Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3981_Библиотеки_им_академика_М_И_Перельмана.pdf
Paediatric Cardiothoracic Surgery: Questions
79
B. more frequently affects upper lobes.
C. in an adult is seen as a water-density mass.
D. is almost always symptomatic.
E. is best diagnosed on plain chest radiograph.
4.33 Cardiopulmonary bypass (CPB) is known to trigger a global inflammatory
response. Which of the following statements regarding the CPB-induced inflammation is
correct?
A. Complement activation mainly occurs through classical pathway.
B. The anaphylatoxins
C3a and C5a cause degranulation of eosinophils with histamine
release.
C. Kallikrein enters a negative feedback loop with factor XIIa.
D. Plasma kallikrein levels significantly decrease after the administration of heparin.
E. The
neutrophil cell membrane is the primary source of arachidonic
acid.
4.34 Congenitally corrected transposition is a rare cardiac malformation.
Congenitally corrected transposition
A. is characterized by concordant atrioventricular and discordant ventriculo-arterial
connections.
B. has morphologically left ventricle usually positioned to the right.
C. has abnormal physiology.
D. does not have recurrence risk in siblings of previously affected children.
E. patients present with cyanosis in earl infancy.
4.35 Complete atrioventricular canal, also referred to as complete atrioventricular
septal defect, is an uncommon congenital heart disease. Complete atrioventricular canal
A. is characterised by an ostium primum atrial septal defect, separate atrioventricular
valves and a variable deficiency of the ventricular septum inflow.
B. predominantly affects males.
C. Rastelli type A has the superior bridging leaflet almost completely adherent to the left
ventricle.
D. Rastelli type B is the most common form of atrioventricular canal.
E. is characterised by common atrioventricular valve with four leaflets.
Section Two: Answers
Chapter I
Basic Sciences
1.1 Answer: C
A forest plot is a graphical display designed to illustrate the relative strength of treatment
effects in multiple quantitative scientific studies addressing the same question. It was
developed for use in medical research as a means of graphically representing a meta-analysis
of the results of randomised controlled trials. In the last twenty years, similar meta-analytical
techniques have been applied in observational studies and forest plots are often used in
presenting the results of such studies also.
Although forest plots can take several forms, they are commonly presented with two
columns. The left-hand column lists the names of the studies, commonly in chronological
order from the top downwards. The right-hand column is a plot of the measure of effect (e.g.,
an odds ratio) for each of these studies (often represented by a square) incorporating
confidence intervals represented by horizontal lines. The graph may be plotted on a natural
logarithmic scale when using odds ratios or other ratio-based effect measures, so that the
confidence intervals are symmetrical around the means from each study and to ensure undue
emphasis is not given to odds ratios greater than 1 when compared to those less than 1. The
area of each square is proportional to the study's weight in the meta-analysis. The overall
meta-analysed measure of effect is often represented on the plot as a vertical line. This meta-
analysed measure of effect is commonly plotted as a diamond, the lateral points of which
indicate confidence intervals for this estimate.
A vertical line representing no effect is also plotted. If the confidence intervals for
individual studies overlap with this line, it demonstrates that at the given level of confidence
their effect sizes do not differ from no effect for the individual study. The same applies for the
meta-analysed measure of effect: if the points of the diamond overlap the line of no effect the
overall meta-analysed result cannot be said to differ from no effect at the given level of
confidence.
References
Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ.
2001;322(7300):1479-80.
