Gastrointestinal Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference Free

The Pediatric Organ Dysfunction Information Update Mandate (PODIUM) Collaborative sought to develop evidence-based criteria for organ dysfunction in critically ill children. In the present article, we report on the systematic review of GI dysfunction scoring tools performed as part of PODIUM, provide a critical evaluation of the available literature, propose evidence-based criteria for GI dysfunction in critically ill children, and make recommendations for future research. The PODIUM Executive Summary details population, interventions, comparators, and outcomes questions; search strategies; study inclusion and exclusion criteria; and processes for risk of bias assessment, data abstraction and synthesis, and drafting and developing agreement for criteria indicating GI dysfunction.¹⁰ 

Of 1722 unique citations published between January 1992 and January 2020, 39 studies were eligible for inclusion, as shown in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart (Fig 1), data tables (Supplemental Tables 1 and 2), and the risk of bias assessment summary (Supplemental Fig 1). The Criterion informed by the evaluated evidence for severe GI dysfunction in critically ill children is listed in Table 1.

Based on the initial literature review, no validated or widely available scores, biomarkers, or direct assays of the primary functions of the GI tract for transport, digestion, absorption, barrier functions, immune function, or host-microbial interactions were identified. Therefore, the assembled expert panel identified surrogate signs and symptoms of primary GI dysfunction and reviewed the literature. Evidence to support a proposed consensus definition was obtained from small cohorts of pediatric patients and administrative datasets. Consensus expert opinion informed but did not determine initial proposed GI dysfunction criteria, as did existing adult GI failure scores. The final approved consensus criteria reflect signs and symptoms of severe GI dysfunction due to GI ischemia, classified as the presence of any 1 of the following: (1a) bowel perforation, (1b) pneumatosis intestinalis, or (1c) bowel ischemia present on plain abdominal radiograph, computed tomography (CT) scan, MRI, or gross surgical inspection or (2) rectal sloughing of gut mucosa. No criteria to diagnose mild or moderate GI dysfunction had sufficient evidence to be included in the final consensus definition.

Of surrogate signs and symptoms for primary GI dysfunction reviewed, only GI ischemia was considered to exclusively represent GI dysfunction and have sufficient supportive literature after consensus voting. Inclusion of bowel perforation, pneumatosis intestinalis, or other findings consistent with bowel ischemia by radiographic or surgical inspection was based on 10 studies in heterogeneous critically ill pediatric populations (Supplemental Tables 1 and 2). Although bowel perforation and pneumatosis intestinalis can occur in the absence of ischemia and reperfusion injury, both were considered clear indicators of GI dysfunction and included in the definition. In infants outside the neonatal age-group, risk factors for pneumatosis intestinalis and/or perforation were graft-versus-host disease, congenital heart disease, hypotension, GI bleeding, and ischemia-reperfusion injury.¹¹  In a retrospective chart review of 37 episodes of pneumatosis intestinalis in 32 pediatric patients where neonates were excluded, the most common inciting events were infectious colitis, acute enteric infection or toxin, bowel ischemia, and GI dysmotility. Preceding ischemia or graft-versus-host disease was associated with need for surgery or mortality.¹¹  In a separate review of 1120 surgical procedures for correction of congenital heart disease, 2.8% had GI complications associated with longer hospital length of stay.¹²  In a review of 69 children with small bowel obstruction, intestinal strangulation was evident on radiologic imaging as a thickened bowel wall or reduced bowel wall enhancement, indicating bowel ischemia; these findings were associated with ICU admission and longer hospital length of stay.¹³  Three studies revealed that bowel perforation after liver transplantation is associated with a 50% mortality rate.^14–16  Several studies on use of somatic near-infrared spectroscopy (NIRS) to identify decreased GI perfusion were reviewed.^17,18  Although decreased NIRS may reveal underperfusion of the GI tract, it can also reveal reduced renal perfusion, making it nonspecific to the GI tract, so these studies were not included.

