The American Journal of Surgery (2016) 211, 645-648
Society of Black Academic Surgeons
Necrotizing enterocolitis and the use of loop diuretics in very low birth weight neonates Mariatu A. Cole, M.D., M.P.H.a, Christopher DeRienzo, M.D., M.P.P.b,c, Maragatha Kutchibhatla, Ph.D.d, Charles Michael Cotten, M.D., M.H.S.b,c, Obinna O. Adibe, M.D., M.H.S.e,* a
University of North Carolina, Chapel Hill School of Medicine, Chapel Hill, NC, USA; bDivision of Perinatal-Neonatal Medicine, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA; cDepartment of Pediatrics, Jean and George Brumley, Jr., Neonatal-Perinatal Research Institute, Duke University Medical Center, Durham, NC, USA; dDepartment of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA; eDivision of Pediatric Surgery, Department of Surgery, Duke University Medical Center, DUMC Box 3815, Durham, NC 27710, USA
KEYWORDS: Necrotizing enterocolitis; Preterm; Very low birth weight; Loop diuretics
Abstract BACKGROUND: Necrotizing enterocolitis (NEC) is a gastrointestinal disease of premature, very low birth weight neonates resulting in sepsis and death. Loop diuretics are widely used in neonates as a treatment for pulmonary fluid retention. An association between diuretic use and NEC has not been explored. METHODS: The medical records of all neonates admitted to Duke Children’s Hospital between 2007 and 2012 with a birth weight %1,500 grams were reviewed. RESULTS: Using multivariable logistic regression analysis, we found that loop diuretic administration was not a risk factor for the development of NEC. On subanalysis, 75% of medical NEC infants had prior exposure to loop diuretics, compared with 100% of surgical NEC infants (P 5 .004). CONCLUSIONS: Loop diuretics do not increase the risk of development of NEC in very low birth weight neonates. However, on diagnosis of NEC, administration of loop diuretics may be associated with the progression of NEC severity from medical NEC to surgical NEC. Ó 2016 Elsevier Inc. All rights reserved.
There were no relevant financial relationships or any sources of support in the form of grants, equipment, or drugs. The authors declare no conflicts of interest. Presented at the 25th Annual Meeting of the Society of Black Academic Surgeons, Chapel Hill, NC; April 9–12, 2015. * Corresponding author. Tel.: 11-919-681-5077; fax: 11-919-6818353. E-mail address: [email protected] Manuscript received April 20, 2015; revised manuscript September 10, 2015 0002-9610/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2015.11.015
Necrotizing enterocolitis (NEC) is a devastating disease of premature and very low birth weight (VLBW) infants. The mean prevalence of NEC is about 7% among infants with a birth weight of 500 to 1,500 grams.1 Despite advancements in neonatal medicine, the estimated mortality from NEC has remained 20% to 30% for the past 30 years.1,2 Over 90% of NEC cases occur after the initiation of enteral feeds; however, its underlying pathophysiology remains poorly understood. Furosemide, a loop diuretic, is one of the most widely used medications in the neonatal intensive care unit.3 It acts
646
The American Journal of Surgery, Vol 211, No 4, April 2016
by inhibiting sodium and chloride resorption at the thick ascending limb of the loop of Henle.3,4 Administration of diuretics to premature, VLBW infants result in improved lung mechanics, including decreased pCO2 and improved oxygenation,4 potentially via a decrease in intravascular and interstitial fluid volume. In adults, a decreased intravascular volume may contribute to the pathophysiology of nonocclusive mesenteric ischemia secondary to hypoperfusion; therefore, diuretic use is contraindicated in critically ill adult patients at risk for bowel ischemia (ie, sepsis, severe acute pancreatitis, or recent aortic surgery). It is unclear whether this clinical rationale translates to the critically ill neonatal population. Our hypothesis is that loop diuretic use in the VLBW infant (%1,500 grams) is a risk factor for the development of NEC.
administration of a loop diuretic (furosemide or bumetadine) at any time before the diagnosis of NEC. Statistical analysis was conducted using SAS 9.3 (SAS Institute, Cary, NC). Adjusted odds ratios were derived by a multivariable logistic regression model: the dependent variable was the diagnosis of NEC, and the primary independent variable was diuretic exposure. Model covariates included race, gestational age, 5-minute Apgar score, respiratory failure, presence of a patent ductus arteriosus, and anemia requiring blood transfusion up to 7 days before the diagnosis of NEC. Patient demographics were compared using the Student’s t-test or Mann–Whitney U test for parametric or nonparametric continuous distribution, respectively. The chi-square with Yates correction or Fisher’s exact test was used for categorical data, where appropriate. Statistical significance was defined as P , .05.