Shahzad G. Raja
84
1.2 Answer: B
Dopamine, an endogenous central neurotransmitter, is the immediate
precursor to
norepinephrine in the catecholamine synthetic pathway. When administered therapeutically, it
acts on dopaminergic
and adrenergic receptors to elicit a multitude of clinical effects. At low
doses (0.5 to 3 µg · kg
–1
· min
–1
), stimulation of dopaminergic D
1
postsynaptic
receptors
concentrated in the coronary, renal, mesenteric, and
cerebral beds and D
2
presynaptic
receptors present in the vasculature
and renal tissues promotes vasodilation and increased
blood
flow to these tissues. Dopamine also has direct natriuretic
effects through its action on
renal tubules. The clinical significance
of "renal-dose" dopamine is somewhat controversial,
however,
because it does not increase glomerular filtration rate, and
a renal protective effect
has not been demonstrated. At intermediate
doses (3 to 10 µg · kg
–1
· min
–1
),
dopamine
weakly binds to β
1
-adrenergic receptors, promoting
norepinephrine release and inhibiting
reuptake in presynaptic
sympathetic nerve terminals, which results in increased cardiac
contractility and chronotropy, with a mild increase in systemic vascular resistance.
At higher
infusion rates (10 to 20 µg · kg
–1
· min
–1
),
1
-adrenergic receptor–mediated
vasoconstriction
dominates.
References
Overgaard CB, Dzavík V. Inotropes and vasopressors: review of physiology and clinical use
in cardiovascular disease. Circulation. 2008;118:1047-56.
Bellomo R, Chapman M, Finfer S, et al. Australian and New Zealand Intensive Care Society
(ANZICS) Clinical Trials Group. Low-dose dopamine in patients with early renal
dysfunction: a placebo-controlled randomised trial. Lancet. 2000; 356: 2139-2143.
1.3 Answer: B
Nearly all chemical energy used by the heart is generated by
oxidative phosphorylation.
Anaerobic metabolism is very limited
because anaerobic enzymes are not present in sufficient
concentrations.
The major fuels for the myocardium are carbohydrates (i.e.,
glucose and
lactate) and free fatty acids. When sufficient oxygen
is present, these fuels are used to
generate adenosine triphosphate (ATP). Most of the
ATP used by the heart (60 to 70%) is
expended in the cyclic
contraction of the muscle; 10 to 15% is required for maintaining
the
concentration gradients across the cell membrane; the rest
is used in the constant uptake and
release of calcium by mitochondria,
the breakdown and regeneration of glycogen, and the
synthesis
of triglycerides.
The heart is quite flexible in the aerobic state in its use
of fuels. In the fasting state, lipids
may account for 70% of
the fuel used by the heart. After a high-carbohydrate meal,
blood
glucose and insulin levels are high and free fatty acids
are low, and glucose accounts for close
to 100% of the metabolism.
During exercise, elevated lactate levels inhibit the uptake
of free
fatty acids, and carbohydrates, mostly lactate, can
account for up to 70% of the metabolism.
References
Savage EB, et al. Cardiac Surgical Physiology. Cohn LH, ed. Cardiac Surgery in the Adult.
New York: McGraw-Hill, 2008:51-76.
Stanley WC, Chandler MP. Energy metabolism in the normal and failing heart: potential for
therapeutic interventions. Heart Fail Rev. 2002;7:115-30.
Basic Sciences: Answers
85
1.4 Answer: C
In the well-perfused heart, ∼60–90% of the acetyl-CoA comes from β-oxidation of fatty
acids, and 10–40% comes from the oxidation of pyruvate that is derived in approximately
equal amounts from glycolysis and lactate oxidation. The glycolytic pathway converts
glucose 6-phosphate and NAD
+
to pyruvate and NADH and generates two ATP for each
molecule of glucose. The NADH and pyruvate formed in glycolysis are either shuttled into
the mitochondrial matrix to generate CO
2
and NAD
+
and complete the process of aerobic
oxidative glycolysis or converted to lactate and NAD
+
in the cytosol (nonoxidative
glycolysis).
The healthy nonischemic heart is a net consumer of lactate even under conditions of near-
maximal cardiac power. The myocardium becomes a net lactate producer only when there is
accelerated glycolysis in the face of impaired oxidation of pyruvate, such as occurs with
ischemia or poorly controlled diabetes. There is a high rate of bidirectional lactate
transmembrane flux and conversion to pyruvate. Lactate transport across the cardiac
sarcolemma is facilitated by the monocarboxylic acid transporter-1 (MCT-1).
