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Basic Sciences: Answers
89
assumption can indicate publication bias. A funnel plot is a scatterplot of treatment effect
against a measure of study size. It is used primarily as a visual aid to detecting bias or
systematic heterogeneity. A symmetric inverted funnel shape arises from a ‗well-behaved‘
data set, in which publication bias is unlikely. An asymmetric funnel indicates a relationship
between treatment effect and study size. This suggests the possibility of either publication
bias or a systematic difference between smaller and larger studies (‗small study effects‘).
Asymmetry can also arise from use of an inappropriate effect measure. Whatever the cause,
an asymmetric funnel plot leads to doubts over the appropriateness of a simple meta-analysis
and suggests that there needs to be investigation of possible causes.
A variety of choices of measures of ‗study size‘ is available, including total sample size,
standard error of the treatment effect, and inverse variance of the treatment effect (weight). In
common with confidence interval plots, funnel plots are conventionally drawn with the
treatment effect measure on the horizontal axis, so that study size appears on the vertical axis,
breaking with the general rule. Since funnel plots are principally visual aids for detecting
asymmetry along the treatment effect axis, this makes them considerably easier to interpret.
The funnel plot is not without problems. If high precision studies really are different from
low precision studies with respect to effect size (e.g., due to different populations examined) a
funnel plot may give a wrong impression of publication bias. The appearance of the funnel
plot can change quite dramatically depending on the scale on the y-axis — whether it is the
inverse square error or the trial size.
References
Sterne JA, Egger M.Funnel plots for detecting bias in meta-analysis: guidelines on choice of
axis. J Clin Epidemiol. 2001;54:1046-55.
Biljana M, Jelena M, Branislav J, Milorad R. Bias in meta-analysis and funnel plot
asymmetry. Stud Health Technol Inform. 1999;68:323-8.
1.11 Answer: B
Nitric oxide is an endothelial-derived relaxing factor. In arteries
and veins, NO is
synthesized in endothelial cells and smooth
muscle cells. Endothelial cells contain the
constitutive isoenzyme
of nitric oxide synthase (NOS), which is responsible for the
continuous production and release of NO from the amino acid
precursor L-arginine. Calcium
activates constitutive
NOS in response to receptor stimulation on the endothelial membrane
by
agonists such as adenosine diphosphate, acetylcholine, bradykinin,
and thrombin. The calcium
ionophore A23187 stimulates NOS by
opening calcium channels on the endothelial cell
membrane, thus
activating constitutive NOS in a receptor-independent manner.
Under
physiologic conditions, an important stimulant of constitutive
NOS is the shear stress of blood
flowing across the endothelium,
which increases the influx of calcium into the endothelium to
activate constitutive NOS. A second isoenzyme of NOS, inducible
NOS, is calcium-
independent. It is found in vascular smooth
muscle and is undetectable under basal conditions.
It is induced
by endotoxin, tumor necrosis factor, and interleukins. Nitric oxide produced
within vascular smooth muscle cells by inducible
NOS may explain hypotension during
sepsis.
To place the role of endogenous NO in the context of pulmonary
vasomotor control it is
first important to delineate the basic
mechanisms of pulmonary vasorelaxation. The principal
intracellular
mechanisms of pulmonary vasorelaxation are ultimately mediated
through either
Shahzad G. Raja
90
cyclic adenosine 3`,5` monophosphate (cAMP) or
cyclic guanine 3`,5` monophosphate
(cGMP). The
latter can be generated through processes that are endothelial
dependent or
endothelial independent. Pharmacologic agents such
as acetylcholine bind to muscarinic
receptors on pulmonary vascular
endothelial cells, thus causing the synthesis and release of
endothelial-derived NO. Nitric oxide then diffuses into subjacent
smooth muscle cells and
activates guanylate cyclase to generate
cGMP. In turn, cGMP produces vascular smooth
muscle relaxation
by mechanisms as yet unclear. Nitrovasodilators (nitroprusside,
nitroglycerin) donate NO to directly activate guanylate cyclase
and generate cGMP
independently of the endothelium. On the other
hand, cAMP–mediated pulmonary
vasorelaxation is accomplished
by a variety of receptor-linked pathways. For example,
isoproterenol
hydrochloride stimulates ß
2
-adrenergic receptors on
the pulmonary vascular
smooth muscle cell membrane to activate
adenylate cyclase to generate cAMP.
