Conference Lectures
Dr.Ganesan C
ANTI -INFLAMMATORY EFFECTS OF PERIOPERATIVE STATIN THERAPY
Anesthesia and surgery are associated with a dramatically increased inflammatory response. Most long-termmorbidiyand mortality following surgeryare due to cardiovascular and cerebrovascular events .
The growingprevalence of atherosclerosis means that perioperative myocardial infarction and strokeis a significant issue for the anaesthesiologist.To this aim , efforts have been undertaken to reduce the risk of perioperative MI by risk stratification during preoperative assessment and subsequent initiation of preventive medical treatment .
Currentuncertainty over the best approachfor preventing fatal perioperative myocardial
infarctionlies in our inability, despitesophisticated testing methods to detect unstablecoronary plaque prior to surgery. Unstable plaque canbe present in patients with coronary luminathat appearnormal on coronary angiography. Therefore, relianceon medical therapy to blunt inflammation is currentlythe best practice for minimizing the risk that unstableplaque poses.
Atherosclerosis is generally held to be an inflammatory disease of the vascular wall, and it responds to treatment with diverse classes of anti-inflammatory medications, such as aspirin, beta-blockers, HMG-CoA reductase inhibitors (statins).Beyond lipid-lowering activity in the prevention of atherosclerosis, statins exhibit action by improving vascular endothelial function, modulatinginflammatory responses, and maintaining plaque stabilitythereby preventing thrombus formation. These so-called‘‘pleiotropic’’ effects of statins are believed to occur within24 hr after statin initiation and prior to the reduction inserum cholesterol levels (weeks).The rapid onset of thepleiotropic effects was considered potentially useful toprevent perioperative MI, as plaque instability / disruption,most likely associated with perioperative inflammation, has been recognized as a relevant cause of MI that is potentiallyresponsible for up to 50% of perioperative MIs.Ifstatin therapy can effectively diminish the inflammatoryresponse to surgical trauma, a perioperative MI might beprevented.
ATHEROSCLEROSIS — AN INFLAMMATORY DISEASE
Various factors can damage the endothelium. Diabetes, hypertension, smoking, ischemia and homocystinemia . High levels of LDL –C initiates atherosclerosis , over half of death from atherosclerosis occurs in patients without raised LDL-C , other non traditional risk factors such as“ inflammation” now considered to play an aggravating factor .
High LDL levels augments accumulation of LDL particles in the intima of arteries.These lipoproteins undergo various chemical alteration. Oxidised and glycated LDL are powerful pro inflammatory agents that these chemical alteration induces local chemo-attractant cytokine production that contributes subsequent events that triggers atherosclerosis.
Local factorsand circulating cytokines such as TNF-alpha and inerleukin-1 stimulate certain cell adhesion molecule. When the endothelium is stimulated by cytokinesand endotoxins ,these cell adhesion molecule induces attachment of monocytes and T-lymphocytes to arterial endothelial wall . On entering the intimamonocytes transform into macrophages.Stimulated macrophages that ingest the LDL cholesterol have a characteristic vacuolated appearance termed as “foam cells”. Collections of foam cells termed as “fatty streak”.The macrophage foam cells present in atherosclerotic plaque are metabolically active
These macrophage-foam cells rich source of factor such as smooth muscle cell mitogens, oxygen radicals andmettalloproteinases. Also these foam cells destroy nitric oxide radicals decreasing the effect of nitricoxide .Smooth muscle cell migration in the tunica media in to arterial intima . This smooth muscle cells proliferation responsible for the production of the fibrous cap that overlies the atherosclerotic plaques .
This fibrous cap exhibits significant metabolic activity and can undergo considerableremodelling and produce cytokines.Inflammatory cytokines cause the death, predominantly by apoptosis,of smooth muscle and foam cells. Necrosis of smooth muscle and foam cells results in the development of a necrotic lipid core in the plaque.
The initial fatty streak evolves into fibrofatty lesion containing both atherosis and sclerosis and transforms in to mature plaque.Atherosclerosis causes endothelial dysfunction , reduced levels of nitric oxide, promotes thrombotic status . In general endothelium in atherosclerosis favours aprothrombotic, vasoconstrictory environment,promoting a greater chance of thrombus formation .
For anaesthesiologists myocardial infarction represents more common acute complication of atherosclerosis with stroke occurring less frequently but to similar pathology .Fibrous cap fissuring or rupture is responsible for 60-70% of all non-surgical and anesthesia related myocardial infarctions and stroke.If the fibrous cap is thick , the plaque is relatively stable and will not tend to rupture . Should the fibrous cap is thin, the plaque may becomevulnerable to rupture .Indeed vulnerable plaque rupture at maximum wall stress , such increase in wall stress with increase in blood pressure / raise in heart rate.The extracellular matrix confers biomechanical strength to the plaque’s fibrous cap.decreased synthesis and increased degradation of extracellular matrix in the presence of inflammation results in a thinning and weakening of fibrous cap.
