Perioperative Critical Care Cardiology - part 9 docx

Cardiac surgery per se may cause additional myocardial damage by numerous mechanisms such as diffuse ischemia from inadequate myocardial Fig.. Myocardial ischemia before the start of car

Causes of Postoperative Myocardial Dysfunction and Failure

Increasing severity of surgical trauma and anesthesia can initiate increasing

inflammatory and hypercoagulable states [1] The inflammatory state

involves increases in tumor necrosis factor-α, interleukin-1 (IL-1), IL-6, andC-reactive protein These factors may have a direct role in initiating plaque

fissuring and acute coronary thrombosis The hypercoagulable state involves

increases in plasminogen activator inhibitor-1, factor VIII and platelet tivity, as well as decreases in antithrombin III All these factors can lead to

reac-acute coronary thrombosis The stress state involves increased levels of

cate-cholamines and cortisol Increased stress hormone levels result in increases

in blood pressure, heart rate, coronary artery sheer stress, relative insulindeficiency, and free fatty acid levels Coronary artery shear stress may triggerplaque fissuring and acute coronary thrombosis The other factors increaseoxygen demand and can result in perioperative myocardial ischemia, which

is strongly associated with perioperative myocardial infarction Factors that

can initiate a hypoxic state include anemia, hypothermia (through

shiver-ing), and suppression of breathing

Cardiac surgery per se may cause additional myocardial damage by

numerous mechanisms such as diffuse ischemia from inadequate myocardial

Fig 1.Time course of ventricular function after cardiopulmonary bypass Reproduced with permission from [5]

protection and myocardial reperfusion injury, inadequate repair, myocardialinfarction, inflammation, coronary spasm, local trauma by surgical manipu-lation, air embolism, or residual hypothermia Myocardial injury during car-

diac surgery can be divided into three phases: prebypass ischemia, including preoperative disease status (unprotected ischemia); protected ischemia, elec-

tively initiated by cardioplegia and hypothermic extracorporeal circulation

(ECC); and reperfusion injuries after ECC After brief periods of myocardial

ischemia the myocardial depression is usually mild and transient, but itbecomes worse as the ischemic episodes that precede it are more severe andlonger-lasting Patients with preexisting severe underlying disease, poorischemic conditions, and reduced cardiac reserves have limited ability tocope with ischemia-related myocardial dysfunction Ischemia is more preva-lent postoperatively than preoperatively or before ECC

Prebypass Ischemia

Patients with severe coronary artery disease continue to have frequentepisodes of silent myocardial ischemia despite intensive medical therapy.Before induction of anesthesia almost half the–mostly silent–ischemicepisodes occur randomly as well as in response to hemodynamic abnormali-ties Myocardial ischemia before the start of cardiopulmonary bypass (CPB)has been observed in 38% of coronary artery bypass graft (CABG) patients,and myocardial infarction was three times more frequent than in patientswithout ischemia (6.9% vs 2.5%) [11] Although perioperative myocardialischemia appears not always to be induced by hemodynamic stress, it hasbeen shown that patients with perioperative myocardial ischemia had previ-ous tachycardia more frequently [12] A preoperative heart rate above 100bpm was also associated with increased risk of perioperative myocardialinfarction Preoperative regional wall motion score index and new regionalwall motion abnormalities immediately after CPB have been shown to be themost important independent predictor for the use of inotropes after cardiacsurgery [13]

Elevated serum troponin I (cTnI) concentrations as sensitive markers ofmyocardial damage measured 24 h before surgery have been demonstrated

to identify patients at high risk for developing perioperative myocardialinfarction or low cardiac output syndrome, and at increased risk of in-hospi-tal death Perioperative myocardial infarction and low cardiac output syn-drome occurred at rates of 5.9% and 1.6% respectively in patients with pre-operative cTnI levels less than 0.1 ng/ml, compared to 17.2% and 10.9% inpatients with preoperative cTnI levels greater than 1.5 ng/ml [14]