Inhaled NO is particularly well suited as a ―selective‖ pulmonary
vasodilator. Inhaled into
the alveolus, it readily diffuses
across the alveolar-capillary membrane to relax pulmonary
vascular
smooth muscle. As it diffuses into the blood vessel
lumen, it is bound to
haemoglobin and inactivated; the affinity
of haemoglobin for NO is 3,000 times greater than it
is for oxygen.
In binding the NO, haemoglobin converts to nitrosyl-haemoglobin
and then to
methaemoglobin. Methaemoglobin converts to nitrates
and nitrites by methaemoglobin
reductase found in erythrocytes.
Most of the circulating nitrates and nitrites in blood derive
from metabolism of endogenous NO. Because of the binding to
haemoglobin, the actions of
inhaled NO are clinically focused
in the pulmonary circulation without producing unwanted
systemic
vasorelaxation. The vasodilating action of NO stops when inhaled
NO is withdrawn
from the breathing circuit. The half-life of
cGMP is less than 1 minute. Thus the
pharmacologic effects of
NO are eliminated with cessation of the drug.
References
Troncy E, Francoeur M, Blaise G. Inhaled nitric oxide: clinical applications, indications, and
toxicology. Can J Anaesth. 1997;44:973-88.
Fullerton DA, McIntyre RC Jr. Inhaled nitric oxide: therapeutic applications in cardiothoracic
surgery. Ann Thorac Surg. 1996;61:1856-64.
1.12 Answer: C
Sildenafil is a selective and potent inhibitor of phosphodiesterase (PD) type 5 which
specifically degrades cyclic guanosine monophosphate and is found in high concentrations in
pulmonary arteries and the corpora cavernosum. Normally, endothelium-derived NO
stimulates intracellular soluble guanylate cyclase resulting in increased levels of cGMP,
which then acts to mediate smooth muscle relaxation. Sildenafil inhibits the degradation of
cGMP by PD-5 and prolongs the actions of cGMP.
Metabolism of sildenafil occurs primarily by hepatic cytochrome P450 enzymes yielding
one active metabolite with a potency of approximately 50% of the parent drug. Patients with
age greater than 65, with creatinine clearance less than 30, and with hepatic cirrhosis have
reduced clearance of sildenafil.
Sildenafil is highly selective for the cGMP-hydrolyzing isoform
PD-5, with a half-
maximal inhibition (IC
50
) of PD-5 activity
at a concentration of 3.5 nmol/L, followed by IC
50
values of
34 to 38 nmol/L for PD-6 (cGMP-hydrolyzing PD in the retina)
and 280 nmol/L for
PD-1 (cAMP- and cGMP-hydrolyzing PDE isoform). The cAMP-hydrolyzing PDE-3 and
Basic Sciences: Answers
91
PD-4, and the cAMP-
and cGMP-hydrolyzing isoform PDE-2, as well as PD-7 to PD-11,
are
inhibited by sildenafil with an IC
50
of more than 2600 nmol/L.
Unlike cAMP-specific PD-3 inhibitors (milrinone, vesnarinone,
and enoximone) that
increase long-term mortality in patients
with heart failure, sildenafil is highly selective
(>
4000-fold) for human PD-5 over human PD-3 and has not been
found to elevate cAMP. The
cardiotoxic effects of PD-3
inhibitors are thought to be related to increases in intracellular
cAMP in the myocardium.
In a study published in 2003, Corbin and colleagues demonstrated
that sildenafil does not
have any direct inotropic effect on
segments from dog or human heart. These findings agree
with
other animal and clinical studies. For example, in anesthetized
dogs, no changes in
cardiac output were found at therapeutically
relevant sildenafil concentrations; similarly, in
patients
with severe coronary artery disease or stable ischemic heart
disease, no or small
decreases in cardiac output were observed
after oral (100 mg) or intravenous (40 mg)
sildenafil administration,
respectively.