Glycolytic substrate is derived from exogenous glucose and glycogen stores. Glucose
transport into cardiomyocytes is regulated by the transmembrane glucose gradient and the
content of glucose transporters in the sarcolemma (mainly GLUT-4, and to a lesser extent
GLUT-1). There is a translocation of glucose transporters from intracellular vesicles to the
sarcolemmal membrane in response to insulin stimulation, increased work demand, or
ischemia, which increases the membrane capacitance for glucose transport and the rate of
glucose uptake.
References
Stanley WC, Chandler MP. Energy metabolism in the normal and failing heart: potential for
therapeutic interventions. Heart Fail Rev. 2002;7:115-30.
Gertz EW, Wisneski JA, Stanley WC, and Neese RA. Myocardial substrate utilization during
exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J Clin Invest.
1988: 82; 2017–2025.
1.5 Answer: D
Under nonischemic conditions almost all (>95%) of ATP formation in the heart comes
from oxidative phosphorylation in the mitochondria, with the remainder derived from
glycolysis and GTP formation in the citric acid cycle. The heart has a relatively low ATP
content (5 µmol/g wet wt) and high rate of ATP hydrolysis (∼0.5 µmol · g wet wt
–1
· s
–1
at
rest), thus there is complete turnover of the myocardial ATP pool approximately every 10 s
under normal conditions. Approximately 60–70% of ATP hydrolysis fuels contractile
shortening, and the remaining 30–40% is primarily used for the sarcoplasmic reticulum Ca
2+
-
ATPase and other ion pumps. In the healthy heart the rate of oxidative phosphorylation is
exquisitely linked to the rate of ATP hydrolysis so that ATP content remains constant even
with large increases in cardiac power, such as occur during intense exercise or acute
catecholamine stress. Mitochondrial oxidative phosphorylation is fueled with energy from
electrons that are transferred from carbon fuels by dehydrogenation reactions that generate
nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH
2
)
produced primarily in the fatty acid β-oxidation pathway, the citric acid cycle, and to a lesser
Shahzad G. Raja
86
extent from the pyruvate dehydrogenase reaction and glycolysis. There is a stoichiometric
link between the rate of oxidation of carbon fuels, NADH and FADH
2
reduction, flux through
the electron transport chain, oxygen consumption, oxidative phosphorylation, ATP
hydrolysis, actin-myosin interaction, and external contractile power produced by the heart.
Thus an increase in contractile power results in a concomitant increase in all of the
components in the system.
References
Stanley WC, Chandler MP. Energy metabolism in the normal and failing heart: potential for
therapeutic interventions. Heart Fail Rev. 2002;7:115-30.
Goldfarb AH, Bruno JF, and Buckenmeyer PJ. Intensity and duration effects of exercise on
heart cAMP, phosphorylase, and glycogen. J Appl Physiol. 1986:60;1268-1273.
1.6 Answer: C
Dobutamine is a synthetic catecholamine with a strong affinity for both β
1
- and β
2
-
receptors, which it binds to at a 3:1 ratio. With its cardiac β
1
-stimulatory effects, dobutamine
is a potent inotrope, with weaker chronotropic activity. Vascular smooth muscle binding
results in combined α
1
-adrenergic agonism and antagonism, as well as β
2
-stimulation, such
that the net vascular effect is often mild vasodilation, particularly at lower doses (≤5 μg · kg
−1
· min
−1
). Doses up to 15 μg · kg
−1
· min
−1
increase cardiac contractility without greatly
affecting peripheral resistance, likely owing to the counterbalancing effects of α
1
-mediated
vasoconstriction and β
2
-mediated vasodilation. Vasoconstriction progressively dominates at
higher infusion rates.