Methods After institutional review board approval, the medical records of all neonates with a birth weight of %1,500 grams admitted to the Duke Children’s Hospital from January 2007 to December 2012 were reviewed for this case-control study. The intensive care nursery at Duke Children’s Hospital is a level 3 neonatal intensive care unit, offering tertiary care to both inborn and outborn infants. It serves as one of central North Carolina’s 3 referral centers for VLBW neonates requiring surgical care. Gestational age was based on best obstetrical estimate. The neonatology team who cared for the infant made the diagnosis of NEC. NEC was diagnosed when the infant’s clinical picture correlated with radiographic evidence. Medical NEC was defined as abdominal distention with pneumatosis intestinalis and/or portal venous gas. Surgical NEC was defined as pneumoperitoneum, abdominal distention with erythema, and/or a prolonged ileus pattern (ie, fixed, distended bowel loop for .48 hours). Radiographs were assessed by attending pediatric radiologists using the Duke Abdominal Assessment Scale, a 10-point scale used to assess severity of disease in an infant with a clinical suspicion of NEC.5 Diuretic exposure was defined as
Table 1
Results Between 2005 and 2012, there were 72 patients diagnosed with NEC in our institution. These patients were compared with 332 control patients with similar clinical characteristics (Table 1). On multivariable logistic regression analysis, exposure to diuretics in the VLBW population was not a risk factor for NEC. Anemia requiring blood transfusion by one week of life, and low 5-minute Apgar scores were predictors of NEC, respectively. Respiratory failure and presence of a patent ductus arteriosus were not predictors of NEC (Table 2). Table 3 represents a subanalysis comparing the use of diuretics in children with medical and surgical NEC. Patients with surgical NEC had a lower birth weight and a younger gestational age than those with medical NEC. Although 33/44 infants with medical NEC (75%) were exposed to loop diuretics before diagnosis, 100% of surgical NEC patients (28 of 28) were exposed to diuretics before diagnosis (P 5 .004). Multivariable logistic regression analysis of this cohort demonstrated low
Patient demographics
Variable
Controls (no NEC; n 5 332)
Cases (NEC; n 5 72)
Gestational age, weeks (mean, [sd]) Birth weight, grams (mean, [sd]) White (n [%]) Black (n [%]) Other (n [%]) Male (n [%]) Breast milk (n [%]) Mortality (n [%])
27 949.6 126 161 45 142 273 27
27 912.7 26 38 8 41 60 16
NEC 5 necrotizing enterocolitis; sd 5 standard deviation.
(2.56) (274.08) (37.95) (48.49) (13.55) (44.38) (82.48) (8.13)
(2.4) (272.62) (17.11) (52.78) (11.11) (57.75) (84.51) (22.22)
P value .61 .29 .75
.04 .68 .0004
M.A. Cole et al.
NEC and loop diuretics in VLBW neonates
Table 2 Odds ratios after multivariate logistic regression, cases vs controls Variable Loop diuretic use Anemia requiring transfusion Apgar at 5 min Gestational age
Adjusted odds ratio
Lower 95% CI
Upper 95% CI
.998 14.77
.423 4.02
2.352 54.25
.837 1.19
.713 1.039
.982 1.362
CI 5 confidence interval; NEC 5 necrotizing enterocolitis.
postconceptual age to be a significant predictor of surgical NEC (Table 4).
