Cardiovascular Disorders in Pediatrics

Cardiovascular Disorders in Pediatrics
Congenital heart disease occurs in about 1% of children. Heart murmurs are much more
common, and may be heard in virtually every child if examined carefully.
I. Clinical Evaluation of Cardiovascular Disorders
A. History
1. For neonates, a history of feeding problems, cyanosis, tachypnea, irritability or
grunting respirations may indicate serious cardiac pathology. A history of
feeding less than 2 ounces at each feeding in a term infant may indicate
pathology. A family history of congenital heart disease may be helpful, but the
incidence of congenital heart disease in families where the mother has
congenital heart disease is only 5-10%.
2. For older children, it is unusual for a pathologic murmur to present for the first
time outside of infancy. Two notable exceptions are hypertrophic
cardiomyopathy and murmurs associated with dilated cardiomyopathy.
Symptoms which indicate serious pathology include exercise-induced chest
pain, exercise induced syncope, or cyanosis. Easy fatigability is non specific,
and not helpful in differentiating pathologic from non-pathologic murmurs.
B. Physical Examination
1. Congenital heart disease is more common in infants with congenital anomalies.
a. Trisomy 21. The incidence of heart disease is about 50% in these children.
Anomalies include ventricular septal defects, atrioventricular canal defects,
and patent ductus arteriosus.
b. Trisomy 18. The incidence of heart disease is almost 100%in these
children. Ventricular septal defect is the most common anomaly.
c. Trisomy 13. The incidence of heart disease is about 80%, usually VSD.
d. Turner syndrome (coarctation, hypertension), Marfan syndrome (aortic
aneurysms), and Noonan syndrome (pulmonic stenosis, coarctation) are
other congenital anomalies.
2. Growth parameters may suggest failure to thrive that is caused by
cardiovascular disease. Infants with cardiovascular disease usually have a
normal head circumference, and height may be normal, but the weight is usually
lower than anticipated.
3. Blood pressure determination. All children 3 years of age and older should
have their blood pressure measured on a yearly basis. The blood pressure cuff
should be appropriate for the patient’s size. The width of the cuff should be at
least 2/3 the length of the upper arm, and the bladder should be long enough
to almost encircle the upper arm. Blood pressure levels vary depending on the
age of the child, and hypertension is defined as a blood pressure consistently
greater than the 95th percentile for age.
a. Presenting symptoms of severe hypertension in infants include congestive
heart failure (caused by coarctation), respiratory distress, and failure to
thrive.
b. Symptoms of severe hypertension in older children may include headache,
nausea, vomiting, mental status changes, and epistaxis.
4. Cardiovascular Examination
a. Inspection
(1) Conditions that cause cardiac enlargement (ventricular septal defect,
The recommendations in blood pressure management are from the National
High Blood Pressure Education Project provides tables that will give you
normal data for blood pressure that varies by age, by height of the patient.
Blood pressure should be measured in all children greater than three years of
age. Blood pressure should be measured from the patient's right arm after they
have been sitting in a quiet room for three to five minutes. Blood pressure
should be measured twice and the results averaged, and the blood pressure
should be measured with an appropriate size cuff. The simplest way to
remember that is to try and get the largest cuff you can get on the child's arm.
They recommend that in a pediatric practice you have six cuffs. Three small
cuffs, one adult cuff, a large adult cuff and then a thigh cuff.
For definition of the diastolic blood pressure, the fifth Korotkoff sound is used.
The fifth sound is when the sound totally disappears. There are patients in
whom the fifth Korotkoff sound never occurs. In other words, the sound never
disappears, but then if it goes all the way down to zero, they don't have diastolic
hypertension, which makes sense.
Hypertension is defined as a child that has an average systolic or diastolic
blood pressure greater than the 95th percentile on three separate occasions,
not all done in the same day. So don't rush into the diagnosis of hypertension.
Most children that have modest elevations in blood pressure are overweight
and possibly have a family history of high blood pressure. Those people might
get just a very basic routine screening evaluation which might include a
urinalysis (looking for casts, hematuria, proteinuria), a BUN creatinine, looking
for elevation of creatinine consistent with renal disease, and also a good
cardiac physical exam, feeling femoral pulses. Those people would be treated
with weight reduction, dietary restrictions, and emphasis on physical activity.
Patients should not be restricted from physical activity because of mild
elevations in blood pressure.
People that have significantly elevated blood pressure, and these are the
people in the 99th and above percentile, frequently have underlying disease
that is causing their hypertension. It is not idiopathic or familial hypertension.
The two organ systems that are most commonly implicated are the renal
system and the cardiovascular system. Remember to listen for bruits over the
abdomen because renal artery stenosis is a fairly common cause of significant
hypertension in children, and remember to feel the femoral pulses.
Now, I am going to briefly go over the cardiovascular exam, specifically the
acyanotic category for an atrioseptal defect (ASD). In order to diagnose an
ASD it is not what is outside your ears that is most important. It is what is
between your ears that is most important. You need to know what you are
listening for. If you can do a good ASD exam, then you know how to use your
stethoscope. If you can rule out an ASD every time you listen to a patient, you
will refer many fewer functional murmurs for evaluation, and you will miss many
fewer ASDs.

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atrioseptal defect, and a large patent ductus arteriosus) often cause the
left side of the chest to protrude further than the right.
(2) In patients with pectus chest deformities, functional murmurs are often
heard.
b. Palpation
(1) In situations where there is a large left to right shunt (ie VSD, ASD) the
precordial activity is often increased.
(2) Displacement of the apical impulse may be associated with cardiac
enlargement.
(3) Palpation of femoral pulses is critical in diagnosing coarctation of the
aorta.
c. Auscultation
(1) Each sound should be listened to separately.
(2) The first heart sound (S1) is caused by closure of the mitral and
tricuspid valves, and it should be a single sound heard at the lower left
sternal boarder.
(a) The first heart sound may become inaudible at the lower left
sternal border when it is obscured by some pathologic sound. The
most common pathologic sound obscuring S1 is caused by
turbulent flow through a ventricular septal defect (VSD). VSD
murmurs are termed "holosystolic". Other sounds that could
obscure S1 are caused by AV valve regurgitation or by a PDA.
(b) First heart sounds that are "split" or double may be caused by
"clicks", or by some a slight timing difference between the closure
of the mitral and the tricuspid valves.
(c) Aortic valve clicks are heard best at the apex and do not vary with
respiration.
(d) Pulmonary valve clicks are best heard at the upper left sternal
border and do vary with respiration.
(e) Mitral valve prolapse clicks are a not pathological, and should be
ignored unless mitral valve regurgitation is present.
(3) The second heart sound (S2) is caused by the closure of the aortic
and pulmonic valves. The second heart sound should "split" with
respiration.
(a) A "fixed split" second heart sound may indicate the presence of
an ASD, especially if associated with increased precordial activity.
A fixed split S2 may also be seen in patients with complete right
bundle branch block.
(b) A loud single S2 indicates either pulmonary hypertension or the
absence of a closure sound from one semilunar valve. This may
be seen in severe forms of congenital heart disease, such as
truncus arteriosus, tricuspid atresia, tetralogy of Fallot,
transposition of the great vessels, pulmonary atresia, and
hypoplastic left heart syndrome.
(4) Systolic Murmurs
(a) Innocent Systolic Murmurs
i) Peripheral pulmonary flow murmur is heard in most babies
outside of the newborn period.
ii) Still's murmur is often heard for the first time in a 3 to 5 year
old.
The first heart sound at the lower left sternal border, closure of the mitral and
tricuspid valve. It should be a single sound that you hear with your stethoscope.
The second heart sound is heard at the upper left sternal border. It is the
closure sound of the aortic and pulmonic valves. In ordinary people, it should
split and move with respiration. You can't get a two-year-old to take a deep
breath and hold it, but what you listen for is that the second heart sound is not
the same every time. The splitting of the second heart sound is caused by the
patient taking in a breath, augmenting right ventricular filling, and increasing
the time it takes for the right ventricle to eject its contents. In a patient with an
atrial septal defect, the second heart sound is widely split and fixed. The right
ventricle is always filling. It doesn’t matter whether the patient took a deep
breath or not because blood is going from the left atrium through the atrial
septum into the right atrium. So you hear a widely split and fixed second heart
sound. It doesn't vary with respiration.
The systolic murmur heard in someone with an ASD can be very soft and not
easily audible. Many patients with large atrial septal defects have no systolic
murmur. Don't make the diagnosis of an ASD based solely on the presence or
absence of a systolic murmur. The cause of a systolic murmur in someone
with an ASD is flow across the pulmonary valve. It is just a flow murmur, so it
may sound like other innocent, benign flow murmurs. The fourth and final part
of the examination is the presence of a diastolic sound or a diastolic rumble
across the tricuspid valve. The blood that courses from the left atrium through
the ASD into the right atrium and across the tricuspid valve in diastole makes
noise. The classic exam is increased precordial activity, normal first heart
sound, a widely split second heart sound, a systolic ejection murmur at the
upper left sternal border and a diastolic rumble across the tricuspid valve.
To examine the precordial activity, put your hand on the chest. You'll feel this
dilated right ventricle beneath your hand and that should be the first tipoff that
this patient has an ASD and not a functional or innocent murmur. The second
is the wideness of that second heart sound. But if you don't put your
stethoscope at the upper left sternal border and really pay attention to what the
second heart sound is doing, you'll miss it. The last is the diastolic rumble
across the tricuspid valve. It is heard best with the bell of the stethoscope
placed over the tricuspid valve. Push down with the bell of the stethoscope and
make it function like a diaphragm, so then you'll just hear the systolic and high-
frequency sounds. When you let up on the bell of the stethoscope it will begin
to act like a bell and you will start to hear low frequency sounds.