It appears that inflammation plays a central role at all stages of atherosclerosis and makes plaques more vulnerable to rupture . Inflammation that is in adventitia of arteries and systemic inflammatory process are so important. Indeed systemic inflammation predict severity of atherosclerosis and future coronary events .
HS-CRP levels have been shown to be an extremely useful predictor of overall levels of inflammation, plaque stability and future cardiac events even in adults without known coronary artery disease. HS-CRP levels of 1.0 mg/L,1.0 mg/L to 3.0 mg/L and 3.0 mg/L represent low, medium and high cardiovascular risk respectively.
Large epidemiological studies have also found increased risk of vascular events in subjects withelevated basal levels of other inflammatory mediators such as the cytokines IL-6 and TNF-alpha. The focus on inflammation and the vulnerable plaque is an important aspect of current thinking about pathophysiology of atherosclerosis.
PATHOPHYSIOLOGY OF PERIOPERATIVE MYOCARDIAL INFARCTION:
Early PMI, the highest incidence occurring immediatelypostoperatively, is associated with the presence of high grade coronary lesions. Ischemia and infarction associated with this type of lesion are due to perioperative stress (most often during laryngoscopy and intubation, or extubation) causing tachycardia and hypertension that results in myocardial ischemia
The other 50% of PMI’s are caused by vulnerable coronary plaque rupture or endothelial desquamation with subsequent thrombosis and occlusion of coronary arteries. This type of PMI is spread out over the perioperative period. They can even occur in the late postoperative period as long as 3 to 4 days after surgery. It has been suggested that the transformation from a chronic stable atherosclerotic lesion to a vulnerable plaque can indeed be an acute event. In this regard,it has been proved that perioperative inflammatory response with release of inflammatory cytokines TNF alpha and IL-1 and IL-6 may make plaques more vulnerable and explain late PMI.
Perioperative MI % of total |
Causes of peri op MI |
Coronary stenosis |
Time of death |
Therapeutic options |
54% |
Stress |
High grade |
Days 1-3 |
Beta-blockers |
46% |
Plaque rupture |
Absent or low grade |
Evenly spread over perioperative period |
Statins |
STATINS MECHANISMS OF ACTIONS ; Statins competitively inhibit HMG-CoA reductase , the rate limiting step in cholesterol biosynthesis in the liver. The reduction in cholesterol in hepatocytes causes an increase in the expression of cell surface LDL receptors, resulting in improved extraction of LDL cholesterol from the circulation .Inhibition of this enzyme further prevents the conversion of HMG Co-A to mevalonate, thus, preventing the downstream production of the isoprenoidgeranylpyrophosphate . The reduction of isoprenoid intermediates affect theG-proteins Rho, Rac, and Ras, which have a role in many intracellular signalling pathways.
The multiple non-LDL mediated effects of statins predominantly promote anti-inflammatory and anti-coagulant processes. This results in less inflammation, greater endothelial health and ultimately, greater plaque stability. The plethora of non-LDL effects have been called the“pleiotropic” effects of statins . (The word “pleiotropy”, which is derived from two Greek words, pleion and tropos, meaning “many turns”, was originally used in genetics to describe the ability of a single gene to affect multiple phenotypic effects in an organism.) That the pleiotropic effects of statins are dose dependent and occur within hours of administration, is potentially of great importance to anesthesiologists.
Inhibition of the isoprene pathway and also lowering of LDL cholesterol by statins has 3 main consequences in atherosclerotic tissue ;
1.Statin therapy reduces inflammation,the anti-inflammatory effects are related to the
lower levels of LDL cholesterol and oxidised LDL, but also to better functioning of the endothelium, especially greater levels of nitric oxide. Nitric oxide is not only a vasodilatory agent, but also possesses atheroprotective and anti-inflammatory properties. This is because nitric oxide decreases endothelial cell over-expression of leukocyte adhesion molecules, an important promoter of the atherosclerotic process and a process that makes plaques vulnerable to rupture . The result is that fewer macrophages become adherent to the endothelium, endothelial adhesion of leukocytes being a hallmark of inflammation.Less apoptosis of smooth muscle cells and greater production of collagen and elastin. Greater amounts of smooth muscle cells result in more collagen being present in plaques which enhances the strength of the fibrous cap.
2. Endothelial dysfunction is improved because of increase in endothelial nitric oxide levels
3. Statin therapy lowers the risk of thrombosis and facilitates fibrinolysis. A decrease in LDL cholesterol reduces endothelial and intimal inflammation reducing expression of factor 7 while improving nitric oxide production.Decreasing LDL levels also reduces
excessive platelet aggregation.
