2011

QUICK REVIEW OF

SOME MEDICAL

TOPICS

ETSUBE

TAHC

2011

Acute Respiratory Failure A. Definition Acute respiratory failure is defined as hypoxemia (i.e., a PaO2 of <50 mm Hg) with or without associated hypercapnia (i.e., a PaCO2 of >45 mm Hg). B. Classification Acute respiratory failure can be divided into two types. 1. Type I: respiratory failure without carbon dioxide retention (i.e., low PaO2 with low or normal PaCO2). This type of respiratory failure is characterized by marked [V]/[Q] abnormalities and intrapulmonary shunting. Type I respiratory failure occurs in such clinical settings as: a. Acute respiratory distress syndrome (ARDS) [see VI] b. Diffuse pneumonia (viral and bacterial) c. Aspiration pneumonitis d. Fat embolism e. Pulmonary edema 2. Type II: respiratory failure with carbon dioxide retention (i.e., low PaO2 with elevated PaCO2). Type II respiratory failure, or ventilatory failure, has two basic physiologic abnormalities - [V]/[Q] imbalance and inadequate alveolar ventilation. Patients with type II respiratory failure are divided into two categories. a. Patients with intrinsic lung disease characterized by both [V]/[Q] imbalance and inadequate alveolar ventilation. Respiratory failure is precipitated by additional clinical insult, usually infection, which worsens the physiologic abnormalities. Examples of such lung diseases include: (1) COPD (chronic bronchitis, emphysema) and cystic fibrosis (2) Acute obstructive lung disease (asthma, severe acute bronchitis) b. Patients with intrinsically normal lungs but with inadequate ventilation due to: (1) Disorders of respiratory control [e.g., as a result of drug overdose, central nervous system(CNS) disease, trauma, or cerebrovascular accident (CVA)] (2) Neuromuscular abnormalities (e.g., poliomyelitis, myasthenia gravis, Guillain Barre syndrome) (3) Chest wall trauma, kyphoscoliosis, upper airway obstruction C. Pathophysiologic mechanisms of hypoxemia 1. [V]/[Q] imbalance, the most common pathophysiologic cause of hypoxemia, arises when alveolar ventilation decreases with respect to perfusion in the lung. Hypoxemia resulting from a moderate alteration in the [V]/[Q] can be reversed with relatively small increases in the inspired oxygen concentration (i.e., 24% - 40% inspired oxygen). 2. Intrapulmonary shunting occurs when ventilation approaches or reaches zero in perfused areas (e.g., due to collapsed or fluid-filled alveoli), so that venous blood is shunted directly to the arterial circulation without first being oxygenated. Hypoxemia due to a shunt frequently cannot be corrected, even with 100% inspired oxygen. 3. Hypoventilation with resulting hypercapnia may contribute to hypoxemia. This results in type II respiratory failure. 4. An abnormality in the diffusion of oxygen across the alveolar-capillary membrane may contribute to hypoxemia during exercise or in conditions of lowered inspired oxygen content [most commonly due to high altitude, e.g., during a commercial airline flight). However, the contribution of this mechanism to respiratory failure, if any, is insignificant. D. Therapy 1. Principles. Treatment is directed toward the underlying disease as well as toward the ventilatory and hypoxic components. In addition, the acute and chronic aspects of respiratory failure must be considered. Patients with chronic respiratory failure frequently can tolerate a lower PaO2 and a higher PaCO2 than those with acute respiratory failure. 2. Oxygen therapy a. In type I respiratory failure, patients may be given high concentrations of inspired oxygen, because carbon dioxide retention is not a risk. Oxygen

may be delivered by mask or nasal cannula. The use of devices to increase endexpiratory lung volumes, such as continuous positive airway pressure (CPAP) or, in more severe cases, intubation with mechanical ventilation (see VI E 1 b), may be required. b. In type II respiratory failure, treatment depends on the cause. (1) When the cause is an exacerbation of COPD, the basis of therapy is controlled administration of oxygen (i.e., low-flow oxygen treatment), with care taken not to increase the PaCO2. Mechanical ventilation may be needed. Noninvasive mask ventilation with bilevel positive airway pressure (BiPAP) or preset volume ventilation has been used with some success, thereby avoiding the need for airway intubation. (2) Type II respiratory failure that arises from causes other than COPD usually is an indication for either noninvasive or invasive mechanical ventilation.

Acute Respiratory Distress Syndrome (ARDS) A. Definition 1. Clinical definition. ARDS is an important form of acute hypoxemic, hypocapnic (i.e., type I) respiratory failure characterized by severe dyspnea, hypoxia, loss of lung compliance, and pulmonary edema. The synonym wet lung� emphasizes the presence of increased extravascular lung water (the basic pathophysiologic mechanism underlying this condition). 2. Physiologic definition a. The ratio of PaO2 to FIO2 is <200, regardless of the presence or level of positive end-expiratory pressure (PEEP). b. There is a finding of bilateral pulmonary infiltrates.  c. There is pulmonary capillary wedge pressure (PCWP) of <18 mm Hg or no clinical evidence of elevated left atrial pressure. B. Etiology ARDS can be initiated by many different events and conditions, including shock, aspiration of fluid, disseminated intravascular coagulation (DIC), bacterial septicemia, trauma, blood transfusion, pancreatitis, smoke inhalation, and heroin overdose.  C. Therapy 1. Oxygenation. The ultimate goal of therapy is to provide adequate tissue oxygenation. Overall tissue oxygenation can be estimated from the mixed venous oxygen content (CVO2). In addition, concomitant measurement of cardiac output by thermodilution may aid in the correction of abnormal oxygen transport. a. Hypoxemia can be corrected by maintaining the PaO2 at approximately 60-80 mm Hg. This results in approximately a 90% oxygen saturation, which ensures that tissue oxygen needs are met as long as cardiac output and hemoglobin levels are normal. b. Mechanical ventilation is required by most patients with ARDS. (1) PEEP commonly is used to increase lung volume (i.e., FRC), reduce intrapulmonary shunt, and improve [V]/[Q] relationships. PEEP may cause barotrauma or a reduced cardiac output. In patients whose cardiac output is compromised, the PaO2 increases but oxygen delivery to the tissues may decrease. Therefore, it is important to measure mixed venous PaO2 (MVO2) when using PEEP. (2) A large multicentered National Institutes of Health (NIH)-supported trial showed that the use of a low tidal volume strategy (e.g., 6 mL/kg) decreased mortality compared with one using a larger tidal volume (12 mL/kg). (3) Other methods of ventilation such as inverse ratio, pressure release, and high-frequency ventilation may be useful in certain situations. (4) Some studies have demonstrated that placing patients in the prone position or using inhaled nitric oxide may improve oxygenation, but neither treatment improves survival. 2. Other measures. The underlying disease process must be treated. In addition, patients who require more than 24-48 hours of mechanical ventilation should receive nutritional support, preferably through the gastrointestinal tract. 3. Possible new treatments. Other novel therapies have been investigated for treatment of ARDS. None have shown consistent, unequivocal benefit. They include surfactant replacement; b2-agonists; inhaled nitric oxide; corticosteroids (given after 3 days); ibuprofen; ketoconazole (inhibition of thromboxane synthesis); antiendotoxin antibodies; TNF-a antibodies and IL-1 receptor antagonists; and therapies limiting fluid administration to decrease the development of extravascular lung water.

ADPKD Diagnosis The diagnosis of ADPKD is most often obtained by ultrasonography. Given that detection rates are less than 85% for individuals and that ultrasonography positively identifies >98% at risk individuals by age 30, imaging has remained the primary diagnostic approach. The presence of enlarged kidneys with multiple cysts is required for the diagnosis of ADPKD. Age-specific, ultrasound-based diagnosis guidelines for ADPKD have been developed, primarily for PKD1-related disease. These same guidelines are less reliable sensitive for PKD2-related disease, in which a later age of onset occurs. In young individuals with PKD2 alterations who undergo screening, there is an increased likelihood of false-negative results by ultrasonography. The presence of two cysts in each kidney in an at-risk individual younger than 30 years is 99% specific and sensitive for the presence of ADPKD. For those older than 30 years and younger than 60 years, four cysts bilaterally in an at-risk individual (i.e., someone with a known affected parent) are necessary for the same level of diagnostic precision. For those older than 60 years, more than eight cysts bilaterally are needed for a positive diagnosis. In the 10% to 15% of ADPKD individuals who do not have a family history, stricter criteria are required for a diagnosis, and at least five cysts bilaterally by the age of 30 and a phenotype consistent with ADPKD (discussed later) must be present. A negative ultrasound result in an at-risk individual at age 20 years reduces the likelihood of disease inheritance to below 10% and at age 30 years to below 5%. Mutation screening using direct sequencing of the PKD1 or PKD2 genes is commercially available. Current mutation detection rates in known affected individuals for PKD2 and PKD1 are 95% and 75%, respectively. Kidney Manifestations and Complications Kidney enlargement is a universal feature of ADPKD; therefore, individuals with multiple cysts but small kidneys should be screened for other cystic diseases. Significant progression of cyst growth and kidney enlargement precedes the loss of kidney function in ADPKD (Fig. 42-2). The volume of ADPKD kidneys usually exceeds 1000 mL (normal, 300 mL) before a decline in the glomerular filtration rate (GFR) occurs. In a large, multicenter study of 243 individuals with ADPKD with intact renal function using MRI, the Consortium for Radiological Imaging in the Study of Polycystic Kidney Disease (CRISP) made several observations. Before the loss of kidney function, the total kidney volume increases by approximately 5.2% per year. Total cyst volume accounts for more than 95% of the total kidney volume in ADPKD patients. Younger individuals with larger kidneys (>1500 mL) have the greatest kidney growth rates, and the GFR declines significantly over a 3-year period in those with larger kidneys (−4.9 ± 2.4 mL/yr). PKD2 patients have smaller kidney volumes and lower age-adjusted cyst number per kidney than PKD1 patients (694 ± 221 versus 986 ± 204 mL) while maintaining similar rates of kidney growth (4.9 ± 2.3% versus 5.2 ± 1.6%/yr), indicating that cyst formation rather than cyst expansion differs between the two genotypes. Flank and back pain are common complaints in ADPKD, and they usually result from massive enlargement of the kidneys or liver, or both. Pain is more common in older individuals. Chronic pain is often dull and persistent, but the cause of back and flank pain is complicated and multifactorial in ADPKD. It may be related to stretch of the capsule or pedicle. Cyst hemorrhage occurs more commonly as kidneys enlarge and may be associated with hematuria or fever. The diagnosis of cyst hemorrhage is clinical. However, CT is sometimes helpful in identifying complicated cysts. Pain related to cyst hemorrhage is treated with analgesics and bed rest. Hydration may shorten the duration of hematuria. Renal cyst infection may manifest with localized pain. Blood cultures identify the infecting organism more often than urine cultures. Treatment of cyst infections requires 4 weeks of antibiotics that penetrate cysts adequately, such as trimethoprim-sulfamethoxazole,

a fluoroquinolone such as ciprofloxacin, chloramphenicol, or vancomycin. Cephalosporins and aminoglycosides do not adequately penetrate renal cysts. Hematuria, gross or microscopic, occurs in 35% to 50% of affected individuals. It is associated with increased kidney size and with poorer kidney outcomes in patients with ADPKD. Hematuria is usually accompanied by a precipitating event, including trauma or heavy exercise, and may be caused by cyst hemorrhage, cystitis, cyst or other kidney parenchymal infection, or nephrolithiasis. Nephrolithiasis affects as many as 20% of patients, with urate stones accounting for 50% and calcium oxalate accounting for most of the remaining cases. Although mechanical deformities contribute to stone formation, other risk factors may include low urinary volume and hypocitraturia; the latter is present in two thirds of patients. Nephrolithiasis should be suspected in any ADPKD patient with acute flank pain. Diagnosis by imaging is difficult given the nature of stones and the interference of large, calcified cysts. CT is the most sensitive modality for the detection of small or radiolucent stones. A decrease in kidney concentrating ability is one of the earliest manifestations of ADPKD. It is initially mild, and it worsens with increasing age and declining kidney function. Plasma vasopressin levels are increased in ADPKD, with normal serum osmolarity consistent with the concentrating defect. Approximately 60% of affected children demonstrate a decreased response to desmopressin. Disruption of tubular architecture and alterations in principal cell function may contribute to the reduced response to vasopressin. ADPKD individuals maintain normal kidney function for decades, with significant cyst and kidney enlargement occurring before any loss of kidney function. After kidney function becomes impaired, progression is universal, with an average decline in the GFR of 4.0 to 5.0 mL/min/yr (similar to the rate of decline found in those with large kidney volumes in the CRISP study). Predictors of progression to ESRD include male gender, PKD1, hypertension, increased kidney size, and increased level of proteinuria. However, increased proteinuria is not a major feature, with an average level of 260 mg of protein excretion per day in adults with ADPKD. Consistent with other tubulointerstitial diseases, only 18% of adults have urinary protein excretion rates greater than 300 mg/day. In individuals whose urine protein excretion exceeds 2 g/24 hr, evaluation for a second kidney disease is warranted. Hypertension is a common and early manifestation of ADPKD, occurring in 60% of patients with normal kidney function. The mean age at onset of hypertension is 31 years. It is associated with larger kidney size in children and adults. Unlike the difference between PKD1 and PKD2 patients, hypertension is associated with a greater rate of kidney enlargement (6.2%/year versus 4.5%/year), suggesting a relationship between elevated blood pressure and cyst expansion. Given that polycystins are also expressed in vascular smooth muscle cells, PKD mutations involving this protein may contribute directly to a vasculopathy or hypertensive state, independent of their effects on the kidney. The renin-angiotensin system is activated early in the course of ADPKD as a result of cyst expansion, causing bilateral intrarenal ischemia. Hypertension contributes to an accelerated loss of kidney function and should be treated aggressively. There is no evidence that angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are more effective than other antihypertensive agents in retarding progression to ESRD in ADPKD; however, the Halt Progression of Polycystic Kidney Disease clinical trial is determining whether rigorous control of blood pressure or maximal inhibition of the renin-angiotensin system is effective in slowing progression of ADPKD. Kidney transplant recipients with ESRD due to ADPKD survive longer than patients transplanted for other causes. Potential transplant recipients are screened for the possible presence of an ICA. Native polycystic kidneys do not have to be removed before transplantation unless chronic infections are present or their large size interferes with nutritional intake or quality of life.

AF - CONVERSION TO AND MAINTENANCE OF SINUS RHYTHM CONVERSION TO SINUS RHYTHM.

Anticoagulation for conversion to sinus rhythm • If AF is of less than 48 hrs’ duration, cardioversion can be attempted. • The presence of AF for more than 48 hours necessitates three to four weeks of therapeutic anticoagulation prior to conversion, unless TEE demonstrates absence of clot in the LA and its appendage. • Regardless of whether a TEE is performed, systemic anticoagulation is required for three weeks following cardioversion in all patients with AF of greater than 48 hours’ duration. The ACUTE trial • Patients were assigned to TEE followed by DC cardioversion (if no intracardiac clot was found) versus conventional therapy consisting of three weeks of anticoagulation before DC cardioversion. • All subjects (TEE group and conventional therapy group) received therapeutic anticoagulation for four weeks after cardioversion. • At 8 wks (from the time of enrollment), there was no significant difference in primary endpoint of CVA, TIA, and peripheral embolus. • Fewer bleeding events were noted in the TEE group. • The risk of thromboembolic events is higher in the first three to four weeks immediately following conversion to sinus rhythm. • This may be due to atrial stunning, a term describing the observation of reduced atrial systolic function following conversion to sinus rhythm. • Atrial stunning can allow relative stasis of blood within the atrium, potentially resulting in thrombus formation. • Patients should receive anticoagulation with warfarin for three weeks following conversion to sinus rhythm even if they are in a low risk category or thromboembolic events. • Patients with indications for chronic anticoagulation with warfarin mentioned above (valvular heart disease, age above 65, prior thromboembolic event, hypertension, heart failure, coronary artery disease, or diabetes) should receive long-term anticoagulation following cardioversion. DC cardioversion • Emergent electrical cardioversion is indicated if the patient is hemodynamically unstable as a result of tachycardia. • Cardioversion can either be performed with a standard monophasic or biphasic defibrillator. If a standard defibrillator fails, cardioversion should be repeated using a biphasic defibrillator. Rectilinear biphasic defibrillation • During biphasic defibrillation there is a change in the polarity of the waveform during delivery of energy. • Biphasic defibrillation allows for similar current delivery (which is the most important variable for achieving cardioversion) with lower energy. • Number of shocks required to achieve cardioversion is also reduced. • Biphasic defibrillation is superior to monophasic defibrillation. Chemical cardioversion • Ibutilide: Class III anti-arrhythmic can be used for cardioversion alone or as an adjuvant to facilitate DC cardioversion, esp if later fails initially. • Ibutilide is administered intravenously 1 mg over 10 minutes. • 10-15 % of pts with new onset AF may convert to NSR with ibutilide alone. • When cardioversion is performed after the administration of ibutilide, the success rate may approach 100% and the amount of energy required may also be less. • Pts should be monitored for 4 hours after administration of ibutilide. • Risk factors for ibutilide induced ventricular arrhythmias include prolonged QT, depressed left ventricular function (ejection fraction <0.30), hypokalemia, or hypomagnesemia. MAINTENANCE OF SINUS RHYTHM. • Anti-arrhythmic therapy is indicated for patients with symptomatic AF. • Rate control alone can be used for elderly minimally symptomatic pts. • For moderate to severe left ventricular systolic dysfunction the agent of choice is amiodarone. Dofetilide can be used.

• All other antiarrhythmics are relatively contraindicated in patients with LV dysfunction because of the potential for proarrhythmias. • For patients with ischemic heart disease and preserved left ventricular systolic function, sotalol may be useful because of its β-blocker effects. • Disopyramide can be used in pts suspected of having AF due to increased vagal tone. • Class IC agents such as flecainide and propafenone can be used in pts without ischemic heart disease and normal LV wall thickness and function. These agents can be administered daily for maintenance of sinus rhythm. They can also be used on an as needed basis for acute conversion of symptomatic paroxysmal AF. 300 mg of Flecainide or 600 mg of propafenone can be administered orally. • β-Blocker or CCB should be administered 30–60 min prior to administration of the anti-arrhythmic agent to prevent accelerated AV conduction. The first trial of this approach should be performed while the patient is being monitored. • Treatment of lone AF with Class IC agents can result in conversion to atrial flutter because of prolongation of the atrial refractory period and slowing of conduction velocity. • This “Class IC atrial flutter” can be treated with ablation of the right atrial cavotricuspid isthmus followed by continuation of the AAD. • Class III agents include amiodarone, sotalol, and dofetilide. Amiodarone • Evidence supporting the efficacy of amiodarone comes from the Canadian Trial of Atrial Fibrillation (CTAF) trial. • At 1 year follow-up, 69% of pts treated with amiodarone were in sinus rhythm compared with 39% treated with sotalol or propafenone. • Amiodarone was associated with a higher discontinuation rate due to side effects that was not statistically significant. • There was no significant difference in total mortality b/n the groups. • Amiodarone has multiple adverse reactions; patients receiving amiodarone need monitoring of pulmonary function tests (carbon monoxide diffusion test), thyroid function, liver function, and ocular examination for corneal deposits. • Although there is no FDA indication for amiodarone in AF this is a most commonly prescribed anti-arrhythmic agent for treatment of AF. • Amiodarone can be initiated as an outpatient, usually at 400 mg per day for a period of 2-4 wks, then decreasing to 200 mg per day. Dofetilide • It requires in-hospital initiation and monitoring for arrhythmias. • Safety of dofetilide in patients with heart failure is supported by the Danish Investigations of Arrhythmia and Mortality on Dofetilide in Congestive Heart Failure (DIAMOND-CHF) Study. Patients with left ventricular ejection fractions <35% were enrolled. The dofetilide dose was 500 μg BID. It was adjusted to 250 μg BID for creatinine clearances between 40–60 ml/min and 250 μg QD for patients with creatinine clearance of <40 ml/min. Patients with creatinine clearance of less than 20 ml/min were excluded. • There was no significant difference in total mortality. Retrospective analysis of the results demonstrated that 12% of patients with AF in the treatment arm converted to sinus rhythm, compared with 1% in the placebo arm, with significant reduction in subsequent dvt of AF. Sotalol • It should not be given to patients with renal dysfunction, left ventricular hypertrophy, prolonged QT intervals, bradycardia, or electrolyte abnormalities (hypokalemia). • Nodally active agents should be stopped or decreased before initiation of sotalol because of the risk of bradycardia from β-blocking properties seen at 40 mg bid. The Class III effect (action potential prolongation) appears at 120–160 mg bid. • Sotalol should be initiated in hospital while monitoring for proarrhythmias and prolongation of the QT interval. It can be administered as follows: 80 mg tid for 1 day; Then 120 mg bid on the second day; Then 160 mg bid on the third day; Discharge on 120 mg bid, with increase to 160 mg bid if needed.

ATRIAL FIBRILLATION MECHANISM, PATHOPHYSIOLOGY AND CLASSIFICATION

& Rate Control versus Rhythm Control Aspect of Mgt • Atrial fibrillation (AF) is the most common chronic rhythm disorder, affecting 5% of adults over age 65. AF occurs in 40% of the patients suffering from congestive heart failure (CHF). • Mortality in patients with AF is twice as high when compared with patients in sinus rhythm. • AF could be due to persistent rapid firing from the single focus termed as focal driver or it could be maintained by multiple wavelets after being initiated by premature atrial beats called focal triggers. • These episodes of paroxysmal focal AF tend to occur in young patients without structural heart disease and are often preceded by frequent premature atrial contractions (PACs) of short coupling interval. • Factors affecting the conduction and refractoriness in the atrium such as inflammation, fibrosis, and ischemia are conducive to initiation and maintenance of AF. AF can be classified into the following categories: 1 Paroxysmal AF: starts and stops spontaneously. 2 Persistent AF: requires electrical or pharmacologic cardioversion to terminate an episode. 3 Chronic AF: persists in spite of therapeutic intervention or based on a decision not to restore sinus rhythm. • Lone AF can either be paroxysmal, persistent, or chronic. It is defined as AF occurring in patients less than 60 years of age who have no associated cardiovascular diseases. • Paroxysmal AF often progresses to chronic AF. Conversion & maintenance of NSR becomes increasingly difficult with chronic AF. • Chemical and electrical cardioversion for maintenance of sinus rhythm is easier in AF of short duration. During chronic AF the following structural and electrical changes may occur: 1 Atrial dilatation. 2 Apoptosis, resulting in loss of myofibrils. 3 Fibrosis, which alters conduction velocity. 4 There may be reduction in Connexion 43. Shortening of the atrial refractory period occurs for the following reasons: • A rapid atrial rate induces atrial ischemia, which results in shortening of the atrial refractory period. Inhibitors of Na/H exchanger abolish ischemia-induced shortening of the refractory period. • There is a decrease in sodium channel density and current. • Increase in the intracellular calcium load shortens the refractory period. • Rate adaptation of the refractory period is lost. • In AF ICaL is reduced. This results in shortening of action potential duration (APD) and refractory period. • Shortening of the refractory period may persist after recovery from AF and predispose one to reoccurrences. • Atrial dilatation and stretch may result in a decrease in the refractory period. • Shortening of the effective refractory period (ERP) and APD and an increase in dispersion of refractoriness perpetuates AF. • Human atrial repolarization uses IKur. Ito and IKur are decreased in AF, resulting in shortening of the refractory period. Neurohumoral changes during AF: • Atrial natriuretic factor increases due to atrial stretch and dilation. • Elevated ANF decreases after cardioversion. • ANF may shorten the atrial refractory period. Clinical presentation • Most common symptoms are fatigue, reduced exercise tolerance, dyspnea, and palpitation, although most episodes of AF remain asymptomatic. • Tachycardia from AF can exacerbate angina or CHF. • Irregular rhythm is consistent with but not diagnostic of AF. Other conditions, such as sinus rhythm with frequent supraventricular or ventricular ectopic beats, sinus arrhythmia, or multifocal atrial

tachycardia, can cause irregular pulse. An ECG is necessary to confirm the diagnosis. The absence of P waves is characteristic of AF. Extremely rapid ventricular response may appear regular. • AF with rapid ventricular response and aberrant ventricular conduction can result in a wide complex tachycardia which may be mistaken for ventricular tachycardia. Treatment Rate control versus rhythm control • The issue of treating patients with AF with rate control agents versus using antiarrhythmic drugs to maintain sinus rhythm has been addressed by two clinical trials. AFFIRM • The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial: Patients were randomized between a strategy of rate control with β blockers and calcium channel blockers targeted to a resting heart rate of 80 bpm versus rhythm control using anti-arrhythmic drugs. • There was a non-significant trend toward higher total mortality in the rhythm control group, the study’s primary endpoint. • Pre-specified subgroup analysis demonstrated a statistically significant mortality benefit with rate control for patients above the age of 65. There was no significant difference in the incidence of stroke (roughly 1% per year); the majority (73%) of ischemic strokes occurred in patients who had discontinued warfarin or had an INR < 2.0. • These findings support the recommendation that anticoagulation be continued in patients even if AF is successfully suppressed. • AFFIRM demonstrated no advantage to a rhythm control strategy for recurrent AF, and suggests a rate control strategy may be superior in patients above the age of 65. • Patients enrolled in this study were minimally symptomatic. • These results do not apply to patients with symptomatic AF. • Higher mortality in rhythm control group may be due to proarrhythmic effects of antiarrhythmic drugs rather than due to maintenance of sinus rhythm. RACE • The RACE (Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation). • No significant difference in cardiovascular death or thromboembolic events was noted, but 83% of all thromboembolic events occurred in patients who had discontinued warfarin or had an INR <2.0. • The study demonstrated no significant advantage to a rhythm control strategy for the management of persistent AF. Any benefits derived by rhythm control may have been neutralized by the proarrhythmic effects of the antiarrhythmic drugs. 1 A rate control strategy is an acceptable approach to management of patients with AF, particularly if they are asymptomatic and elderly. 2 Rhythm control should be reserved for patients with symptomatic AF. This strategy should also be considered in minimally symptomatic young patients with AF. Rate Control • If the patient is hemodynamically unstable immediate cardioversion should be considered. • Rate control can be achieved by AV node (AVN) blocking drugs. • Digoxin is least effective in controlling the rate especially in physically active patients. • β-Blockers and/or calcium channel blockers are effective AVN blocking agents. • Calcium channel blockers are preferred in patients with bronchial asthma. • The aim should be to achieve a ventricular response between 80 and 100 bpm. • AVN blocking agents should be avoided in the presence of ventricular preexcitation. Amiodarone could be used in this setting because it prolongs the refractory period of accessory pathway.