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iii) Outflow tract murmurs are often heard in the adolescent and
adult.
(b) Pathologic Systolic Murmurs
i) Ejection-aortic stenosis, pulmonic stenosis, atrial septal
defect.
ii) S1 coincident- VSD, PDA, AV valve regurgitation.
(5) Diastolic murmurs are always pathologic, except venous "hums".
(a) Aortic valve insufficiency
(b) Pulmonic valve insufficiency
(6) Differentiation of Functional Murmurs from Pathologic Murmurs
(a) Serial Exams. Functional murmurs are often louder if the child is
examined during a high output state, such as when febrile or
when anxious.
(b) Functional murmurs change with position. They are often heard
best when the patient is supine. Standing may result in complete
resolution of the murmur.
II. Cyanotic Congenital Heart Disease
A. Transposition of the Great Vessels
1. Because these patients are often quite cyanotic, they commonly present in the
delivery room, or in the nursery when the patent ductus arteriosus begins to
close. Occasionally, very dark skinned infants with transposition may go
unrecognized.
2. Physical Exam. Increased precordial activity, cyanosis, a single second heart
sound, and a systolic "flow" murmur may be apparent.
3. Immediate treatment may include prostaglandin E1 to maintain ductal patency.
The initial dose is usually 0.05 micrograms/kg/min. Apnea is a common and
dangerous side effect.
4. Surgery usually is performed early in life, and it usually consists of an arterial
switch operation.
B. Tetralogy of Fallot. Four primary features consist of ventricular septal defect, right
ventricular outflow tract obstruction, right ventricular hypertrophy, and an
"overriding" aorta. Only the VSD and the right ventricular outflow tract obstruction
are responsible for the physiology.
1. Presentation depends on the amount of pulmonary blood flow. Patients with little
pulmonary blood flow are very cyanotic, and may need prostaglandin E1 to
maintain ductal patency. Patients with less right ventricular outflow tract
obstruction may present with signs of a large left to right shunt, the so-called
"pink-tetralogy".
2. Tetralogy spells should be recognized as a dangerous event that require
surgical intervention (if possible). A tetralogy spell often occurs early in the
morning (upon awakening), is accompanied by intense cyanosis, and usually
occurs when the child is quiet and tachypneic.
3. Treatment of Tetralogy Spells
a. Knee chest position
b. Oxygen
c. Sedation (morphine)
d. Volume expansion
4. Intervention consists of repair in the neonatal period or palliation, followed by
repair at an older age. Survival should exceed 95%.
5. Because of abnormalities of the pulmonary arteries, some patients may be not
As an example of cyanotic heart disease I am using Tetralogy of Fallot.
Cyanosis is caused by the presence of blue blood coming out into the aorta.
So patients with ASDs and VSDs should be acyanotic. They have left to right
shunts. They have too much red blood going into their lungs but they don't
have blue blood going out into their aorta unless they have some additional
problem like pulmonary vascular disease. The four features of Tetralogy of
Fallot are ventricular septal defect, which sits beneath the aortic valve, the aorta
sitting on top of the VSD, a so-called overriding aorta, right ventricular outflow
tract obstruction and right ventricular hypertrophy.
The physiology of Tetralogy of Fallot is based solely on the presence of the
VSD and obstruction between the right ventricle and the pulmonary artery. So
as long as blood finds it easier to get from the right ventricle into the aorta, the
patient will be blue. Exactly when patients get intervened upon, that have
Tetralogy of Fallot, depends upon the severity of their pulmonary stenosis.
Their physical examination, besides the cyanosis, which again is dependent
upon their amount of pulmonary stenosis, will be that of a child with pulmonary
stenosis. You hear only the most distal obstruction. You won't hear the VSD
murmur because there is such a large hole between the left and right ventricles
that the pressure in the two ventricles is identical, so you won't hear a classic
VSD murmur. All that you will hear is a pulmonary stenosis murmur.
Pulmonary stenosis murmurs are unique in that they are associated with clicks.
Clicks sound like split first heart sounds. As the mitral and tricuspid valves
close, the pulmonary valve opens and it clicks as it opens, so the split first
heart sound is the simultaneous closure of the mitral and tricuspid valves
followed shortly thereafter by the clicking open of the pulmonary valve.
Pulmonary ejection clicks vary with respiration. So a click that varies with
respiration, murmur of the pulmonary valves, is a pulmonary ejection click. In
patients with Tetralogy of Fallot, these clicks can be so loud that you can even
palpate and feel the clicks and they will disappear when the patient takes in a
breath. The systolic murmur is caused by the blood rushing across the right
ventricular outflow tract.
Early problems depend upon on the amount of decreased blood flow that the
patient has. Hypercyanotic spells, so-called "Tetrology spells". Frequently that
the mother will call and say that the baby was found in the morning, very
tachypneic and extremely cyanotic. Treatment for that should be knee chest
position, calm down the infant, oxygen. If possible, give morphine once they get
into the Emergency Room. Long term treatment for that should be surgery.
Treatment for patients with Tetralogy of Fallot. Everyone that is operating on
these patients should achieve a mortality rate in the long run that is somewhere
less than 5%, probably in the 1-2% range. Long term complications of
Tetralogy of Fallot repair include arrhythmias, right ventricular failure, and aortic
valve insufficiency, and probably the most common now is right ventricular
failure.

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be candidates for surgery. These patients may have long term complications
related to the cyanosis and the polycythemia, including:
a. Headache
b. Altered mental status
c. Stroke
d. Epistaxis
e. Hemoptysis
f. Hyperuricemia and gout
III. Acute Management of Rhythm Disorders
A. A 12 lead ECG should be obtained during and after the tachycardia episode.
B. Narrow QRS complex tachycardia
1. Sinus tachycardia (less than 220 beats/minute) may be caused by exogenous
substances (beta agonist) or hyperthyroidism.
2. If the rate is very rapid and the child is hemodynamically unstable, direct current
cardioversion is recommended with 0.5 watt-seconds/kg, synchronize the
defibrillator.
3. If the child is stable, vagal maneuvers such as an ice bag, abdominal pressure
or rectal stimulation may be successful. If vagal maneuvers are not successful,
adenosine may be given IV. The initial dose is 50 micrograms/kg given iv push.
The dose may be increased up to a dose of 300 micrograms/kg. Adenosine will
only momentarily block AV conduction; therefore, if the patient has recurrent
SVT, adenosine will not help for more than a few seconds, and some other
intervention should be used.
C. Wide QRS Complex Tachycardia
1. If the patient is hemodynamically unstable, DC cardioversion is necessary.
2. If the patient is stable, vagal maneuvers may help differentiate between SVT
with aberrant conduction and ventricular tachycardia.
D. Bradycardia. If the patient is stable hemodynamically the bradycardia may be of
long standing duration. Sinus bradycardia is common in the athletes, or it may
occur with complete heart block. Unstable bradycardia may be palliated with
isoproterenol or
transthoracic pacing. Long term therapy involves placement of a pacemaker.
IV. Rheumatic Fever
A. Diagnosis is based on a modification of the Jones criteria. The criteria are divided
into major and minor categories. Diagnosis requires two major criteria, or one major
and two minor criteria. The patients must have evidence of a preceding
streptococcal infection (should be present in all cases except some patients with
chorea). Evidence of a preceding streptococcal infection includes either a positive
culture, positive ASO titre or recent history of scarlet fever.
Jones Criteria for Rheumatic Fever
Major Criteria Minor Criteria
Long term survival after Tetralogy of Fallot repair should be excellent. After
surgery patients have a 93% 20 year survival rate. In current years, this long
term survival rate should be even higher. So just as a reminder, when you do
a cardiovascular exam, I would implore you to try to do an ASD exam anytime
you are trying to critically evaluate a murmur. If you go through that whole
scenario, precordial activity, first heart sound, second heart sound, systole and
diastole, I think that you will have to refer fewer functional or innocent murmurs
and you won't miss many ASDs.
A pediatric cardiologist referral. Anybody that is symptomatic; If they are
cyanotic, failure to thrive, or if you suspect that they have congestive heart
failure, they should be sent when you suspect it. Also, patients that have
syndromes. All children with Trisomy 21 should be evaluated by a pediatric
cardiologist at least once. There is no other screening test that you run in
medicine that has a 50% true positive rate other than cardiology evaluation of
Down's syndrome because half of them will have significant congenital heart
disease. Asymptomatic patients with pathological murmurs, and I don't mean
the grade 5, PS murmurs, but I'm talking about somebody that you're not sure
if they have a tiny little muscular VSD or not. Or you're not sure if they have
mild pulmonary stenosis. You should not send them until the children are over
two years of age, because many of those VSDs will close spontaneously. Many
of the children that have right ventricular outflow tract murmurs, as the
pulmonary arteries dilate, those murmurs will go away. If they didn't have that
done when they were three-months-old for this outflow tract murmur, frequently
the cardiologist is going to see an ASD and have to see them back to do
another surgery.