References
Raja SG, Nayak SH. Sildenafil: emerging cardiovascular indications. Ann Thorac Surg.
2004;78:1496-506.
Barnett CF, Machado RF. Sildenafil in the treatment of pulmonary hypertension. Vasc Health
Risk Manag. 2006;2:411-22.
1.13 Answer: E
While each of the class I agents blocks Na
+
channels, they may
be subclassified based on
electrophysiologic differences. These
differences can be explained, to some extent, by
consideration
of the kinetics of the interaction of the drug and the Na
+
channel.
Class I drugs
bind most avidly to open (phase 0 of the action
potential) or inactivated (phase 2) Na
+
channels.
Dissociation from the channel occurs during the resting (phase
4) state. If the time
constant for dissociation is long in comparison
with the diastolic interval (corresponding to
phase 4), the
drug will accumulate in the channel to reach a steady state,
slowing conduction
in normal tissue. This occurs with class
Ia (e.g., procainamide, quinidine, and disopyramide)
and class
Ic (e.g., encainide, flecainide, and propafenone) drugs. In
contrast, for the class Ib
drugs (e.g., lidocaine and mexiletine),
the time constant for dissociation from the Na
+
channel
is short,
drug does not accumulate in the channel, and conduction velocity
is affected
minimally. However, in ischemic tissue, the depolarized
state is more persistent, leading to
greater accumulation of
agent in the Na
+
channel and slowing of conduction in the damaged
myocardium.
Ibutilide, dofetilide, sotalol, and bretylium are class III
agents. Class III agents have a
number of complex ion channel-blocking effects,
but possibly the most important activity is
K
+
channel blockade.
Since the flux of K
+
out of the myocyte is responsible for repolarization,
an important electrophysiologic effect of class III drugs is
prolongation of the action potential.
Calcium entry blockers (class IV in the Vaughan Williams scheme),
including verapamil
and diltiazem, are antiarrhythmics. In sinoatrial
and atrioventricular nodal tissue, Ca
2+
channels contribute
significantly to phase 0 depolarization, and the atrioventricular
(AV)
nodal refractory period is prolonged by Ca
2+
entry blockade.
This explains the effectiveness
of verapamil and diltiazem in
treating supraventricular arrhythmias. It is also clear why
these
drugs are negative inotropes. Both verapamil and diltiazem
are effective in slowing the
Shahzad G. Raja
92
ventricular response to atrial
fibrillation, flutter, and paroxysmal supraventricular tachycardia
and in converting to sinus rhythm. Verapamil has
greater negative inotrope effects than
diltiazem, and therefore,
it is used rarely for supraventricular arrhythmias. The intravenous
dose of diltiazem is 0.25 mg/kg, with a second dose of 0.35
mg/kg if the response is
inadequate after 15 minutes. The loading
dose should be followed by an infusion of 5 to 15
mg/h. Intravenous
diltiazem, although useful for rate control, has been replaced
by
intravenous amiodarone in clinical therapy of supraventricular
tachycardia (SVT) and
prophylaxis.
References
Levy JH, et al. Cardiac Surgical Pharmacology. Cohn LH, ed. Cardiac Surgery in the Adult.
New York: McGraw-Hill, 2008:77-110.
Ganjehei L, Massumi A, Nazeri A, Razavi M. Pharmacologic management of arrhythmias.
Tex Heart Inst J. 2011;38:344-9.
1.14 Answer: B
Amiodarone was developed
originally as an antianginal agent because of its vasodilating
effects, including coronary vasodilation. It has various ion
channel-blocking activities. The
resulting electrophysiologic
effects are complex, and there are differences in acute
intravenous
and chronic oral administration. Acute intravenous administration
can produce
decreases in heart rate and blood pressure, but
there are minimal changes in QRS duration or
QT interval. After
chronic use, there may be significant bradycardia and increases
in action
potential duration in AV nodal and ventricular tissue,
with increased QRS duration and QT
interval.
Amiodarone is a complex drug, markedly lipophilic, that undergoes
variable absorption
(35 to 65%) after oral administration and
is taken up extensively by multiple tissues with
interindividual
variation and complex pharmaco-kinetics. The short
initial context-sensitive
half-life after intravenous administration
represents drug redistribution. The true elimination
half-life
for amiodarone is extremely long, up to 40 to 60 days. Because
of the huge volume of
distribution (~60 L/kg) and a long duration
of action, an active metabolite loading period of
several months
may be required before reaching steady-state tissue concentrations.