AF - NONPHARMACOLOGIC OPTIONS OF MANAGEMENT Radiofrequency (RF) ablation • Arrhythmias are produced by abnormality of impulse generation or impulse propagation. RF ablation seeks to eliminate these abnormalities. • When RF current passes through the tissue it produces heat, which is proportional to the power density within tissue. It is an alternating current. • Maximum heating occurs at the tip of the electrode and it diminishes as the distance from the tip increases. Increase in the radius (distance) from the tip will decrease the heat by 4-fold. For this reason the depth and the volume of the tissue that is affected by heat is small (2 mm). Deeper tissue heating is due to heat conduction. • Commonly used RF is 300–1000 kHz. Lower frequency may produce muscle stimulation. At higher frequency mode of heating changes from resistive to dielectric. • RF energy is delivered in a unipolar fashion from the catheter tip to the dispersive patch electrode placed on the skin. • The surface area of catheter electrode is 12 mm2 and the surface area of the patch electrode is 100–250 cm.2 This results in an increase in power density and heating at the catheter tip. • Catheter tip electrodes with a large surface area or when the catheter tip is cooled by irrigation allows lower system impedance and delivery of higher power. This results in deeper and larger lesion. Since the temperature is measured at the catheter tip it does not reflect actual tissue temperature, which may be very high. • Very high tissue temperature results in heat expansion of the tissue, crater formation and may produce tissue pop. • RF energy delivery should be at least for 60 seconds. • Rise in temperature at deeper tissue level may continue if high power or temperature settings are used, producing thermal latency even after termination of energy delivery. • RF generated heat produces coagulation necrosis of the myocytes. Healing by fibrosis is complete by eight weeks. Radiofrequency ablation for AF • This procedure is typically reserved for patients with lone or paroxysmal AF who have failed one or more trials of anti-arrhythmic therapy. • AF can be cured with catheter ablation techniques. • The best results of this procedure (up to 85% success) have been achieved in patients with lone AF. Lower success rates (50–70%) have been reported in other subsets of AF patients. • Potential complications of this procedure include pulmonary vein stenosis, stroke, LA esophageal fistula, and pericardial tamponade. • The approach to AF ablation could be classified as elimination of the triggers, substrate, or autonomic facilitators (parasympathetic ganglion). Elimination of the triggers • It was noted that the AF is initiated by rapidly firing triggers located in pulmonary veins. • This may manifest as frequent PACs or clearly discernible atrial activity in the form of atrial tachycardia at the onset of AF or during AF. • These foci arise from the myocardial muscular sleeve that extends few centimetres into the pulmonary veins. • Initial approaches included identification of PACs with earliest activation and elimination of these foci within the pulmonary vein. Apossible risk of pulmonary vein stenois shifted the focus to ablation outside the orifice of the pulmonary vein in a quadrantic fashion. Pulmonary vein isolation using RF ablation in LA • In this approach an attempt is made to isolate all the four pulmonary vein orifices from the LA. It reduces the probability of the pulmonary vein stenosis. • The rationale is that PACs (triggers) could arise from any of the four pulmonary veins. • It may also produce compartmentalization and “debulking” of the LA. • The drawback of this approach includes reoccurrences, creation of the isthmus that may predispose to atrial tachycardia.

• Esophageal perforation following posteromedial left atrial or right superior pulmonary vein ablation may occur. This is a serious and often fatal complication. Elimination of the substrate • Identification and elimination of the fractionated electrograms may result in termination of the AF during the procedure. A success rate of 80% has been reported. • Fractionated electrograms may be recorded from the LA around the pulmonary veins, left atrial appendage or interatrial septum. In the right atrium (RA) the fractionated electrograms could be recorded from the crista terminalis, the orifices of the vena cava, the orifice of the coronary sinus (CS), or up to 2–3 cm within the CS. • Like pulmonary veins, muscular extension into proximal CS may produce rapidly firing automatic foci responsible for initiating AF. Modification of the autonomic substrate • The posterior wall of the LA is richly innervated by vagal (parasympathetic) fibers. • Parasympathetic stimulation produces bradycardia and shortening of the atrial refractory period. These electrophysiologic changes are conducive to initiation and maintenance of AF, termed as vagally induced AF. • Vagally induced AF occurs during sleep and may be responsible for the atrial arrhythmias that occur during sleep apnea. • During ablation of the vagal neural terminals, located in the posterior wall of the LA, bradycardia, or junctional rhythm may occur. • It may be necessary to tailor these three approaches when using ablation as the therapeutic modality in the management of AF. For example, a paroxysmal AF in a young patient with a structurally normal heart where focal tachycardia or premature beats are identified as the initiator of the AF may benefit from elimination of that focus. Atrioventricular node ablation with permanent pacemaker implantation • Patients with left ventricular dysfunction or chronic pulmonary disease or those who cannot tolerate the doses of AVN blocking agents necessary to achieve rate control or the agents for rhythm control may be candidates for this approach. • AVN blocking agents may produce negative inotropic effects or bronchospasm in these patients. • The overall survival of patients undergoing AVN ablation and pacemaker insertion is the same as a matched group of patients treated with antiarrhythmic drugs. • The drawback of AVN ablation and the pacemaker approach include persistence of AF, need for anticoagulation, pacemaker dependence and ventricular dys-synchrony from RV pacing. • AVN ablation should rarely be performed in young patients with AF. Electrical therapies for AF • In patients who have or need pacemaker for other indications, programming to eliminate PACs or abolish post-PAC pauses may decrease the burden of AF. • Defibrillators with atrial arrhythmia therapy options such as high frequency pacing at 50 Hz and cardioversion may decrease the frequency and duration of the AF. These features can be set to automatically cardiovert the patient upon detection of AF using specified criteria or it can be triggered by the patient or the physician. • Defibrillator with atrial therapy features is implanted in patients who are undergoing ICD implant and also have paroxysmal AF. Surgical Maze procedure • Incisions are made in the LA around the pulmonary veins, posterior wall and extended to the mitral annulus. • This procedure can be performed in conjunction with other cardiac surgery such as mitral valve replacement. Success rates are approximately 80–90%. • The epicardial approach, using minimally invasive thoracotomy and microwave, attempts to isolate the pulmonary veins.

CLASS I ANTIARRHYTHMIC DRUGS • CLASS I antiarrhythmics are subdivided into IA Prolong conduction and repolarizatiom IB No effect on conduction shorten repolarization IC Prolong conduction no effect on repolarization Class 1A Quinidine • It binds to alpha1 acid glycoprotein. • It is metabolized in the liver through oxidation by the cytochrome P450 system. Its active metabolite is 3-hydroxy-quinidine. 20% is excreted unchanged in the urine. It crosses the placenta and is excreted in breast milk. • It blocks the sodium and potassium channels, thus affecting depolarization and repolarization. It produces greater depression of upstroke velocity in ischemic tissue. It produces use dependent block of the Na channel during the activated state. This results in suppression of automaticity. • It also blocks IK1 (inward rectifier), IK (delayed rectifier), steady state sodium current, ICa, IKatp, Ito, and IKach. • Quinidine blocks alpha 1 and alpha 2 adrenergic receptors. Its vagolytic effect is produced by M2 receptor blocked. It does not cause -ve inotropy. • Prolongation of QRS duration is directly related to the plasma level of quinidine while QT interval is not. It may produce prominent U waves. • Alpha blocking effect may cause orthostatic hypotension. • Vagolytic effect may enhance atrio-ventricular node (AVN) conduction and may increase ventricular response in atrial fibrillation (AF)/Atrial Flutter. • Side effects include diarrhea, loss of hearing, tinnitus, blurred vision, TCP, coombs positive HA, QRS widening, and ventricular arrhythmias, which may respond to sodium lactate or sodium bicarbonate infusion. • Proarrhythmias include TDP, which is due to prolongation of the QT interval. The plasma level does not predict the occurrence of arrhythmia. Hypokalemia facilitates quinidine-induced early after depolarization (EAD) and arrhythmias. The arrhythmias are treated by IV infusion of Mg & pacing. • It is 50% effective in controlling AF. It blocks conduction in accessory pathways. It is not very effective in controlling ventricular arrhythmias. • Oral dose is 300–600 mg every 6 hours. Procainamide • 60% is excreted by the kidney, 40% by the liver. Protein binding is weak. • NAPA is an active metabolite. NAPA has a half life of 6 hours; 90% is excreted by the kidney. Procainamide therapeutic level is 4–12μg/ml and for NAPA it is 9–20μg/ml. Both are removed by hemodialysis. • It crosses the placenta and is excreted in breast milk. • Pharmacologic effects are similar to quinidine. • Neuromuscular side effects may occur when given with amnioglycosides. • It may cause hypotension when given IV. Other side effects include haemolytic anemia. Antinuclear antibodies may develop in 80% of the patients in the first 6 months of therapy. Lupus syndrome occurs in 30%. Antibodies to DNA do not occur commonly. Slow acetylators are more likely to develop lupus. • It may cause TDP. • It is useful in the treatment of AF in the presence of WPW syndrome. • IV bolus administration should not exceed 50 mg/min and infusion rate of 1–6 mg/min. Oral dose is 3–6 gm/day. Disopyramide • It is metabolized by N-dealkylation to desisopropyldisopyramide, which is electrophysiologically active. It binds to AAG. • 50% of the drug is excreted unchanged in urine. • Plasma half life is 4–8 hours. Dose reduction is warranted in hepatic and renal failure. It passes through the placenta and is excreted in breast milk. • It causes use dependent block of INa. May also block IK, IK1, ICa and Ito. • The time to recovery from the block is 700 milliseconds to 15 seconds. • It prolongs the QT interval and may cause TDP. • Its anticholinergic effects are due to block of M2 cardiac, M4 intestinal, and M3 exocrine gland muscarinic receptors. • It produces a significant negative inotropic effect. • Anticholinergic side effects include dry mouth, constipation, and urinary retention. Hypoglycemia may occur due to enhanced insulin secretion. • It may cause cholestatic jaundice and agranulocytosis. • It is effective in the treatment of atrial arrhythmias. It may also suppress digitalis-induced arrhythmias. It has been effectively used in the treatment of neurocardiogenic syncope and hypertrophic cardiomyopathy. • The usual dosing is 100–150 mg every 6 hours or 200–300 mg every 12 hours of slow release preparation. The dose should be reduced in the presence of hepatic and renal insufficiency. Class 1B Lidocaine • Lidocaine blocks INa by shifting voltage for inactivation to more negative. It binds to activated and inactivated state of the sodium channel. • Lidocaine, Quinidine, and Flecainide exert use dependent block with fast intermediate and slow kinetics, respectively. • Continuous activation of INa may cause an increase in action potential duration (APD) (LQT3). This current is blocked by Lidocaine and Mexiletine, which may result in correction of long QT interval.

• It is metabolized in the liver to glycinexylidide and monoethylglycinxylidide, which are less active than the parent compound. • It binds to AAG, which is elevated in cute MI and CHF. This protein binding results in a decreased level of free unbound drug. • Its clearance is equal to hepatic blood flow. A decrease in the blood flow due to propranolol or CHF will result in decreased clearance. • Half life of rapid distribution is 8–10 min after IV bolus. EHL is 1–2 hrs. • In CHF because of a decrease in the volume of distribution and clearance the EHL remains unchanged. • It crosses the placenta. • Its antiarrhythmic effects are the result of sodium channel blocked in its inactivated state. • Because of rapid binding and unbinding of the drug the conduction slowing occurs during rapid heart rates or in tissue with partially depolarized membrane such as in the presence of ischemia, hyperkalemia, and acidosis. In ischemic ventricular muscle cells lidocaine depresses excitability and conduction velocity. • It suppresses normal and abnormal automaticity in Purkinje fibers. This may result in asystole in the presence of complete AV block. • EAD and delayed after depolarization (DAD) are also suppressed. • It does not alter hemodynamics. • Central nervous system (CNS) side effects include perioral numbness, paresthesias, diplopia, slurred speech, and seizures. It does not cause proarrhythmias. • In acute MI lidocaine reduces ventricular tachycardia (VT) ventricular fibrillation (VF) but does not alter mortality. Prophylactic use of lidocaine in post-acute MI showed an increase in the death rate in the treated group. • The bolus dose is 1.5 mg/kg. Continuous IV infusion rate is 1–4 mg/min. • Because of rapid distribution plasma levels fall in 8–10 min. Three added boluses of half of the amount of the initial dose can be given every 10 min. • The bolus and the infusion dose should be reduced in the presence of CHF and liver disease. Renal dysfunction does not affect dosing. Mexiletine • It is an oral congener of lidocaine. It is eliminated by the liver utilizing the P450 system. Side effects include tremor, blurred vision, dysarthria, ataxia, confusion, nausea, and thrombocytopenia. • The usual oral dose is 150–200 mg every 8 hours. Class 1C Flecainide • It is a fluorinated analogue of procainamide. It is metabolized in the liver to meta-O-dealkylated-flecainide. 30% is excreted by the kidneys. • It is a potent sodium channel blocker. The time constant for recovery from the block is 21 seconds. It causes use dependent block. It also blocks IK and slow inward calcium currents. It prolongs the atrial refractory period. • It has a negative inotropic effect. Its use is not recommended in CHF. It may be useful in patients with diastolic dysfunction and arrhythmias. • Its side effects include blurred vision, headache, ataxia, and CHF. • Flecainide-induced proarrhythmias occur in patients with ischemic heart disease, VT, and/or left ventricular dysfunction. Because of use dependent block proarrhythmias may occur during exertion. An exercise test is recommended after achieving a steady state. • Use of β blockers and hypertonic sodium bicarbonate has been successful in the treatment of proarrhythmias. • It is useful in controlling paroxysmal AF. • The initial dose is 100mg every 12 hours and it could be increased to 200mg every 12 hours. A single dose of 300mg can be used for converting recent onset AF. • QRS duration should be monitored and it should not be allowed to exceed more than 20% of the baseline interval. Propafenone • High first pass metabolism results in low bioavailability. It is metabolized in the liver to 5-hydroxypropafenone, which is an active metabolite. • N-dealkylation produces a weak metabolite N-dealkyl propafenone. • 7% of the Caucasians are poor metabolizers. They have high levels of propafenone and low levels of 5-hydroxypropafenone. Hepatic dysfunction decreases clearance. In renal failure the propafenone level remains unchanged, however, 5-hydroxypropafenone levels double. • Propafenone and its metabolites are excreted in milk. • It is an effective Na channel blocker in a use dependent manner. It demonstrates slow binding unbinding. • 5-hydroxy and N-dealkyl propafenone also blocks INa. However, 5-hydroxy compound is as potent as the parent drug. • It is a weak IK and ICa channel blocker. • It is a nonselective β blocker. This effect is enhanced in slow metabolizers. • It has a negative inotropic effect. Blood pressure may decrease. • Side effects include nausea, metallic taste, dizziness, blurred vision, exacerbation of asthma, and abnormal liver function test. • Proarrhythmias occur in 5% of the patients. Sodium lactate can be used to reverse arrhythmogenic effects. It may cause atrial flutter. • QRS duration monitoring and exercise test is recommended. • The initial dose is 150–300mg every 8 hours. Dose adjustment may be necessary in hepatic and renal failure. A single dose of 600mg can be used in patients with PAF.

Anticoagulant Therapy in Acute STEMI Introduction. The central role of thrombosis in the pathogenesis of acute myocardial infarction (MI) is illustrated by the presence of coronary occlusion and thrombus in the vast majority of patients presenting with infarction and ST segment elevation. Rupture of an atheromatous plaque begins the following cascade, which culminates in thrombus formation: -Exposure of thrombogenic lipids and subendothelial components -Platelet adhesion, activation, and aggregation -Thrombin generation -Fibrin deposition -Formation of occlusive thrombus Thrombin activity at the site of plaque rupture may result in delayed or incomplete reperfusion of occluded vessels and contributes to reocclusion. Thrombin is a central mediator of clot formation through its activation of platelets, conversion of fibrinogen to fibrin, and activation of factor XIII, leading to fibrin cross-linking and clot stabilization. Thrombin molecules are bound to fibrin within the evolving mural coronary thrombus, becoming exposed during endogenous or exogenous fibrinolysis. In addition, fibrinolytic agents lead to thrombin generation directly or indirectly through the activation by plasmin of prothrombin and factors V and X. Experimental animal models reveal that concurrent thrombin inhibition enhances coronary fibrinolysis and limits reocclusion. Large-scale randomized trials of fibrinolytic therapy for acute ST elevation (Q wave) MI (STEMI) have shown that improved survival of patients with evolving MI is linked to rapid, complete, and sustained restoration of infarct vessel patency. We recommend anticoagulant therapy in all patients with STEMI. The use of parenteral anticoagulants to maintain infarct vessel patency early in the treatment of patients with STEMI, including the supporting evidence, will be reviewed here. An overview of the total therapeutic approach to STEMI, the role of antiplatelet agents in STEMI, and chronic oral anticoagulation in this setting are discussed separately. Background. Formation of an occlusive thrombus at the site of plaque rupture in a coronary artery is central to the pathogenesis of STEMI. Anticoagulant therapy with unfractionated heparin (UFH), low molecular weight (LMW) heparin, direct thrombin inhibitors, and fondaparinux (factor Xa inhibitor) has been evaluated for its ability to improve outcomes of death, recurrent myocardial infarction, and refractory myocardial ischemia after STEMI. The evidence to support anticoagulant therapy in most cases of STEMI is strong. However, the evidence to recommend one agent over another is less robust, in part because it is largely derived from trials that were performed before the current era of aggressive antiplatelet therapy or trials that conflict with each other. As these drugs are used in conjunction with fibrinolytic therapy, aggressive antiplatelet therapy with multiple agents, and often in the setting of an invasive strategy, bleeding complications are common and may be life-threatening. The choice of anticoagulant is also determined by the patient's underlying risk for bleeding. In multiple trials, bivalirudin and fondaparinux caused less major bleeding than either enoxaparin or heparin. Our recommendations are largely consistent with the 2004 ACC/AHA guidelines on the management of acute ST elevation MI and its 2007 focused update, which were both were published before the results of the HORIZONS AMI trial of bivalirudin became available, as well as with the 2008 American College of Chest Physicians guideline on acute ST-segment elevation MI. These guidelines recommend anticoagulant therapy in most patients with STEMI. Choice of anticoagulant. The choice of agent depends upon the overall treatment strategy designed for each patient: primary PCI, thrombolytic therapy with either fibrin specific or non-fibrin specific agents, or no reperfusion. For patients with STEMI referred for primary PCI, we recommend initiation of intravenous therapy with either UFH (plus planned GP IIb/IIIa inhibitor) or bivalirudin (and provisional GP IIb/IIIa inhibitor), in addition to oral antiplatelet therapy, as soon as possible after presentation (Grade 1B). The bivalirudin regimen is associated with a lower rate of bleeding. There is no rationale for subcutaneous LMW heparin at the time of primary PCI. For all patients with STEMI not treated with primary PCI, we recommend initiation of anticoagulant therapy with enoxaparin, UFH, or fondaparinux, in addition to antiplatelet therapy, as soon as possible after presentation (Grade 1A). - In STEMI patients undergoing reperfusion with thrombolytic therapy, who are at average or low risk of bleeding, we suggest enoxaparin as opposed to UFH or fondaparinux (Grade 2A). For those patients in whom PCI is possible or likely after thrombolytic therapy, we consider UFH a reasonable alternative. For patients at high risk of a bleeding complication, we suggest fondaparinux (Grade 2A).

Bivalirudin was associated with a higher rate of major bleeding after streptokinase compared to UFH. There are insufficient data to make a recommendation for or against its use after fibrinolytic agents such as alteplase. Its use should be limited to patients who have received fibrinolytic therapy and have a history of heparin induced thrombocytopenia. - In STEMI patients not treated with reperfusion therapy, we recommend initiation of anticoagulant therapy with enoxaparin, fondaparinux or UFH, in addition to antiplatelet therapy, as soon as possible after presentation (Grade1A). Dosing. Effective in early October 2009, heparin will be manufactured in the United States according to a new standard and concerns about potency have arisen. For patients who are managed early in their course with activated clotting times (ACT), this change in formulation will not likely affect practice. For those patients who are managed with only activated PTTs (aPTT), the management strategy should be determined at the local institution. This issue is discussed in detail separately. The dosing schedules depend upon the clinical situation: 1. UFH: - For patients receiving streptokinase (thrombolysis) we suggest an intravenous bolus of 5000 units followed by 1000 units/h in patients > 80 kg or 800 unit/h in patients <80 kg to achieve an activated partial thromboplastin time of 50 to 75 seconds. - For patients receiving fibrinolysis we suggest an intravenous bolus of 60 units/kg (maximum of 4000 units) followed by 12 units/kg/h (maximum 1000 units/h) intravenously to achieve an activated partial thromboplastin time of 50 to 70 s. - For patients undergoing primary PCI who are receiving a glycoprotein IIb/IIIa inhibitor, we suggest an intravenous bolus of 50 to 70 units/kg (target activated clotting time > 200 seconds). For those patients not receiving a glycoprotein IIb/IIIa inhibitor, we suggest an intravenous bolus of 60 to 100 units/kg (target activated clotting time 250 to 350 s). 2. Enoxaparin: - For patients receiving fibrinolysis and <75 years and whose serum creatinine is <2.5 mg/dL [220 micromol/L] in men and < 2.0 mg/dL [175 micromol/L] in women , we use a loading dose of 30 mg intravenous bolus followed by 1 mg/kg subcutaneously every 12 hours (maximum of 100 mg for the first two doses); in patients ≥ 75 years we use no loading dose and 0.75 mg/kg subcutaneously every 12 hours (maximum of 75 mg for the first two doses). In patients with a creatinine clearance <30 mL/min using the Cockroft-Gault formula, irrespective of age, we suggest 1 mg/kg every 24 hours without a loading dose. - For patients who are not reperfused, we use no loading dose and administer 1 mg/kg every 12 hours. 3. Fondaparinux: — When used in patients with STEMI, the first dose is given intravenously (2.5 mg) and then followed by 2.5 mg subcutaneously once daily. It should be avoided in patients with estimated creatinine clearance less than 30 ml/min. Fondaparinux is not recommend for use in patients undergoing primary PCI. For patients undergoing PCI, who have previously been treated with fondaparinux, intravenous heparin or bivalirudin should be given during the procedure to prevent catheter related thrombosis. 4. Bivalirudin: — Initial bolus of 0.75 mg/kg followed by an intravenous infusion of 1.75 mg/kg per h that discontinued after PCI. Duration of therapy. The duration of anticoagulant therapy depends on the initial management strategy. Although the optimal treatment length has not been determined for these, the following represent commonly employed regimens in clinical practice: For patients undergoing PCI, anticoagulant therapy is stopped at the end of the procedure in uncomplicated cases. For patients receiving fibrinolytic therapy or no reperfusion therapy, anticoagulant therapy is continued until hospital discharge. Continuation of anticoagulation beyond the times suggested above should be undertaken only if: The PCI is complicated and there is an ongoing risk or recurrent ischemia. There is evidence of high risk for systemic or venous thromboembolism (anterior STEMI, severe left ventricular dysfunction, heart failure, history of systemic or pulmonary embolus, atrial fibrillation, or echocardiographic evidence of mitral or left ventricular thrombus) or a preexistent rational for long term anticoagulation, such as patients with prosthetic heart valves. In these situations, the intravenous regimen may be continued or consideration given to subcutaneous administration of UFH (7500 units every 12 hours to maintain aPTT at 1.5 to 2 times control), subcutaneous LMWH, and conversion to oral warfarin (target INR 2.5, range 2.0 to 3.0).

Examination of Speech and Language Directed Neurological Examination

Speech The examination of speech includes the assessment of speech volume, rate, articulation, prosody, and initiation. Each component of speech can be affected differently in various disorders. The examiner should assess speech through spontaneous conversation or by having the patient read a standardized passage to elicit a wide range of sounds, including labials (sounds dependent on the lips), linguals (sounds dependent on the tongue), dentals (sounds requiring placing the tongue behind the front teeth), and gutturals (sounds depending on laryngeal control). Speech volume may be increased with auditory perceptual problems. Reduced volume (hypophonia) is seen in extrapyramidal motor disorders and in peripheral disorders such as vocal cord paresis. The rate of speech may be increased in Parkinson's disease, in which patients speak rapidly, and in patients with Wernicke's aphasia, who have pressured speech. In general, nonfluent aphasics speak slowly. Articulation defect is a sign of motor impairment. Dysarthric speech often results in stereotyped speech errors—that is, repeating the same errors when trying to produce certain sounds. This helps distinguish dysarthric speech from paraphasic speech, in which substituted letters occur in a variable pattern. Prosody evaluation includes assessment of the spontaneous inflection, prosodic matching of sentence structure (declarative sentence, questions, and boundaries between clauses), assessment of affective intent, and assessment of pragmatic intent (humor, declarative, sarcastic, and defensive). Speech inflection and prosodic matching of sentence structure are mediated by the left hemisphere, whereas affective intent is mediated by right hemisphere and basal ganglia functions. Timing of speech initiation is related to supplementary motor area function and its outflow. Laryngeal phonation, or breathiness, and resonance, or nasality, are two other qualities of speech that aid in localization. They are seen most often in patients with upper motor neuron lesions and spastic speech. Language The six main parts of the language examination can be performed at the patient's bedside. These parts are (1) expressive speech, (2) comprehension of spoken language, (3) repetition, (4) naming, (5) reading, and (6) writing. The examiner can classify most aphasic syndromes after evaluating spontaneous speech, repetition, and comprehension. Expressive Speech The evaluation of aphasia traditionally begins by observing the spontaneous or conversational speech of the patient. Aphasic verbal output is either nonfluent or fluent. Normal English output is 100 to 150 words per minute. Nonfluent aphasic output is sparse (<50 words per minute), produced with considerable effort, poorly articulated, of short phrase length (often only a single word), and dysprosodic (abnormal rhythm). Also, it features a preferential use of substantive meaningful words with a relative absence of functor words (prepositions, articles, adverbs). In contrast, fluent aphasic output features many words and is easily produced, with normal phrase length and prosodic quality but often omitting semantically significant words. Fluent aphasia, when severe, may sound empty and devoid of content. In addition, paraphasic errors (substitution of phrases or words) are often abundant in fluent aphasic output.

Nonfluent aphasic output is associated with pathology involving the anterior left hemisphere, and fluent aphasia results from pathology posterior to the fissure of Rolando. Comprehension of Spoken Language Comprehension can be assessed in many ways; examples of clinical evaluations of comprehension are (1) conversation—engaging the patient in ordinary conversation probes the patient's ability to understand questions and commands; (2) commands—a series of single or multistep commands, such as asking the patient to pick up a piece of paper, fold it in two, and place it on a bedside stand; (3) yes and no answers—require only elementary motor function and can be used to assess various comprehension levels (e.g., Are the lights on in this room?); and (4) pointing—requires a limited motor response (patients can be asked to point to the window, the door, and the ceiling; the patients are asked to point to these places in a specific sequence, and more difficult tasks can also be given [e.g., point to the source of illumination in this room]). Despite all of these methods, comprehension remains difficult to assess. Patients may derive significant meaning from nonverbal cues (e.g., tone of voice and facial or arm gesture) and may lead the clinician to underestimate the comprehension deficit. Apraxia and other motor disorders may cause a failure to perform, leading to an overestimation of the deficits. Perseverative answers may further complicate comprehension assessment. Comprehension is compromised by dysfunction of the heteromodal association cortex or Wernicke's area of the left hemisphere. Repetition The examiner tests repetition by requesting that the patient repeat digits, words, and sentences. A phrase such as “no ifs, ands, or buts” poses special difficulty. Aphasics with impaired repetition have pathology that involves the perisylvian region. In contrast, a strong, often mandatory tendency to repeat (echolalia) suggests an extrasylvian locus of pathology, often involving the vascular borderzone areas. Naming Disturbances in confrontational naming are the least specific language abnormalities. Naming is disturbed in most aphasic patients. Testing should evaluate the patient's ability to name objects (both high and low frequency), body parts, colors, and geometrical figures. If the patient fails, the examiner provides a phonemic cue (such as pronouncing the initial phoneme of the word) or a semantic cue (such as “You write with a ___.”). Anomia is generally not a reliable localizing abnormality; it occurs with lesions of the angular gyrus, posterior inferior temporal cortex, and temporal pole on the left but may occur in concert with other lesions. Reading The examination tests both reading aloud and reading for comprehension. In some cases, the two abilities are dissociated. Writing Writing is nearly always disturbed in aphasic patients. Writing provides a further sample of expressive language and permits evaluation of spelling, syntax, visuospatial layout, and mechanics. The examiner assesses writing to dictation and to command (e.g., describe your job), as well as copying.