1. Carditis 1. Fever
2. Polyarthritis 2. Arthralgia (not when arthritis is used
Inflammatory heart disease. Kawasaki's syndrome consists of fever over
3. Chorea as a major)
4. Subcutaneous nodules 3. Prolonged PR interval on the ECG
101.5ºF for greater than five days, rash, conjunctivitis, swollen hands and feet,
5. Erythema marginatum (not when carditis is used as a
oral mucous membrane changes, and lymphadenopathy. The
major)
lymphadenopathy is the least specific of all the signs, and it is only seen in
between 50-70% of children with diagnosis of Kawasaki's. The rash can be
4. Increased acute phase reactants
anything from a diaper dermatitis looking rash to a rash that looks like scarlet
(ESR, WBC or C-reactive protein)
fever. The conjunctivitis is very helpful. It usually spares the area around the
5.Previous history of rheumatic fever
iris; beet red conjunctivitis but nonpurulent. If they have purulent conjunctivitis
V. Endocarditis you probably need to look for some other diagnosis. The hands can look like
A. Incidence is between 11 and 50 cases per million/year. they were banging them on something hard. They can get swollen and the feet
B. can be so involved that the children cannot walk. The lips, dry, cracked, red. Most common organisms
Also the tongue will have a "strawberry" appearance. Two weeks after the 1. Alpha hemolytic strep
2. Staphylococcus aureus illness, their hands and feet will peel.
3. Staphylococcus epidermidis
4. Enterococci The etiology. In 1996 a paper was published where patients that had
C. Clinical Evaluation Kawasaki's syndrome, had oral, rectal and skin cultures performed. Twelve of
the 16 patients were culture positive for superantigen producing1. Fever, heart murmur, splenomegaly (seen in <50%).
2. Less common features include petechiae, splinter hemorrhages, retinal staphylococcus. The hypothesis is that the Staph produces the superantigen,
hemorrhages (Roth spot), systemic emboli, renal insufficiency. and then it is the immunogenic reaction to that superantigen that causes
3. Positive blood cultures, elevated ESR. Kawasaki's.
4. Echocardiography is indicated if endocarditis is suspected clinically.
Therapy for Kawasaki's. Aspirin is also given concurrent with the gamma 5. Antibiotic Prophylaxis Against Endocarditis
globulin. The current dose of gamma globulin is 2 gm/kg given intravenously. a. Prophylaxis is necessary for all children with high velocity jets in their hearts
(VSD, aortic stenosis, pulmonic stenosis, history of rheumatic fever with It is a one time dose. It is no longer the 400 mg over 5 days. Remember though
valve damage, mitral or tricuspid regurgitation, patent ductus arteriosus, that these patients are under some bit of cardiovascular stress when they're
surgically created shunts) sick and you're giving them a large protein load when you give them the gamma
globulin. So they can get tachypneic or tachycardic while they're getting their b. Prophylaxis is not necessary for atrial septal defect or mitral valve prolapse
gamma globulin. You might have to decrease the rate a little bit and you might without mitral regurgitation because there are no areas of high velocity blood
flow. have to give them diuretics, but the gamma globulin is the cure. Don't stop
c. Endocarditis prophylaxis is given when bacteremia is anticipated, such as giving it just because they appear to be having some problems with the protein.
with dental cleanings, tonsillectomy, or cystoscopy.
d. Complications of Kawasaki's syndrome are coronary artery aneurysms. Around Prophylaxis is not recommended for cardiac catheterization, orthodontic
5% of patients develop coronary artery aneurysms. Patients that do badly and manipulation, or tympanostomy tube placement.
e. SBE prophylaxis usually consists of one dose of amoxicillin, one given require a lot of intensive follow up are those that have so-called giant
before the dental procedure. aneurysms. By giant I mean greater than 8 mm. One of the major problems is
VI. Kawasaki Syndrome that giant aneurysms develop and that is stenosis. You see the left anterior
A. KS is a multisystem probably infectious disease with an uncertain etiology. Recent descending coronary artery stops right there. This patient might benefit from
coronary artery bypass grafting.theories suggest the patients with KS have a high incidence of superantigen
producing staphylococcus aureus or group A beta-hemolytic streptococci.
B. Diagnosis of KS is based on the presence of five of the following: Follow up in patients with Kawasaki's depends on the severity of their coronary
1. Fever lasting five days or longer involvement. People that have no pulmonary involvement or minimal pulmonary
2. Polymorphous exanthem involvement that returns to normal can be released and followed up after
approximately one year and should be treated as normal for the remainder of 3. Redness or induration of the hands and/or feet
their lives.4. Bilateral non purulent conjunctival injection
5. Erythema of the lips or tongue
6. Non-purulent swelling of the cervical lymph nodes Endocarditis. There are between 11 and 50 cases per million population per
C. Complications include coronary artery aneurysms, seen in as many as 20% of year, which comes out to about 4,000 to 8,000 cases of endocarditis across
untreated cases. the United States per year. Most of those people that develop endocarditis, at
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1. Treated cases have a 2% incidence of aneurysms.
2. About 50% of aneurysms resolve spontaneously
D. Treatment of Kawasaki Syndrome
1. High dose aspirin (100 mg/kg) is continued until signs of inflammation have
subsided. This may be based on laboratory (ESR) or clinical grounds.
2. IV gamma globulin (2 grams/kg given over 8 to 12 hours).
a. Most gamma globulin contains high concentrations of antibodies that inhibit
T cell response to staphylococcal superantigens.
b. Patients with clinical failure to IV gamma globulin should be retreated.
3. Long Term Follow-up
a. The vast majority of children with Kawasaki syndrome will have no
aneurysms and will have completed therapy within 6 to 8 weeks.
b. Children with coronary changes that resolve quickly do not require
medication and should have no exercise restrictions.
c. Children with chronic aneurysms require long term follow up, exercise
testing, and exercise restrictions.
least 75% have some underlying cardiovascular etiology - either mitral valve
insufficiency, a ventricular septal defect, an abnormal aortic valve, etc.
Diagnosis is based not on fever and go straight to an echo, but repeated
positive blood cultures with the same organism, possibly associated with
systemic emboli and then go to an echo. But an echo has extremely low
sensitivity and specificity if used as a sort of front line tool to rule out
endocarditis. Prevention of endocarditis. The best we can do is so-called
antibiotic prophylaxis at times of endocarditis risk. What that means is that any
patient that you have that is at risk for developing endocarditis and what that
means is that they have a high velocity jet lesion somewhere in their
cardiovascular system, those people should receive antibiotics prior to
becoming predictably bacteremic. That doesn't mean that the child just fell in
a mud puddle and scraped his knee. You couldn't predict that. So they don't
get antibiotics retrospectively for something like that. But they do get it when
they do to the dentist, if they are going to have cystoscopy, rigid bronchoscopy,
sigmoidoscopy, etc. Procedures that would cause them to become predictably
bacteremic. Even in cases with prosthetic valves, the American Heart
Association recommends that the prophylaxis be performed with amoxicillin.
No longer do you have to admit them and put them on IV antibiotics unless they
have things like antibiotic allergies or other problems.
Just to hammer home the point of the high velocity jets. Patients with VSDs,
for example, where blood is flying through from the left ventricle to the right
ventricle. Those patients should receive antibiotic prophylaxis at time of
endocarditis risk. Patients with mitral valve regurgitation. This echocardiogram
depicts the turbulence of blood as it comes across the mitral valve in systole.
Patients that have mitral valve prolapse clicks, just the click, but no mitral valve
insufficiency, the American Heart Association is very clear that those people
do not require antibiotic prophylaxis at time of endocarditis risk. Six percent of
normal females in your practice should have clicks of mitral valve prolapse
which I would hope you would diagnose as split first heart sounds. Two
percent of males should have those same clicks, but only about 0.2 or 0.4%
should have a click and murmur of mitral valve regurgitation. Those are the
people that have true mitral valve disease that would have an echocardiogram
like this and would be at risk for developing endocarditis.
Children that are not at risk for developing endocarditis are those that have low
velocity shunts within their heart. This is an echocardiogram of a child with an
atrial septal defect. You can see blood coursing through the ASD and it is
laminar, it doesn’t speed up, it doesn't change colors, it doesn't make any
noise. So it doesn't denude the epithelium as blood comes across the atrial
septum, across the tricuspid valve in diastole. Patients with ASD do not require
antibiotic prophylaxis at times of endocarditis risk. Procedures that do not
cause you to become bacteremic are for example tympanostomy tubes. There
are not enough blood vessels in the tympanic membrane to cause you to
become bacteremic when you put the tympanostomy tubes in place.
In summary, when we talk about blood pressure measurement, I would
encourage you to try and get a hold of that article that was in Pediatrics in

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October of 1996. Those tables can be very useful. Don't overcall hypertension.
Somebody has got to be in the 95th percentile on average for three separate
evaluations. Remember how to do the ASD exam and try to do that on every
single patient that you evaluate before referring to a pediatric cardiologist. For
inflammatory heart disease remember the diagnostic criteria for Kawasaki's.

Antibiotics and Outpatient Infections

Antibiotics and Outpatient Infections

David Kramer, M.D.

Antibiotic Therapy

Factors in Choosing an Antibiotic

Clinical syndrome

Host characteristics

Focused history

Antibiotic characteristics

When you are choosing an agent to use, you are looking at

what clinical symptoms the patient has, who is this patient, an

immunocompromised or normal host. You are taking a little bit

more of a detailed history to include infectious risks, and you

are thinking about the antibiotic itself.



3 Assessment of Clinical Syndromes

Identify predominant symptoms and signs

Determine the site of infection

Identify disease process

Determine likely causative organisms

Identify likely susceptibility pattern

In a clinical syndrome, you are trying to identify what is the

predominant symptom and signs. You are trying to see where

the site of infection is. Is this infection in the joint? Is this

infection in the bone? Where are we treating this infection?

Does this patient have a central nervous system infection?

Then, identify the disease process because if you identify that

this is osteomyelitis, it is a little bit different than if you think that

the patient has pyogenic arthritis. The causative organisms

might change and then what you need do, is you need to think

of what the disease is, what are the most likely pathogens

associated with this disease and what is their susceptibility

pattern in the area where you practice. This is essential. To pick

a drug, you have to know what organism you are dealing with.

Because if not, you are really doing it blindly. So you have to

have an idea of what organisms cause what specific diseases

so that then you can make a good choice about antibiotic

therapy.



4 Host Characteristics

Age

Underlying conditions

Medical devices

Nutritional status

When you look at hosts, you need to know the age of the

patient. A 10-year-old is different from a neonate. The patho-

gens are different. Think about underlying conditions. Is this a

patient with cystic fibrosis with pneumonia, or is this a well child

with pneumonia? Different pathogens. So you are thinking

about that host. Does this patient have an indwelling catheter?

Does the patient have a prosthetic heart valve? All these things

make it a little different to know which antibiotic to choose.

Then, is the patient malnourished because that might be a

cause for immunodeficiency.



5 Focused History

Travel

Exposures

Immunizations

Drug abuse

Sexual activity

When you are looking at a focused history, you need to know if

the patient you are seeing with fever for 10 days has just come

back from a safari in Africa, or is this a patient who has just

been in the community where there is a lot of influenza. So you

are going to ask about travel, about exposure to people who

have contagious diseases such as tuberculosis, or whether the

child is exposed to more infections because he is in daycare.

Are immunizations up to date? That is very important. That

patient may have measles if they have never been immunized

and there is an increase in your community of Hemophilus

influenza type E,. which is now very rare but can occur. Is this

adolescent an IV drug abuser? Unfortunately, this happens

occasionally and it brings in another set of organisms and

diseases we have to think about, and then sexual activity brings

up another whole host of organisms and disease processes.



6 Antibiotic Selection Factors

Spectrum of activity

Absorption

Distribution

Metabolism

Excretion

Adverse Effects

Safety

Routes of administration

Drug-drug interactions

Cost

Palatability

Effect on Resident Flora

Selective Pressure on environment

When we finally make that decision to select an antibiotic, we

must ask, Does the antibiotic cover the organisms that I am

thinking about? Is it well absorbed? Does it get to the site of

infection? Oral vancomycin is not good to treat Staph aureus

because it does not get absorbed from the GI tract. What are

the adverse effects? How safe is this drug? Do I have to

monitor drug levels? What is the route of administration? Can

I give it orally? Is it as good orally as it is IV? Are there other

interactions with other drugs, I might not want to use

erythromycin because it might change the levels of the

cyclosporin? How much does it cost? Is there a cheaper

alternative? Does it taste good? Because if it doesn't taste good

nobody, is going to take it. And no matter how good the

antibiotic is for that infection, if it is not taken, it is not of use.

Then, things that we think of in a more global setting are what

will this do to the patient's flora, and will this alter the flora and

then transmit resistant organisms? So, usually when you are

selecting an antibiotic, you are looking at all of these factors

and then making the decision based on the best antibiotic.



