Acute Abdominal Pain

Albert Ross and Neal S. LeLeiko

Pediatr. Rev. 2010;31;135-144
DOI: 10.1542/pir.31-4-135

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located on the World Wide Web at:
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 Article gastrointestinal

Acute Abdominal Pain

Albert Ross, MD,*
Objectives After completing this article, readers should be able to:
Neal S. LeLeiko, MD, PhD*
1. Understand the principal causes of acute abdominal pain in children.
2. Describe the characteristics of visceral versus somatic abdominal pain.
Author Disclosure 3. Be familiar with the differential diagnosis of abdominal pain based on symptoms and
Drs Ross and LeLeiko location of pain.
have disclosed no 4. Discuss the evaluation of acute abdominal pain.
financial relationships 5. Distinguish surgical from medical abdominal pain.
relevant to this
article. This
commentary does not The Problem
contain a discussion
“Hello, Doctor Jones, Billy has an awful tummy ache!” For such a simple statement, so many
possible outcomes exist. Is this an emergency? Does he have appendicitis? Does he need a
of an unapproved/
surgeon? Is this something trivial? Has Billy eaten something harmful? Is he constipated?
investigative use of a Acute abdominal pain can be caused by myriad conditions whose outcomes vary from rapid
commercial product/ improvement to surgery, posing a diagnostic Gordian Knot. However, through evaluation
device. of the patient’s history and symptoms and the use of technology, a pediatrician usually can
arrive at a reasonable conclusion about the care of the patient, even if the diagnosis still is
undetermined.
Acute abdominal pain can be classified according to its location and nature, history, or
associated signs (Table 1).

Location and Nature

Some conditions can cause pain in different regions, and it may be difficult to associate the
disease with the location of the pain. Localization of the source of abdominal pain is
confounded by the nature of the pain receptors involved. Further, the type of pain
associated with a particular disease may change as the disease process progresses, as in
appendicitis. Abdominal pain may be classified as visceral, somatoparietal, and referred
pain. Most abdominal pain is associated with visceral pain receptors.
Visceral pain receptors are located in the muscles and mucosa of hollow organs, in the
mesentery, and on serosal surfaces. These pain receptors typically respond to stretch, such
as when the bowel is distended or mesentery is stretched or torsed. Visceral pain response
is not well localized because the afferent nerves associated with this pain have fewer nerve
endings in the gut, are not myelinated, are bilateral, and enter the spinal cord at several
levels. However, there are three broad areas of association. Visceral pain in the stomach,
lower esophagus, and duodenum is perceived in the epigastric area. Pain emanating from
the small intestine is felt in the umbilical area. Colonic visceral pain is felt in the lower
abdomen. The pain can be described as dull, diffuse, cramping, or burning and may
prompt the child to move in an attempt to decrease the pain. Because autonomic nerves
may be involved secondarily in the same pathologic process, patients also may exhibit
sweating, nausea, vomiting, pallor, and anxiety.
Somatoparietal pain receptors are located principally in the parietal peritoneum, muscle,
and skin. These pain receptors typically respond to stretching, tearing, or inflammation.
The nerves that convey somatoparietal pain travel within specific spinal nerves that are
myelinated and numerous and that transmit to specific dorsal root ganglia. The pain is
more localized, associated with one side or the other, more intense, and more often is

*Division of Pediatric Gastroenterology, Nutrition and Liver Diseases, Hasbro Children’s Hospital/Rhode Island Hospital,
Providence RI.

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gastrointestinal acute abdominal pain

Table 1. Differential Diagnosis Mapped to Location of Abdominal Pain

Epigastric Right Upper Quadrant Left Upper Quadrant
Gastroesophageal reflux Hepatitis Splenomegaly
Esophagitis Cholecystitis Splenic infarction
Gastritis Cholelithiasis Traumatic spleen injury
Gastric ulcer Biliary colic Lower left lobe pneumonia
Duodenal ulcer Cholangitis Kidney disease
Pancreatitis Right lower lobe pneumonia Urinary tract disease
Gastric volvulus Kidney disease
Small bowel volvulus Urinary tract disease
Erythromycin induced
Non-steroidal inflammatory medication-induced
Hypogastric Left Lower Quadrant Right Lower Quadrant
Constipation Constipation Constipation
Colon spasm Colon spasm Mesenteric adenitis
Colitis Colitis Crohn disease
Bladder disease Ovarian torsion Acute obstruction
Uterine conditions Ectopic pregnancy Localized perforation
Pelvic inflammatory disease Testicular torsion Appendicitis
Hernia Intussusception
Sigmoid volvulus Ovarian torsion
Ectopic pregnancy
Testicular torsion
Hernia
Periumbilical “All Over” “All Over”
Functional disease Gastroenteritis Porphyria
Constipation Perforation Sickle cell crisis
Gastroenteritis Constipation Volvulus
Early appendicitis Functional disease Abdominal migraine
Pancreatitis Colic Cyclic vomiting syndrome
Small bowel volvulus Streptococcal pharyngitis Lead poisoning
Henoch-Schönlein purpura Intussusception Iron ingestion
Incarcerated umbilical hernia Inflammatory bowel disease Familial Mediterranean fever
Henoch-Schönlein purpura Angioneurotic edema
Diabetic ketoacidosis Venomous bite
Location Varies
Trauma
Infarction
Gluten-sensitive enteropathy

described as having a sharp quality. Movement usually History and Symptoms

intensifies parietal pain so the child will stay still or splint Often, the most important component needed for diag-
when walking. nosis is a history. The order of onset of symptoms, their
Referred pain arises when visceral pain fibers affect progress, characteristics of emesis (Table 2) and stools
somatic nerve fibers in the spinal cord or central nervous (Table 3), and application of knowledge of the nature of
system. This pain generally is well localized but distant pain are important. For example, the pain of appendicitis
from the affected site. For example, any inflammatory may have started a day or two before presentation, grad-
process that affects the diaphragm can be perceived as ually increasing in severity and changing location. That
pain in the shoulder or lower neck because of conver- pain generally begins as poorly localized and vague (ie,
gence of the nerve pathways of these two regions. visceral receptors are affected), but as the inflammation

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 gastrointestinal acute abdominal pain

Differential Diagnosis Based

Table 2. Laboratory Diagnosis
In perplexing cases, laboratory studies frequently are
on the Color of the Vomitus requested and, with notable exceptions, are remarkably
unhelpful. Studies generally include a complete blood
Emesis Suggested Diagnosis
count, erythrocyte sedimentation rate, and urinalysis.
Bile-colored Obstruction Adolescent females should have a pregnancy test (re-
Midgut volvulus gardless of whether they have experienced menarche).
Coffee ground- Esophagitis
colored Gastritis
The white blood cell count can be misleading and
Gastric ulcer only can confirm the examiner’s suspicions; it cannot be
Trauma from forceful vomiting relied on to exclude serious illness. The sedimentation
Bright red blood, Esophagitis rate, when elevated, can indicate the presence of an
small volume Gastritis inflammatory process. However, like the white blood cell
Bright red blood, Esophageal tear (Mallory Weiss tear)
large volume Gastric ulcer
count, it cannot be diagnostic.
Duodenal ulcer The urinalysis is relatively easy to obtain and can reveal
Esophageal varices the presence of a urinary tract infection, diabetes, nephri-
Food or gastric Infectious gastroenteritis tis, and sometimes, chronic kidney disease.
contents Obstruction Other specific laboratory studies may be appropriate
Fecal appearance Obstruction
based on the conditions being considered, but generally
they are not helpful in the immediate acute setting.
continues and the appendix swells, pain fibers in the pari-
etal peritoneum are stretched, and the pain becomes more General Symptoms and Assessment
localized toward the right lower quadrant. The classic pat- of Severity
tern in intussusception is intermittent crampy pain. Acute abdominal pain can be caused by an easily reme-
Besides location, associated signs and symptoms can diable problem or by a serious condition that requires
help determine the cause of the pain. The color of emesis surgery. Confounding the presentation is the variety of
can be a useful clue, as can the appearance of the stool. patient responses to pain, from the stoic to the hysterical.
Some of the loudest patients have functional pain. Un-
fortunately, no signs of illness are absolute, but certain
Table 3. Appearance of Stool warning signs can suggest more serious illness.
First, does the patient look ill? If the child is bouncing
Stool Suggested Diagnosis
around the room, it is easier to provide reassurance and
Watery diarrhea Infection avoid excessive testing. When the patient appears ill, it is
Bacterial important to distinguish whether the child is improving
Viral
or worsening. Observing the patient in the office or
Parasitic
Appendicitis with perirectal emergency department for several hours allows serial
abscess examinations. A rapid revisit or even admission may be
Hard or large stool Constipation prudent until serious disease is excluded. History of
Decrease in stool Constipation abdominal trauma, pain worsening with movement, in-
frequency Obstruction
voluntary guarding, rebound tenderness, and tenderness
Mucus-containing Colitis (can be normal)
Bright red blood, Constipation with percussion are indications for prompt surgical eval-
small volume Fissure uation. Are there signs of bleeding or significant volume
Hemorrhoid, suggesting loss or dehydration? These clues may not lead to surgery
constipation but need to be addressed to restore well-being. When in
Colitis
doubt, the pediatrician should detain the patient, per-
Henoch-Schönlein purpura
Polyp form serial examinations, and ask the surgeon for help.
Bright red blood, Colitis
large volume Polyp Gastroenteritis
“Currant jelly stool” Intussusception Probably the most common cause of acute abdominal
Melena Gastric ulcer
pain is infectious gastroenteritis. Obtaining a history of
Duodenal ulcer
Pale, acholic stools Biliary or hepatic disease recent travel, ill contacts, and diet (food-borne patho-
gens) is important. Viruses are the more common cul-

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gastrointestinal acute abdominal pain

prits, but bacteria and parasites also can produce acute obstructing the lumen may be the precipitating cause.
illness. Clinical findings vary, based on the infectious Acute appendicitis is the most common reason for emer-
organism, but many of these agents cause fever, vomit- gent abdominal surgery in children.
ing, and diarrhea along with pain. The pain usually is Unfortunately, it still is difficult to be certain of a
nonspecific in location, and the child also can have diffuse diagnosis of acute appendicitis. Timely diagnosis is criti-
tenderness, although “guarding” is unlikely. If bloody cal, but it can be extremely challenging, especially in
diarrhea is present, stool cultures and stool examination young children. As the inflammation starts, the visceral
for parasites should be requested. Antibiotics can worsen nerves send a message of general unease, which may
serious illness such as hemolytic-uremic syndrome and manifest as pain referred to the umbilical region, then
should not be used without clear indication. An acute anorexia, typically followed by nausea. A young child has
presentation with blood in the stool is more likely a sign
a hard time explaining this feeling and may show only
of infectious colitis but may be the initial presentation of
anorexia and decreased activity.
inflammatory bowel disease. Positive bacterial cultures
Vomiting, fever, guarding, and abdominal pain with
must be reported to appropriate authorities.
any movement (especially walking) are important signs
Most causes of acute abdominal pain that require
when present. Requesting the patient to hop off of the
surgery do not present in this manner. Generally, fever,
vomiting, and diarrhea indicate acute-onset infection examination table or hop up and down usually is refused
rather than surgical disease. In some cases, particularly or elicits a dramatic increase in abdominal pain.
when the child looks ill, making the distinction can be As inflammation increases and the parietal perito-
difficult. neum becomes irritated, the somatic nerves begin to
Rehydration is beneficial. Oral rehydration is pre- signal that something is wrong. This pain usually is
ferred, but intravenous fluids may be used until oral appreciated in the area two thirds of the distance from the
therapy can be started. Rehydration during acute gas- umbilicus to the anterior superior iliac spine (McBurney
troenteritis usually makes the child feel much better. point). Pain and tenderness in this location are sensitive
Improving appearance with rehydration is reassuring. signs for appendicitis but, unfortunately, are not specific
for appendicitis (Table 4).
Acute Appendicitis If the appendix ruptures, a child can show clinical
Inflammation of the appendix results in distention lead- improvement as the pressure in the organ is released, thus
ing to ischemia. Necrosis, perforation, and peritonitis or decreasing pain. Over the next day, the child may worsen
abscess may ensue. It is not known why the appendix due to peritonitis; sometimes, a localized abscess forms
becomes inflamed, but a fecalith or lymphoid tissue instead. With abscess formation, the right lower quad-

Table 4. Signs of Appendicitis

Tenderness at McBurney point Percussion or palpation in the right lower quadrant results in pain in an area
approximately two thirds of the distance from the umbilicus to the anterior
superior iliac spine
Involuntary guarding Abdominal wall muscle spasm to protect inflamed abdominal organs from motion
Pain on movement Significant increase in pain with walking, hopping off of the table, or jumping up
and down
Rovsing sign Pressure in the left lower quadrant results in pain in the right lower quadrant
Rebound tenderness Sudden release of deep palpation of the abdomen results in a large increase in
pain. (Save this test for the end of the examination to stay in the child’s good
graces.)
Psoas sign With the patient on his or her left side, extend the right thigh while applying
stabilizing resistance to the right hip. This maneuver should cause an increase in
pain due to the location of the appendix over the iliopsoas muscle.
Obturator sign Increased pain with passive flexion and internal rotation of the right thigh
Anorexia
Nausea
Vomiting
Fever
Bent knees The child is most comfortable while lying with knees bent

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 gastrointestinal acute abdominal pain

rant pain can continue, and a tender mass becomes tion, which would make diagnosing appendicitis more
palpable. difficult.
Many maneuvers can elicit pain associated with ap-
pendicitis, and the clinician should be familiar with at Intussusception
least some of them (Table 4). Probably the most frequent cause of intestinal obstruc-
Diagnostic laboratory tests for appendicitis include tion in children is an intussusception. This condition
the white blood cell count, which typically is mildly occurs when part of the intestine is pulled antegrade into
elevated and may have a shift toward neutrophils but is the adjacent part of intestine, trapping the more proximal
not a reliable diagnostic test. Radiologic studies have bowel in the distal segment. The most common site is the
become more helpful in determining the presence of junction of the ileum and colon, where the ileum is
appendicitis and can help define an abscess and demon- pulled into the colon. In some cases, a lead point such as
strate other causes of pain such as a renal stone, Crohn a polyp, tumor, or Meckel diverticulum is pulled down-
disease, or gynecologic problems. Right lower quadrant stream. The cause in infants typically is unknown. Some
ultrasonography often can show enlargement of the have suggested hypertrophy of mesenteric lymph nodes
appendix as well as changes in the wall, presence of caused by a viral infection.
increased fluid around the appendix, or an abscess if the Like a volvulus, intussusception occurs more com-
appendix has ruptured. Because ultrasonography does monly in infants than in older children. The signs and
not expose a child to radiation or contrast, it is pre- symptoms include abdominal pain, lethargy, vomiting,
ferred to computed tomography (CT) scan, although pallor, and if the obstruction is prolonged, abdominal
CT scan may be necessary when the physical findings are distention and rectal bleeding. The bloody bowel move-
uncertain and an experienced ultrasonographer is not ment in this illness often is described as looking like red
available. currant jelly. Such a stool, however, is not seen com-
Because there is no perfect test for appendicitis other monly, but when seen, it suggests vascular compromise.
than the pathology report, the best diagnostic instru- The child may show signs of crampy pain when peri-
ment is the examiner. Appendectomy is the appropriate stalsis occurs and causes additional stretching and
treatment. squeezing of the trapped intestine. The child may lie
quietly between the peristaltic waves.
Small Bowel Volvulus Older children often localize the pain to the perium-
Volvulus is a surgical emergency; delay in surgical inter- bilical region, but it can be in the right lower quadrant.
vention can cause short gut or death. Incomplete rota- Appendicitis may be suspected, but the pain often is
tion of the embryonic bowel results in the vascular intermittent in intussusception rather than continuous.
supply of the small intestine flowing through a narrow In the most common form of intussusception, ileo-
pedicle of mesentery, which can twist about its base, colic, a sausage-shaped mass may be palpable on the right
cutting off blood flow. Dull, aching abdominal pain may side or in the right upper quadrant of the abdomen.
be the first symptom, but more dramatic pain also may be Abdominal radiographs may show obstruction, and a
the presentation. Obstructive symptoms are followed by mass also may be visible. Ultrasonography demonstrates
an acutely inflamed abdomen. bowel within bowel or a “target.” Ultrasonography is
Volvulus typically presents early, before 1 year of very accurate in detecting intussusceptions and is consid-
age, but it can occur at any age. The obstruction results ered the test of choice.
in bile-stained emesis and pain, although the pain can Treatment (and confirmation of the intussusception)
be hard to detect in infants. Bile-stained emesis signals a is with an air contrast enema. Air is safer and cleaner than
surgical emergency. Rectal bleeding is a late sign indicat- liquid and is more effective. If the enema fails, surgery
ing vascular compromise to the mucosa. must be performed to reduce the intussusception.
A plain radiograph may show a dilated stomach and
proximal duodenum, but the primary test for a volvulus Henoch-Schönlein Purpura
is a contrast upper gastrointestinal study. Recently, Because the rash of Henoch-Schönlein purpura (HSP)
Doppler ultrasonography has been used to detect volvu- may present after the onset of abdominal pain, severe
lus and malrotation. acute pain can be the initial sign of the condition. HSP is
The bowel must be untwisted before vascular necrosis a vasculitis that can be triggered by infection, medica-
occurs. An appendectomy typically is performed be- tions, or even insect bites. The rash begins on the but-
cause the appendix would be left in an abnormal loca- tocks or extensor surfaces of the legs and may spread

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gastrointestinal acute abdominal pain

peripherally. It can start as urticaria but progresses to angiopancreatography or endoscopic retrograde chol-
“palpable purpura.” angiopancreatography should be considered.
The intestine also shows purpuric lesions, and the Treatment is supportive. The patient may eat if food
edema and inflammation result in colicky pain. Children does not cause pain. Narcotics should be used for severe
also may vomit with HSP, and the abdomen can be pain. Intravenous fluids and intravenous acid suppression
tender to palpation. The lesions can lead to gastrointes- are used. If vomiting continues with gut “rest,” a naso-
tinal bleeding or complications of intussusception or gastric tube can be used to decompress the stomach. In
perforation. HSP usually affects children younger than severe cases, patients require intensive care due to the
10 years of age, but it is rare in infants. HSP recurs in fluid shifts and hypotension accompanying necrotic
about one third of cases. pancreatitis.
Arthralgias or arthritis are seen in most cases, with the
lower extremity large joints affected most often. HSP
also can lead to nephropathy in up to 50% of the children. Ulcer Disease
The renal involvement usually is mild and may present Epigastric or right upper quadrant pain can signify a
weeks after the abdominal pain. peptic ulcer. These lesions usually occur in the distal
If the typical rash is seen, no testing is indicated. stomach or proximal duodenum. In severe cases, bleed-
Ultrasonography or contrast radiographs of the intes- ing or perforation can occur. Ulcer symptoms are com-
tines show the edematous lesions in the gut. Endoscopy mon because many children have nonulcer dyspepsia, in
demonstrates purpuric lesions. The white blood cell which there is pain similar to that caused by an ulcer, but
count can be increased, and markers of inflammation no ulcer is present.
such as the sedimentation rate usually are elevated. Oc- Nonsteroidal anti-inflammatory drugs (NSAIDs)
casionally, there are no other signs of HSP apart from the such as ibuprofen are an important cause of ulcers and
abdominal pain, and the diagnosis may be made after dyspepsia in children. Some ulcers are caused by infection
observing purpuric lesions of the gastrointestinal tract on with Helicobacter pylori. H pylori ulcers are less common
endoscopy. in children than in adults, and more ulcers fall into the
Treatment is supportive. In the case of severe joint or idiopathic category. Eosinophilic gastroenteritis, Crohn
abdominal pain, prednisone can be used to decrease disease, and any severe illness can be associated with ulcer
symptoms. disease as well.
Ulcers are diagnosed with upper gastrointestinal en-
Pancreatitis doscopy. Biopsies should be taken to look for H pylori as
Upper abdominal pain and tenderness, especially when well as other causes of ulcers.
associated with vomiting, are typical features of pancre- Treatment is with acid suppression, typically with
atitis as well as many other diseases. To determine if proton pump inhibitors (PPIs). Histamine-2 receptor
pancreatitis is present, serum amylase or lipase must be antagonists (H2RAs) also are used but are not as effec-
measured. If concentrations of these enzymes are greater tive as PPIs at suppressing acid production. Antacid
than three times the upper limit of normal, pancreatitis preparations can help with symptoms and provide addi-
most likely is the cause of the symptoms. Normal values tional buffering. If H pylori is found, antibiotics also are
do not exclude the diagnosis. necessary.
Pancreatitis arises from many different infections, Bleeding ulcers can be treated endoscopically with
medications, or trauma. Other causes include gallstones, cautery, injection, and mechanical methods. Surgery is
abnormal ductular anatomy, systemic illness, and meta- used when endoscopic therapy and medications fail or
bolic problems. The cause in any specific patient can be when there is a perforation.
hard to determine, and finding the cause can be expen-
sive. Therefore, in an isolated case, an exhaustive search is
not necessary. Most children who experience acute pan- Gastritis
creatitis do not suffer additional episodes. Gastritis can feel the same as an ulcer, and diagnosis is
CT scan or ultrasonography can help diagnose pan- made by endoscopy. Gastritis has many different causes,
creatitis as well as look for anatomic causes or gallstones. with acute infectious gastritis and NSAID therapy being
In recurrent episodes of acute pancreatitis, pancreatic- two of the more frequent. Treatment is to remove any
sufficient cystic fibrosis should be excluded, along with precipitating agent, provide acid suppression, and give
genetic forms of pancreatitis. Magnetic resonance chol- supportive care.