ATRIAL FLUTTER There are 200 000 new cases of atrial flutter (AFL) in the United States each year. Of these, 88,000 present solely as AFL. The number of AFL cases rises exponentially in relationship to advancing age. Atrial fibrillation (AF) has a 10 times greater prevalence than AFL. It has been reported that over a year’s follow-up, 56% of patients presenting with typical AFL develop AF. AFL is associated with an increased risk of morbidity. However, not as profoundly as when it is coupled with AF. RISK FACTORS Independent Risk Factors include advanced age, male gender, congestive heart failure, chronic pulmonary disease, prior CVA & myocardial infarction. Conditions Associated with AFL include thyrotoxicosis, valvular heart disease, pericardial disease, congenital cardiac disease, after open heart surgery, after major cardiac surgery, possible genetic predisposition, alcohol intoxication, pulmonary embolus, hypertrophic cardiomyopathy, cardiac tumors & sodium channel blocking agents to treat AF (5%). CLINICAL PRESENTATION AFL, an organized macroreentrant arrhythmia, often presents as paroxysmal, short episodes ranging from seconds to hours; however, it can also present as sustained & persistent. The atria usually contract at a rate of 250–350 beats per minute (bpm) while in AFL. The ventricular rate is generally a 2:1 ratio. A 1:1 ratio can be seen in cases where the atrial rate is relatively slower or when atrioventricular (AV) nodal conduction is enhanced due to increased sympathetic tone or anticholinergic medications. Acutely, patients often complain of shortness of breath, palpitations, diaphoresis, chest discomfort, dizziness, & weakness. Patients may also complain of polyuria, which occurs as a result of increased atrial pressure from rapidly contracting atria against a closed AV valve, & the subsequent release of atrial natriuretic factor (ANF). AFL may also present more subtly in the form of exercise-induced fatigue, worsening heart failure, or pulmonary disease. Patients tend to be more symptomatic when the ventricular response rate is rapid and/or when they present with episodes of both AF & AFL. AFL can coexist with AF in 25% of patients with AF.On physical examination, the peripheral pulse is generally rapidand regular (less often irregular); cannon ‘a’ waves may be observed, & S1 is of variable intensity. DIAGNOSIS OF AFL Generally, the diagnosis of AFL can be made on a 12-lead surface ECG by identifying flutter waves in leads II, III, aVF, & V1. When it is difficult to distinguish flutter waves, AV nodal blockers (e.g. adenosine or diltiazem) remove QRS complexes. Vagal maneuvers (Valsalva or gentle carotid sinus message) can also assist in slowing the heart rate down enough to distinguish flutter waves. Flutter waves resemble the edge of a wood saw, hence the name ‘saw-tooth’ wave. In ‘typical’ flutter the saw-tooth waves are negative in the inferior leads & positive in V1. The negative waves can be described in succession: (i) a slowly descending segment, (ii) a rapid negative deflection, (iii) a sharp upstroke, that (iv) with a slight overshoot leads to the slowly descending segment of the next cycle. RE-ENTRANT MECHANISM OF AFL In a primary sense, re-entry occurs as a repetitive excitation of an area of the heart & transmission of that impulse around a conduction or functional barrier. In order for re-entry to initiate, propagate, & perpetuate certain criteria must be present: 1. Initiation of the tachycardia circuit requires unidirectional block in one limb of the circuit. A unidirectional block can occur as an acceleration of the heart rate or a blocked premature beat that affects the refractory time of the circuit. 2. A zone of slowed conduction is required for both initiation & perpetuation. Atrial flutters circus around an unexcitable anatomic or functional barrier. In 1940 Rosenbleuth10 demonstrated that creating a crushing lesion on the posterior wall of the right atrium extending from the IVC to the SVC provided an obstacle which could support atrial flutter. The wavefront was demonstrated to circulate in a clockwise direction up the septum, around the roof down the free lateral wall & bounded anteriorly by the tricuspid orifice. Rosenbleuth further demonstrated that the circulating wavefront could be extinguished by creating a lesion between the IVC & the inferior edge of the tricuspid orifice, thus providing the first stepping stones which would later give insight into how to successfully ablate atrial flutters. Re-entrant circuits include normal anatomic boundaries such as the tricuspid ring, mitral ring, & orifices of the superior vena cava (SVC), inferior vena cava (IVC), pulmonary veins, & the coronary sinus (CS). Functional barriers are created due to an inability to conduct action potentials as rapidly as that seen in AFL. In 1980, Spach12 suggested that the right atrium is able to support re-entry due to anisotropic conduction. The crista terminalis (CT) is a thick bundle of myocardial fibers that run in a superior/inferior direction, extending from the roof of the right atrium adjacent to the SVC opening laterally & inferiorly to the IVC. This band of tissue is able to conduct rapidly in the longitudinal direction but very slowly in the transverse direction. The conduction ratio is 10:1. This remarkable difference in conduction is due to the non-homogeneous distribution of gap junctions. The longitudinal spindle-shaped cells have ten times as many gap junctions in an end-to-end direction for conduction compared to the transverse ones in a side-to-side direction. This property allows for a functional barrier. The openings of the IVC & the SVC linked by the CT constitute the posterior obstacle, the tricuspid orifice (TR) constitutes the anterior obstacle; this creates a ring that is able to support re-entry in either a clockwise or counterclockwise direction. TOOLS FOR DIAGNOSING ATRIAL FLUTTER A multi-polar reference catheter that covers the septal & anterior walls allows recording of almost the entire circuit. An electrogram of the IVC–TR isthmus, recorded with a mapping/ablation catheter, will provide information on the remaining circuit. When a characteristic ECG pattern is identified & the endocardial activation map is ‘circular’ a diagnosis can be made without pacing studies. However, it is routine to test local return

cycles after a couple of pacing runs to verify isthmus involvement. This practice should not be ignored in patients with multiple different ECG patterns recorded or in those with anyhistory of cardiac surgery or structural damage. The length of the pacing cycle should be similar to that of the cycle length of the atrial flutter thus not to disturb the arrhythmia. This is especially true if there are multiple circuits as in those cases of scar-dependent macro-re-entry. In the face of this activation sequence it is not necessary to show the presence of double potentials on the posterior or posterior lateral RA. NOMENCLATURE In the past, there has been some confusion about how to describe the different types of AFL. Recently, Scheinman & his colleagues have provided a classification system based on the location & mechanism of AFL. Right atrial cavotriscuspid-isthmus-dependent flutter Counterclockwise (CCW) atrial flutter This represents 90% of clinical AFL cases.13 ECG findings include negative sawtooth waves in the inferior leads & positive waves in V1 that transition tonegative in V6. The wavefront of the CCW–AFL circuit propagates up the posterior & septal wall of the right atrial (RA) & down the RA anterior & lateral walls when viewed from left atrial oblique (LAO) perspective. This wavefront perpetuates in a circular CCW direction until it is interrupted. Anatomically, the circuit is anteriorly bound by the tricuspid orifice, & posteriorly bound by the vena cava orifices, Eustachian ridge, & the coronary sinus (cs). Clockwise (CW) atrial flutter This represents 10% of clinical AFL cases. ECG findings include positive saw-tooth waves in the inferior leads & negative waves in V1. The wavefront of the CW-AFL circuit propagates down the posterior & septal wall of the RA & up the RA anterior & lateral walls when viewed from the LAO perspective. This wavefront propagates in a circular CW direction until it is interrupted. The CW–AFL circuit has the same anatomic boundaries as CCW–AFL. Double-wave re-entry (DWR) DWR flutter occurs when a carefully timed stimulus is delivered to the isthmus between the tricuspid annulus & the Eustachian ridge, resulting in a unidirectional antidromic block of the paced impulse & acceleration of the CCW–AFL. The acceleration of the tachycardia is due to two successive activation fronts traveling in the same direction in the re-entrant circuit. DWR flutter is not sustained. Termination of DWR AFL results in complex atrial arrhythmias which include AF. Lower loop re-entry Lower loop re-entry AFL propagates around the IVC in either a CW or CCW direction or around the IVC & tricuspid annulus in a figure of 8 double-loop configuration. Intra-isthmus re-entry The intra-isthmus re-entry AFL circuit is localized to the CTI. The circuit is bound medial CTI & the coronary sinus ostium the lateral CTI is not involved. Fractionated or double potentials can be recorded at the CTI just outside the coronary sinus ostium & the circuit can be entrained. Right atrial non-cavotricuspid-isthmus-dependent flutter Scar-related atrial flutter Macro-re-entrant circuits can occur at sites other than the CTI. Areas that have low voltage provide an anatomic obstacle for macro-re-entry. Surgical repair of congenital heart defects may cause a right atrial scar, resulting in regions of low voltage. Scar tissue located within the posteriolateral & inferiolateral right atrium, & in regions of low conduction within the scar located in the free right atrial wall can all create & support re-entrant circuits. Upper loop re-entry Upper loop re-entry circuits are due to functional obstacles rather than anatomic obstacles. Upper loop re-entry circuits are localized to the upper portion of the right atrium with the crista terminalis & its slowed conduction serving as the functional obstacle. Maintenance of the conduction gap is vital for the perpetuationof the circuit. The circuit can travel in either a clockwise or counterclockwise direction. Left atrial flutter Left atrial flutter occurs less frequently than right atrial CTI-dependent tachycardias & often co-exists with AF. Left atrial flutters arise in structurally damaged left atria. Areas of slowed conductance, block, or electrically silent areas serve as a substrate for left atrial flutter. ECG findings of CCW left atrial circuits include low amplitude flutter waves & positive waves in leads V1 & V2. Mitral annular atrial flutter The anatomic boundaries of the circuit include the mitral annulus & low voltage area or scar in the posterior wall of the left atrium. The circuit rotates around the mitral annulus in either a CW or CCW direction. Scar & pulmonary vein related atrial flutter This circuit rotates around one or more of the pulmonary veins or scar in the posterior wall. Coronary sinus atrial flutter The circuit travels from the coronary sinus to the lateral left atrium down the interatrial septum & back to the cs. One case has been reported in a patient with no structural abnormality. Left septal atrial flutter The circuit rotates in either a CW or CCW manner around the left septum primum. ECG findings include dominant positive waves in V1. The critical isthmus is located between the septum primum & pulmonary veins or between the septum primum to the right inferior pulmonary vein & the mitral annular ring. In the cases that have been reported with left septal atrial flutter the patients had no prior history of surgery but low-voltage areas were found on the posterior wall & the roof of the left atrium. It is hypothesized that atrial conduction slowing is secondary to either atrial dilated cardiomyopathy or anti-arrhythmics (sotalol, amiodarone).

AUTONOMIC FUNCTION TESTS In order to evaluate the reaction of the autonomic reflex system, a combination of various tests in the form of a test battery is often used. Tests for the evaluation of the parasympathetic nervous system are combined with tests for the evaluation of the sympathetic nervous system. POWER SPECTRAL ANALYSIS OF HEART RATE AND BLOOD PRESSURE VARIABILITY (HRV AND BPV) A high resolution ECG enables the calculation of the heart rate variability within a frequency range. This so-called POWER SPECTRAL ANALYSIS allows the evaluation of parasympathetic and sympathetic dysfunctions. Furthermore, the combination of heart rate and blood pressure variability increases the specificity of the assessment of sympathetic functions and sympatho-vagal balance. By means of the power spectral analysis malfunctions of the cardiovascular autonomic function can be detected earlier than by traditional functional tests. Furthermore, this method does not require active participation of the patient. Example: A patient suffering from diabetic autonomic neuropathy showing a very low power spectral density. During tilt testing only little modulation of the spectral components can be seen, and sympathetic activity decreases in the course of the tilting phase. EWING BATTERY In the 70’s Ewing defined a series of tests for the evaluation of the autonomic function by means of heart rate variability and blood pressure. The Task Force Monitor analysis can be performed either by means of the tool-tip function in the Graphic view “Short Trend” or in the Data View “Beat-to-Beat”. Both analyses are specified by means of the following examples. TIP: The analysis from the Data View is to be preferred; due to rounding ups the values from the Graphic View may vary marginally. HRV During Deep Breathing – Cardiovagal Function An evaluation of heart rate variability during controlled breathing with 6 deep breathes per minute (5 sec inspiration and 5 sec expiration) allows the calculation of the age-related quotient from the longest RR intervals during expiration over the shortest RR intervals during inspiration – the E/I ratio. In a healthy subject this quotient should be higher than 1.2, abnormal values are under 1.1. See table for normal values. E/I-Difference The E/I difference results from the difference of the RR intervals during expiration minus the RR intervals during inspiration. The E/I difference should be >15 beats per minute, values below 10 beats per minute are regarded as abnormal. Normal values are 18 bpm and more for 10-40, 16 bpm and more for 41-50, 12 bpm and more for 51-60, 8 bpm and more for 61-70. Analysis from Graphic View (Tool-tip Function) After having completed the measurement or after having reloaded the file (if it is an earlier measurement), please open the graphic view “short trend” means of the tool-tip function (keep right mouse click pressed). You detect the lowest heart rate (=longest RR interval) as well as the higher heart rate (shortest RR interval) and calculate the E/I difference from the mean value for 6 breaths. Breath Inspiration - Expiration Difference 1 79bpm – 59 bpm = 20 2 - 6 -- bpm - -- bpm = -- Total sum of difference/6 = ---- bpm (mean value) Active Orthostasis In healthy subjects the blood pressure only slightly decreases after standing up due to intact sympathetic and parasympathetic nervous systems. In patients with autonomic neuropathy such as those with diabetes, the blood pressure regulation through baroreceptors and/or autonomic nervous system is disturbed. The result of the test is considered abnormal when the diastolic blood pressure decreases more than 10 mmHg or the systolic blood pressure decreases by 30 mmHg within 3 minutes after standing. A Task Force of the American Academy of Neurology and the American Autonomic Society defines a blood pressure decrease of > 20 mmHg systolic and > 10 mmHg diastolic as orthostatic hypotension. The change in heart rate within the first 30 seconds after standing up permits an evaluation of the cardiovagal system. The relation between the longest RR

interval at approximately the 30th beat after standing and the shortest RR interval at approximately the 15th beat after standing is defined as 30:15 ratio and describes an age-related index of the cardiovagal function. In a healthy subject the 30:15 ratio should be higher than 1.04. values below 1.0 are considered abnormal. Analysis from the Data View (Beat-to-Beat) The exact analysis of autonomic function tests can be perfomed by means of the Beat-to-Beat Data View. After having completed the measurement or after having reloaded the file (if it is an earlier measurement), please open the Data View “Beat-to-Beat”. Detect the longest RR interval approximately at the 30th heart beat (ideally between the 20th and 40th beats) as well as the shortest RR interval approximately at the 15th heart beat (ideally between the 5th and 25th heart beats) and calculate the 30:15 ratio. Example Start Beat 768 15th heart beat (= 783 + 10 beats) 773-793 30th heart beat (= 798 + 10 beats) 788-808 From these ranges select the required values for calculating the 30:15 ratio. 30:15 ratio = 898/712 = 1.26 For a patient of any age range, this would fall into the normal values. Attention: in patients with isolated sympathetic vasomotoric lesion with intact cardiovagal function the bradycardia is limited after 20-30 seconds. The cause of the changed ratio is a malfunction of the sympathetic drive resulting in an absence of vasoconstriction and therefore altered rise in blood pressure. Therefore the test should always be performed in combination with a beat-to-beat blood pressure measurement. Valsalva Maneuver The patient forcibly exhales for 15 seconds against a fixed resistance (40 mmHg). By means of the beat-to-beat blood pressure measurement blood pressure variations initiated by intrathoracic pressure changes can be detected and an insight in the function of the sympathetic nervous system and the baroreflex can be gained. PHASE 1: Transient rise in blood pressure and a reflex fall in heart rate due to compression of the aorta. PHASE 2: Early fall in blood pressure with a subsequent recovery of blood pressure later in this phase. The blood pressure changes are accompanied by an increase in heart rate. There is a fall in cardiac output due to impaired venous return, the resulting fallin blood pressure causes via the baroreflexes compensatory cardiac acceleration and increased peripheral resistance. PHASE 3: Blood pressure falls for 1-2 seconds. And heart rate increases with cessation of expiration. PHASE 4: Blood pressure increases above baseline values ( overshoot) because of delayed vasoconstriction and restored normal cardiac output. Blood pressure overshoot causes a decrease in heart rate due to baroreflexes. Abnormal Blood Pressure Reactions to Valsalva Maneuver See table. The age-related valsalva ratio is calculated by the ratio of the longest RR interval after the maneuver (reflecting the bradycardic response to the blood pressure overshoot) to the shortest RR interval during or shortly after the maneuver. The physiologic value ranges over 1.21. Abnormal values are below 1.1. Analysis In order to analyse the test performed with the Task Force Monitor, please open the Data View “Beat-to-Beat” after the measurement is complete. Detect the longest RR interval after the manoeuvre as well as the shortest RR interval during or shortly after the end of the test and calculate the valsalva ratio. Sustained Handgrip Test/Cold Pressor Test The sustained handgrip test provides valuable evidence for the function of the efferent sympathetic system: sustained muscle contraction causes a rise in blood pressure and heart rate. The normal response is a rise of diastolic blood pressure >16 mmHg, whereas a response of <10 mmHg is considered abnormal. In weak and elderly patients the sustained hand-grip test can be replaced by the cold pressor test (ice water test).

CALCIUM CHANNELS AND CURRENTS • The process of channel opening and closing is called gating. • Open channels are active. Closed channels are inactive. Calcium and sodium channels open in response to depolarization and enter the nonconducting state during repolarization, a gating process known as inactivation. • Alpha 1 subunit of the Ca channel contains the binding site for calcium channel blocking drugs. • Calcium channels are very selective and allow Ca permeability 1000-fold faster. • There are four types of calcium channels:

I L-type expressed on surface membrane. II T-type expressed on surface membrane. III Sarcoplasmic reticulum (SR) Ca release channel. IV Inositol triphosphate (IP3) receptor channels are present on internal membrane.

L-type calcium channel (L = Large and lasting) • It is a major source of Ca entry into the cell. It opens when depolarization reaches positive to −40 mV. • It is responsible for excitation in sino atrial node (SAN) and atrio-ventricular node (AVN). It produces inward current that contributes to depolarization in SAN and AVN. • It produces inward current responsible for plateau of AP. • Increased calcium current prolongs depolarization and increases the height of the AP plateau. • Calcium channel dependent inward current is responsible for EAD. • ICaL is responsible for excitation, contraction, and coupling. Blockade of these channels results in negative inotropic effects. • In AF decrease activity of the ICaL channel shortens APD and perpetuates arrhythmia (electrical remodeling). Regulation of pacemaker and Ca currents β-Adrenergic receptor stimulation • It increases L-type calcium channel activity. • This results in increased contractility, heart rate, and conduction velocity. • Stimulation of receptors activates guanosine triphosphate binding protein Gs, which in turn stimulates adenylyl cyclase activity, thus increasing the Camp level. • β-Blockers have no direct effect on calcium channel. • Sympathetic stimulation may also activate alpha1 receptors. Parasympathetic stimulation • It decreases L-type calcium activity through muscarinic and cholinergic receptors. • Acetylcholine, through G protein, activates inwardly rectifying IKach, which makes MDP more negative and decreases the slope of diastolic depolarization. This results in slowing of the heart rate. • Magnesium acts as an L-type calcium channel blocker. T-type calcium channel • These are found in cardiac and vascular smooth muscles, including coronary arteries. i It opens at more negative potential.

ii It rapidly inactivates (Transient T). iii It demonstrates slow deactivation. iv Has low conductance (tiny T).

• It is found in high density in SAN and AVN. • It does not contribute to AP upstroke which is dominated by sodium channel. • It is implicated in cell growth. • T-type Ca channel density is increased in the presence of the growth hormone,endothelin-1, and pressure overload. • Failing myocytes also demonstrate increase density of T-type Ca channels. • Drugs and compounds that block T-type Ca channels include the following: Amiloride, 3,4-Dichrobenzamil, Verapamil, Diltiazem, Flunarizine, Tetradrine, Nickel, Cadmium, Mibefradil

• T-type Ca channel is up regulated by norepinephrine, alpha agonist (phenylephrine), extracellular ATP, and LVH. Sarcoplasmic calcium release channels (also called Ryanodine receptors) • These are intracellular channels that are regulated by calcium. • These channels mediate the influx of calcium from SR into cytosol. • It provides calcium for cardiac contraction. SR controls the cytoplasmic Ca level by release or uptake during systole and diastole, respectively. • Calcium release from SR is triggered by increase in intracellular calcium, produced by L-type Ca channel. It is called calcium-induced calcium release (CICR). • When a cell is calcium overloaded SR releases calcium spontaneously and asynchronously causing DAD (delayed after depolarization) seen in digitalis toxicity. • Caffeine releases calcium from SR. • Doxorubicin decreases cardiac contractility by depleting SR calcium. • Magnesium and ATP potentiates channel flux. • In ischemia decreased intracellular ATP decreases calcium release and causes ischemic contractile failure. • Verapamil has no effect on sarcoplasmic Ca release channel (SCRC). • SR also has potassium, sodium, and hydrogen channels. Inositol triphosphate receptors (IP3) • These receptors are found in smooth muscles and in specialized conduction tissue. • These are up regulated by angiotensin II and α-adrenergic stimulation. • Stimulation of myocytes angiotensin II receptor by angiotensin increases intracellular IP3. • The arrhythmogenic effect of angiotensin II in CHF may be due to elevated IP3. • These receptors have been implicated in apoptosis. Tetrodotoxin (TTX) sensitive calcium channel • It produces inward current. It is blocked by TTX. • The channel that carries this current is permeable to both sodium and calcium. • Elevated intracellular Na may activate reverse Na/Ca exchange, thus increasing the levels of intracellular Ca which may trigger SR calcium release. • It may contribute to cardiac arrhythmias. Sodium and calcium exchange • Opening of voltage operated calcium channel, during the plateau phase of APD, increases the flux of calcium into cytoplasm. This causes CICR from SR. • During diastole calcium is removed from the cell by sodium/calcium exchange located in the cell membrane. • Lowering of pH blocks sodium/calcium exchange. • SR calcium ATPases, Sarcolemmal calcium ATPases and sodium/calcium exchange decrease cytoplasmic calcium from elevated systolic level to baseline diastolic level by pumping Ca back into SR or by extruding Ca out of the cell. • During calcium removal inwardly directed current is observed, which may cause DAD. • DAD occurs when there is pathologically high calcium load either due to digitalis toxicity or following reperfusion. • Na/Ca exchange is able to transport calcium bi-directionally. Reverse mode will increase intracellular calcium, which may trigger SR calcium release. Effect of antiarrhythmic drugs on calcium channel • Most Na and K channel blocking drugs also affect Ca channels. • Quinidine, Disopyramide, Lidocaine, Mexiletine, Diphenylhydantoin, Flecainide, Propafenone, Moricizine, and Azimilide suppress L-type calcium current. • Amiodarone blocks both L and T-type Ca currents. • Sotalol has no effect on Ca channel. • Digoxin inhibits sodium/potassium ATPases. This inhibition results in an increase in intracellular Na, which in turn leads to an increase in intracellular Ca through Na/Ca exchange. • Verapamil blocks Ca current and decreases calcium activated chloride current.

CAP TREATMENT IN THE OUTPATIENT SETTING TREATMENT REGIMENS

Treatment regimens for outpatients with CAP are based upon studies of the effectiveness of antibiotics, the severity of illness, the presence of comorbid conditions, and the prevalence of risk factors for drug resistant S. pneumoniae (DRSP). The following approach to empiric antimicrobial therapy is suggested. No comorbidities or recent antibiotic use For uncomplicated pneumonia in patients who do not require hospitalization, have no significant comorbidities and/or use of antibiotics within the last three months, and where there is not a high prevalence of macrolide-resistant strains, we recommend any one of the following oral regimens: *Azithromycin (500 mg on day one followed by four days of 250 mg a day); 500 mg a day for three days, or 2 g single dose (microsphere formulation) are acceptable alternative regimens *Clarithromycin XL (two 500 mg tablets once daily) for five days or until afebrile for 48 to 72 hours *Doxycycline (100 mg twice a day) for seven to 10 days There is concern that widespread use of fluoroquinolones in outpatients will promote the development of fluoroquinolone-resistance among respiratory pathogens (as well as other colonizing pathogens) and may lead to an increased incidence of C. difficile colitis. In addition, empiric use of fluoroquinolones should not be used for patients at risk for Mycobacterium tuberculosis without an appropriate assessment for tuberculosis infection. The administration of a fluoroquinolone in patients with tuberculosis has been associated with a delay in diagnosis, increase in resistance, and poor outcomes. Because of these concerns, the use of fluoroquinolones is discouraged in ambulatory patients with CAP without comorbid conditions or recent antimicrobial use, unless it is known that there is a high prevalence of high-level macrolide-resistant S. pneumoniae in the local community. When such resistance is present, the regimen for patients with comorbidities or recent antibiotic use described in the next section can be followed. Despite these recommendations, fluoroquinolones continue to be given, often inappropriately, for CAP. In one report of 768 ambulatory patients with CAP seen in an emergency department in 2000 and 2001, 245 (32 percent) were treated with levofloxacin; one-half of these patients did not meet the criteria for appropriate fluoroquinolone therapy. Telithromycin is NOT recommended as a first-line empiric regimen because of concerns about toxicity. Although erythromycin is the least expensive macrolide, we rarely use this drug for three reasons: *multiple daily doses over several days are required; *compliance is limited by gastrointestinal side effects, as well as dosing; and *there is a risk of sudden cardiac death due to QT interval prolongation, particularly when other drugs metabolized by CYP3A4 are taken concurrently. The drugs noted above are as effective, more convenient to use, and less toxic. Comorbidities or recent antibiotic use The presence of significant comorbidities (ie, chronic obstructive pulmonary disease [COPD], liver or renal disease, cancer, diabetes, chronic heart disease, alcoholism, asplenia, or immunosuppression), and/or use of antibiotics within the prior three months, increases the risk of infection with more resistant pathogens. We recommend one of the following oral regimens for such patients: *A respiratory fluoroquinolone (gemifloxacin 320 mg daily, levofloxacin 750 mg daily, or moxifloxacin 400 mg daily) for a minimum of five days. *Combination therapy with a beta-lactam effective against S. pneumoniae (high-dose amoxicillin, 1 g three times daily or amoxicillin-clavulanate 2 g twice daily or cefpodoxime 200 mg twice daily or cefuroxime 500 mg twice daily) PLUS either a macrolide (azithromycin 500 mg on day one followed by four days of 250 mg a day or clarithromycin 250 mg twice daily or

clarithromycin XL 1000 mg once daily) or doxycycline (100 mg twice daily). Treatment should be continued for a minimum of five days. These regimens are also appropriate where there is a high prevalence of "high-level" macrolide-resistant S. pneumoniae, even in the absence of comorbidity or recent antimicrobial use. When choosing between fluoroquinolones, in vitro studies of moxifloxacin and gemifloxacin show more activity against penicillin-resistant pneumococci strains than levofloxacin; the clinical significance of these findings is not yet clear. Gemifloxacin causes a rash in 2.8 percent of patients overall, but a higher rate (14 percent) in women under 40 years of age who received the drug for seven or more days. The rash is generally mild, occurs after the fifth day of therapy, and resolves with discontinuation of the agent. The rash is not associated with phototoxicity or hypersensitivity and does not preclude the use of other fluoroquinolones in the future, although repeated courses of gemifloxacin should be avoided in such patients. Telithromycin should be reserved as an option for patients at risk for drug-resistant pneumococcal infection in whom alternative agents are not appropriate. However, it should NOT be prescribed in patients with known liver disease. Pathogen-directed therapy Once the etiology of CAP has been identified using reliable microbiologic methods, antimicrobial therapy should be directed at that pathogen. Treatment duration and response With respect to treatment duration, we generally agree with the 2007 IDSA/ATS guidelines. Ambulatory patients with CAP should be treated for a minimum of five days; because of the prolonged half-life of azithromycin, a shorter duration of drug administration may be indicated for this agent. Support for this recommendation comes from a meta-analysis of 15 randomized controlled trials of almost 2800 patients with mild to moderate CAP, which found comparable clinical outcomes with less than seven days compared to more than seven days of antimicrobial therapy. Antibiotic therapy should not be stopped until the patient is afebrile for 48 to 72 hours and is clinically stable. Most patients with CAP begin to improve soon after the initiation of appropriate antibiotic therapy as evidenced by resolution of symptoms, physical findings, and laboratory signs of active infection. However, some symptoms often persist as the patient convalesces. This was illustrated in a study of sequential interviews in 134 ambulatory patients with CAP. The median time to resolution ranged from three days for fever to 14 days for both cough and fatigue. At least one symptom (eg, cough, fatigue, dyspnea) was still present at 28 days in one-third of patients. In another report, 76 percent had at least one symptom at 30 days, most commonly fatigue, compared to 45 percent by history in the one month prior to the onset of CAP. These symptoms are usually not sufficient to interfere with work as illustrated in a review of 399 ambulatory patients with CAP in which the median time of return to work was six days even though one-third had at least one persistent symptom at 14 days. Persistence of such symptoms is not an indication to extend the course of antibiotic therapy as long as the patient has demonstrated some clinical response to treatment. The nonresponding patient Among patients with CAP, nonresponse is primarily seen in those who require hospitalization, occurring in 6 to 15 percent of such patients. The incidence of treatment failure is not well defined in ambulatory patients with CAP because population-based studies would be required.