7 General Principles of Antibiotic Therapy

May initiate with broad spectrum awaiting culture results

Obtain pertinent cultures to narrow therapy

Use narrowest spectrum antibiotic as possible

The general principle is that you initiate broad spectrum

antibiotics awaiting culture results, then based on culture

results, you can narrow therapy. It is really best to use the

narrowest spectrum antibiotic possible for the infection,

especially now in the era of increasing antimicrobial resistance.

We really want to keep the very broad spectrum antibiotics for

when we need them. Ceftriaxone for treatment of otitis should

not be used because we have other, much narrower, alterna-

tives for otitis media and I want to save ceftriaxone to have an

antibiotic to treat the patient who comes in with meningitis. If

you don't use it in this fashion, I think that we are going to end

up with a lot of ceftriaxone resistance, and you are going to

have a lot of patients for which we have no antibiotics. So use

the narrowest spectrum possible.

The ideal antibiotic would be one that would be broad enough

to cover everything we want to cover, but very narrow to also

not cause resistance. It would have a very good absorption. It

would have a long half life, preferably that could be given in a

once a day or b.i.d. dosing. I actually prefer a b.i.d. dosing

schedule. Once a day, if a patient forgets to take it, then you

could be without an antibiotic for a long period of time. I want an

antibiotic that has no side effects. I want one that is very cheap

and one that has a great taste that the child will actually say,

Mom. It s my antibiotic time. I want to take it. Unfortunately, it

doesn t exist. There is no perfect antibiotic. Unfortunately, there

are good antibiotics or there are better antibiotics, but there is

no perfect one. There is no magical antibiotic for every infection.



8

Penicillins

Agent Activity Clinical Uses

Penicillin G oral anaerobes Gp A streptococcus

pharyngitis

Penicillin V streptococci RF prophylaxis

Benzathine Eikenella Syphilis

Procaine Pasteurella

Treponema

aspiration

pathogen specific

The different classes of antibiotics. I am starting with the

penicillins and they are divided into the name of the antibiotic,

their activity and then the clinical uses. Penicillin is a very useful

antibiotic still. Very active against oral anaerobes, streptococci

and the treatment of choice for Eikenella infections. Eikenella

is an organism that lives in the mouth, and with boxers or

people who punch each other in the mouth, you can get

infections with Eikenella in the hand. That is not uncommon.

Occasionally bites from animals can have Eikenella.

Pasteurella. Bites from animals. Penicillin is also for syphilis.

Penicillin is still very useful. We use it as the treatment of

choice for group A strep pharyngitis. We use it for rheumatic

fever prophylaxis. It is the therapy of choice for syphilis. For

aspiration pneumonia, it is still a very good agent to use initially

in that patient that may have aspirated in the community, not

the patient that has aspirated and has hospital acquired

organisms. But definitely, that patient coming from the commu

nity with an aspiration pneumonia. If you have a specific

infection with any of these pathogens, then that is when you

would use the penicillin.



9

Penicillin - Adverse Effects

Allergic reactions

Hemolytic anemia

Interstitial nephritis

Seizures and hyperkalemia in patients with underlying renal

disease

Adverse effects. The one that you most commonly hear about

is allergic reactions. A lot of people say that they are penicillin

allergic. I think that if you are penicillin allergic, you re really

going to take out all of the penicillins and most of the

cephalosporins if you are truly allergic with anaphylaxis. So

when the patient says they had a rash from penicillin or a rash

from amoxicillin, I investigate it further. I would hesitate to label

a patient as allergic to penicillin. Is it hives, not hives? I try to

bring pictures so the patient can see if it was hives or not. Or

was there wheezing, no wheezing? Was it true anaphylaxis? Try

to limit the labeling of patients as penicillin allergic if they just

had a rash.



10

Penicillinase-Resistant Penicillins

Agents Activity Clinical Uses

Methicillin

Nafcillin

Oxacillin

Cloxacillin

Dicloxacillin

S. aureus

S. epidermidis

less active for

penicillin suscepti-

ble bacteria

S. aureus infec

tions

After the penicillins were introduced, Staph aureus became very

rapidly resistant to penicillin. The penicillinase-resistant

penicillins were developed basically for treatment of Staph

aureus infections. These include methicillin, nafcillin, oxacillin

and oral agents such as cloxacillin and dicloxacillin. Their

activity is for Staph aureus. Occasionally, some Staph

epidermidis may be susceptible but the penicillinase resistant

penicillins are less active against penicillin susceptible bacteria,

especially anaerobes. The clinical uses are limited to Staph

aureus infections.



11

Adverse Effects of Penicillinase Resis-

tant Penicillins

Neutropenia - dose and duration related

Cholestasis and cholestatic jaundice

Interstitial nephritis - most common with methicillin

Poor palatability of oral preparations (dicloxacillin and

cloxacillin)

Adverse effects. Neutropenia is very common and it really

depends on how prolonged the usage is. In patients that we

treat for four or six weeks for Staph aureus osteomyelitis with

nafcillin, we frequently see neutropenias, and we have to stop

that agent and switch to something different like clindamycin.

So you should look for neutropenia with prolonged use. If it is

going to be a short course, it is very unlikely to produce

neutropenia. The other one that I just wanted to mention is

interstitial nephritis which is much more common with methicillin

than it is with nafcillin or oxacillin. Methicillin may not be

available any more.

The oral preparations of dicloxacillin and cloxacillin. There is no

child who has taste buds that would actually take this prepara-

tion because it tastes so terrible. The use of dicloxacillin and

cloxacillin is limited to the adolescent who can take a pill and

not worry about an aftertaste. But in a child, this becomes a

very big problem because they are really terrible tasting.



12

Aminopenicillins

Agents Activity Clinical Uses

Ampicillin

Amoxicillin

Penicillin suscep

tible

Some GNR

Enterococcus

Listeria

H influenzae

Borrelia

Otitis media

Sinusitis

UTI

Lyme disease

The aminopenicillins, ampicillin and amoxicillin, were developed

so that they could have a broader spectrum of activity than

penicillin. This broader spectrum includes all of the penicillin

susceptible ones, some gram negative rods, such as E. coli or

occasionally Proteus, enterococcus that is not resistant,

Listeria. Listeria in the neonate can cause infection in neonatal

meningitis. You cannot use a cephalosporin alone for neonatal

meningitis because Listeria would not respond. So ampicillin is

the drug of choice for Listeria. If H. influenza is susceptible, you

could use ampicillin, although we know that there is increasing

resistance. For Lyme disease amoxicillin is a good choice.

Clinical uses for amoxicillin. We know it is the drug of choice for

otitis and sinusitis. If you have an E. coli that is susceptible in

the urinary tract or you have enterococcal urinary tract infection,

it is useful, although most people would not start with amoxicillin

for a UTI because E. coli is becoming amoxicillin resistant and

is the most frequent cause of UTI. Lyme disease is one of the

uses you can use it for.



13

Adverse Effects of Aminopenicillins

Allergic reactions

Non-allergic mediated rashes associated with viral infections,

particularly EBV

Diarrhea

C difficile colitis

Seizures in patients with renal disease

The adverse effects are really non-allergic mediated rashes.

The rash from amoxicillin, if it is not hives, is usually not an

allergy. Remember that it is particularly evident in patients with

EBV. It can cause diarrhea. It can cause C. difficile. Seizures

are a very rare side effect.



14

Extended Spectrum Penicillins

Agents Activity Clinical Uses

Mezlocillin

Piperacillinn

Ticarcillin

Carbenicillin

Ampicillin suscep

tible

More GNR

Pseudomonas

GNR infection

Extended spectrum penicillins cover more Gram-negative rod

infections, and these include, mezlocillin, piperacillin, ticarcillin

and carbenicillin. Their activity is the same as ampicillin but they

include more Gram negative rods, and particularly piperacillin

and ticarcillin and orally carbenicillin are quite good for Pseudo-

monas infections if they are susceptible. So their clinical uses

are really Gram-negative rod infections. These are frequently

antibiotics that are used in hospitalized patients, except for

carbenicillin which is a p.o. preparation.



15

Adverse Effects of Extended Spectrum

Penicillins

Allergic reactions

Thrombophlebitis

High sodium load

Hypokalemia

Platelet dysfunction and bleeding

The extended spectrum penicillin have the same kind of

adverse profile. Ticarcillin has a high sodium load so we don't

use it in patients that have congenital heart disease or any

propensity to go into failure. Ticarcillin can also cause platelet

dysfunction and bleeding even with a normal platelet count.



16

Penicillins + Beta Lactamase Inhibitor

Agents Activity Clinical Uses

Amoxicillin +

clavulanate

ticarcillin +

clavulanate

Ampicillin +

sulbactam

Piperacillin +

tazobactam

Ampicillin suscep

tible

S. aureus

Anaerobes

H influenzae

M catarrhalis

Polymicrobic In

fections

Bites

Otitis media

Sinusitis

Nosocomial infec-

tions

Penicillin plus a beta lactamase inhibitor. We have come up

with amoxicillin + clavulanate, ticarcillin + clavulanate, ampicillin

+ sulbactam and piperacillin + tazobactam. These are all

ampicillin susceptible, but because of the clavulanate and the

addition of this beta-lactamase inhibitor, they get Staph aureus

as well as very good anaerobe coverage. Then because we

have ampicillin and the beta-lactamase, we now get H. influ-

enza and Moraxella catarrhalis included in the spectrum. The

clinical uses are usually polymicrobic infections. One of the

major clinical uses in pediatrics is bites. So that for cat bites,

extensive dog bites and even human bites, Augmentin or one

of these extended spectrum plus the beta-lactamase inhibitors

are the ones that are used in the hospital as well for bites. It is

a second line agent for otitis media and sinusitis. And they can

be used for nosocomial infection for Gram-negative rods that

are susceptible, or in patients infected with Gram-negative rods

plus Staph aureus and anaerobes, as in the hospitalized patient

who may have an aspiration pneumonia.



17

Adverse Effects of Penicillin +Beta

Lactamase Inhibitors

Gastrointestinal effects, especially diarrhea

All adverse reactions of the penicillin component can occur with

combinations

The adverse effects are an increased incidence of diarrhea.

Then remember that all the adverse effects of penicillin can

occur with the combination of preparations.



18

Cephalosporins

Cephalosporins are divided into first, second and third genera-

tions.



19

First Generation Cephalosporins

Excellent activity against Gram-positive organisms

Good activity against enteric Gram-negative bacilli

No CNS penetration

The first generations have excellent activity against Gram

positive organisms and their mainstay is for Staph aureus

infections. They have okay activity against enteric Gram

negative bacilli, so occasionally you will see that there is an E.

coli or Klebsiella that s susceptible to Keflex. But remember that

first generation agents have no central nervous system penetra-

tion so do not use Ancef or Keflex if meningitis is a possibility.

