COMMENTARIES
Opinions expressed in authors are those of the and not necessarily those of the American Academy of
Pediatrics or its Committees.
Studies of Feeding Intolerance in
Very Low Birth Weight Infants:
Definition and Significance
ABBREVIATIONS. VLBW, very low birth weight; NEC, necrotiz-
ing enterocolitis; GRV, gastric residual volumes; ICC, interstitial
cells of Cajal.
H
ow neonatologists feed very low birth
weight (VLBW) neonates has traditionally
been based on local practices and until re-
cently has not been subjected to rigorous scientific
investigation.1 Furthermore, the outcome variables
used to assess the efficacy and safety of neonatal
feeding practices are often arbitrary and based on
local customs. With the prevailing fear of necrotizing
enterocolitis (NEC) in most caregivers, feeding strat-
egies are generally based on evidence of intolerance
based on increased pregavage residuals or greenish
aspirates. Whether this is based on a myth or scien-
tific evidence has not been clearly ascertained. In-
deed, there is no uniform definition of feeding in-
tolerance. As discussed by Mihatsch and colleagues
and as evident in the literature, the definition of
feeding intolerance varies and is based on an assess-
ment of prefeed gastric residual volumes (GRVs), the
color of these GRVs, and associated clinical manifes-
tation such as abdominal distention, emesis, the pres-
ence of blood in stool, and apnea with bradycar-
dia.25 Even if properly defined, the clinical
significance of each of these criteria for feeding in-
tolerance has yet to be determined. Are they predic-
tive of serious disease, such as NEC, a delayed time
to achieve full enteric alimentation, or are they de-
velopmental physiologic expectations when feeding
VLBW neonates?
Pregavage residuals and bilious residuals reflect
poor gastric emptying, duodeno-gastric reflux, and
gastroduodenal hypomotility. Although gastric emp-
tying may be dependent on infant position, duodenal
motility continues to facilitate aboral propagation by
virtue of the phase II activity, although coordinated
phase III activity (migrating motor complexes) does
not appear consistently until 32 weeks gestational
age.6 Very immature infants have poor gastroduode-
From the Department of Pediatrics, Medical College of Wisconsin, Milwau-
kee, Wisconsin.
Received for publication Nov 9, 2001; accepted Nov 9, 2001.
Address correspondence to Robert M. Kliegman, MD, Department of Pedi-
atrics, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwau-
kee, WI 53226.
PEDIATRICS (ISSN 0031 4005). Copyright 2002 by the American Acad-
emy of Pediatrics.
516 PEDIATRICS Vol. 109 No. 3 March 2002
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nal coordination and excessive quiescence in motor
activity. It is likely, but not proven in human neo-
nates, that colonic motility also is slow and delayed.
The evidences in support of this are: 1) delayed
stooling pattern in VLBW neonates, 2) delayed or
altered stooling pattern preceding decreased gas-
troduodenal motility and delayed gastric emptying,
and 3) emesis in bowel obstruction or functional ileus
is similar to gastric residuals/bilious residuals, as
peristalsis is orad.
Studies in young animals suggest that the control
systems of gastrointestinal motility are immature at
birth because interstitial cells of Cajal (ICC), nerve,
and muscle control systems are not fully differenti-
ated. ICC in circular muscle of small intestine and
colon were found associated with nerves in lower
esophageal sphincter, pylorus, and duodenum, but
not in small intestine and colon. Axons in circular
muscle were present everywhere usually free of glial
covering, indicating ongoing migration or develop-
ment. No organized deep muscular plexus in small
intestine or submuscular plexus in colon was
present. Development of nerves and ICC of circular
muscle in esophagus and stomach precedes that in
the remaining gut.7
Thus, isolated findings related to gastric emptying
alone should not be the sole criteria in initiating or
advancing feeds. Stooling pattern, abdominal disten-
tion, vagal effects from bowel distention, and nature
of stools should also be considered.
