11  Pathophysiology of Cyanotic Congenital Heart Defects 145

VC 75 96 PV VC 40 98 PV

RA (5) 75 96 (8) LA RA (5) 40 95 (5) LA

RV 90/6 80 96 90/6 LV RV 90/5 40 90 90/5 LV

PA 40/20 80 94 90/60 AO PA 15/10 40 60 90/60 AO

(26) (70) (12) (70)
A B
FIGURE 11-8  Hemodynamics of acyanotic (A) and cyanotic (B) tetralogy of Fallot. Numbers within the diagram denote
oxygen saturation values, and those outside the diagram denote pressure values. In both conditions, the systolic pressure in
the right ventricle (RV) is identical to that in the left ventricle (LV) and the aorta (AO) and there is a significant pressure gra-
dient between the RV and the pulmonary artery (PA). Whereas in the acyanotic form (A), pulmonary blood flow is slightly
to moderately increased, in the cyanotic form (B), pulmonary blood flow is decreased. Other abbreviations are the same as
those in Figure 11-5.

findings are determined by the magnitude of PBF—if the magnitude of the PBF is large,
the heart size is large, and the pulmonary vascularity increases; if the magnitude is small,
the heart size is small, and the pulmonary vascularity decreases. With increased PBF and
resulting pulmonary hypertension, CHF and later pulmonary vascular obstructive disease
(i.e., Eisenmenger’s syndrome) may develop.

Tetralogy of Fallot
The classic description of TOF includes the following four abnormalities: VSD, pulmonary
stenosis (PS), right ventricular hypertrophy (RVH), and overriding of the aorta. From a
physiologic point of view, TOF requires only two abnormalities—a VSD large enough to
equalize systolic pressures in both ventricles and a stenosis of the right ventricular outflow
tract (RVOT) in the form of infundibular stenosis, valvular stenosis, or both. RVH is sec-
ondary to PS, and the degree of overriding of the aorta varies widely and it is not always
present. The severity of the RVOT obstruction determines the direction and the magnitude
of the shunt through the VSD. With mild stenosis, the shunt is left to right, and the clinical
picture resembles that of a VSD. This is called acyanotic or pink TOF (Fig. 11-8, A). With a
more severe stenosis, the shunt is right to left, resulting in “cyanotic” TOF (Fig. 11-8, B). In
the extreme form of TOF, the pulmonary valve is atretic, with right-to-left shunting of the
entire systemic venous return through the VSD. In this case, the PBF is provided through a
patent ductus arteriosus (PDA) or multiple collateral arteries arising from the aorta. In TOF,
regardless of the direction of the ventricular shunt, the systolic pressure in the RV equals
that of the LV and the aorta (see Fig. 11-8, A and B). The mere combination of a small VSD
and a PS is not TOF; the size of the VSD must be nearly as large as the annulus of the aortic
valve to equalize the pressure in the RV and LV.
In acyanotic TOF, a small to moderate left-to-right ventricular shunt is present, and the
systolic pressures are equal in the RV, LV, and aorta (see Fig. 11-8, A). There is a mild to
moderate pressure gradient between the RV and PA, and the PA pressure may be slightly
elevated (because of a less severe stenosis of the right ventricular outflow tract). Because
the presence of the PS minimizes the magnitude of the left-to-right shunt, the heart size
and the pulmonary vascularity increase only slightly to moderately. These increases are
indistinguishable from those of a small to moderate VSD. However, unlike VSDs, the ECG
always shows RVH because the RV pressure is always high. Occasionally, LVH is also pres-
ent. The heart murmurs are caused by the PS and the VSD. Therefore, the murmur is a
superimposition of an ejection systolic murmur of PS and a regurgitant systolic murmur
of a VSD. The murmur is best audible along the lower left and mid-left sternal borders,
and it sometimes extends to the upper left sternal border. Therefore, in a child who has
physical and radiographic findings similar to those of a small VSD, the presence of RVH or
146 PART 3  Pathophysiology

S1 A2 S1 S1EC A2
P2 S1
P2
Mild Mild

Moderate Moderate

EC
S4
Severe Severe

A Tetralogy of fallot B Pulmonary stenosis

FIGURE 11-9  Comparison of ejection systolic murmurs in tetralogy of Fallot (A) and isolated pulmonary
valve stenosis (B) (see text). EC, ejection click.