That is one of the major reasons we use them very infrequently

in neonates or preterm neonates where we can't easily exclude

central nervous system infection.



20

Second Generation Cephalosporins

Retain activity against Gram-positives

Enhanced activity against Gram-negatives

Some with good anaerobic coverage

Limited CNS penetration

Second generation cephalosporins retain activity against Staph

aureus and the Gram-positives. They have enhanced activity

against Gram-negatives, especially Hemophilus and Moraxella.

Some of them, especially cefoxitin, have good anaerobic

coverage and you may see them used for pelvic inflammatory

disease or for abdominal infections because of their anaerobic

coverage. Second generation cephalosporins have limited

central nervous system penetration and should not be used for

meningitis.



21

Third Generation Cephalosporins

Decreased activity against Gram-positives

Much enhanced activity against Gram-negatives

Some with antipseudomonal activity

Excellent CNS penetration

The third generations have much decreased activity against the

Gram-positive, so we do not use the third generation

cephalosporins, like cefotaxime or ceftriaxone, for infections

that are due to Staph aureus. They have much enhanced

activity against Gram-negatives. Some, like ceftazidime

particularly, have anti Pseudomonal activity and they have

excellent CNS penetration. Therefore, that is why we use them

for meningitis.



22

First Generation Cephalosporins

Agents Activity Clinical Uses

cephalothin

cephalexin

cefazolin

cefadroxil

Penicillin suscep

tible

S. aureus

GNR (some)

S. aureus infec

tions

First generation cephalosporins include cephalexin (Keflex),

cefazolin (Ancef) and cefadroxil (Duricef) with b.i.d. preparation.

Their activity is really for Staph aureus. Their clinical uses are

for Staph aureus. Remember that group A strep is also suscep-

tible. So for lacerations or cellulitis or osteomyelitis, where you

think Staph aureus is a player, these are good alternative drugs.



23

Second Generation

Activity Clinical Uses

Cefaclor

Cefuroxim

e

Cefprozil

Loracarbe

f

Cefoxitin

1st gen suscep-

tible

H. influenzae

M. catarrhalis

GNR (more)

Anaerobes

Second-line therapy for

otitis media and sinus

itis

Intraabdominal infections

Pelvic inflammatory disease

Second generation cephalosporins include cefaclor, cefuroxime,

cefprozil, loracarbef. They have the activity of the first genera-

tion and they include Hemophilus and Moraxella. Some to a

better degree than others. The clinical uses are really as

second line agents for otitis media and sinusitis. Cefoxitin is a

second generation that has increased activity against

anaerobes, and is used for intra-abdominal infections and pelvic

inflammatory disease.



24

Third Generation Cephalosporins

Agent Activity Clinical Uses

Cefotaxime

Ceftriaxone

Ceftazidime*

GNR

Streptococci

Nosocomial infections

Meningitis

*increased antipseudomonal activity

Third generation cephalosporins include cefotaxime,

ceftriaxone, and ceftazidime. They truly are Gram-negative rod

drugs. They are good for Strep pneumoniae, and that is why we

use them for meningitis. But we are seeing increased resis

tance to cephalosporins and their clinical uses should be

reserved for nosocomial infections and serious meningitis.

Other clinical uses of these can be for Gram-negative rod

infections, such as Salmonella in sickle cell patients or Salmo-

nella infections in general.



25

Oral Third Generation Cephalosporins

Agent Activity Clinical Uses

Cefixime

Ceftibuten

GNR

Poor coverage

against S. aureus,

pneumococcus

Resistant urinary tract infec

tions

Limited pediatric use

Oral third generation cephalosporins include cefixime (Suprax),

ceftibuten (Cedax). Their activity is really very good for Gram

negative rods. They have extraordinarily poor Staph aureus

activity and very poor pneumococcus activity. These basically

should really be used for Gram-negative rod infection. This

limits their pediatric use because otitis, pharyngitis and sinusitis

are not commonly caused by Gram-negative rods. I think that

one of the good uses for these agents is for resistant UTIs. So

our nephrologists use them quite frequently for complicated

UTIs with resistant Gram-negatives that they don't want to put

into the hospital and this is a very good oral alternative. Using

it routinely for otitis and sinusitis in patients where it really has

poor pneumococcal activity really doesn't make much bug-

drug" sense.



26

Fourth Generation Cephalosporins

Agent Activity Clinical Uses

Cefepime S. aureus

GNR

Pseudomonas

Undetermined

Cefepime is a new fourth generation. I really have not used it at

all yet. Its activity is said to be good for Staph aureus, Gram

negative rods and for Pseudomonas and I am really not sure

what clinical uses it will have in pediatrics. This is really a

relatively new drug that we don't have experience with.



27

Oral Cephalosporin Activity

PSP PRP H/M GAS SA

Cepha

lexin

Keflex + + +

Cefad

roxil

Durice

f

+ + +

Cefpr

ozil

Cefzil + +/ + +

Cefacl

or

Ceclor + +/ +

Cefur

oxime

Ceftin + + + +

Cefpo

doxim

e

Vantin + + + +/

Lorac

arbef

Lorabi

d

+ +/ +

Cefixi

me

Supra

x

+/-+ +

Ceftib

uten

Cedax +/ + +

Activity of antibiotics for otitis. Really you have to distinguish

between all of these oral cephalosporins and pick the ones that

you think have the best activity for the organisms that are

prevalent in your community and make a decision according to

that. Don t switch between these for second line drugs. There

is really no reason to switch. New information on Cedax

indicates that it is not very good for pneumococcus, so I think

it had a plus there before. You want to change that to a +/- as

well as cefixime. Loracarbef and Cefzil as well as cefaclor

really are +/- against Hemophilus and none of them are

better than high dose amoxicillin for resistant

pneumococcus.



28

Adverse Effects of Cephalosporins

Allergic reactions - 15% cross reactivity in penicillin allergic

patients

Serum sickness reaction (cefaclor)

Interstitial nephritis

Autoimmune thrombocytopenia

Biliary cholestasis and cholelithiasis (ceftriaxone)

Fungal overgrowth and infections

The adverse effects of cephalosporins. Cross reactivity may be

as high as 15% with penicillin allergic patients. It is said that the

cross reactivity is much greater with first generation

cephalosporins than with second generations and thought to be

really not very high at all in third generations. I am very conser

vative. If the patient truly has an anaphylaxis to penicillin I really

do not use any of the cephalosporins. However, some people

say that you could very safely use the third generations

because they are so different. Ceftriaxone is very unique in that

it causes biliary cholestasis and cholelithiasis. Then I really

want to point out that these are very a broad spectrum agents,

especially the third generations. We do see a lot of fungal

overgrowth and this may be a precipitating factor of the

nosocomial fungal infections in patients who are hospitalized.



29

Disadvantages of Cephalosporins

Not cure all drugs

Pneumococci may be resistant

Increasing resistant of hospital GNR

Broad spectrum

May lead to changes in normal flora and superinfection

High cost

Disadvantages. Pneumococci may be resistant. There is

increasing resistance of some hospital Gram-negative rods

such as Enterobacteriaceae, that are hospital acquired flora

may be resistant to cephalosporins. They are very broad

spectrum. They lead to especially fungal superinfection and

they are relatively high cost.



30

Causes of Cephalosporin Failure

Methicillin resistant S. aureus

Coagulase negative Staphylococcus

Listeria monocytogenes

Enterococcus spp.

C. difficile

Rickettsia

Chlamydia

Cephalosporin failure. The instances where it can fail include

methicillin-resistant Staph aureus or coagulase negative

Staphylococcus infections because you have an indwelling

catheter or a ventriculoperitoneal shunt. Listeria is resistant. For

Enterococcus they are not good at all. C. difficile and then

Rocky Mountain Spotted fever and chlamydia, especially

chlamydia pneumonia.



31

Carbapenems

Agent Activity Clinical Uses

Imipenem

Meropenem

Ceftriaxone

susceptible

Resistant GNR

anaerobes

Resistant infec-

tions

Carbapenems. Imipenem, and meropenem are really extraordi

narily broad spectrum drugs that have their use in pediatrics

really for resistant infections and particularly have been used for

meningitis. For pneumococcus that is resistant to ceftriaxone,

sometimes they are susceptible to imipenem or to meropenem.

Its activity is really against ceftriaxone susceptible plus resistant

Gram-negative rods as well as anaerobes.



32

Adverse Effects of Carbapenems

Allergic reactions - cross reactivity in PCN allergic parents

Diarrhea

Lowers seizure threshold (imipenem)

Adverse effects are that if you are penicillin allergic you are

going to be allergic to meropenem and imipenem. So it is not an

alternative for the penicillin allergic patient. Remember that

imipenem lowers the seizure threshold so that for use in

meningitis this might become a problem and it is better to use

meropenem in those instances. It is really nice to reserve this

for when you have a ceftriaxone resistant organism, this is a

good alternative.



33

Macrolides

Erythromycin

Clarithromycin

Azithromycin

Roxithromycin

Dirithromycin

Macrolides. Erythromycin is the prototype but now we have

clarithromycin, azithromycin. There is increasing use of

clarithromycin and azithromycin.



34

Erythromycin - Activity

Spectrum Clinical Uses

Penicillin susceptible

S. aureus

Mycoplasma

Legionella

B. pertussis

Campylobacter

Chlamydia

Penicillin allergic ptatients

Specific pathogens

The spectrum of activity. It is the penicillin susceptible organ-

isms. Then you have Staph aureus, although there is an

increase in Staph aureus that is resistant to erythromycin and

if they're resistant to erythromycin, they're going to be resistant

to azithromycin and clarithromycin as well. Organisms that are

covered include Mycoplasma pneumoniae, Legionella which is

an infrequent cause of infection in children but may occasionally

happen, Pertussis. It is our drug of choice for pertussis,

Campylobacter, and also chlamydia pneumoniae. So the

erythromycins are really good alternatives. The clinical uses are

for penicillin allergic patients for pharyngitis. They can be used

as second line agents for otitis and sinusitis and against,

specific pathogens, it is the drug of choice for pertussis

infections.