Comments This study does not support the hypothesis that loop diuretic administration is a risk factor for the development of NEC in VLBW preterm infants. The study does suggest, however, that loop diuretics may be associated with the transition from medical to surgical NEC. Loop diuretics inhibit the Na1-K1-2Cl2 transport channels located on the luminal surface of the nephron’s ascending limb of the loop of Henle,6 resulting in decreased electrolyte resorption from the nephron back into systemic circulation. Water is subsequently pulled into the nephron ductules via osmosis, causing diuresis. Adverse effects of loop diuretics include hypotension, dehydration, and diarrhea.7 Profound dehydration has been known to cause nonocclusive mesenteric ischemia in critically ill adults secondary to low-flow states and hypoperfusion.8 Consequently, diuretic use has been contraindicated in a subset of acute perioperative or critically ill, hypotensive, septic patients. Our study suggests that the bowel of the VLBW premature infant, a critically ill patient requiring intensive care soon after birth, may not be directly affected by drug-induced diuresis. This may also suggest that the pathophysiology of nonocclusive mesenteric ischemia differs greatly from NEC. Animal models that use hypoxia or vascular insult to induce
Table 3
647 intestinal ischemia9 may not be the best models for the study of NEC. Although several studies have reported an increased risk of NEC in black infants,2 we did not appreciate this in our study. There was a statistically significant male proportion within the NEC group (67.8% vs 44.4; P 5 .04). Our results concur with findings of other authors.10,11 Anemia requiring blood transfusion within 7 days before the diagnosis of NEC was strongly associated with developing NEC. Our results correlate with other studies that have shown similar association between blood transfusion and NEC.11 Explanations for this phenomenon include decreased nitric oxide in stored packed red blood cells, and an exaggerated intestinal immune response from transfusion.11 Our intensive care nursery has developed a blood transfusion protocol for VLBW neonates to decrease the incidence of NEC.12 Medical NEC is usually treated with bowel rest, nasogastric decompression, and a course of antibiotics, whereas surgical NEC requires operative intervention. Our study suggests that loop diuretic administration during this critically ill condition of medical NEC may be associated with the transition to the more serious surgical NEC, thereby increasing mortality from 21% to 35%,10 possibly via the aforementioned mechanism of dehydration and mesenteric low-flow state. We observed that 43 of the patients with NEC (59.7%) were on at least one vasopressor before the diagnosis of NEC. Whether the combination of vasopressors and diuretics contributes to the severity of NEC remains to be discerned. For 60 of the 72 cases, the median (range) for length of exposure to loop diuretics in days was 22.5 (0 to 77). We excluded this covariate from our model because it would have greatly altered the results of the logistic regression analysis secondary to small sample size and incomplete data. Our study has a number of important limitations. The retrospective nature of this study prevents us from making a definitive causation between loop diuretics and surgical NEC. The study’s retrospective nature also deems it susceptible to information bias. Chart reviews of cases were based on the International Classification of Diseases, 9th revision (ICD-9) coding using clinician discretion. In
Demographics of medical NEC vs surgical NEC
Variable
Medical NEC (n 5 44)
Surgical NEC (n 5 28)
P value
Gestational age, weeks (mean, [sd]) Birth weight, grams (mean, sd) White (n [%]) Black (n [%]) Other (n [%]) Male (n [%]) Breast milk (n [%]) Exposure to loop diuretic before NEC (n [%])
28 978.3 16 23 5 21 39 33
25 809.6 10 15 3 20 21 28
.0001 .003 .99
NEC 5 necrotizing enterocolitis.
(2.2) (245.47) (36.36) (52.27) (11.36) (48.84) (90.7) (75)
(2.1) (285.39) (35.71) (53.57) (10.71) (71.43) (75) (100)
.06 .07 .004
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The American Journal of Surgery, Vol 211, No 4, April 2016
Table 4 Odds ratios after multivariate logistic regression, surgical vs medical NEC Variable Birth weight Postconceptual age at diagnosis of NEC
Adjusted odds ratio
Lower 95% CI
Upper 95% CI
.999 .623
.996 .475
1.002 .816
NEC 5 necrotizing enterocolitis.
particular, cases of spontaneous intestinal perforation, which does not elicit as high an inflammatory response as NEC, therefore considered a different disease entity,1 may be coded as such. This study also suffers from low sample size, although the results from our model correlate with those from other authors. Finally, the high prevalence of loop diuretic exposure within the cohort of neonates with NEC at our institution (84.7%) makes it difficult to elucidate a true association between loop diuretics and surgical NEC. Application of this model to a larger database may help clarify this sample bias.
Conclusions The etiology of NEC is multifactorial: a combination of disrupted neonatal microbiota, an immature intestinal mucosa, and genetic predisposition. Although certain external factors, such as blood transfusions, may be risk factors for the development of NEC, loop diuretics do not appear to play such a role. However, once the extensive
inflammatory process has ensued, diuretic use may accentuate the progression of the disease.