BVH on the ECG should raise the possibility of acyanotic TOF. (A small VSD is associated
with LVH or a normal ECG rather than with RVH or BVH). Right aortic arch, if present,
confirms the diagnosis. Infants with acyanotic TOF become cyanotic over time, usually by
1 or 2 years of age, and have clinical pictures of cyanotic TOF, including exertional dyspnea
and squatting.
In infants with classic cyanotic TOF, the presence of severe PS produces a right-to-left
shunt at the ventricular level (i.e., cyanosis) with decreased PBF (see Fig. 11-8, B). The PAs
are small, and the LA and LV may be slightly smaller than normal because of a reduction in
the pulmonary venous return to the left side of the heart. Therefore, chest radiograph films
show a normal heart size with decreased pulmonary vascularity. The systolic pressures are
identical in the RV, LV, and aorta. The ECG demonstrates RVH because of the high pressure
in the RV. The right-to-left ventricular shunt is silent, and that the heart murmur audible in
this condition originates in the PS (ejection-type murmur). The ejection systolic murmur is
best audible at the mid-left sternal border (over the infundibular stenosis) or occasionally at
the upper left sternal border (in patients with pulmonary valve stenosis). The intensity and
the duration of the heart murmur are proportional to the amount of blood flow through
the stenotic valve. When the PS is mild, a relatively large amount of blood goes through the
stenotic valve (with a relatively small right-to-left ventricular shunt), thereby producing a
loud, long systolic murmur (Fig. 11-9, A). However, with severe PS, there is a relatively
large right-to-left ventricular shunt that is silent, and only a small amount of blood goes
through the PS, thereby producing a short, faint systolic murmur (see Fig. 11-9, A). In
other words, the intensity and duration of the systolic murmur are inversely related to the
severity of the PS. These findings are in contrast to those seen in isolated PS (Fig. 11-9, A
and B). Because of low pressure in the PA, the P2 is soft and often inaudible, resulting in a
single S2. The heart size on chest radiograph films is normal in TOF because none of the
heart chambers handle an increased amount of blood. If a cyanotic infant has a large heart
on the chest radiograph films, especially with an increase in pulmonary vascularity, TOF is
extremely unlikely unless the child has undergone a large systemic-to-PA shunt operation.
Another important point is that an infant with TOF does not develop CHF. This is because
no cardiac chamber is under volume overload, and the pressure overload placed on the RV
(not higher than the aortic pressure, which is under baroreceptor control) is well tolerated.
The extreme form of TOF is that associated with pulmonary atresia, in which the only
source of PBF is through a constricting PDA or through multiple aortic collateral arteries
(feeding into pulmonary arteries). All systemic venous return is shunted right to left at the
ventricular level, resulting in a marked systemic arterial desaturation. Probably the more
important reason for such severe cyanosis is the markedly reduced PBF, with resulting
reduction of pulmonary venous return to the left side of the heart. Unless the patency of
the ductus is maintained, the infant may die. Infusion of prostaglandin E1 has been suc-
cessful in keeping the ductus open in this and other forms of cyanotic congenital heart
defects that rely on the patency of the ductus arteriosus for PBF. Heart murmur is absent,
or a faint murmur of PDA is present. RVH is present on the ECG as in other forms of TOF.
Chest radiographs show a small heart and a markedly reduced PBF.
 11  Pathophysiology of Cyanotic Congenital Heart Defects 147

FIGURE 11-10  Simplified concept of tetralogy of Fallot that demonstrates PA AO

how a change in the systemic vascular resistance (SVR) or right ventricular
outflow tract obstruction (pulmonary resistance [PR]) affects the direction SVR
and the magnitude of the ventricular shunt. AO, aorta; LV, left ventricle; PR
PA, pulmonary artery; RV, right ventricle.