Despite its mild chronotropic effects at low to medium doses, dobutamine significantly
increases myocardial oxygen consumption. This exercise-mimicking phenomenon is the basis
upon which dobutamine may be used as a pharmacological stress agent for diagnostic
perfusion imaging, but conversely, it may limit its utility in clinical conditions in which
induction of ischemia is potentially harmful. Tolerance can develop after just a few days of
therapy, and malignant ventricular arrhythmias can be observed at any dose.
References
Overgaard CB, Dzavík V. Inotropes and vasopressors: review of physiology and clinical use
in cardiovascular disease. Circulation. 2008;118:1047-56.
Ruffolo RR Jr. The pharmacology of dobutamine. Am J Med Sci. 1987;294:244-248.
1.7 Answer: E
Norepinephrine (noradrenaline), the major endogenous neurotransmitter liberated by
postganglionic adrenergic nerves, is a potent α
1
-adrenergic receptor agonist with modest β-
agonist activity, which renders it a powerful vasoconstrictor with less potent direct inotropic
properties. Norepinephrine primarily increases systolic, diastolic, and pulse pressure and has a
minimal net impact on CO. Furthermore, this agent has minimal chronotropic effects, which
makes it attractive for use in settings in which heart rate stimulation may be undesirable.
Coronary flow is increased owing to elevated diastolic blood pressure and indirect stimulation
of cardiomyocytes, which release local vasodilators. Prolonged norepinephrine infusion can
have a direct toxic effect on cardiac myocytes by inducing apoptosis via protein kinase A
activation and increased cytosolic Ca
2+
influx.
Basic Sciences: Answers
87
References
Overgaard CB, Dzavík V. Inotropes and vasopressors: review of physiology and clinical
use in cardiovascular disease. Circulation. 2008;118:1047-56.
Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine stimulates apoptosis
in adult rat ventricular myocytes by activation of the β-adrenergic pathway. Circulation.
1998;98:1329-1334.
1.8 Answer: B
The nonapeptide vasopressin or ―antidiuretic hormone‖ is stored primarily in granules in
the posterior pituitary gland and is released after increased plasma osmolality or hypotension,
as well as pain, nausea, and hypoxia. Vasopressin is synthesized to a lesser degree by the
heart in response to elevated cardiac wall stress and by the adrenal gland in response to
increased catecholamine secretion. It exerts its circulatory effects through V
1
(V
1a
in vascular
smooth muscle, V
1b
in the pituitary gland) and V
2
receptors (renal collecting duct system).
V
1a
stimulation mediates constriction of vascular smooth muscle, whereas V
2
receptors
mediate water reabsorption by enhancing renal collecting duct permeability.
Vasopressin causes less direct coronary and cerebral vasoconstriction than
catecholamines and has a neutral or inhibitory impact on cardiac output, depending on its
dose-dependent increase in systemic vascular resistance and the reflexive increase in vagal
tone. A vasopressin-modulated increase in vascular sensitivity to norepinephrine further
augments its pressor effects. The agent may also directly influence mechanisms involved in
the pathogenesis of vasodilation, through inhibition of ATP-activated potassium channels,
attenuation of nitric oxide production, and reversal of adrenergic receptor downregulation.
The pressor effects of vasopressin are relatively preserved during hypoxic and acidotic
conditions, which commonly develop during shock of any origin.
References
Overgaard CB, Dzavík V. Inotropes and vasopressors: review of physiology and clinical use
in cardiovascular disease. Circulation. 2008;118:1047-56.
Guillon G, Grazzini E, et al. Vasopressin: a potent autocrine/paracrine regulator of mammal
adrenal functions. Endocr Res. 1998; 24: 703-710.
1.9 Answer: D
Levosimendan, a pyridazinone-dinitrite and a member
of a new class of agents, the
calcium sensitizers, that increase
myocardial contractility without increasing intracellular
calcium,
has emerged as an inotropic agent. In preclinical
and clinical studies, levosimendan
has been shown to exert potent
dose-dependent positive inotropic and vasodilatory activity
and has emerged as a promising alternative to conventional inotropic
agents for patients with
decompensated heart failure.
