Sladen: Inflammatory Response to CPB. Page 1
Title:
The Inflammatory Response to CPB: Why Am I So Vasodilated?
Author:
Robert N. Sladen, MBChB, FCCM
Affiliation:
College of Physicians & Surgeons of Columbia University, New York, NY
Learning Objectives:
1.
2.
3.
4.
To describe the pathogenesis of the inflammatory response to CPB.
To understand the mechanism and consequences of contact activation induced by CPB.
To explore biochemical pathways that lead to refractory vasodilatory shock.
To review the role of, and evidence for, norepinephrine, arginine vasopressin and
methylene blue therapy in vasodilatory shock.
THE INFLAMMATORY RESPONSE TO CPB
The inflammatory response to cardiopulmonary bypass (CPB) is characterized by
profound, sometimes refractory vasodilation, known as vasodilatory shock or vasoplegia.
In its extreme manifestation, it can result in a systemic inflammatory response syndrome
(SIRS). Vasodilatory shock may accompany heart failure, especially with protracted
cardiogenic shock; sepsis; occur as an idiosyncratic response to cardiopulmonary bypass
(CPB) or after prolonged CPB; with extracorporeal membrane oxygenation (ECMO) or
ventricular assist device (VAD) insertion (Fig. 1). It may be exacerbated by certain
vasodilatory drugs, e.g. angiotensin converting enzyme (ACE) inhibitors or milrinone1.
Figure 1: Inflammatory Response to Cardiopulmonary Bypass. SBE = subacute
bacterial endocarditis, ACEI = angiotensin converting enzyme inhibitors, CPB =
cardiopulmonary bypass, ECMO = extracorporeal membrane oxygenation; VAD =
ventricular assist device, SIRS = systemic inflammatory response syndrome.
Sladen: Inflammatory Response to CPB. Page 2
CPB AND CONTACT ACTIVATION
The inflammatory response to CPB appears to be mediated by complement
activation, neutrophil migration, cytokine production and arachidonic acid metabolites.
Contact activation of the blood by the extracorporeal circuit (Fig. 2) triggers a series of
amplification cascades mediated by proteolytic enzymes, especially serine proteases.
Figure 2. Contact Activation. DIC = disseminated intravascular coagulation, C’ =
complement.
Contact activation with the foreign surface of CPB triggers the activation of
Hageman (Factor XII), which simultaneously activates the intrinsic pathway of
coagulation, fibrinolysis and the complement system. Contact activation may be
continued beyond CPB by the insertion of devices such as ECMO or a VAD.
Activation of the intrinsic pathway immediately triggers thrombogenesis, so full
anticoagulation is essential to prevent lethal macroclot during CPB. However, microclot
formation may proceed despite heparinization, resulting in consumption of circulating
procoagulants (consumption coagulopathy), obstruction of the microcirculation (DIC),
bleeding and organ injury. Hagemann Factor simultaneously activates kallikrein, an
enzyme that cleaves plasminogen to plasmin, inducing fibrinolysis. Recognition of the
central role of fibrinolysis activation during CPB has led to the ubiquitous administration
of antifibrinolytic agents such as epsilon aminocaproic acid (EACA) or tranexamic acid.
An endogenous kallikrein inhibitor, aprotinin, was used for many years during CPB for
its potent antifibrinolytic and anti-inflammatory actions, but it is being currently withheld
from the US market on the basis of an adverse outcomes study.
Activation of complement, especially the C’3a and C’5a anaphylatoxins, triggers
vasospasm and leukocyte activation. Leukocytes may also be activated by shear stress
and contact with the CPB circuit2-4. Levels of neutrophil elastase, a measure of neutrophil
activation, peak at the end of CPB and are associated with intrapulmonary shunt and
postoperative pulmonary dysfunction5. The consequence is leukocyte degranulation,
adhesion, aggregation and embolization, and release of toxic oxygen free radicals and
Sladen: Inflammatory Response to CPB. Page 3
proteolytic enzymes6. Activated leukocytes also produce peptide cytokines such as tumor
necrosis factor-alpha (TNF-alpha) and interleukins (IL). Elevated levels of TNF-alpha,
IL-6 and IL-8 are observed after CPB7,8. Cytokines exacerbate the inflammatory
response by exacerbation neutrophil adhesion and aggregation9.
Complement activation and neutrophil arachidonic acid metabolites (e.g.
leukotriene B4) increase vascular permeability and cause mast cell degranulation. The
net result is an acute inflammatory response, which may culminate in SIRS, and
characterized by abnormal vascular response, capillary leak syndrome with diffuse
interstitial edema, and multiorgan dysfunction. Plasma complement concentrations,
duration of CPB, and the degree of elevation of C’3a levels have been correlated with the
degree of postoperative organ dysfunction6.