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 gastrointestinal acute abdominal pain

NSAID-induced Dyspepsia to the back. A positive Murphy sign is strongly suggestive

Patients who must be treated with NSAIDs are at risk of of gall bladder disease. The examiner palpates the right
developing NSAID-related gastrointestinal dyspepsia, upper quadrant at the costal margin while the patient
which may be a manifestation of gastritis or gastric ulcer. breathes in. The sign is considered to be positive if the
The risk of NSAID-related complications is increased patient feels pain. Gallstones are seen more frequently
by a history of ulcer disease or bleeding or by use of with hemolytic disorders, such as sickle cell disease, and
corticosteroids. In patients receiving NSAIDs, com- in infants and children who have received peripheral
plications can be lessened by providing adequate acid alimentation. Acalculous cholecystitis typically occurs
suppression. Standard doses of H2RAs do not prevent during a significant systemic illness such as sepsis or an
most NSAID-related gastric ulcers. Doubling the dose illness requiring a stay in the intensive care unit.
may be effective, but single daily doses of a PPI are Ultrasonography can show the presence of stones and
superior to H2RAs and other treatments (including mi- a thickened gall bladder wall with possible gall bladder
soprostol) in reducing ulcers and NSAID-associated dilatation. The ultrasonographer can produce a positive
dyspepsia. Murphy sign with the transducer, which helps to diag-
nose cholecystitis.
Esophagitis Laboratory tests should show an elevation in liver en-
Gastroesophageal reflux disease (GERD) and esophagitis zymes, especially gamma-glutamyltranspeptidase (GGTP)
can present acutely as epigastric abdominal pain. GERD and alkaline phosphatase. The white blood cell count is
is present when gastric contents move into the esophagus elevated, and direct bilirubin is increased. The amylase
and produce symptoms or damage. Esophagitis can re- value can be elevated, making it harder to know if the
sult from GERD or from other inflammation such as problem is cholecystitis or pancreatitis.
eosinophilic esophagitis or from infections such as herpes Treatment consists of bowel rest, intravenous pain
or Candida. control, and intravenous fluids. If fever is present or the
Treatment is with antacids and acid suppression for child looks ill or unstable, antibiotics are needed for
the pain and ongoing therapy for reflux. If the child enteric bacteria. The timing of curative cholecystectomy
does not improve, endoscopy to look for inflammation, is determined best with the surgeon. Complications of
infection, or possibly even a foreign body should be cholecystitis include perforation of the gall bladder, with
performed. peritonitis or abscess formation.
Acute hydrops of the gall bladder can look like acal-
Hepatitis culous cholecystitis, but the gall bladder wall is not
Inflammation of the liver can cause right upper quad- inflamed. The symptoms usually are the same, but ultra-
rant pain. Anorexia, nausea, and vomiting also are com- sonography shows an enlarged gall bladder without wall
mon in hepatitis. The liver can be inflamed due to thickening. Treatment is supportive rather than surgical,
infection, reactions to medications or chemicals, or but perforation can result, which requires surgery.
autoimmune hepatitis. Clues to hepatitis being the
source of the acute pain include jaundice, hepatomegaly, Stones in the Bile Duct
and liver tenderness. Choledocholithiasis, or bile duct stones, can present
Liver enzyme concentrations are elevated in acute much like cholecystitis, but jaundice is more likely to be
hepatitis. The child also should have direct hyperbili- present. Right upper quadrant pain, fever, and tender-
rubinemia. Urinalysis can be a screening test for liver ness are consistent with impacted stones.
disease by detecting bilirubin and urobilinogen. GGTP, alkaline phosphatase, and conjugated bili-
Acute infectious hepatitis is treated with supportive rubin concentrations are elevated, as might be
care and is prevented best by immunization for hepatitis aminotransferase values. Because duct obstruction can
A and B and avoiding behaviors that can lead to hepatitis cause pancreatitis, amylase and lipase values should be
C or E infection. assessed.
Ultrasonography usually demonstrates the stone, but
Biliary Tract Disease sometimes stones can be hard to see. A dilated duct also
Cholelithiasis and Cholecystitis may be present.
Right upper quadrant abdominal pain can result from If fever is present, antibiotics should be started. The
gallstones and cholecystitis. Pain, fever, vomiting, and child is given nothing by mouth but should receive
jaundice often are present. The pain occasionally radiates intravenous fluids and narcotic analgesics.

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gastrointestinal acute abdominal pain

The gastroenterologist and surgeon should be con- nancy are not rare events. Ovarian cysts and sexually
sulted if the stone does not pass spontaneously because transmitted infections can cause abdominal pain.
either surgery or an endoscopic retrograde cholangio- Testicular torsion manifests as a tender scrotum with
pancreatography with stone removal may be necessary. an enlarged testis. Pain radiates into the abdomen. Nau-
sea may accompany the pain and sometimes progresses
Constipation to vomiting. Adolescent boys may be embarrassed to
One of the more common treatable causes of acute describe testicular pain and instead report hip or ab-
abdominal pain is constipation, which can cause severe dominal pain. This condition reinforces the importance
pain in some children and raise concerns about more of the physical examination when evaluating a child for
serious illness. Constipation can follow a social change acute abdominal pain. If in doubt, ultrasonography can
such as toilet training, starting school, changing the diet, evaluate blood flow to the testicle. Emergent surgery is
or taking a trip. The child frequently does not know that necessary to save the affected testicle.
his or her pattern of stooling has become abnormal, and Ovarian torsion is harder to differentiate from other
the parent is not aware of a change. Nausea can accom- causes of acute abdominal pain due to the location of
pany constipation, but other symptoms are rare. the ovaries. The pain is in the lower abdomen. Besides
Examination may show distention, a mass in the left pain, nausea and vomiting can be present. As with many
lower quadrant or low mid-abdomen, and mild tender- other conditions, infants who have this problem simply
ness when the mass is palpated. The rectal examination may be fussy, feed poorly, and vomit. The torsed organ
usually demonstrates a full rectal vault in contrast to swells, resulting in a palpable mass. Ultrasonography is
Hirschsprung disease, in which the rectum contains little needed for this diagnosis. As with testicular torsion,
stool. Guarding is not typical. An abdominal radiograph emergent surgery is necessary to preserve the organ.
should show a full rectal vault and fecal loading, but signs Ovarian cysts are common in postmenarchal adoles-
of obstruction are absent. cents and usually cause acute pain only if there is hem-
Treatment varies, depending on the age of the child orrhage into the cyst or the cyst ruptures and releases
and the degree of constipation. blood into the abdomen. Analgesics and time may be
appropriate treatment. In cases of complicated cysts,
Incarcerated Inguinal Hernia surgery sometimes is required. A pregnancy test should
Signs of intestinal obstruction with abdominal pain ac- be performed.
company an incarcerated inguinal hernia. Examination An ectopic pregnancy must be considered in any
should reveal a groin mass that may be tender and postmenarchal female presenting with lower abdominal
sometimes can be red due to the underlying inflamma- pain. Because adolescents sometimes are confused or
tion. An abdominal radiograph may show obstruction or untruthful about their sexual histories, every female ad-
an air bubble in the groin. olescent presenting with acute abdominal pain should
The best therapy is early repair. Therefore, health undergo a pregnancy test.
supervision examinations should include an evaluation Pelvic inflammatory disease can produce acute ab-
for hernias. Emergent surgery is required to treat an dominal pain with rebound tenderness that can be diffi-
incarcerated hernia. cult to distinguish from a surgical abdomen. The pain
usually is in the lower abdomen, but sexually transmitted
Urinary Tract Disease infections also can cause a perihepatitis that leads to
Urinary tract infections and renal stones can present as pain in the right upper quadrant. Fever may be present.
abdominal pain. Vomiting may be present and mask the If pelvic inflammatory disease is suspected, gynecologic
diagnosis, especially in small children. A urinalysis is evaluation by appropriate colleagues may be critical,
necessary, and if results are suggestive of infection, urine along with assuring appropriate follow-up and protec-
can be sent for a culture. Acute pyelonephritis often is tion of the child where necessary.
accompanied by costovertebral angle tenderness; supra-
pubic tenderness may be elicited in a child who has Pneumonia
localized cystitis. Because of visceral innervation, a lower lobe pneumonia
can present as abdominal pain. In the febrile child who
Reproductive Tract Diseases has abdominal pain, the lung fields must be auscultated
Disorders of the reproductive system can cause abdomi- and a chest radiograph considered if the findings are
nal pain. Ovarian or testicular torsion and ectopic preg- suspicious.

142 Pediatrics in Review Vol.31 No.4 April 2010

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 gastrointestinal acute abdominal pain

Streptococcal Pharyngitis Malingering

Many children who have streptococcal pharyngitis expe- Malingering must be differentiated from organic and
rience abdominal pain due to the pharyngitis. The pain functional pain. The child does not necessarily con-
can mimic appendicitis. Some surgeons require a rapid sciously seek secondary gain from the abdominal pain.
streptococcal screen as part of the evaluation for appen- Malingering is a complex and potentially serious condi-
dicitis. Why streptococcal pharyngitis causes abdominal tion that requires evaluation by a team of specialists,
pain is not known. including an expert in child behavior.

Diabetic Ketoacidosis
Acute abdominal pain can be the initial presentation of Summary
diabetes mellitus as a feature of diabetic ketoacidosis
(DKA). The review of systems should be positive for • Although acute abdominal pain usually is self-
polyuria or the parent may relate increased urinary fre- limited, there are serious consequences to
quency, which should prompt a urinalysis that can lead to overlooking conditions that require surgery.
• The pediatrician should use the examination to
the correct diagnosis. Weight loss and thirst (polydipsia) decide if the child is likely to have appendicitis or
also are common complaints in those who have diabetes. other surgically treated disease, and when suspicious,
The serum amylase value can be elevated, but true pan- consult a surgeon early in the process.
creatitis is rare. • Vomiting bile is a sign that requires consultation
The pain resolves with appropriate treatment for with a surgeon.
• If in doubt about the seriousness of the illness,
DKA. Therefore, if the pain remains despite improve- detain the child and perform serial examinations.
ment in the ketoacidosis, the child should be evaluated Ask another physician to provide an opinion because
for other causes of abdominal pain. On occasion, DKA is experience is one of the most sensitive tools
precipitated by the stress of another condition that may available for evaluating acute abdominal pain.
account for the abdominal pain (such as a urinary tract
infection.)
Suggested Reading
Sickle Cell Crisis Blakelock RT, Beasley SW. Infection and the gut. Semin Pediatr
Surg. 2003;12:265–274
The vascular occlusion of sickle cell crisis can result in a Bundy DG, Byerley JS, Liles EA, Perrin EM, Katznelson J, Rice HE.
surgical abdomen due to infarction as well as to gallstone Does this child have appendicitis? JAMA. 2007;298:438 – 451
formation. In the child who has sickle cell disease, the Cervero F, Laird JMA. Visceral pain. Lancet. 1999;353:2145–2148
diagnosis may be difficult. The venous occlusive disease Erkan T, Cam H, Ozkan HC, et al. Clinical spectrum of acute
in affected patients is more likely to be accompanied by abdominal pain in Turkish pediatric patients: a prospective
study. Pediatr Int. 2004;46:325–329
chest pain or limb pain due to the same sludging in blood Green R, Bulloch B, Kabani A, Hancock BJ, Tenenbein M. Early
vessels that causes the abdominal pain. The pain in sickle analgesia for children with acute abdominal pain. Pediatrics.
cell crisis improves with oxygen and hydration. 2005;116:978 –983
Hayes R. Abdominal pain: general imaging strategies. Eur Radiol.
Functional Disease 2004;14:L123–L137
Justice FA, Auldist AW, Bines JE. Intussusception: trends in clinical
Although functional abdominal pain more often is presentation and management. J Gastroenterol Hepatol. 2006;
chronic, the initial presentation can be the complaint of 21:842– 846
acute pain. Objective signs of pain are less likely to be Kharbanda AB, Taylor GA, Fishman SJ, Bachur RG. A clinical
present. decision rule to identify children at low risk for appendicitis.
Functional pain usually is felt at the umbilicus, but it Pediatrics. 2005;116:709 –716
Kwok MY, Kim MK, Gorelick MH. Evidence-based approach to
can be epigastric, as in nonulcer dyspepsia. Either diar- the diagnosis of appendicitis in children. Pediatr Emerg Care.
rhea or constipation can be present. The child can have 2004;20:690 – 698
derangements in the autonomic nervous system, with Scholer SJ, Pituch K, Orr DP, Dittus RS. Clinical outcomes of children
flushing or pallor. The gait more often is normal com- with acute abdominal pain. Pediatrics. 1996;98:680 – 685
pared with the stooped, guarded posture of a patient Williams H. Green for danger! Intestinal malrotation and volvulus.
Arch Dis Child Ed Pract. 2007;92:ep87– ep91
who has a surgical abdomen. Williams NMA, Johnstone JM, Everson NW. The diagnostic value
Functional disease results from complex biopsycho- of symptoms and signs in childhood abdominal pain. J R Coll
social features that are beyond the scope of this article. Surg Edinb. 1998;43:390 –392

Pediatrics in Review Vol.31 No.4 April 2010 143

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gastrointestinal acute abdominal pain

PIR Quiz
Quiz also available online at http://pedsinreview.aappublications.org.

1. What is the correct approach to an 8-week-old infant who has bile-colored (bilious) vomiting?
A. Admit for observation.
B. Obtain surgical consultation immediately.
C. Perform an urgent upper gastrointestinal endoscopy.
D. Provide intravenous fluids to maintain hydration.
E. Provide reassurance as long as there is no blood.

2. Inflammation of the abdomen that involves the diaphragm may be referred to the:
A. Inguinal region.
B. Lower back.
C. Shoulder.
D. Sternum.
E. Testicle.

3. Which of the following conditions should be excluded in a child who has recurrent episodes of acute
pancreatitis?
A. Cow milk protein allergy.
B. Crohn disease.
C. Cystic fibrosis.
D. Helicobacter pylori infection.
E. Malrotation of the intestine.

4. The diagnostic test of choice for peptic ulcer disease is:

A. Abdominal ultrasonography.
B. Computed tomography scan of the abdomen.
C. Upper gastrointestinal endoscopy.
D. Upper gastrointestinal series (barium radiograph).
E. Urea breath test for Helicobacter pylori.

5. A 15-year-old girl presents with a 36-hour history of worsening right lower quadrant pain. Her last
menstrual period was 2 weeks ago. She has tenderness to palpation. Which of the following conditions is
the most likely cause of her pain?
A. Cholelithiasis.
B. Ovarian torsion.
C. Pyelonephritis.
D. Right lower lobe pneumonia.
E. Small bowel volvulus.

144 Pediatrics in Review Vol.31 No.4 April 2010

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 Acute Abdominal Pain
Albert Ross and Neal S. LeLeiko
Pediatr. Rev. 2010;31;135-144
DOI: 10.1542/pir.31-4-135

Updated Information including high-resolution figures, can be found at:

& Services http://pedsinreview.aappublications.org/cgi/content/full/31/4/135

Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
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 Intimate Partner Violence
Megan H. Bair-Merritt
Pediatr. Rev. 2010;31;145-150
DOI: 10.1542/pir.31-4-145

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/31/4/145

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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 Article psychosocial issues

Intimate Partner Violence

Megan H. Bair-Merritt,
Objectives After completing this article, readers should be able to:
MD, MSCE*
1. Describe the prevalence of intimate partner violence and childhood exposure to
intimate partner violence.
Author Disclosure 2. Identify risk factors associated with intimate partner violence.
Dr Bair-Merritt has 3. Explain the relationship of child maltreatment in the setting of intimate partner
disclosed no financial violence.
relationships relevant 4. Recognize the impact of intimate partner violence exposure on children’s social-
to this article. This emotional and physical health and health-care use.
commentary does not 5. Discuss strategies for screening and responding to intimate partner violence in the pe-
contain a discussion diatric setting.
of an unapproved/
investigative use of a
commercial product/ Case Study
device.
You are seeing a healthy 4-month-old infant for a health supervision visit. As part of a routine
social history, you inquire about intimate partner violence (IPV). The infant’s mother discloses
that her partner frequently yells at her, pushes her, and makes her feel afraid. On additional
questioning, she describes the infant as “fussy.” The baby’s physical examination findings are
unremarkable, but you note that he missed his 2-month visit and is behind on his immuniza-
tions. How do you proceed?

Definition
Family violence and domestic violence often are used synonymously and refer to violence
occurring between any family member dyad, including parent-child, intimate partner-
intimate partner, or sibling-sibling. IPV refers specifically to violence perpetrated between
romantic partners and has been defined by the Family Violence Prevention Fund as “a
pattern of purposeful coercive behaviors that may include inflicted physical injury, psycho-
logical abuse, sexual assault, progressive social isolation, stalking, deprivation, intimidation
and threats. These behaviors are perpetrated by someone who is, was, or wishes to be
involved in an intimate or dating relationship with an adult or adolescent victim and are
aimed at establishing control of one partner over the other.” (1)

Epidemiology
Over the course of a lifetime, between one fourth and one third of women in the United
States are abused by an intimate partner. Every year, 2 to 4 million women and 0.5 to
1 million men report IPV victimization. IPV occurs in families of all races, ethnicities, and
socioeconomic classes. Certain sociodemographic factors, however, have been associated
with increased risk of IPV, including young age (with the highest rates in women 18 to
24 years old), lower socioeconomic status, mental health problems, and substance abuse.
Separated or divorced women report higher rates of IPV than married women.
Male-perpetrated IPV initially was recognized as a significant public health problem in
the 1960s. Since that time, experts have achieved a greater understanding of the epidemi-
ology and health consequences of male-perpetrated IPV. However, recent peer-reviewed
papers and population-based surveys have reported that women perpetrate IPV as often as
or more frequently than do men (2). These studies often are limited by failure to identify
acts of self-defense and to recognize that men are much more likely than women to incite

*Assistant Professor of Pediatrics, Associate Director, Primary Care Fellowship Program, Johns Hopkins School of Medicine,
Baltimore, Md.

Pediatrics in Review Vol.31 No.4 April 2010 145

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psychosocial issues intimate partner violence

fear. (3) Despite the prevalence of female-perpetrated Social-Emotional Health

IPV, women still remain significantly more likely than Since the 1980s, increasing attention has been focused
men to be injured or killed by their partners. on infants and children as the “silent victims” of IPV,
Fifteen million children in the United States are ex- and research related to the social-emotional health con-
posed to IPV each year. (4) Almost 50% of these children sequences of childhood IPV exposure has grown expo-
are exposed to severe IPV, such as one parent beating up nentially. Childhood IPV exposure likely leads to adverse
another parent or one parent using a knife or gun against child health through a number of pathways, including
another parent. (4) Rates of IPV are disproportionately trauma, altered stress physiology, and disruption of
high in families who have children younger than 5 years the caregiver-child attachment relationship. Children
of age. Childhood exposure may include being present in exposed to IPV also frequently perceive the world as
the room while the violence is occurring, overhearing hostile and unsafe and learn via social modeling that
the violence from another room, or observing the after- aggression is an acceptable means through which to
math of a violent argument, including parental injuries or resolve conflict.
destruction of property. It is unclear whether exposure Strong evidence links childhood IPV exposure with
to male- or female-perpetrated IPV affects child health a wide variety of adverse social-emotional health out-
differentially, and most of the literature on the IPV-child comes in childhood. (9) Specific problems vary accord-
health relationship focuses on the impact of male- ing to age and developmental stage but include develop-
perpetrated IPV. Therefore, the remainder of this review mental delay, depression, anxiety, peer aggression, and
posttraumatic stress disorder/hypervigilance. Infants
focuses predominantly on male-initiated violence.
may display symptoms of trauma, including excessive
crying and resisting comfort. IPV also may disturb infant
routines such as sleeping and feeding and may affect
Clinical Aspects
maternal-infant attachment. Common symptoms in tod-
Child Abuse
dlers include extreme separation anxiety, excessive tan-
In 1998, the American Academy of Pediatrics (AAP)
trums, and aggression with peers.
recommended routine IPV screening during health su-
School-age children living in homes in which IPV
pervision visits, stating that “identifying and intervening
occurs are more likely than their peers to exhibit aggres-
on behalf of battered women may be one of the most
sive and antisocial behaviors and are more likely to be
effective means of preventing child abuse.” (5) This
anxious, fearful, and hypervigilant. IPV exposure in
statement was based on the well-documented overlap
school-age children also has been linked with poor peer
between child maltreatment and IPV. Although the as-
relations, perhaps due to poor self-esteem and sensitiza-
sociations between physical IPV and child maltreatment tion to hostility. Adolescents in homes where IPV is
are most prominent in the literature, risk for child mal- present have higher rates of school failure, substance
treatment also is elevated in families in which intimate abuse, and risky sexual behaviors. These adolescents are
partners engage in psychological abuse. more likely than their peers to enter into a violent dating
In populations of families either reported to Child relationship.
Protective Services (CPS) for child maltreatment or in
domestic violence shelters, the co-occurrence of child Physical Health and Patterns of
maltreatment and IPV ranges from 30% to 60%. (6)(7) Health-care Use
Rates of overlap between IPV and child maltreatment in Research about the impact of IPV on children’s physical
community-based samples are notable, although lower health and health-care use is in its infancy, although some
than rates in high-risk samples. Poverty, parental de- patterns are emerging. Compared with peers, children
pression, and substance abuse increase the risk of co- exposed to IPV are less likely to attend health supervision
occurrence. visits and to be fully immunized and are more likely to
Children living in homes where IPV occurs also may have emergency department visits. Children exposed to
be injured inadvertently by being “caught in the cross- IPV also may incur greater overall health-care costs than
fire” of parental altercations. (8) Infants and toddlers their peers. Less is known about the impact of IPV on
may be injured if they are being held in a parent’s arms children’s physical health, although recent studies have
during a physical altercation. Older children, on the associated IPV exposure with a higher incidence of child-
other hand, may be injured while trying to intervene to hood asthma and with infant failure to thrive and child-
stop a fight. hood malnutrition. (10)

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 psychosocial issues intimate partner violence

Childhood IPV exposure also affects adult health Options to routine screening include no screening or
adversely. Felitti and colleagues (11) published a series performing targeted screening. In the pediatric setting,
of articles examining the association between “adverse targeted screening includes children in whom concern
childhood experiences,” including exposure to a bat- exists for child abuse and neglect. Pediatric clinicians also
tered mother, and a host of adult health outcomes. The should be concerned about IPV based on findings for
authors enrolled more than 20,000 men and women and both the mother and child. They should be concerned
found a consistent, graded relationship between the if the patient’s mother appears depressed or overly anx-
number of adverse childhood experiences and poor adult ious, has obvious physical injuries, repeatedly cancels or
health outcomes. When analyzed separately, exposure to misses appointments or has difficulty following through
a battered mother was consistently linked with adverse with medical advice, or is abusing alcohol or other drugs.
adult health sequelae ranging from depression to sub- In addition, concern is raised if the child has emotional
stance use. problems, including depression, anxiety, or attention-
deficit/hyperactivity disorder, and has frequent nonor-
Diagnosis ganic symptoms, such as headaches or stomachaches. In
Screening for IPV addition, certain situational factors may precipitate IPV,
Screening caregivers for IPV may improve the pediatric including pregnancy, parental separation or divorce, or
clinician’s understanding of the child’s current illness, efforts to leave the current relationship. The risk of a
home environment, and ability to follow physician rec- targeted screening approach, however, is that many
ommendations. Screening also communicates that IPV women affected by IPV will not be identified.
is a common public health problem, reduces the isolation When screening patients’ mothers, the topic of IPV
commonly associated with IPV, and conveys that IPV can be introduced with a statement such as: “The safety
exposure affects children. In addition, abused women and well-being of mothers affects the safety and well-
may be more likely to seek health care for their children being of children, so I ask all mothers a number of
than for themselves, making the pediatric setting an questions about themselves and about their safety.”
important site for screening. Mothers generally support The psychometric properties of numerous IPV
screening for IPV in the pediatric setting and feel that screening questions have been tested in health-care set-
the pediatric office is a safe location to discuss IPV and tings. The general consensus is that precise, behaviorally
its consequences. Most major medical organizations anchored questions are more sensitive and specific
(AAP, American College of Obstetrician-Gynecologists, than are general questions such as “Do you feel safe at
American Medical Association) recommend routine IPV home?” or “Are you a victim of IPV?” A comprehensive
screening. compendium of IPV screening questions, published
It is unclear, however, whether screening leads to by the Centers for Disease Control and Prevention, can
short- or long-term benefits for women. MacMillan and be found at http://www.cdc.gov/NCIPC/pub-res/
colleagues (12) recently found that female patients ran- images/IPVandSVscreening.pdf. Notably, most of the
domized to IPV screening, compared with nonscreened validated IPV screening instruments have been tested
control women, did not report decreased IPV or in- exclusively on women; two sets of screening questions
creased health or quality of life over time. In 2004, the have been validated in a pediatric setting.
United States Preventive Services Task Force published When a child 3 years of age or older is in the exami-
guidelines stating that there was not sufficient empiric nation room, abused women have expressed concern
evidence to recommend either for or against routine IPV about clinicians using behaviorally anchored questions.
screening. (13) Criticisms of these guidelines include: (14) When these older, verbal children are present,
1) Asking about IPV should be viewed as a routine women worry that the child may be traumatized or later
behavioral health inquiry rather than as a “screening inadvertently relay the conversation about IPV to the
test”; 2) Benefits of screening may extend beyond de- perpetrator. If the child and mother can be separated
creasing violent episodes, and these benefits should be (such as during hearing and vision screening), clinicians
considered in evaluating the merits of screening; and can screen the mother when she is alone. If not, the
3) IPV is a complex issue, and qualitative research or clinician should use more general questions such as
studies outside of the traditional medical literature “How do you and your partner work out arguments?”
should be considered. Benefits and risks for children and “In general, how would you describe your relation-
related to screening mothers for IPV remain uninvesti- ship with your partner: a lot of tension, some tension, or
gated. no tension?” Attention to the response and to nonverbal