ECC and Cardiac Arrest

In most cardiac surgical patients, the use of ECC is a precondition for cal cardiac repair However, during ECC the heart is subjected to a number ofevents that eventually lead to myocardial ischemia: inadequate myocardialperfusion, ventricular distension or collapse, coronary embolism, and ven-tricular fibrillation, as well as aortic cross-clamping and reperfusion Inaddition, ECC per se may cause myocardial dysfunction as a result of severehemodilution and hyperkalemia or as a result of cardioplegia-induced sys-temic hypocalcemia Thus, the operation originally designed to preserve orimprove myocardial function may be associated with deleterious effects.Those adverse effects may be well tolerated in patients with normal ventric-ular function, but may become serious in patients with compromised ven-tricular function

surgi-During ECC, perfusion of the coronary arteries may be compromised byperfusion via the aortic route or direct cannulation of the arteries or elevat-

ed vascular resistance In addition, autoregulation may be lost due tohypothermia Ventricular distension and the use of catecholamines mayupset the oxygen supply/demand ratio Ventricular fibrillation increasesmyocardial wall tension and oxygen consumption and impairs subendocar-

dial blood flow Aortic cross-clamping per se is potentially a major cause of

myocardial injury The extent of necrosis in unprotected myocardium isdirectly related to the duration of aortic cross-clamping and cardiac reperfu-

sion injury[15] Increased aortic cross-clamp time and longer duration of

CPB are indeed associated with a significant reduction in ventricular tion [16]

func-Inadequate Cardioplegic Arrest

Cardioplegic arrest provides protected ischemia by reducing the oxygendemand below 10% of the demand of the working heart and also avoidsreperfusion injury by specifically targeting the pathophysiologic mechanismand mediators of postischemic injury Effective myocardial protectionthrough either cold or warm blood cardioplegia is essential, because late sur-vival is significantly reduced in patients with even nonfatal perioperative car-diac outcomes [17] Cardioplegic arrest neutralizes some negative aspects ofhypothermia including a paradoxical increase in the inotropic state and oxy-gen demands per beat or the induction of ventricular fibrillation [18] Thegreatest degree of myocardial protection is achieved by combining (tepid)hypothermia with chemical cardioplegia Normothermic cardioplegia may beused to overcome some of the disadvantages of hypothermia

Inability to establish or maintain electromechanical quiescence is a nal that cardioplegic solution does not reach some regions in adequate con-centration This can be the consequence of the underlying artery disease,inadequate pressure in the aortic root, or even steal phenomena An insuffi-cient cardioplegic procedure results in anaerobic metabolism during car-diac arrest with subsequent lactate accumulation, which is regarded as apredictor of low cardiac output syndrome In addition, the type of cardio-plegia and route of administration may play a role in protecting themyocardium Blood cardioplegia provides a closer approximation to normalphysiology and superior myocardial protection compared to crystalloid car-dioplegia, including lower rates of hospital stay and myocardial-bound crea-tine kinase increase, whereas the incidence of myocardial infarction anddeath is similar [19].

sig-During cardiac surgery the right ventricle is at special risk of inadequateprotection by disparate distribution of cardioplegia and cooling Especially

in the presence of a significant stenosis or obstruction of the right coronaryartery (RCA), uneven cooling of the right ventricle has been reported [20] In

a group of patients with RCA occlusion the right ventricular ejection tion (RVEF), right ventricular stroke work index (RVSWI) and cardiac index(CI) were significantly reduced after CPB In patients with severe right coro-nary stenosis, off-pump cardiac surgery seemed to provide better right ven-tricular protection because of the avoidance of cardioplegic arrest.Inadequate cardioplegic protection of the atria, myocardial ischemia, andalso atrial cannulation may increase the frequency of postoperative atrialfibrillation Compared to patients operated on off-pump, the incidence ofpostoperative atrial fibrillation was significantly higher in on-pump patients,and ECG during cardioplegic arrest has been found to be the main indepen-dent predictor of postoperative atrial fibrillation in CABG patients

frac-Hypothermia

Hypothermic ECC decreases metabolic rate and oxygen requirements and inconsequence increases tolerance of ischemia Hypothermia also helps to pre-serve high-energy phosphate stores and reduces excitatory neurotransmitterrelease, which is especially important for protection of the central nervoussystem Strict maintenance of normothermia during ECC is in fact associat-

ed with increased neurologic risk However, hypothermia is also associatedwith several disadvantages for the myocardium Transient, readily reversibleedema of the myocardium after reperfusion may occur In addition, topicalcooling injury of extracardiac structures is a matter of concern Topical cool-ing yielded no additional benefit but increased the incidence of diaphragm

paralysis and associated pulmonary edema [21] Furthermore, citrate

toxici-ty may be augmented, leading to additional myocardial depression andthrombocytopenia