Mihatsch and coworkers2 have provided neonatol-
ogists a service as they attempt to begin to shed light
on the significance of GRV and the color of the
gastric residuals. Excessive GRV, either determined
by percent of the previous feeding or an absolute
volume, has been used as a proxy for feeding intol-
erance and as an early sign of NEC. The current
study demonstrated that a GRV of 2 mL for infants
750 g or 3 mL for infants 750 g did not neces-
sarily affect feeding success as determined by the
volume of total feeding on day 14. Similarly, the
color of the GRV (green, milky, clear) did not predict
feeding intolerance. Nonetheless, the volume of feed-
ing on day 14 did correlate with a higher proportion
of episodes of zero GRVs and with predominantly
milky gastric residuals. Other studies have sug-
gested that feeding intolerance is also correlated with
lower birth weight, birth weight 1000 g, a delay to
full enteral feedings, and a delay in achieving dis-
charge weight.5 In addition, improvements in feed-
ing tolerance have been consistently reported with
trophic feedings (gut-priming, minimal caloric feed-
ings).8,9
The study by Mihatsch et al 2 is valuable in that it
raises more questions that need to be answered in a
scientific manner. These important questions in-
clude: What is the absolute volume or percentage of
a prior feeding that represents feeding intolerance or
an early sign of NEC? Studies have not consistently
demonstrated a large increase in GRV preceding the
onset of NEC.2,4 Is there a threshold effect or is there
a gradient that increases risks as the GRV increases?
What is the proper response to an at-risk GRV? Is
it nothing by mouth and for how long? Is it to refeed
the GRV, discard it, or to reduce the volume of the
subsequent enteral feedings?
The results of Mihatschs study2 must not be gen-
eralized because they may not be appropriate for
infants fed at incremental rates greater than 12 mL/
kg/d or with a different formula. Furthermore, the
significance of the GRV must always be correlated
with the presence of abdominal distention or tender-
ness, emesis, bloody stools, or apnea and bradycar-
dia. To date, we have yet to define the at-risk GRV
or the appropriate therapeutic response once it is
identified. We look forward to more scientifically-
based investigations to help provide recommenda-
tions for safe, effective feeding protocols for VLBW
neonates.
Sudarshan R. Jadcherla, MD
Robert M. Kliegman, MD
Department of Pediatrics
Medical College of Wisconsin
Milwaukee, WI 53226
REFERENCES
1. Kliegman RM. Experimental validation of neonatal feeding practices.
Pediatrics 1999;103:492 493
2. Mihatsch WA, von Schoenaich P, Fahnenstich H, et al. The significance
of gastric residuals in the early enteral feeding advancement of ex-
tremely low birth weight infants. Pediatrics. 2002;109:457 459
3. Dollberg S, Kuint J, Mazkereth R, et al. Feeding tolerance in preterm
infants: randomized trial of bolus and continuous feeding. J Am Coll
Nutr. 2000;19:797 800
4. Rayyis SF, Ambalavanan N, Wright L, et al. Randomized trial of slow
versus fast feed advancements on the incidence of necrotizing enter-
colitis in very low birth weight infants. J Pediatr. 1999;134:293297
5. Akintorin SM, Kamat M, Pildes RS, et al. A prospective randomized
trial of feeding methods in very low birth weight infants. Pediatrics.
1997;100(4). Available at: http://www.pediatrics.org/cgi/content/
full/100/4/e4
6. Jadcherla SR, Klee G, Berseth CL. Regulation of migrating motor com-
plexes by motilin and pancreatic polypeptide in human infants. Pediatr
Res. 1997;42:365369
7. Daniel EE, Wang YF. Control systems of gastrointestinal motility are
immature at birth in dogs. Neurogastroenterol Motil. 1999;11:375392
8. Slagle TA, Gross SJ. Effect of early low-volume enteral substrate on
subsequent feeding tolerance in very low birth weight infants. J Pediatr.