Gut mucosal sloughing was included as a criterion for bowel ischemia on the basis of expert consensus. Bowel ischemia after prolonged cardiac arrest and/or colonic blood flow restriction resulting in sloughing is a known clinical sign of restriction of blood supply in the gut. Although arguably a subjective measure, the presence of gut mucosal sloughing is a clear marker of severe GI injury.

Existing literature for additional candidate variables considered as criteria to define pediatric GI organ dysfunction during critical illness was reviewed. These variables included feeding intolerance; ileus or partial and total bowel obstruction; GI bleeding; measurement of intra-abdominal hypertension (IAH) or abdominal compartment syndrome (ACS); and biomarkers to assess host-microbial interactions, intestinal barrier function, and GI immune function in the GI tract. Several GI dysfunction or failure scores existed in the adult ICU and surgical literature, but none included critically ill pediatric patients.^3,4  Only criteria for feeding intolerance, ileus or small bowel obstruction, GI bleeding, IAH or ACS, and GI ischemia were eligible upon literature review as initial variables for consideration for consensus voting. As noted, GI ischemia criteria represent the final consensus criteria. The expert panel identified scientific priorities after completion of the literature review to address key gaps in knowledge or promising novel targets to characterize GI dysfunction in pediatric critical illness; these are listed in the Supplemental Information.

Several large, retrospective studies revealed that enteral nutrition (EN) adequacy in the first 48 hours of critical illness is associated with lower 60- or 90-day mortality in children undergoing mechanical ventilation.^19,20  However, tolerance of EN as currently defined is subjective; provider dependent; and, therefore, not a good objective marker for GI dysfunction.⁵  Literature on variables of EN adequacy and tolerance, such as gastric residual volumes, emesis, diarrhea, constipation, impaired gastric emptying, impaired intestinal motility, and malabsorption, were reviewed. Feeding intolerance was variably determined, and there were no validated scales of clinical or biomarker values to reliably assess feeding intolerance indicative of GI dysfunction in the PICU. We excluded delivery of EN as a GI dysfunction criterion as it was a marker of provider discretion rather than of true GI dysfunction. In current US enteral feeding guidelines, measurement of gastric residual volumes is not recommended because it is not an accurate method to assess EN tolerance or risk of EN-associated complications.²¹ 

Ileus is defined as failure of passage of enteric contents through the small bowel and colon that are not mechanically obstructed. Ileus is recognized on plain abdominal radiograph or CT scan by proportional dilation of loops of small and large bowel with lack of a transition point. Small bowel obstruction is recognized by proximal dilation of bowel with an identified transition point. Most patients who present to the PICU with abdominal complaints undergo a flat, plain abdominal radiograph because it is widely available, accurate, and inexpensive. We excluded plain radiographic imaging evidence and clinical characteristics of ileus and small/total bowel obstruction because of the limited number and size of studies on the association between specific radiographic and clinical findings and patient outcomes in pediatric critical illness.^13,22  A definition of pediatric GI dysfunction that includes plain abdominal radiograph assessment of ileus and partial or total bowel obstruction has face validity and is pragmatic but would be based on expert opinion. Therefore, ileus was not included in the final consensus pediatric GI dysfunction definition. The severe consequences of partial or total small bowel obstruction to indicate bowel ischemia remain in the definition because these have literature to support a clear association with patient outcome.¹³ 

Several large pediatric cohort studies and 1 randomized controlled trial of clinically significant upper and lower GI bleeding were reviewed (Supplemental Tables 1 and 2). Risk factors for upper GI bleeding were respiratory failure, coagulopathy, and Pediatric Risk of Mortality Score ≥10.²³  Clinically significant upper GI bleeding was associated with mortality. Coagulopathy may increase risk for upper and lower GI bleeding. Although clinically significant bleeding would indicate coexisting GI dysfunction due to impaired intestinal absorption and barrier functions, it is potentially confounded by coagulopathy, so it was not included in the final consensus definition.