References 1. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011;364: 255–64. 2. Lin PW, Stoll BJ. Necrotizing enterocolitis. Lancet 2006;368:1271–83. 3. Hagadorn JI, Sanders MR, Staves C, et al. Diuretics for very low birth weight infants in the first 28 days: a survey of the US neonatologists. J Perinatol 2011;31:677–81. 4. Cotton R, Suarez S, Reese J. Unexpected extra-renal effects of loop diuretics in the preterm neonate. Acta Paediatr 2012;101:833–45. 5. Coursey CA, Hollingsworth CL, Wriston C, et al. Radiographic predictors of disease severity in neonates and infants with necrotizing enterocolitis. AJR 2009;193:1408–13. 6. Pacifici GM. Clinical pharmacology of the loop diuretics furosemide and bumetadine in neonates and infants. Pediatr Drugs 2012;14:233–46. 7. Mackenzie JF, Cochran KM, Russell RI. The effect of frusemide on water and electrolyte absorption from the human jejunum. Clin Sci Mol Med 1975;49:519–21. 8. Kolkman JJ, Mensink PBF. Non-occlusive mesenteric ischaemia: a common disorder in gastroenterology and intensive care. Best Pract Res Clin Gastroenterol 2003;17:457–73. 9. Lu P, Sodh CP, Jia H. Animal models of gastrointestinal and liver diseases. Animal models of necrotizing enterocolitis: pathophysiology, translational relevance, and challenges. Am J Physiol Gastrointest Liver Physiol 2014;306:G917–28. 10. Hull MA, Fisher JG, Gutierrez IM, et al. Mortality and management of surgical necrotizing enterocolitis in very low birth weight neonates: a prospective cohort study. J Am Coll Surg 2014;218:1148–55. 11. Paul DA, Mackley A, Novitsky A, et al. Increased odds of necrotizing enterocolitis after transfusion of red blood cells in premature infants. Pediatrics 2011;127:635–41. 12. DeRienzo C, Smith PB, Tanaka D, et al. Feeding practices and other risk factors for developing transfusion-associated necrotizing enterocolitis. Early Hum Dev 2014;90:237–40.
Society of Black Academic Surgeons
Necrotizing enterocolitis and the use of loop diuretics in very low birth weight neonates Mariatu A. Cole, M.D., M.P.H.a, Christopher DeRienzo, M.D., M.P.P.b,c, Maragatha Kutchibhatla, Ph.D.d, Charles Michael Cotten, M.D., M.H.S.b,c, Obinna O. Adibe, M.D., M.H.S.e,* a
University of North Carolina, Chapel Hill School of Medicine, Chapel Hill, NC, USA; bDivision of Perinatal-Neonatal Medicine, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA; cDepartment of Pediatrics, Jean and George Brumley, Jr., Neonatal-Perinatal Research Institute, Duke University Medical Center, Durham, NC, USA; dDepartment of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA; eDivision of Pediatric Surgery, Department of Surgery, Duke University Medical Center, DUMC Box 3815, Durham, NC 27710, USA
KEYWORDS: Necrotizing enterocolitis; Preterm; Very low birth weight; Loop diuretics
Abstract BACKGROUND: Necrotizing enterocolitis (NEC) is a gastrointestinal disease of premature, very low birth weight neonates resulting in sepsis and death. Loop diuretics are widely used in neonates as a treatment for pulmonary fluid retention. An association between diuretic use and NEC has not been explored. METHODS: The medical records of all neonates admitted to Duke Children’s Hospital between 2007 and 2012 with a birth weight %1,500 grams were reviewed. RESULTS: Using multivariable logistic regression analysis, we found that loop diuretic administration was not a risk factor for the development of NEC. On subanalysis, 75% of medical NEC infants had prior exposure to loop diuretics, compared with 100% of surgical NEC infants (P 5 .004). CONCLUSIONS: Loop diuretics do not increase the risk of development of NEC in very low birth weight neonates. However, on diagnosis of NEC, administration of loop diuretics may be associated with the progression of NEC severity from medical NEC to surgical NEC. Ó 2016 Elsevier Inc. All rights reserved.
