). The primary outcome was death before 1 year of age or hospital discharge. Multivariable logistic regression modeling was performed. Multivariate logistic regression modeling was performed with adjustments for clustering of infants within hospitals (generalized estimating equations were used to account for correlation between infants at a given hospital). Model covariates included gestational age, small for gestational age, maternal race, sex, multiple births, Apgar score at 1 minute, birth location, and vaginal delivery (because these are independent predictors of mortality on multivariable analysis). Additional multivariable analysis was performed to assess factors associated with treatment by PPD vs laparotomy. Values of p < 0.05 were considered significant. Categorical measures were compared using z-tests and continuous measures were assessed by unpaired t-test.
RESULTS There were 215,057 very low birth weight neonates identified from 655 VON centers in the United States (Fig. 1). A total of 26,354 were excluded: 10,821 with a major congenital malformation or unknown congenital
Hull et al
Surgical Necrotizing Enterocolitis Mortality
3
malformation status, 15,493 with length of stay 3 or fewer days or unknown, and 40 with unknown NEC status. Of the remaining 188,703 patients, 17,159 were diagnosed with NEC (incidence 9%). Demographic characteristics are listed in Table 1. There were small but significant differences between the medical and surgical NEC groups. Infants with surgical NEC had lower birth weights, younger gestational age, and lower Apgar scores. The overall mortality for all patients with NEC was 28%. Mortality declined with birth weight. There were 8,221 patients with medical NEC and 8,935 with surgical NEC. Medical NEC mortality was 21% overall, with significantly lower mortality in neonates of larger birth weight. Surgical NEC mortality was 35% overall (higher than medical NEC, p < 0.0001) and, unlike that of medical NEC, it did not consistently improve with larger birth weight (Fig. 2). The surgical group was subdivided into those undergoing laparotomy (n ¼ 6,126, 69%) and those receiving PPD (n ¼ 2,804, 31%). The PPD group was also divided into those with PPD alone (n ¼ 1,521) and those who underwent PPD and laparotomy (n ¼ 1,283). In other words, 46% of the PPD group also had a laparotomy. Mortality in the laparotomy only group was 31% overall
Figure 1. Study design schema. LOS, length of stay; NEC, necrotizing enterocolitis; PPD, primary peritoneal drain; VLBW, very low birth weight.
4
Hull et al
Table 1.
Demographic and Obstetric Characteristics
J Am Coll Surg
Surgical Necrotizing Enterocolitis Mortality
Characteristic
Male sex, n (%) Vaginal delivery Multiple birth Small for gestational age Birth location (inborn) Antenatal steroids Birth weight, g, mean SD Gestational age, wk, mean SD Apgar 1 min, mean SD Apgar 5 min, mean SD
Medical NEC (n ¼ 8,221)
Surgical NEC (n ¼ 8,935)
p Value
4,508 (54.8) 2,500 (30.4) 1,967 (23.9) 1,117 (13.6) 6,518 (79.3) 6,360 (79.0) 938 273 26.9 2.4 5.0 2.5 7.1 1.9
5,220 (58.4) 2,955 (33.1) 2,237 (25.0) 952 (10.7) 5,802 (64.9) 6,741 (76.3) 841 248 25.9 2.3 4.5 2.4 6.7 2.0