Further, in
life-threatening arrhythmias, intravenous loading
often is started to establish initial plasma
levels. Measuring
amiodarone plasma concentrations is not useful owing to the
complex
pharmacokinetics and the metabolites of the parent drug.
Plasma concentrations greater than
2.5 mg/L have been associated
with an increased risk of toxicity. The optimal dose of
amiodarone
has not been well characterized and may vary depending on the
specific
arrhythmias treated. Further, there may be differences
in dose requirements for therapy of
supraventricular and ventricular
arrhythmias.
Because of these distinctive pharmacokinetic properties, steady-state
plasma levels are
achieved slowly. Oral administration for a
typical adult consists of a loading regimen of 80 to
1600 mg/d
(in two or three doses) for 10 days, 600 to 800 mg/d for 4 to
6 weeks, and then
maintenance doses of 200 to 600 mg/d. For
intravenous loading, specific studies will be
reviewed, but
recommended dosing is 150 mg given over 10 minutes for acute
therapy in an
adult, followed first by a secondary loading infusion
of 60 mg/h for 6 hours and then by a
maintenance infusion of
30 mg/h to achieve a 1000 mg/d dosing.
Basic Sciences: Answers
93
The electrophysiologic actions of amiodarone are complex and
incompletely understood.
Amiodarone produces all four effects
according to the Vaughan Williams classification. It
also has
been shown to have use-dependent class I activity, inhibition
of the inward sodium
currents, and class II activity. The
antiadrenergic effect of amiodarone, however, is different
from
that of beta-blocker drugs because it is noncompetitive and
additive to the effect of beta
blockers. Amiodarone depresses
sinoatrial (SA) node automaticity, which slows the heart rate
and conduction and increases refractoriness of the AV node,
properties useful in managing
supraventricular arrhythmia. Its
class III activity results in increases in atrial and ventricular
refractoriness and in prolongation of the QTc interval. The
effects of oral amiodarone on SA
and AV nodal function are maximal
within 2 weeks, whereas the effects on ventricular
tachycardia
(VT) and ventricular refractoriness emerge more gradually during
oral therapy,
becoming maximal after 10 weeks or more.
The primary indication for amiodarone is ventricular tachycardia
or fibrillation refractory
to other therapy. It is
the most efficacious agent for reducing ventricular arrhythmias
and
suppresses the incidence of post–myocardial infarction
sudden death. It is also effective, in
doses lower than those
used for ventricular dysrhythmia, for the treatment of atrial
dysrhythmia and is effective in converting atrial fibrillation
to sinus rhythm.
Although there are numerous adverse reactions to amiodarone,
they occur with long-term
oral administration and have not been
associated with acute intravenous administration. The
most serious
is pulmonary toxicity, which has not been reported with acute
administration in a
perioperative setting. Some case series
have reported an increased risk of marked bradycardia
and hypotension
immediately after cardiac surgery in patients already on amiodarone
at the
time of surgery.
References
Levy JH, et al. Cardiac Surgical Pharmacology. Cohn LH, ed. Cardiac Surgery in the Adult.
New York: McGraw-Hill, 2008:77-110.
Connolly SJ. Evidence-based analysis of amiodarone efficacy and safety. Circulation.
1999;100:2025-2034.
Chow MS. Intravenous amiodarone: Pharmacology, pharmacokinetics, and clinical use. Ann
Pharmacother. 1996;30:637-643.
1.15 Answer: E
Heparin is purified from either porcine intestine or beef lung.
Heparin that is used for
cardiac surgery includes fragments
that range from 3000 to 30,000 Da and is also called
unfractionated.
Heparin acts as an anticoagulant by binding to antithrombin
III (AT III),
enhancing the rate of thrombin–AT III complex
formation and also inhibiting other clotting
factors. One
major advantage of unfractionated heparin is that it can be
reversed immediately
by protamine. Because heparin also binds
to other proteins, it can produce platelet
dysfunction. Heparin
dosing for cardiopulmonary bypass ranges from 300 to 500 units/kg.