There were no relevant financial relationships or any sources of support in the form of grants, equipment, or drugs. The authors declare no conflicts of interest. Presented at the 25th Annual Meeting of the Society of Black Academic Surgeons, Chapel Hill, NC; April 9–12, 2015. * Corresponding author. Tel.: 11-919-681-5077; fax: 11-919-6818353. E-mail address: [email protected] Manuscript received April 20, 2015; revised manuscript September 10, 2015 0002-9610/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2015.11.015
Necrotizing enterocolitis (NEC) is a devastating disease of premature and very low birth weight (VLBW) infants. The mean prevalence of NEC is about 7% among infants with a birth weight of 500 to 1,500 grams.1 Despite advancements in neonatal medicine, the estimated mortality from NEC has remained 20% to 30% for the past 30 years.1,2 Over 90% of NEC cases occur after the initiation of enteral feeds; however, its underlying pathophysiology remains poorly understood. Furosemide, a loop diuretic, is one of the most widely used medications in the neonatal intensive care unit.3 It acts
646
The American Journal of Surgery, Vol 211, No 4, April 2016
by inhibiting sodium and chloride resorption at the thick ascending limb of the loop of Henle.3,4 Administration of diuretics to premature, VLBW infants result in improved lung mechanics, including decreased pCO2 and improved oxygenation,4 potentially via a decrease in intravascular and interstitial fluid volume. In adults, a decreased intravascular volume may contribute to the pathophysiology of nonocclusive mesenteric ischemia secondary to hypoperfusion; therefore, diuretic use is contraindicated in critically ill adult patients at risk for bowel ischemia (ie, sepsis, severe acute pancreatitis, or recent aortic surgery). It is unclear whether this clinical rationale translates to the critically ill neonatal population. Our hypothesis is that loop diuretic use in the VLBW infant (%1,500 grams) is a risk factor for the development of NEC.
administration of a loop diuretic (furosemide or bumetadine) at any time before the diagnosis of NEC. Statistical analysis was conducted using SAS 9.3 (SAS Institute, Cary, NC). Adjusted odds ratios were derived by a multivariable logistic regression model: the dependent variable was the diagnosis of NEC, and the primary independent variable was diuretic exposure. Model covariates included race, gestational age, 5-minute Apgar score, respiratory failure, presence of a patent ductus arteriosus, and anemia requiring blood transfusion up to 7 days before the diagnosis of NEC. Patient demographics were compared using the Student’s t-test or Mann–Whitney U test for parametric or nonparametric continuous distribution, respectively. The chi-square with Yates correction or Fisher’s exact test was used for categorical data, where appropriate. Statistical significance was defined as P , .05.
Methods After institutional review board approval, the medical records of all neonates with a birth weight of %1,500 grams admitted to the Duke Children’s Hospital from January 2007 to December 2012 were reviewed for this case-control study. The intensive care nursery at Duke Children’s Hospital is a level 3 neonatal intensive care unit, offering tertiary care to both inborn and outborn infants. It serves as one of central North Carolina’s 3 referral centers for VLBW neonates requiring surgical care. Gestational age was based on best obstetrical estimate. The neonatology team who cared for the infant made the diagnosis of NEC. NEC was diagnosed when the infant’s clinical picture correlated with radiographic evidence. Medical NEC was defined as abdominal distention with pneumatosis intestinalis and/or portal venous gas. Surgical NEC was defined as pneumoperitoneum, abdominal distention with erythema, and/or a prolonged ileus pattern (ie, fixed, distended bowel loop for .48 hours). Radiographs were assessed by attending pediatric radiologists using the Duke Abdominal Assessment Scale, a 10-point scale used to assess severity of disease in an infant with a clinical suspicion of NEC.5 Diuretic exposure was defined as
Table 1
Results Between 2005 and 2012, there were 72 patients diagnosed with NEC in our institution. These patients were compared with 332 control patients with similar clinical characteristics (Table 1). On multivariable logistic regression analysis, exposure to diuretics in the VLBW population was not a risk factor for NEC. Anemia requiring blood transfusion by one week of life, and low 5-minute Apgar scores were predictors of NEC, respectively. Respiratory failure and presence of a patent ductus arteriosus were not predictors of NEC (Table 2). Table 3 represents a subanalysis comparing the use of diuretics in children with medical and surgical NEC. Patients with surgical NEC had a lower birth weight and a younger gestational age than those with medical NEC. Although 33/44 infants with medical NEC (75%) were exposed to loop diuretics before diagnosis, 100% of surgical NEC patients (28 of 28) were exposed to diuretics before diagnosis (P 5 .004). Multivariable logistic regression analysis of this cohort demonstrated low
Patient demographics
Variable
Controls (no NEC; n 5 332)
Cases (NEC; n 5 72)
Gestational age, weeks (mean, [sd]) Birth weight, grams (mean, [sd]) White (n [%]) Black (n [%]) Other (n [%]) Male (n [%]) Breast milk (n [%]) Mortality (n [%])
27 949.6 126 161 45 142 273 27
27 912.7 26 38 8 41 60 16
NEC 5 necrotizing enterocolitis; sd 5 standard deviation.