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psychosocial issues intimate partner violence

cues is important. If the response or the reaction to these

questions is a concern, the clinician should attempt to Table. Options for Safety Planning
interview the woman alone to pursue more specific ques-
tions. A woman may answer “no” many times before she Each recommendation should be discussed with the
discloses. woman to decide whether it is safe and feasible:
● Advise women to collect the following items in
preparation for leaving: money, an extra set of house
Management and car keys, important documents (Social Security
Documentation cards, driver’s license, birth certificates, passports,
In the pediatric setting, the child is the patient, and both marriage license, rent and utility receipts, car
legal guardians have access to the medical record. If the registration, bank account numbers and check books,
insurance policies and numbers, medical information)
perpetrator is the child’s father, he has access to the chart and a hidden bag with extra clothing, necessary
and could become aware of the caregiver-clinician IPV medications for mother and children, toiletries, and
conversation, potentially increasing the risk of violence. food.
In contrast, it may be legally beneficial (eg, in restraining ● Ask neighbors to call the police if they overhear
orders or child custody cases) to document IPV in the violence.
● Have a code with family or friends that communicates
child’s medical record. Although the risks of documen- that the intimate partner violence is occurring or is
tation are more theoretical than evidence-based, it is about to occur and establish what the family or
important to discuss the risks and benefits of documen- friends will do if the woman uses the code.
tation with the mother and abide by her wishes. A second ● Remove or disarm weapons in the home.
option is to include in the chart a code known to other
clinicians in the practice that would not be readily under-
standable to others, such as ⫹MIPV (for positive mater- should recognize that addressing IPV and helping
nal IPV). women make positive changes often takes time.
Clinicians should recognize that advising the woman
Response to a Positive IPV Screen to leave the relationship may not be the safest solution
Although there is a dearth of empiric data about effective for her or her children. The risk of homicide for women
interventions in reducing IPV victimization or perpetra- increases by 75% around the time of leaving an abusive
tion or in improving health, the following responses to a relationship. Further, leaving an abuser may mean going
positive IPV screen are recommended: 1) An empathetic into a shelter, removing children from their current
statement supporting the woman and emphasizing that schools, and losing significant economic support.
she does not deserve to be treated that way; 2) Questions
about escalation of violence, weapons, and comfort in Mandated Reporting
going home to assess the woman and child’s current With any disclosure of IPV, a careful assessment of the
safety; 3) Detailed history and physical examination child’s well-being and safety is essential. Pediatric clini-
looking for possible child abuse; 4) Provision of social cians are obligated to report to CPS any suspicion of
work assistance or national (1-800-799-SAFE) and local child abuse or neglect or any concern that the child is in
IPV resources; 5) Planning for safety (Table); and 6) An imminent danger. It can be helpful to have the mother
assessment of whether the child would benefit from file the report with the clinician and to document, as
mental health intervention or from frequent visits with appropriate, ways in which she has attempted to protect
his or her primary care clinician. If violence is escalating the child. CPS should be made aware of the co-occurring
or the family is in immediate danger, safe housing must IPV, and planning for safety is critical.
be established, which IPV hotlines can help to facilitate. States vary regarding whether pediatric reporters are
Most IPV organizations offer shelter and counseling mandated reporters of childhood IPV exposure. Some
as well as legal and social advocacy for abused women. states’ laws explicitly say that pediatric clinicians are
Therefore, pediatricians should familiarize themselves mandated reporters of childhood exposure to IPV. In
with the services offered by local IPV organizations. If other states, it is not explicitly written. However, case
the woman wishes, call the hotline from the pediatric law has interpreted IPV exposure as falling under emo-
office. The pediatric office also may be a safe place for tional abuse, thereby making pediatric clinicians man-
an IPV advocate from a local organization to meet the dated reporters. In some states, health-care clinicians also
woman to provide assistance. Establishing a trusting may be mandated reporters of IPV. Clinicians should
caregiver-clinician relationship is critical, and clinicians know their specific state’s reporting requirements prior

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 psychosocial issues intimate partner violence

women’s likelihood of disclosing IPV and seeking help

Summary also is a concern.

• Based on strong research evidence, IPV and

childhood exposure to IPV are prevalent public
health problems. (4)(5)(13) References
• Based on strong research evidence, IPV and child 1. Identifying and Responding to Domestic Violence: Consensus Rec-
maltreatment commonly co-occur, particularly in ommendations for Child and Adolescent Health. San Francisco,
families that have additional psychosocial risk Calif: The Family Violence Prevention Fund; 2004. Available at:
factors such as poverty, parental depression, and http://www.endabuse.org/userfiles/file/HealthCare/pediatric.
substance abuse. (6)(7) pdf
• Based on strong research evidence, IPV negatively 2. Archer J. Sex differences in aggression between heterosexual
affects children’s social-emotional health, increasing partners: a meta-analytic review. Psych Bull. 2000;126:651– 680
the risk for internalizing and externalizing disorders 3. Anderson K. Perpetrator or victim? Relationships between in-
and aggression with peers. (9) timate partner violence and well-being. J Marr Fam. 2002;64:
• Based on some research evidence, IPV may negatively 851– 853
affect children’s physical health and health-care 4. McDonald R, Jouriles EN, Ramisetty-Mikler S, Caetano R,
use. (10) Green CE. Estimating the number of American children living in
• Based on consensus and some research evidence, partner-violent families. J Fam Psychol. 2006;20:137–142
screening for IPV in the pediatric health-care setting 5. American Academy of Pediatrics. The role of the pediatrician in
may help identify abused women and connect them recognizing and intervening on behalf of abused women. Pediat-
to resources. (5) rics. 1998;101:1091–1092
6. Appel A, Holden G. The co-occurrence of spouse and physi-
cal child abuse: a review and appraisal. J Family Psych. 1998;12:
to screening. Websites such as www.endabuse.org or 578 –599
http://www.childwelfare.gov/ may help discern state- 7. Jouriles EN, McDonald R, Smith Slep AM, Heyman RE,
specific laws about mandated reporting. Garrido E. Child abuse in the context of domestic violence: preva-
lence, explanations, and practice implications. Violence Vict. 2008;
If practicing in a state that has mandated reporting 23:221–235
laws for either IPV or childhood exposure to IPV, clini- 8. Christian CW, Scribano P, Seidl T, Pinto-Martin JA. Pediatric
cians should inform the mother of their responsibility to injury resulting from family violence. Pediatrics. 1997;99:e8
report before screening. If practicing in a state that has 9. Kitzmann KM, Gaylord NK, Holt AR, Kenny ED. Child wit-
less specific reporting laws and there is no suspicion of nesses to domestic violence: a meta-analytic review. J Consult Clin
Psych. 2003;71:339 –352
child maltreatment, the pediatrician should consider 10. Bair-Merritt MH, Blackstone M, Feudtner C. Physical health
each situation individually to determine what is best for outcomes of childhood exposure to intimate partner violence: a
the child and mother. systematic review. Pediatrics. 2006;117:e278 – e290
Although proponents of mandated reporting for 11. Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of
childhood IPV exposure state that reporting is justified childhood abuse and household dysfunction to many of the lead-
ing causes of death in adults. The Adverse Childhood Experiences
due to the negative health outcomes, others are con- (ACE) study. Am J Prev Med. 1998;14:245–258
cerned about such requirements. Apprehension about 12. MacMillan HL, Wathen CN, Jamieson E, et al. Screening for
mandated reporting for IPV exposure stems from fear intimate partner violence in health care settings: a randomized trial.
that reporting is punitive to the victim, implying that she JAMA. 2009;302:493–501
failed to protect the child. Universal reporting also incor- 13. United States Preventive Services Task Force. Screening for
family and intimate partner violence. Ann Intern Med. 2004;140:
rectly assumes that all children are affected similarly by 382–386
IPV exposure and may increase demands on an already 14. Zink T, Jacobson J. Screening for intimate partner violence
overburdened CPS. Mandated reporting decreasing when children are present. J Interpers Viol. 2003;18:872– 890

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psychosocial issues intimate partner violence

PIR Quiz
Quiz also available online at http://pedsinreview.aappublications.org

6. Which of the following is true regarding children exposed to intimate partner violence?
A. They are less likely to be involved in violent relationships later in life.
B. They are less likely to use the emergency department for care.
C. They are more likely to be shy and withdrawn in their peer relationships.
D. They are more likely to exhibit extreme separation anxiety in toddlerhood.
E. They rarely are injured themselves during episodes of intimate partner violence.

7. You are considering initiating routine screening for intimate partner violence for parents in your pediatric
clinic. Which of the following is the most appropriate action in this screening?
A. All mothers should be screened routinely by their child’s pediatrician because this has been shown to
decrease violent episodes at home.
B. Children older than age 3 years should be asked questions routinely about the presence of violence at
home.
C. Mothers of children who have frequent nonspecific symptoms, such as headache, should be queried with
respect to intimate partner violence.
D. Targeting mothers who are depressed and anxious or those who have children who have emotional
problems likely will identify most cases of intimate partner violence.
E. Women should be asked general questions such as “Are you concerned about safety?” rather than more
specific questions related to intimate partner violence.

8. You have just identified a mother in your practice who is the victim of sporadic intimate partner violence.
She states that the child’s father never has hit or spanked the child. The child’s physical examination
reveals no evidence of abuse. After additional questioning of the mother and examination of the child, you
believe that she is the only direct victim of the violence. Which of the following is true regarding your
responsibilities to this child and his mother?
A. The mother should be strongly encouraged to leave the father as soon as possible.
B. You are legally obligated to report the abuse of the child only if physical evidence of abuse is present.
C. You should order mandatory psychological counseling for the child.
D. Your legal obligation to report the violence against the mother and the child’s exposure to it depends
on your state laws.
E. Your staff should set up safe housing for both of them immediately.

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 Intimate Partner Violence
Megan H. Bair-Merritt
Pediatr. Rev. 2010;31;145-150
DOI: 10.1542/pir.31-4-145

Updated Information including high-resolution figures, can be found at:

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Patient Safety and Quality Improvement: Medical Errors and Adverse Events
Michael S. Leonard
Pediatr. Rev. 2010;31;151-158
DOI: 10.1542/pir.31-4-151

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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 Article patient safety

Patient Safety and Quality Improvement:

Medical Errors and Adverse Events
Michael S. Leonard, MD,
Objectives After completing this article, readers should be able to:
MS*
1. Define terms commonly used in patient safety discourse.
2. Describe the scope of medical errors and adverse events, focusing on medication-
Author Disclosure related issues.
Dr Leonard has 3. Identify barriers to improving patient safety.
disclosed no financial 4. Address disclosure of medical errors and adverse events.
relationships relevant 5. Review principles and practices that can reduce the risk of harm to patients.
to this article. This
This is the first in a series of articles to review the topics of patient safety and quality im-
commentary does not
provement in pediatrics.
contain a discussion
of an unapproved/
investigative use of a Introduction
commercial product/ Patient safety is a subject that traverses all medical specialties and affects every health-care
device. professional. The attention to medical errors and adverse events as well as the resultant
literature has grown exponentially over the past decade. A number of practicing physicians,
however, remain unaware of the extent of the problem, the impact on patients, and the
burden on the health-care system. Many also are unfamiliar with strategies to reduce the
risk of harm.

Terminology
It is important to note that definitions used in patient safety can vary across studies,
between organizations, and over time. A medical error, as defined by the Institute of
Medicine (IOM), is “the failure to complete a planned action as intended or the use of a
wrong plan to achieve an aim.” (1)(2) It is a mistake in action or judgment. A medical error
must be distinguished from an adverse event, which is “an injury caused by medical
management rather than by the underlying disease or condition of the patient.” An adverse
event results in harm to the patient. Not all medical errors lead to adverse events. In fact,
most do not.
A medication error is the most common type of medical error (3)(4) and can occur at
any point in the medication management process. (5) This chain of events includes
ordering, transcribing, preparing, delivering, and administering a drug. Medication errors
can be classified as errors of commission or omission. (6) An error of commission occurs
when an incorrect action is taken, such as prescribing ceftriaxone for a neonate who has
hyperbilirubinemia. An error of omission results when a correct action is not taken, such as
not premedicating a patient who has a history of red man syndrome with an antihistamine
before administering vancomycin.
An adverse drug event (ADE) is an injury due to a medication. ADEs are the most
common type of adverse events. Fortunately, less than 1% of medication errors result in an
ADE. (5) A preventable ADE is an ADE that, based on the medical information known at
the time, could have been avoided, such as a patient who has a known allergy to macrolides
being prescribed azithromycin and developing urticaria. This occurrence is in contrast to a
nonpreventable ADE, which could not have been foreseen based on the medical informa-
tion known at the time. For example, a patient who has no known allergies is given
azithromycin and develops urticaria. An adverse drug reaction is synonymous with a
nonpreventable ADE. It is an event defined by the World Health Organization as “noxious

*Chief Quality & Safety Officer for Children’s Services, Associate Professor of Pediatrics, University of Rochester Medical Center,
Rochester, NY.

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patient safety adverse events

and unintended, and which occurs at doses used in man

for prophylaxis, diagnosis or therapy.” (7)(8)
A potential ADE is a medication error that places a
patient at significant risk of injury but does not actually
result in harm. (7) Potential ADEs often are referred to as
“near misses.” There are two subtypes of potential
ADEs: intercepted and nonintercepted. An intercepted
ADE is an error that is identified and corrected before it
reaches the patient. For example, a patient is prescribed
an overdose of ranitidine that is detected by a pharmacist,
who does not dispense the drug, but instead refers the
prescription back to the prescriber for correction. A non-
intercepted ADE is an error that reaches the patient but,
by pure happenstance, does not cause harm to the pa- Figure. The relationship between medication errors, adverse
tient. For example, a patient is prescribed and given an drug events, and harm. ADEⴝadverse drug event, ADRⴝ
overdose of ranitidine without suffering any ill effects. adverse drug reaction.
The Figure shows the relationship among medication
errors, ADEs, and harm.
A sentinel event is “an unexpected occurrence involv- 4,000 admissions at two large Boston hospitals over a
ing death or serious physical or psychological injury, or 6-month period in 1993, investigators identified 247
the risk thereof.” (9) An ADE or a potential ADE may ADEs. (14) This translates to 6.5 ADEs per 100 admis-
qualify as a sentinel event. Not all sentinel events are the sions, a rate greater than nine times that found in the
result of a medical error. A never event, as described by Harvard study. Twenty-eight percent of the ADEs were
the National Quality Forum, is one of 28 events resulting considered preventable. These investigators also identi-
from an error in medical care that is serious, unambigu- fied 194 potential ADEs, of which 43% were intercepted
ous, and usually preventable. (10) Never events, which before they reached the patient.
also are referred to as serious adverse events, serious The IOM released its landmark report To Err is
reportable events, and serious reportable adverse events, Human at the end of 1999, heralding a new age for the
never should occur within a health-care institution and field of patient safety. (1) Extrapolating the results of the
generally signal a system safety failure. Utah-Colorado study and the Harvard study over the
33.6 million admissions to United States hospitals in
General Epidemiology 1997, the report estimated that 44,000 to 98,000 pa-
Patient safety has become a national health-care focus tients die from medical errors annually. The IOM issued
over the past 10 years, but medical errors and adverse recommendations in four strategic areas to improve pa-
events have been addressed for a far longer time. The tient safety: leadership and knowledge, identifying and
investigators for the Harvard Medical Practice Study learning from errors, setting performance standards and
reviewed more than 30,000 records from patients dis- expectations for safety, and implementing safety systems
charged in 1984 from 51 hospitals across the state of in health-care organizations.
New York. (11) Adverse events occurred in 3.7% of these The financial impact of medical errors and adverse
hospitalizations, most of which were preventable. (12) If events is enormous. Based on the IOM report, the esti-
generalized to all hospitals in the United States, this mated cost of medical errors in the United States is
incidence translates to more than 1 million people expe- $37.6 billion annually. Preventable adverse events com-
riencing an adverse event and approximately 180,000 prise an estimated $17 to $29 billion, more than 50% of
patients dying from an adverse event every year. (7) which represent direct costs to the health-care system.
Medication-related incidents were the most common (1)(2) An ADE extends the length of hospital stay by
type of adverse event, at a rate of 0.7 ADEs per 100 1.74 to 2.2 days and increases costs by $2,000 to $3,200.
admissions. (5)(12) A preventable ADE extends the hospital stay by 4.6 days
A study of nearly 15,000 discharges across 28 hospi- and increases costs by $5,800. (14)(15)(16) These fig-
tals in Utah and Colorado in 1992 identified 459 adverse ures represent dollar values from the 1990s; current
events. (13) Fifty-eight percent of these adverse events estimates are likely even higher.
were found to be preventable. In a study of more than The financial burden of adverse events is shifting

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 patient safety adverse events

toward health-care institutions. Medicare no longer re- for this additional step in the medication delivery process
imburses the cost of treatment for some events occurring introduces risk of error and, therefore, risk of harm. (4)
during a hospital admission, and many state Medicaid Children who experience extended lengths of stay,
agencies are considering similar financial disincentives. complex medication regimens, and higher severity of
Private third-party payers may begin pursuing similar illness are at increased risk of ADEs. (21) Neonates and
practices. young infants are at even greater risk due to their im-
mature hepatic, renal, and immune systems. (4)(22) In
Pediatric Epidemiology settings such as the neonatal intensive care unit, where
The prevalence of medical errors and adverse events in lengths of stays often are measured in months, patients
children is becoming clearer. Investigators analyzed a can have significant changes in weight over the course of
subset of data from the Utah-Colorado study represent- a hospitalization. This change requires vigilance to assure
ing more than 3,700 pediatric hospitalizations, including that medication dosing regimens remain within safe and
birth admissions. (17) They found that adverse events therapeutic ranges.
occurred in 1% of these hospitalizations, 60% of which Medication errors and ADEs occur in the community
were deemed preventable. Extrapolated to the entire as well, although this venue has been less researched.
United States population, approximately 70,000 hospi- (6)(23) In a prospective study across six outpatient of-
talized children experience an adverse event each year, of fices, 14% of pediatric patients experienced an ADE. (24)
which 42,000 could be avoided. Twenty-three percent of these events were judged to be
Children have been recognized as a high-risk popula- preventable. Again, complex medication regimens in-
tion for medication errors and ADEs. The risk for an creased the likelihood of preventable ADEs. Of note,
ADE is estimated to be three times higher in hospitalized parents whose English proficiency was limited were less
children than in adults. (4)(18) In a prospective study of likely to report an ADE, which may represent a sub-
medication orders in a children’s hospital, 23.7% con- population of children at even greater risk of harm.
tained errors. (19) In a study of more than 10,000 Not all outpatient errors and preventable adverse
medication orders representing 1,120 patients across events are iatrogenic; they also can be caused by well-
two children’s hospitals, the investigators found 5.7% of meaning parents and nonmedical caregivers. Many
the orders contained errors, with 1.1% representing po- over-the-counter children’s medications are available in a
tential ADEs. (18) They identified 2.3 ADEs per 100 variety of preparations and concentrations, which can
admissions, 19% of which were preventable. In a more contribute to confusion and subsequent dosing errors.
recent study across 12 children’s hospitals, investigators Outpatient medication errors and ADEs are not limited
reported a rate of 11.1 ADEs per 100 patients, 15.7 to oral drugs. For example, in 2007, a 17-year-old athlete
ADEs per 1,000 patient-days, and 1.23 ADEs per 1,000 died of salicylate toxicity from excessive use of over-the-
medication doses. (20) Rising ADE rates actually may counter topical sports ointments. (25) A tragic event
reflect an improved ability to detect such events over time such as this underscores the need for pediatricians to take
rather than a true increase in incidence. every opportunity to stress to patients and families the
For many reasons, children are more vulnerable to importance of using medications only as instructed and
medication errors and ADEs. Unlike adults, for whom the potential hazards of using seemingly benign drugs
dosing tends to be a single or limited number of options, inappropriately.
dosing for children usually is tailored to the patient based
on his or her weight. Proper dosing requires that the Detection of Medical Errors and
prescriber have an accurate weight for the child as well as Adverse Events
the proficiency to perform weight-based calculations. Difficulty in identifying medical errors and adverse events
Many settings in which children are treated are predom- creates a significant barrier to assessing risk reduction
inantly adult-oriented, with pediatric patients compris- strategies. Although the data presented in this article are
ing only a small fraction of admissions. In such venues, staggering, they are likely to represent considerable un-
staff may not always be trained in safe pediatric medica- derestimates. In the absence of an accurate, reliable
tion practices, and if they are, their skills may wane due to methodology to measure errors and events, the ability to
the infrequency of providing care to these young pa- assess the impact of patient safety initiatives remains
tients. Most drugs are packaged commercially for adult challenging.
use. Such preparations require compounding for pediat- Historically, identification of medical errors and ad-
ric usage, a task that requires a specific skill set. The need verse events relied on incident reports, a methodology