Heparin-induced thrombocytopenia (HIT) is an
adverse effect of heparin produced by
antibodies (IgG) to the
composite of heparin–platelet factor 4 (PF4) that leads
to the formation
of immune complexes. These immune complexes
bind to platelets via platelet Fc-receptors
(CD32), producing
intravascular platelet activation, thrombocytopenia, and platelet
activation
with potential thromboembolic complications that
can result in limb loss or death.
Shahzad G. Raja
94
Low-molecular weight heparin (LMWH) is manufactured by depolymerizing
unfractionated heparin to produce a mean molecular weight of
approximately 5000. A
pentasaccharide sequence is required
for attachment of a heparin fragment to antithrombin,
and additional
13-saccharide residues are necessary to allow the heparin fragment
to attach
itself simultaneously to the heparin-binding domain
of thrombin. LMWH fragments of less
than 18 saccharides retain
the critical pentasaccharide sequence required for formation
of a
factor Xa–antithrombin complex; LMWH inhibits both
factor Xa and thrombin, but the ratio
of factor Xa to thrombin
is increased. LMWH is used widely in cardiovascular medicine
but
poses a problem for cardiac surgical patients because of
its long half-life. Partial
thromboplastin time and activated
clotting time are not affected by LMWH, and LMWH is
not readily
reversible with protamine.
References
Levy JH, et al. Cardiac Surgical Pharmacology. Cohn LH, ed. Cardiac Surgery in the Adult.
New York: McGraw-Hill, 2008:77-110.
Hirsh J, Raschke R, Warkentin TE, et al. Heparin: Mechanism of action, pharmacokinetics,
dosing considerations, monitoring, efficacy and safety. Chest. 1995; 108:258S-275S.
1.16 Answer: A
Furosemide, bumetanide, and ethacrynic acid are three chemically dissimilar compounds
that have
the same primary diuretic mechanism of action. They act on the
tubular epithelial
cell in the thick ascending loop of Henle
to inhibit the Na
+
-K
+
-2Cl
–
cotransport mechanism.
Their
peak diuretic effect is far greater than that of the other diuretics
currently available.
Administered intravenously, they have a
rapid onset and relatively short duration of action,
the latter
reflecting both the pharmacokinetics of the drugs and the body‘s
compensatory
mechanisms to the consequences of diuresis. These
three diuretics increase renal blood flow
without increasing
glomerular filtration rate and redistribute blood flow from the medulla to
the cortex
and within the renal cortex. These changes in renal blood flow
are also short-lived,
reflecting the reduced extracellular fluid
volume resulting from diuresis. Minor actions,
including carbonic
anhydrase inhibition by furosemide and bumetanide and actions
on the
proximal tubule and on sites distal to the ascending
limb, remain controversial. All three of
the loop diuretics
increase the release of renin and prostaglandin, and indomethacin
blunts the
release as well as the augmentation in renal blood
flow and naturesis. All three of the loop
diuretics produce
an acute increase in venous capacitance for a brief period of
time after the
first intravenous dose is administered, and this
effect is also blocked by indomethacin.
Potassium, magnesium, and calcium excretion is increased in
proportion to the increase in
sodium excretion. In addition,
there is augmentation of titratable acid and ammonia excretion
by the distal tubules leading to metabolic alkalosis, which
is also produced by contraction of
the extracellular volume.
Hyperuricemia can occur but usually is of little physiologic
significance. The nephrotoxicity of cephaloridine, and possibly
other cephalorsporins, is
increased. A rare but serious side
effect of the loop diuretics is deafness, which may reflect
electrolyte changes in the endolymph.
Because of their high degree of efficacy, prompt onset, and
relatively short duration of
action, the high-ceiling or loop
diuretics are favored for intravenous administration in the
perioperative period to treat the three principal problems cited
earlier.
Basic Sciences: Answers
95
References
Levy JH, et al. Cardiac Surgical Pharmacology. Cohn LH, ed. Cardiac Surgery in the Adult.
New York: McGraw-Hill, 2008:77-110.