Agents currently available for the treatment of decompensated
heart failure increase
myocardial concentrations of cyclic adenosine
monophosphate (cAMP), which ultimately
causes an inotropic effect
by increasing myocardial concentrations of calcium.
Catecholamines
such as dobutamine stimulate beta-1 adrenoceptors on the myocardial
cells,
causing increases in cAMP, while phosphodiesterase inhibitors
such as milrinone prevent the
breakdown of cAMP by phosphodiesterase.
The increase in cAMP provided by
catecholamines and phosphodiesterase
inhibitors causes an up-regulation in the activity of
Shahzad G. Raja
88
protein
kinase C, which increases the calcium current into myocytes
during systole to cause an
increased inotropic effect.
In contrast, levosimendan reduces the calcium-binding coefficient
of troponin C by stabilizing the conformational shape of the
protein in its active form. This
enhances myocardial contraction
similar to traditional agents but with lower intracellular
calcium
concentration requirements. Even though levosimendan
does not enhance
intracellular calcium, there is a concentration-response
relationship between intracellular
calcium and inotropy.
Levosimendan offers the advantage of increasing systolic force
without compromising
coronary perfusion due in part to a synergistic
mechanism of action attributed to opening of
the adenosine triphosphate-sensitive
potassium channels. The opening of adenosine
triphosphate-sensitive potassium channels by adenosine triphosphate
(ATP) produces
peripheral vasodilation, coronary artery dilation,
and myocyte mitochondrial activation. All
these beneficial
effects work synergistically with calcium sensitization to improve
myocardial
performance.
Unlike classic inotropes, levosimendan does not impair diastolic
function or lusitropy. In
vitro studies have consistently demonstrated
either a neutral or a positive lusitropic effect. It is
hypothesized that the neutral effect on diastolic function is
secondary to the calcium-
dependent binding to troponin C.
The mechanism for the positive lusitropic effects can be
attributed
to PD III inhibition at higher concentrations. Phosphodiesterase (PD)
inhibition
leads to increased cAMP levels, augmented phosphorylation
of phospholamban, and thus
enhanced removal of cytosolic calcium
by the sarcoplasmic-endoplasmic reticulum ATPase
pump, resulting
in accelerated relaxation of the myofilaments.
Although levosimendan is a potent and highly selective inhibitor
of PD III, this action, at
low doses, does not contribute to
its inotropic and vasodilator properties because the extent
of
this activity does not cause an increase in the intracellular
levels of cAMP. Furthermore, in
contrast to specific
PD III inhibitors such as amrinone and milrinone, the positive
inotropic
effect of levosimendan in cardiac tissue is not attenuated
by disease.
At therapeutic doses, levosimendan exhibits enhanced myocardial
contractility with no
increase in oxygen demands. Intravenous levosimendan significantly increases cardiac output
or cardiac index and decreases ventricular filing pressures
in the acute treatment of stable or
decompensated congestive
heart failure. It is also of benefit in the setting
of pulmonary
vasoconstriction and right ventricular dysfunction.
The drug has been shown to increase
ventricular contractility
and hydraulic power without changing pulmonary vascular resistance
in experimental setup. In patients with heart failure,
the drug has been shown to reduce
pulmonary vascular resistance.
References
Raja SG, Rayen BS. Levosimendan in cardiac surgery: current best available evidence. Ann
Thorac Surg. 2006;81:1536-46.
Rognoni A, Lupi A, Lazzero M, Bongo AS, Rognoni G. Levosimendan: from basic science to
clinical trials. Recent Pat Cardiovasc Drug Discov. 2011;6:9-15.
1.10 Answer: C
A funnel plot is a useful graph designed to check the existence of publication bias in
systematic reviews and meta-analyses. It assumes that the largest studies will be near the
average, and small studies will be spread on both sides of the average. Variation from this