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–

CAROTID ATHEROSCLEROSIS SYMPTOM MECHANISMS

MECHANISM OF SYMPTOMS — Carotid atherosclerosis is usually most severe within 2 cm of the bifurcation of the common carotid artery, and predominantly involves the posterior wall of the vessel. The plaque encroaches on the lumen of the internal carotid artery and often extends caudally into the common carotid artery. An hourglass configuration to the stenosis typically develops with time. Regardless of their location, carotid plaques were associated with an increased risk of stroke in an observational study of elderly men and women and an increased risk of mortality in an observational study of elderly men. In addition to a reduction in vessel diameter induced by the enlarging plaque, thrombus can become superimposed on the atheroma which will further increase the degree of stenosis. Thus, the mechanism of stroke may be embolism of the thrombotic material or low-flow due to the stenosis with inadequate collateral compensation. The most compelling argument for emboli as the cause of transient ischemic attack (TIA) and stroke has been the angiographic evidence of a stem or branch occlusion above a carotid stenosis. In addition, several investigators have observed material passing through small retinal arteries during an attack of monocular ischemia, and transcranial Doppler ultrasound has verified the passage of formed element emboli into the intracranial cerebral circulation downstream from severe internal carotid artery stenosis . Transient ischemic attacks — Transient ischemic attacks may be due to either low flow or embolization. When TIAs are due to low flow with inadequate collateral blood supply, they are brief, repetitive, stereotyped spells . They often herald strokes occurring in the territory of the internal carotid artery. In comparison, embolic TIAs are usually single and more prolonged, and the symptoms are related to the vascular territories involved. Most often, an embolic ischemic event related to carotid artery stenosis will produce symptoms referable to the middle cerebral artery territory, although the anterior cerebral artery can also be involved. Amaurosis fugax refers to transient monocular blindness caused by a small embolus to the ophthalmic artery. Total carotid artery occlusion — When the internal carotid artery occludes completely, it can also cause low flow or embolic ischemic events depending upon the adequacy of collateral flow through the orbit and across the circle of Willis. The greatest risk of low flow TIA or stroke is at the time of occlusion; the risk diminishes after the first year . There is, however, a phenomenon of delayed stroke, occurring many months after carotid occlusion, presumably due to propagation of thrombus or embolism from the distal portion of the clot . The apparent diagnosis of carotid occlusion by carotid Doppler ultrasound (CDUS) or magnetic resonance angiography (MRA) in a symptomatic patient is a special clinical problem. This topic is discussed separately. The management of total carotid occlusion is also discussed separately. Impaired vasoreactivity — An alteration in cerebral hemodynamic function may be an important factor in the occurrence of symptoms and stroke in patients with carotid stenosis. The prognosis of patients with a stroke due to carotid occlusion may be related to collateral flow . Moreover, symptomatic patients have more impaired cerebrovascular reserve compared to those who are asymptomatic . The role of vasoreactivity and the risk of a stroke in patients with an asymptomatic unilateral carotid stenosis was evaluated in a series of 94 patients who underwent transcranial Doppler ultrasound during hypercapnia produced by breath-holding for 30 seconds . A breath-holding index was obtained by dividing the percentage increase in mean flow velocity in the middle cerebral artery occurring during breath-holding by the length of time (in seconds) that the breath was held. After a median follow-up of 28.5 months, patients with impaired vasoreactivity, defined as a breath-holding index <0.69, had a significantly greater incidence of ipsilateral ischemic events (14 versus 4 percent in those with a normal index). CLINICAL MANIFESTATIONS — The clinical manifestations of carotid artery stenosis are a carotid bruit and symptoms of ischemia. Carotid stenosis may also exist in the absence of any clinical signs or symptoms. Classification of the symptomatic status of the artery is important to the

neurologist in making diagnostic and treatment decisions. A history of more than one discrete episode occurring in the same carotid territory, especially the combination of ipsilateral ophthalmic and hemispheric events (see "Ischemic symptoms" below), is very suggestive of underlying carotid disease. Carotid bruit — An important sign of carotid stenosis is a carotid bruit heard over the site of the stenosis. However, a carotid bruit in asymptomatic patients is a poor predictor for the presence of an underlying carotid stenosis and for the subsequent development of stroke. Similarly, ocular bruits and abnormalities or asymmetries of facial pulses are not reliable predictors of carotid stenosis. These relationships can be illustrated by the following observations: In one series of 331 patients referred to a cerebrovascular clinic, one-third had carotid bruits . Using carotid duplex ultrasonography, only 37 percent of these patients had a moderate or severe carotid stenosis compared to 17 percent without a bruit. The carotid arteries were normal in 32 percent of those with a bruit. Prospective natural history studies of asymptomatic carotid artery bruits suggest that the rate of ipsilateral stroke increases dramatically when the residual lumen diameter narrows to greater than 70 percent stenosis. In one series of 500 patients, for example, the incidence of stroke was 1.7 percent per year overall but 5.5 percent per year in those with more than a 75 percent carotid artery stenosis. In the Systolic Hypertension in the Elderly Program (SHEP), the presence of a carotid bruit was associated with a nonsignificant relative risk of 1.29 for stroke over a mean follow-up of 4.2 years. Similar findings were noted in the Framingham Heart Study as an asymptomatic carotid bruit was associated with an approximate doubling of the expected stroke risk. However, the stroke more often than not occurred in a vascular territory different from the carotid bruit, suggesting that a carotid bruit can act as a nonfocal marker of advanced atherosclerosis. In a report from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) of patients with symptoms of cerebrovascular disease, carotid bruits alone were not sufficiently predictive of high-grade carotid stenosis to be useful in selecting patients for angiography; bruits were absent in over one-third of such patients. However, 75 percent of patients with a bruit had a moderate to severe stenosis (≥ 60 percent stenosis). Some experienced clinicians believe that there are several characteristics of a carotid bruit, if they can be heard, that give an indication of the location and severity of the stenosis: A focal bruit suggests an internal carotid artery stenosis, as opposed to a transmitted cardiac or aortic murmur A high-pitched bruit suggests increased blood flow velocity in the region of arterial stenosis A long duration bruit in systole suggests a tighter stenosis These bruit characteristics are most often heard at the origin of the internal carotid artery when the stenosis is ≥ 70 percent of the lumen diameter and/or the residual lumen diameter is ≤ 1.5 mm. With that degree of stenosis, the blood pressure drops across the stenotic lesion and cerebral autoregulation begins to compensate for the diminished pressure distal to the lesion Ischemic symptoms — Other symptoms and signs of internal carotid artery stenosis and occlusion reflect ipsilateral ocular and cerebral hemisphere ischemia. These may be transient, representing TIAs, or permanent, resulting in cerebral infarction. Features of ocular ischemia or infarction include partial or complete blindness in one eye and an absent pupillary light response. Fundoscopic examination may demonstrate arterial occlusion or ischemic damage to the retina. Hemispheric signs of cerebral infarction from carotid disease include contralateral homonymous hemianopsia, hemiparesis, and hemisensory loss. Specific signs of left hemisphere ischemia include aphasia, while right hemisphere ischemia may be manifest by left visuospatial neglect, constructional apraxia (ie, inability to perform purposeful movements) and dysprosody. Atypical symptoms of internal carotid artery stenosis include unilateral limb shaking and transient loss of monocular vision upon exposure to bright light. These generally occur as ischemic symptoms downstream from severe internal carotid artery disease. Syncope may be a rare consequence of bilateral carotid occlusive disease. None of the above symptoms and signs is specific to carotid stenosis. As an example, temporal arteritis may produce ocular symptoms that are similar to those produced by carotid stenosis and should be considered in the differential diagnosis.

DiagnScreeAs pawhethpreseshould(SCr) methomeassampmethoor serPrevethe AmAmerihyperresperecomtestingtheraptestinghyperthose AssesThe Nand thdetermassesdiagnomL/mCurrevarietyConseGFR mrangereflectdeclinreasoespeccleararequirfrequeThe MCockcMDRDCockcapprothese and smay bgeogrexpechigh leampuequatexampeoplhave these preseaboutclearacolleciothalafiltratiothan testimagenerwouldhave sor GF

nosis of Chronicening Procedureart of routine checher they are at incnce of susceptibd at minimum ha to estimate GFRod for assessmenurement of the ale. Clinical judgmods of detecting krum markers, or bention, Detection,merican Diabetesica recommend yrtension, and humctively. The Kidn

mmended annual g at the initiation py. At resent, theg for CKD in indivrtension. Until evi at increased riskssment of Kidne

National Institute ohe American Socmined from the Sssment of kidney osed when the ein/1.73 m2 on twont guidelines focy of reasons. SCequently, there ismust decline by a

e. This is particulat the age-related

ne in muscle masns, it is difficult to

cially to detect eaance (CrCl) can ares collection of aently inaccurate. Modification of Diecroft-Gault equatD study equationcroft-Gault equat

oximately 60 mL/m and other estimaettings other thanbe inaccurate in praphic groups; or cted to differ fromevels of dietary mtation, or conditiotions should be uple, given the ime with estimated a measured GFR instances, a clinnce of kidney dat the presence of ance measuremection for CrCl or camate or iohexolon marker to SCrthe SCr alone; hoating equations. ration, kidney hand limit its widespreshown that cysta

FR estimated from

c Kidney Diseases ckups, all patientscreased risk for dility or initiation fave a measureme

R and assessmennt of proteinuria ilbumin-to-creatin

ment should deterkidney damage, ibiopsy of the kidn Evaluation and Ts Association, anyearly testing for man immunodeficney Disease Impr testing for CKD of any cancer di

ere are few data rviduals who haveidence is availabk be tested at leaey Function of Diabetes, Dige

ciety of NephrologSCr with an estim function in standstimated GFR is o occasions moreus on estimated

Cr is affected by ins a wide range ofapproximately 50arly important in t decline in GFR b

ss and reduced cro use the SCr aloarlier stages of CKavoid some of thea timed urine sam et in Renal Diseaion provide usefu is more accurateion or CrCl for pemin/1.73 m2. Howating equations dn those in which populations witho in individuals in

m the general popmeat intake, malnons associated wsed in conjunctioprecision in the G GFR of slightly lR that is actually nician must turn tomage or CKD ris CKD. If an accur

ent should be obtclearance of an ex. Cystatin C has r. It has been repowever, there is lIn addition, manyndling, or assay mead application a

atin C is a better pm SCr, particularl

se

s should be evaludeveloping CKD bactors. Those deent of serum creant of proteinuria. Tn most individual

nine ratio in an unrmine the necessincluding imagingney. The Joint NaTreatment of Hig

nd the Infectious DCKD in patients

ciency virus (HIV)roving Global Outin patients with hagnosis and withregarding the opte risk factors othele, it is reasonab

ast every 3 years.

estive and Kidneygy recommend thating equation, a

dard clinical pract found to be less e than 3 months GFR rather than nfluences other thf “normal” SCr, an0% before SCr risthe elderly, in whbecause of a conreatinine productone to estimate thKD. Measuremene limitations of SCmple, which is inc

ase (MDRD) Studul estimates of Ge and more preciersons with a GFwever, as indicatedo not perform asthey were develo

out CKD; in otherwhom creatinine

pulation (e.g., extnutrition, spinal cowith muscle wastion with the clinicaGFR estimating eess than 60 mL/mgreater than 60 mo alternative inforsk factors, to guidrate estimate of Gained, either a 24xogenous filtratio been suggested ported to correlateittle or no improvy studies now sugmay differ amongas a filtration marpredictor of advey in elderly patie

uated to determinbecause of the emed at high risk

atinine concentratThe recommendels at increased risntimed (“spot”) ursity of additional g studies, other uational Committeegh Blood PressurDisease Society with diabetes, ) infection, tcomes (KDIGO)

hepatitis C as welh each change in timal frequency oer than diabetes ale to suggest tha.

y Diseases, the Nhe use of GFR, as the primary tice. CKD is than 60 apart. SCr alone, for a han GFR. nd in many patienses above the nohom the SCr doesncomitant age-reltion. For these he level of GFR, nt of creatinine Cr; however, it convenient and

dy equation and tFR in adults. Theise than the R less than ed in Chapter 2, s well in populatiooped. GFR estimr racial, ethnic, or production woulremes of body siord injury, ng). GFR estimaal context. For equations, some min/1.73 m2 woumL/min/1.73 m2. rmation, such as de clinical decisioGFR is required, 4-hour urine on marker, such a as an alternativee better with GFR

vement over GFRggest that cystatig populations, whrker. Many studierse events than Snts or those with

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CVD. OveC as a filtrKidney DaMarkers oabnormalitThe most and therefexcretion oUrine protfiltered by derived froderived froto 100 mgnormal vamg/day to protein seinjury. It isglomerulaa specific The ratio ourine specmethod fosuch a rathydration “positive” rthan 17 mmg/g are cdetectablein men; in greater thamacroalbu(P/C) ratiousually indpresent in measuremacceptablethe spot uTable 1: D

Proteinuriasecondarythe first voacceptablehours befoincreased albumin-spalbuminurof the A/Ctesting couresults on persistent level of kidUrine dipspatients win selectedkidney disthey may hrisk for ong

erall, more work isration marker in camage f kidney damageties of the urinarycommon causesfore the most comof protein, and spein includes albu the kidney and inom tubular epitheom the lower urin/day of protein inlues, and the upp avoid false-positen in patients wit

s the earliest signr diseases, or hysign of kidney daof concentrationscimen has replacer measuring albuio corrects for vaand is far more cresult for a spot ug/g in men or 25 considered to be e by spot or timed women, the corran these upper liuminuria. A positio is 200 mg/g or hdicate a glomerul interstitial and va

ment of total protee. Clinical featurerine P/C ratio is g

Definitions of pr

a can be seen inty to vigorous exeoiding after awakee. Ideally, patientore sample collec risk begins with pecific dipstick. Pia (≥20 mg/L or 1 ratio on a spot uuld begin with the quantitative tests proteinuria and adney function. stick or sediment who are at high risd individuals, sucease or a historyhave chronic scagoing progressiv

s required to undclinical practice.

e include proteinuy sediment, and r of CKD in adults

mmon marker forpecifically of albuumin as well as otncompletely reabelium (e.g., Tammnary tract. Healthyn the urine. Howeper limit usually istive evaluations. th CKD is albumi of kidney diseas

ypertension. An eamage. s of albumin or toed 24-hour excre

uminuria and protariations in urinaryconvenient than turine albumin-to- mg/g in women. in the microalbud urine collection responding rangemits are consideive result for the higher. P/C ratioslar disease (althoascular diseasesein, instead of albes of the nephrotgreater than 3000roteinuria and al

termittently in peorcise, fever, or inening is preferredts should refrain fction. The algorithtesting of a rando

Patients with a po1+) should underurine sample withe A/C ratio. Paties temporally spacare considered to

examination shosk for CKD. Imagch as those with ay of vesicoureteraarring from the reve kidney disease

derstand how to b

uria, hematuria, oradiologic evidens are diabetes anr kidney damage umin. ther LMW protein

bsorbed by the tum-Horsfall proteiny persons usually

ever, there is a wis extended as higThe most common, which is relate

se caused by dialevated albumin

tal protein to creaetion rates as theteinuria (see Taby protein concentimed urine colleccreatinine (A/C) Values betweenminuria range (i.e for the detectione is 25 to 355 mgred to represent urine total protein

s greater than 500ough such valuess). At this level of bumin, on a spot ic syndrome typic0 mg/g. lbuminuria

ople without kidnnfection. A sampled, but a random sfrom vigorous exhm for adults whoom spot urine saositive result on argo confirmation bhin 3 months. Alteents with two or mced over 3 montho have CKD irres

ould also be perfoging studies shoua family history oal reflux in childhomote injury that i

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ns that are ubules; proteins n); and proteins y excrete only 50ide range of gh as 200 to 300on type of

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n to creatinine 0 to 1000 mg/g

s may also be proteinuria, urine sample is cally arise when

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DiagnsimplinondinephrStatesmanifstage tubuloEvaluto detdiseasfor prononstparticvascudisrupthe filtspeciffunctioquantsedimserumon clinanatoFurtheabnormL/mserumevaluaas a liinsulinevaluapatienBecauan estdiagnoto kidnCVD. compevaluaGFR, attentestimaManaThe e

1. 2.

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Evauation ng treatment earl

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nosis of CKD is trified classificationabetic in origin) aropathy is the largs, accounting for festation is microa 1). Nondiabetic ointerstitial, and cation of CKD statect any signs anse and, in particuogression of CKDeroidal anti-inflamular attention to d

ular examination. ptions of other kidtration barrier forfic solutes (e.g., sons. In individualtified with spot ur

ment examinationm electrolytes. Imnical clues. Ultrasmic abnormalitieer testing may bermalities. Individuin/1.73 m2) shou

m calcium, phospation should alsoipid profile, and pn resistance and ate symptoms of nts with multiple ruse of the age-retimate GFR of lesosis of CKD stagney failure but ar In the absence olications of CKD,ation for CKD. Ho adjustment of mtion to CVD risk fated GFR are ap

agement essential features

Treat specific cTreat other revdecreased GFTreat progressTreat uremic ctherapy if apprTreat CVD andAvoid exposur

ment of progress Close attention tvement of the tartensin system arure for patients wtors or angiotensnts with diabetic kse who have spo

aluation and Ma

ly in CKD is essen are to stage of CKD he type of kidneyersible causes k factors for progrk factors for CVD

mplications of decraditionally basedn emphasizes disand diseases in tgest single cause approximately oalbuminuria with kidney disease incystic kidney disorts with a thorougd symptoms thatular, any reversibD or for CVD (e.gmmatory drugs). details such as fu Laboratory testsdney functions ber plasma proteinssodium, potassiuls known to haveine examination f, urine specific graging studies shosonography shous and to exclude

e indicated if theruals with CKD stald have measurehate, albumin, an

o include a searchpossibly tests for inflammation. Adf CVD more fully orisk factors. elated decline in Gss than 60 ml/mi

ge 3. These indivire at increased risof risk factors for clinicians may eowever, a searchedication dosage

factor managemeppropriate measu

s of managementcauses of kidneyversible conditionR

sion factors complications, anropriate d its risk factors e to medications

sion factors is theto returning the erget blood pressue key componen

with CKD is belowin receptor blockkidney disease aot urine P/C ratios

nagement of CK

ential to prevent a

y disease

ression of kidney

creased GFR d on pathology anseases in native kransplanted kidne of kidney failurene third of new c a normal or elevncludes glomerulorders. gh history and pht may be clues toble elements or trg., uncontrolled hyThe physical exaunduscopy, bloods should be perfoesides GFR, inclus; resorption or exum, bicarbonate); CKD, urine protefor the P/C or A/Cravity, urine pH, aould be performeuld be performed obstruction of th

re is concern aboages 3 through 5 ements of hemognd parathyroid hoh for traditional C nontraditional risdditional studies mor to detect asym

GFR, many eldern/1.73 m2 and fuiduals are at low sk for CKD comp CKD, markers ofelect to defer somh for reversible caes for decreased ent, and subsequres.

t are as follows: y disease ns causing kidney

d prepare for kid

that are toxic to e cornerstone of cextracellular fluid ure, and blockadets of therapy. Th

w 130/80 mm Hgkers (ARBs) is recnd for those withs greater than 20

KD

adverse outcome

y disease

nd etiology. A kidneys (diabeticeys. Diabetic e in the United cases. Its earliest vated GFR (CKD lar, vascular,

hysical examinati the cause of kideatable risk factoypertension, useamination should d pressure, and rmed to detect uding maintenancxcretion of water and endocrine ein should be C ratio, urine and measuremened if indicated bas in all cases to de

he urinary tract. out anatomic (GFR <60 lobin as well as ormone. LaboratoCVD risk factors, ssk factors such asmay be necessar

mptomatic CVD in

rly individuals havlfill the criteria for risk for progressplications and for f kidney damage

me parts of the auses of decreas GFR, appropriatent monitoring of

y damage or

ney replacement

the kidneys care for patients wvolume to normae of the renin-e usual target blo. Use of ACE commended for a nondiabetic kidn

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Table. NatAction Pla

documents the efst patients requirehis blood pressureas the second ag

with spot urine P/Cood pressure goaoteinuria, includinhannel blockers. ease progressiontrict glycemic cons with CKD are con patients withountion of initial ande are several diffes. Hypertensive pssure goal of lessnded goal of 140/ earlier, an ACE

g of proteinuria. Then the GFR is lounlike many of itspendent on the kis may need to be

ment of dyslipidemL is recommende of fibrates becauon therapy with s be altered; carefcontrast agents oe imaging. omplications shoue abnormalities (hathyroidism, hypeystem disorders

ducation is a centy in that CKD is a

may not understany testing without esease requires beestyle alterationsg of blood pressuducation is also imns that are toxic t

herbal remedies mdjustment for the tional Kidney Fousion and Antihype

tional Kidney Fouan for Stages of C

fficacy of these the more than two ae target. For mosgent. Additional thC ratios greater thal or initiation or ing ACE inhibitorsOther potential tan are dietary protntrol in diabetes, onsidered to be a

ut CKD, treatmend subsequent eveerences in managatients with CKD

s than 130/80 mm/90 mm Hg in othinhibitor or ARB

The use of oral diow. Glipizide is prs counterparts, it dneys for elimina

e lowered, and memia, a plasma LDed in patients withuse of the increasstatins. Investigatful consideration or gadolinium for

uld be monitored hyperkalemia, meerphosphatemia, (neuropathy, cogtral aspect of the a chronic and oftend the importanceexplicit educationehavioral change, adherence to m

ure, and adherencmportant with resto the kidneys. Pmay be directly ne level of kidney fuundation K/DOQIertensive Agents

undation K/DOQIChronic Kidney D

herapies to slow antihypertensive st diseases, diureherapies may be han 500 to 1000 increased dosages, ARBs, and nonargets of interventein restriction, lip and smoking cesat high risk for det of CVD risk factents. However, ingement of these

D are recommendm Hg, which is lowher populations; ais the preferred fabetes agents mreferred to other s is not degraded ation. Dosages ofetformin should bL cholesterol valuh CKD, and care sed risk of myopations for the diagnmust be given in angiography or m

and treated. Theetabolic acidosis)bone disease, m

gnitive changes). management stren asymptomatice of multidrug reg

n. Complete manae by the patient, w

medication regimece to plans for mpect to avoidancatients must be aephrotoxic or maunction. I: Clinical Practic in Chronic Kidne

I: Classification, PDisease

progression of agents to etics are considered for mg/g, including e of agents that

ndihydropyridine ntion to slow pid-lowering ssation. evelopment of tors is critical for

n patients with risk factor

ded to have a wer than the also, as first-line agent in

must often be sulfonylureas to a metabolite f incretin be avoided. In ue of less than must be taken athy in nosis of CVD the use of magnetic

ese include ), anemia, alnutrition, and rategy, c disease and gimens and agement of which may ens, self-edical follow-up.

ce of exposure to aware that any ay require a

e Guidelines on ey Disease

Prevalence, and

CONDUCTION AND BLOCK Electrophysiology of action potential (AP) • Normal APD is 180 milliseconds. • Maximum negative membrane potential is defined as a resting potential. • Ik repolarizes the membrane to the resting potential. • When the membrane potential reaches the threshold level it results in the onset of AP. When the threshold stimulus excites the cell, INa depolarizes the membrane at 382 V/s. This produces phase 0 of AP. Phase 1 of AP is a result of early repolarization produced by Ito. Plateau phase is phase 2 of AP. • ICaL (inward current) supports AP plateau against repolarizing (outward current) Ik. ICaL triggers calcium release from sarcoplasmic reticulum (SR) through calcium induced calcium release (CICR). • INa/Ca pump, during repolarization, extrudes calcium. It takes in three sodium ions for each calcium ion that is removed. This causes significant inward current, which slows repolarization and prolongs APD. • IKr increases during the early phase of AP. Its level of activity is low due to instantaneous inward rectification. IKr is potassium selective. • IKs attains a large magnitude during a plateau. It is a major repolarizing current. • The end of the plateau phase heralds the beginning of phase 3 of AP. During this phase depolarizing Ca and Na currents decline and K currents enhance repolarization. The end of phase 3 occurs when the resting potential is reached. Cells capable of producing spontaneous depolarization initiate phase 4 of AP. Depolarizing and repolarizing currents • Inward movement of positive ions depolarizes the cell by increasing the positive charge on the inner surface of the cell membrane as compared with the outer surface of the membrane. Outward movement of positive ions repolarizes the cell membrane by making the inner surface more negative than the outer surface. Potassium currents are outward currents. • During the plateau phase of AP current flow activity is reduced. It separates phase 2 from phase 3 of AP. • The length of the plateau phase of the AP determines the strength and duration of cardiac contraction and produces a cardioprotective window during which reexcitation by sodium and calcium channel cannot occur. • A small net current is needed to maintain the plateau and a small change in the current markedly influences the time course of the plateau. • Repolarization begins when the net current flow becomes outward either by an increase in outward or by a decrease in inward currents. Supernormal conduction • During a recovery phase of APD supernormal conduction may exist when a subthreshold stimulus may evoke a response. The same stimulus may fail to produce a response before or after the supernormal conduction period. • An Impulse arriving during supernormal excitability conducts better than expected or conducts when the block was expected. It is not faster than normal. • Supernormal conduction depends on supernormal excitability and exists only in Purkinje fibers, not in His bundle or myocardium. It may be noted in the presence of a complete AV block. • Supernormal conduction is recorded in diseased cardiac tissue. • Improved AV conduction (not supernormal conduction) may be due to gap phenomenon, peeling of refractory period and dual AV nodal physiology. • The period of supernormal excitability correlates with the end of the T wave and the beginning of diastole. • Supernormal conduction may manifest as unexpected normalization of bundle branch block at a shorter RR interval. • The PR interval remains unchanged or is shorter, thereby excluding equal delay in both bundles as a cause of normalization of the QRS. • In the presence of acceleration dependent aberration during atrial fibrillation (AF) or sinus rhythm with premature atrial contractions (PACs), supernormal conduction may manifest as normalization of QRS. • Atrial impulse may propagate during a supernormal period and result in displacement of the subsidiary pacemaker due to concealed conduction. • The duration of the preceding cycle length (CL) determines the location of supernormal conduction. Longer CL shifts the supernormal period to the right. • During AV block a sinus impulse may conduct or an electronic pacemaker may capture during the period of supernormal excitability.