PATHOGENESIS OF VASODILATORY SHOCK
There are multiple mechanisms of vasodilatory shock, but three are most
important: (1) opening of potassium-adenosine triphosphate (KATP) channels; (2) acute
arginine vasopressin (AVP) deficiency and (3) widespread activation of inducible nitric
oxide synthase (iNOS) and massive release of nitric oxide.
Opening of KATP Channels
Vasoconstrictors such as norepinephrine (NE) and angiotensin stimulate Gprotein coupled endothelial receptors that open cell membrane calcium channels and
promote an influx of calcium. This, together with the release of calcium from
intracellular stores, activates a kinase that enhances the phosphorylation of myosin and
results in muscle contraction and vasoconstriction. In the presence of intracellular
acidosis, lactate accumulation and ATP depletion, membrane KATP channels open and
allow an efflux of potassium. This hyperpolarizes the membrane and closes the calcium
channels, resulting in vasodilation that is refractory to NE.
Acute AVP Deficiency
Landry et al. serendipitously found that relatively modest dose AVP infusion (0.5
- 6 units/hr) results in remarkable improvement in blood pressure and urine flow in
patients with vasodilated septic shock, allowing rapid tapering of catecholamines.
Normally, AVP exerts an antidiuretic effect on V2-receptors in the distal renal
tubule and collecting duct in response to tiny (1%) elevations in serum osmolality.
Plasma AVP over the range of 1 through 5 pg/L increases urine osmolality from 300 to
1200 mOsm/kg. Severe hypotension induces a baroreceptor response that releases large
amounts of AVP from the posterior pituitary. Plasma AVP of 10 through 200 pg/L exerts
a vasoconstrictor effect on V1-receptors in vasculature and helps to restore blood
pressure.
Patients in severe vasodilated septic shock have paradoxically low plasma AVP
(about 3 pg/L)10. In animal models of hemorrhagic shock. AVP stores in the posterior
pituitary become quite depleted that within an hour of the induction of profound
hypotension. Thus, the response to infused AVP is in part accounted for by the
restoration of plasma AVP to appropriate levels for the degree of hypotension.
In addition, AVP appears to block the KATP channel, thereby restoring membrane
polarity and vascular responsiveness to catecholamines and angiotensin. AVP also has a
salutary effect on renal function because it preferentially constricts the efferent arteriole,
thereby enhancing glomerular filtration pressure, filtration rate and urinary flow.
Sladen: Inflammatory Response to CPB. Page 4
Massive Release of Nitric Oxide
Endogenous nitric oxide (NO) is formed by the action of nitric oxide synthase
(NOS) on the amino acid arginine. Nitric oxide in turn activates soluble guanosine
cyclase (sGC), which acts on guanosine triphosphate (GTP) to produce cyclic guanosine
monophosphate (cGMP), which induces vasodilation. A form of constitutive NOS,
endothelial NOS (eNOS) is responsible for the continuous (“tonic”) production of low
levels of nitric oxide that maintain vascular patency.
Inducible NOS (iNOS) is activated by the action of cytokines on macrophages in
sepsis or the systemic inflammatory response syndrome (SIRS) and produces huge
amounts of nitric oxide over protracted periods of time. A similar situation is
encountered after prolonged cardiogenic shock, CPB or VAD insertion. This induces
profound systemic vasodilation refractory to NE, and also inhibits beta-adrenergic
inotropy and results in myocardial depression.
In animal models of sepsis, hypotension is reversed and response to
catecholamines restored by NOS inhibitors. However, mortality is increased because
non-selective NOS inhibitors (e.g. L-NAME, L-NMMA) also suppress eNOS, thus
impairing tonic vasodilation and tissue oxygen delivery.
Studies using selective iNOS inhibitors show promise in decreasing the
inflammatory and vasodilator response to sepsis while maintaining tissue oxygen
delivery.
THERAPEUTIC OPTIONS IN POST-CPB VASODILATORY SHOCK
The “standard” treatment of vasodilatory shock after cardiac surgery consists of
NE infusion 1-14 mcg/min plus AVP 1-4 units/hr. Concomitant infusion of AVP repletes
endogenous AVP, closes KATP channels and restores the response to NE and decreases its
dose requirement. When severe hypotension persists despite NE > 14 mcg/min and AVP
up to 6 units/hr (maximum dose), a state of vasoplegia is considered to exist and it is at
this stage that infusion of methylene blue (MB) is usually considered.