Reperfusion

Reperfusion injury is defined as additional myocardial injury occurring afterrestoration of blood flow to ischemic myocardium It causes inflammatorycell activation from cytokine generation, up-regulation of neutrophil adhe-sion molecules with neutrophil activation, oxygen free radical formation,and lipoperoxidation, and enables important pathways for postoperativemyocardial dysfunction Reperfusion injury has an early phase (< 4 h)based on early neutrophil and adhesion molecule-dependent interaction and

a later phase (4–6 h) with still unknown mediators Reperfusion injuriesinclude structural deterioration (edema, platelet deposition, etc.) and bio-chemical (decreased oxygen utilization, complement activation, acidosis,etc.) and elec t romechanical patholog ies (dysrhy thmias, impairedsystolic/diastolic function) Experimental studies showed possible preven-tion of myocardial dysfunction by using free radical scavengers However,whether this protection confers meaningful clinical benefits is uncertain[22] There is also a time link between cytokine release and the timing ofventricular dysfunction Cytokines can release nitric oxide from endotheli-

um, resulting in myocardial dysfunction

Reperfusion injury can cause atrial and ventricular dysrhy thmias,reversible systolic and diastolic dysfunction (stunning), endothelial dysfunc-tion, myocardial necrosis, and apoptosis [23] After short periods of ischemiathe negative effect on contractile function is benign but might be injurious

to other targets like endothelium or neutrophil accumulation Long periods

of ischemia cause injury of the myocardium, leading to persistent contractiledysfunction In the absence of morphologic injury, postischemic contractiledysfunction may be reversible w ithin hours (stunned myocardium)

Stunning is common after ECC and is defined as prolonged postischemic

contractile dysfunction of the myocardium salvaged by reperfusion In anumber of studies increased chamber stiffness and dilatation were foundafter blood reperfusion following normothermic or hypothermic ischemia[24] Acute increases in postischemic chamber stiffness are caused bymyocardial edema and abnormal calcium handling in the myocardium Adecrease in diastolic relaxation impairs diastolic filling and reduces strokevolume independently of any postischemia or postcardioplegia abnormali-ties in inotropic state or contractility

The question of whether reperfusion causes myocardial necrosis is still a

matter of discussion However, endothelial dysfunction in the pathogenesis

of reperfusion injury is well documented Endothelial damage occurs duringreperfusion rather than after short periods of global and/or regionalischemia, but more prolonged periods of ischemia also cause endothelialdamage Apart from ischemia–reperfusion, inflammatory mediators andgaseous microemboli may also induce endothelial damage during ECC Forexample, pulmonary endothelial dysfunction may be impaired until 3–4days after exposure to ECC [25]

Reperfusion dysrhythmias manifest themselves as premature ventricularcontractions and ventricular fibrillation Poor myocardial protection (global

or distal to severe coronary artery occlusions) causes failure to

spontaneous-ly resume sinus rhythm or persistence of arrhythmias requiring therapeuticinterventions The incidence and severity of reperfusion arrhythmias isstrongly related to the severity of the preceding ischemia The induction ofcalcium-dependent arrhythmias by accumulation of intracellular calciumduring ischemia is another mechanism Furthermore, oxygen-derived freeradicals may cause reperfusion arrhythmias by altering membrane lipids andvarious transport proteins The combination of oxygen-derived free radicalsand calcium-related events especially might act as a trigger for reperfusiondysrhythmias

Prevention of Postoperative Myocardial Dysfunction and Failure

The healthy heart has enormous functional reserve However, when lar performance is marginally matched to the individual patient’s physiolog-

ventricu-ic needs, even small decrements in myocardial function may cause anincrease in morbidity and mortality Therefore, in addition to the surgicalprocedure, efficient myocardial protection should to be one of the maingoals for all members of the surgical team throughout the perioperativeperiod Surgical myocardial protection includes optimal surgical technique,adequate performance of ECC and cardioplegic arrest, as well as liberal (pro-phylactic) use of assist devices in patients who are severely hemodynamical-

ly unstable Perioperative stress protection by the anesthesiologist includespreoperative optimization, adequate treatment of pain and anxiety, and pre-cise hemodynamic management including heart rate control and (“earlygoal”) volume management Also, additional cardioprotective drugs may beused However, the best approach to medical protection of patients from car-diovascular complications during surgery is still a matter of discussion