Statins have reduced expressions of cytokines, chemokines, and adhesion molecules and a lowering of C-reactive protein (CRP) levels. CRP levels have been shown to correlate with cardiovascular disease risk. In patients with elevated high-sensitivity CRP levels,
but withouthyperlipidemia, treatment with statins decreased the incidence of stroke, myocardial infarction (MI) , and death from cardiovascular causes . Many of these pleiotropic effects of statins occur before a significant reduction in serum cholesterol levels . In normocholesterolemicand hypercholesterolemic patients, endothelial function improved within 24 hours of statin initiation , prior to significant serum cholesterol reduction.
PERIOPERATIVE STATIN USE, PRACTICAL CONSIDERATIONS ;
Inflammation, not cholesterol, should be the target .The optimal statin choice and the target level of LDL cholesterol immediately prior to surgery remain controversial . Regardless, the purpose of perioperative statin use should be reduction of the inflammatory stress response to surgery , with the long-term goal being achievement of recommended target lipid levels.
Patients with multiple cardiac risk factors represent an especially high-risk group that benefits the most from statin therapy prior to vascular surgery, as they are likely to have more extensive disease and more extensive inflammation in the coronary artery tree. Given the low incidence of side effects associated with statins, initiating a statin in patients with multiple cardiacrisk factors who are undergoing intermediate risk surgery may seem to be appropriate.It isadvisbaleto initiate a statin preferably as long before surgery as possible .
BEWARE THE REBOUND EFFECT WITH STATIN WITHDRAWAL
Statin withdrawal for several days following non cardiac surgery is a common practice . Acute withdrawal has been associated with an increase in markers of inflammation and oxidative stress, and an increase in cardiac events when compared with continuation of statin therapy.For these reasons, a long-acting statin is preferred preoperatively in patients whose oral intake will be compromised for several days after surgery (eg, in gastric surgery).
Not all statins have similar effects on reducing LDL cholesterol levels. For example although atorvastatin is extremely effective in lowering LDL-cholesterol, it does not increase HDL -C as much as simvastatin.There may also be differences between statins in terms of their pleiotropic effects . An example of this is that all statins powerfully inhibit apoptosis of smooth muscle cells in atherosclerotic plaque, thereby improving plaque stability . However, pravastatin seems to be superior to simvastatin and lovastain in this respect.
Drugs |
Solubility |
Daily dose |
Bioavailability |
Protein binding |
Metabolism |
Elimination half-life (hr) |
Renal excretion |
Lovastatin |
Lipophilic |
20-80 |
5 |
>90 |
CYP3A4 |
2-3 |
10 |
Simvastatin |
Lipophilic |
10-80 |
5 |
95-98 |
CYP3A4 |
1-3 |
13 |
Pravastatin |
Hydrophilic |
10-40 |
20 |
43-67 |
Sulfation |
2-3 |
20 |
Flucastatin |
Lipophilic |
20-80 |
24 |
98 |
CYP2C9 |
0.5-3.0 |
6 |
Atorvastatin |
Lipophilic |
10-80 |
12 |
98 |
CYP3A4 |
13-16 |
2 |
Rosuvastatin |
Hydrophilic |
10-40 |
20 |
90 |
CYP2C9 |
19 |
10 |
Pitavastatin |
Lipophilic |
1-8 |
80 |
96 |
Hepatic |
11 |
NA |
Cerivastatin |
Lipophilic |
0.2 -0.3 |
60 |
99 |
CYP3A4 |
2-3 |
30 |
SAFETY OF PERIOPERATIVE STATINS
Statins are well tolerated , side effects such as skeletal muscle and hepatic toxicities, which are rare but can be severe. Skeletal muscle toxicity associated with statin use can range from myalgiasto myositis (11 per 100 000 patient years)and, most severely , rhabdomyolysis (1.6 to 3.4 per 100 000 patient years).Cerivastatin was withdrawn from the market in 2001 because of an increased incidence of rhabdomyolysis and associated fatalities. During the perioperative period, patients may be at higher risk for drug interactions ; in addition , perioperative use of analgesics may mask symptoms of
myalgia. Asymptomatic elevation of hepatic transaminases ( 110 per 100 0000 patient years) is quite common in statin users whichseems to be dose related and comparable among different statins .
CONTRAINDICATIONS TO PERIOPERATIVE STATIN THERAPY
As in the nonoperative setting, statins should not be initiated in patients with chronic liver disease, inflammatory muscle disease, severe renal disease, on concurrenttreatment with cyclosporine , fibrates, or high dose niacin, or in females with child bearing potential.