35

Macrolides - Adverse Effects

Gastrointestinal disturbances

Hepatotoxicity

IV erythromycin - cardiotoxicity hepatotoxicity venous irritation

Many drug interactions

The adverse effects are really gastrointestinal disturbances and

this is why the new macrolides exist. Because clarithromycin

and azithromycin have less gastrointestinal intolerance than

erythromycin. They may be hepatotoxic and remember that IV

erythromycin is a very dangerous drug to use. It can be

cardiotoxic and hepatotoxic and causes a lot of venous irritation.

It should not be given IV unless you have an infectious disease

consult and a very good reason such as Legionella infection in

a child. Remember that there are many drug interactions with

the erythromycins and these interactions don't go away be-

cause you are using the newer preparations. It is terrible for

cyclosporin levels but it also interacts with theophylline.



36

New Macrolides

Activity Clinical Uses

Clarithromyc

in

azithromycin

Erythromycin sus

ceptible

H influenzae

M catarrhalis

Non-tuberculous

mycobacterium

Toxoplasma

Cryptosporidium

N gonorrhoeae

Second line therapy

for otitis media and

sinusitis

Pathogen specific

Clarithromycin and azithromycin. Their activity is that of

erythromycin susceptible. They have better Hemophilus and

Moraxella coverage than penicillin, but they may not achieve

adequate middle ear concentrations. It is very interesting that

this is a very good use for non-tuberculous mycobacteria.

Those patients that have cervical lymphadenitis that we think

are secondary to non-tuberculous, might respond to

clarithromycin. I may use clarithromycin initially for these

patients. Also in patients with HIV with MAI, clarithromycin is a

good drug. Toxoplasma also in immunocompromised patients.

Azithromycin has the same activity in Cryptosporidium and

gonorrhea. The clinical uses are really as second line agents for

otitis and sinusitis and for pathogen specific infections.



37

Advantages of New Macrolides

Retain spectrum of activity of erythromycin

Increased spectrum against H. influenzae and nontuberculous

mycobacteria

Improved pharmacokinetics

Decreased gastrointestinal side effects

The advantages are that they retain the spectrum of

erythromycin, they increase the spectrum against these things,

they have improved pharmacokinetics, but really the main

advantage of clarithromycin and azithromycin is in their dosing

and their improvement in altered side effects. So that b.i.d. or

once a day dosing is preferable to four times a day dosing, and

the decrease in side effects is really the major advantage.



38

Disadvantages New Macrolides

Broader spectrum of activity

Does not broaden spectrum for erythromycin resistant

pneumococcus

High cost

Adverse effect of clarithromycin headache, neurologic changes

The disadvantage is that they have a broader spectrum of

activity. It does not really broaden the spectrum for

erythromycin resistant pneumococcus. So, if your

pneumococcus is resistant to erythromycin, it is equally

resistant to clarithromycin and azithromycin. The relative cost

is higher, and azithromycin is extraordinarily expensive, but

because it s been used for half of the time for five days rather

than the usual 10 day course, it is pretty equivalent to

clarithromycin, but it is about 10 or 12 times higher in cost than

erythromycin. The uncommon effects of clarithromycin such as

headache and neurologic changes are uncommon but can

occur.



39

Clindamycin

Activity Clinical Uses

PCN susceptible

S. aureus

Anaerobes

Toxoplasma

No H. influenzae

or M.

catarrhalis

Penicillin allergic

Resistant pneumococci

Intraabdominal infections

Toxoplasmosis

Clindamycin. Clindamycin is a drug that we had not used

previously as much as we are using now, but now with resistant

infections, we are seeing new uses for clindamycin. It has

activity against penicillin susceptible organisms, Staph aureus,

anaerobes, Toxoplasma. It doesn't have activity against

Hemophilus or Moraxella catarrhalis. Especially in bite wounds,

it doesn't cover Eikenella, so that it cannot be used as a single

agent in this. That is why we use amoxicillin-clavulanate or the

combination ones for bite wounds. The clinical uses of

clindamycin are in the penicillin allergic, in the resistant

pneumococcal infection, intra-abdominal infections, not alone

but with other Gram negative rod agents, and then in patients

with toxoplasmosis.



40

Adverse Effects of Clindamycin

Clostridium difficile colitis

Hepatotoxicity

Stevens-Johnson syndrome

Eosinophilia

Clindamycin adverse effects are C. difficile colitis. It definitely

has been associated with colitis, but I am not really sure that it

is more associated than any of the other antibiotics. Amoxicillin

is the one that is used the most, and amoxicillin is the antibiotic

that is most associated with C. difficile by the sheer numbers of

its usage. Clindamycin can cause hepatotoxicity. It can cause

Stevens-Johnson, and it may cause eosinophilia. Overall, it is

used a lot and it is a safe alternative.



41

Quinolones

Nalidixic Acid

Ciprofloxacin

Norfloxacin

Quinolones have been increasingly used in pediatrics, and

although they are not approved for use in pediatrics, we do

have an increasing experience with the quinolones and may

choose them as alternatives in some patients for specific

reasons.



42

Quinolones

Spectrum of Activity

Gram positives +/- S. pneumoniae

+/- S. aureus

Gram negatives Pseudomonas aeruginosa

Other Chlamydia, Mycoplasma,

Mycobacterium, Bartonella,

Plasmodium

They are not wonderful for pneumococcus or for Staph aureus,

these are not drugs for resistant pneumococcal infections or for

Staph aureus infections. But they are good for Gram negatives,

particularly Pseudomonas. That is one of the areas of major

use is as an outpatient drug for pseudomonal infection. Other

uses include Bartonella henslae which is the agent of cat

scratch disease.



43

Potential Uses of Quinolones

Pulmonary infections in cystic fibrosis

Complicated urinary tract infections

Chronic suppurative otitis media

Complicated osteomyelitis

Resistant nosocomial infections

Prophylaxis for N. meningitidis

Gastrointestinal infections

The potential uses for the quinolones. We have lots of experi

ence in the cystic fibrosis patients, with very little adverse

effects that we can attribute to the quinolones. Complicated

urinary tract infections caused by Gram-negative rods that are

resistant to other drugs. For chronic suppurative otitis media

when Pseudomonas may be one of the pathogens. Compli

cated osteomyelitis such as that associated with decubital

ulcers with Gram-negative rods and where resistant Pseudomo

nas may be a problem. Resistant infections. There are theoreti

cal risks of growth problems with quinolones. It is also used for

gastrointestinal infections such as Salmonella.



44

Adverse Effects of Quinolones

Diarrhea

Arthralgias and tendon rupture

Increased liver enzymes

Possible effect human cartilage growth

Adverse effects. Quinolones do cause diarrhea. It has been

reported to cause arthralgias and there was recently a report of

an Achilles tendon rupture associated with quinolone use,

particularly ciprofloxacin. But the question of the effect on

human cartilage growth is becoming more and more of a

question. This is definitely seen in animals, but in cystic fibrosis

patients where we use large quantities of ciprofloxacin, in doing

MRIs of their joints there is really no detectable damage to the

cartilage. So I think we are getting more and more comfortable

with quinolones. Obviously not as a first choice. But their

potential uses in pediatrics are going to be becoming more and

more prevalent.



45

Sulfonamides

Agent Activity Clinical Uses

TMP/sulfamethoxaz

ole (Bactrim, Septra)

PCN susceptible,

except Gp A

strep and

anaerobes

GNR Salmonella,

Shigella

H. influenzaee

Pneumocystis

Second-line therapy

for otitis media and

sinusitis

Bacterial enteritis

Pneumocystis

Erythro/sulfamethox

azole Pediazole)

Erythromycin sus

ceptible

H. influenzae

M. catarrhalis

Second-line therapy

for otitis media and

sinusitis

Sulfonamides. TMP/sulfa does not have activity against group

A strep. It has no anaerobic activity at all. The Gram-negative

rods, that it is very good for are Salmonella, shigella,

Hemophilus influenza. It is the drug of choice for Pneumocystis

carinii pneumonia infections. Its clinical uses are as a second

line agent for otitis and sinusitis. For bacterial enteritis and for

Pneumocystis. Erythro/sulfa (Pediazole) takes the activity of all

the erythromycin and increases activity for Hemophilus and

Moraxella. It is a second line agent for otitis and sinusitis.



46

Adverse Effects of Sulfonamides

Gastrointestinal disturbances

Skin rashes - more common in HIV infected patients

Erythema multiforme and Stevens-Johnson syndrome

Adverse effects of the sulfonamides. Skin rashes are very

prominent and are more common in HIV patients than in non-

HIV infected patients. Erythema multiforme and Stevens

Johnson syndrome seem to have a higher association with

sulfonamides than with other antibiotics, although it can occur

with other antibiotics. But there seems to be somewhat of a

higher association with sulfonamides and Stevens-Johnson.



47

Vancomycin

Activity Clinical Uses

PCN susceptible

MRSA

S. epidermidis

Enterococcus sp

C. difficile

pathogen specific

infection of medical devices

Vancomycin. The activity of vancomycin is that it is penicillin

susceptible. It includes methicillin resistant Staph aureus and

is really the best drug for methicillin resistant Staph aureus

infections. It is the drug that we use when Staph epidermidis

infection is thought of, such as in patients with indwelling

devices and indwelling venous catheters. Enterococcus is

usually susceptible, although now we know that enterococcus

has the ability to develop vancomycin resistance, and this is an

increasing problem that is going to becoming even more of a

problem in pediatric institutions. Then we use the oral prepara-

tion for C. difficile. Really the clinical uses are for infection of

medical devices and truly pathogen specific when you have

MRSA or if you have a susceptible Enterococcus. The routine

use of vancomycin for C. difficile colitis is not recommended

because we do not want to encourage Enterococcus resistance.

Metronidazole should be used instead.



48

Adverse Effects of Vancomycin

Ototoxicity - in patients with renal disease or concurrent

aminoglycosides

Red man syndrome

Hypotension associated with infusion

The infusion of the intravenous vancomycin can cause a red

man syndrome that is not an allergy. It responds very nicely to

decreasing the rate of infusion or stopping it for a little bit and

starting up again at a lower rate. It also responds nicely to

antihistamines. There have been patients with hypotension

associated with the infusion, which readily gets better with

stopping it.



49

Aminoglycosides

Agents Activity Clinical Uses

Gentamicin

Netilmicin

GNR GNR infections

Amikacin Resistant GNR Hospital GNR

Tobramycin P. aeruginosa

Aminoglycosides. Their activity is for Gram-negative rods and

Gram-negative rods only. It is a little bit better for resistant

Gram-negative rods, so some are no longer using gentamicin

but have switched to amikacin because they have a problem

with a particular Gram-negative rod that may be resistant.

Tobramycin is specific for Pseudomonas aeruginosa. They are

used for Gram-negative rod infections, and apart from urinary

tract infections, should not be used as the sole agent.