Concealed conduction • It is characterized by unexpected behavior of a subsequent impulse in response to incomplete conduction of a preceding electrical impulse. Its diagnosis is made by deductive analysis and exclusion of the other conduction abnormalities such as block of conduction. • A concealed impulse may become intermittently manifest in other parts of the same tracing. • ECG reflects conduction and electrophysiologic properties of the myocardium. Propagation of an impulse through specialized conduction tissue is not recorded on a surface electrocardiogram but can be inferred. • Concealment is commonly encountered at the level of AVN or bundle branches. Exit block • It is commonly seen in sino atrial, junctional, and ventricular pacemaker. • A repetitive pattern or group beating of type I or II periodicity is suggestive of exit block. • Type I exit block presents with gradual shortening of PP or RR interval and failure to record P or R resulting in a pause that is less than the sum of two basic CLs. This is typical of Wenckebach periodicity. Atypical Wenckebach delay may resemble sinus arrhythmia. • Type II exit block is characterized by a pause that is multiple of basic CL. • In a parasystole, failure of the impulse to manifest may be due to an exit block or physiologic refractoriness. If a tachycardia presents with two different CLs in which short CL is longer than basic CL and long CL is less than the sum of two basic CL and the sum of short and long CL equals three basic CL then 3 : 2 type I exit block is present. Gap junction • Gap junctions are for intercellular transfer of current. Connexion 43 (CX43) is a major gap junction protein. It is found in human atrium and ventricles.A 50% reduction in CX43 produces a marked slowing of conduction velocity. • These are located at or near the ends of working atrial and ventricular myocytes where intercalated discs connect adjacent cells. • Longitudinal conduction velocity in myocardium is 0.7 m/s and transverse velocity of 0.2 m/s. This produces the substrate for anisotropic conduction. • In crista terminalis the ratio of longitudinal to transverse conduction is 10:1. • Slow conduction in the SA and AV nodes is due to small and sparsely distributed gap junctions. • Gap junctions in Purkinje tissue facilitate rapid conduction. • CX40 is a major conductor of intercellular currents in atrium. CX43 is a major conductor of intercellular currents in ventricle. Continuous and discontinuous conduction • The difference between the electrical potential of excited and nonexcited tissue produces a flow of current. As the current flows through the cell membrane it shifts membrane potential to threshold potential by activating sodium and calcium currents. During normal propagation, sodium (inward) current provides the charge for membrane depolarization except in atrio-ventricular node (AVN) and sino atrial node (SAN). • Delay in propagation may occur in the gap junction. Calcium inward current is essential for allowing the current to pass through the cell junction. • Atrial trabeculation may contribute to conduction discontinuities. • In ventricle connective tissue, hypertrophy, a scar from myocardial infarction (MI) may add to discontinuities. • Impedance of a scar is lower than that of normal myocardium. • Capillaries may contribute to anisotropic conduction. Electrical heterogeneity • AP of ventricular epicardium and M cells shows a prominent notch due to Ito mediated phase 1. • Absence of a notch in endocardium correlates with weaker Ito. • Spike and dome morphology of AP is absent in the neonate. Its gradual appearance correlates with the appearance of Ito. • Ito2 is a calcium activated chloride current. • The magnitude of Ito and spike and dome in right ventricular epicardium is more prominent than left ventricular epicardium. Ito and J wave • Transmural voltage gradient between epicardium and endocardium due to Ito results in J wave (Osborn wave). • Prominent J waves may occur in the presence of hypothermia and hypercalcemia. • Occurrence of elevated J point may be due to transmural gradient and dispersion of early repolarization.

Quick Examination of the Cranial Nerves Olfactory Nerve • This is usually not tested. • Ask the patient if he has problem with smell • Look for external abnormalities such as rash or deformity • Test each nostril separately with familiar scents • Note that pungent or painful stimuli are detected by CN 5. Optic Nerve Visual Acuity • “Do you wear visual aids for near and distance vision?” • Use Snellen’s chart at 6 meters (or hand-held chart or

Rosenbaum Pocket Vision Screener at 35 centimeters/14 inches)

• If visual acuity is less than 6/60, bring closer, or use counting fingers, perception of hand movements or perception of light.

• 6 meter = 20 feet • 60 meter = 200 feet N.B. Near vision may be recorded in 1 of 3 standard notations. • The Jaeger system (J1, J2, J3, etc) is a century-old standard

in which the lower numerals represent better vision. For instance, J3 is equivalent to 20/40, and J1+ is 20/20.

• Another notation is the point system used commercially to denote print size, with N3 being 20/20 and higher numbers indicating poorer vision.

• Finally, the distance equivalent, a recalibration for the near test, can be used (20/20, 20/50, etc); these are usually printed on the near card.

Visual Fields • “Look at my nose – are any parts of my face missing?” -

macular degeneration. • Screen with finger wiggle in four quadrants (left, right, both) • Define with white pin; abnormal to normal, horizontally and

vertically (red for scotomata) Color vision not routine (red desaturation in optic neuritis) Fundoscopy • Optic atrophy – pallor of the nerve head. • Swelling of the optic head – papilledema, papillitis • Hemorrhages: • Liner/flame or ecchymoses – hypertensive/diabetic

retinopathy • Petechiae – diabetes • Subhyaloid (crescent) – subarrachnoid hemorrhage Oculomotor, Trochlear and Abducens Pupils • Shape, relative size, symmetry, ptosis • Direct and consensual reaction • Swinging flashlight – keep on each pupil just long enough to

maintain constriction, abnormal dilatation (relative afferent pupillary defect)

Eye Movements - SO4, LR6 • Both eyes, cardinal directions and corners • Ask about diplopia, look for nystagmus • Beware of internuclear palsy from lesion in medial longitudinal

fasciculus between V1 (crosses over) and III (does not)

Tigeminal • Look for wasting of temporal fossa • Muscles of mastication (open mouth, clench and palpate) • Light touch and pinprick in V1, V2, V3 • Jaw jerk (exaggerated in UMN lesions) Facial Nerve • Forehead wrinkling and power (bilateral cortical

representation – normal in UMN) • Close eyes tightly and power • Smile, blow out cheeks (check naso-labial grooves) • Taste in anterior 2/3 of tongue – not usually tasted • Corneal reflex (Afferent is V, Efferent motor is VII) Auditory/Vestibulocochlear • Whisper numbers at arm’s length, rub fingers in other ear • Rinne test (tuning fork on mastoid) – normal = air conduction

more than bone conduction; sensorineural loss = air bone than bone; conduction loss = bone more than air.

• Weber test (tuning fork on forehead) – normal is R=L; sensorineural loss – best in normal; conductive – best in abnormal.

Glossopharyngeal and Vagus Nerves • Palate/Uvula at rest and when saying “Ah”. • Swallow saliva/sip of water. • Ask patient to say “Eee” (recurrent laryngeal nerve) • Gag reflex (both sides) Spinal Accessory • Trapezius (also C2-C4) – shrug the shoulders and test power. • SCM – turn head to side, test power Hypoglossal Nerve • Look at the tongue for wasting and fasciculations • Poke out tongue (deviates to weak side), test power • Coordination – ask to say “la la la”

ATP III GUIDELINES FOR TREATMENT OF HIGH BLOOD CHOLESTEROL IDENTIFICATION OF PATIENTS AT RISK ATP III recommendations for risk assessment The ATP III recommendations for the treatment of hypercholesterolemia are based upon the LDL-cholesterol (LDL-C) fraction and are influenced by the coexistence of CHD and the number of cardiac risk factors. There are five major steps to determining an individual's risk category, which serves as the basis for the treatment guidelines. Step 1 The first step in determining patient risk is to obtain a fasting lipid profile; the results are classified as shown in Table 1 (show table 1).

Step 2 CHD equivalents, that is, risk factors that place the patient at similar risk for CHD events as a history of CHD itself, are identified: *Diabetes mellitus *Symptomatic carotid artery disease *Peripheral arterial disease *Abdominal aortic aneurysm *Multiple risk factors that confer a 10-year risk of CHD >20 percent (see "Step 4" below). In addition to the conditions identified by ATP III as CHD equivalents, we consider chronic renal insufficiency (defined by a plasma creatinine concentration that exceeds 1.5 mg/dL [133 µmol/L] or an estimated glomerular filtration rate that is less than 60 mL/min per 1.73 m2) to be a CHD equivalent. Step 3 Major CHD factors other than LDL are identified: *Cigarette smoking *Hypertension (BP ≥ 140/90 or antihypertensive medication) *Low HDL-cholesterol (HDL-C) (<40 mg/dL [1.03 mmol/L]) *Family history of premature CHD (in male first degree relatives <55 years, in female first degree relative <65 years) *Age (men ≥ 45 years, women ≥ 55 years) -HDL-C ≥ 60 mg/dL (1.55 mmol/L) counts as a "negative" risk factor; its presence removes one risk factor from the total count. Step 4 If two or more risk factors other than LDL (as defined in step 3) are present in a patient without CHD or a CHD equivalent (as defined in step 2), the 10-year risk of CHD is assessed using the ATP III modification of the Framingham risk tables. Risk does not need to be assessed in people without CHD who have 0 to 1 risk factors since individuals in this category have a 10-year risk of CHD that is <10 percent. A validation study found that the Framingham CHD predictor performed well for prediction of CHD events in white men and women and black men and women, but it overestimated risk among Japanese American and Hispanic men and Native American women. Several studies have suggested that the Framingham criteria also overestimate the risk in European and Asian populations. It is not clear in all cases if these differences are real or if they are due to differences in research methods, adjudication procedures, or time intervals studied. Step 5 The last step in risk assessment is to determine the risk category that establishes the LDL goal, when to initiate therapeutic lifestyle changes, and when to consider drug therapy. Importance of other risk factors A number of other risk factors for CHD have been suggested by epidemiologic data, such as obesity, physical inactivity, impaired fasting glucose, markers for inflammation, homocysteine, abnormalities of thrombosis, and endothelial dysfunction. However, there has been no evidence from controlled trials that targeting these risk factors improves outcomes. Thus, their presence does not influence current guidelines for cholesterol lowering, although ATP III suggests that these factors can be used to modify clinical judgment in some circumstances.

Number of patients affected The ATP III guidelines include absolute risk and lower LDL-C levels to assess eligibility for lipid lowering therapy. The impact of these changes on the treatment-eligible population was examined by analyzing data from 13,589 subjects in the NHANES III survey. Overall eligibility for treatment increased by 157 and 122 percent for men and women, respectively, and 131 and 201 percent for those ≥ 65 or <45 years of age, respectively. Other methods of risk assessment Total-to-HDL-cholesterol ratio Given the protective value of serum HDL-C, it has been suggested that the serum total-to-HDL-C is of greater predictive value than the serum total or LDL-C. Data from the Lipid Research Clinics and the Framingham Heart Study demonstrated the following advantages of the ratio: Among men, a ratio of 6.4 or more identified a group at 2 to 14 percent greater risk than predicted from serum total or LDL-C Among women, a ratio of 5.6 or more identified a group at 25 to 45 percent greater risk than predicted from serum total or LDL-C In contrast, serum total or LDL-C did not add independent predictive value to the ratio. Risk tables have been constructed that use both the ratio and presence or absence of other risk factors to predict coronary risk and possible indications for therapy. Other ratios Other lipoprotein ratios have also been proposed, such as the apolipoprotein B to apolipoprotein A ratio, which measures the major proteins in LDL-C and HDL-C respectively, and the LDL particle number to HDL particle number. Non-HDL-cholesterol Non-HDL-C is defined as the difference between the total cholesterol and HDL-C. Non-HDL-C includes all cholesterol present in lipoprotein particles that is considered atherogenic, including LDL, lipoprotein(a), intermediate-density lipoprotein, and very-low-density lipoprotein. It has been suggested that the non-HDL-C fraction may be a better tool for risk assessment than LDL-C. ATP III identifies the non-HDL-C concentration as a secondary target of therapy in people who have high triglycerides (≥ 200 mg/dL [2.26 mmol/L]). The goal for non-HDL-C in this circumstance is a concentration that is 30 mg/dL (0.78 mmol/L) higher than that for LDL-C (show table 4).

ECHO IN MR TWO-DIMENSIONAL ECHOCARDIOGRAPHIC PARAMETERS FOR GRADING MR SEVERITY LV Performance Indices of LV systolic function—left ventricular end-systolic and end-diastolic dimensions, ejection fraction, wall thickness, and fractional shortening—are the most important echocardiographic barometers of the hemodynamic effects of MR on global cardiac function. There are 3 major phases of MR and they produce various impact on LV performance.

1. Acute MR phase. 2. Chronic compensated MR. 3. Chronic decompensated MR.

LV end-systolic dimensions and LV ejection fraction (LVEF) reflect the heart’s ability to adapt, and therefore influence the frequency of clinical follow-up, timing of surgical intervention, and outcomes following mitral valve surgery. In chronic compensated MR, cardiac output is maintained via an increase in the LVEF, and such patients typically have LVEFs greater than 65%. LV hypertrophy is not a feature of isolated MR as the regurgitant chamber—the left atrium (LA)— usually adapts and dilates to accommodate increases in preload (EDV). Even in the acute setting, LV contractility and LVEF increase in response to an increase in preload. However, LV contractility can decrease silently and irreversibly in chronic MR. For this reason, increasingly earlier surgical interventions for less severe degrees of MR are being recommended. LA Size The LA will dilate in response to chronic volume and pressure overload. Its dimensions may help to assess MR severity and chronicity. Acute-onset severe MR, as occurs with papillary muscle rupture, does not cause LA dilatation. The excess regurgitant blood entering the small noncompliant atrium causes acute increase in LA pressures and can precipitate acute pulmonary hypertension and right heart pressure overload. Increased LA pressures and systolic flow into reversal pulmonary veins may be the only echocardiographic findings that document the severity of acute-onset MR. LA size may predict the onset of atrial fibrillation, but is otherwise of little prognostic value in MR itself, in the absence of heart failure. Measurements should be adjusted for age and body surface area. DOPPLER METHODS FOR GRADING MR SEVERITY Color Flow Doppler Parameters Color flow Doppler imaging is perhaps the most intuitive of all measures, is useful for detecting the jet origin, direction, and spatial relationships and has excellent sensitivity and specificity. Each of the 3 components of the MR jet—flow convergence zone, vena contracta, and jet profile—can provide a semiquantitative or quantitative measure of MR severity. MR jets are best assessed using multiple windows to obtain a three-dimensional (3D) perspective. Qualitative estimates of MR jets are categorized on a scale of 0–4: grade 0 = none or trace MR, grade 1 = mild MR through to grade 4 = severe MR. The notation 1+, 2+, and so on, to denote increasing grades of MR severity is also popular. COLOR JET AREA The same color jet profiles can be measured within the LA. Color jet areas are influenced by jet velocity, momentum, and direction. Mild MR jets cover less than 20% of total LA area (or a maximal jet area < 4.0 cm2), with severe MR jets more than 40% of total LA area (or a maximal jet area > 10 cm2). At least two orthogonal views should be used with the Nyquist limit set at 50–60 cm/s. Larger color jet areas indicate more severe MR when the jet is centrally directed, but can be misleading with eccentrically directed jets. Hugging or entrainment (Coanda effect) of the eccentric jet to the LA wall results in smaller jet areas even when MR is severe. A thorough evaluation of eccentrically directed jets should include evaluation for etiologies, such as a flail leaflet, prolapse or perforation. Severe MR with eccentrically directed jets sometimes exhibit a “wrap around” effect in the LA. In acute MR, even centrally directed jets may be misleadingly small. A small nondilated atrium in the setting of acute regurgitation constrains the regurgitant jet momentum and hence the visible color jet area. VENA CONTRACTA WIDTH The vena contracta is the narrow neck of the MR jet as it traverses the regurgitant orifice. The vena contracta measured from the parasternal long-axis view is best optimized by using a narrow sector scan, optimal color gain, and Nyquist limit between 40–70 cm/s. The vena contracta appears as the well-defined light blue or light yellow high-velocity core on the red-blue color Doppler scale. This portion of the regurgitant jet, unlike the flow convergence zone and the distal turbulent jet profile, most closely mirrors that of the actual regurgitant orifice. It is, therefore, a more reliable marker of MR severity with significant advantages over other methods provided that the recommended technique is used. A single vena contracta width (VCW) measurement, however, is a 2D snapshot across an elongate regurgitant orifice area that extends to a variable degree along the crescenticleaflet coaptation line. A closer approximation of the actual regurgitant orifice area is best obtained by scanning through multiple planes and selecting the greatest VCW. Such considerations are better appreciated and measured on 3D echocardiography. Averaging VCW measurements over at least three beats and using two orthogonal planes is recommended. A VCW less than 0.3 cm indicates mild MR; a VCW more than 0.7 cm indicates severe regurgitation. The effective regurgitant orifice area (EROA)—a marker of MR severity that is less affected by loading conditions—can be calculated from the VCW using the formula: EROA = π(VCW/2)2

Good agreement exists between this EROA formula and other validated measures of MR severity. VCW measurements are not valid for assessing MR severity with multiple MR jets. PROXIMAL FLOW CONVERGENCE AND PROXIMAL ISOVELOCITY SURFACE AREA According to fluid dynamics, fluids within an enclosure stream symmetrically toward a narrowed outlet or orifice in near concentric isovelocity zones. This is akin to water being drained from a kitchen sink, or when water from a lake flows into a narrowed estuary. The same principle applies when blood in the LV stream converges toward a narrowed (stenosed or regurgitant) orifice. This method can be used for estimating the area of the regurgitant orifice—which is hard to measure directly because actual regurgitant orifice is dynamic, functional, and 3D. As regurgitant blood converges toward the regurgitant orifice at the proximal convergence zone, the size and velocity of the innermost shell or hemisphere can be measured. Furthermore, according to the continuity principle, the amount of fluid that passes through the regurgitant orifice is the sameamount that flows in the regurgitant jet (the law of conservation of mass). Therefore, total flow at the proximal isovelocity surface area (PISA) will equal total flow in the distal MR jet. The apical four-chamber view is recommended for optimal visualization of the MR jet PISA measurement. The area of interest is optimized by lowering imaging depth and lowering the Nyquist limit (on the color Doppler scale) to approx 40 cm/s. The velocity at which the blue-red color shift occurs identifies the PISA shell. The PISA radius (r) is then measured and multiplied by the PISA velocity, i.e., the aliasing velocity (Nyquist limit)—VALIAS —to give the regurgitant flow rate. If the base of the PISA hemisphere is not horizontal, it should be corrected to 180°. Reguritant flow rate = 2πr2 × VALIAS (mL/s). From this, the EROA can be quantified using the continuity principle equation for flow rate: Area1 × Velocity1 = Area2 × Velocity2; and VMAX is the peak velocity of the MR jet on CW Doppler: EROA = 2πr2 × VALIAS/VMAX Regurgitant volume and the regurgitant fraction can then be calculated. The PISA method can also be assessed by transesophageal echocardiography when indicated. The PISA method makes several assumptions—many of which are violated in the clinical setting. 3D echocardiography may ultimately assist in overcoming some of these limitations. Other Doppler Methods SYSTOLIC FLOW REVERSAL IN THE PULMONARY VEINS The presence and the degree of reversal of blood flow from the LA into the pulmonary veins can indicate the hemodynamic impact of the MR jet. Visualization of flow reversal into one or more pulmonary veins on color flow Doppler, or more reliably—pulsed Doppler evidence of flow reversal into the pulmonary veins are measures of MR severity. In normal individuals, a positive systolic (S) wave followed by a smaller positive diastolic (D) wave is seen, but with moderate or severe MR, blunting or reversal of this pattern may be seen. Systolic flow reversal may be indicative of severe MR even if the color jet area suggests milder disease. Atrial fibrillation and elevated LA pressures from any cause can blunt forward systolic pulmonary vein flow. Blunting of pulmonary forward flow may lack specificity, but is nonetheless a useful parameter that provides information independent from color Doppler methods used to assess MR severity. MITRAL E-POINT VELOCITY The progressive increase in trans-mitral flow that occurs with increasing MR severity can be detected as higher flow velocities during early diastolic filling. A dominant E-wave more than 1.2 m/s may indicate more severe MR, providing there is no concomitant mitral stenosis. CONTINUOUS-WAVE JET INTENSITY AND MORPHOLOGY Peak MR jet velocities by continuous-wave (CW) Doppler typically range between 4 and 6 m/s—a reflection of the systolic pressure gradient between LV and LA. If the blood pressure at the time of the study is low, the peak velocities and gradients will also be low. Peak MR jet velocities alone, therefore, are not reliable measures of MR severity. The signal intensity (jet density) of the CW envelope of the MR jet can be a guide to MR severity, but this should be assessed relative to the density of antegrade flow signal (mitral inflow). A dense mitral regurgitant signal with a full envelope of equal in intensity to the antegrade flow signal indicates more severe regurgitation than a faint signal. The CW Doppler envelope may show blunting or notching of the CW envelope. This results from the rapid surge in LA pressures in severe MR—the atrial V-wave. This may reflect an LA that has not yet dilated and show discordance with color Doppler severity. LV SYSTOLIC PERFORMANCE The rate of rise of LV systolic pressure over time (dP/dT) may be a useful index of the LV systolic function in MR. In patients with preserved systolic function, the MR jet velocity shows a rapidly early in systole. A lower dP/dT can unmask patients with declining systolic function, and therefore serve as a guide to more aggressive intervention, especially when supported by other indicators of severity. Integrating Indices of Severity Integrated scores have been devised to improve the diagnostic validity of parameters of MR severity. The MR index is a composite score comprising six echocardiographic parameters—jet length, PISA, CW jet density, pulmonary artery systolic pressure, pulsed wave Doppler, pulmonary vein flow pattern, and LA size. Such scores should be integrated with global cardiac function and the patient’s clinical status.

Echocardiography in Mitral Stenosis In mitral stenosis, the normal, rapid, biphasic motion of the valve is altered because the valve can open only partly and as a single unit. Anatomically, the commissural separation between the anterior and posterior or mural leaflets is diminished by partial fusion and the subvalvular apparatus is altered by chordal foreshortening. Immobility of the posterior leaflet is a common early finding with a "hockey stick/knee bend" appearance to the anterior mitral leaflet due to leaflet tethering. Doming of the anterior leaflet corresponds temporally to the opening snap on auscultation. These changes cause a limiting orifice that obstructs diastolic transit of blood from atrium to ventricle. One hemodynamic consequence of this alteration is a holodiastolic pressure gradient between the left atrium and ventricle. Echocardiography can identify the pathologic entity of mitral stenosis and quantitate its severity with sufficient accuracy to make reliable decisions about the suitability for catheter-based balloon valvotomy or the need for surgery. Quantitation of mitral stenosis severity can be accomplished by direct methods, and its qualitative estimation by a number of indirect observations. The 2006 ACC/AHA guidelines of valvular heart disease gave a Class I recommendation for the use of echocardiography in diagnosing the presence and evaluating the severity of mitral stenosis. M-mode echocardiography M-mode confirmation of the altered pattern of mitral motion in mitral stenosis remains a useful tool. Mitral stenosis alters the appearance of the M-mode tracing of the mitral valve so that its normal early diastolic closure is delayed or abolished. The early diastolic closure slope, the E-F slope, produces an easily recognized pattern and can also be quantitated to separate normal atrial inflow from obstructed and to differentiate among the degrees of obstruction. Although this method is the least reliable means of quantitating the severity of obstruction, a slope of less than 10 mm/sec (normal is >60 mm/sec) from a valve recording made during suspended respiration is evidence for severe mitral stenosis. The opening snap (OS) of the mitral valve coincides with the initial peak opening (E) of the valve. Two dimensional echocardiography Mitral stenosis alters the appearance of the valve on two dimensional echocardiography because it partially fuses the normally independent leaflets and a creates a persistent gradient between the left ventricle and atrium. This gradient keeps the stenotic diastolic orifice opened to its maximum and causes the entire valve to dome or bulge into the ventricle throughout diastole. The elevated gradient initiates the opening motion in an abrupt manner, generating the opening snap and a characteristic "knee bend" appearance on the precordial long axis view. In the parasternal short axis plane, the opening of the valve can be imaged just above the tips of the papillary muscles. From this orientation, its maximum diastolic opening area can be measured by direct planimetry of the two dimensional image. This method is a reliable means of judging the severity of obstruction. Typically, a valve orifice area of <1 cm2 is considered severe, regardless of the method used to calculate its size. Other features of mitral stenosis on the two dimensional echocardiogram include chordal foreshortening and atrial thrombi; the latter are rarely seen in echocardiograms taken from the precordial windows. Doppler echocardiography Doppler methods provide a constellation of measurements by which the severity of mitral stenosis can be gauged. These variables include the gradient across the valve at rest and with exercise, the inferred area by the pressure half-time method, the continuity equation or the proximal flow convergence method, and the pulmonary pressure at rest and during exercise from the tricuspid regurgitant jet velocity. Doppler methods can measure the velocity of mitral inflow. In mitral stenosis, this velocity increases at rest from a normal value of less than 1 m/sec to greater than 1.5 m/sec. The algorithm to convert Doppler velocity into pressure gradient is the modified Bernoulli equation. The peak gradient between two reservoirs connected by a narrow orifice or pipe (in this case the left ventricle and the left atrium connected by the stenotic mitral valve) can be calculated by the modified Bernoulli formula, taking the square of the peak velocity of fluid flowing between them (in this case, blood) and multiplying by four. Peak gradient, in mmHg = 4 x peak velocity(2) Thus, a peak velocity of 1 m/sec indicates a peak gradient of 4 mmHg; a peak velocity of 2 m/sec indicates a peak gradient of 16 mmHg; 3 m/sec indicates a peak gradient of 36 mmHg.

The mean transmitral gradient can be measured by tracing the area-under-the-curve of the mitral E and A waves obtained by continuous Doppler. Severe mitral stenosis is defined by a mean transmitral gradient greater than 10 mmHg. The most frequently used measurement for the determination of the transmitral gradient during diastole is the pressure half-time, which is derived from hemodynamic data. The pressure half-time is the time required for the gradient between the left atrium and the left ventricle to fall to one-half of its initial value. In order to convert Doppler velocity into a pressure gradient, the initial flow velocity is divided by 1.41 (square root of 2), because velocity bears a second order relationship to pressure. Empirically, a pressure half-time of 220 msec is equivalent to a mitral valve area (MVA) of 1 cm2; therefore: MVA = 220 ÷ pressure half-time Calculating the MVA using the pressure half-time may be an inaccurate approach whenever abrupt changes in the transmitral gradient occur for reasons other than inflow obstruction. An example of such a change is additional ventricular filling from aortic regurgitation. Among the methods for estimating mitral stenosis severity, direct planimetry of the orifice is probably the most accurate when performed correctly. However, in a clinical setting, it is the universal practice to achieve cross validation by applying the full array of methods. Indirect methods to identify the severity of mitral stenosis include observing the degree of foreshortening of the chordae tendineae, estimating the extent of leaflet calcification, noting the degree of left atrial enlargement, noting the degree of left ventricular underloading (ie, volume decrease), noting the presence of right ventricular and atrial dilatation, and noting the degree of tricuspid regurgitation and pulmonary hypertension, as determined by Doppler of tricuspid regurgitant jet. The 2006 ACC/AHA guidelines on valvular heart disease defined severe mitral stenosis as typically having a mean transmitral gradient >10 mmHg, pulmonary artery systolic pressure >50 mmHg, and a mitral valve area <1 cm2. Exercise and stress echocardiography During exercise, the increase is heart rate reduces diastolic filling. Documentation of a transmitral gradient pulmonary pressure elevation during exercise is useful in patients whose symptoms do not seem concordant with the degree of mitral stenosis at rest. In patients who cannot exercise, dobutamine has been used to increase heart rate. The 2006 ACC/AHA recommended exercise echocardiography in evaluating the severity of mitral stenosis when there is a discrepancy between the resting echocardiographic findings and clinical findings. Three dimensional echocardiography Three-dimensional echocardiography (3-D echo) has been evaluated for its utility in assessing mitral stenosis. This technique can provide an en-face cross sectional view of the mitral orifice, to which planimetry can be applied to determine the valve area. Compared with two dimensional echocardiography, it performs better when cardiac catheterization derived mitral valve area is used as the gold standard. Echocardiography in balloon valvuloplasty The role of echocardiography in mitral stenosis has become even more demanding with the development of catheter-based palliative interventions. These interventions require a transseptal puncture to deliver a dilating balloon across the obstructed mitral orifice. When successful, these techniques offer dramatic relief of symptoms and may avoid surgery. The likelihood of success of balloon valvotomy can be judged with transthoracic echocardiography (TTE) by grading the severity of involvement of elements of the mitral valve on scale of 1 through 4, with a score of 1 representing normal. The four elements are the mobility of the anterior leaflet, the severity of subvalvular disease, the calcification of the anterior leaflet, and the thickness of the anterior leaflet. The value for each of these four scores is added together for a total "splitability index" of 4 to 16, with a score of 8 or less indicating a higher probability of success than higher scores. Other studies have proposed an alternate means of judging suitability for valvotomy by the location and distribution of calcium around the stenotic orifice. Mitral regurgitation is not included in any of these indices, but a degree of regurgitation more than mild is considered a relative contraindication to the procedure. Indeed, severe mitral regurgitation, occurring as a complication of the procedure, often requires urgent valve replacement.