Role of the Anesthesiologist in Myocardial Protection

Although brief periods of ischemia can contribute to prolonged left ular dysfunction and even heart failure, they paradoxically play a cardiopro-tective role Episodes of ischemia as short as 5 min, followed by reperfusion,protect the heart from a subsequent longer coronary artery occlusion bymarkedly reducing the amount of necrosis that results from the test episode

ventric-of ischemia This phenomenon, called ischemic preconditioning, has been

observed in virtually every species in which it has been studied and has apowerful cardioprotective effect [23, 26] Volatile anesthetics appear to berelated to better and earlier recovery of myocardial function and lessermyocardial damage manifested as minor elevation in myocardial enzymes.CABG patients on a sevoflurane-based anesthetic regimen demonstratedmore preserved cardiac performance, reduced requirement of inotropic sup-port, and lower serum concentrations of cardiac enzymes compared to those

on an intravenously based anesthetic regimen [27, 28] In addition, adecreased inflammatory response to CPB–measured as reduced release of IL-

6, CD11b/CD18, and TNF-α–as well as significant reduction in new regionalwall motion abnormalities after sevoflurane anesthesia suggest effective pro-tection against ischemia reperfusion injury [29] The cardiac protectiveproperty of volatile anesthetics may depend on the duration and timing of

administration [27].

Increasing evidence shows that perioperative β-blocker treatment cantly reduces the risk and the incidence of perioperative cardiac complica-

signifi-tions after cardiac and noncardiac surgery [30] In noncardiac surgery

β-blockers were shown to reduce the number of deaths from cardiac events,

as well as nonfatal myocardial infarction but did not have a significantimpact on the total number of deaths.β-blockers reduce sympathetic tone,heart rate, and contractility, decrease share stress, and reduce the prothrom-botic effect of sympathetic activation Despite extensive investigations,important questions such as the ideal target population, ideal dose, route ofadministration, duration of therapy, or even type ofβ-blocker remain unre-solved [31] In addition, the observation that there may be some disadvan-tages associated with β-blocker therapy in low-risk patients has not been

fully explained Furthermore, in patients receiving chronicβ-blocker therapythe adequacy of cardiac protection has been questioned The required dose

of isoproterenol needed to increase heart rate by 25 bpm was similar inpatients receiving chronic β-blocker treatment compared to those without Ithas been suggested that patients undergoing chronic β-blocking therapy

compensate to such a degree that cardiovascular β-receptor function actuallybecomes normal (receptor up-regulation) As a matter of fact, chronic β-blocker therapy has been shown to be associated with higher risk of myocar-dial infarction, cardiac death, and major cardiac complications in noncardiacsurgery [32] On the other hand, discontinuing β-blocker therapy immedi-ately after surgery may increase the risk of postoperative cardiovascularmorbidity and mortality and may be associated with a higher risk of ventric-ular heart failure Additional perioperative β-blockade and the combination

of β-blockers with statin therapy may be beneficial in patients receivingchronic β-blocker therapy and high-risk patients with coronary artery dis-ease The combined use of β-blocker and simvastatin may prevent the up-regulation of β-adrenoceptors induced by chronic β-blocker therapy andtherefore enable better stress protection [33] In noncardiac surgery benefi-cial effects have been shown to be greatest in patients with higher cardiacrisk factors and in those with more wall motion abnormalities Bisoprololtreatment before noncardiac surgery significantly decreased the rate of car-diac death (3.4% vs 17%) and nonfatal myocardial infarction (0% vs 17%) Arecent meta-analysis relating to ?-blocker use in noncardiac surgery hasdemonstrated a 65% reduction in perioperative myocardial ischemia (11.0%

vs 25.6%), a 56% reduction in myocardial infarction (0.5% vs 3.9%), and a67% in the composite endpoint of cardiac death and nonfatal myocardialinfarction reduction (1.1% vs 6.1%) [34]