Sica DA, Carter B, Cushman W, Hamm L. Thiazide and loop diuretics. J Clin Hypertens
(Greenwich). 2011;13:639-43.
1.17 Answer: B
All blood leukocytes and endothelium
produce cytokines, but many tissue cells including
fibroblasts,
smooth muscle cells, cardiac myocytes, keratinocytes, chrondrocytes,
hepatocytes,
microglial cells, astrocytes, endometrial cells,
and epithelial cells also produce cytokines. IL-
1-beta and
TNF-alpha are early response cytokines that are promptly produced at
the site of
injury by resident macrophages. These cytokines
stimulate surrounding stromal and
parenchymal cells to produce
more IL-1-beta and TNF-alpha and chemokines, particularly IL-
8
and MCP-1, which are powerful chemoattractants for neutrophils
and macrophages,
respectively. Together with IL-6, the cytokine
that regulates production of acute-phase
proteins (e.g., C-reactive
protein and alpha
2
-macroglobulin) by the liver, these five
cytokines
are the major proinflammatory cytokines involved in the
acute inflammatory response to
cardiopulmonary bypass (CPB).
The major anti-inflammatory cytokine involved during CPB is
IL-10. IL-10 inhibits
synthesis of proinflammatory cytokines
by monocytes and macrophages and induces
production of IL-1
receptor antagonist (IL-1ra), which downgrades the response to
IL-1. IL-13
down-regulates production of IL-1, IL-8,
and IL-10 and reduces monocyte production of
reactive oxidants; its role during CPB is undetermined.
References
Hammon JW. The response of humoral and cellular elements of blood to extracorporeal
circulation. Cohn LH, ed. Cardiac Surgery in the Adult. New York: McGraw-Hill,
2008:370-389.
Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg.
2003;75:S715-20.
1.18 Answer: D
Aprotinin is a natural serine protease inhibitor in the kinin
superfamily that strongly
inhibits plasmin and weakly inhibits
kallikrein. Plasma concentrations of 4 to 10 KIU
(kallikrein
inhibitory units) of aprotinin completely inhibit plasmin, but
250 to 400 KIU are
required to fully inhibit kallikrein.
Clinical doses of aprotinin totally inhibit plasmin, but are
not sufficient to completely inhibit kallikrein. The antifibrinolytic
and platelet-sparing effects
of the drug are well known and
significantly reduce blood losses during and after complex
cardiac
surgery. The anti-inflammatory effects of aprotinin
are more difficult to quantitate and
may reflect multiple mechanisms
including partial kallikrein inhibition, direct effects, and
inhibition of NF- B.
In vitro aprotinin inhibits kallikrein formation, and attenuates complement
activation and
release of platelet beta thromboglobulin and
neutrophil elastase. Aprotinin also reduces
neutrophil transmigration
and expression of ICAM-1 and vascular cell adhesion molecule-1
by endothelial cells. Clinically, aprotinin reduces
circulating TNF-alpha, IL-6, IL-8, and
Shahzad G. Raja
96
neutrophil CD11b expression,
and synergistically increases IL-10 synthesis. The drug
may
also attenuate neutrophil activation and myocardial damage during
aortic cross-clamping and
reduce overall mortality. Nevertheless, low-
or high-dose aprotinin used in large, randomized
controlled
clinical trials fails to show a reduction in proinflammatory
cytokines, activated
complement, neutrophil elastase, and myeloperoxidase.
Thus the efficacy of aprotinin as an
anti-inflammatory agent
remains unresolved.
References
Hammon JW. The response of humoral and cellular elements of blood to extracorporeal
circulation. Cohn LH, ed. Cardiac Surgery in the Adult. New York: McGraw-Hill,
2008:370-389.
Hill GE, Diego RP, Stammers AH, et al. Aprotinin enhances the endogenous release of
interleukin-10 after cardiac operations. Ann Thorac Surg. 1998;65:66-69.
Asimakopoulos G, Lidington EA, Mason J, et al. Effect of aprotinin on endothelial cell
activation. J Thorac Cardiovasc Surg. 2001;122:123-128.