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patient safety adverse events

that has many pitfalls. The reporting of incidents pre- experienced an adverse event. They may observe worsen-
sumes that an individual recognizes a medical error or an ing of clinical status, the need to perform additional
adverse event when it occurs. If an error or adverse event testing, or adjustments made to treatments. They may
is identified, staff may assume, mistakenly, that someone perceive a change in the behavior of the physician or
else will report it. Incident report forms generally require other staff. They may overhear conversations between
a large amount of information, which makes them both staff members. Patients and families want to be told when
time-consuming and cumbersome to complete. Person- an error has occurred. They want to know what hap-
nel who do take the time to report events often receive no pened, why it happened, how it will affect their health,
feedback. They may not see their efforts resulting in and what is being done to prevent such an error from
noticeable improvement, which can act as a disincentive recurring. (30)
for reporting subsequent events. (26) Informing patients and families when medical errors
Staff may have valid apprehensions about reporting cause harm is the right thing to do, but despite physi-
errors and adverse events. (27) There is a natural hesi- cians’ best intentions, full disclosure of such events is
tancy to point out one’s own mistakes for fear of being uncommon. Practitioners often fear that such disclosure
labeled incompetent and a reluctance to point out oth- may result in litigation, loss of trust by the patient and
ers’ mistakes for fear of being labeled a whistleblower. family, or tarnishing of their professional reputation.
Although institutions across the country are transition- Health-care professionals must overcome the instinct to
ing to a culture of blameless reporting, staff still may ignore, hide, or worst of all, deny when an adverse event
worry about discipline by their institutions or licensing occurs. Disclosure relieves the anxiety of not knowing
organizations. Fear of litigation also remains a major and reaffirms an open, honest physician-patient-family
deterrent. relationship. Such transparency has been demonstrated
Chart reviews in search of medical errors and adverse to decrease litigation as well as the average settlement
events are time- and labor-intensive. The cost often is amount for claims that are filed. (30)(31)(32)
prohibitive, and generally only a sampling of records can Patients and families also want an apology. An apol-
be evaluated. Trigger methodology can streamline the ogy historically has been viewed as an admission of guilt,
process and help capture occurrences that otherwise and for this reason, practitioners often ignore their in-
might go undetected. A trigger is an action or indicator stincts to say “I’m sorry.” However, this omission is
that might signal the presence of an adverse event. For perceived as cold, heartless, and impersonal by patients
example, flumazenil usually is prescribed in response to a and families. They correctly feel angry and distanced,
benzodiazepine-related ADE. An order for flumazenil, which is toxic to the physician-patient-family relationship
therefore, can serve as a trigger. Groups of triggers have and actually may increase the likelihood of litigation. The
been combined into trigger tools to increase the ability to importance of an apology and the reluctance by physi-
identify actual and potential ADEs. (28) The resultant cians to provide one due to fear of litigation has resulted
focused chart reviews save time and resources by improv- in legislative changes. As of January 2008, 35 states have
ing efficiency. Trigger methodology has been applied in enacted statutes that prevent an apology from being used
children’s hospitals and has been shown to increase de- against a physician in a law suit. (30) Other states have
tection of ADEs. (20) similar legislation in progress. The impact, effectiveness,
and protection afforded by these recent statutes have yet
Disclosure to be established. Policies vary across organizations, and
The general public is becoming increasingly aware of legislation varies among states. Health-care professionals
issues of patient safety. A study reviewing newspaper should consult risk management experts or legal counsel
articles over a 10-year period found increasing coverage for guidance with disclosure of adverse events and saying
of pediatric medication safety. (29) The United States “I’m sorry.”
had the highest absolute number of articles of the five Although patients are the primary and most visible
countries included in the study. Nearly two thirds of the victims of medical errors and adverse events, it is impor-
articles covered specific adverse events. The good news is tant to remember the “second victims”: the clinicians.
that three quarters of the articles were written in a tone (33) The emotional impact of medical errors on health-
characterized as neutral, a positive step as health care care personnel, especially those errors that cause harm to
transitions from a culture of individual blame to one of patients, should not be underestimated. In many cases,
system-based improvement. more than one clinician is involved and may feel respon-
Patients and families often know when they have sible. Resultant feelings of guilt, anxiety, or incompe-

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 patient safety adverse events

tence can be devastating, leading to inappropriate behav-

iors such as lashing out at patients, families, and Practices to Help Prevent
Table.
colleagues and to unhealthy behaviors such as substance
abuse. Health-care professionals must be supportive and
Medication Errors and Adverse
nonjudgmental of their colleagues when medical errors Drug Events
occur. Debriefing sessions can provide a therapeutic
● Obtain a thorough list of the patient’s current
venue to discuss not only the medical aspects of the
medications.
event, but also the emotional issues as they relate to the ● Obtain an accurate list of the patient’s allergies and
clinicians involved. adverse reactions.
● Print legibly.
● Avoid the use of unsafe abbreviations.
● Obtain an accurate patient weight.
Prevention ● Mind your decimals.
Patient safety initiatives can be framed within a public ● Include indication for therapy on orders and
health model of prevention. (27) The disease we are prescriptions.
trying to eradicate is medical errors, and specifically for ● Educate patients and families.
this discussion, medication errors. It is logical for physi-
cians’ efforts to focus on prescribing, the step in the
medication management process at which errors most Joint Commission has compiled a list of abbreviations
commonly occur. (7)(18)(34) that should not be used, (35), such as:
The goal of primary prevention is to reduce the inci-
• QD, which easily can be mistaken for QID, result-
dence or risk of disease. For example, the purpose of the
ing in fourfold overdosing. Write “daily” instead.
influenza vaccine is to prevent or decrease the likelihood
• U, which can be misinterpreted as a zero (0), result-
that a patient will become ill from the virus. For medica-
ing in 10-fold overdosing. Write out the word
tion errors, there is no vaccine, but our armamentarium
“units” instead.
for preventing errors includes a host of strategies. The
A good maxim is: When in doubt, write it out.
following is a list of simple practices that can be employed
by prescribers in any setting to help prevent errors and 5. Obtain an accurate patient weight. Most pediatric
adverse drug events (Table): dosing is based on the child’s weight, at least until adult
size is reached. Weigh the patient in kilograms and
1. Obtain a list of your patient’s current medications. include weight-based dosing information on the order or
This is part of a process termed medication reconcilia- prescription. (4)(36) This practice allows a pharmacist or
tion, one of the National Patient Safety Goals. It helps to nurse to double-check your calculations.
prevent inadvertent drug interactions and ensure that 6. Mind your decimals. Dosing errors are the most com-
patients receive the intended therapy. (35) Include all mon type of prescribing errors; children, in particular, are
prescription drugs, over-the-counter medications, vita- at high risk for 10-fold errors due to misplaced decimals.
mins, and supplements. (18)(34)(37)(38)(39)(40)(41) The adage “Always lead,
2. Obtain an accurate list of allergies and adverse reac- never follow” can help avoid this type of error. Always
tions. Include all drugs, foods, and relevant substances. precede a decimal with a zero (eg, 0.3 mg, not .3 mg).
Document the specific symptom(s) the patient experi- Never follow a decimal with a zero (eg, 7 mg, not
ences when he or she is exposed. 7.0 mg). (35)
3. Print legibly. Few settings are completely paperless, 7. Include the indication for therapy on orders and
and handwriting that is difficult to decipher can be prescriptions. (36) This practice helps to prevent ortho-
misinterpreted, propagating misinformation. This out- graphic, or look-alike, medication errors. Zyprexa威 can
come is true not only for orders and prescriptions, but for be mistaken easily for Zyrtec威 on a poorly handwritten
other documents as well, such as progress notes, medi- prescription and has been. (42) Specifying the indication
cation lists, and even the self-stick message notes affixed “allergic rhinitis” on a prescription for Zyrtec威 drastically
to charts. reduces the likelihood that Zyprexa威 will be dispensed.
4. Avoid the use of unsafe abbreviations. Many histori- The indication for therapy also should be included
cally used abbreviations have been identified as danger- with verbal orders to prevent phonetic, or sound-alike,
ous, increasing the likelihood of medication errors and medication errors. Diamox威 and Trimox威 may not be
ADEs. As part of the National Patient Safety Goals, the mistaken for each other on paper or on a computer

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patient safety adverse events

screen, but a nurse working on a noisy unit receiving a influenza to minimize symptom severity. Secondary pre-
verbal order from a physician on a cell phone with only vention for medication safety is the rapid detection and
“one bar” easily could mistake them. Including the indi- removal of errors introduced into the medication man-
cation for therapy decreases the risk that these two drugs agement system, intercepting them before they have the
will be interchanged. opportunity to become preventable ADEs. Review of
8. Educate patients and families. Review the dosing regi- medication orders by pediatric pharmacists has been
men, indications for therapy, and potential adverse effects shown to be an effective means of preventing potential
for every new prescription. Provide written instructions and ADEs from reaching the bedside. (37)(52) Pharmacists
information whenever possible. Encourage patients and and nurses should be empowered and encouraged to
families to contact you with any questions or concerns. double-check orders (53) and contact the prescriber
when an error is identified. Physicians should be grateful
Institution-based primary prevention strategies also rather than annoyed by these calls; each represents
can be implemented. Computerized physician (or pro- averted harm to a patient.
vider) order entry (CPOE) refers to a broad spectrum of The goal of tertiary prevention is to minimize se-
electronic prescribing systems that have been shown to quelae associated with disease. Physical therapy assists
decrease medication errors and ADEs. (43)(44)(45) patients whose baseline status has been compromised by
CPOE can ascertain that required information is in- a severe bout of influenza. For patient safety, having
cluded in an order or prescription using forced format reversal agents readily available such as naloxone for
screens and essentially can eliminate the issue of illegibil- narcotics and having interventional systems in place such
ity. Weight-based calculators with pediatric guardrails as rapid response teams (54) may help reduce the short-
can ensure that dosing remains within safe parameters. and long-term morbidity associated with adverse events
Clinical decision support functionalities embedded in when they do occur.
many CPOE systems include checks for allergies and Primordial prevention strives to reduce environmen-
drug interactions, integration of available laboratory tal, societal, cultural, and behavioral factors that increase
data, reminders to monitor serum drug concentrations, risk of disease. (55) For influenza, this is accomplished
and promotion of standardized order sets. through public health campaigns to promote immuniza-
However, CPOE is not a panacea. CPOE may help tion and measures to reduce disease spread. For patient
solve some problems, but it can introduce new sources of safety, primordial prevention entails increasing awareness
error. For example, forced format screens can facilitate of the problem, an objective of this article; building
incorrect orders in some instances. (46) Implementation systems that minimize the risk of error and swiftly inter-
of CPOE requires an enormous investment in human cept them before they have an opportunity to cause
and financial resources. The cost of the technology re- harm; and establishing a culture in which safe practices
mains prohibitive for many institutions. In a 2002 sur- are the standard, error and event reporting is nonpuni-
vey, less than 10% of United States hospitals had CPOE tive, and continual improvement is the paradigm.
systems completely available. (47) Paper-based order
forms with forced formats can provide a temporizing,
fiscally friendly solution for ensuring that all necessary Summary
information is included in an order, (48) but they cannot
resolve poor handwriting or provide the automated safe- • Strides are being made to keep patients safe despite
guards of an electronic system. the enormity of the challenge and the inherent
difficulties in assessing improvement.
Clinical pharmacist participation on inpatient rounds
• Pediatricians need to be cognizant of general patient
has been shown to be another effective means of primary safety principles as well as those specific to children.
prevention in various settings. (22)(49)(50)(51) Recom- • We must adopt safe practices and remain vigilant in
mendations, including choice of drug, dosing regimen, our efforts to reduce the risk of harm to our
and pharmacokinetic monitoring, help reduce errors and patients. To err may be human, but to improve is
divine.
preventable ADEs. Unfortunately, the cost in human
and financial resources precludes this solution for many
organizations.
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patient safety adverse events

45. Kaushal R, Shojania KG, Bates DW. Effects of computerized tion on physician rounds and adverse drug events in the intensive
physician order entry and clinical decision support systems on medica- care unit. JAMA. 1999;282:267–270
tion safety: a systematic review. Arch Intern Med. 2003;163:1409–1416 51. Kaushal R, Bates DW, Abramson EL, Soukup JR, Goldmann
46. Koppel R, Metlay JP, Cohen A, et al. Role of computerized DA. Unit-based clinical pharmacists’ prevention of serious medica-
physician order entry systems in facilitating medication errors. tion errors in pediatric inpatients. Am J Health Syst Pharm. 2008;
JAMA. 2005;293:1197–1203 65:1254 –1260
47. Ash JS, Gorman PN, Seshadri V, Hersh WR. Computerized 52. Krupicka MI, Bratton SL, Sonnenthal K, Goldstein B. Impact
physician order entry in U.S. hospitals: results of a 2002 survey. of a pediatric clinical pharmacist in the pediatric intensive care unit.
J Am Med Inform Assoc. 2004;11:95–99 Crit Care Med. 2002;30:919 –921
48. Shaha S, Brodsky L, Leonard MS, et al. Establishing a culture 53. Walsh KE, Kaushal R, Chessare JB. How to avoid paediatric
of patient safety through a low-tech approach to reducing medica- medication errors: a user’s guide to the literature. Arch Dis Child.
tion errors. In: Advances in Patient Safety. Rockville, Md: Agency 2005;90:698 –702
for Healthcare Research and Quality; 2005 54. Mistry KP, Turi J, Hueckel R, Mericle JM, Meliones JN.
49. Kaboli PJ, Hoth AB, McClimon BJ, Schnipper JL. Clinical Pediatric rapid response teams in the academic medical center. Clin
pharmacists and inpatient medical care: a systematic review. Arch Pediatr Emerg Med. 2006;7:241–247
Intern Med. 2006;166:955–964 55. Last J, ed. A Dictionary of Epidemiology. 4th ed. New York NY:
50. Leape LL, Cullen DJ, Clapp MD, et al. Pharmacist participa- Oxford University Press, Inc; 2001

Clarification
A perceptive reader notes a discrepancy between PIR’s policy not to discuss “unapproved
commercial products” and comments on the use of the unapproved natriuretic peptide
nesiritide by Madriago and Silberbach in their article “Heart Failure in Infants and Children”
(January 2010, pp. 4 –12). In their PIR-online reply (http://pedsinreview.aappublications.
org/cgi/eletters/31/1/4), the authors lament that the majority of drugs routinely
employed in pediatrics are neither studied nor approved by the United States Food and
Drug Administration (FDA) and state that nesiritide may, in fact, be more effective than
some of the drugs that are approved by the FDA for use in pediatric heart failure.

158 Pediatrics in Review Vol.31 No.4 April 2010

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Patient Safety and Quality Improvement: Medical Errors and Adverse Events
Michael S. Leonard
Pediatr. Rev. 2010;31;151-158
DOI: 10.1542/pir.31-4-151

Updated Information including high-resolution figures, can be found at:

& Services http://pedsinreview.aappublications.org/cgi/content/full/31/4/151

Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
http://pedsinreview.aappublications.org/misc/Permissions.shtml
Reprints Information about ordering reprints can be found online:
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 Clarification
Pediatr. Rev. 2010;31;158
DOI: 10.1542/pir.31-4-158

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/31/4/158

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

Downloaded from http://pedsinreview.aappublications.org by Enrique Mendoza-Lopez on April 2, 2010

patient safety adverse events

45. Kaushal R, Shojania KG, Bates DW. Effects of computerized tion on physician rounds and adverse drug events in the intensive
physician order entry and clinical decision support systems on medica- care unit. JAMA. 1999;282:267–270
tion safety: a systematic review. Arch Intern Med. 2003;163:1409–1416 51. Kaushal R, Bates DW, Abramson EL, Soukup JR, Goldmann
46. Koppel R, Metlay JP, Cohen A, et al. Role of computerized DA. Unit-based clinical pharmacists’ prevention of serious medica-
physician order entry systems in facilitating medication errors. tion errors in pediatric inpatients. Am J Health Syst Pharm. 2008;
JAMA. 2005;293:1197–1203 65:1254 –1260
47. Ash JS, Gorman PN, Seshadri V, Hersh WR. Computerized 52. Krupicka MI, Bratton SL, Sonnenthal K, Goldstein B. Impact
physician order entry in U.S. hospitals: results of a 2002 survey. of a pediatric clinical pharmacist in the pediatric intensive care unit.
J Am Med Inform Assoc. 2004;11:95–99 Crit Care Med. 2002;30:919 –921
48. Shaha S, Brodsky L, Leonard MS, et al. Establishing a culture 53. Walsh KE, Kaushal R, Chessare JB. How to avoid paediatric
of patient safety through a low-tech approach to reducing medica- medication errors: a user’s guide to the literature. Arch Dis Child.
tion errors. In: Advances in Patient Safety. Rockville, Md: Agency 2005;90:698 –702
for Healthcare Research and Quality; 2005 54. Mistry KP, Turi J, Hueckel R, Mericle JM, Meliones JN.
49. Kaboli PJ, Hoth AB, McClimon BJ, Schnipper JL. Clinical Pediatric rapid response teams in the academic medical center. Clin
pharmacists and inpatient medical care: a systematic review. Arch Pediatr Emerg Med. 2006;7:241–247
Intern Med. 2006;166:955–964 55. Last J, ed. A Dictionary of Epidemiology. 4th ed. New York NY:
50. Leape LL, Cullen DJ, Clapp MD, et al. Pharmacist participa- Oxford University Press, Inc; 2001

Clarification
A perceptive reader notes a discrepancy between PIR’s policy not to discuss “unapproved
commercial products” and comments on the use of the unapproved natriuretic peptide
nesiritide by Madriago and Silberbach in their article “Heart Failure in Infants and Children”
(January 2010, pp. 4 –12). In their PIR-online reply (http://pedsinreview.aappublications.
org/cgi/eletters/31/1/4), the authors lament that the majority of drugs routinely
employed in pediatrics are neither studied nor approved by the United States Food and
Drug Administration (FDA) and state that nesiritide may, in fact, be more effective than
some of the drugs that are approved by the FDA for use in pediatric heart failure.

158 Pediatrics in Review Vol.31 No.4 April 2010

Downloaded from http://pedsinreview.aappublications.org by Enrique Mendoza-Lopez on April 2, 2010
 Clarification
Pediatr. Rev. 2010;31;158
DOI: 10.1542/pir.31-4-158

Updated Information including high-resolution figures, can be found at:

& Services http://pedsinreview.aappublications.org/cgi/content/full/31/4/158

Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
http://pedsinreview.aappublications.org/misc/Permissions.shtml
Reprints Information about ordering reprints can be found online:
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Downloaded from http://pedsinreview.aappublications.org by Enrique Mendoza-Lopez on April 2, 2010

Pediatrics in the Community: Integrating Community Pediatrics into Residency
Training
Beth Rezet, Benjamin D. Hoffman and Jeffrey Kaczorowski
Pediatr. Rev. 2010;31;159-160
DOI: 10.1542/pir.31-4-159

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/31/4/159

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

Downloaded from http://pedsinreview.aappublications.org by Enrique Mendoza-Lopez on April 2, 2010

 pediatrics in the community

Integrating Community Pediatrics

into Residency Training
Since 1999, the American Academy Training Initiative (CPTI), in its
of Pediatrics (AAP) has asserted that Structured Approach to Community
pediatricians should “reaffirm their Health and Child Advocacy Train-
role as professionals in the commu- ing: Integrating Goals, Activities,
nity and prepare themselves for it, and Competencies, has identified ed-
Author Disclosure
just as diligently as they prepare for ucational goals and objectives to help
Drs Rezet, Hoffman, Kaczorowski, traditional clinical roles.” (1) Fur- frame all community pediatrics expe-
and Aligne have disclosed no thermore, as of 2001, the Accredita- riences while also meeting require-
financial relationships relevant to tion Council for Graduate Medical ments of the ACGME. This docu-
this article. This commentary does Education (ACGME) Residency Re- ment and additional resources are
not contain a discussion of an view Committee for Pediatrics man- available on the CPTI web site:
dated, ‘‘there must be structured ed- http://www.aap.org/commpeds/
unapproved/investigative use of a
ucational experiences that prepare CPTI. This approach is based on
commercial product/device.
residents for the role of advocate for the work published in a supplement
the health of children within the to Pediatrics in 2005 by the Dyson
community.” (2) As with clinical re- Initiative curriculum committee.
sponsibilities, the best approach to (4) The CPTI workgroup (5) iden-
preparing for such a role is with active tified eight domains of community
hands-on learning. Accomplishing pediatrics practice:
this task generally means participat- 1. Culturally effective care
ing in a community-based project or 2. Child advocacy
other activity. 3. Medical home
Fortunately, the skills gained dur- 4. Special populations
ing project participation translate 5. Pediatrician as a consultant/
smoothly into ACGME competen- collaborative leader/partner
cies. The Table illustrates how this 6. Educational and child care set-
teaching can be accomplished by us- tings
ing, as an example, one of the 7. Public health and prevention
projects highlighted in this series. 8. Inquiry and application
The Children’s Hospital of Philadel- For each domain, a goal and three
phia pediatric residents have engaged to six specific objectives are listed in a
in Ballroom Dance for L.I.F.E. to table with sample activities and doc-
increase physical activity for inner umentation, as well as corresponding
city fifth graders. (3) This endeavor ACGME competencies. The Table
not only allowed the residents to in this article presents one domain as
serve the community but also helped an example. We believe that commu-
them to attain numerous proficien- nity pediatrics eventually will become
cies. Faculty review of this project, an integral part of pediatric training.
with recording of feedback, progress, (Beth Rezet, MD, Associate Clinical
and outcome, fulfills the documenta- Professor of Pediatrics, Assistant Di-
tion needs for ACGME competen- rector Pediatric Residency Training
cies of medical knowledge, interper- Program, The Children’s Hospital of
sonal and communication skills, Philadelphia; Benjamin D. Hoffman,
professionalism, and systems-based MD, Associate Professor of Pediatrics,
practice. Director, Pediatric Residency Pro-
The AAP Community Pediatrics gram, University of New Mexico; Jef-