ESTIMATION OF CARDIAC RISK PRIOR TO NONCARDIAC SURGERY SUMMARY AND RECOMMENDATIONS

The process of estimating and reducing the risk of perioperative cardiac events (eg, cardiac death and nonfatal MI), includes the following four components: 1. Defining the urgency of surgery, which may supersede risk stratification. 2. Initial risk assessment. 3. Refinement of initial risk assessment with noninvasive testing in selected patients. 4. Efforts to reduce risk in high-risk patients (eg, beta blockers, revascularization). 1. Urgency of Surgery Emergent surgery Emergent surgery carries unique, often substantial risks. In these cases, risk indices derived from elective surgery cohorts are not accurate. Further testing and interventions are unlikely to be beneficial. Despite the elevated risk, patients are usually best served by proceeding directly to surgery. Beta blockers may be helpful in patients who are hemodynamically stable and in whom benefit has been shown. Urgent surgery

For urgent surgery (eg, required during the same admission but a delay of days may be acceptable), initial risk estimates should be made. However, the value of additional testing and treatment is often limited except for identifying and stabilizing patients with unstable cardiac disease .

Such patients are usually not candidates for CABG and the need for prolonged dual antiplatelet therapy markedly limits the use of PCI. The main option for risk reduction is a beta blocker, and recommendations are often made on the basis of initial risk indices. If the surgical approach would be altered on the basis of additional risk stratification (eg, surgery would be delayed, canceled, or performed on dual antiplatelet therapy), additional testing and treatment may be warranted.

The following approach to cardiac risk stratification primarily applies to elective surgery. In this setting there is adequate time to complete recommended tests and, if necessary, revascularization procedures. If preoperative PCI is considered, any potential benefit must be balanced against the requirements for a full course of aggressive antiplatelet therapy with aspirin and clopidogrel. Premature discontinuation of antiplatelet therapy carries a substantial risk of stent thrombosis. 2. Initial risk assessment

The initial risk assessment consists of three steps: *Does the patient have a high risk condition that is considered a major predictor of risk in the ACC/AHA guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery? Such patients require intensive management and often a delay in or cancellation of surgery. *What is the surgery-specific risk of the planned operation? *What is the patient-specific risk?

Various indices are used to help define the risk. All combine surgery- and patient-specific risks to provide an initial estimate of operative risk. We and others suggest the revised Goldman cardiac risk index. It is the best validated risk index, is simple to use, and appears to have greater predictive value than the original Goldman and Detsky risk indices. However, it may underestimate a patient's true risk. Revised Goldman cardiac risk index (RCRI) A. Six independent predictors of major cardiac complications *High-risk type of surgery (includes any intraperitoneal, intrathoracic, or suprainguinal vascular procedures) *History of ischemic heart disease (history of MI or a positive exercise test, current complaint of chest pain considered to be secondary to myocardial ischemia, use of nitrate therapy, or ECG with pathological Q waves; do not count prior coronary revascularization procedure unless one of the other criteria for ischemic heart disease is present) *History of HF *History of cerebrovascular disease *Diabetes mellitus requiring treatment with insulin *Preoperative serum creatinine >2.0 mg/dL (177 mol/L) B. Rate of cardiac death, nonfatal myocardial infarction, and nonfatal

cardiac arrest according to the number of predictors *No risk factors - 0.4 % (95% CI 0.1-0.8 percent) *One risk factor - 1.0 % (95% CI 0.5-1.4 percent) *Two risk factors - 2.4 % (95% CI 1.3-3.5 percent) *Three or more risk factors - 5.4 % (95% CI 2.8-7.9 percent) C. Rate of cardiac death and nonfatal myocardial infarction, cardiac arrest or

ventricular fibrillation, pulmonary edema, and complete heart block according to the number of predictors and the nonuse or use of beta blockers

*No risk factors - 0.4 to 1.0 % versus <1 % with beta blockers *One to two risk factors - 2.2 to 6.6 % versus 0.8 to 1.6 % with beta blockers *Three or more risk factors - >9 % versus >3 % with beta blockers 3. Refinement of initial risk estimate

The initial risk estimate derived from one of the above indices is often adequate to guide decisions regarding perioperative management. However, it is

helpful in some cases to refine this estimate with noninvasive stress testing. In selected patients, the results of noninvasive testing will affect both the timing of surgery and the need for preoperative revascularization.

The algorithmic approaches cited above provide strategies to determine which patients require additional risk stratification prior to surgery, with indications for noninvasive testing and cardiac catheterization.

We prefer either the ACC/AHA guidelines or the Fleisher-Eagle algorithm, because the predictors used largely overlap with the revised Goldman cardiac risk index. A subsequent algorithm from Auerbach and Goldman is virtually identical to the Fleisher-Eagle algorithm. Fleisher-Eagle criteria A subsequent review by Fleisher and Eagle emphasized six factors, the first five of which are also in the revised Goldman cardiac risk index, associated with increased cardiac risk in patients undergoing noncardiac surgery, including vascular surgery: Ischemic heart disease (angina or prior MI) Heart failure High-risk surgery (including intraperitoneal, intrathoracic, and suprainguinal vascular procedures) Diabetes mellitus (especially insulin-requiring) Renal insufficiency Poor functional status (defined as the inability to walk four blocks or climb two flights of stairs)

The authors recommended that further evaluation was required in patients with one or more of these risk factors.

The Fleisher-Eagle algorithm is easier to use, but refers only to patients who are candidates for surgery. It does not include patients with high-risk conditions that are considered major predictors of risk. Stress testing

Recommendations for preoperative stress testing are based upon clinical risk factors, functional capacity, and the surgery-specific risk. The 2007 ACC/AHA guidelines concluded that the evidence was in favor of benefit of preoperative stress testing for: Patients deemed to be at high risk (≥ 3 revised Goldman cardiac index criteria) and with poor functional capacity (<4 METS) who are scheduled for vascular surgery when such testing will change management.

The evidence was considered less well established for the benefit of preoperative stress testing in the following circumstances: Patients with at least one clinical risk factor and poor functional capacity (<4 METS) who are scheduled for intermediate-risk surgery when such testing will change management Patients with at least one clinical risk factor and good functional capacity (≥ 4 METS) who are scheduled for vascular surgery

Stress testing has a very high negative predictive value for postoperative cardiovascular events (between 90 and 100 percent) but a low positive predictive value (between 6 and 67 percent, with a value of 18 % in a review of five large studies of thallium perfusion imaging). Thus, stress testing is more useful for reducing estimated risk if negative (or normal) than for identifying patients at very high risk when positive.

When stress testing is performed, patients who are able to exercise sufficiently to reach the target heart rate (eg, those who are not limited by claudication, orthopedic degenerative joint disease, or severe deconditioning) can undergo exercise ECG testing often with concurrent imaging to better identify high-risk features that would warrant referral for angiography (eg, reversible large anterior wall defect, multiple reversible defects, ischemia occurring at a low heart rate, extensive stress-induced wall motion abnormalities, transient ischemic dilatation).

In addition, concurrent imaging is essential if the ECG has abnormalities that interfere with interpretation of exercise stress, exercise perfusion imaging or echocardiography. Patients who are unable to ambulate sufficiently to increase their cardiovascular workload should undergo pharmacologic stress with either dipyridamole-thallium rMPI or dobutamine stress echocardiography. The choice of test should be based upon local experience and availability and the relative safety of the different procedures in the individual patient. Resting echocardiography We suggest resting echocardiography to quantify valvular dysfunction in patients with a murmur, to evaluate ventricular dysfunction in poorly controlled HF or in dyspnea of uncertain cause, or to evaluate for possible pulmonary hypertension. Routine echocardiography is not recommended. Preoperative revascularization

The proportion of noncardiac surgery patients who undergo preoperative cardiac catheterization and revascularization appears to be very low. In three studies that used the approach in the ACC/AHA guidelines, 2 to 11 % of patients underwent coronary angiography and only 0 to 2 % underwent preoperative revascularization. The rate of intervention may be even lower in asymptomatic patients, since these studies included symptomatic patients who may have been more likely to undergo revascularization.

These findings indicate that there are few asymptomatic intermediate-risk patients who are candidates for preoperative revascularization.

HYPERLIPIDAEMIA Hyperlipidaemia results from genetic predisposition interacting with an individual's diet . Secondary hyperlipidaemia If a lipid disorder has been detected it is vital to carry out a clinical history, examination and simple special investigations to detect causes of secondary hyperlipidaemia, which may need treatment in their own right. Table. Causes of secondary hyperlipidaemia Hypothyroidism Diabetes mellitus (when poorly controlled) Obesity Renal impairment Nephrotic syndrome Dysglobulinaemia Hepatic dysfunction Drugs: Oral contraceptives in susceptible individuals

Retinoids, thiazide diuretics, corticosteroids, op'DDD (used in the treatment of Cushing's syndrome), sirolimus (and other immunosuppressive agents)

CLASSIFICATION, CLINICAL FEATURES AND INVESTIGATION OF PRIMARY HYPERLIPIDAEMIAS As the genetic basis of lipid disorders becomes clearer, the genetic classification of Goldstein and colleagues is proving of greater clinical relevance than the Fredrickson (WHO) classification (based on the pattern of lipoproteins found in plasma). The lack of direct correspondence between these two systems of classification can be confusing. For clarity we have used the functional/genetic classification and not the Fredrickson classification. This has the advantage that the genetic disorders may be grouped by the results of simple lipid biochemistry into causes of: -- Disorders of VLDL and chylomicrons – hypertriglyceridaemia alone -- Disorders of LDL - hypercholesterolaemia alone -- Disorders of HDL -- Combined hyperlipidaemia. Disorders of VLDL and chylomicrons -hypertriglyceridaemia alone The majority of cases appear to be due to multiple genes acting together to produce a modest excess of circulating concentration of VLDL particles, such cases being termed polygenic hypertriglyceridaemia. In a proportion of cases there will be a family history of a lipid disorder or its effects (e.g. pancreatitis). Such cases are often classified as familial hypertriglyceridaemia. The defect underlying the vast majority of such cases is not understood. The main clinical feature is a history of attacks of pancreatitis or retinal vein thrombosis in some individuals. Lipoprotein lipase deficiency and apoprotein C-ll deficiency These are rare diseases which produce greatly elevated triglyceride concentrations owing to the persistence of chylomicrons (and not VLDL particles) in the circulation. The chylomicrons persist because the triglyceride within cannot be metabolized if the enzyme lipoprotein lipase is defective, or because the triglycerides cannot gain access to the normal enzyme owing to deficiency of the apoprotein C-II on their surface. Patients present in childhood with eruptive xanthomas, lipaemia retinalis and retinal vein thrombosis, pancreatitis and hepatosplenomegaly. If not identified in childhood, it can present in adults with gross hypertriglyceridaemia resistant to simple measures. The presence of chylomicrons floating like cream on top of fasting plasma suggests this diagnosis. It is confirmed by plasma electrophoresis or ultracentrifugation. An abnormality of apoprotein C can be deduced if the hypertriglyceridaemia improves temporarily after infusing fresh frozen plasma, and lipoprotein lipase deficiency is likely if it does not. Disorders of LDL - hypercholesterolaemia alone Heterozygous familial hypercholesterolaemia is an autosomal dominant monogenic disorder present in 1 in 500 of the normal population. The average primary care physician would therefore be expected to have four such patients on his or her list, but because of clustering within families the prevalence is lower in some lists and much higher in others. There is an increased prevalence in some racial groups (e.g. French Canadians, Finns, South Africans). Surprisingly, most individuals with this disorder remain undetected. Patients may have no physical signs, in which case the diagnosis is made on the presence of very high plasma cholesterol concentrations which are unresponsive to dietary modification and are associated with a typical family history of early cardiovascular disease. Diagnosis can more easily be made if typical clinical features are present. These include xanthomatous thickening of the Achilles tendons and

xanthomas over the extensor tendons of the fingers. Xanthelasma may be present, but is not diagnostic of familial hypercholesterolaemia. The genetic defect is the underproduction or malproduction of the LDL cholesterol uptake receptor in the liver. Over 150 different mutations in the LDL receptor have been described to date. Fifty per cent of men with the disease will die by the age of 60, most from coronary artery disease, if untreated. Homozygous familial hypercholesterolaemia is very rare indeed. Affected children have no LDL receptors in the liver. They have a hugely elevated LDL cholesterol concentration, and massive deposition of lipid in arterial walls, the aorta and the skin. The natural history is for death from ischaemic heart disease in late childhood or adolescence. Repeated plasmapheresis has been used to remove LDL cholesterol with some success in these patients. Liver transplantation offers the possibility of cure, but the numbers of patients having undergone this procedure is small. The possibility of gene therapy offers a glimmer of hope on the horizon for affected individuals. Mutations in the apoprotein B-100 gene cause another relatively common single gene disorder. Since LDL particles bind to their clearance receptor in the liver through apoprotein B-100, this defect also results in high LDL concentrations in the blood, and a clinical picture which closely resembles classical heterozygous familial hypercholesterolaemia. The two disorders can be distinguished clearly only by genetic tests. The approach to treatment is the same. Polygenic hypercholesterolaemia is a term used to lump together patients with raised serum cholesterol concentrations, but without one of the monogenic disorders above. They exist in the right-hand tail of the normal distribution of cholesterol concentration. The precise nature of the polygenic variation in plasma cholesterol concentration remains unknown. Variations in the apoprotein E gene (chromosome 19) appear to contribute towards the problem in some individuals in this heterogeneous group. Disorders of HDL - normal total cholesterol and triglycerides Tangier disease Tangier disease is an autosomal recessive disorder characterized by a low HDL cholesterol concentration. Cholesterol accumulates in RES tissue and arteries causing enlarged orange-coloured tonsils and HSM. Cardiovascular disease, corneal opacities and a polyneuropathy also occur. This has been shown to be due to a mutation in the ATP-binding cassette transporter 1 gene (ABC1 gene - see HDL physiology above) which normally promotes cholesterol uptake from cells by HDL particles. Other mutations in this gene have been found in a few families with autosomal dominant HDL deficiency. It is as yet unknown whether abnormalities of this gene contribute to the low HDL cholesterol concentrations commonly seen in cardiovascular disease patients. Combined hyperlipidaemia (hypercholesterolaemia and hypertriglyceridaemia). The most common patient group is a polygenic combined hyperlipidaemia. Patients have an increased cardiovascular risk due to both high LDL concentrations and suppression of HDLby the hypertriglyceridaemia. Familialcombined hyperlipidaemia This is relativelycommon, affecting1 in 200 of thegeneral population. The genetic basis for the disorder has not yet been characterized. It is diagnosed by finding raised cholesterol and triglyceride concentrations in association with a typical family history. There are no typical physical signs. Remnant hyperlipidaemia This is a rare (1 in 5000) cause of combined hyperlipidaemia. It is due to accumulation of LDL remnant particles and is associated with an extremely high risk of cardiovascular disease. It may be suspected in a patient with raised total cholesterol and triglyceride concentrations by finding xanthomas in the palmar creases (diagnostic) and the presence of tuberous xanthomas, typically over the knees and elbows. Remnant hyperlipidaemia is almost always due to the inheritance of a variant of the apoprotein E allele (apoprotein E2) together with an aggravating factor such as another primary hyperlipidaemia. When suspected clinically the diagnosis can be confirmed using ultracentrifugation of plasma, or phenotyping apoprotein E.

SPONTANEOUS ICH – PROGNOSIS AND TREATMENT The 30-day mortality from intracerebral hemorrhage ICH ranges from 35 to 52 percent. Among survivors, the prognosis for functional recovery depends upon the location of hemorrhage, size of the hematoma, level of consciousness, patient age, and overall medical health and condition. Prognostication for individual patients with acute ICH remains an uncertain science at best. Current guidelines suggest consideration of aggressive full care during the first 24 hours after ICH onset and postponement of new DNR orders during that time. Patients with acute ICH should be managed in an intensive care unit. All anticoagulant and antiplatelet drugs should be discontinued acutely, and anticoagulant effect should be reversed immediately with appropriate agents. Sources of fever should be treated. We suggest use of antipyretic medications to lower body temperature to normothermia in febrile patients. We suggest insulin treatment for elevated serum glucose >185 mg/dL (>10.3 mmol/L). The prevention of venous thromboembolism and deep venous thrombosis in patients with ICH is discussed separately. Initial management of elevated intracranial pressure (ICP) includes elevating the head of the bed to 30 degrees and use of analgesia and sedation. Suggested intravenous agents for sedation are propofol, etomidate, or midazolam. Suggested agents for analgesia and antitussive effect are morphine or alfentanil. More aggressive therapies for reducing elevated ICP include osmotic diuretics (eg, mannitol), ventricular catheter drainage of cerebrospinal fluid, neuromuscular blockade, and hyperventilation. We suggest continuous monitoring of ICP and arterial blood pressure when using these aggressive therapies, with the goal of maintaining cerebral perfusion pressure above 70 mmHg. Severe elevations in blood pressure may worsen ICH by representing a continued force for bleeding. - For patients with SBP >200 mmHg or MAP >150 mmHg, we suggest aggressive reduction of blood pressure with continuous intravenous infusion of medication accompanied by blood pressure monitoring every five minutes - For patients with SBP >180 mmHg or MAP >130 mmHg and evidence or suspicion of elevated ICP, we suggest monitoring ICP and reducing blood pressure using intermittent or continuous intravenous medication to keep cerebral perfusion pressure in the range of 61 to 80 mmHg - For patients with SBP >180 mmHg or MAP >130 mmHg and no evidence or suspicion of elevated ICP, we suggest a modest reduction of blood pressure to a target MAP of 110 mmHg or target blood pressure of 160/90 mmHg using intermittent or continuous intravenous medication accompanied by reexamination of the patient every 15 minutes Labetalol, nicardipine, esmolol, enalapril, hydralazine, nitroprusside, and nitroglycerin are useful intravenous agents for controlling blood pressure. Appropriate intravenous antiepileptic treatment should be used to quickly control seizures for patients with ICH and clinical seizures. For patients with cerebellar hemorrhages >3 cm in diameter who are deteriorating or who have brainstem compression and/or hydrocephalus due to ventricular obstruction, we recommend surgical removal of hemorrhage. Surgery for supratentorial ICH is controversial, and current guidelines suggest consideration of standard craniotomy only for those who have lobar clots within 1 cm of the surface. The routine evacuation of supratentorial ICH in the first 96 hours is not recommended. Recombinant factor VIIa treatment for acute ICH is investigational and should not be used for the treatment of ICH outside the context of a clinical trial. Treating hypertension is the most important step to reduce the risk of ICH, and probably recurrent ICH. Stopping smoking, heavy alcohol use, and cocaine use are also recommended.

ICH score A simple six-point clinical grading scale called the ICH score has been devised to predict mortality after ICH. This scale incorporates several clinical components that may be independent predictors of outcome. The ICH score is determined by adding the score from each component as follows: Glasgow Coma Scale (GCS) score 3 to 4 (= 2 points); GCS 5 to 12 (= 1 point) and GCS 13 to 15 (= 0 points) ICH volume ≥ 30 cm3 (= 1 point), ICH volume <30 cm3 (= 0 points) Intraventricular extension of hemorrhage present (= 1 point); absent (= 0 points) Infratentorial origin yes (= 1 point); no (= 0 points) Age ≥ 80 (= 1 point); <80 (= 0 points) Thirty-day mortality rates increased steadily with ICH score; mortality rates for ICH scores of 1, 2, 3, 4, and 5 were 13, 26, 72, 97, and 100 percent, respectively. No patient with an ICH score of 0 died, and none had a score of 6 in the cohort. The ICH score has been validated by retrospective and prospective analysis. A modified ICH score using the National Institutes of Health Stroke Scale (NIHSS) score in place of the GCS score may be a better predictor of good outcome than the original ICH score. Reducing ICP CPP equals mean arterial pressure (MAP) minus ICP. Lowering ICP helps to maintain CPP in an adequate range. Intravenous mannitol is the treatment of choice to lower ICP. It is administered as an initial bolus of 1 g/kg, followed by infusions of 0.25 to 0.5 g/kg every six hours. The goal of therapy is to achieve plasma hyperosmolality (300 to 310 mosmol/kg) while maintaining an adequate plasma volume; major side effects include hypovolemia and a hyperosmotic state. Normal saline initially should be used for maintenance and replacement fluids; hypotonic fluids are contraindicated. Mild hypernatremia should be tolerated, but marked hyperosmolality should be avoided to prevent precipitation of acute renal failure. Barbiturate anesthesia can be used if mannitol fails to lower ICP to an acceptable range. Barbiturate coma acts by reducing cerebral metabolism, which results in a lowering of cerebral blood flow and thus decreases ICP. It is of variable benefit for the treatment of elevated ICP from a variety of causes and is associated with a high rate of severe side effects, especially arterial hypotension. Continuous electroencephalogram monitoring is suggested during high-dose barbiturate treatment, with the dose titrated to a burst-suppression pattern of electrical activity. The ICP lowering effect of hyperventilation to a PaCO2 of 25 to 30 mmHg is dramatic and rapid. However, the effect only lasts for minutes to a few hours. Thus, we reserve hyperventilation until the above therapies have been maximized. Neuromuscular blockade is sometimes employed to reduce ICP in patients who are not responsive to analgesia and sedation alone, as muscle activity can contribute to increased ICP by raising intrathoracic pressure, thereby reducing cerebral venous outflow. Drawbacks of neuromuscular blockade include an increased risk of pneumonia and sepsis. In addition, the ability to evaluate the neurologic status is lost once the patient is paralyzed. Cerebrospinal fluid drainage by intraventricular catheter placement (ventriculostomy) is an effective means of lowering ICP. However, there are no prospective studies. Ventriculostomy is often used in the setting of obstructive hydrocephalus, which is a common complication of thalamic hemorrhage with third ventricle compression, and of cerebellar hemorrhage with fourth ventricle compression. Ventriculostomy allows a means of both monitoring ICP and relieving hydrocephalus. Some patients will develop communicating hydrocephalus and require a ventriculoperitoneal shunt. Available evidence suggests its use is associated with high rates of morbidity and mortality. Infectious complications include bacterial colonization in 0 to 19 percent of patients and bacterial meningitis in 6 to 22 percent.

POTASSIUM CHANNELS AND CURRENTS Inward Rectifying and Background Currents

• There are more than eight types of potassium currents. • The plateau phase of the action potential (AP) depends on the balance between inward (depolarizing) and outward (repolarizing) currents. • Potassium currents (outward movement of the K through the potassium channels) are the main contributors to repolarization. Classification of potassium currents

1. Voltage gated currents = Ito ; IKur ; IKr ; IKs 2. Inwardly rectifying currents = IK1; IKach; IKatp 3. Background currents = IKp

Inwardly rectifying currents Inward rectifier IK1 • IK1 rectification allows it to carry substantial current at negative potentials which maintains the resting potential. • Resting potassium conductance is produced by voltage independent inwardly rectifying potassium channels. • These channels permit inward potassium flux on membrane hyperpolarization but resist outward potassium flux on depolarization. It prevents potassium ion leak during prolonged depolarization. In addition to IK1, IKatp and IKach are also inward rectifiers. • Intracellular magnesium, calcium, and polyamines block IK1. Increase in intracellular pH inactivates IK1. Increase in extracellular potassium depolarizes the resting membrane. • Inwardly rectifying potassium channels (K1) produce less outward currents than inward currents. They stabilize the resting membrane potential by high resting potassium conductance, but during depolarization produce little outward current. ATP sensitive potassium channel (Katp) • Katp channel opens when the intracellular ATP level falls and closes when the ATP levels rise. ATP produced by the glycolytic pathway is preferentially sensed by the Katp channel. • IKatp is a weak inward rectifier but produces a large outward current during depolarization and its activation decreases APD. • It is responsible for ischemia preconditioning where brief episodes of ischemia protect the myocardium from prolonged episodes of ischemia. • During ischemia, intracellular magnesium and sodium levels increase, IKatp current decreases, and extracellular potassium increases. • Protons, lactates, oxygen free radicals, adenosine, and muscarinic receptor stimulation desensitize the Katp channel to the effects of the ATP level. • Sodium and potassium pump and other ATPases degrade ATP. • Cromakalim, Bimakalim, Aprikalim, Nicorandil, Adenosine, and protein kinase C open the Katp channel and mimic preconditioning. Sulfonylureas such as Glipizide and Tolbutamide block Katp and abolish preconditioning. • During ischemia there is loss of intracellular potassium and increase in extracellular potassium resulting in membrane depolarization, slow conduction, and altered refractoriness resulting in reentrant arrhythmias. Katp counteracts these effects by shortening APD, decreasing workload, promoting inexcitability, and increasing potassium conductance during ischemia and hypoxia. Increased potassium conductance is a result of an increased level of intracellular sodium that occurs during ischemia. • IKatp decreases APD and calcium influx. It preserves high-energy phosphates. • Diazoxide does not activate IKatp in sarcolemma but mimics preconditioning. This suggests that there may be other pathways involved in preconditioning. • IKatp causes coronary vasodilatation. IKach (Acetylcholine-dependent K current) • Stimulation of muscarinic receptors activates this current. It is mediated by acetylcholine. IKach is inwardly rectifying potassium current. • Parasympathetic stimulation slows heart rate by activating muscarinic receptors, which reduces If (hyperpolarizing cation current; f stands for funny) in pacemaker cells. • The effect of potassium channel blockers on atrial repolarization depends on their ability to counteract cholinergic activation of IKach, either by direct blocking of the channel (Quinidine) or by muscarinic receptor antagonism (Ambasilide, Disopyramide). Background K currents IKp • These currents contribute to repolarization and resting membrane potential. • These currents are inhibited by decreasing intracellular pH. • Arachidonic acid and polyunsaturated fatty acids modulate these channels. Characteristics of potassium channel block • Voltage gated potassium channels are activated during upstroke of AP. • Rapidly activating and inactivating voltage sensitive transient outward current produces phase 1 of repolarization.