1.19 Answer: C
The brain uses up to 20% of total-body oxygen consumption, with 40%
of its energy used
in the preservation of cellular integrity
and 60% in the transmission of nerve impulses.
Hypothermia
reduces the metabolic rate of the central nervous system and
lengthens the
period of ischemia tolerated. The central nervous
system almost exclusively extracts its
energy through aerobic
glycolysis. The uptake of oxygen or glucose consequently is
a reliable
parameter of the cerebral metabolic rate. Using oxygen
and glucose consumption, animal
studies showed a drop in the
brain metabolic rate of 50% at 28°C, 19% at 18°C, and 11%
at
8°C. Comparable results using less precise methods
of measurement were obtained in
humans. The reduction
in metabolic rate in relation to temperature espouses an exponential
curve, with a greater drop at high temperatures (about 6% for
1°C around 37°C) than at low
temperatures (about 1%
at 15°C). A luxurious perfusion of the brain is rapidly
set when the
metabolic rate is reduced and perfusion flow rate
maintained. The arteriovenous difference of
oxygen, glucose, and
brain-produced metabolites decreases. The luxurious perfusion is,
however, of limited help in view of an ischemic period because additional
energetic reserve
cannot be stored in neurons. The obvious clinical
implication of these findings is that
although reduced, the metabolism
of the brain is not suppressed by hypothermia and actually
remains
relatively high at 18°C, a common target temperature in surgical
practice. Assuming
an ischemic tolerance of 5 minutes at normothermia,
the calculated safe period of circulatory
arrest for the central
nervous system would not exceed 25 minutes at 18°C and 38
minutes at
13°C.
References
Pretre R, Turina MI. Deep hypothermic circulatory arrest. Cohn LH, ed. Cardiac Surgery in
the Adult. New York: McGraw-Hill, 2008:431-442.
McCullough JN, Zhang N, Reich DL, et al. Cerebral metabolic suppression during
hypothermic circulatory arrest in humans. Ann Thorac Surg. 1999; 67:1895-1899.
Basic Sciences: Answers
97
1.20 Answer: A
Two strategies for blood gas management are possible during
hypothermia. Alpha-stat
management (the mechanism prevailing
in reptiles) aims at maintaining normal pH and blood
gases (a
pH of 7.40 and a PaCO
2
of 40 mm Hg) in the rewarmed (to 37°C)
blood. In vivo, the
hypothermic blood is alkaline and hypocapnic.
pH-stat management (the mechanism
prevailing in hibernating
animals) aims at maintaining normal values in vivo in the
hypothermic
blood. When rewarmed to 37°C, the blood becomes acidotic
and hypercapnic.
Alpha-stat management preserves autoregulation of brain perfusion and
optimizes cellular
enzyme activity. Because of the blood alkalosis, the
curve of oxyhemoglobin dissociation is
shifted toward the right, corresponding
to an increased affinity of oxygen for hemoglobin.
With the
further shift of oxyhemoglobin to the right owing to hypothermia, the
availability of
oxygen carried by the hemoglobin molecule becomes tremendously
reduced. At deep
temperature, oxygen diluted in blood represents
the major source of oxygen to tissues.
The pH-stat strategy, because of the high level of carbon dioxide, results
in a powerful
and sustained dilatation of the cerebral vessels. Autoregulation
of brain perfusion is lost, and
cerebral blood flow is increased
greatly. The time for temperature equilibration between blood
and brain is shortened, resulting in a quick and homogeneous cooling
of the brain.
Hypercapnia shifts the oxyhemoglobin dissociation curve
to the left and results in an
increased availability of oxygen to
tissues.
A comparison between the two strategies has been performed mainly in
neonates and
small animals. In piglets, a pH-stat strategy resulted in
improved recovery of cerebral
metabolism and better histologic and
behavioral scores. In neonates, the same strategy
provided
superior psychometric scores at midterm evaluation. The superiority
of the pH-stat
strategy has not been confirmed in adults, however.
Prospective studies found no differences
or even worse neuropsychological outcomes.