1988;113:526 531
9. Dunn L, Hulman S, Weiner J, et al. Beneficial effects of early hypocaloric
enteral feeding on neonatal gastrointestinal function: preliminary report
of a randomized trial. J Pediatr. 1988;112:622 629
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Oxygen and Resuscitation:
Beyond the Myth
P
erhaps nothing in medicine is more steeped in
myth than oxygen. From its initial success in
treating pulmonary tuberculosis to its failure in
treating cholera, oxygen has fallen in and out of style.
Only gradually did oxygen gain favor as a treatment
for respiratory distress with even the likes of Osler
doubting its effectiveness. But by the early 1900s,
treatment of patients with pulmonary parenchymal
disease was so convincing that a lack of appreciation
for oxygens potentially harmful effects led to its
eventual widespread acceptance.a We started using
oxygen for resuscitation because it seemed like a
good idea. Now we use it because we always have.
The use of 100% oxygen in resuscitation is intu-
itively appealing. Maximizing the gradient driving
oxygen into hypoxic cells may speed recovery. How-
ever, it is well known that long-term exposure to
100% oxygen is toxic. The proponents of oxygen
therapy argue that toxicity simply does not occur
during the short period of resuscitation. Although
this may be true with respect to effects like fibrosis
and pulmonary edema, the real concern is for reper-
fusion injury. In reperfusion injury, hypoxic cells
appear to undergo metabolic changes that prime
them to create free radicals when oxygen is reintro-
duced.13 Experimental resuscitation with 100% ox-
ygen has been associated with a variety of concern-
ing physiologic changes when compared with room
air resuscitation. They include increased generation
of oxygen radicals,4 decreased central nervous sys-
tem sodium-potassium ATPase function,5 and de-
creased dopamine metabolism.6 Although there is
no data on the safety or danger of short-term expo-
sure to 100% oxygen, the reperfusion injury litera-
ture suggests that resuscitation from hypoperfusion
states (ie, sudden cardiac arrest, hypovolemic, or
distributive shock) is precisely the time when oxygen
toxicity from free radicals is likely to occur.
Given the potential harm of supplemental oxygen
use during resuscitation, it would seem that there
must be some data to support its use. In fact, there is
not. Recently, an argument was made supporting the
use of supplemental oxygen during resuscitation,7
but the studies cited were not intended to specifically
address that question. They do address other inter-
esting aspects of resuscitation such as the importance
of establishing circulation,8 the importance of gasp-
ing,9 and the potential harm of having carbon diox-
ide in the resuscitation gas.10 Unfortunately, none
has an appropriate control group for making conclu-
Received for publication Nov 26, 2001; accepted Nov 26, 2001.
The views expressed in this article are those of the author and do not reflect
the official policy or position of the Department of the Army, Department
of Defense, nor the US government.
aAn excellent review of the history of oxygen use by Dr Lawrence Martin
can be found online at: http://www.mtsinai.org/pulmonary/papers/
ox-hist/ox-hist-intro.html. Accessed January 23, 2002.
Address correspondence to William Lefkowitz, MD, Department of Pedi-
atrics, Room C-1066, Uniformed Services University of the Health Sciences,
4301 Jones Bridge Rd, Bethesda, MD 20814. E-mail: wlefkowitz@usuhs.mil
COMMENTARIES 517
Studies of Feeding Intolerance in Very Low Birth Weight Infants: Definition and
Significance
Sudarshan R. Jadcherla and Robert M. Kliegman
Pediatrics 2002;109;516
DOI: 10.1542/peds.109.3.516
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and
trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove
Village, Illinois, 60007. Copyright 2002 by the American Academy of Pediatrics. All rights
reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Studies of Feeding Intolerance in Very Low Birth Weight Infants: Definition and
Significance
Sudarshan R. Jadcherla and Robert M. Kliegman
Pediatrics 2002;109;516
DOI: 10.1542/peds.109.3.516

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/109/3/516.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2002 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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