Treatment of Necrotizing Enterocolitis
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《新英格兰医药杂志》
To the Editor: The study by Moss et al. (May 25 issue)1 is impressive because it represents a successful multicenter, prospective, randomized trial investigating therapies for necrotizing enterocolitis. However, 60 percent of the study cohort did not have evidence of pneumatosis on radiography, 77 percent weighed less than 1000 g at birth, 30 percent were not receiving enteral feeding before perforation occurred, and more than 30 percent had perforation within the first two weeks after birth. These features suggest a diagnosis of spontaneous intestinal perforation rather than necrotizing enterocolitis.2,3,4
Several investigators have reported better outcomes with spontaneous intestinal perforation than with necrotizing enterocolitis with perforation.5,6 Can the authors provide assurance that their findings are not confounded by the enrollment of patients with spontaneous intestinal perforation (who may have a better response to peritoneal drainage than patients with necrotizing enterocolitis)?5
Phillip V. Gordon, M.D., Ph.D.
University of Virginia Children's Hospital
Charlottesville, VA 22908
pvg4n@virginia.edu
References
Moss RL, Dimmitt RA, Barnhart DC, et al. Laparotomy versus peritoneal drainage for necrotizing enterocolitis and perforation. N Engl J Med 2006;354:2225-2234.
Gordon P, Rutledge J, Sawin R, Thomas S, Woodrum D. Early postnatal dexamethasone increases the risk of focal small bowel perforation in extremely low birth weight infants. J Perinatol 1999;19:573-577.
Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (2) two populations of patients with perforations. J Perinatol 2006;26:185-188.
Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (1) SIP is associated with early indomethacin exposure. J Perinatol 2006;26:93-99.
Blakely ML, Lally KP, McDonald S, et al. Postoperative outcomes of extremely low birth-weight infants with necrotizing enterocolitis or isolated intestinal perforation: a prospective cohort study by the NICHD Neonatal Research Network. Ann Surg 2005;241:984-989.
Pumberger W, Mayr M, Kohlhauser C, Weninger M. Spontaneous localized intestinal perforation in very-low-birth-weight infants: a distinct clinical entity different from necrotizing enterocolitis. J Am Coll Surg 2002;195:796-803.
To the Editor: In the report by Moss et al., it appears that the eligible nonenrolled patients who underwent primary peritoneal drainage were more premature than the enrolled patients. Was drainage performed in all 30 patients who were not offered enrollment by surgeons? Also, there is an apparent difference in early mortality (within 30 days) between groups; infants who died after laparotomy appear to have died earlier than infants who died after primary peritoneal drainage. It is important to know whether the deaths were due to necrotizing enterocolitis or to other causes. Other important outcomes were not addressed, including morbidity from respiratory causes and the short-bowel syndrome. Do the authors have data on these outcomes?
Clare M. Rees, M.B., Ch.B.
Simon Eaton, Ph.D.
Agostino Pierro, M.D.
Institute of Child Health
London WC1N 1EH, United Kingdom
The authors report being investigators in the Necrotizing Enterocolitis trial (www.nettrial.net), an international randomized, controlled trial comparing laparotomy with peritoneal drainage for infants with extremely low birth weight who have bowel perforation; the trial was recently closed to recruitment.
The authors reply: Gordon asks whether some neonates in our trial may have had spontaneous intestinal perforation. There is debate as to whether spontaneous intestinal perforation is a distinct entity or a variant of necrotizing enterocolitis. The practicing clinician must devise a treatment strategy for each premature neonate with a perforated bowel on the basis of clinical and radiographic findings at presentation. The presence of pneumatosis is not a uniformly reliable predictor of the extent of disease. In the study by Blakely et al., 57.6 percent of patients with necrotizing enterocolitis at operation presented with pneumatosis.1
We realized that our study would include patients with the full spectrum of disease (from focal perforation to widespread necrotizing enterocolitis). We relied on randomization to ensure that the distribution of disease was similar in the two groups. Our data show that this occurred. In prespecified subgroup analyses, we found that the type of operation performed did not significantly affect the outcomes among patients with and those without pneumatosis.
Rees et al. raise important issues. Outside of clinical trials, peritoneal drainage is used to treat smaller babies than those treated with laparotomy. The prevailing belief that these babies are the best candidates for drainage is not supported by our results. Of the 30 patients not enrolled because the surgeon did not offer enrollment, 30 percent underwent laparotomy (mortality rate, 44 percent) and 70 percent underwent drainage (mortality rate, 62 percent). The possibility of enrollment bias exists in all clinical trials. We have provided as much data as possible on eligible nonenrolled patients, in order to allow readers to draw their own conclusions about the generalizability of our results.
Although the survival curve shows a slightly higher 30-day mortality rate in the laparotomy group than in the drainage group, this difference was not significant. Infants who die of necrotizing enterocolitis typically die of multisystem organ failure related to sepsis. We could not reliably deem some deaths as due to necrotizing enterocolitis and others not. Unfortunately, we do not have data on other outcomes. We look forward to seeing the results of additional trials.
R. Lawrence Moss, M.D.
Cynthia Brandt, M.D.