Pediatrics in Review Vol.31 No.4 April 2010 159

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pediatrics in the community

Table. Matching Community Pediatrics Training With ACGME Competencies

Goals and Objectives
Pediatrician as a consultant/collaborative leader/partner:
Pediatricians must be child health consultants in their communities. Using collaborative skills, they must be able to work
with multidisciplinary teams, community members, educators, and representatives from community organizations and
legislative bodies.
Graduates are expected to:
● Identify potential opportunities to serve as a health consultant in the community where he/she practices pediatrics and
demonstrate the ability to communicate effectively with a variety of audiences within that community.
● Describe and discuss the essential qualities of community partnerships, including shared vision, the use of
complementary strengths, the willingness to collaborate, and the development of agreed-on boundaries.
● Define and discuss principles of consensus building, including fostering inclusiveness, identifying mutual goals, setting
measurable outcomes, using effective problem-solving strategies, and negotiating toward consensus.
Sample Activity and Documentation of Resident Learning
Ballroom Dance For L.I.F.E. (Living Intelligently with Food & Exercise):
A longitudinal senior advocacy project partnering with the community.
Documentation of Resident Learning:
1. The proposal is reviewed with faculty, and feedback and revision are documented. The documentation becomes part of
each resident’s portfolio.
2. Residents are asked to reflect on the project and their involvement with the program coordinator.
3. The presentation of health lessons are documented in handouts, posters, and slides.
4. Attendance at meetings and other communication endeavors provide documentation of involvement.
5. The project is presented at an end-of-year advocacy conference to be shared with faculty, nursing staff, and residents.
6. The project is handed off to the next year’s class for ongoing, sustained involvement.
ACGME Competencies
Practice-based Learning and Improvement: Increasing physical activity in school-age children
● Systems-based Practice: Partnering with a school and school district, obtaining grant funding
● Interpersonal and Communication Skills: Providing leadership, sharing ideas and action, providing health curriculum
● Professionalism: Uncompensated sharing of expertise and resources to benefit the health of the community
● Medical Knowledge: Social determinants of health, barriers to medical care access
AGCME⫽Accreditation Council for Graduate Medical Education

frey Kaczorowski, MD, Director, requires integrating community pe- Accessed February 2010 at: http://www.
Community Pediatrics Training Ini- diatrics into the routine processes of acgme. org/acWebsite/downloads/RRC_
progReq/320_pediatrics_07012007.pdf
tiative, American Academy of Pediat- residency training. Documenting
3. Fieldston E, Aligne CA. Pediatrics in the
rics, Associate Professor of Pediatrics, what residents learned by teaching community: Ballroom Dance for L.I.F.E.:
University of Rochester) children to waltz is not yet as simple mad hot community pediatrics. Pediatr
as 1, 2, 3, but it perhaps just became Rev. 2007;28:276 –277
SECTION EDITOR’S NOTE. Dr Al- easier. (C. Andrew Aligne, MD, MPH) 4. Rezet B, Risko W, Blaschke GS. Anne E.
bert Schweitzer, the great medical Dyson Community Pediatric Training Ini-
tiative Curriculum Committee. Compe-
humanitarian, said, “Example is not
tency in community pediatrics: consensus
the main thing in influencing others,
References statement of the Dyson Initiative Curricu-
it is the only thing.” I hope that the 1. Rushton FE Jr. American Academy of lum Committee. Pediatrics. 2005;115
stories highlighted in this section to Pediatrics Committee on Community (suppl):1172–1183
date have been inspirational. The Health Services. The pediatrician’s role in 5. CPTI Competency Workgroup: Ben
challenge going forward will be to community pediatrics. Pediatrics. 2005; Hoffman, MD, Chair; Lisa Chamberlain,
115:1092–1094 MD, MPH; Susan Guralnick, MD; Amy
multiply such examples systemati-
2. Accreditation Council for Graduate Jost-Starmer, MD; Jeffrey Kaczorowski,
cally so they become the norm rather Medical Education. Program Requirements MD; Anda Kuo, MD, MPH; Gilbert Liu,
than the exception. This article for Residency Education in Pediatrics. Edu- MD; Beth Rezet, MD; Monique Evelyn,
points out that achieving this result cational Program: Community Experiences. MA

160 Pediatrics in Review Vol.31 No.4 April 2010

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Pediatrics in the Community: Integrating Community Pediatrics into Residency
Training
Beth Rezet, Benjamin D. Hoffman and Jeffrey Kaczorowski
Pediatr. Rev. 2010;31;159-160
DOI: 10.1542/pir.31-4-159

Updated Information including high-resolution figures, can be found at:

& Services http://pedsinreview.aappublications.org/cgi/content/full/31/4/159

Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
http://pedsinreview.aappublications.org/misc/Permissions.shtml
Reprints Information about ordering reprints can be found online:
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Downloaded from http://pedsinreview.aappublications.org by Enrique Mendoza-Lopez on April 2, 2010

Research and Statistics: Understanding and Identifying Bias in Research Studies
Jacky M. Jennings and Erica Sibinga
Pediatr. Rev. 2010;31;161-162
DOI: 10.1542/pir.31-4-161

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/31/4/161

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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 research and statistics

Understanding and Identifying Bias in

Research Studies
Jacky M. Jennings, PhD, MPH,* Erica Sibinga, MD*

Case Study epidemiologic studies, discuss com-

You are seeing a healthy 18-year-old pa- mon reasons for the biases, and pro-
tient who is interested in contraception vide a guide for identifying bias when
and, specifically, the “Depo shot” or me- reviewing or reading research studies.
droxyprogesterone. The information you
have gathered from her during your visit Common Types of Bias
and her medical history suggest that she Surveillance bias may result from one
is a good candidate. You take a few population being monitored more
minutes out of the visit to review the closely or more frequently than the
literature for issues of safety. Most of the general population. In the study de-
articles and reviews suggest that me- scribed, in which an association was
Author Disclosure
droxyprogesterone is a good choice for found between medroxyprogesterone
Drs Jennings and Sibinga have healthy young women, but a recent study and hypertension, the young women
disclosed no financial relationships shows an association between medroxy- taking medroxyprogesterone were
relevant to this article. This progesterone and the development of hy- monitored at a greater frequency, ev-
commentary does not contain a pertension. You look more closely at the ery 3 months, than were the young
discussion of an unapproved/ study and discover that the young women who were not taking medroxy-
women taking medroxyprogesterone had progesterone, who were monitored
investigative use of a commercial
their vital signs (including blood pres- annually. The difference in the rate of
product/device. sure) checked every 3 months when they monitoring may have introduced a
came in for the medroxyprogesterone in- surveillance bias. Because hypertension
jection. The other women included in the typically is diagnosed only after at least
study for comparison only had their vital three blood pressure readings have
signs checked every year at annual health been elevated above a certain level, the
supervision visits. You are unclear about young women who were monitored
whether the study design might have in- more frequently had more of an op-
troduced bias and how the bias might portunity to have hypertension diag-
affect your reading of the study results. nosed. The young women who were
monitored less frequently (annual vis-
Bias Defined its only) may have had the same prev-
Bias is a major issue in epidemiologic alence of hypertension, but they may
research studies and can lead to infer- have had less of an opportunity to have
ences that systematically deviate from hypertension diagnosed because of the
truth. Bias has been defined as “any lower frequency of visits. The system-
systematic error in the design, conduct atic difference in the monitoring of the
or analysis of a study that results in a young women taking medroxyproges-
mistaken estimate of an exposure’s ef- terone compared with the young
fect on the risk of disease.” (1) Bias has women not taking medroxyprogester-
been written about extensively. In this one may have resulted in a spurious
article, we review a few of the most association.
common types of bias encountered in Selection bias has two primary vari-
eties. One arises from systematic differ-
ences in the characteristics between in-
*Assistant Professor of Pediatrics, Division of
General Pediatrics & Adolescent Medicine, Johns dividuals selected for a study compared
Hopkins University, Baltimore, Md. with those not selected for the study.

Pediatrics in Review Vol.31 No.4 April 2010 161

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research and statistics

(2) In the study described, for exam- selection of the two groups also are testing), the level of measurement (in-
ple, the study sample population con- related to the likelihood of hyperten- dividual or ecologic), and the specific
sisted entirely of individuals attending sion, the study may show findings that design (cohort, retrospective cohort,
the clinic, who may differ from the are fallacious. cross-sectional, case-control, experi-
general population. Therefore, associ- Misclassification bias results from mental, quasi-experimental)?
ations found are not necessarily gener- misclassifying individuals into diseased The next step is to examine how the
alizable to the larger population. or nondiseased groups or into exposed study sample was selected. Have the
The second variety of selection bias and unexposed groups. Individuals in authors clearly stated where and from
arises from systematic differences in the the medroxyprogesterone study, who what population the study sample was
selection of cases and controls or ex- were followed less frequently (only for selected? What were the eligibility and
posed and unexposed individuals. annual visits), may have had less op-
ineligibility criteria for study selection?
Such systematic differences can lead to portunity to have hypertension diag-
How may the study sample selection
fallacious associations that really do not nosed. This circumstance may have re-
criteria have created a study population
exist but, rather, are a result of the sulted in their misclassification into the
that is representative of the population
selection bias. The medroxyprogester- nonhypertensive (nondiseased) group.
sampled? If the study population selec-
one study described serves as an exam- This type of misclassification bias is
ple of this type of selection bias. termed differential misclassification tion criteria suggest that the study
Despite the flaws in the described because the rate of misclassification dif- population is no longer representative
study, a follow-up study was designed. fers in the comparison study groups. of the larger population, it is likely that
That study prospectively follows indi- (3) Differential misclassification can some biases have been introduced and
viduals taking medroxyprogesterone lead to identifying an association that the study will have limited gener-
(exposed) and those not taking me- where one does not exist or a lack of an alizability.
droxyprogesterone (unexposed) to de- association where one does, indeed, The strategies of sampling for con-
termine the incidence of hypertension exist. trols or other comparison group is im-
in each group and to test for differ- Misclassification bias also can occur portant. Were there any systematic dif-
ences between the two groups. The as a result of nondifferential misclassi- ferences in their selection? Try to assess
eligibility criteria for the two groups fication. (3) This error occurs when whether the controls were selected
include all females between the ages of cases and controls (exposed and unex- similarly to the cases, such as similar
12 and 18 years attending a teen health posed individuals) are misclassified at eligibility and ineligibility criteria, and
clinic. Additional eligibility criteria for similar rates and the misclassification is whether the controls are comparable
the exposed group require that all fe- not related to case-control or exposure to the cases. The comparison groups
males currently are taking medroxy- status. Nondifferential misclassifica- should be similar in all characteristics
progesterone. Do you have any con- tion usually results in an attenuation of except for one: the disease or exposure
cerns about the selection criteria? a relative risk or odds ratio, resulting in under study. Finally, in considering the
One of our concerns is that in the less likelihood of an association appear- results, try to determine whether the
prospective study, individuals selected ing, although it may exist. results and any associations found have
for the study in the two groups may sufficient supporting evidence to sug-
differ systematically from one another. How to Identify Bias gest plausibility and, if available,
For example, the young women taking Knowing the more common types of whether the results are consistent with
medroxyprogesterone presumably are bias in epidemiologic research studies
those of other studies.
sexually active, are aware of medroxy- may not be enough to identify bias in
progesterone as a contraceptive op- research studies. Following are some
tion, and may be more likely to attend basic tips on how to assess a research
their clinic visits regularly. The young study for bias. References
women in the nonmedroxyproges- The most likely areas to contain bi- 1. Schlesselman JJ. Case-Control Studies:
terone group, on the other hand, may ases are in the study design and meth- Design, Conduct, Analysis. New York, NY:
not be sexually active and may differ in ods of the study, so the reader should Oxford University Press; 1982
2. Last JM. A Dictionary of Epidemiology.
other measurable and unmeasurable look closely at the description of these
3rd ed. Oxford, United Kingdom: Oxford
factors (eg, health insurance status, re- procedures. Has the study design been University Press; 1995
liable transportation to and from identified clearly, including the general 3. Gordis L. Epidemiology. Philadelphia,
clinic). If the differences related to the approach (descriptive or hypothesis Pa: WB Saunders Company; 1996

162 Pediatrics in Review Vol.31 No.4 April 2010

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Research and Statistics: Understanding and Identifying Bias in Research Studies
Jacky M. Jennings and Erica Sibinga
Pediatr. Rev. 2010;31;161-162
DOI: 10.1542/pir.31-4-161

Updated Information including high-resolution figures, can be found at:

& Services http://pedsinreview.aappublications.org/cgi/content/full/31/4/161

Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
http://pedsinreview.aappublications.org/misc/Permissions.shtml
Reprints Information about ordering reprints can be found online:
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Ethics for the Pediatrician: Pediatric Research Ethics: Evolving Principles and
Practices
Renee D. Boss
Pediatr. Rev. 2010;31;163-165
DOI: 10.1542/pir.31-4-163

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/31/4/163

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

Downloaded from http://pedsinreview.aappublications.org by Enrique Mendoza-Lopez on April 2, 2010

 ethics for the pediatrician

Pediatric Research Ethics:

Evolving Principles and Practices
Renee D. Boss, MD, MHS*

Introduction In their earliest manifestations, these

Evidence-based medicine requires a principles resulted in the exclusion of
foundation of excellent research. Yet, children from medical research. In
research in infants and children in- 1900, the Prussian Ministry of Reli-
herently poses potential risks to these gious, Educational, and Medical Af-
vulnerable populations. The aca- fairs prohibited research involving
demic pediatrician may experience an subjects who were not fully compe-
ethical conflict in his or her dual roles tent to provide consent, including
as a clinician, with a primary interest children. (1) Without legal binding
Author Disclosure
in benefiting the individual child, power, it is unclear what impact the
Dr Boss has disclosed no financial and as a researcher, with an interest in directive had on medical research at
relationships relevant to this article. advancing science and benefiting so- the time; research involving children
This commentary does not contain a ciety. Understanding the evolution likely continued. In 1931, the Reich
discussion of an unapproved/ of ethical principles for pediatric re- government refined distinctions be-
investigative use of a commercial search permits insight into current tween therapeutic and nontherapeu-
principles and the challenges of put- tic research and continued to exclude
product/device.
ting such principles into practice. children from both.
This information is critical for both Although German principles of
the pediatrician designing human re- human research ethics were among
search protocols and the pediatrician the most advanced in the world at
whose patients are enrolled in those that time, these principles clearly did
protocols. not prevent the practice of unethical
research. The Nuremburg Code of
Pediatric Research Ethics and 1947 was a response to medical ex-
Regulations in the 20th perimentation in Nazi Germany by
Century physicians in concentration camps.
Although documented cases of re- The Code defined ten principles of
search involving pediatric subjects legitimate medical research and again
date 2 and 3 centuries in the past, prohibited research involving sub-
systematic examination and regula- jects who lacked the legal capacity to
tion of human research began in the give consent, including children. (2)
early 1900s. Initially, this oversight The principles outlined in the
occurred in just a few nations. As the Nuremberg Code had no legal bind-
ethical principles of human research ing in the United States, and research
became more widely recognized over involving children continued here
time, accountability at the national throughout the mid-20th century.
or international level historically has Multiple studies exposing infants and
been uncertain. children to radiation and radioactive
The ethical principles of consent isotopes were documented in the
and noncoercion were among the 1950s and 1960s. Between 1943 and
first to be applied to human research. 1973, investigators from the Massa-
chusetts Institute of Technology and
Harvard University conducted re-
*Assistant Professor, Division of Neonatology,
Department of Pediatrics, Johns Hopkins School of search in mentally retarded children
Medicine, Baltimore, Md. living in a state-run residential facil-

Pediatrics in Review Vol.31 No.4 April 2010 163

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ethics for the pediatrician

ity. Radioactive iodine-131, radioac- the United States in 1991 by the tical application of these principles to
tive calcium, and iron tracers were Department of Health and Human research involving children and fam-
administered to the children. (3) The Services with the adoption of the ilies is complicated by children’s de-
research was not disclosed to parents, “Common Rule,” a minimal stan- velopmental variability, a heightened
and parental consent was not ob- dard of protection for human partic- concern about risk, and the complex-
tained. ipants. (6) Although institutions are ities of family decision-making.
The first document of human re- bound to the Common Rule if they
search ethics authored by members receive federal research funding, Assessing Risk Versus Benefit
of the international medical commu- most academic institutions abide by A primary function of IRBs is to as-
nity was the Declaration of Helsinki, the principles. The Rule’s three basic sess the risks and benefits associated
developed by the World Medical As- principles of research ethics include: with any research protocol, particu-
sociation in 1964. (4) The Declara- 1) Respect for persons, which en- larly those that target vulnerable
tion is considered the basis for most sures informed, voluntary consent; populations such as children. Until
contemporary guidelines for human 2) Beneficence, which maximizes recently, however, IRBs were not
research, stipulating that the welfare benefits while minimizing risks; and compelled to have members who had
of the research participant must take 3) Justice, which assures that some pediatric expertise. In 2004, an Insti-
priority over the interests of science individuals are not exploited to ben- tute of Medicine (IOM) study com-
and society. The Declaration in- efit others. Subparts specifically ad- mittee examined the regulations cov-
cluded a more complex principle for dress research in fetuses, neonates, ering clinical research with children,
research consent. It allowed for con- pregnant women (Subpart B), and with a focus on maximizing safety for
sent to be provided by legal guard- children (Subpart D). The guidelines pediatric research participants. A key
ians, thereby permitting research in for research involving children are committee recommendation was
children (Articles 23, 24). In 1983, more specific than, but not substan- that IRBs reviewing pediatric re-
the second revision acknowledged a tially different from, those of the Bel- search protocols have at least three
child’s emerging autonomy by stat- mont Report. members who have pediatric exper-
ing that assent from minors should In the past decade, the pendulum tise. (8)
be obtained whenever possible in pe- has continued to swing away from a Contemporary IRBs often mea-
diatric research (Article 25). historical prohibition against re- sure risk and benefit according to the
Over the past 50 years, standards search in children toward active pur- standards of the Common Rule. The
for the practical application of the suit of access to medical research for Common Rule states that healthy
ethical principles for human research children. In response to concerns by children may participate only in re-
have become more defined. In the the United States House of Repre- search that involves no more than
United States, the National Com- sentatives and Senate that children minimal risk, defined as “The prob-
mission for the Protection of Human were denied fair access to medical ability and magnitude of harm or dis-
Subjects of Biomedical and Behav- advances as a result of their routine comfort anticipated in the research
ioral Research was created in 1974. exclusion from research, the Na- are not greater, in and of themselves,
The Belmont Report summarizes the tional Institutes of Health began re- than those ordinarily encountered in
basic ethical principles and guidelines quiring in 1998 that children be in- daily life.” (Subpart D) (6) Healthy
developed by the Commission. (5) It cluded in all human subjects research children may participate in no other
affirmed that research involving chil- protocols unless the researchers type of research. Children who have
dren is permissible if consent is ob- demonstrate a compelling reason to disorders or conditions may be eligi-
tained from a legal guardian acting in exclude them. (7) ble for studies involving greater risk.
the child’s best interest and assent is Research entailing more than mini-
obtained from the child, if possible. Putting Pediatric Research mal risk may be approved if it poten-
The Commission established the re- Ethics Into Practice: tially offers the child a direct benefit,
sponsibility of Institutional Review Continuing Dilemmas as in a study of a novel cancer drug
Boards (IRBs) to evaluate the risks The fundamental ethical principles for treating a child who has brain-
and benefits involved in research pro- relevant to pediatric research are not stem glioma. Research involving
tocols. different from those relevant to adult more than minimal risk that has no
Human research oversight effec- research: respect for persons, justice, direct benefit to the child may be
tively was tied to research funding in and beneficence. However, the prac- approved if the study poses only a

164 Pediatrics in Review Vol.31 No.4 April 2010

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 ethics for the pediatrician

minor increase over minimal risk and with participation in the study. (9) parent wishes to enroll in a family
will add vital information about the The lower age limit for assent varies study? Can a child understand the
disorder. There is agreement that the somewhat with the individual child ramifications of diagnosing a genetic
definition of “minimal risk” should and the complexity of the research. disease years before symptoms de-
be the same for healthy and sick chil- A child’s developmental limitations velop? What potential harm does that
dren and for children whose daily in understanding potential out- information do to a child? For longi-
experiences include poverty and vio- comes, such as death from cancer, tudinal protocols, should a child’s
lence and for those whose experi- can limit frank discussions, even in assent at one developmental stage be
ences do not. older children. revisited, and how often? Can a par-
The practical applications of Many questions about consent ent consent to future research involv-
“minimal risk” and “a minor in- and assent remain. Can a healthy ing the child’s biologic samples? Ad-
crease over minimum risk” are the child be compelled by his or her par- vances in research methodology will
purview of individual researchers and ents to participate in minimal risk require careful adaptations of ethics
local IRBs. Despite attempts by the research as a lesson in altruism? For a principles and practice.
IOM to clarify these concepts and to sick child, how certain are we that the
provide more practical measures, sig- child understands the difference be-
nificant variability in risk assessment tween medical care and medical re- References
by IRBs has been documented. search? Genetics research often en- 1. Vollmann J, Winau R. Informed consent
in human experimentation before the Nurem-
tails family studies or “banking” of berg code. BMJ. 1996;313:1445–1449
Consent and Assent biologic samples; what level of coer- 2. Trials of War Criminals Before the Nurem-
Informed consent remains a complex cion does a child experience whose berg Military Tribunals Under Control Coun-
issue in research with children. It en- cil Law. Vol 10. Washington, DC: US Gov-
tails proxy consent from a parent ernment Printing Office; 1949:181–182
3. The Thyroid Studies: A Follow-up Report
(who may have his or her personal
reasons for wanting the child to par-
Summary on the Use of Radioactive Maternals in Hu-
man Subject Research that Involved Resi-
ticipate in a study) and sometimes • In contrast to a historical dents of State-operated Facilities within the
assent from the child (who will be prohibition against research Commonwealth of Massachusetts from 1943
exposed to the potential risk or ben- involving children, there is a through 1973. Boston, Mass: The Working
current emphasis on enhancing Group on Human Subject Research; 1994
efit). For protocols involving signifi- 4. World Medical Organization. Declara-
children’s access to research to
cant potential risk, both parents may prevent and treat pediatric tion of Helsinki. 1964. Br Med J. 1996;313:
be required to provide consent (who disease. 1448 –1449
may have different views on their • Healthy children may not 5. The Belmont Report. Ethical Principles
child’s participation). Because of a participate in research protocols and Guidelines for the Protection of Human
entailing more than minimal Subjects of Research. Washington, DC: De-
child’s developmental variability, partment of Health, Education and Welfare;
risk. Sick children may be
unique parent-child dynamics, and permitted to participate in 1979
the possibility of a life-limiting dis- protocols involving slightly 6. Code of Federal Regulations. Title 45
ease, research consent must accom- more risk, if they may receive Public Welfare. Part 46 Protection of Hu-
modate the complexities of family direct benefit or if vital man Subjects. Washington, DC: Depart-
information about their ment of Health and Human Services. Office
decision-making. for Human Research Protections; 2005
disorder can be gathered.
As articulated in the American • As the number of pediatric 7. Office of Extramural Research. Inclusion
Academy of Pediatrics Policy State- research participants increases, of Children Policy Implementation. Wash-
ment, the process of obtaining assent there must be a commitment to ington, DC: United Sates Department of
from a child requires: 1) confirma- providing the local, national, Health & Human Services. 1998. http://
and international oversight and grants.nih.gov/grants/funding/children/
tion that a child has a developmen- children.htm
resources necessary to maximize
tally appropriate understanding of safety. 8. Institute of Medicine of the National
her health, 2) a clear explanation of • Pediatricians, researchers, IRBs, Academies. The Ethical Conduct of Clinical
the potential outcomes of tests or and parents must work together Research Involving Children. Washington,
treatments, 3) assessment of the to refine and apply the DC: The National Academies Press; 2004
principles of respect for 9. American Academy of Pediatrics. Com-
child’s understanding and any poten- mittee on Bioethics. Informed consent, pa-
persons, justice, and
tial sources of coercion, and 4) con- beneficence to children. rental permission, and assent in pediatric
firmation of the child’s agreement practice. Pediatrics. 1995;95:314 –317

Pediatrics in Review Vol.31 No.4 April 2010 165

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Ethics for the Pediatrician: Pediatric Research Ethics: Evolving Principles and
Practices
Renee D. Boss
Pediatr. Rev. 2010;31;163-165
DOI: 10.1542/pir.31-4-163

Updated Information including high-resolution figures, can be found at:

& Services http://pedsinreview.aappublications.org/cgi/content/full/31/4/163

Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
http://pedsinreview.aappublications.org/misc/Permissions.shtml
Reprints Information about ordering reprints can be found online:
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Downloaded from http://pedsinreview.aappublications.org by Enrique Mendoza-Lopez on April 2, 2010