(2.56) (274.08) (37.95) (48.49) (13.55) (44.38) (82.48) (8.13)
(2.4) (272.62) (17.11) (52.78) (11.11) (57.75) (84.51) (22.22)
P value .61 .29 .75
.04 .68 .0004
M.A. Cole et al.
NEC and loop diuretics in VLBW neonates
Table 2 Odds ratios after multivariate logistic regression, cases vs controls Variable Loop diuretic use Anemia requiring transfusion Apgar at 5 min Gestational age
Adjusted odds ratio
Lower 95% CI
Upper 95% CI
.998 14.77
.423 4.02
2.352 54.25
.837 1.19
.713 1.039
.982 1.362
CI 5 confidence interval; NEC 5 necrotizing enterocolitis.
postconceptual age to be a significant predictor of surgical NEC (Table 4).
Comments This study does not support the hypothesis that loop diuretic administration is a risk factor for the development of NEC in VLBW preterm infants. The study does suggest, however, that loop diuretics may be associated with the transition from medical to surgical NEC. Loop diuretics inhibit the Na1-K1-2Cl2 transport channels located on the luminal surface of the nephron’s ascending limb of the loop of Henle,6 resulting in decreased electrolyte resorption from the nephron back into systemic circulation. Water is subsequently pulled into the nephron ductules via osmosis, causing diuresis. Adverse effects of loop diuretics include hypotension, dehydration, and diarrhea.7 Profound dehydration has been known to cause nonocclusive mesenteric ischemia in critically ill adults secondary to low-flow states and hypoperfusion.8 Consequently, diuretic use has been contraindicated in a subset of acute perioperative or critically ill, hypotensive, septic patients. Our study suggests that the bowel of the VLBW premature infant, a critically ill patient requiring intensive care soon after birth, may not be directly affected by drug-induced diuresis. This may also suggest that the pathophysiology of nonocclusive mesenteric ischemia differs greatly from NEC. Animal models that use hypoxia or vascular insult to induce
Table 3
647 intestinal ischemia9 may not be the best models for the study of NEC. Although several studies have reported an increased risk of NEC in black infants,2 we did not appreciate this in our study. There was a statistically significant male proportion within the NEC group (67.8% vs 44.4; P 5 .04). Our results concur with findings of other authors.10,11 Anemia requiring blood transfusion within 7 days before the diagnosis of NEC was strongly associated with developing NEC. Our results correlate with other studies that have shown similar association between blood transfusion and NEC.11 Explanations for this phenomenon include decreased nitric oxide in stored packed red blood cells, and an exaggerated intestinal immune response from transfusion.11 Our intensive care nursery has developed a blood transfusion protocol for VLBW neonates to decrease the incidence of NEC.12 Medical NEC is usually treated with bowel rest, nasogastric decompression, and a course of antibiotics, whereas surgical NEC requires operative intervention. Our study suggests that loop diuretic administration during this critically ill condition of medical NEC may be associated with the transition to the more serious surgical NEC, thereby increasing mortality from 21% to 35%,10 possibly via the aforementioned mechanism of dehydration and mesenteric low-flow state. We observed that 43 of the patients with NEC (59.7%) were on at least one vasopressor before the diagnosis of NEC. Whether the combination of vasopressors and diuretics contributes to the severity of NEC remains to be discerned. For 60 of the 72 cases, the median (range) for length of exposure to loop diuretics in days was 22.5 (0 to 77). We excluded this covariate from our model because it would have greatly altered the results of the logistic regression analysis secondary to small sample size and incomplete data. Our study has a number of important limitations. The retrospective nature of this study prevents us from making a definitive causation between loop diuretics and surgical NEC. The study’s retrospective nature also deems it susceptible to information bias. Chart reviews of cases were based on the International Classification of Diseases, 9th revision (ICD-9) coding using clinician discretion. In
Demographics of medical NEC vs surgical NEC
Variable
Medical NEC (n 5 44)
Surgical NEC (n 5 28)
P value
Gestational age, weeks (mean, [sd]) Birth weight, grams (mean, sd) White (n [%]) Black (n [%]) Other (n [%]) Male (n [%]) Breast milk (n [%]) Exposure to loop diuretic before NEC (n [%])
28 978.3 16 23 5 21 39 33
25 809.6 10 15 3 20 21 28
.0001 .003 .99
NEC 5 necrotizing enterocolitis.