Yale University School of Medicine
New Haven CT 06520
larry.moss@yale.edu
References
Blakely ML, Lally KP, McDonald S, et al. Postoperative outcomes of extremely low birth-weight infants with necrotizing enterocolitis or isolated intestinal perforation: a prospective cohort study by the NICHD Neonatal Research Network. Ann Surg 2005;241:984-989.
Several investigators have reported better outcomes with spontaneous intestinal perforation than with necrotizing enterocolitis with perforation.5,6 Can the authors provide assurance that their findings are not confounded by the enrollment of patients with spontaneous intestinal perforation (who may have a better response to peritoneal drainage than patients with necrotizing enterocolitis)?5
Phillip V. Gordon, M.D., Ph.D.
University of Virginia Children's Hospital
Charlottesville, VA 22908
pvg4n@virginia.edu
References
Moss RL, Dimmitt RA, Barnhart DC, et al. Laparotomy versus peritoneal drainage for necrotizing enterocolitis and perforation. N Engl J Med 2006;354:2225-2234.
Gordon P, Rutledge J, Sawin R, Thomas S, Woodrum D. Early postnatal dexamethasone increases the risk of focal small bowel perforation in extremely low birth weight infants. J Perinatol 1999;19:573-577.
Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (2) two populations of patients with perforations. J Perinatol 2006;26:185-188.
Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (1) SIP is associated with early indomethacin exposure. J Perinatol 2006;26:93-99.
Blakely ML, Lally KP, McDonald S, et al. Postoperative outcomes of extremely low birth-weight infants with necrotizing enterocolitis or isolated intestinal perforation: a prospective cohort study by the NICHD Neonatal Research Network. Ann Surg 2005;241:984-989.
Pumberger W, Mayr M, Kohlhauser C, Weninger M. Spontaneous localized intestinal perforation in very-low-birth-weight infants: a distinct clinical entity different from necrotizing enterocolitis. J Am Coll Surg 2002;195:796-803.
To the Editor: In the report by Moss et al., it appears that the eligible nonenrolled patients who underwent primary peritoneal drainage were more premature than the enrolled patients. Was drainage performed in all 30 patients who were not offered enrollment by surgeons? Also, there is an apparent difference in early mortality (within 30 days) between groups; infants who died after laparotomy appear to have died earlier than infants who died after primary peritoneal drainage. It is important to know whether the deaths were due to necrotizing enterocolitis or to other causes. Other important outcomes were not addressed, including morbidity from respiratory causes and the short-bowel syndrome. Do the authors have data on these outcomes?
Clare M. Rees, M.B., Ch.B.
Simon Eaton, Ph.D.
Agostino Pierro, M.D.
Institute of Child Health
London WC1N 1EH, United Kingdom
The authors report being investigators in the Necrotizing Enterocolitis trial (www.nettrial.net), an international randomized, controlled trial comparing laparotomy with peritoneal drainage for infants with extremely low birth weight who have bowel perforation; the trial was recently closed to recruitment.
The authors reply: Gordon asks whether some neonates in our trial may have had spontaneous intestinal perforation. There is debate as to whether spontaneous intestinal perforation is a distinct entity or a variant of necrotizing enterocolitis. The practicing clinician must devise a treatment strategy for each premature neonate with a perforated bowel on the basis of clinical and radiographic findings at presentation. The presence of pneumatosis is not a uniformly reliable predictor of the extent of disease. In the study by Blakely et al., 57.6 percent of patients with necrotizing enterocolitis at operation presented with pneumatosis.1
We realized that our study would include patients with the full spectrum of disease (from focal perforation to widespread necrotizing enterocolitis). We relied on randomization to ensure that the distribution of disease was similar in the two groups. Our data show that this occurred. In prespecified subgroup analyses, we found that the type of operation performed did not significantly affect the outcomes among patients with and those without pneumatosis.
Rees et al. raise important issues. Outside of clinical trials, peritoneal drainage is used to treat smaller babies than those treated with laparotomy. The prevailing belief that these babies are the best candidates for drainage is not supported by our results. Of the 30 patients not enrolled because the surgeon did not offer enrollment, 30 percent underwent laparotomy (mortality rate, 44 percent) and 70 percent underwent drainage (mortality rate, 62 percent). The possibility of enrollment bias exists in all clinical trials. We have provided as much data as possible on eligible nonenrolled patients, in order to allow readers to draw their own conclusions about the generalizability of our results.
Although the survival curve shows a slightly higher 30-day mortality rate in the laparotomy group than in the drainage group, this difference was not significant. Infants who die of necrotizing enterocolitis typically die of multisystem organ failure related to sepsis. We could not reliably deem some deaths as due to necrotizing enterocolitis and others not. Unfortunately, we do not have data on other outcomes. We look forward to seeing the results of additional trials.
R. Lawrence Moss, M.D.
Cynthia Brandt, M.D.
Yale University School of Medicine
New Haven CT 06520
larry.moss@yale.edu
References
Blakely ML, Lally KP, McDonald S, et al. Postoperative outcomes of extremely low birth-weight infants with necrotizing enterocolitis or isolated intestinal perforation: a prospective cohort study by the NICHD Neonatal Research Network. Ann Surg 2005;241:984-989.