RANDOMIZED CONTROLLED TRIAL

Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation

A Multicenter Randomized Clinical Trial

Blakely, Martin L. MD, MS^∗; Tyson, Jon E. MD, MPH^†; Lally, Kevin P. MD, MS^‡; Hintz, Susan R. MD, MS, Epi^§; Eggleston, Barry MS^||; Stevenson, David K. MD^§; Besner, Gail E. MD^¶; Das, Abhik PhD^#; Ohls, Robin K. MD^{∗∗,††}; Truog, William E. MD^‡‡; Nelin, Leif D. MD^§§; Poindexter, Brenda B. MD, MS^||||; Pedroza, Claudia PhD^†; Walsh, Michele C. MD, MS^¶¶; Stoll, Barbara J. MD^†; Geller, Rachel RN, BSN^##; Kennedy, Kathleen A. MD, MPH^†; Dimmitt, Reed A. MD, MSPH^∗∗∗; Carlo, Waldemar A. MD^∗∗∗; Cotten, C. Michael MD, MHS^†††; Laptook, Abbot R. MD^‡‡‡; Van Meurs, Krisa P. MD^§; Calkins, Kara L. MD, MS^##; Sokol, Gregory M. MD^§§§; Sanchez, Pablo J. MD^§§; Wyckoff, Myra H. MD^||||||; Patel, Ravi M. MD, MSc^¶¶¶; Frantz, Ivan D. III MD^{∗∗∗∗,††††}; Shankaran, Seetha MD^‡‡‡‡; D’Angio, Carl T. MD^§§§§; Yoder, Bradley A. MD^††; Bell, Edward F. MD^||||||||; Watterberg, Kristi L. MD^∗∗; Martin, Colin A. MD^¶¶¶¶; Harmon, Carroll M. MD, PhD^{¶¶¶¶,‡‡‡‡‡‡‡}; Rice, Henry MD^####; Kurkchubasche, Arlet G. MD^{∗∗∗∗∗}; Sylvester, Karl MD^{†††††}; Dunn, James C. Y. MD, PhD^{†††††,‡‡‡‡‡}; Markel, Troy A. MD^§§§§§§; Diesen, Diana L. MD^||||||||||; Bhatia, Amina M. MD, MS^¶¶¶¶¶; Flake, Alan MD^#####; Chwals, Walter J. MD^{∗∗∗∗∗∗}; Brown, Rebeccah MD^{††††††}; Bass, Kathryn D. MD, MBA^{‡‡‡‡‡‡‡}; St. Peter, Shawn D. MD^{‡‡‡‡‡‡}; Shanti, Christina M. MD^§§§§§§; Pegoli, Walter Jr MD^||||||||||||; Skarda, David MD^¶¶¶¶¶¶; Shilyansky, Joel MD^######; Lemon, David G. MD^{∗∗∗∗∗∗∗}; Mosquera, Ricardo A. MD, MS^†; Peralta-Carcelen, Myriam MD, MPH^∗∗∗; Goldstein, Ricki F. MD^†††; Vohr, Betty R. MD^‡‡‡; Purdy, Isabell B. PNP, NNP, PhD^##; Hines, Abbey C. PsyD^§§§; Maitre, Nathalie L. MD, PhD^§§; Heyne, Roy J. MD^||||||; DeMauro, Sara B. MD, MSCE^###; McGowan, Elisabeth C. MD^{∗∗∗∗,‡‡‡}; Yolton, Kimberly PhD^||||; Kilbride, Howard W. MD^‡‡; Natarajan, Girija MD^‡‡‡‡; Yost, Kelley PhD^§§§§; Winter, Sarah MD^††; Colaizy, Tarah T. MD, MPH^||||||||; Laughon, Matthew M. MD, MPH^{†††††††}; Lakshminrusimha, Satyanarayana MD^§§§§; Higgins, Rosemary D. MD^{§§§§§§§,||||||||||||||}

Author Information

^∗Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN

^†Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX

^‡Department of Pediatric Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX

^§Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, CA

^||Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, NC

^¶Department of Pediatric Surgery, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH

^#Social, Statistical and Environmental Sciences Unit, RTI International, Research Rockville, MD

^∗∗University of New Mexico Health Sciences Center, Albuquerque, NM

^††Department of Pediatrics, Division of Neonatology, University of Utah School of Medicine, Salt Lake City, UT

^‡‡Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO

^§§Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH

^||||Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH

^¶¶Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, OH

^##Department of Pediatrics, University of California, Los Angeles, CA

^∗∗∗Division of Neonatology, University of Alabama at Birmingham, Birmingham, AL

^†††Department of Pediatrics, Duke University, Durham, ND

^‡‡‡Department of Pediatrics, Women's & Infants Hospital, Brown University, Providence, RI

^§§§Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN

^||||||Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX

^¶¶¶Emory University School of Medicine, Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, GA

^###Department of Pediatrics, University of Pennsylvania, Philadelphia, PA

^∗∗∗∗Department of Pediatrics, Division of Newborn Medicine, Floating Hospital for Children, Tufts Medical Center, Boston, MA

^††††Department of Neonatology, Beth Israel Deaconess Medical Center, Boston, MA

^‡‡‡‡Department of Pediatrics, Wayne State University, Detroit, MI

^§§§§University of Rochester School of Medicine and Dentistry, Rochester, NY

^||||||||Department of Pediatrics, University of Iowa, Iowa City, IA

^¶¶¶¶Division of Pediatric Surgery, University of Alabama at Birmingham, Birmingham, AL

^####Division of Pediatric General Surgery, Duke University, Durham, NC

^{∗∗∗∗∗}Department of Pediatric Surgery, Hasbro Children's Hospital, Brown University, Providence, RI

^{†††††}Department of Pediatric Surgery, Stanford University School of Medicine, Palo Alto, CA

^{‡‡‡‡‡}Department of Pediatric Surgery, University of California, Los Angeles, CA

^§§§§§§Department of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN

^||||||||||Department of Pediatric Surgery, University of Texas Southwestern Medical Center, Dallas, TX

^¶¶¶¶¶Department of Pediatric Surgery, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA

^#####Department of Pediatric Surgery, University of Pennsylvania, Philadelphia, PA

^{∗∗∗∗∗∗}Department of Pediatric Surgery, Floating Hospital for Children, Tufts Medical Center, Boston, MA

^{††††††}Department of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH

^{‡‡‡‡‡‡}Department of Pediatric Surgery, Children's Mercy Hospital, Kansas City, MO

^§§§§§§Department of Pediatric Surgery, Wayne State University, Detroit, MI

^||||||||||||Department of Pediatric Surgery, University of Rochester School of Medicine and Dentistry, Rochester, NY

^¶¶¶¶¶¶Department of Pediatric Surgery, University of Utah School of Medicine, Salt Lake City, UT

^######Department of Surgery, University of Iowa, Iowa City, IA

^{∗∗∗∗∗∗∗}Department of Pediatric Surgery, University of New Mexico Health Sciences Center, Albuquerque, NM

^{†††††††}Division of Neonatal/Perinatal Medicine, Department of Pediatrics, University of North Carolina, Chapel Hill, NC

^{‡‡‡‡‡‡‡}Division of Pediatric Surgery, University of Buffalo, John R. Oishei Children's Hospital, Buffalo, NY

^{§§§§§§§}Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD

^{||||||||||||||}College of Health and Human Services, George Mason University, Fairfax, VA.

[email protected].

Requests for reprints should be addressed to Dr. Martin Blakely as above.