Norepinephrine
Norepinephrine (NE) is a potent alpha-1 agonist that induces dose-related
peripheral vasoconstriction. It is also a potent beta-1 inotropic agent that may provide
important myocardial support in vasodilatory states associated with myocardial
depression. There is considerable evidence in vasodilated, oliguric septic shock that
restoration of blood pressure by NE infusion also restores urine flow and glomerular
filtration rate (GFR)11,12. However, with increasing doses, NE has the potential to induce
a number of adverse effects. These include afferent arteriolar constriction that negates its
beneficial effects on GFR; increasing pulmonary vasoconstriction that may progressively
impair right ventricular function; and increasing splanchnic constriction that could
ultimately result in visceral ischemia.
Arginine Vasopressin (AVP)
Actions, benefits and limitations of AVP infusion in vasodilatory shock:
Low dose AVP infusion (1-4 u/hr, or 0.015-0.067 u/min) has a number of
potentially beneficial effects in vasodilatory shock13. AVP appears to inhibit activation of
inducible nitric oxide. It binds to and closes KATP channels, restores membrane polarity
and the vasoconstrictor response to catecholamines. Depleted endogenous AVP levels
are restored: infusion of 1-4 u/hr achieves plasma AVP levels of 20-30 pg/mL.
Sladen: Inflammatory Response to CPB. Page 5
These actions consistently result in increased blood pressure and decreased
catecholamine requirement. Diminution of high-dose NE decreases pulmonary vascular
resistance (PVR) and cardiac arrhythmias. Compared to NE, AVP preferentially induces
efferent arteriolar constriction and thereby may enhance glomerular filtration rate (GFR)
and renal function.
The 2008 Surviving Sepsis Campaign recommends that AVP infusion (0.03
u/min) may be added to NE (still recommended for initial therapy) if the mean arterial
pressure (MAP) cannot be maintained above 65 mmHg14. In our current clinical practice
we administer AVP 1-4 u/hr (maximum 6 u/hr) in all forms of vasoplegia where
hypotension is refractory to increasing doses of NE (> 3 mcg/min), where the PVR is
increased, or when oliguria occurs. This includes sepsis, contact activation states and
high-dose milrinone therapy for severe right ventricular failure1. The goal is to decrease
(but not eliminate) the NE infusion rate.
AVP is not beneficial in doses > 6 U/h and is contraindicated in the presence of
hypotension secondary to hypovolemia or low cardiac output, and should not be used to
“make blood pressure”. Excessive dosing or inappropriate usage can induce severe acral
cyanosis (and even cutaneous gangrene), splanchnic and coronary constriction. AVP
should always be infused via a central catheter, because extravasation from a peripheral
catheter can cause severe cutaneous necrosis15.
Evidence basis for use of AVP and its analogues in vasodilatory shock
The most definitive randomized controlled study (RCT) performed on AVP thus
far is the Vasopressin and Septic Shock Trial (VASST) 16. It was designed to test the
hypothesis that low-dose AVP infusion (0.01-0.03 u/min or 0.6-1.8 u/hr) would decrease
28-day mortality among patients with septic shock who were being treated with NE 515mcg/min. In the 778 patients studied, there was no significant difference in mortality
between the AVP and NE (35.4% vs. 39.3%). However, in patients with less severe
septic shock (prospectively defined as requiring NE 5-14 mcg/min), there was a
significant improvement in mortality with AVP over NE (26.5% vs. 35.7%, p < 0.05). It
is possible that the lack of benefit in more severe septic shock (NE > 14 mcg/min) was
due to an inadequate dose of AVP or late intervention.
Role of corticosteroids in vasodilatory shock
An retrospective analysis of the VASST study by its authors demonstrated that the
concomitant administration of corticosteroids with AVP significantly decreased mortality
(35.9% vs. 44.7%, p = 0.03), and increased plasma AVP levels by one to two thirds17.
This further implicates the relationship between AVP and steroid metabolism,
considering that V3 receptor activation increases ACTH release and cortisol levels. It
also warrants future prospective studies.
Indeed, the role of steroids in septic shock remains in flux18. The use of ACTHstimulation tests to evoke adrenal hyporesponsiveness as an indication for hydrocortisone
therapy has been discredited by subsequent equivocal outcomes, intra-study use of
etomidate (which impairs cortisol synthesis), and the observation that these studies were
based upon total rather than free cortisol levels19. The 2008 Surviving Sepsis Campaign
recommends the administration of hydrocortisone ( 300 mg/day) when hypotension
responds poorly to adequate fluid resuscitation and vasopressors , and that it should be
weaned once vasopressors are no longer required14.