Faster heart rate may be a marker of the under-use ofβ-blocker therapy

A preinduction heart rate of 80 bpm or higher was indeed associated withincreased in-hospital mortality after CABG surgery (Fig 2) [12] The delete-rious consequences of tachycardia may be particularly aggravated by sys-temic hypotension and increased ventricular filling pressures Yet,β-blockertherapy is still titrated to a heart rate of 80 bpm or higher in many patients[35]

In the setting of CABG surgery preoperative β-blocker therapy was ciated with a small but consistent survival benefit for patients, except amongthose with an LVEF of less than 30% [36] After coronary surgery chronic

asso-preoperative β-blocker therapy reduces 30-day mortality Death was evenmore likely after nitrate therapy than after β-blocker therapy [37].Prophylactic treatment with β-blockers also reduces the incidence of postop-erative atrial fibrillation, particularly in elderly patients

In patients with overt or underlying cardiac disease the actions of α2adrenoceptor agonists, which include maintenance of stable systemic bloodpressure and low heart rate and a reduction in overall oxygen consumption,can be expected to reduce the risk of procedure-related cardiac events Thisexpectation has been corroborated in clinical trials w ith clonidine,

-dexmedetomidine, and mivazerol in noncardiac surgery Large controlled

tri-als would be instructive in establishing a robust estimate of the benefit.These drugs could be used as an alternative or as second-line agents when β-blocker therapy is contraindicated.

Several clinical trials clearly demonstrated that, although inotropicagents like α2-agonists and phosphodiesterase (PDE) inhibitors may improvehemodynamic parameters, their use may be associated with increased mor-bidity and mortality [38] The new calcium-sensitizing agent levosimendanprotects against myocardial ischemia and reperfusion injury and may serve

as a promising alternative to conventional therapy in cardiac surgery Incomparison to dobutamine in patients with low-output heart failure the pri-mary hemodynamic endpoint–defined as an increase of 30% or more in car-diac output and a decrease of 25% or more in pulmonary capillary wedgepressure–was achieved in 28% of patients in the levosimendan group and15% of those in the dobutamine group [39] Because levosimendan decreasespulmonary capillary wedge pressure more effectively than dobutamine, thesubstance may be of value in patients with reversibly increased pulmonarypressures or right ventricular dysfunction (Fig 3) [39, 40] When compared

to milrinone as well as dobutamine in patients undergoing elective coronaryartery surgery, treatment with levosimendan was associated with significant-

Fig 2.Preinduction heart rate (HR) and in-hospital mortality Reproduced with sion from [12]

permis-ly higher cardiac index and mixed venous oxygen saturation, whereas monary capillary wedge pressure, systemic vascular resistance, and oxygenextraction ratios were significantly higher in the milrinone treatment group[41] Furthermore, despite improved myocardial performance in patientsundergoing CABG, no increase in myocardial oxygen consumption has beenobserved Significant cardioprotection by levosimendan may also be provid-

pul-ed by the vasodilatory effects as a result of opening ATP-dependent

potassi-um channels and reducing the calcipotassi-um sensitivity of contractile proteins invascular smooth muscles Decreases in vascular resistance and augmentedblood flow in coronary arteries and internal mammary artery have beendemonstrated in cardiac surgery as having a potentially protective effect inpatients with compromised coronary blood flow and vasospasm in the arter-ial grafts after coronary bypass grafting

After levosimendan treatment, a reduction of the number of hypokineticsegments and an improvement in left ventricular function without impair-ment of diastolic function have been reported in patients with acute coro-nary syndrome immediately after reperfusion during angioplasty [42] In thesetting of off-pump coronary artery bypass surgery, increases in stroke vol-