50

Adverse Effects of Aminoglycosides

Nephrotoxicity

Ototoxicity

Reversible neuromuscular blockade

Need to monitor levels

Adverse effects. They have nephrotoxicity and ototoxicity. It can

cause neuromuscular blockade, which is an important factor in

patients with botulism because this small neuromuscular

blockade becomes clinically significant in those patients, and it

may precipitate respiratory arrest in that patient. There is new

information that once daily dosing of aminoglycosides may be

as effective as the three times a day dosing, with less side

effects. More pediatric information is coming forward with that.



51

Tetracyclines

Agents Activity Clinical Uses

Tetracycline

Doxycycline

Chlamydia

Mycoplasma

Rickett-

sia/Ehrlichia

Borrelia

Brucella,

Francisella

Propionobacteria

Eikenella

Pathogen specific

Not for Gp A

Strep

Tetracyclines are really pathogen specific. It includes very

broad pathogens that are kind of unusual. It really is not for

group A streptococcus.



52

Adverse Effects of Tetracycline

Gastrointestinal disturbances

Deposition of drug in bones and teeth

Contraindicated in children <8 years

Photosensitivity

Hepatotoxicity - especially with IV tetracycline

Bacterial overgrowth

They are not used often in pediatric patients because they are

contraindicated because they deposit in bones and teeth and

stain the teeth. Remember if you are using it for patients for

acne, tell them that it causes photosensitivity so that they can

get ready when they get out into the sun.



53

Chloramphenicol

Activity Clinical Uses

Penicillin susceptible

H. influenzae

Anaerobes

Salmonella

Shigella

Rickettsia

Rocky mountain spotted fe

ver in children less than 8

years old

Chloramphenicol is something that has a very good spectrum

activity, but it is not used very much because we have very

good alternatives. But remember one of the main clinical uses

is for Rocky Mountain Spotted fever in that patient that is less

than eight years of age. There have been failures when it has

been used for resistant pneumococcus despite its good in vitro

activity. So it is not recommended.



54

Adverse Effects of Chloramphenicol

Idiosyncratic aplastic anemia

Bone marrow suppression

Gray baby syndrome

Hepatotoxicity

Need to monitor levels

Adverse effects include bone marrow suppression and aplastic

anemia; these have precluded its use in pediatrics.



55

Rifampin

Activity Clinical Uses

S. aureus

Streptococci

N. meningitidis

H. influenzae

Mycobacterium

Synergy device infection

Mycobacterial infection

Prophylaxis for H. influenzae

and N. meningitides

Rifabutin has better activity for MAI than rifampin

Rifampin. We use it a lot as synergistic for microbacterial

infections and prophylaxis. It really should not be used to treat

infections alone because organisms become rapidly resistant

to rifampin.



56

Rifamycins - Adverse Effects

Hepatotoxicity especially with other drugs or pre-existing

liver disease

Changes color of all body secretions to orange

It does change the color of all body secretions. It makes them

a bright orange. That is how you know the patient is getting

rifampin but you have to warn the patient about this.



57

Metronidazole

Activity Clinical Uses

Anaerobes

G. vaginalis

Entamoeba

Trichomonas

Giardia

Anaerobic infections

C. difficile

Pathogen specific

Metronidazole is good for anaerobes, and that includes all of

these organisms as well as Giardia. Its clinical uses are

anaerobic infections, C. difficile, and pathogen specific infec

tions.



58

Adverse Effects of Metronidazole

Neurotoxicity

Peripheral neuropathy

Gastrointestinal disturbances

Metallic taste

Mutagenic and carcinogenic in lab animals

A peripheral neuropathy and neurotoxicity can occur, which is

more frequent in adults. I has a metallic taste. We use it quite

frequently for anaerobes and for C. difficile colitis.



59

References

1. Jacobs RF, Schutze GE, Young RA, et al. Antimicrobial

Agents In: Principles and Practice of Pediatric Infectious

Diseases. Eds: Long SS, Pickering LK, Prober CG New

York, Churchill Livingstone 1997

2. Spect WT, Blumer I (eds). The Pediatric Clinics of North

America: Symposium of Anti-Infective Therapy. Philadel

phia, WB Saunders Co, 1983

3. Smith AL (ed). Antibiotic Update. Pediatric Annals 1993;

22. 155-200

Treatment of Acute Renal Failure

General Therapy for Acute Renal Failure


Treatment of acute renal failure usually should be conservative and largely supportive. It requires careful and precise management. All patients will require close monitoring, many of them within intensive care settings.

Supportive care includes stabilizing the patient, monitoring input and output strictly, weighing daily, determining electrolyte values frequently, preventing sepsis via reducing the number of intravenous lines and removing an indwelling urinary catheter, culturing periodically, and using antibiotics when indicated clinically. It is important to adjust medication dosage according to renal function and to avoid nephrotoxins whenever possible. Because serum creatinine values increase daily, it is best to calculate drug doses based on GFR <10 mL/min per

1.73 m², rather than on the serum creatinine level.

Conservative therapy may be symptomatic or specific. Symptomatic therapy consists of treating the underlying prerenal conditions that led to renal failure; maintaining the fluid and electrolyte balance; initiating therapy for complications such as hyperkalemia, hypertension, acidosis, and infection; and instituting appropriate nutrition. Specific therapy consists of using medications for specific underlying causes and may include steroids (conventional or high-dose pulse steroid therapy) and other immunosuppressive agents, anticoagulation agents, plasmapheresis, or intravenous immunoglobulin.

THERAPY FOR PRERENAL FAILURE

Rapid volume replacement and treatment of the underlying condition that resulted in prerenal failure are the cornerstones of therapy. Initial fluid administration of isotonic saline (0.9%) or 5% albumin (10 to 20 mL/kg per dose) should be used to restore intravascular volume. This can be both a diagnostic and a therapeutic trial. Fluid administration also can convert oliguric to nonoliguric renal failure in its early stage.

Unless a patient is suffering congestive heart failure (CHF), fluid administration should be repeated, followed by the use of loop diuretics, including furosemide (2 to 5 mg/kg per dose) or bumetanide (0.25 to 0.5 mg/dose IV). After each bolus, the patient's volume needs to be reevaluated. Response to the therapy will be indicated by a urine output of greater than 1 to 3

D:\FILES\A_Journals\Pediatrics 5 Minute Review\Unused\Acute Renal Failure Therapy.wpd 1 mL/kg per hour.

Patients who have CHF will need inotropic support, such as dopamine (5 µg/kg per minute IV), dobutamine (5 to 20 µg/kg per minute), or digoxin. Therapeutic digitalis values should be achieved slowly and the maintenance dose reduced as dictated by renal function (Table 6).

THERAPY FOR POSTRENAL FAILURE

Therapy for postrenal failure includes removal of obstruction by decompression or diversion of the urinary tract, stabilization of electrolyte abnormalities, management of postobstructive diuresis, and therapy for voiding dysfunction and for urinary tract infection. Surgical intervention will require urologic consultation. The site of the obstruction will determine the approach: placement of a Foley catheter, vesicostomy, ureteral catheters (stents), or nephrostomy tubes. Prompt relief of a partial obstruction is indicated in cases of severe pain, where the possibilities for severe renal damage predominate, and whenever there is a history of frequent urinary tract infections.

Postobstructive diuresis is characterized by marked polyuria. The excessive excretions of salt and water may result in hypokalemia, hyponatremia, and hypotension and lead to collapse. Fluid replacement should be guided by what is excreted and based on frequent measurements of urine volume, urinary electrolytes, and serum electrolytes, including calcium and phosphorus.

THERAPY FOR ESTABLISHED RENAL FAILURE

Maintaining Balance of Fluid and Electrolytes

In a euvolemic state, fluid intake, including water generated from endogenous metabolism (insensible fluid gain), is balanced by fluid output. Most of the fluid output involves sensible fluid losses by urine, stool, and sweat and insensible losses by water evaporation from the skin and respiratory tract. Only small amounts of water normally are lost in the stool (100 to 150 mL/d), and fluid loss by sweat is minimal. Therefore, patients who are in ARF should have fluid restricted to net insensible water loss (insensible losses minus endogenous water production, which is 400 mL/m² per day or 25% to 30% of caloric expenditure) plus all measured fluid losses (urine output, gastrointestinal losses, chest tube drainage). Net insensible loss should be restored with 5% to 10% dextrose in water (D5%W - D10%W). Urine output should be replaced with fluid that has the composition and quantity of these losses. Usually, normal saline (0.45% NS) mL for mL of losses every 4 to 6 hours is appropriate. If this therapy is sufficient, the patient will lose

2 0.5% to 1% of body weight per day over the initial few days. The patient should be weighed at leastonce daily, and input and output should be monitored strictly, with clinical status assessed constantly. Once urine output begins to rise, fluid intake should be increased. Fluid balance is easier to manage in children who have nonoliguric renal failure. Dialysis is indicated in the case of a severe fluid overload (Table 6).

Metabolic acidosis will change the activity of cellular enzymes and depress cardiac function. A serum bicarbonate (HCO3) of less than 12 mEq/L may require correction. The goal is to keep the serum pH greater than 7.2 or serum bicarbonate level above 16 mEq/L. The amount of NaHCO3 needed to correct metabolic acidosis can be estimated by using this formula:

Base deficit (BD) = 0.6×BW (kg) × (desired - observed serum HCO3)

The base deficit can be added to the urine output or maintenance fluid. Half of the replacement can be given within the first 2 to 3 hours and the rest evenly over 24 hours. Caution must be taken to avoid salt and fluid overload. In the patient who has hypocalcemia, sodium bicarbonate must be administered cautiously because it may lead to tetany.

Patients who have CHF will not tolerate a large sodium load, and the use of intravenous tromethamine (THAM) can be considered; it is available as a 0.3 M solution. The dose of THAM in mL can be calculated as:

mL of 0.3 M THAM = BW (kg) × base deficit (mEq/L)

THAM can be given only in intensive care settings. If the patient has respiratory acidosis (increased pCO2), administration of base will not be effective and it is not indicated.

Hyponatremia can lead to cerebral overhydration and neurologic symptoms. It is necessary to keep the serum sodium in the range of 130 to 135 mEq/L, restricting excessive free water.

Hyperkalemia is the most life-threatening condition in ARF, resulting in muscular weakness and abnormal cardiac conduction, which can lead to fatal arrhythmias. Potassium must be monitored by serial determination and electrocardiogram. A peaked T wave, prolongation of the PR interval, widening of the QRS, disappearance of the P wave, and ventricular fibrillation are electrocardiographic (EKG) changes associated with an elevated serum potassium level.