Sladen: Inflammatory Response to CPB. Page 6
Terlipressin
Terlipressin (tricyl-lysine vasopressin) is an AVP analogue used in Europe but not
currently available in the US or Canada. It is twice as potent at the V1 receptor than
AVP, but has a much more prolonged half-life (4-6 hr), which makes it more difficult to
titrate20. A small European RCT (TERLIVAP) compared continuous infusion of AVP
(0.03 u/min) and terlipressin (1.3 mcg/kg/hr) with NE (15 mcg/min) as first-line therapy
in septic shock in 45 patients21. Terlipressin appeared superior to AVP in decreasing NE
requirements, with lower bilirubin levels and less rebound hypotension, but had a greater
effect in lowering platelet count.
Methylene Blue
Mechanisms of Action
Methylene blue (MB) is an industrial dye and redox indicator that has been found
to be effective in reversing vasoplegia. The vasoconstrictor activity of MB appears to be
mediated by selective inhibition of the action of iNOS and sGC and also by scavenging
NO22,23. Although decreases in endogenous production of NO, interleukins and tumor
necrosis factor (TNF) have not been noted24, urinary excretion of NO metabolites is
substantially lower25. Attenuation of the urinary excretion of renal tubular injury markers
has also been noted. MB may also have other beneficial effects such as improved
myocardial performance by depressing effects of molecules such as TNF-alpha. MB also
inhibits superoxide radical formation by competing with oxygen for the transfer of
electrons by xanthine oxidase26.
Methylene Blue: Evidence Basis
There have been numerous clinical reports of a favorable response to MB in
refractory vasoplegia associated with septic shock, anaphylaxis, CPB and
transplantation27-32. MB has been administered prophylactically during CPB in a patient
with vasoplegia due to bacterial endocarditis33, and to treat a protamine reaction and
vasoplegia after CPB34.
A favorable response is characterized by an increase in mean arterial pressure
(MAP) and decreased requirement for inotropic and vasopressor agents. Some early nonrandomized studies noted an improvement in cardiac indices and oxygen balance35, and a
decrease in arterial lactate, thought to be due to the reductive action of MB36. However,
PVR also increases37 and arterial oxygenation may decrease, presumably because of
ventilation-perfusion mismatch38,39. In susceptible subjects at high doses, MB may
induce hemolytic anemia, and the pigment interferes with pulse oximetry.
There have been very few randomized controlled trials (RCTs) with MB. Most
have utilized a loading infusion of MB of 1–3 mg/kg over 10–30 min, followed by a
continuous infusion of 0.25–1 mg/kg/hr.
A small dose-ranging RCT on 15 patients evaluated MB at 1 mg/kg, 3 mg/kg or 7
mg/kg over 20 min. The authors noted a dose-dependent enhancement of hemodynamic
function even at the lowest dose, with improved left ventricular filling, cardiac index,
oxygen delivery, but cautioned that high doses of MB increase PVR and may
compromise splanchnic perfusion40.
In another small RCT of 20 patients with septic shock, patients were randomized
to placebo or MB 2 mg/kg, followed 2 hrs later by increasing infusion rates between 0.25
and 2 mg/hr over 4 hrs41. The most striking finding was a 40-87% decrease in dose
requirement for NE, epinephrine and dopamine.
Sladen: Inflammatory Response to CPB. Page 7
In the largest postoperative RCT performed to date, the vasoplegic syndrome was
defined as a combination of hypotension due to low SVR, low cardiac filling pressures,
normal or high cardiac index, and high vasopressor requirement42. 56 of 638 consecutive
cardiac surgery patients met criteria and were randomized to MB 1.5 mg/kg or placebo.
Patients who received MB had a striking decrease in mortality (0% vs. 21.4%, p = 0.01)
and shorter duration of vasoplegia (6 vs. > 48 hrs, p = 0.0007).
Perhaps the most enterprising RCT is that performed by Ozal et al., who
administered MB 2 mg/kg over 30 min or placebo 1 hr preoperatively to 100 CABG
patients at high risk for vasoplegic syndrome because they were on ACE inhibitors,
calcium channel blockers or heparin43. Patients who received MB before surgery had a
significant reduction in postoperative vasoplegic syndrome (0% vs. 26%, p < 0.001), ICU
length of stay (1.2 ± 0.5 d vs. 2.1 ± 1.2 d, p < 0.001) and hospital length of stay (6.1 ± 1.7
d vs. 8.4 ± 2.0 d; p < 0.001).
Methylene Blue: Unanswered Questions
There are many as yet unanswered questions about the use of MB. What are its
specific indications? Should it be administered early – even preoperatively - or as a
rescue drug, in which case, are we waiting too long? What is the most beneficial dosing
regimen? What is the potential for adverse effects? What is the potential for unwanted
pulmonary vasoconstriction? Should we always administer it with inhaled nitric oxide to
prevent this? I will attempt to address some of these questions in this presentation.
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