 Index of Suspicion
Pediatr. Rev. 2010;31;167-172
DOI: 10.1542/pir.31-4-167

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/31/4/167

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

Downloaded from http://pedsinreview.aappublications.org by Enrique Mendoza-Lopez on April 2, 2010

 index of suspicion

Case 1 Presentation Case 2 Presentation

A 7-week-old girl presents to the ED A 12-year-old African American boy
with respiratory distress. She has had presents with increasing bilateral
increasingly labored breathing over neck swelling and left-sided abdomi-
the past several hours without ac- nal pain of 3 weeks’ duration. He
companying fever, cough, or rhinor- denies fever, throat pain, weight loss,
rhea. During evaluation, she devel- or night sweats. Recently, he had a
ops apnea and requires intubation. viral infection diagnosed. When the
Chest radiography demonstrates neck swelling continued to worsen,
diffuse bilateral opacities. Echocardi- he came to the ED.
The reader is encouraged to write ography reveals dilated cardiomyop- On physical examination, his
possible diagnoses for each case before athy. During a 2-week hospitaliza- weight is 58.1 kg, temperature is
turning to the discussion. We invite
tion, her clinical status and cardiac 37.0°C, heart rate is 80 beats/min,
readers to contribute case presentations
and discussions. Please inquire first by function gradually improve on med- blood pressure is 130/58 mm Hg,
contacting Dr. Deepak Kamat at ical therapy. respiratory rate is 20 breaths/min,
[email protected]. Her cardiac function normalizes and oxygen saturation is 100% on
within months of discharge. Labora- room air. He has bilateral anterior
tory evaluation and endomyocardial cervical and supraclavicular lymphad-
Author Disclosure biopsy do not identify a cause for her enopathy as well as a spleen tip pal-
Drs Zadeh, Bernstein, Stiasny, Callaghan, cardiomyopathy. Viral titers are neg- pable below the left costal margin.
Flores, Tytko, and Mannarino and Mr ative. During this interval, she is
He has no hepatomegaly or abnor-
Moore have disclosed no financial noted to have nystagmus. Dilated
mal findings on the cardiovascular,
ophthalmologic examination and
relationships relevant to these cases. This respiratory, or neurologic examina-
MRI of the head yield normal results.
commentary does not contain a tions.
An attempt is made to take her off
discussion of an unapproved/investigative Laboratory results in the ED show
angiotensin-converting enzyme in-
use of a commercial product/device. a WBC count of 42.9⫻103/mcL
hibitors at 1 month of age. However,
(42.9⫻109/L), with 58% neutro-
after the withdrawal of medications,
phils, 11% lymphocytes, 13% mono-
her cardiac function decreases but
cytes, 5% bands, 5% myelocytes, and
normalizes within 4 weeks of reinitia-
8% blasts. His Hgb is 14.0 g/dL
Frequently Used Abbreviations tion of the medication.
(140 g/L), platelet count is
At 3 years of age, the patient has
ALT: alanine aminotransferase
slightly delayed developmental mile- 123⫻103/mcL (123⫻109/L), uric
AST: aspartate aminotransferase acid concentration is 10.6 mg/dL
stones and photophobia. Her height
BUN: blood urea nitrogen (630.5 mcmol/L), and lactate dehy-
and weight are at the 95th percentile
CBC: complete blood count drogenase (LDH) is 2,244 U/L.
for age, with a body mass index
CNS: central nervous system Leukemia is suspected, based on
(BMI) of 20 kg/cm2 (⬎97th percen-
CSF: cerebrospinal fluid his high WBC count, markedly ele-
tile). She has acanthosis nigricans at
CT: computed tomography vated uric acid and LDH values, and
the posterior neck and truncal obe-
ECG: electrocardiography presence of blasts on peripheral
sity. Follow-up ophthalmology eval-
ED: emergency department
uation performed at age 3 years smear. He is hospitalized after receiv-
EEG: electroencephalography
reveals decreased visual acuity; pho- ing two doses of recombinant urate
ESR: erythrocyte sedimentation
tophobia; high-frequency, small- oxidase for hyperuricemia in the ED.
rate
amplitude pendular nystagmus; and Two and one-half hours after admis-
GI: gastrointestinal
hypoplastic optic nerves with poor sion, his oxygen saturation is 80% on
GU: genitourinary
foveal reflex, consistent with cone room air by transcutaneous pulse
Hct: hematocrit
Hgb: hemoglobin dysfunction. The patient does not oximetry. He is transferred to the
MRI: magnetic resonance imaging have electroretinography (ERG) per- pediatric intensive care unit, where
WBC: white blood cell formed. Review of the family history additional laboratory evaluation
identifies remote consanguinity. leads to the diagnosis.

Pediatrics in Review Vol.31 No.4 April 2010 167

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index of suspicion

Case 3 Presentation
An 11-year-old boy presents to the
sports medicine clinic with a
5-month history of worsening pain
and swelling of both ankles. He has
been referred by a pediatric rheuma-
tologist who evaluated him recently.
His pain is located at the anterior
aspect of his ankles and is worse with
high-impact activities such as basket-
ball. He cannot recall an acute injury.
His mother reports that sometimes
he walks “like an old man” because of
the pain. He has had no fever, weight
loss, rash, night pain, or swelling of
any other joints. Family history is not
contributory.
Examination of his ankles reveals a
Figure 2. Radiographs of the ankles reveal an irregularity along the medial aspects of
mild effusion and pes planus with the talar domes.
valgus orientation of both ankles
(Fig. 1). Passive range of motion of
both ankles is normal and does not of his talar domes (Fig. 2), and a Cardiomyopathy during infancy
elicit any pain or crepitus. The ankles diagnosis is suspected. and toddlerhood may be a presenting
are not warm, and he is neurovascu- He is advised to stop high-impact sign of multiple syndromic and non-
larly intact. There is generalized ten- activities while his evaluation is being syndromic genetic disorders. These
derness along the anterior aspects of completed. A subsequent imaging conditions include familial dilated
his ankles in the location of his talar- study helps to delineate the diagno- and hypertrophic cardiomyopathies,
tibial joint. His gait appears normal. sis. lysosomal storage disease, disorders
CBC, comprehensive metabolic of fatty acid oxidation and carnitine
profile, urinalysis, C-reactive protein, transport, mitochondrial disorders,
and HLA-B27 results are normal. Case 1 Discussion connective tissue disorders, Noonan
Radiographs of the ankles reveal an Multiorgan disease in infancy should and related genetic syndromes, and
irregularity along the medial aspects prompt consideration of genetic dis- Alstrom syndrome. The differential
orders. In this case, the family history diagnosis for nongenetic causes of
of consanguinity as well as co- early-onset cardiomyopathy includes
occurrence of disease in more than infectious myocarditis, sequelae of
one organ system (ie, cardiac and congenital heart disease, and ar-
ophthalmologic) greatly increases rhythmias.
suspicion for a genetic disorder. The findings of nystagmus and di-
lated cardiomyopathy in this patient
Differential Diagnosis supported mitochondrial disease and
A variety of infectious and noninfec- Alstrom syndrome. The patient’s in-
tious conditions should be consid- creased BMI favored Alstrom syn-
ered in the differential diagnosis of drome rather than mitochondrial
respiratory distress in an infant. Non- disease. Normalization of cardiac
infectious causes include structural function in a fairly short period of
airway anomalies, disorders of the time after initial onset has been ob-
chest wall and diaphragm, cardiac served in Alstrom syndrome and may
disease, and neurologic disorders. reassure the clinician falsely and delay
Figure 1. Pes planus with valgus orien- Anemia and metabolic disorders also identification of an already diagnos-
tation of both hind feet. are considerations. tically challenging condition.

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 index of suspicion

Alstrom syndrome was diagnosed should include audiology, cardiol- urate oxidase and G6PD deficiency.
clinically on the basis of the patient’s ogy, endocrinology, genetics, ne- Urate oxidase was discontinued, and
history of dilated cardiomyopathy, phrology, gastroenterology, and he was started on allopurinol for hy-
photophobia, nystagmus, obesity, ophthalmology. peruricemia. In addition, the diagno-
and acanthosis nigricans. The diag- Early recognition of Alstrom syn- sis of T-cell acute lymphoblastic leu-
nosis was confirmed by molecular drome is important for optimal man- kemia was confirmed by bone
testing for the ALMS1 gene. The agement as well as counseling re- marrow studies.
sensitivity of molecular diagnosis is garding recurrence risk and
limited and is estimated to be in the prognosis. Affected families should The Condition
range of 25% to 40%. Thus, the phys- be advised that blindness is to be Methemoglobinemia is a disorder
ical examination and associated clin- expected and that early training for encountered in a number of settings
ical findings often are essential in nonvisual skills is recommended. Es- in children (Table). Methemoglobin
making this diagnosis. tablishing a healthy diet and regular is the result of heme-bound iron
exercise at an early age may help to locked in the Fe3⫹ (ferric) form, and
The Condition minimize obesity. Periodic screening this compound gives the Hgb pig-
Alstrom syndrome is an autosomal for insulin resistance also is indicated. ment a bluish-gray hue. Methemo-
recessive condition resulting from globin is unable to deliver oxygen to
mutations of the ALMS1 gene. Clin- Lessons for the Clinician tissues. It is important to identify this
ical diagnosis is based on recognition diagnosis early because the cause and
● Unexplained severe illness in an in-
of a distinctive constellation of find- treatment are distinct from other
fant should raise concern for a ge-
ings. As observed in this case, dilated causes of cyanosis.
netic disorder, especially when
cardiomyopathy, cone-rod dystro- Congenital causes of methemo-
multiple organ systems are af-
phy, truncal obesity, and insulin re- globinemia, including Hgb M vari-
fected.
sistance are common in the first de- ants, usually are diagnosed in the
● Identifying a specific genetic disor-
cade of life. ERG is considered the perinatal period. Newborns have a
der allows for accurate counseling
gold standard for detecting cone-rod relative deficiency of methemoglobin
about recurrence risk, better antic-
dystrophy because retinal examina- reductase, the enzyme responsible
ipation of expected complications,
tion may yield normal results during for conversion of methemoglobin to
and proper medical management,
infancy. Later retinal findings may native Hgb. Thus, methemoglobin-
with the aim of maximizing patient
include narrowing of retinal vessels, emia sometimes is encountered in
and family quality of life.
patchy atrophy of retinal pigment ep- the newborn intensive care unit. This
ithelium, increased visibility of cho- (Neda Zadeh, MD, Jonathan A. pathway requires reductive capacity
roidal vessels, macular sheen, and Bernstein, MD, PhD, Stanford Uni- in the form of reduced glutathione,
pale optic discs. Hyperlipidemia and versity, Stanford, Calif.) which is provided by the pentose
sensorineural hearing loss are fre- phosphate shunt.
quent findings in infancy. By the sec- The most common cause of met-
ond decade, vision loss is prominent. Case 2 Discussion hemoglobinemia is diarrheal illness
Cardiomyopathy usually develops Blood gas analysis revealed 15.3% associated with metabolic acidosis in
prior to the onset of visual distur- methemoglobin. The boy was given infancy. This condition occurs fre-
bances but may occur later in life as a dose of methylene blue as treat- quently in children 2 to 6 months of
well. A small proportion of patients ment for methemoglobinemia, but age and is believed to result from
develop renal disease due to intersti- he continued to demonstrate low ox- increased intestinal permeability to
tial fibrosis. ygen saturation and worsening of re- nitrites, increased concentrations of
spiratory distress and, therefore, was fetal Hgb (which is more susceptible
Management started on 100% oxygen via nonre- to oxidation), and age-related dimin-
There is no specific therapy for Al- breather mask, with which he ished capacity to reduce methemo-
strom syndrome. Management is showed moderate improvement. The globin. Another acquired cause of
supportive and aimed at minimizing patient was found to have low methemoglobinemia is exposure to
complications of the condition. In- glucose-6-phosphate (G6PD) activ- oxidizing medications (Table), such
terdisciplinary treatment is recom- ity. The cause of his methemoglobin- as, in this case, recombinant urate
mended. Contributing specialists emia was the administration of the oxidase. Recombinant urate oxidase

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index of suspicion

Signs and symptoms of methemo- oxidative stress. Exposure to oxi-

Causes of
Table. globinemia include a cyanotic or dants results in accumulation of free
grayish appearance, which usually is radicals, which affect red blood cell
Methemoglobinemia noted at methemoglobin concentra- RBC membranes, resulting in hemo-
in Children tions in excess of 16%, and respira- lysis. Symptoms usually develop 1 to
tory distress. The treatments for met- 2 days after ingestion of the sub-
Congenital hemoglobinemia are removal of the stance causing the oxidative stress.
● Hemoglobin M variants source, supplemental oxygen, meth- Laboratory studies demonstrate a de-
● Methemoglobin reductase ylene blue, and when severe, ex- cline in Hgb and Hct as well as serum
deficiency
change transfusion. haptoglobin. Hgb often is present in
Acquired G6PD deficiency is the most com-
the urine. Peripheral smear reveals
● Diarrheal illness of infancy mon red blood cell (RBC) enzy-
“basket” or “bucket handle” RBCs,
● Oxidant drugs mopathy, with approximately
–Urate oxidase and Heinz bodies are seen on supra-
200 million people affected. This
–Nitroprusside vital stains.
–Nitroglycerin
X-linked recessive disorder can cause
The patient can be determined to
–Nitric oxide episodic hemolytic anemia from in-
fections, medications (such as sulfa be deficient by testing for enzyme
–Silver nitrate
–Lidocaine drugs, antimalarials, or aspirin), or activity in RBCs, although tests
–Prilocaine fava beans (especially common in the yielding negative results should be
–Benzocaine repeated several weeks after an acute
–Nitrous oxides
diets of Middle Eastern cultures).
Chronic hemolysis occurs rarely. episode because concentrations can
–Dapsone
–Phenazopyridine Males are affected commonly, al- be elevated in reticulocytes, which
–Primaquine though extreme lyonization of the ordinarily are increased during an
–Chloroquine unaffected X chromosome can cause acute episode. Acute treatment may
–Acetaminophen
some women to be affected. Muta- require RBC transfusion as well as
–Cyclophosphamide
–Ifosfamide tions can occur on multiple sites in removal of the substance causing the
–Celecoxib the G6PD gene, causing a wide range oxidative stress.
● Inorganic agents of manifestations. There are two ma- When oxidized glutathione con-
–Nitrates jor mutation categories: the A vari- centrations within RBCs are low in
–Chlorates
–Copper sulfate
ant, usually seen in individuals of Af- patients who have G6PD deficiency,
● Organic nitrites/nitrates rican descent and associated with a free radicals and other oxidized sub-
–Amyl nitrite milder form of the disease, and the B stances can induce oxidation of iron
–Isobutyl nitrite variant, usually seen in individuals of in Hgb from Fe2⫹ to Fe3⫹, inducing
–Sodium nitrite Mediterranean or Middle Eastern
–Nitrogen dioxide methemoglobinemia. Patients born
–Trinitrotoluene
descent. with G6PD deficiency who receive
● Industrial/household agents G6PD is an essential enzyme in
urate oxidase can develop methemo-
–Aniline dyes the pentose phosphate pathway that
globinemia by this process. The reac-
–Nitrobenzene normally oxidizes glucose-6-
–Naphthalene (moth balls) tion catalyzed by urate oxidase causes
phosphate to 6-phosphogluconic
–Aminophenol oxidation of uric acid to allantoin and
–Nitroethane
acid through reduction of nicotin-
reduction of oxygen to H2O2-, which
amide adenine dinucleotide phos-
phate (NADP) to nicotinamide then can participate additionally in
is an enzyme that catalyzes the con- adenine dinucleotide phosphate hy- reactions that cause oxidation of
version of uric acid into allantoin to drogen (NADPH) (Fig. 3). NADPH Fe2⫹ in the Hgb molecule to its ferric
enable its excretion through the uri- subsequently is reoxidized to NADP form through reduction of H2O2 to
nary tract (allantoin is five times more through the reduction of oxidized water. Without resolution of stores
soluble than uric acid) and, thus, can glutathione to reduced glutathione. of reduced glutathione or removal
decrease serum uric acid concentra- However, enzyme deficiency causes a of the oxidative stress, a vicious cy-
tions rapidly and protect the kidneys deficiency of NADPH, leading to de- cle of methemoglobinemia and he-
in patients who have tumor lysis syn- creased concentrations of reduced molytic anemia ensues in affected
drome. glutathione and impaired response to patients.

170 Pediatrics in Review Vol.31 No.4 April 2010

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 index of suspicion

dissecans (OCD) of the talus, ex-

plaining his chronic ankle pain and
effusion.

The Condition
The term OCD is a misnomer and
originated in 1888 when Konig tried
to describe the pathologic process
that led to atraumatic loose bodies in
the knee and hip joints. He believed
that an underlying inflammatory re-
action of bone and cartilage was the
primary component of this process,
but inflammatory cells in histologic
specimens of removed osteochondral
loose bodies never have been identi-
fied. Thus, the more accepted termi-
nology today is “osteochondral le-
Figure 3. Mechanism by which urate oxidase causes methemoglobinemia in patients sion.” Nevertheless, use of the term
who have G-6-PD deficiency. OCD has persisted. We use the more
appropriate term of osteochondral
lesion of the talus (OLT).
Treatment and Prognosis ● Clinicians should be aware of the
The articular cartilage and sub-
Methylene blue (1%) in an intrave- presentation, causes, and treat-
chondral bone are involved in an
nous dose of 1 to 2 mg/kg is the ment of this disorder. Specifically,
osteochondral lesion. It is character-
treatment of choice for methemoglo- this report highlights the associa-
ized by separation of an osteochon-
binemia not associated with G6PD tion of G6PD deficiency and met-
dral fragment from the underlying
deficiency. Methylene blue helps to hemoglobinemia and the contrain-
bone. It occurs in the knee 75% of
reduce iron to its Fe2⫹ state by ac- dication to the use of methylene
the time, the elbow 6% of the time,
cepting electrons from NADPH, blue in G6PD deficiency patients.
and the ankle 4% of the time. OLT is
producing NADP in the process via ● Physicians should take great care in
rare in children and occurs more of-
the enzyme NADPH methemoglo- considering the possible adverse ef-
ten in males than in females, usually
bin reductase. This mechanism is not fects and contraindications of
presenting at 15 to 35 years of age.
feasible when G6PD is deficient. newer medications used in clinical
The cause for OLT is unknown,
This patient recovered well from practice.
although trauma, ischemia, and he-
his episode of methemoglobinemia
(David Stiasny, MD, Michael U. Cal- reditary propensity have been pro-
as well as from the early onset of
laghan, MD, Children’s Hospital of posed. Most experts believe that the
tumor lysis syndrome. He responded
Michigan, Detroit, Mich.) development of osteochondral le-
well to the induction phase of his
sions is multifactorial.
chemotherapeutic protocol for T-cell
Clinically, the patient who has
acute lymphocytic leukemia and con-
tinues to undergo treatment for his
Case 3 Discussion traumatic or atraumatic OLT pre-
Due to his ankle effusion and the sents with a few or all of the ensuing
malignancy. He has not had any re-
abnormality noted on his talar domes signs and symptoms: 1) unresolving
current episodes of methemoglobin-
on plain radiographs, MRI of the ankle pain after an inversion injury or
emia.
boy’s ankles was obtained, which re- chronic ankle pain without a specific
vealed two medial osteochondral le- injury; 2) stiffness, swelling, or re-
Lessons for the Clinician
sions in the right talus and one me- duced range of motion; 3) ecchymo-
● Methemoglobinemia is a condition dial osteochondral lesion in the left sis (rare); and 4) catching, clicking,
encountered in a number of cir- talus. These findings confirmed the locking, or giving way at the ankle
cumstances in pediatrics. diagnosis of bilateral osteochondritis joint. In children, the predominant

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index of suspicion

presenting complaints are pain and for underlying joint pathology. In suffering persistent ankle pain and
swelling. most cases, plain radiographs have effusion with or without a previous
One classification catalogs the been sufficient for diagnosing OLT. injury.
OLT into four different radiographic If the radiographs appear normal and ● It is important to inquire about a
stages: stage I involves a small area of the symptoms persist, MRI can be specific injury in any child who has
compression of subchondral bone, used to identify injuries of the sub- ankle pain because such knowledge
stage II represents a partially de- chondral bone and cartilage that may can help differentiate between an
tached osteochondral fragment, not be detected on radiographs. MRI acute ankle sprain or fracture and
stage III is characterized as a com- also can be used to assist with the an underlying disorder such as
pletely detached osteochondral frag- diagnosis of OLT identified via plain OLT.
ment remaining in the crater bed, radiograph, to aid in classification, ● Plain radiographs should be ob-
and stage IV is a displaced (loose) and to evaluate for loose fragments in
tained for any child suspected of
osteochondral fragment. the joint that usually require surgical
having OLT, followed by MRI to
removal.
assist in diagnosis, classification of
Evaluation the lesion, and detection of loose
Treatment
The history of chronic pain without a fragments.
Patients diagnosed with or suspected
specific injury combined with the ● If OLT is diagnosed, referral to an
of having OLT should be referred to
physical findings of an effusion orthopedic surgeon is warranted
an orthopedic surgeon for additional
should raise suspicion for an osteo- for additional evaluation, treat-
evaluation. Symptomatic lesions in
chondral lesion or rheumatologic ment, and possible surgical inter-
children or skeletally immature pa-
disease. Absence of constitutional vention.
tients who do not have loose frag-
symptoms in this patient made an ● For asymptomatic lesions diag-
ments on radiographic examination
infectious process less likely. In addi-
can be treated initially with a trial of nosed incidentally after an acute
tion, when any child has musculo-
conservative therapy. This regimen ankle injury, MRI may not be nec-
skeletal pain, it is vital to ask about
includes rest from high-impact activ- essary; instead, treating the acute
pain at night; an underlying onco-
ity, with an initial period of immobi- injury, monitoring for symptoms
logic process or osteoid osteoma can
lization of the limb in a cast, Cam- over time, and following with ra-
be associated with night pain.
Walker boot, or brace. diographs every 6 months to eval-
Physical examination of any pa-
This patient was provided with uate for loose fragments is suffi-
tient who has ankle problems should
ankle braces and advised to rest until cient.
begin with inspection of his or her
he was pain-free and his effusion had
stance and gait. The physical finding
resolved. At his 4-week follow-up (Charles E. Flores, MD, Pediatrics
in this patient of pes planus with val-
visit, he had no pain or effusion and Day and Night, Hamilton, NJ; James
gus alignment suggested the possi-
was permitted to resume full activi- M. Tytko, MD, Frank P. Mannarino,
bility of an abnormal distribution of
ties. He returns to the clinic every 6 MD, Jim Moore, ATC, Kettering
forces in the ankle joint. Although
months for monitoring of his condi-
this type of malalignment could con- Sports Medicine Center, Kettering,
tion.
tribute to this type of pain, it would Ohio)
not explain the ankle effusions.
Lessons for the Clinician To view Suggested Reading lists for
If ankle effusion or tenderness is
detected, plain radiographs with an- ● OLT is a rare disorder in children these cases, visit http://pedsinreview.
teroposterior, lateral, and mortise that should be considered in the aappublications.org and click on In-
views of the ankle are needed to look differential diagnosis of any child dex of Suspicion.