Fig 3. Comparison of hemody namic effects of levosimendan and dobuta- mine Changes in cardiac output and pulmonary capillary wedge pressure were recorded from base- line to 30 h in patients with low-output heart fail- ure Reproduced with per- mission from [39]

ume and cardiac output and decreases in systemic vascular resistance wereobserved when levosimendan was administered [43] Levosimendan admin-istered 15 min before separation of CPB and continued for 6 h had benefi-cial effects on cardiac performance in low-risk patients but no detrimentaleffects on arterial oxygenation and perioperative arrhy thmias [44].Levosimendan also appears to be useful in failure-to-wean from CPB aftercardiotomy when conventional inotropic therapy proves inadequate There isalso evidence that patients receiving a short infusion of levosimendan beforetheir CABG surgery have less myocardial damage as expressed by lower tro-ponin I levels [45] Although the efficacy of levosimendan has repeatedlybeen demonstrated in the perioperative setting, the number of patientsinvestigated is still rather small Therefore, further trials will be necessary toinvestigate the effectiveness and indications for preemptive use of levosi-mendan alone or in combination with other inotropic drugs or assist devices

in patients with severely compromised ventricular function

Role of the Surgeon in Myocardial Protection

Myocardial protection is not necessarily the primary goal and purpose ofcardiac surgery, but a prerequisite for successful postoperative outcome Inaddition to careful avoidance of myocardial ischemia and optimal surgicalrepair, myocardial protection techniques (i.e., cardioplegia) are of centralimportance, especially for the critically ill patients Cornerstones of cardio-plegic myocardial protection are rapid cardiac arrest, maintenance ofelectromechanical quiescence, minimizing myocardial ischemia, and control

of reperfusion Each of these variables has to be considered together with thetype and conduct of ECC Because of the pathophysiologic complexity of car-dioplegic arrest in combination with ECC, and because of the variety of sur-gical techniques, it is almost impossible to provide a general recipe formyocardial protection In hypothermic conditions, longer intervals betweenreadministering cardioplegic solutions allow the team to focus more on thesurgical procedure However, the benefit of hypothermia has to be weighedagainst hypothermia-associated disadvantages such as longer ECC times orgreater postoperative diastolic function More normothermic techniques, onthe other hand, need readministration at more frequent intervals for cardio-plegia, but have the advantage of more rapid restoration of myocardial func-tion, decreased reperfusion time, and less use of inotropic drugs and assistdevices Because of the increased danger of ischemia, with use of normother-mic cardioplegia techniques, more care must be exercised when “normother-mic” cardioplegia is delivered Further, the degree of care that must be exer-cised increases, depending on more close to “normothermic” the cardiople-gia used is

Rapid cardiac arrest is necessary to avoid depletion of high-energy phates After cardiac arrest further ischemia and loss of energy are mainlydetermined by the extent to which electromechanical quiescence is main-tained Inability to obtain electromechanical quiescence may be a conse-quence of the coronary artery disease, inadequate pressure on the aorticroot, or steal phenomena Additional retrograde cardioplegia may help tofacilitate the maintenance of electromechanical quiescence To further mini-mize myocardial ischemia, cold cardioplegic solution can be administeredintermittently, whereas warm solutions should be administered more fre-quently or continuously If ischemia can be eliminated, reperfusion injury isminimized and myocardial protection enhanced.

phos-Worsening ischemia and/or left ventricular systolic dysfunction, withresultant hemodynamic instability, inability to wean off CPB, and death, maycomplicate cardiac surgery In patients at risk of these complications, intra-aortic balloon pump (IABP) support may have beneficial hemodynamic andanti-ischemic effects The use of an IABP provides circulatory support byaugmenting diastolic coronary perfusion pressure and by afterload reduc-tion This increases myocardial oxygen supply and decreases myocardialoxygen demands, leading to improved systolic and diastolic function,decreased pulmonary capillary wedge pressure, and reduced heart rate Alarge body of evidence suggests that preoperative (prophylactic) IABP sup-port should be part of a strategy to protect high-risk patients undergoingcardiac surgery The implementation of IABP may reduce periods of long-duration subendocardial ischemia and help avoid postoperative myocardialinjury and complications As a matter of fact, in high risk-patients, place-ment of IABP before surgery is associated with better short- and long-termsurvival Hospital mortality in patients with elevated cardiac risk (LVEF

≤ 40%, left main stem stenosis ≥ 70%, or undergoing CABG was significantlylower when the IABP was inserted before the start of surgery [46]

In conclusion, meticulous myocardial protection is a must in cardiacsurgery in order to avoid postoperative myocardial dysfunction and failure,especially in patients with compromised myocardial function More complexprocedures and critically ill patients require even more and better optimizedmyocardial protection This can only be achieved through close cooperationbetween surgeons, anesthesiologists, and technicians and using modern car-dioplegic and pharmacologic strategies

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