(2.2) (245.47) (36.36) (52.27) (11.36) (48.84) (90.7) (75)
(2.1) (285.39) (35.71) (53.57) (10.71) (71.43) (75) (100)
.06 .07 .004
648
The American Journal of Surgery, Vol 211, No 4, April 2016
Table 4 Odds ratios after multivariate logistic regression, surgical vs medical NEC Variable Birth weight Postconceptual age at diagnosis of NEC
Adjusted odds ratio
Lower 95% CI
Upper 95% CI
.999 .623
.996 .475
1.002 .816
NEC 5 necrotizing enterocolitis.
particular, cases of spontaneous intestinal perforation, which does not elicit as high an inflammatory response as NEC, therefore considered a different disease entity,1 may be coded as such. This study also suffers from low sample size, although the results from our model correlate with those from other authors. Finally, the high prevalence of loop diuretic exposure within the cohort of neonates with NEC at our institution (84.7%) makes it difficult to elucidate a true association between loop diuretics and surgical NEC. Application of this model to a larger database may help clarify this sample bias.
Conclusions The etiology of NEC is multifactorial: a combination of disrupted neonatal microbiota, an immature intestinal mucosa, and genetic predisposition. Although certain external factors, such as blood transfusions, may be risk factors for the development of NEC, loop diuretics do not appear to play such a role. However, once the extensive
inflammatory process has ensued, diuretic use may accentuate the progression of the disease.
References 1. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011;364: 255–64. 2. Lin PW, Stoll BJ. Necrotizing enterocolitis. Lancet 2006;368:1271–83. 3. Hagadorn JI, Sanders MR, Staves C, et al. Diuretics for very low birth weight infants in the first 28 days: a survey of the US neonatologists. J Perinatol 2011;31:677–81. 4. Cotton R, Suarez S, Reese J. Unexpected extra-renal effects of loop diuretics in the preterm neonate. Acta Paediatr 2012;101:833–45. 5. Coursey CA, Hollingsworth CL, Wriston C, et al. Radiographic predictors of disease severity in neonates and infants with necrotizing enterocolitis. AJR 2009;193:1408–13. 6. Pacifici GM. Clinical pharmacology of the loop diuretics furosemide and bumetadine in neonates and infants. Pediatr Drugs 2012;14:233–46. 7. Mackenzie JF, Cochran KM, Russell RI. The effect of frusemide on water and electrolyte absorption from the human jejunum. Clin Sci Mol Med 1975;49:519–21. 8. Kolkman JJ, Mensink PBF. Non-occlusive mesenteric ischaemia: a common disorder in gastroenterology and intensive care. Best Pract Res Clin Gastroenterol 2003;17:457–73. 9. Lu P, Sodh CP, Jia H. Animal models of gastrointestinal and liver diseases. Animal models of necrotizing enterocolitis: pathophysiology, translational relevance, and challenges. Am J Physiol Gastrointest Liver Physiol 2014;306:G917–28. 10. Hull MA, Fisher JG, Gutierrez IM, et al. Mortality and management of surgical necrotizing enterocolitis in very low birth weight neonates: a prospective cohort study. J Am Coll Surg 2014;218:1148–55. 11. Paul DA, Mackley A, Novitsky A, et al. Increased odds of necrotizing enterocolitis after transfusion of red blood cells in premature infants. Pediatrics 2011;127:635–41. 12. DeRienzo C, Smith PB, Tanaka D, et al. Feeding practices and other risk factors for developing transfusion-associated necrotizing enterocolitis. Early Hum Dev 2014;90:237–40.