• Slowly activating delayed rectifier potassium current, and inward rectifier IK1, which includes fast inactivating rapid component IKr and slow component IKs, contributes to plateau and phase 3 of AP. • Potassium channel blockers prolong APD. This is xic of Class III action. • Some potassium channel blockers produce less block at a fast heart rate and more blocks at a slower heart rate. This phenomenon is called reverse use dependence. • Potassium channels contribute to repolarization; thus, reverse use dependent block will manifest itself during repolarization at the channel level. • Blocking of K channel may not consistently affect repolarization because: i Many potassium channels are involved in repolarization. Ii Blocking of potassium channels (outward currents) may be counterbalanced by inward currents ICa, INa, and INa/Ca. Thus no one current dominates repolarization. iii Nonspecific effects of potassium channel blockers. Iv Extracellular potassium level may affect K currents. v Potassium channel distribution may be variable. Potassium channel expression varies within different layers of myocardium. IKur is found in the atria but not in the ventricles. vi IKr block could shift repolarization to IKs at rapid rates. Inability of IKs to deactivate rapidly and fully will produce less of an increase in APD. vii Many antiarrhythmics are capable of causing potassium channel block and other ion channel blocks simultaneously. viii Drugs that need a long plateau phase to work will be more effective in the ventricle than the atrium. • Open channel block occurs when the drug is present during activated or open state. • Trapping block occurs when the channel closes around the drug without need for the drug to unbind. Activation is required to remove the drug from the binding site. • The drug may bind the channel during the inactive state, but cannot bind it during the resting state. Effect of pharmacologic agents on action potential • Acetylcholine in low concentration prolongs and in high concentration produces abbreviation of epicardial AP. These effects are as follows:

i Reversed by atropine. ii Do not occur when Ito is blocked. iii Accentuated by isoproterenol. iv Persist in the presence of Propranolol. v Caused by inhibition of ICa or activation of IKach.

• Isoproterenol causes epicardial AP abbreviation more than endocardial. It influences Ito, ICa, IK, and ICl. These currents contribute to phase 1 and phase 3 of AP. • Organic calcium channel blockers (Verapamil) and inorganic calcium channel blocker MnCl2 decreases the ICa (inward current) and leaves the outward currents unopposed, resulting in decrease of APD and loss of dome in epicardium and not in endocardium. • Ito block may establish electrical homogeneity and abolish arrhythmias due to dispersion of repolarization caused by drugs and ischemia. • Quinidine inhibits Ito. • Amiloride, a potassium sparing diuretic, prolongs APD and refractoriness. • Antiarrhythmics, Antimicrobial, Antihistamine, Psychotropic, GI prokinetic, and a host of other pharmacologic agents may alter repolarization. M cells, potassium currents, and APD • M cells are found in the mid-myocardium of anterior, lateral wall, and outflow tract. • Electrophysiologically they resemble Purkinje cells. • M cells show disproportional AP prolongation in response to slow heart rate. This may be due to weaker IKs and stronger late INa. • M cells may enforce pump efficiency at slow rates. Long depolarization permits longer efficient contraction. • Epicardium and endocardium electrically stabilize and abbreviate APD of M cells. • Loss of either layer by infarction will lead to prolongation of APD. This may be the mechanism of increase in QT interval and QT dispersion seen in non-Q wave myocardial infarction (MI). These differences could be aggravated by drugs that prolong QT interval or in patients with LQTS. • M cells play an important role in the inscription of T waves by producing a gradient between epicardium, endocardium, and M cells. • U waves are due to repolarization of His Purkinje cells. • Amiodarone prolongs APD in epicardium and endocardium and to a lesser extent in M cells; this may prevent transmural dispersion of refractoriness.

CLINICAL FEATURES OF LACUNAR INFARCTS. Acute identification of lacunar syndromes is important in triaging medical resources, choosing among treatment modalities, and predicting clinical outcome. As a general rule, lacunar syndromes lack findings such as aphasia, agnosia, neglect, apraxia, or hemianopsia (so-called "cortical" signs). Monoplegia, stupor, coma, loss of consciousness, and seizures also are typically absent. Penetrating artery occlusions usually cause symptoms that develop over a short period of time, typically minutes to hours. However, a stuttering course may ensue, as with large artery thrombosis, and symptoms sometimes evolve over several days. In fact, lacunar infarction is the main ischemic stroke subtype associated with worsening motor deficits after hospital admission. More than 20 lacunar syndromes have been described. Five have been validated as being highly predictive for the presence of lacunes radiologically: Pure motor hemiparesis Pure sensory stroke Ataxic hemiparesis Sensorimotor stroke Dysarthria-clumsy hand syndrome As a group, the presence of these syndromes has a positive predictive value of 87 to 90 percent for detecting a radiological lacune, although some clinical syndromes are more predictive than others . Preceding TIAs and nonsudden onset may increase the positive predictive value for these lacunar syndromes. Predicted infarct locations in relation to clinical manifestations are shown in Table 1. Syndrome recognition may be more difficult in the hyperacute setting. A study of patients admitted within 6 hours of symptom onset reported only a 30 percent positive predictive value. Other syndromes that have not been studied in large clinical series but that may be related to lacunar infarcts are shown in Table 2. The syndrome of multiple subcortical infarcts will be discussed in addition to the five syndromes mentioned above since interest has arisen regarding whether this entity can cause dementia. Pure motor hemiparesis Pure motor hemiparesis is the most frequent syndrome in most clinical series, accounting for 45 to 57 percent of all lacunar syndromes. It is characterized by weakness involving the face, arm, and leg on one side of the body in the absence of "cortical" signs (aphasia, agnosia, neglect, apraxia, or hemianopsia) or sensory deficit. The motor deficit may develop as a single event or, less frequently, be preceded by hemiplegic TIAs. A series of the latter cases has been described as the "capsular warning syndrome," which was found to be predictive of an acute internal capsule infarct on head CT. Some of these cases may arise due to penetrating branch ischemia from a diseased "parent" vessel (MCA stem or basilar) causing intermittent and fluctuating symptoms. Pure sensory stroke Pure sensory stroke is defined as numbness of the face, arm, and leg on one side of the body in the absence of motor deficit or "cortical" signs. It is found in 7 to 18 percent of lacunar syndromes in case series, but its prevalence is probably underestimated because many cases present as TIA and were not included in the series.

Ataxic hemiparesis Ataxic hemiparesis is responsible for 3 to 18 percent of lacunar syndromes in case series. Patients characteristically develop ipsilateral weakness and limb ataxia that is out of proportion to the motor deficit. Some patients may exhibit dysarthria, nystagmus, and gait deviation towards the affected side. As with other lacunar syndromes, the above-mentioned "cortical" signs are absent. Sensorimotor stroke Sensorimotor stroke is characterized by weakness and numbness of the face, arm, and leg on one side of the body in the absence of the aforementioned "cortical" signs. It is responsible for 15 to 20 percent of lacunar syndromes. Sensorimotor strokes arise from infarcts involving the posterolateral thalamus and posterior limb of the internal capsule. The exact vascular anatomy is debated. Theoretically, penetrating arteries from the posterior cerebral artery (PCA) supply the thalamus and the internal capsule is supplied from the lenticulostriate branches of the MCA. Occlusion of a single penetrating artery involving both arterial territories is difficult to implicate; the site of vascular occlusion was not identified in the original case description. Dysarthria-clumsy hand syndrome Dysarthria-clumsy hand syndrome is the least common of all lacunar syndromes in most case series, accounting for 2 to 6 percent of lacunar syndromes. Facial weakness, dysarthria, dysphagia, and slight weakness and clumsiness of one hand are characteristic. There are no sensory deficits or "cortical" signs. Multiple subcortical infarcts and dementia As previously mentioned, the first description of a lacunar syndrome in 1901 included a chronic neurologic course with episodes of mild hemiparesis progressing to abnormal gait, pseudobulbar signs, dysarthria, incontinence, and dementia. Cases such as these have become rare, even in patients with multiple subcortical infarcts, and questions have been raised about whether the patients in the original description had unrecognized normal-pressure hydrocephalus. The relationship between subcortical strokes and cognitive deficits has been explained by interruption of neural connections with an indirect effect upon cortical metabolism and perfusion, so-called "diaschisis." This hypothesis is supported by case series of CT-demonstrated subcortical infarcts presenting with transcortical aphasia or neglect, as well as by functional studies using SPECT or positron emission tomography (PET). One study using PET compared cortical glucose metabolism in patients with dementia and subcortical infarcts, patients with subcortical strokes and normal cognitive function, and controls without cognitive impairment or stroke. Global metabolism was impaired proportionally to cognitive decline, while regional right-sided frontal lobe metabolism was impaired in relationship to the presence of subcortical infarcts. No relationship was found between the number or location of the subcortical infarcts and the presence of cognitive impairment. However, in a prospective MRI study of 1015 patients without baseline dementia, silent subcortical infarcts were associated with later development of dementia over four years of follow-up. Patients developing dementia more often had thalamic strokes at baseline and accumulated new subcortical lesions on a second MRI scan. Taken together, these findings indicate a potential mechanism for dementia in subcortical strokes and the need to develop more effective strategies to prevent the accumulation of silent subcortical infarcts.

MENTAL STATUS EXAMINATION Level of alertness — No special testing is required to determine the level of alertness. While taking the history and examining the patient, observe whether the patient is alert, attentive, sleepy, or unresponsive. Language — Language function is assessed by testing and noting deficits in fluency, content, repetition, naming, comprehension, reading, and writing. The assessment of language function and the categorization of aphasias are discussed separately. (See "Approach to the patient with aphasia"). Memory Immediate — Ask the patient to repeat a string of seven digits immediately after you complete it. Lengthen or shorten the string until you find the longest string the patient can repeat correctly. Despite its categorization as "immediate memory," this is really more appropriately considered "attention." Short-term — Ask the patient to memorize three unrelated words (eg, baseball, horse, purple), distract him or her for five minutes (usually by performing other parts of the examination), then ask the patient to recall the list. Give clues if an item is missed (eg, "One was an animal"); offer a multiple choice if this isn't enough (eg, "It was either a cat, a bear, or a horse"). Long-term — Long-term memory includes both recent and remote memory. Assess recent memory by testing orientation to time (eg, day, date, month, season, year), place (eg, state, city, building), person, and by asking questions about events of the past few days or weeks, (eg, "Who are the current candidates for president?" or, assuming an independent source is available for verification, "What did you have for supper last night?"). Remote memory can be tested by asking for the names of the presidents in reverse order as far back as the patient can remember, or by asking about important historical events and dates. The patient can also be asked about details of personal life such as birth date, names and ages of children and grandchildren, and work history, assuming independent verification is available. Calculation — Ask some straightforward computation problems (eg, 5 + 8; 6 x 7; 31 - 18) and some word problems (eg, "How many nickels are there in $1.35?"; "How many quarters in $3.75?"). Construction — Ask the patient to draw a clock, including all the numbers, and to place the hands at 4:10. Ask the patient to draw a cube; for patients who have trouble doing so, draw a cube and ask them to copy it. Abstraction — Ask the patient to explain similarities ("What do an apple and an orange have in common?"; "... a basketball and a grapefruit?"; "... a tent and a cabin?"; "... a bicycle and an airplane?") and differences ("What's the difference between a radio and a television?"; "... a river and a lake?"; "...a baby and a midget?"). Reporting the mental status examination — The portion of the neurologic examination for which presentation in a consistent sequence is most important is the mental status examination. Certain findings on the mental status examination can only be interpreted by knowing a patient's ability to perform other more fundamental tasks. As an example, difficulty with simple calculations may have some localizing significance in a patient who is otherwise cognitively intact, but not in a patient who is unable to answer any questions because of impaired language function or a depressed level of consciousness. This ambiguity is avoided by reporting the level of alertness first, then language function, and then memory. The remainder of the mental status examination can be presented in any order. When reporting the results of mental status testing, it is most informative to convey patients' actual responses, rather than interpretations such as "mildly abnormal" or "slightly concrete." A confusing array of terminology is often used to report the findings on mental status testing; some are defined in Table 2 (show table 2).

Interpreting mental status — Patient background will influence performance on mental status testing; there is no reliable way to correct for this. Some tests are affected more than others. The ability to copy a sequence of repetitive hand movements is relatively independent of education. In contrast, interpretation of proverbs is so dependent upon cultural and educational background that I consider it useless, and instead rely upon the interpretation of similarities and differences as an assay of abstract thought. All of the categories used to describe mental status are convenient simplifications, but they do not necessarily reflect the way in which the brain functions. As an example, it is very unlikely that any region or circuit in the brain is devoted specifically to calculation. This complicates interpretation of the mental status examination. When patients are asked to subtract serial sevens, for example, they must be alert, comprehend language well enough to understand a fairly abstract command, retain the command in memory long enough to process it, possess the necessary calculation skills, be able to verbalize the response, and maintain attention on the task so that the current result can be taken as the basis for generating the next one. Thus, it is not possible to assign a one-to-one correlation between a task on the mental status examination and a single cognitive function in the same way that abduction of an eye correlates to the function of a lateral rectus muscle. The examiner must observe the response to a variety of tasks, determine which ones are difficult for the patient, and try to determine the kinds of cognitive processing common to those tasks. Decreased level of alertness occurs only with dysfunction of both cerebral hemispheres or of the brainstem reticular activating system. The usual cause is a generalized metabolic abnormality such as hypoxia or hyperglycemia. Less often, appropriately placed structural lesions (especially expanding ones) may produce the same result. Mental status changes in alert patients can result from either focal or generalized processes. The latter usually affect all cognitive functions equally, although early on the main manifestations may just be inattention or word finding difficulty. Focal lesions typically affect some cognitive functions more than others; the pattern of cognitive deficits can have some localizing significance. The most common examples of selective mental status abnormality involve language function. Other cognitive abnormalities that may be seen in relative isolation include acalculia, agraphia, alexia, and apraxia. Each of these deficits is associated with focal lesions in the dominant hemisphere. The left hemisphere is dominant for language in almost all right-handed individuals. The left hemisphere is also language-dominant in most lefthanded subjects, but the relationship is less predictable. Neglect of one side of the environment is seen with a focal lesion in either hemisphere, but it is much more common and tends to be more severe when the lesion is in the nondominant hemisphere, especially the parietal lobe. Nondominant parietal lesions may also produce anosognosia (the inability to recognize the existence or severity of one's own impairment). Unilateral disease of prefrontal cortex often has surprisingly few clinical consequences, but bilateral prefrontal disease is associated with difficulty maintaining and shifting attention. Such patients will demonstrate impersistence (an inability to stick with a task or topic of conversation) and perseveration (a tendency to continue returning to tasks and topics of conversation even when they are no longer appropriate). None of these focal findings has any localizing significance unless it occurs out of proportion to other cognitive deficits. Each can occur as part of a general dementing illness. In fact, it is often impossible to assess language function or other "focal" functions when significant dementia is present, or when there is reduction in the level of alertness. Patients with generalized cognitive impairment perform poorly on all aspects of the mental status examination, and it is usually futile to try to determine if one function is more severely affected than another.

Motor Examination – Upper Limb Inspection:

• Wasting • Fasciculations • Abnormal movements (tremor, chorea, athetosis, myoclonic

jerks, ballismus, tics, dystonia, other involuntary activity) • Check outstretched arm for drift – UMN down, cerebellar up,

proprioception any Tone:

• Elbow flexion and extension • Pronation and supination • Wrist flexion and extension

Power:

• Sholder abduction (C5-C6), adduction (C6-C8) • Elbow flexion (C5-C6), extension (C7-C8) • Pronation and supination (C5-C6) • Wrist flexion (C6-C7), extension (C7-C8) • Finger flexion (C7-C8), extension (C7-C8; radial) • Finger abduction (C8-T1; ulnar), thumb adduction (median)

Reflexes:

• Biceps (C5-C6) • Triceps (C7-C8) • Brachioradialis (C5-C6) • Finger jerks (C8)

Coordination

• Finger-nose finger test (intention tremor) • Rapid alternating movements (slow and clumsy if cerebellar,

slows down if EPS) Motor Examination – Lower Limb Inspection:

• Wasting • Fasciculations • Abnormal movements • Posture • Gait including turning and heel-toe, toe walking (L5-S1), heel

walking (L4-L5) • Romberg test – stand feet together, eyes closed (proprioception)

Tone:

• Roll legs side to side • Knee flexion and extension, lift from below • Rapidly dorsiflex foot and maintain (clonus)

Power:

• Hip flexion (L1-L3), extension (L5) • Hip abduction (L4-S1), adduction (L2-L4) • Knee flexion (L5-S1; sciatic), extension (L3-L4; femoral) • Ankle plantar flexion (S1-S2; sciatic), dorsiflexion (L4-L5;

common peroneal) • Ankle inversion (L4-L5), eversion (L5-S1)

Reflexes

• Knee jerk (L3-L4) • Ankle jerk (S1-S2) • Plantar reflex (L5-S2)

Coordination:

• Heel-shin-heel test • Rapid alternating movements

Notes Grading of Power: 0 = no contraction 1 = visible muscle twitch/flicker without joint movement 2 = active movement insufficient to overcome gravity 3 = active movement against gravity 4 = active movement against some resistance 5 = normal power; able to overcome full resistance Grading of Reflexes: 0 = absent + = just present/reduced/hypoactive ++ = normal +++ = brisk normal/increased/hyperactive ++++ = clonus

Examination of Peripheral Nerves Important PN of the Upper Limb (Beware Brachial Plexus) Axillary Nerve (C5-C8; deltoid, teres minor)

• Test should abduction • Test sensation at regiment badge area

Radial Nerve (c5-c8; triceps, brachioradialis and hand extensors)

• Look for wrist drop, test extension (wrist/elbow) • Test sensation at anatomical snuff box

Median Nerve (C6-T1; palmar forearm muscles except FCU and ulnar half of FDP; lateral two lumbricals, opponens pollicis, abductor pollicis brevis, and flexor pollicis brevis)

• Test APB if lesion at wrist, flexor digitorum if at cubital fossa (Ochsner’s clasping test)

• Test sensation at pup of index figner (digital), radial heel of hand (palmar) Ulnar Nerve (C8-T1; other small muscles of the hand, FCU and ulnar half of FDP)

• Look for claw hand (note loss of FDP less flexion) • Test little finger abduction or thumb adduction (Froment’s sign) • Test sensation at pulp of finger (digital), ulnar heel of hand

(palmar) Important PN of the Lower Limb Lateral Cutaneous Nerve of the Thigh (L2-L3)

• Test sensation at lateral thigh Femoral Nerve (L2-L4; anterior thigh muscles)

• Test knee extension (reflex lost), hip flexion • Test sensation at medial thigh

Sciatic Nerve (L4-S2; all muscles below knee, some hamstrings)

• Look for foot drop • Test knee flexion (reflex intact, none below) • Test sensation at posterior thigh, lateral/posterior calf, foot

Common Peroneal Nerve (L4-S1; anterior/lateral compartument muscles of the leg)

• Look for foot drop • Test dorsiflexion/eversion (reflexes intact) • Test sensation at lateral aspect of dorsal foot

MOTOR EXAMINATION Gait — Observe the patient's casual gait, preferably with the patient unaware of being observed. Have the patient walk toward you while walking on the heels, then walk away from you on tiptoes. Finally, have the patient walk in tandem, placing one foot directly in front of the other as if walking on a tightrope. Note if the patient is unsteady with any of these maneuvers or if there is any asymmetry of movement. Also look for festination, an involuntary tendency for steps to accelerate and become smaller. Coordination — Coordination testing is often referred to as cerebellar testing, but this is a misnomer. Although the cerebellum is very important in the production of coordinated movements and particular abnormal findings on coordination testing may suggest cerebellar disease, other systems also play critical roles. As an example, severe arm weakness will prevent a patient from performing finger-to-nose testing even though the cerebellum and its pathways may be intact. Finger tapping — Ask the patient to make a fist with the right hand, and then to extend the thumb and index finger and tap the tip of the index finger on the tip of the thumb as quickly as possible. Repeat with the left hand. Observe for speed, accuracy, and regularity of rhythm. Rapid alternating movements — Have the patient alternately pronate and supinate the right hand against a stable surface (eg, a table, the patient's own thigh or left hand) as rapidly as possible; repeat for the left hand. Observe speed, accuracy, and rhythm. Impaired ability to perform this task is referred to as dysdiadochokinesis. Finger-to-nose testing — Ask the patient to use the tip of his or her right index finger to touch the tip of your index finger, then the tip of his or her nose, then your finger again, and so forth. Hold your finger so that it is near the extreme of the patient's reach, and move it to several different positions during the testing. Repeat the test using the patient's left arm. Observe for accuracy and tremor. Heel-to-shin testing — Have the patient lie supine, place the right heel on the left knee, and then move the heel smoothly down the shin to the ankle. Repeat using the left heel on the right shin. Again, observe for accuracy and tremor. Involuntary movements — Observe the patient throughout the history and physical examination for the following: Tremor Myoclonus — rapid, shock-like muscle jerks Chorea — rapid, jerky twitches, similar to myoclonus but more random in location and more likely to blend into one another Athetosis — slow, writhing movements of the limbs Ballismus — large amplitude flinging limb movements Tics — abrupt, stereotyped, coordinated movements or vocalizations Dystonia — maintenance of an abnormal posture or repetitive twisting movements Other involuntary motor activity Pronator drift — Have the patient stretch out the arms so that they are level and fully extended with the palms facing straight up, and then close the eyes. Watch for 5 to 10 seconds to see if either arm tends to pronate (so that the palm turns inward) and drift downward. A unilateral pronator drift in one arm suggests an upper motor neuron lesion affecting that arm. Strength testing — In the upper extremities, test shoulder abduction, elbow extension, elbow flexion, wrist extension, wrist flexion, finger extension, finger flexion, and finger abduction. In the lower extremities, test hip flexion, hip extension, knee flexion, knee extension, ankle dorsiflexion, and ankle plantar flexion. Additional testing may be necessary if some of these muscles are weak or if the patient complains of focal weakness to determine if the weakness is in the distribution of a specific nerve or nerve root. For each movement, place the limb near the middle of its range, and then ask the patient to resist you as you try to move the limb from that position. As an example, in testing shoulder abduction, the patient's arms should be horizontal, forming a letter T with the body, and the patient should try to maintain that position while you press down on both

arms at a point between the shoulders and the elbows. When possible, place one hand above the joint being examined to stabilize the joint, and exert pressure with your other hand just below the joint, to isolate the specific movement you are trying to test. Grading strength — The most common convention for grading muscle strength is the 0 to 5 Medical Research Council scale: 0 = no contraction 1 = visible muscle twitch but no movement of the joint 2 = weak contraction insufficient to overcome gravity 3 = weak contraction able to overcome gravity but no additional resistance 4 = weak contraction able to overcome some resistance but not full resistance 5 = normal; able to overcome full resistance The most compelling feature of this scale is its reproducibility; an examiner is unlikely to assign a score of 1 to a muscle that another examiner graded 3 or stronger. A major limitation of the scale is that it is insensitive to subtle differences in strength. In particular, grade 4 covers a wide range, so that in most clinical situations the scale does not allow precise differentiation of the severity of weakness from one muscle to the next. Similarly, it is not a sensitive tool for documenting moderate changes in strength over time. Many clinicians try to compensate for this by using intermediate grades, such as 3+ or 5-, but this results in less reproducibility because there is no consensus on how these intermediate grades should be defined. Terminology of weakness — Monoparesis refers to weakness of a single limb. Hemiparesis is weakness of one side of the body. Paraparesis is weakness of both lower extremities. Quadriparesis is weakness of all four limbs. Monoplegia, hemiplegia, paraplegia, and quadriplegia are analogous terms that refer to complete or nearly complete paralysis of the involved limbs. Diplegia is a term that is best avoided because it is used differently by different authors. Muscle bulk — The muscles active in each movement should be inspected and palpated for evidence of atrophy while testing strength. Fasciculations (random, involuntary muscle twitches) should also be noted. Muscle tone — Muscle tone is the slight residual tension present in voluntarily relaxed muscle. Tone is qualitatively assessed by asking the patient to relax and let you manipulate the limbs passively. This is harder for most patients than you might imagine, and you may need to try to distract them by engaging them in unrelated conversation, or ask them to let their limbs go limp, "like a wet noodle." Several forms of increased tone (hypertonia) are distinguished, including spasticity, rigidity, and paratonia. Decreased tone (hypotonia) also occurs. Spasticity — Spasticity depends upon the limb position and on how quickly the limb is moved, classically resulting in a "clasp-knife phenomenon" when the limb is moved rapidly. The limb moves freely for a short distance, but then there is a "catch" and you must use progressively more force to move the limb until at a certain point there is a sudden release and you can move the limb freely again. Spasticity is generally greatest in the flexors of the upper extremity and the extensors of the lower extremity. Rigidity — Rigidity, in contrast to spasticity, is characterized by increased resistance throughout the movement. Lead-pipe rigidity applies to resistance that is uniform throughout the movement. Cogwheel rigidity is characterized by rhythmic interruption of the resistance, producing a ratchet-like effect. Rigidity is usually accentuated by distracting the patient. Paratonia — Paratonia (also called gegenhalten) is increased resistance that becomes less prominent when the patient is distracted; without such distraction, the patient seems unable to relax the muscle. This is particularly common in patients who are anxious or demented. When it is prominent, other abnormalities of tone are difficult to assess.

MITRAL REGURGITATION-EKG AND ECHO Electrocardiogram

The electrocardiogram in chronic MR most often reflects the hemodynamic burden placed on the left atrium, which can lead to left atrial enlargement, similar to that seen in mitral stenosis. The P wave broadens (>0.12 sec in lead II), becomes increased in amplitude, has a notching and has a significant negative component in V1 (called "P-mitrale"). Other changes are less specific:

• When there is left ventricular hypertrophy, the QRS amplitude increases, especially in the precordial leads and lead aVL. ST-T wave abnormalities (ST segment is depressed and the T wave is inverted) are also common in this setting.

• When pulmonary hypertension is present, there may be evidence of right ventricular hypertrophy, which includes a tall R wave in V1 or V2 with R/S ratio >1. Although right ventricular hypertrophy tends to shift the axis to the right, this may not occur in patients who also have left ventricular hypertrophy.

Chest radiograph

The most common finding on the chest radiograph is cardiomegaly, resulting from enlargement of the left ventricle and left atrium. However, left ventricular size does not correlate with the degree of mitral regurgitation nor does left atrial size correlate with the elevation of left atrial pressure.

Left ventricular enlargement causes the cardiac silhouette to be displaced towards the left chest wall and the chamber becomes globular. Enlargement of the left atrium results in a straightening of the left heart border with the appearance of a double density and elevation of the left main stem bronchus.

The right ventricle is usually normal in size, unless there is pulmonary hypertension. Similarly, the lung fields are usually clear unless congestive heart failure is present. Calcification of the mitral valve annulus may be seen. Echocardiogram

Echocardiography is essential for establishing the etiology and hemodynamic consequences of mitral regurgitation. Other important echocardiographic features are left atrial size, left ventricle size and systolic function, and pulmonary artery pressures. Left atrial size is usually increased. Left ventricular size and systolic function are normal early in the disease course but progressive ventricular dilation and a decline in ejection fraction occur with chronic severe regurgitation. Serial studies permit measurement of changes in ventricular dimensions or left ventricular ejection fraction. Pulmonary pressures also can be noninvasively estimated using Doppler echocardiography.

Transthoracic imaging is diagnostic in most cases, but if image quality is suboptimal, transesophageal imaging is recommended. One study of 248 patients found that, when compared to surgical diagnosis, the accuracy of transesophageal echocardiography was high: 99 percent for etiology and mechanism, presence of vegetations, and prolapsed or flail segment, and 88 percent for ruptured chordae; diagnostic accuracy was higher for transesophageal echocardiography compared to transthoracic echocardiography. Severity of MR

Doppler and color flow Doppler can be used to measure the severity of MR. The simplest approach is measurement of the narrowest segment of the jet, or vena contracta, on color flow imaging. Mitral regurgitant severity can be measured more precisely, when clinically indicated, by calculation of the regurgitant volume, regurgitant fraction, and regurgitant orifice area using standard Doppler approaches.

Based upon the 2003 American Society of Echocardiography guidelines, the following findings are consistent with severe MR:

• A vena contracta width ≥ 7 mm • A regurgitant orifice area ≥ 0.40 cm2 • A regurgitant volume ≥ 60 mL • A regurgitant fraction ≥ 50 percent • A jet area >40 percent of left atrial area, but this is not so

reproducible and less often used

These values are based on an average adult size and may need to be adjusted for body size in small or large patients; however, there is no specific formula for making this adjustment. The diagnosis of severe regurgitation is most secure when more than one of these findings is present.