Because it maintains a physiologic coupling
between cerebral
blood flow and metabolism, the alpha-stat strategy appears advantageous
in
adults where the risk of under- or overperfusion within the
brain is substantial. Cerebral
edema, which can be a consequence
of cerebral overperfusion, is less likely to occur. Finally,
the preservation of cerebral autoregulation may attenuate the
inhomogeneous distribution of
blood that is prone to occur in patients
with an underlying vasculopathy such as
atherosclerosis, hypertension,
and diabetes.
References
Pretre R, Turina MI. Deep hypothermic circulator arrest. Cohn LH, ed. Cardiac Surgery in
the Adult. New York: McGraw-Hill, 2008:370-389.
Murkin JM, Martzke JS, Buchan AM, et al: A randomized study of the influence of perfusion
technique and pH management strategy in 316 patients undergoing coronary artery
bypass surgery: II. Neurologic and cognitive outcomes. J Thorac Cardiovasc Surg.
1995;110:349-362.
Halstead JC, Spielvogel D, Meier DM, et al. Optimal pH strategy for selective cerebral
perfusion. Eur J Cardiothorac Surg. 2005;28:266-273.
1.21 Answer: B
In a typical fast-response action potential that occurs in atrial
and ventricular myocytes
and special conduction fibers as the transmembrane potential decreases to approximately –65
mV, the "fast" sodium channels open. These channels remain open
for a few milliseconds
Shahzad G. Raja
98
until the inactivation gate of the fast
sodium channel closes. The large gradient of sodium ions
(extracellular
145 mM, intracellular 10 mM) promotes rapid influx, depolarizing
the cell to a
slightly positive transmembrane potential. This
is phase 0 of the action potential. A transient
potassium current
(i
to
) causes a very early repolarization (phase 1) of the action
potential, but
this fast channel closes quickly. The plateau
of the action potential (phase 2) is sustained at a
neutral
or slightly positive level by an inward-flowing calcium current,
first from the transient
calcium channel and second through
the long-lasting calcium channel. The plateau also is
sustained by
a decrease in the outward potassium current (i
k1
). With time,
the long-lasting
calcium channel begins to close, and the repolarizing
potassium current (i
k
, the delayed
rectifier current) leads
to the initiation of phase 3 of the action potential. As repolarization
progresses, the stronger first potassium current (i
k1
) dominates,
leading to full repolarization
of the membrane to the resting
negative potential. During the bulk of the depolarized interval
(phase 4), the first potassium current predominates in myocytes.
Because the sodium channels
cannot respond to a second wave
of depolarization until the inactivation gates are reopened
(by repolarization during phase 3), the membrane is refractory
to the propagation of a second
impulse during this time interval,
referred to as the absolute refractory period. As the
membrane
is repolarized during early phase 3 of the action potential,
and some of the sodium
channels have been reactivated, a short
interval exists during which only very strong impulses
can activate
the cell, which is termed the relative refractory period. A
drug that acts to speed
up the kinetics of the inactivation gate
will shorten both the absolute and the relative
refractory periods.
References
Savage EB, et al. Cardiac surgical physiology. Cohn LH, ed. Cardiac Surgery in the Adult.
New York: McGraw-Hill, 2008:51-76.
Katz AM. The cardiac action potential.Katz AM, ed. Physiology of the Heart. New York:
Raven Press, 1992:438.
1.22 Answer: B
The function of the heart can be described and quantified based on
the relative
intraventricular pressure and volume during the
cardiac cycle (Figure 1). Based on this
relationship, various
measures can be derived to assess cardiac performance (discussed
below). The ventricular pressure-volume relationship derives
from the Frank-Starling
relationship of sarcomere length and peak
developed force: The force and extent of
contraction (stroke volume)
is a function of end-diastolic length (volume).
End diastole (ED) is represented at the lower right corner of the loop in Figure 1A.
The
pressure-volume loop then successively tracks changes through
isovolumic contraction (up to
the upper right corner), ejection
[left to the upper left corner—which represents end systole
(ES)], isovolumic
relaxation (down to the bottom left corner), and then filling
(right to the
lower right corner). Descriptive data to assess
ventricular function are derived from the end-
systolic pressure-volume
point located in the upper left corner of the loop and the end-
diastolic
pressure-volume point located in the lower right corner of the
loop. The area within
the pressure-volume loop represents the
internal work of the chamber.