Nine studies characterizing IAH or ACS in critically ill children were reviewed (Supplemental Tables 1 and 2). Despite an association with patient outcomes, ACS was excluded because it was defined by the presence of additional organ dysfunction. Expert agreement was that a definition of GI dysfunction should solely reflect the GI system and not depend on the presence of additional organ dysfunction. IAH may be due to primary GI causes or to external pathology (sepsis, trauma, burns, fluid resuscitation, capillary leak) and is characterized on abdominal radiographic imaging by findings consistent with GI dysfunction, such as bowel wall edema and bowel distention, and is associated with feeding intolerance.²⁴  In a prospective cohort of 175 critically ill children admitted to the PICU, 12.6% had IAH defined as bladder pressure ≥10 mm Hg.²⁵  The presence of IAH was associated with increased mortality (40.9% vs 15.6%; P = .01) and longer PICU length of stay (median 19.5 [3–97 range] vs 8 [1–104] days; odds ratio [OR], 1.02; 95% CI, 1.00–1.04; P = .02). IAH was an independent risk factor for mortality (OR, 6.98; 95% CI, 1.75–27.86; P = .006). Based on Pediatric Guidelines Sub-Committee for the World Society of the Abdominal Compartment Syndrome recommendations, a threshold of bladder pressure of ≥10 mm Hg was considered but not included in the final consensus criteria.²⁶  Additional studies are needed to identify whether a threshold of bladder pressure ≥10 mm Hg is sensitive and specific to primary GI dysfunction and is associated with patient outcomes. We also evaluated use of abdominal perfusion pressure as a criterion for GI dysfunction. In a prospective cohort of 35 patients 1 month to 18 years of age, serial measurements of bladder pressure and mean arterial pressure were obtained to determine abdominal perfusion pressure.²⁷  By receiver operator curve analysis, the optimal cutoff point for abdominal perfusion pressure was 53 mm Hg, and low perfusion pressure was associated with mortality. Additional studies of abdominal perfusion pressure as a criterion for primary GI dysfunction are needed.

The gut microbiome is profoundly altered during pediatric critical illness and characterized by decreased relative abundance of beneficial commensal bacteria and increased relative abundance of harmful pathobionts.^28,29  This dysbiosis and altered homeostasis between host and microbes are implicated in the pathophysiology of intestinal and extraintestinal organ dysfunction.^1,30  The intestinal epithelial barrier is the largest surface area in contact with the human external environment and is the critical interface between the gut microbiome and host immune system.²  Impaired intestinal barrier function either due to critical illness or in response to dysbiosis can result in translocation of bacteria or their metabolites, influence host immune responses, and increase exposure to pathogens.^1,31  Minimally invasive urine or plasma biomarkers of intestinal barrier functions exist but are not validated outside research use.⁶  Whether a multiomics approach will yield key diagnostic indicators of gut dysbiosis, impaired intestinal immune functions, or pathologic host-microbial interactions measured in the urine, blood stream, or feces relevant to patient outcomes is yet to be determined.²⁹ 

The current literature for pediatric GI dysfunction during critical illness is limited and affects the validity of the proposed consensus criteria. We propose consensus criteria that reflect signs and symptoms of severe GI dysfunction due to GI ischemia, classified as the presence of any 1 of the following: (1a) bowel perforation, (1b) pneumatosis intestinalis, or (1c) bowel ischemia present on plain abdominal radiograph, CT scan, MRI, or gross surgical inspection or (2) rectal sloughing of gut mucosa. The limitations of the supporting literature lead to a weak recommendation based on expert consensus. Given the emerging links between MODS pathophysiology and GI dysfunction, prospective evaluation of these criteria is urgently needed to identify and define the incidence and outcomes of GI dysfunction during pediatric critical illness. Additional research is needed to develop and test whether criteria scaled according to the severity of GI dysfunction and incorporating validated tests or biomarkers of primary GI functions are associated with patient outcomes. Additionally, a better understanding of the emerging role of gut-host microbial interactions on GI dysfunction and patient outcomes of pediatric critical illness is essential (Supplemental Information).

ACS

abdominal compartment syndrome

CT

computed tomography

EN

enteral nutrition

GI

gastrointestinal

IAH

intra-abdominal hypertension

MODS

multiple organ dysfunction syndrome

NIRS

near-infrared spectroscopy

OR

odds ratio

PODIUM

Pediatric Organ Dysfunction Information Update Mandate