RV LV

It is important to understand what determines the amount of PBF, which in turn deter-
mines the degree of cyanosis, in patients with TOF because this concept relates to the
mechanism of the “hypoxic” spell of TOF. Because the VSD of TOF is large enough to
equalize systolic pressures in both ventricles, the RV and LV may be viewed as a single
chamber that ejects blood to the systemic and pulmonary circuits (Fig. 11-10). The ratio
of flows to the pulmonary and systemic circuits (Qp/Qs) is related to the ratio of resis-
tance offered by the right ventricular outflow obstruction (shown as pulmonary resistance
[PR] in Fig. 11-10) and the systemic vascular resistance (SVR). Either an increase in the
pulmonary resistance or a decrease in the SVR will increase the degree of the right-to-left
shunt, producing a more severe arterial desaturation. On the contrary, more blood passes
through the right ventricular outflow obstruction when the SVR increases or when the
pulmonary resistance decreases. Although controversies exist over the role of the spasm of
the RVOT as an initiating event for the hypoxic spell, there is no evidence that the spasm
actually occurs as a primary event. Pulmonary valve stenosis has a fixed resistance and
does not produce spasm. The infundibular stenosis, which consists of disorganized muscle
fibers intermingled with fibrous tissue, is almost nonreactive to sympathetic stimulation
or catecholamines. Hypoxic spell also occurs in patients with TOF with pulmonary atresia
in which the presence or absence of spasm would have no role in the spell. Therefore, it
is more likely that changes in the SVR plays a primary role in controlling the degree of
the right-to-left shunt and the amount of PBF. A decrease in the SVR increases the right-
to-left shunt and decreases the PBF with a resulting increase in cyanosis. In this case, the
RVOT dimension may decrease, but it is likely secondary to the decreased amount of blood
flowing through it rather than primary spasm. Conversely, an increase in SVR decreases
the right-to-left shunt and forces more blood through the stenotic RVOT. This results in
an improvement in the arterial oxygen saturation. Therefore, the likelihood of the RVOT
spasm initiating the right-to-left shunt is remote. Also, excessive tachycardia or hypovole-
mia can increase the right-to-left shunt through the VSD, resulting in a fall in the systemic
arterial oxygen saturation. The resulting hypoxia can initiate the hypoxic spell. Tachycardia
or hypovolemia may narrow down the RVOT, and hypovolemia with reduction of blood
pressure can initiate a hypoxic spell by increasing right-to-left ventricular shunt. Slowing
of the heart rate by β-adrenergic blockers, volume expansion, or interventions that increase
the SVR have all been used to terminate the hypoxic spell.
The hypoxic spell, also called the cyanotic spell, tet spell, or hypercyanotic spell, occurs in
young infants with TOF. It consists of hyperpnea (i.e., rapid and deep respiration), worsen-
ing cyanosis, and disappearance of the heart murmur. This occasionally results in com-
plications of the CNS and even death. Any event such as crying, defecation, or increased
physical activity that suddenly lowers the SVR or produces a large right-to-left ventricular
shunt may initiate the spell and, if not corrected, establishes a vicious circle of hypoxic
spells (Fig. 11-11). The sudden onset of tachycardia or hypovolemia can also cause the
spell as discussed earlier. The resulting fall in arterial Po2, in addition to an increase in Pco2
and a fall in pH, stimulates the respiratory center and produces hyperpnea. The hyperpnea,
in turn, makes the negative thoracic pump more efficient and results in an increase in the
systemic venous return to the RV. In the presence of fixed resistance at the RVOT (i.e., pul-
monary resistance) or decreased SVR, the increased systemic venous return to the RV must
go out the aorta. This leads to a further decrease in the arterial oxygen saturation, which
establishes a vicious circle of hypoxic spells (see Fig. 11-11).
148 PART 3  Pathophysiology

SVR FIGURE 11-11  Mechanism of hypoxic spell. A decrease

? Spasm of in the arterial Po2 stimulates the respiratory center, and
RVOT Crying hyperventilation results. Hyperpnea increases systemic
venous return. In the presence of a fixed right ventricular
outflow tract (RVOT), the increased systemic venous return
R-L SHUNT results in increased right-to-left (R-L) shunt, worsening cya-
nosis. A vicious circle is established. SVR, systemic vascular
resistance.

pO2
SYST. VENOUS
RETURN pCO2
pH

HYPERPNEA

Treatment of hypoxic spells is aimed at breaking this circle by using one or more of the
following maneuvers:
  
1. Picking up the infant in such a way that the infant assumes the knee–chest position
and traps systemic venous blood in the legs, thereby temporarily decreasing systemic
venous return and helping to calm the baby. The knee–chest position may also increase
SVR by reducing arterial blood flow to the lower extremities.
2. Morphine sulfate suppresses the respiratory center and abolishes hyperpnea.
3. Sodium bicarbonate (NaHCO3) corrects acidosis and eliminates the respiratory center–
stimulating effect of acidosis.
4. Administration of oxygen may slightly improve arterial oxygen saturation.
5. 
Vasoconstrictors such as phenylephrine raise SVR and improve arterial oxygen
saturation.
6. Ketamine is a good drug to use because it simultaneously increases SVR and sedates the
patient. Both effects are known to help terminate the spell.
7. Propranolol has been used successfully in some cases of hypoxic spell, both acute and
chronic. Its mechanism of action is not entirely clear. When administered for acute
cases, propranolol may slow the heart rate and perhaps reduce the spasm of the RVOT
(although not likely as discussed earlier). More important, propranolol may also
increase SVR by antagonizing the vasodilating effects of β-adrenergic stimulation. The
successful use of propranolol in the prevention of hypoxic spells is more likely the result
of the drug’s peripheral action. The drug may stabilize vascular reactivity of the systemic
arteries, thereby preventing a sudden decrease in SVR (see Chapter 14).
Infants and toddlers with untreated TOF often assume a squatting position after playing
hard. During playing, these infants become tachypneic and dusky. When they assume
a squatting position and rest a little while, these symptoms disappear, and then they
resume playing. What is the mechanism of recovery from these symptoms during
squatting? The squatting position is the same as the knee–chest position (which is used
to treat hypoxic spells). Squatting or the knee–chest position increases systemic arterial
oxygen saturation as shown in an experimental study (Fig. 11-12). Three mechanisms
may be involved. First, reduction of the systemic venous return by trapping venous blood
in the lower extremities reduces right-to-left shunt at the ventricular level (evidenced by
a reduced arterial lactate levels in Fig. 11-12). Second, a reduced arterial blood flow to
the legs reduces venous washout from the leg muscles. Third, squatting might also
increase SVR, a known mecha-nism to reduce right-to-left ventricular shunt.