The effects of hyperkalemia can be reversed by direct antagonism of its membrane actions and by lowering of the serum K^+ concentration either by promoting K^+ uptake into the cells or by removing K^+ from the body. Severe symptoms usually do not occur until the serum

3 level is above 7.5 mEq/L, but acid-base disbalance and a low serum Ca^++ level can modify the toxicity of hyperkalemia. In the absence of obvious artifactual changes (extravascular hemolysis, thrombocytosis, leukocytosis), an asymptomatic elevation of the serum K^++ to >5.8 mEq/L should be treated via a cation exchange resin (sodium polystyrene sulfonate). All sources of potassium should be eliminated in ARF. Usually ignored sources of K^+ are blood transfusions and drugs (penicillin).

If serum K+ is greater than 6.5 mEq/L and is accompanied by EKG changes, emergency steps must be instituted to lower the potassium level (Table 6).

1 Calcium gluconate--10% solution (0.5 to 1.0 mL/kg per dose) will oppose the effect of hyperkalemia on the heart and stabilize myocardial membranes. It should first be given intraveneously (IV) slowly over 10 to 15 minutes under careful EKG monitoring. The protective effect of Ca++ is relatively short and can be repeated within 5 minutes if indicated by EKG.

2 Glucose and insulin will promote the cellular uptake of potassium by increasing the Na+-glucose cotransport and Na+-K+ ATP-ase. Regular insulin in a dose of 0.1 to 0.2 U/kg and dextrose 0.5 to 1.0 g/kg are given after calcium gluconate. One can mix 100 mL D25%W with 6 U of regular insulin and administer slowly (1 to 2 mL/kg per dose IV).

3 Sodium bicarbonate (NaHCO3 7.5% 1 to 2 mEq/kg per dose IV slow push or fast drip) will raise the blood pH and shift potassium into cells. An increase of serum pH by 0.1 will lower serum K+ by 0.6 to 1 mEq/L, but this effect in ARF is transient; there is only a moderate, unpredictable response on the serum potassium concentration, which often is accompanied by significant volume expansion.

4 Albuterol aerosol and other beta2-adrenergic agonists can be given in an emergency. Like insulin, the beta2-adrenergic agents will cause a shift of potassium from the extracellular space into the cells. In some patients, albuterol aerosol can lower the serum K+ level by 1.0 to



1.5 mEq/L within 30 minutes. This measure is safer than giving sodium bicarbonate. All of these steps are only temporizing measures and must be accompanied by removal of potassium from the body.

5. Sodium polystyrene sulfonate, an ion exchange resin, will bind potassium in the gut in exchange for sodium (1 mEq K+ for 1 mEq Na+) and remove excess potassium from the body. The usual dose is 1 g/kg orally or by nasogastric (NG) tube given with 70% sorbitol or rectally (1 g in 2 to 4 mL of 25% to 30% sorbitol or 10% dextrose in water) as a retention enema placed through a Foley catheter for 30 to 60 minutes. Doses can be repeated every 2 to 4 hours.

When all of the aforementioned therapies fail to control plasma K^+ excess adequately, dialysis, usually in the form of hemodialysis, should be initiated. Mild hyperphosphatemia does not require therapy. Higher levels of phosphate in serum

 4 can be controlled with calcium carbonate as a phosphate binding agent (300 to 400 mg/kg per day orally). The dose should be adjusted to maintain the serum phosphorus level in the 5- to 6-mg/dL range. In general, magnesium or aluminum phosphate binders should be avoided in ARF.

Hypocalcemia does not require therapy unless tetany is present. If the child has tetany, 10% Ca gluconate (0.5 to 1.0 mL/kg per dose IV) should be administered.

Treating Hypertension

ARF in any form can present as hypertension and hypertensive encephalopathy. It is essential to lower the blood pressure quickly and safely. The blood pressure should be reduced by at least 25% within 1 hour with an antihypertensive medicine whose onset of action is rapid. It is advisable to start with one antihypertensive medicine and increase the dose to its maximum recommended level. Therapy is individualized and needs titration (Table 6). In most cases, hypertension is the result of sodium and fluid retention, but other factors, such as activation of the renin-aldosterone-angiotensin II and/or the alpha-adrenergic system, may have roles as well.

For immediate control of blood pressure, orally administered medication is less feasible in severely sick patients. Rather, a dose of the following should be considered:

1 Nifedipine, a calcium channel blocker (0.25 to 1.0 mg/kg per dose sublingually intrabuccally) usually is very effective. The dose can be repeated within 30 minutes and then every 3 or 4 hours as needed. Maximum is 30 mg/dose or 180 mg/24 hours.

2 Diazoxide, a vasodilator, given as a rapid IV infusion (3 to 5 mg/kg per dose) will lower blood pressure effectively within a few minutes. Its effect lasts several hours. Slow infusion should be avoided because it allows diazoxide to bind to plasma proteins and lose its efficacy. If the first dose is ineffective, another higher dose (maximum 10 mg/kg per dose) can be given. Doses can be repeated every 30 minutes. The maximum dose is 150 mg.

3 Hydralazine is a peripheral vasodilator that acts within 5 to 20 minutes when administered as 0.1 to 0.5 mg/kg per dose IV bolus or IM. Doses can be given every 4 to 6 hours as needed, but subsequent doses usually will result in undesirable side effects, such as headache, flushing, and tachycardia. The maximum to be given is 3.5 mg/kg per 24 hours.

4 Labetalol, with its alpha1- and nonselective beta-adrenergic blocking characteristics, can be used in a single dose. The starting dose is 0.25 mg/kg IV. It should be increased by 0.5 mg/kg per dose after 10 minutes, if needed, to 1.0 mg/kg IV, or it should be given as a continuous infusion (1 to 5 mg/kg per hour). The maximal dose is 300 mg/day.

5 Sodium nitroprusside continuous IV infusion (0.5 to 10 µg/kg per minute) will correct the



 5 blood pressure rapidly, but close monitoring of vital signs, lactic acid, and the thiocyanate level are needed. This agent probably should be used only in an intensive care setting. The maximum dose to be used is 800 µg/min.

Treating Anemia

There is no need for transfusion unless the patient is symptomatic and the hematocrit falls below 25%.

Nutrition

The provision of adequate and appropriate nutrition is a fundamental part of the nondialytic therapy of ARF, regardless of the etiology. Generally, enteral nutrition is preferred, either by oral intake or gastric tube. In many cases, the oliguric phase of ARF is short and self-limited, and special nutritional support is not needed. Some experimental studies suggest that infusion of nutrients (amino acids) in the early phase of ARF may increase oxygen requirements and aggravate tissue injury. The goal is to provide sufficient nutrients and adequate caloric intake to restrain the catabolic response and to hasten renal recovery. About 400 kcal/m² per day (45 to 50 kcal/kg per day) are required mainly as simple carbohydrates (>70%) and fats (<20%) orally and/or glucose solution (10%) parenterally. A patient whose nutritional status is normal and in whom ARF is uncomplicated may resume a normal diet within 5 to 7 days. If renal function is below 30% of normal (GFR <50 mL/min per 1.73 m²), the nutritional requirement should be adapted to renal failure. There are special formulas designed for enteral feedings in patients who are in renal failure.

Hyperalimentation should be considered early in the hypercatabolic patient. With dialysis, daily protein and caloric intake can be more generous (0.5 to 1 g/kg per day high biologic value protein), but more frequent dialysis may be necessary to control azotemia. If the BUN is greater than 50 mg/dL, a patient can benefit from special "nephro" solutions (essential amino acids and various nonessential amino acids). Depending on serum electrolyte concentrations, solutions should contain minimal amounts of sodium and no potassium or phosphorus.

Nutritional therapy requires monitoring for potential metabolic complications, such as fluid and electrolyte derangements, excessive BUN accumulation, hyperglycemia, and hypertriglyceridemia.

Renal replacement therapy (dialysis) usually is needed in about 20% of patients. The use

 6 of dialysis always should be individualized, but in general, the indications include severe fluid overload resulting in severe hypertension, CHF, pulmonary edema, and/or metabolic derange¬ments refractory to therapy, such as severe acidosis, severe hyperkalemia, hyponatremia, hypernatremia, hyperuricemia, or hyperphosphatemia. Dialysis is indicated when the BUN is greater than 100 mg/dL and there are symptoms of uremia, usually manifested in children as central nervous system depression. Preemptive dialysis can be used to prevent rather than treat uremic symptoms, as in the case of rapidly decompensating hemolytic-uremic syndrome and acute uric acid nephropathy or for removal of toxins as in oxalate overload. Early dialysis can simplify management and help in the administration of a specific therapy (chemotherapy) or diet (hypercatabolic cases).

The choice between hemodialysis, continuous arteriovenous hemofiltration, continuous venovenous hemofiltration, continuous arteriovenous hemodialysis, and peritoneal dialysis will depend on the availability of the technique, the etiology of the renal failure, and specific indications and relative contraindications. In patients whose major problem is excess extracellular volume (eg, in patients who have cardiac problems), hemofiltration offers some distinct advantages because this technique removes excess fluid quickly.

Prevention

Prevention of ARF, obviously, is the best form of therapy. Certain clinical situations may predispose to the development of ARF and should be recognized. Some preventive measures include:

1 Monitor the patient at risk.

2 Provide adequate hydration and maintenance of extracellular fluid volume (ECV) prior to the administration of radiocontrast material, amphotericin B, or aminoglycosides.

3 Administer nephrotoxic drugs in appropriate doses and monitor drug levels carefully. If possible, use alternative medication and limit the length of patient exposure.

4 Alkalize urine (pH >6.5) and adequately hydrate patients who have hyperuricemia or pigmenturia.

5 Use xanthine oxidase inhibitors to prevent hyperuricemia, such as in tumor lysis syndrome.

6 Treat prerenal conditions promptly via intravenous fluid to expand ECV and via osmotic and loop diuretics to increase blood flow and decrease cast formation if cardiovascular status allows.

7 Administer low-dose dopamine infusion (3 to 5 µg/kg per minute) to patients who are in

8. Ameliorate ARF with nutrients and hormones; vasodilatators and cytoprotective agents can help. Experimental studies have indicated a role for the following agents in animal studies and limited clinical trials. However, the beneficial effects of thyroxine, atrial natriuretic factor, insulin growth factor, prostaglandin analogs, adenosine triphosphate-magnesium chloride, calcium channel blockers, and dopamine need to be established more firmly.