Funding for trial: The following grants from the NICHD supported this trial: UG1 HD27904 (Brown University), UG1 HD21364 (Case Western), UG1 HD68284 (Children's Mercy), UG1 HD27853, UL1 TR77 (Cincinnati Children's), UG1 HD40492, UL1 TR1117 (Duke and UNC), UG1 HD27851, UL1 TR454 (Emory), UG1 HD27856, UL1 TR6 (Indiana U), UG1 HD21373 (UT Houston), UG1 HD68278 (Nationwide Children's), UG1 HD36790 (RTI International), UG1 HD27880, UL1 TR93 (Stanford), U10 HD53119 (Tufts), UG1 HD34216 (UAB), UG1 HD68270 (UCLA), UG1 HD68270 (Iowa), UG1 HD53089, UL1 TR41 (U New Mexico), UG1 HD68244 (U Pennsylvania), UG1 HD68263, UL1 TR42 (Rochester), UG1 HD40689 (UT Southwestern), UG1 HD87226, U10 HD53124, UL1 RR25764 (U Utah), UG1 HD21385 (Wayne State), U10 HD27871, UL1 TR142 (Yale)

Participating NRN sites collected data and transmitted it to RTI International, the data coordinating center (DCC) for the network, which stored, managed, and analyzed the data for this trial. On behalf of the NRN, RTI International had full access to all of the data in the trial, and with the NRN Center Principal Investigators, take responsibility for the integrity of the data and accuracy of the data analysis.

Author contributions: M.L.B., J.E.T.—conceptualization; methodology, investigation, writing original draft, writing review and editing, visualization, project administration, funding acquisition; K.P.L., G.E.B., R.G.—conceptualization, methodology, investigation, writing review, and editing; S.R.H., D.K.S., R.K.O., W.E.T., L.D.N., B.B.P., M.C.W., B.J.S., R.D.H.—conceptualization, methodology, investigation, writing review and editing, funding acquisition; B.E., MD—methodology, software, validation, formal analysis, investigation, data curation, writing review and editing, visualization, project administration; A.D.—methodology, software, validation, formal analysis, investigation, data curation, writing review and editing, visualization, supervision, project administration, funding acquisition; C.P., PhD—methodology, software, validation, formal analysis; writing original draft; writing review, and editing; K.A.K., W.A.C., C.M.C., A.R.L., K.P.V., K.L., G.M.S., P.J.S., I.D.F. III, S.S., C.T.D., B.A.Y., E.F.B., K.L.W.—methodology, investigation, writing review and editing, funding acquisition; R.A.D., C.A.M., T.A.M., D.A.D.—investigation, writing review, and editing; M.H.W., R.M.P.—methodology, investigation, writing review and editing;

C.M.H., H.R., A.G.K., K.S., J.C.Y.D., A.M.B., A.F., W.J.C., R.B., K.D.B., S.D.S., C.M.S., W.P., D.S., J.S., D.G.L.—conceptualization, investigation, writing review and editing; R.A.M., M.P.C., I.B.P., A.C.H., N.L.M., R.J.H., S.B.D., E.C.M., K.Y., H.W.K., G.N., K.Y., S.W., T.T.C., M.M.L., S.S.L.—investigation; data acquisition; writing review and editing;

R.F.G., B.R.V.—conceptualization; investigation; data acquisition; writing review and editing.

The authors report no conflict of interests.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.annalsofsurgery.com).

Annals of Surgery 274(4):p e370-e380, October 2021. | DOI: 10.1097/SLA.0000000000005099

Abstract

Objective:

The aim of this study was to determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP).

Summary Background Data:

The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown.

Methods:

We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18 to 22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches.

Results:

Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage [adjusted relative risk (aRR) 1.0; 95% confidence interval (CI): 0.87–1.14]. A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (P = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR 0.81; 95% CI: 0.64–1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference <0) for a preoperative diagnosis of NEC was 97%. For preoperative diagnosis of IP, death or NDI occurred in 69% after laparotomy versus 63% with drainage (aRR, 1.11; 95% CI: 0.95–1.31); Bayesian probability of benefit with laparotomy = 18%.

Conclusions:

There was no overall difference in death or NDI rates at 18 to 22 months corrected age between initial laparotomy versus drainage. However, the preoperative diagnosis of NEC or IP modified the impact of initial treatment.

Article Keywords

Keywords
isolated intestinal perforation, neonatal surgery, premature infant, randomized clinical trial, surgical necrotizing enterocolitis

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Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation

A Multicenter Randomized Clinical Trial