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 Index of Suspicion
Pediatr. Rev. 2010;31;167-172
DOI: 10.1542/pir.31-4-167

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 Adenovirus
Nasreen Bhumbra and Mary Elizabeth Wroblewski
Pediatr. Rev. 2010;31;173-174
DOI: 10.1542/pir.31-4-173

The online version of this article, along with updated information and services, is
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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of
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 in brief

In Brief
Adenovirus
Nasreen Bhumbra, MD discovered. Most children become in- disease include a pertussislike illness
Mary Elizabeth Wroblewski, MD fected with at least one strain within and bronchiolitis obliterans in young
University of Toledo the first 5 years after birth, and infec- infants. Occasionally, especially in im-
Toledo, Ohio tion is more likely in child care and munocompromised children, severe in-
overcrowded conditions. Community fection can lead to meningitis, myocar-
outbreaks of adenoviral disease have ditis, pericarditis, hemorrhagic cystitis,
Author Disclosure or hepatitis. Fulminant infections with
been recognized worldwide. Infection
Drs Bhumbra, Wroblewski, and can be asymptomatic, and reinfection multiorgan failure can occur in neo-
Serwint have disclosed no financial also is possible. nates. Gastroenteritis follows infection
relationships relevant to this In Brief. Adenovirus is transmitted from per- with enteric adenovirus serotypes 40
son to person through contact with or 41 and less often with serotype 31.
This commentary does not contain a
respiratory secretions, through fecal- More recently, severe and fatal infec-
discussion of an unapproved/
oral transmission, and via fomites. Ex- tions due to serotype 14 have been
investigative use of a commercial reported in all age groups.
posure to contaminated swimming pool
product/device. Adenoviral infections are highly
water and lakes has caused outbreaks.
contagious, but spread can be reduced
Nosocomial transmission in health-care
by using proper hand hygiene, surface
settings from personnel and improperly
Adenoviruses. Cherry JD, Chen TK. In: cleaning with bleach, and contact and
cleaned equipment also can occur. Ad-
Feigin RD, Cherry JD, Demmler- droplet precautions when treating hos-
enoviral infection can take place at any
Harrison GJ, Kaplan SL, eds. Feigin pitalized patients known to have ad-
and Cherry’s Textbook of Pediatric
time throughout the year, but out-
enoviral disease. Pharyngoconjunctival
Infectious Diseases. 6th ed. Philadel- breaks usually are concentrated in win-
fever prevention requires proper chlori-
phia, Pa: Elsevier Saunders; 2009: ter, spring, and early summer. Although
nation of swimming pools. Infection is
1949 –1972 the virus can survive on surfaces for
most communicable during the initial
Adenovirus Infections. American Acad- days, the incubation period varies from
illness, but virus shedding can persist
emy of Pediatrics. In: Pickering LK, 2 to 14 days for respiratory infections
Baker CJ, Kimberlin DW, Long SS,
long after symptoms have resolved.
and 3 to 10 days for gastrointestinal Several diagnostic techniques can
eds. Red Book: 2009 Report of the disease.
Committee on Infectious Diseases. identify an adenoviral infection. The
The respiratory and gastrointestinal most readily available tests are direct
28th ed. Elk Grove Village, Ill: Ameri-
can Academy of Pediatrics; 2009: systems are affected most commonly. antigen detection and viral isolation in
204 –206 Symptoms of respiratory tract infection clinical specimens from various body
Laboratory Approaches to the Diagnosis in children include those associated sites and fluids. A rapid antigen test for
of Adenovirus Infection Depending with a nonspecific febrile illness, upper adenovirus has a high sensitivity and
on Clinical Manifestations. respiratory tract infection, otitis media, specificity compared with viral culture.
Terletskala-Ladwig E, Leinmuller M, pharyngitis, exudative tonsillitis, and Traditional viral culture detection takes
Schneider F, Meier S, Enders M. pneumonia. Pharyngoconjunctival fever longer, with cytopathic effects com-
Infection. 2007;35:438 – 443
is characterized by fever, tonsillitis monly noted within 1 week. A modifi-
Adenoviruses. Langley JM. Pediatr Rev.
(sometimes suppurative), follicular con- cation of viral culture known as the
2005; 26:244 –248
junctivitis, coryza, and diarrhea. Cervi- rapid shell vial technique can detect
Adenoviruses, so named because they cal and preauricular lymphadenopathy virus growth 1 to 2 days after specimen
were discovered initially in adenoidal is common. The presence of a general- inoculation. Enteric serotypes 40 and
tissue, are DNA viruses that can cause a ized rash in association with fever, 41 are identified best by antigen detec-
multitude of clinically significant hu- conjunctivitis, and pharyngitis can be tion in stool specimens.
man disease syndromes. More than 50 mistaken for Kawasaki disease. Other Other identification methods in-
different strains of the virus have been clinical manifestations of adenoviral clude restriction endonuclease analysis,

Pediatrics in Review Vol.31 No.4 April 2010 173

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in brief

polymerase chain reaction, serology, such as ribavirin and cidofovir have circumstances. Because the signs and
and electron microscopy. These tech- been used with inconsistent results. symptoms of adenovirus may mimic
niques are not universally available, Kawasaki disease, differentiation be-
despite both restriction endonuclease Comment: The discovery of the clin- tween Kawasaki and adenovirus is es-
analysis and polymerase chain reaction ical manifestations of adenovirus spans sential because of the time sensitivity
being even more sensitive and specific the past century. Although viral strains of treatment for Kawasaki disease. Pre-
than antigen detection by immunoflu- initially were isolated in 1953, epidem- cise diagnosis in immunocompromised
orescence. Suitable clinical specimens ics of keratoconjunctivitis were de- patients, especially pediatric transplant
include nasopharyngeal aspirate or scribed in Austria as early as 1889, patients, can be equally important, as is
swab, throat swab or wash, rectal swab, followed by descriptions of pharyngo- diagnosis during outbreaks or for hos-
conjunctival swab or scrapings, stool, conjunctival fever in the 1920s and pital “cohorting” procedures. When di-
urine, cerebrospinal fluid, and tissue. reports of adenovirus strains that agnosis is important, polymerase chain
Specimens should be obtained as early caused enteritis in 1975. With such a reaction and shell viral culture have
as possible after the onset of disease to wide array of presentations, clinicians enhanced sensitivity over rapid immu-
increase the chances of virus detection. need to consider adenoviral infections nofluorescence tests; practitioners need
Although adenoviral infections gen- when evaluating all of these symptoms. to be aware of the types of tests
erally are self-limited and require no Although immunocompetent children available in the laboratories they use.
more than supportive care, more severe may be asymptomatic or have self-
disease can occur in immunocompro- limited disease, specific diagnosis of Janet R. Serwint, MD
mised patients, and antiviral agents adenovirus can be important in certain Consulting Editor

In Brief
Toxic Plants
Kevin Carter, MD stein A, Spyker D, Cantilena L Jr, is a valuable source of information to
Daniel R. Neuspiel, MD, MPH Green J, Rumack B, Heard S. Clin assist in management.
Department of Pediatrics Toxicol. 2008;46:927–1057 Most ingestions of plant material by
Levine Children’s Hospital of Carolinas Toxic Plant Ingestions. Graeme KA. In:
young children are of small quantity,
Wilderness Medicine. 5th ed. Phila-
Medical Center and symptoms, if present, typically are
delphia, Pa: Mosby; 2007
Charlotte, NC Plants. Palmer M, Betz J. In: Goldfrank’s short-lived and self-limited. Gastroin-
Toxicologic Emergencies. 8th ed. testinal effects are common and may
New York, NY: McGraw-Hill; 2006 be a clue to seek other, more subtle
Author Disclosure Toxic Mushroom Ingestions. Schneider signs of poisoning. Plant ingestions in
Drs Carter, Neuspiel, and Serwint S, Donnelly M. In: Wilderness Medi- older children and adolescents gener-
have disclosed no financial cine. 5th ed. Philadelphia, Pa: Mosby;
ally are intentional and of larger quan-
2007
relationships relevant to this In Brief. tity, the result of either substance ex-
This commentary does not contain a perimentation or attempted self-harm.
discussion of an unapproved/ More than 60,000 calls are made an- Autonomic toxidromes can be seen
investigative use of a commercial nually to poison control centers (PCCs) in many plant poisonings. Deadly night-
product/device. for cases of suspected plant toxicity. shade (Atropa belladonna) and Jimson
Children younger than age 6 years weed (Datura stramonium) produce at-
comprise two thirds of cases, due to ropine, scopolamine, and hyoscyamine,
their natural curiosity and limited judg- all anticholinergic toxins. Victims can
2007 Annual Report of the American
Association of Poison Control Cen- ment. Most of these exposures are be- present with classic symptoms of flush-
ters’ National Poison Data System nign; fewer than 10% result in treat- ing, hyperthermia, blurred vision, dry
(NPDS): 25th Annual Report. Bron- ment by a health professional. The PCC mouth, and hallucinations. Common

174 Pediatrics in Review Vol.31 No.4 April 2010

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 Adenovirus
Nasreen Bhumbra and Mary Elizabeth Wroblewski
Pediatr. Rev. 2010;31;173-174
DOI: 10.1542/pir.31-4-173

Updated Information including high-resolution figures, can be found at:

& Services http://pedsinreview.aappublications.org/cgi/content/full/31/4/173

Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
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 Toxic Plants
Kevin Carter and Daniel R. Neuspiel
Pediatr. Rev. 2010;31;174-175
DOI: 10.1542/pir.31-4-174

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/31/4/174

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

Downloaded from http://pedsinreview.aappublications.org by Enrique Mendoza-Lopez on April 2, 2010

in brief

polymerase chain reaction, serology, such as ribavirin and cidofovir have circumstances. Because the signs and
and electron microscopy. These tech- been used with inconsistent results. symptoms of adenovirus may mimic
niques are not universally available, Kawasaki disease, differentiation be-
despite both restriction endonuclease Comment: The discovery of the clin- tween Kawasaki and adenovirus is es-
analysis and polymerase chain reaction ical manifestations of adenovirus spans sential because of the time sensitivity
being even more sensitive and specific the past century. Although viral strains of treatment for Kawasaki disease. Pre-
than antigen detection by immunoflu- initially were isolated in 1953, epidem- cise diagnosis in immunocompromised
orescence. Suitable clinical specimens ics of keratoconjunctivitis were de- patients, especially pediatric transplant
include nasopharyngeal aspirate or scribed in Austria as early as 1889, patients, can be equally important, as is
swab, throat swab or wash, rectal swab, followed by descriptions of pharyngo- diagnosis during outbreaks or for hos-
conjunctival swab or scrapings, stool, conjunctival fever in the 1920s and pital “cohorting” procedures. When di-
urine, cerebrospinal fluid, and tissue. reports of adenovirus strains that agnosis is important, polymerase chain
Specimens should be obtained as early caused enteritis in 1975. With such a reaction and shell viral culture have
as possible after the onset of disease to wide array of presentations, clinicians enhanced sensitivity over rapid immu-
increase the chances of virus detection. need to consider adenoviral infections nofluorescence tests; practitioners need
Although adenoviral infections gen- when evaluating all of these symptoms. to be aware of the types of tests
erally are self-limited and require no Although immunocompetent children available in the laboratories they use.
more than supportive care, more severe may be asymptomatic or have self-
disease can occur in immunocompro- limited disease, specific diagnosis of Janet R. Serwint, MD
mised patients, and antiviral agents adenovirus can be important in certain Consulting Editor

In Brief
Toxic Plants
Kevin Carter, MD stein A, Spyker D, Cantilena L Jr, is a valuable source of information to
Daniel R. Neuspiel, MD, MPH Green J, Rumack B, Heard S. Clin assist in management.
Department of Pediatrics Toxicol. 2008;46:927–1057 Most ingestions of plant material by
Levine Children’s Hospital of Carolinas Toxic Plant Ingestions. Graeme KA. In:
young children are of small quantity,
Wilderness Medicine. 5th ed. Phila-
Medical Center and symptoms, if present, typically are
delphia, Pa: Mosby; 2007
Charlotte, NC Plants. Palmer M, Betz J. In: Goldfrank’s short-lived and self-limited. Gastroin-
Toxicologic Emergencies. 8th ed. testinal effects are common and may
New York, NY: McGraw-Hill; 2006 be a clue to seek other, more subtle
Author Disclosure Toxic Mushroom Ingestions. Schneider signs of poisoning. Plant ingestions in
Drs Carter, Neuspiel, and Serwint S, Donnelly M. In: Wilderness Medi- older children and adolescents gener-
have disclosed no financial cine. 5th ed. Philadelphia, Pa: Mosby;
ally are intentional and of larger quan-
2007
relationships relevant to this In Brief. tity, the result of either substance ex-
This commentary does not contain a perimentation or attempted self-harm.
discussion of an unapproved/ More than 60,000 calls are made an- Autonomic toxidromes can be seen
investigative use of a commercial nually to poison control centers (PCCs) in many plant poisonings. Deadly night-
product/device. for cases of suspected plant toxicity. shade (Atropa belladonna) and Jimson
Children younger than age 6 years weed (Datura stramonium) produce at-
comprise two thirds of cases, due to ropine, scopolamine, and hyoscyamine,
their natural curiosity and limited judg- all anticholinergic toxins. Victims can
2007 Annual Report of the American
Association of Poison Control Cen- ment. Most of these exposures are be- present with classic symptoms of flush-
ters’ National Poison Data System nign; fewer than 10% result in treat- ing, hyperthermia, blurred vision, dry
(NPDS): 25th Annual Report. Bron- ment by a health professional. The PCC mouth, and hallucinations. Common

174 Pediatrics in Review Vol.31 No.4 April 2010

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 in brief

garden vegetables in the Solanum ge- Ingestion of mushrooms also may Parents should be aware of the
nus, including tomatoes, potatoes, and have fatal consequences. Species that types of plants kept inside the home
eggplants, also can cause anticholin- harbor amatoxins (Amanita) and re- as well as in any landscaping in the
ergic symptoms when blossoms or un- lated compounds typically cause de- yard or neighborhood. Unknown plants
ripe buds are ingested. Physostigmine layed onset (6 hours) of nausea, vom- or shrubs, especially those that have
may be indicated to treat severe or iting, and diarrhea. A second latent bright colors or other features that
persistent symptoms. period is followed by acute and possibly might seem inviting to the curious
A variety of central nervous system fulminant hepatitis beginning 48 to child, can be identified with the help of
(CNS) responses follow plant ingestion. 72 hours after ingestion. Effective de- a local nursery.
Hallucinations are common with mari- contamination and therapies directed
juana ingestion by children and with at the toxins generally are ineffective,
Comment: Although pediatricians
ingestion of nutmeg or morning glory and supportive care, including liver
may consider drug ingestion readily in
seeds by teenagers. Tobacco plant ex- transplant if necessary, is the mainstay
the differential diagnosis for certain
posure results in parasympathetic of therapy. Other species of mushrooms
signs and symptoms, I dare say we do
symptoms (miosis, bronchorrhea, gas- can cause hallucinations, muscarinic
not consider toxic plant exposures as
trointestinal distress) as well as neuro- toxicity, or general gastrointestinal ir-
often as we should, especially in
muscular derangement due to un- ritation. Although most mushroom spe-
younger children. Plant exposures in
checked nicotinic receptor response. cies are nontoxic, caretakers of a child
children 6 years of age and younger
Cardioactive glycosides are pro- who has eaten or who is suspected of
accounted for 4.6% of calls to PCCs,
duced by foxglove (Digitalis), but they eating any wild mushroom should call
and this figure only represents in-
also are found in lily of the valley the PCC for guidance.
stances when exposure was considered.
(Convallaria) and oleander (Nerium and The PCC can be an important aid in
The prevalence, therefore, is probably
Thevetia). Symptoms cannot be distin- medical decision making, particularly
underestimated. Another important as-
guished from those of digoxin toxicity with symptomatic patients for whom
pect to consider is the overlap of pre-
and include hyperkalemia, CNS depres- the identity of the plant is unknown.
sentations between herbal remedies
sion, and cardiac conduction abnormal- Electronic transmission of digital im-
and plant exposures, another area
ities. Treatment with digoxin-specific ages may allow the PCC and expert
where we need to expand our question-
antibody fragments can be lifesaving. botanists to identify the offending
ing. Consideration of toxic plant expo-
Potentially dangerous toxins can plant quickly and confidently and pro-
sures in our patients reinforces the
show up in unexpected sources. Berries vide data on managing the exposure.
importance and value to parents and
of the holly and mistletoe plants, com- Management of a potentially lethal
pediatricians of PCCs and the vast
mon in holiday decorations, carry a risk exposure always should include com-
knowledge of diagnosis and treatment
of significant gastrointestinal distress. munication with a toxicologist. In these
their staff impart. The website http://
Amygdalin, contained in seeds and pits situations, establishing control of air-
www.aapcc.org contains useful infor-
of Prunus species fruits (cherries, apri- way, breathing, and circulation should
mation about poison centers.
cots, peaches, apples, plums), generates be priorities. Aggressive decontamina-
cyanide when metabolized. The result- tion, with gastric emptying, activated
ing inhibition of cellular respiration can charcoal, and possibly whole bowel ir- Janet R. Serwint, MD
be lethal. rigation, may be warranted. Consulting Editor, In Brief

Pediatrics in Review Vol.31 No.4 April 2010 175

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 Toxic Plants
Kevin Carter and Daniel R. Neuspiel
Pediatr. Rev. 2010;31;174-175
DOI: 10.1542/pir.31-4-174

Updated Information including high-resolution figures, can be found at:

& Services http://pedsinreview.aappublications.org/cgi/content/full/31/4/174

Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
http://pedsinreview.aappublications.org/misc/Permissions.shtml
Reprints Information about ordering reprints can be found online:
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Downloaded from http://pedsinreview.aappublications.org by Enrique Mendoza-Lopez on April 2, 2010

 Diagnosis and Management of Dengue Fever in Children
Ashlesha Kaushik, Carol Pineda and Helen Kest
Pediatr. Rev. 2010;31;e28-e35
DOI: 10.1542/pir.31-4-e28

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/31/4/e28

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

Downloaded from http://pedsinreview.aappublications.org by Enrique Mendoza-Lopez on April 2, 2010

Article infectious diseases

Diagnosis and Management of Dengue Fever

in Children
Ashlesha Kaushik, MD,*
Objectives After completing this article, readers should be able to:
Carol Pineda, MD,*
Helen Kest, MD, MPH, 1. Describe the epidemiology and clinical spectrum of dengue viral infections.
CPH † 2. Recognize when to consider dengue in the differential diagnosis of acute fever.
3. Discuss the diagnosis and management of this common tropical illness.
4. Identify other diseases that can mimic dengue viral infections.
Author Disclosure
Drs Kaushik, Pineda,
and Kest have Case 1 Presentation
disclosed no financial A 17-year-old Hispanic girl presents with a 5-day history of temperature of 39.4°C to 40.5°C
relationships relevant and a 4-day history of severe bifrontal and intermittent headaches. She also has a 3-day history
to this article. This of malaise, generalized body aches, and mild epigastric pain. On the day of admission, she
commentary does not
develops a dark reddish-purple, nonpruritic, and nonblanching rash over her arms and thighs
and is brought to the emergency department. There is no cough, sore throat, vomiting, or
contain a discussion
diarrhea. She denies illicit drug use, tick exposure, sexual activity, or allergies.
of an unapproved/ On physical examination, the girl appears alert, oriented, and in no acute distress. Her
investigative use of a temperature is 38.5°C, heart rate is 119 beats/min, respiratory rate is 18 breaths/min, and
commercial product/ blood pressure is 130/68 mm Hg (90th to 95th percentile). Capillary refill time is less than
device. 2 seconds. A petechial rash is present over her arms and anterior thighs. She has mild epigastric
tenderness, with no rebound tenderness, guarding, hepatosplenomegaly, or masses. Tourniquet
test is positive. Kernig and Brudzinski signs are negative. The remainder of the physical
examination findings are normal.
Her white blood cell count is 3.5⫻103/mcL (3.5⫻10 9/L) with 59% neutrophils, 33%
lymphocytes, 6% monocytes, and 1% eosinophils; hemoglobin is 13.4 g/dL (134 g/L); hematocrit
is 39.6% (0.396); platelet count is 126⫻103/mcL (126⫻10 9/L); and erythrocyte sedimen-
tation rate is 13 mm/hour. The electrolytes, urinalysis, and coagulation profile are normal.
The stool is negative for blood. Liver function test results include a protein concentration of
6.9 g/dL (69 g/L), albumin of 4 g/dL (40 g/L), aspartate aminotransferase of 39 U/L,
alanine aminotransferase of 18 U/L, alkaline phosphatase of 103 U/L, total bilirubin of
0.9 mg/dL (15.4 mcmol/L), and direct bilirubin of 0.3 mg/dL (5.1 mcmol/L). Thick and
thin smears are negative for malarial parasites.
The patient is admitted for monitoring, and intravenous hydration is started. On addi-
tional questioning, she states that she had returned from the Dominican Republic yesterday.
Additional serum testing reveals the diagnosis of classic dengue fever. Viral serology reveals
a dengue virus immunoglobin M (IgM) enzyme-linked immunosorbent assay (ELISA) titer
of 4.93 (negative, ⬍1.11) and dengue virus IgG ELISA titer of 9.69 (negative, ⬍1.11).
Platelet counts and hematocrit values are monitored every day. On the second hospital day, her
platelet count declines to 96⫻10 3/mcL (96⫻10 9/L) with no evidence of bleeding. The counts
increase to 109⫻10 3/mcL (109⫻10 9/L) on the third hospital day and 121⫻10 3/mcL
(121⫻10 9/L) on the following day. Her hematocrit value remains stable at 40% (0.40). Three
days after hospitalization, the fever resolves, the patient has stable vital signs, and she is
discharged.

Case 2 Presentation
A 15-year-old boy who has a 5-day history of a temperature of 39.0°C to 39.5°C with chills and
severe pain in both legs is admitted to the hospital for evaluation. Three days ago, he developed

*Department of Pediatrics, St Joseph’s Children’s Hospital, Patterson, NJ.

†
Division of Pediatric Infectious Disease, Department of Pediatrics, St. Joseph’s Children’s Hospital, Patterson, NJ.

e28 Pediatrics in Review Vol.31 No.4 April 2010

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 infectious diseases dengue fever

nausea, headache, myalgias, and severe fatigue. He denies is afebrile. By the sixth hospital day, the child is feeling better
any vomiting, somnolence, abdominal pain, or neck pain. and has stable vital signs. His hematocrit and platelet
Findings on past and family histories are unremarkable. counts have improved, and he is discharged the following
Physical examination reveals a tired-looking adolescent day.
who has a temperature of 39.4°C, heart rate of 95 beats/
min, respiratory rate of 16 breaths/min, and blood pressure Case 3 Presentation
of 120/70 mm Hg (75th to 90th percentile). No neck An 11-year-old Hispanic boy develops a temperature of
stiffness, rash, or lesions are apparent. After the blood 39.1°C with diarrhea. Two days later, the diarrhea sub-
pressure cuff is removed, he develops petechiae all over his sides, but he develops severe abdominal pain and vomiting,
antecubital fossa. He has shotty cervical lymphadenopathy. becomes increasingly lethargic, and is brought to the emer-
All other physical findings are normal. gency department. His parents state that he has been com-
Initial laboratory results reveal a white blood cell count plaining of severe back pain and headache. They deny any
of 3.6⫻103/mcL (3.6⫻10 9/L) with 55% neutrophils, 29% medication use, previous hospitalization, or tick bites.
bands, 14% lymphocytes, and 10% monocytes; hemoglobin of Physical examination reveals a sick-looking boy who is
15.7 g/dL (157 g/L); hematocrit of 42.2% (0.422); and somnolent but arousable. His temperature is 40.0°C, heart
platelet count of 87⫻103/mcl (87⫻10 9/L). Electrolytes rate is 140 beats/min, respiratory rate is 26 breaths/min,
and fibrinogen values are normal. Prothrombin time is blood pressure is 80/50 mm Hg (⬍5th percentile), and
15.2 seconds, international normalized ratio (INR) is 1.2, Glasgow Coma Scale score is 12. He has a weak pulse, cold
and activated partial thromboplastin time is 41.2 seconds. extremities, and a capillary refill time of 6 to 8 seconds. His
D-dimers are 3.3 mcg/mL (normal, ⬍0.50 mcg/mL). abdomen is diffusely tender, with the liver enlarged 4 cm
Thick and thin smears for malarial parasites are negative. below the right costal margin. A petechial rash is present
Liver function tests include a total protein of 6.2 g/dL over his chest and trunk. Meningeal signs are absent. All
(62 g/L), albumin of 3.4 g/dL (34 g/L), aspartate ami- other physical findings are unremarkable.
notransferase of 587 U/L, alanine aminotransferase of Initial laboratory results reveal a white blood cell count
412 U/L, alkaline phosphatase of 157 U/L, total bilirubin of 2.5⫻103/mcL (2.5⫻10 9/L) with 58% neutrophils, 8%
of 1 mg/dL (17.1 mcmol/L), and direct bilirubin of bands, 10% lymphocytes, 18% atypical lymphocytes, and
0.2 mg/dL (3.4 mcmol/L). 4% monocytes; hemoglobin of 14 g/dL (140 g/L); hemato-
Additional questioning reveals that the boy had been in crit of 42% (0.42); and platelet count of 27⫻103/mcL
the Dominican Republic for 2 weeks and returned the day (27⫻10 9/L). Electrolyte values are normal, and urinalysis
his fever started. He is admitted with a diagnosis of sus- shows trace blood. Coagulation profile reveals a prothrom-
pected dengue hemorrhagic fever. bin time of 17.8 seconds, activated partial thromboplastin
Viral studies sent on admission reveal an acute-phase time of 44 seconds, D-dimers of 4.4 mcg/mL (normal,
dengue virus IgM ELISA titer of 1.8 (negative, ⬍1.11) ⬍0.50 mcg/mL), and fibrinogen value of 200 mg% (nor-
and a dengue virus IgG ELISA titer of 8.8 (negative, mal, 183 to 503 mg%). Liver function tests reveal a total
⬍1.11). On the second hospital day, he has one episode of protein of 5.6 g/dL (56 g/L), albumin of 3 g/dL (30 g/L),
vomiting containing blood. Laboratory results reveal a aspartate aminotransferase of 455 U/L, alanine amino-
platelet count of 37⫻103/mcL (37⫻10 9/L), prothrombin transferase of 324 U/L, alkaline phosphatase of 140 U/L,
time of 16.2 seconds, INR of 1.2, and partial thromboplas- total bilirubin of 1.2 mg/dL (20.5 mcmol/L), and direct
tin time of 42.9 seconds. bilirubin of 0.1 mg/dL (1.7 mcmol/L). Smears for malar-
On the third hospital day, due to another episode of ial parasites are negative.
hematemesis and a low platelet count of 21⫻103/mcL The parents share their concern about multiple relatives
(21⫻10 9/L), he receives a platelet transfusion. On the who had self-limiting fevers and body aches in the Carib-
same day, he develops diarrhea and mild lower abdominal bean, from where they had returned 4 days ago. The child
tenderness. He has a hemoglobin of 18.3 g/dL (183 g/L) has been to the Caribbean twice within the past 2 years.
and hematocrit of 52.6% (0.53), which is a 20% increase The clinical and laboratory picture suggest dengue shock
from the baseline. Liver function tests yield normal results syndrome. The boy is admitted to the intensive care unit
except for an albumin of 3.1 g/dL (31 g/L). Ultrasonog- and started on intravenous hydration. On the second hos-
raphy of the abdomen shows normal results, and stool ex- pital day, he has two episodes of vomiting containing blood
amination for parasites and culture produces negative and develops frank hematuria. Laboratory results show a
results. Serum amylase and lipase values are normal. On platelet count of 14⫻103/mcL (14⫻10 9/L), prothrombin
the fifth hospital day, the diarrhea subsides and the patient time of 19.5 seconds, INR of 1.2, and partial thromboplas-

Pediatrics in Review Vol.31 No.4 April 2010 e29

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infectious diseases dengue fever

tin time of 52 seconds. His hematocrit is 33% (0.33), a 22% findings, and laboratory markers. There are four major
decrease from the initial value. He receives platelet and clinical syndromes: 1) undifferentiated fever, 2) dengue
fresh frozen plasma transfusions. There is no recurrence of fever, 3) dengue hemorrhagic fever (DHF), and 4) den-
bleeding, and by the fourth hospital day, he is hemodynam- gue shock syndrome (DSS). Most cases are mild. How-
ically stable and has improvement in hematocrit and plate- ever, DHF case fatality rates can reach 20% if not treated
let counts (34% [0.34]and 90⫻103/mcL [90⫻10 9/L], appropriately or in a timely manner. It is highly likely
respectively). On day 5, he continues to be afebrile, is feeling that dengue cases are unreported in the United States
better, and is discharged. Viral studies sent on the third because physicians often do not include it in the differ-
hospital day are strongly positive for dengue virus infec- ential diagnosis of travelers returning from endemic
tion, with a dengue virus IgM ELISA titer of 5.4 (nega- areas. (6)(7)
tive, ⬍1.11) and dengue virus IgG ELISA titer of 12
(negative, ⬍1.11).
Pathogenesis
Dengue virus is an arbovirus of the flavivirus family that
Introduction has four different serotypes (DEN-1, -2, -3, and -4). Its
According to the World Health Organization, about
classification is based on biologic and immunologic char-
50 million dengue infections and 25,000 deaths occur
acteristics. (8) Because there is no cross-protection be-
worldwide annually, making dengue one of the most
tween the different serotypes, lifetime immunity is ob-
important arthropod-borne viral diseases in humans. All
tained only after infection by each type. Therefore,
continents are endemic for dengue except Europe. An
persons living in endemic areas may be infected more
estimated 2.5 billion of the world’s population live in
than once with different serotypes. Genetic variation
areas at risk for epidemic dengue transmission, and it
within each serotype confers distinct virulence capacity
remains a leading cause of morbidity and mortality
and epidemic potential that may result in epidemics by
among children in some Asian countries. Most of the
the same serotype in different years and locations. (5)
severe cases and deaths occur in children younger than
After repeated infections, the chance of developing DHF
15 years of age. (1)(2)
and DSS increases. (9)
The first reported epidemic occurred in the French
West Indies in the 17th century, (3) but it was the
Southeast Asia pandemic created by the ecological dis- Mosquito Cycle
ruption that followed World War II that is credited for its A aegypti is the primary vector responsible for transmis-
worldwide spread. Over the past several decades, the sion; other vectors include A albopictus, A polynesiensis,
gradually increasing incidence has been attributed to and A niveus. A aegypti is primarily a daytime feeder. It
multiple factors, including global demographic changes breeds mainly in artificial water collections created by
with associated uncontrolled urbanization and popula- poor sanitation or infrastructure such as jars, plates,
tion growth, overcrowding with inappropriate sanita- flowerpots, glass containers, drainpipes, and cupboards.
tion, infrastructural problems, lack of preventive pro- Although transmission is year round, the rainy season
grams for epidemic transmission, and poor mosquito creates ideal larval habitats and ecologically suitable
control efforts. (4)(5) Most cases in the United States are niches for mosquito breeding and subsequent endemic-
imported from other countries. Currently, dengue fever ity. (10)
is the most common cause of fever in travelers returning The life cycle begins when an uninfected female mos-
from certain high-risk areas that include the Caribbean, quito takes blood from an infected person during the
Central America, and South Central Asia. viremic phase of illness. Within the mosquito’s digestive
Areas bordering Mexico and southeastern states serve system, the virus replicates for 8 to 12 days (extrinsic
as niches for imported and locally acquired cases of incubation period). When this infective mosquito bites
dengue due to population migration. According to the again, it transmits the virus to another person by inject-
Centers for Disease Control and Prevention, Aedes ae- ing its salivary fluid. Once the virus is in the body, it
gypti and Aedes albopictus are the established vectors in replicates in target organs and is released into the blood
these areas and are a potential threat for dengue trans- (intrinsic incubation period). Symptoms appear 3 to
mission throughout the United States. 14 days after inoculation and may last up to 7 days or
Dengue fever is caused by the dengue virus and is more. Dengue should not be considered in the differen-
transmitted by the bite of an infective female Aedes tial diagnosis of a patient who develops fever more than
mosquito. The diagnosis is based on history, physical 2 weeks after leaving a dengue endemic area. (2)

e30 Pediatrics in Review Vol.31 No.4 April 2010

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 infectious diseases dengue fever

Clinical Presentation of Dengue Infection and occasionally is described as having two peaks or
Infection with dengue viruses in children can have varied being “saddle-backed,” that is, the initial 2 to 5 days of
presentations, ranging from asymptomatic to severe fever are followed by 1 to 2 days of defervescence, after
shock and death. Table 1 lists definitions of probable and which the temperature may rise again. (8)(14)(15)
confirmed dengue syndromes. (2)(11) Dengue fever rash may be erythematous, macular, or
maculopapular, and lymphadenopathy may be present.
Undifferentiated Fever Infants and young children usually present with nonspe-
Patients are mildly symptomatic, with nonspecific flulike cific symptoms such as fever, runny nose, rash, and
symptoms. This pattern usually occurs during a primary diarrhea; older children and adults have the classic break
infection with dengue viruses and may be the most bone fever, as described previously. Dengue fever can
common manifestation. have hemorrhagic manifestations without including the
entire constellation of DHF. The hemorrhagic manifes-
Dengue Fever tations associated with dengue fever include a positive
Classic dengue fever is characterized by abrupt onset of tourniquet test (Figure), petechiae/purpura, mucosal
high-grade fever (temperature of 38.9°C to 40.6°C) bleeding, and gastrointestinal bleeding. (8)(14) The
associated with headache (especially retroorbital pain child in the first case had petechiae and a positive tour-
that worsens with eye movement), severe myalgia, ar- niquet test.
thralgia, nausea/vomiting, altered taste sensation (often Most patients who have dengue fever recover un-
described as metallic), and sometimes a rash. (2)(12)(13) eventfully. Rarely, patients may present with uncommon
The constellation of symptoms of severe and incapacitat- manifestations such as seizures, paresis, meningitis, and
ing body ache, back pain, and arthralgia often is called mental status changes that can include lethargy, somno-
“break bone fever.” Fever may last from 2 days to 1 week lence, and coma.

Table 1. WHO and CDC Definitions of Dengue Clinical Syndromes (2)(11)

Type Clinical Case Definition

Dengue Fever Probable dengue fever: Fever of 2 to 7 days’ duration, with two or more of the
following:
Headache, retroorbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations,
leukopenia, and supportive serology or occurrence at the same location and time as
other confirmed cases of dengue.
Confirmed dengue fever: Confirmed by laboratory criteria (isolation of the dengue
virus, demonstration of the dengue virus antigen, serology, or genomic sequence).
Dengue Hemorrhagic Fever All of the following criteria must be fulfilled:
(DHF) 1. Fever or history of acute fever, lasting 2 to 7 days, occasionally biphasic
2. Hemorrhagic manifestations in the form of at least one of the following:
- A positive tourniquet test
- Petechiae, ecchymosis, or purpura
- Bleeding from the mucosa or injection sites
- Hematemesis, melena, hematochezia, hematuria, increased menstrual flow
3. Thrombocytopenia (<100ⴛ103/mcL [100ⴛ109/L])
4. Objective evidence of plasma leakage caused by increased vascular permeability, as
evidenced by one or more of the following:
- A rise in the hematocrit (defined as >20% over baseline)
- A drop in hematocrit following volume replacement treatment <20% of baseline
- Low albumin or
- Pleural effusion, ascites, or other effusions
Dengue Shock Syndrome DHF plus evidence of circulatory failure manifested by shock or all of the following:
(DSS) - Rapid and weak pulse
- Narrow pulse pressure (<20 mm Hg) or hypotension for age (systolic pressure
<80 mm Hg for children younger than 5 years of age or <90 mm Hg for
children 5 years of age and older)
- Cold, clammy skin and altered mental status
CDC⫽Centers for Disease Control and Prevention, WHO⫽World Health Organization

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infectious diseases dengue fever

Grades of Dengue
Table 2.

Hemorrhagic Fever (11)

Grades Definitions
Grade I Fever and nonspecific constitutional
symptoms, with a positive
tourniquet test being the only
hemorrhagic manifestation
Grade II Grade I manifestations plus
spontaneous bleeding
Grade III* Circulatory failure manifested as
rapid /weak pulse, with cold skin,
restlessness, and narrow pulse
pressure or hypotension
Grade IV* Profound shock with nondetectable
pulse or blood pressure
Figure. Positive tourniquet test.
* Grades III and IV constitute dengue shock syndrome.
Dengue Hemorrhagic Fever
DHF is a potentially fatal illness marked by high fever,
symptoms and has a high mortality rate of 10% to 47%.
hemorrhagic manifestations, and evidence of plasma leak-
(2)(17) Warning signs of DSS include severe abdominal
age (Table 1). DHF begins with the sudden onset of a high
pain; persistent vomiting (with or without blood);
temperature that lasts 2 to 7 days, with accompanying chills,
abrupt change of temperature from fever to hypother-
flulike constitutional symptoms, and a flushed face. As the
mia; and altered mental status, including irritability,
fever subsides, patients may recover or progress to a state of
somnolence, or obtundation. In DSS, capillary leakage
plasma leakage. Features of plasma leakage include ascites,
and loss of intravascular volume result in shock rather
pleural effusion (right-sided in most cases), and rarely,
than in hemorrhage (Table 1). (11)
pericardial effusion associated with a high mortality. (8)(16)
If untreated, the condition may deteriorate rapidly to pro-
found shock and death within hours. (12) The hemorrhagic
Complications of Dengue Infections
Severe dengue complications include liver dysfunction, en-
manifestations of DHF include skin hemorrhages such as
cephalitis, cardiomyopathy (usually reversible), pancreatitis,
petechiae, purpura, and ecchymoses; bleeding from mucous
acalculous cholecystitis, peripheral neuropathy, and acute
membranes (epistaxis, gingival bleeding); and bleeding from
renal failure. (8)(13)(18) Liver involvement is one of the
the gastrointestinal, vaginal, and urinary tracts. These manifes-
most important gastrointestinal manifestations, especially
tations usually occur after the fever subsides, with the gastro-
with infection by DEN-3 and DEN-4 serotypes, (19) and it
intestinal tract being the most common site of bleeding.
can present as acute hepatitis with elevated liver enzyme
DHF is classified into four grades according to severity
values (aspartate aminotransferase being more significantly
(Table 2). Laboratory abnormalities associated with DHF
elevated than alanine aminotransferase), jaundice, altered
include thrombocytopenia (⬍100⫻103/mcL [100⫻109/
mental status, seizures, and severe hypoglycemia. Transam-
L]), leukopenia, prolonged prothrombin time and acti-
inase values are highest on day 9 of illness and normalize
vated partial thromboplastin time, elevated fibrin degrada-
within 3 weeks. (18) Central nervous system (CNS) disease
tion products, low serum albumin, and elevated liver
is attributed to various factors, including direct viral inva-
enzymes, as in the patient in case 2. Atypical lymphocytosis
sion of the CNS, liver failure, electrolyte disturbances, and
(⬎15%) and electrolyte abnormalities also may be seen.
cerebral edema. Some case series have reported a high
Recovery from DHF usually is uneventful, marked by a
mortality rate (up to 20%) in children who develop enceph-
return of appetite and often a recovery rash (erythematous
alopathy. (20) (21)
petechial rash with islands of clearing). (2)(8) In a few
patients, symptoms such as weakness and malaise may per-
sist for several weeks after the acute illness has subsided.
Diagnosis
Dengue infection can be diagnosed via serologic meth-
Dengue Shock Syndrome ods, virus isolation, or molecular methods (Table 3).
Most patients who have DHF do not develop DSS. DSS Table 4 shows the characteristics of similar infections that
occurs during defervescence 3 to 6 days after the onset of should be in the differential diagnosis of dengue fever.

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 infectious diseases dengue fever

Table 3. Methods of Laboratory Diagnosis of Dengue Infection

Diagnostic Method Comments
Serology:
● ELISA The IgM ELISA is the most common test for serologic diagnosis. Sensitivity is
● Hemagglutination inhibition test 83.9% to 98.4% and specificity is 100%. IgM antibodies remain detectable
● Complement fixation tests from day 5 to 4 to 5 weeks of illness. (2)(22)
● Antigen capture enzyme
immunosorbent assay
Virus Isolation: Virus isolation methods are employed to determine the serotype of the
● Mosquito cell cultures infecting virus. Because this procedure takes 2 weeks and is costly, it is
● Mosquito inoculation: used primarily for research purposes. Mosquito inoculation technique is
Toxorhynchites amboinensis more sensitive than cell cultures and is the preferred method of virus
or Aedes albopictus are isolation. (23)
used commonly for inoculation
Molecular Methods: RT-PCR is a rapid method of diagnosis (allowing detection within 24 hours).
● RT-PCR for viral RNA It is more sensitive than virus isolation and useful in the early phase of
illness when antibodies are not circulating. However, this method is costly
and needs expertise. (2)(24)
ELISA⫽enzyme-linked immunosorbent assay, IgM⫽immunoglobulin M, RT-PCR⫽reverse transcription polymerase chain reaction

Table 4. Differential Diagnosis of Dengue Fever

Disease Classic Signs and Symptoms Differentiating Features of Dengue
Influenza Fever, headache, myalgias, malaise, respiratory tract ● Similar to undifferentiated fever form
symptoms. (25) ● Dengue should be included in differential
diagnosis when there is a history of travel
to endemic area
Malaria High fever, chills, rigor, sweats that may be ● Fever can have a biphasic pattern but is
paroxysmal. Vomiting, diarrhea, cough, arthralgias, not cyclic
abdominal and back pain, hepatosplenomegaly, ● Thrombocytopenia may be present in
anemia, and thrombocytopenia are common. (26) both; diagnostic studies are needed
Typhoid fever Fever, headache, malaise, anorexia, abdominal pain, ● Typical break bone features are absent
hepatosplenomegaly, rose spots, altered mental ● Severe disease may be difficult to
status. (27) differentiate from DSS, and diagnostic
studies may be needed
Leptospirosis Initial phase: Fever, chills, headache, vomiting, transient ● Biphasic presentation in leptospirosis and
rash, myalgias of calf and lumbar regions, and eye findings
conjunctival discharge (nonpurulent). Second phase: ● Usually exposure to animals/farms
meningitis, liver disease, and renal failure. (28) ● Travel history to high-risk areas may be
absent in leptospirosis
Meningococcemia Fever, chills, malaise, prostration, rash (macular, ● DHF or shock due to dengue may be
maculopapular, petechial). Can progress to fulminant undistinguishable from meningococcemia;
with disseminated intravascular coagulation, purpura, it is reasonable to manage as
shock, and death. (29) meningococcemia, and dengue fever
should be considered as a possibility in
returned travelers
Chikungunya Fever, rash (petechial or maculopapular) of trunk or ● Febrile illness in dengue does not last as
limbs, arthralgias, arthritis. Other: Headache, long and is not followed by arthralgic
conjunctivitis, and photophobia. disease, which is prolonged in
Travel history is usually positive for Africa or Asia. (30) chikungunya
Rubella Rash, posterior auricular or suboccipital ● Rash does not have the cephalocaudal
lymphadenopathy, headache, conjunctivitis, distribution of rubella; similar to
polyarthritis. (31) undifferentiated fever form
DHF⫽dengue hemorrhagic fever, DSS⫽dengue shock syndrome

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infectious diseases dengue fever

Treatment travel, global migration, and climate change continue to

Treatment is supportive. Fever is controlled with acetamin- affect this global reemergence. (32) Dengue never
ophen. Nonsteroidal anti-inflammatory agents should be should be overlooked in countries whose prevalence is
avoided due to their anticoagulant properties and risk of low, such as the United States. Dengue fever continues
Reye syndrome in children. Most cases of dengue fever to appear, and the possibility of epidemics exists even
are mild and occur as undifferentiated fever or classic after several years of sporadic outbreak.
dengue fever.
Early recognition and treatment decreases morbidity
and mortality. Home therapy with adequate fluid intake Summary
and bed rest should be reinforced. Patients do not have
to be admitted to the hospital or receive intravenous • Today, dengue is considered among the most
important arthropod-borne viral diseases in humans.
fluids unless they present with severe vomiting, dehydra-
It is transmitted by the bite of an infective female
tion, bleeding, altered mental status, clinical deteriora- Aedes mosquito. (2)(6)
tion, or evidence of DHF or DSS. Patients who have • According to the World Health Organization and
DHF and can be managed as outpatients include those Centers for Disease Control and Prevention, the
who have platelet counts of at least 50⫻103/mcL incidence of dengue in the United States is
increasing and may be underreported due to
(50⫻109/L), no active bleeding (besides the petechiae),
inadequate disease recognition and low index of
and a hematocrit that is not elevated. Patients who have suspicion. (1)(7)
DHF and those who are in shock should be treated in • Children younger than 15 years of age are at highest
an intensive care setting. Hematologic, cardiovascular, risk for severe disease and death. (2)(25)
and fluid and electrolyte status should be observed and • The spectrum of dengue viral infections includes
four categories: undifferentiated fever, dengue fever,
supported. The platelet transfusion threshold in DHF
DHF, and DSS. (1)(11)
is controversial, and transfusion is required only in pa- • DHF and shock forms should be managed
tients who have severe thrombocytopenia or hemor- aggressively in an intensive care setting to prevent
rhagic manifestations. (8) When dengue is considered in morbidity and mortality. (2)(12)
a differential diagnosis, acute-phase (0 to 5 days) and • Dengue should be considered in the differential
diagnosis of any child who develops fever within
convalescent-phase samples (14 to 21 days) should be
2 weeks of travel to endemic areas. (2)
collected and sent for viral isolation and serology.

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 Diagnosis and Management of Dengue Fever in Children
Ashlesha Kaushik, Carol Pineda and Helen Kest
Pediatr. Rev. 2010;31;e28-e35
DOI: 10.1542/pir.31-4-e28

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