In addition, assessment of the overall severity of MR should take into account the cause and acuteness of the lesion, left ventricular size and systolic function, left atrial size, and pulmonary artery pressure. Regardless of echo-Doppler grading, severe chronic MR does not exist (with rare exceptions) without clear evidence of left atrial or left ventricular enlargement. If the left ventricular end-diastolic dimension (by echocardiography) is less than 60 mm (approximately 35 mm/m2), the diagnosis of severe chronic MR should be seriously questioned. Left atrial size may reflect the "history" (severity and duration) of chronic MR. Cause of MR 2D imaging allows accurate determination of the cause of MR. If transthoracic echocardiography is nondiagnostic, the next step is transesophageal echocardiography.

• With mitral valve prolapse, there is posterior movement of the leaflets (hammocking) into the left atrium during systole. This generally correlates with the click, which is heard at variable times during systole. Either one or both leaflets may prolapse to variable degrees. In addition, the leaflets are thickened and redundant.

• With endocarditis, vegetations are present, typically on the atrial side of the mitral valve leaflets. Transesophageal echocardiography is more sensitive than transthoracic imaging for detection of vegetations and should be considered when endocarditis is suspected.

• When a perforated mitral valve leaflet is present, a jet can be seen passing through the leaflet.

• When a chordal or papillary muscle rupture is present, the movement of the leaflets is markedly exaggerated and the ruptured chord or papillary muscle is seen in the left atrium in systole.

• With mitral regurgitation due to rheumatic fever, there is significant thickening of the leaflets and some evidence of commissural fusion or chordal shortening

• Secondary (functional) MR due to left ventricular dilation and systolic dysfunction is characterized by failure of the mitral leaflets to close completely and a dilated mitral valve annulus. Ischemic mitral regurgitation, a form of secondary MR, is characterized by restricted leaflet motion, particularly of the posterior leaflet, resulting in inadequate apposition of the leaflets, often called "tenting" or "tethering" of the leaflets.

Cardiac catheterization and angiography

Cardiac catheterization for measurement of intracardiac pressures and/or left ventricular angiography is rarely needed for the evaluation of chronic MR. The major indications for cardiac catheterization are when echocardiography does not provide diagnostic information or the findings are discrepant from the clinical features.

In patients in the ICU with a right heart catheter in place, pressure recordings from the left atrium (or pulmonary capillary wedge position) may demonstrate a significant "cv" wave from the regurgitant blood flow into the left atrium.

In patients undergoing cardiac catheterization for other indications, left ventricular angiography may establish the presence and severity of MR. The diagnostic finding is opacification of the left atrium during systole. The rapidity and density of opacification of the left atrium provides a semiquantitative index of regurgitant severity. The angiogram can also provide a measure left atrial and ventricular dimensions and left ventricular function.

In contrast to its occasional utility in chronic MR, contrast angiography of the left ventricle is generally avoided at the time of catheterization in patients with acute MR because of the contrast load in an already compromised patient, (See "Pathophysiology, clinical features, and management of acute mitral regurgitation", section on Cardiac catheterization).

Coronary angiography prior to mitral valve surgery is recommended in patients with chronic MR who have or are suspected to have coronary disease (and who may have ischemic MR) and those at risk for coronary disease.

TYPE 2 DIABETES MELLITUS NON-INSULIN MEDICATIONS FOR INITIAL THERAPY

Metformin — In the absence of contraindications, metformin is the first choice for oral treatment of type 2 diabetes. It generally reduces A1C by 1.5 percentage points. In contrast with most other antidiabetic drugs, metformin often leads to modest weight reduction or weight stabilization. Furthermore, obese patients in the UKPDS who were assigned initially to receive metformin rather than sulfonylurea or insulin therapy had a decreased risk of the aggregate diabetes-related endpoint and all-cause mortality. During the post-interventional observation period of the UKPDS, reductions in the risk of macrovascular complications were maintained in the metformin group. The cardiovascular benefits of metformin in the UKPDS need to be confirmed before metformin can be recommended to reduce cardiovascular disease. Gastrointestinal side effects are common, but metformin monotherapy does not usually cause hypoglycemia. Metformin can rarely cause lactic acidosis, and because of the potentially fatal outcome of this side effect, metformin should not be administered when conditions predisposing to lactic acidosis are present. Such conditions include impaired renal function (creatinine above 1.4 mg/dL in women and 1.5 mg/dL in men), decreased tissue perfusion or hemodynamic instability due to infection or other causes, concurrent liver disease or alcohol abuse, and heart failure. Factors predisposing to lactic acidosis are discussed in detail elsewhere. Patients who are about to receive intravenous iodinated contrast material (with potential for contrast-induced renal failure) or undergo a surgical procedure (with potential compromise of circulation) should have metformin held until renal function and circulation can be established (normal urine output, normal serum creatinine, and no physical exam evidence of fluid overload or circulatory compromise). Serum creatinine is typically assessed two to three days after contrast administration. Sulfonylureas — Sulfonylureas are the oldest class of oral hypoglycemic agents. They are moderately effective, lowering blood glucose concentrations by 20 percent and A1C by 1 to 2 percent. However, their effectiveness decreases over time. The major adverse effect of sulfonylureas is hypoglycemia. Before beginning a sulfonylurea, the patient should be instructed about the symptoms and treatment of hypoglycemia. Hypoglycemia induced by long-acting sulfonylureas may be severe and is often prolonged in the absence of appropriate therapy. Risk factors for hypoglycemia include increasing age, alcohol abuse, poor nutrition, and renal insufficiency. Shorter acting sulfonylureas, such as glipizide and gliclazide, are less likely to cause hypoglycemia than the older, long-acting sulfonylureas, and therefore are the preferred sulfonylureas, especially in older patients. Initiation of sulfonylurea therapy is also associated with weight gain. The choice of sulfonylurea is primarily dependent upon cost, risk of hypoglycemia, and local availability, since the efficacy of the available drugs is similar. In a patient who is not a candidate for metformin or who cannot tolerate metformin, we suggest a shorter-duration sulfonylurea, such as glipizide. Meglitinides — Repaglinide and nateglinide are short-acting glucose-lowering drugs that act similarly to the sulfonylureas and have similar or slightly less efficacy in decreasing glycemia. Meglitinides are pharmacologically distinct from sulfonylureas and may be used in patients who have allergy to sulfonylurea medications. They have a similar risk for weight gain as sulfonylureas but possibly less risk of hypoglycemia. However, they are considerably more expensive than sulfonylureas, and have no therapeutic advantage over these other drugs that warrant the added cost. Nateglinide is hepatically metabolized, with renal excretion of active metabolites. With decreased renal function, the accumulation of active metabolites and hypoglycemia has occurred. This drug must therefore be used cautiously in this setting, if at all. Repaglinide is principally metabolized by the liver, with less than 10 percent renally excreted. Dose adjustments

with this agent do not appear to be necessary in patients with renal insufficiency. In addition, repaglinide is somewhat more effective in lowering A1C than nateglinide. Thus, repaglinide could be considered as initial therapy in a patient with chronic kidney disease who is intolerant of sulfonylureas. Thiazolidinediones — The thiazolidinediones, rosiglitazone and pioglitazone, lower blood glucose concentrations by increasing insulin sensitivity. The first drug in this class, troglitazone, was removed from the market in the United Kingdom and the United States because of relatively rare, but severe idiosyncratic hepatic injury that was either fatal or necessitated liver transplantation. Hepatotoxicity does not appear to occur with rosiglitazone and pioglitazone. The United States Food and Drug Administration has approved pioglitazone and rosiglitazone for monotherapy. As monotherapy, thiazolidinediones are probably somewhat less effective in lowering glycemia than metformin, lowering A1C by 0.5 to 1.4 percentage points. They are also associated with more weight gain and fluid retention than metformin, and are considerably more expensive than generic sulfonylureas and metformin. In addition, the cardiovascular benefit-risk ratio of individual thiazolidinediones is not entirely clear. Drugs in this class are not recommended in patients with symptomatic heart failure and are contraindicated in patients with New York Heart Association class III or IV heart failure. Furthermore, some meta-analyses have questioned the safety of rosiglitazone with regard to the risk of myocardial infarction. As a result, we do not generally choose thiazolidinediones for initial therapy and reserve their use for second-line treatment in combination with other anti-diabetic medications where synergistic effects can lower A1C substantially. If a thiazolidinedione is used, pioglitazone is recommended because of the greater concern about atherogenic lipid profiles and a potential increased risk for cardiovascular events with rosiglitazone. DPP-IV inhibitors — Sitagliptin is a DPP-IV inhibitor that is approved as initial pharmacologic therapy for the treatment of type 2 diabetes. However, because of modest glucose lowering effectiveness, expense, and limited clinical experience, sitagliptin is more commonly used as a second agent in those who do not respond to a single agent, such as a sulfonylurea, metformin or a thiazolidinedione; or as a third agent when dual therapy with metformin and a sulfonylurea does not provide adequate glycemic control. Sitagliptin can be considered as monotherapy in patients who are intolerant of or have contraindications to metformin, sulfonylureas, or thiazolidinediones. As an example, sitagliptin might be a good choice as initial therapy in a patient with chronic kidney disease at risk for hypoglycemia. However, given the unknown consequences of long-term DPP-IV inhibition, we prefer to use repaglinide in this situation. Although sitagliptin is currently the only DPP-IV inhibitor available for the treatment of type 2 diabetes in the United States, vildagliptin is available in several countries, and other DPP-IV inhibitors (saxagliptin, alogliptin) are in clinical trials. Glucagon-like peptide 1 agonists — Exenatide is a glucagon-like peptide 1 (GLP-1) analog that is administered subcutaneously. It is approved in the United States by the FDA for the treatment of type 2 diabetes in patients not sufficiently controlled with oral agents. Exenatide requires two daily injections and could be considered as an add-on drug for patients with type 2 diabetes who are poorly controlled on maximal doses of one or two oral agents. There are inadequate data to support the use of exenatide as monotherapy. Alpha-glucosidase inhibitors — Because they act by a different mechanism, the alpha-glucosidase inhibitors, acarbose and miglitol, have additive hypoglycemic effects in patients receiving diet, sulfonylurea, metformin, or insulin therapy. This class of drugs is less potent than the sulfonylureas or metformin, lowering A1C by only 0.5 to 0.8 percentage points. The main side effects, which may limit their acceptance, are flatulence and diarrhea. Although these drugs have been studied as monotherapy for initial treatment of diabetes, we do not consider them to be usual first-line therapy because of reduced efficacy, expense, and poor tolerance.

Pulmonary Function Studies A. Introduction Tests of pulmonary function provide three basic kinds of information: 1. Lung volumes are the volumes of the various intrapulmonary compartments. a. Static lung volumes reflect the elastic properties of the lungs and chest wall. b. Dynamic lung volumes reflect the patency of the airways. 2. The expiratory flow rate is the maximum rate of airflow during forced expiration. a. The rate of airflow is influenced by lung volume and by effort (i.e., force of expiration). Airflow increases with increasing effort, especially at high lung volumes [>75% of the vital capacity (VC)]. b. Other factors influencing flow rate include the elastic recoil of the lung, small peripheral airway resistance, and the cross-sectional area of larger central airways. 3. Diffusing capacity of the lung for carbon monoxide (DLCO) is the efficiency of gas transfer from the alveoli to pulmonary capillary blood. B. Spirometry 1. Definition. Spirometry is a simple test of pulmonary function. The spirometer device plots a tracing (the spirogram) of the lung volume against time (in seconds) while the patient takes as deep a breath as possible and then exhales all of the inspired air as rapidly and forcefully as possible. 2. Uses. Spirometry can aid in distinguishing obstructive from restrictive lung diseases (online Table 2-1) as well as suggest the severity of functional impairment and its reversibility with treatment. It is useful both as a diagnostic aid and as a monitoring tool. C. Values obtainable from the spirogram Many spirogram measurements are stated as a percentage of predicted values that are determined from many normal individuals grouped on the basis of sex, age, and height. The range of normal is 80% - 120% of the predicted value. 1. Tidal volume (VT) is the volume of air in one breath during normal quiet breathing. The VT (normal, 500 – 800 mL) varies according to effort and level of ventilation. The portion of the VT that participates in gas exchange is the alveolar volume (VA); the remainder, approximately 30% of the VT, is wasted� or dead space. 2. Vital capacity (VC) is the maximum volume of air that can be expelled from the lungs after a maximal inspiration. Because VC decreases progressively with restrictive lung disease, it is useful, in conjunction with DLCO (see I E 1), for monitoring the course and response to therapy in a patient with a restrictive lung disorder. 3. Forced vital capacity (FVC) is the same as VC, except that the inhalation is performed as rapidly and forcefully as possible. Forced expiration causes the airways to narrow, thereby slowing the rate of expiration. 4. Forced expiratory volume in 1 second (FEV1) is the volume of air forcefully expired during the first second after a deep breath, or the portion of the FVC exhaled in 1 second. The FEV1 primarily reflects the status of large airways. 5. FEV1/FVC is the ratio of the FEV1 to FVC, expressed as a percentage (normal, >70%). (Note: In this case, percentage is not a percentage of predicted normal.) The FEV1/FVC is effort dependent (i.e., it increases with increasing expiratory effort). FEV1/FVC is particularly useful in evaluating obstructive disorders but is also helpful in the evaluation of restrictive disorders. If only the FEV1 is low (FEV1/FVC <70%), obstruction is suggested; if both the FEV1 and FVC are low (FEV1/FVC > 70%), restriction is suggested.

6. FEF25% - 75% is the forced expiratory flow rate over the middle half of the FVC (i.e., between 25% and 75%); it is also called the maximal mid-expiratory flow rate (MMEFR or MMFR). The FEF25% - 75% primarily reflects the status of the small airways, and it is more sensitive than the FEV1 for identifying early airway obstruction. The FEF25% - 75% is effort independent. The FEF25% - 75% has a wide range of normality, and is less reproducible than FEV1. 7. Because spirometry cannot measure residual volume (RV), it can not measure any lung volume containing RV [e.g., RV, functional residual capacity (FRC), total lung capacity (TLC)]. D. Other lung volumes 1. Total lung capacity (TLC) is the volume of air in the lungs after a maximal inspiratory effort. 2. Functional residual capacity (FRC) is the volume of air remaining in the lungs at the end of a normal expiration. The FRC reflects the resting position of the lungs and chest wall; it is the lung volume at which the inward recoil of the lungs is balanced by the outward recoil of the chest wall. The FRC has two components: a. The expiratory reserve volume (ERV) is the amount of the FRC that can be expelled by a maximal expiratory effort. b. The RV is the volume of air remaining in the lungs after a maximal expiratory effort (normal, 25% - 30% of TLC). 3. Lung volume relationships are as follows: a. TLC = VC + RV b. RV = FRC + ERV Patterns of pulmonary function impairment 1. Obstructive lung disorders a. Flow rates. A reduced FEV1/FVC (<70%) is the time-honored indicator of obstructive airway disease. However, the FEV1/FVC may be normal even with considerable peripheral airway obstruction. A reduced FEF25% - 75% (60% or less of predicted value) may detect airway obstruction when the FEV1/FVC is normal. However, the range of normal FEF25% - 75% values is wide. b. Lung volumes. Changes in lung volume may be seen in moderate-to-severe obstructive airway disease. (1) Lung volume measurements are useful in identifying hyperinflation caused by premature airway closure. (a) During a forced expiration, if the terminal airways close before all the air is expelled, hyperinflation results, causing an increase in the FRC, RV, and RV/TLC. (b) In small airway disorders, because of air trapping, the RV may increase while the FRC and FEV1 remain normal. (2) In emphysema, the alveolar wall destruction and loss of lung elastic recoil cause an increase in the TLC. c. Compliance is increased in emphysema, because lung elastic recoil is reduced. d. Raw is increased in obstructive lung disease. 2. Restrictive lung disorders a. Flow rates. FEV1/FVC and FEF25% - 75% may be normal or increased because of increased traction on the intrathoracic airway walls. b. Lung volumes (1) A reduction in VC and TLC is the most useful indicator of a restrictive ventilatory defect. (2) Lung stiffness in restrictive diseases increases the lung elastic recoil, thus lowering the FRC. (3) Chest wall stiffness (e.g., in kyphoscoliosis) lowers lung volumes because it restricts lung expansion. c. Compliance is reduced because lung elastic recoil is increased. d. Raw is decreased because the elastic forces maintain wider airways at any lung volume.

Re-entry 1 Re-entry is a depolarizing wave traveling through a closed path. The exact path of the re-entrant circuit is constant and predefined in zero dimension (single cell automatic impulse) and one dimension re-entrant circuits (single cell width re-entrant circuit). On the other hand, the exact cellular path might be different in a higher dimension re-entrant circuit where an impulse can travel transversely through myocytes. There are three prerequisites for re-entry: 1. At least two pathways: slow and fast AV nodal pathways, accessory pathway or the presence of barrier (anatomic: tricuspid valve; pathologic: incisional scars, myocardial infarction, and functional scar) (Figure 1.5). 2. Unidirectional block: This block can be physiologic: caused by a premature complex, or increased heart rate; or pathologic: caused by changes in repolarization gradients. 3. Slow conduction to prevent collision of the head and the tail of the depolarizing wave: physiologic: caused by AV nodal slow pathway (AVNRT), AV node (AVRT), cavotricuspid isthmus (AFL), slow conduction across the crista terminalis (upper loop tachycardia); pathologic: ischemic or remodeled cells in atrium and ventricle (ventricular tachycardia, atrial flutter). In functional re-entry, unidirectional block can be due to dispersion of refractoriness (repolarization) or dispersion of conduction velocity (anisotropic re-entry). The former can be caused by repolarization gradients due to spatial heterogenicity of repolarization (ischemia, drugs), discordant repolarization alternans (T-wave alternans during ischemia, autonomic abnormalities), and transmural gradients from cell-to-cell uncoupling (drugs, heart failure). A re-entrant circuit can be defined with the following: 1. Cycle length (CL)/period: time required for the depolarizing impulse to return to its spatial origin. � 2. Refractory period (RP): the shortest coupling interval that could capture the re-entrant circuit. 3. Temporal excitable gap (diastolic interval): CL–RP. 4. Path length: spatial length of the physical re-entrant circuit. 5. Wavelength (WL): spatial length of the active tissue that is refractory to excitation which is RP x CV (conduction velocity). 6. Spatial excitable gap (EG): pathlength – wavelength.

Reentry 2 • The size of reentry circuit depends on tissue excitability. • It overdrive suppresses normal pacemaker cells. • Decrease in conduction velocity, increase in the refractory period and/or decrease in the circuit length will make reentry less likely. • Decreasing wavelength will increase the tendency to cause reentry arrhythmias. • Restitution is described as the recovery of excitability after the refractory period. • Multiple reentries may result in fibrillation. • The reentry wave dies when it reaches the border of the tissue. • The spiral of reentry wave may drift or it could be fixed (pin) around the obstacle. • Reentry can be classic (anatomical) or functional. • If a stimulus enters a vulnerable window of an anatomical reentry, it terminates it. • Functional reentry is not terminated by entry of the stimulus inside the vulnerable window. • Pacing induces a drift in the reentry circuit. • Decrease in tissue excitability, by slowing conduction, eliminates reentry. • When an electrical shock is applied to the heart, the tissue near the cathode (negative electrode) is depolarized (positive charge on the membrane) and the tissue near the anode (positive electrode) is hyperpolarized (negative charge on the membrane). This terminates the arrhythmia. • For initiation and maintenance of reentry, whether anatomic or functional, unidirectional conduction block and the presence of excitable tissue ahead of propagating wave front (excitable gap) are essential. Slowing of conduction or shortening of the refractory period or both facilitate the excitable gap. • Half of all cell-to-cell connections are side to side and the other half are end to end. The gap junction membrane provides resistance to current flow

that results in slower conduction transversely than longitudinally. This results in anisotropic conduction through the myocardium. Reduction in myocardial CX43 results in slowing of conduction velocity. • During myocardial ischemia slowing of the conduction occurs due to changes in ion channel function and increased resistance at gap junctions. After 60 minutes of ischemia irreversible damage occurs to the gap junction membrane and CX43. This results in slowing and non-uniform conduction. • Crista terminalis and pectinate muscle produce anisotropic conduction and act as facilitators of reentry. Conduction along the longitudinal axis of the crista and pectinate muscle is faster than along the horizontal axis. • Crista and Eustachian ridge act as anatomic barrier (isthmus) during re-entrant activation. • Discordant activation of atrial epicardium and endocardium at a faster rate promotes reentry. • Crista, pectinate muscles, and Backman bundle propagate sinus impulses rapidly. • Ectopic beat may alter normal conduction and produce changes in refractoriness which promotes reentry. Phase 2 reentries • Prominent outward current due to Ito results in shortening of the APD. • This may occur during ischemia and may result in a decrease of the plateau phase of AP. These changes may occur nonuniformly throughout the myocardium and cause dispersion of repolarization and phase 2 reentries. • When Ito, an outward current, is dominant it results in APD shortening and loss of plateau of AP in some epicardial sites producing dispersion of repolarization. This results in local reexcitation and premature beats. This mechanism is termed as phase 2 reentry. • Phase 2 reentry may occur in the presence of potassium channel opener Pinacidil, sodium channel blockers Flecainide, increase in extracellular calcium, and ischemia. • Ito blockers restore homogeneity and abolish reentrant activity. • Ito is present in ventricular epicardium but not in endocardium. It is responsible for spike and dome morphology of AP in epicardium. • Reduced activity of IKs in M cells prolongs APD. Bradycardia and class III drugs prolong APD in M cells and predispose to arrhythmias. • Repolarization is sensitive to changes in the heart rate. Pharmacological differences in epicardium and endocardium • Ach may alter the epicardial repolarization pattern by blocking ICa or activating IKAch. It has no effect on Ito. • Isoproterenol causes epicardial AP abbreviation more than it does in the endocardium. • Organic calcium channel blockers (Verapamil) and inorganic calcium channel blocker MnCl2 can cause loss of AP plateau phase in epicardium but only a slight abbreviation of AP in endocardium. • Sodium current block decreases APD in epicardium. • Block or decrease in calcium current leaves outward currents unopposed, which may result in shortening of APD. • Ito block may establish electrical homogeneity and abolish arrhythmias due to dispersion of repolarization caused by drugs and ischemia. Quinidine inhibits Ito. • Amiloride, a potassium sparing diuretic, prolongs APD and refractoriness. • M cells, found in mid-myocardium of anterior, lateral wall, and outflow tract exhibit marked AP prolongation in response to bradycardia and on exposure to class III agents. • This may be due to weaker IKs activity and stronger late INa activity. • At slower rates M cells may contribute to pump efficiency because prolonged depolarization permits longer and more efficient contraction. • Epicardium and endocardium electrically stabilize and abbreviate APD of M cells. • Loss of either layer by infarction will lead to prolongation of APD. This may be the mechanism by which QT prolongation and dispersion occurs in non-Q wave MI. These differences could be aggravated by drugs that prolong the QT interval or in patients with LQTS. • M cells play an important role in the inscription of T waves by producing a gradient between epicardium, endocardium, and M cells. • U waves are due to repolarization of His Purkinje cells.

SODIUM CHANNELS AND CURRENTS • Inward movement of the Na or Ca across the cell membrane through the specific channels produces inward current. Na current depolarizes the cell membrane and is voltage dependent. • The process of channel opening is called activation and the process of closing is called inactivation. During inactivation phase channel enters a nonconducting state while depolarization is maintained. • The gating process measures current movement rather than ion movement. • Channels flip between conducting and non-conducting states. Fig 1.2 Inward currents. • Na and Ca L during entire AP period. • Ca T during early period. Fig 1.3 Ion pumps and channels. Ion Channels for K, Na and Ca inward transport. Passive & Electrochemical gradient dependent ion movement. Channels display selectivity and gating properties. Carrier Mediated Ion Transport Pumps require ATP to transport.

1. Na-K Pump 2 K in, 3 Na out. 2. Na-Ca Exchange 3Na in, 1 Ca out 3. Ca Pump Pumps Ca out of the cell.

• When all the gates (active or inactive) are open would a channel allow the passage of the ions. • During the early part of repolarization Na channels become inactive. On completion of repolarization the Na channel returns from the inactive to the closed state. During resting potential the sodium channel is closed. Na ion conduction through the channel occurs when the channel is in the open state and not during the resting state. • Movement of the sodium occurs through channels and pumps (Fig. 1.3). • Repolarization occurs due to outward K currents. It will be delayed if the K currents are blocked as in LQT1 and LQT2 or when inward depolarizing currents persist during repolarization as in LQT3. In LQT3 SCN5A, an Na channel remains open during repolarization resulting in continued inward current. This causes prolongation of the QT interval. • Voltage-dependent opening of Na channel occurs as voltage decreases and conformational change in channel protein occurs (activation). • There are no β2 subunits of sodium channel in cardiac myocytes. Both β1 and β2 subunits are expressed in the Na channels of the brain neurons. • Lidocaine inhibits the inactivated state of the sodium channel. • Chronic exposure to Na channel blocking antiarrhythmic drugs increases the sodium channel messenger RNA which counteracts the effects of channel blockade. Sodium channel block • There are two types of Na channel block: i Tonic block results in a reduction of the peak current with the first pulse of the train of pulses. It is seen in drug-induced reduction of current during infrequent stimulation. ii Phasic block occurs when there is a sequential decline in the peak current from beat to beat. It is also called use dependent or frequency dependent block. It decreases AP upstroke and slows conduction velocity. This type of block increases with repetitive stimulation. If the interval between AP is less than four times the recovery constant of the channel, block accumulates. • During phase 0 Na channels open (open state) for less than 1 millisecond and then become inactive. • During phase 2 and phase 3 (plateau phase) less than 1% of sodium channels remain open (inactivated state). • Most depressants of conduction such as elevated extracellular potassium (as may occur in ischemia) produce membrane depolarization and increase the fraction of inactivated Na channels. Lidocaine produces inactivated state block; thus, it is effective in ischemic zones. The fraction of channels available in the open state is reduced during ischemia.

• Quinidine, Disopyramide, and Propafenone produce open channel block. • During the resting state dissipation of block occurs (drugs dissociate from the site). • Drugs can produce Na channel block during the resting, open, or inactivated state. These are called state dependent blocks. The other type of channel block is voltage dependent. • Two different sodium channel blocking drugs may act synergistically. • Class 1A drugs increase APD, thus increasing the time sodium channels spend in the inactivated state. This will enhance the effectiveness of the drugs that bind to the inactivated state (Class 1B drug such as lidocaine). • Drugs with different binding kinetics may interact. For example, drugs with fast kinetic may displace drugs with slower kinetic, thus reducing the overall block. • Lidocaine may reverse the Quinidine, Propafenone Flecainide induced block. • Ventricular tachycardia due to Flecainide, Yew needle toxin, dextropropoxylene can be treated with Lidocaine. • Class 1B drugs have dissociation constant of less than one second. These drugs have no effect on the conduction of normal tissue but decrease the conduction following closely coupled premature ventricular contractions (PVCs) and in diseased (ischemic) cells. • Class 1C drugs have the slowest dissociation of 12 seconds. This results in slowing of conduction and widening of QRS. • Class 1A drugs have intermediate kinetics of more than 1 second but less than 12 seconds, this may result in slowing of conduction and widening of QRS at the normal heart rate, which increases during tachycardia. • Lidocaine blocks INa by shifting voltage for inactivation to more negative. It binds to the activated and inactivated states of the sodium channel. • Lidocaine, Quinidine, and Flecainide exert use dependent block with fast, intermediate, and slow kinetics, respectively. Drug kinetics and channel state • Membrane depressants such as increased extracellular potassium, hydrogen, and stretch reduce the resting membrane potential. This increases the fraction of inactivated channels and potentiates the effects of the drugs that act on the inactivated state. Fewer channels are available in the open state, thus decreasing the effectiveness of the drugs that are open state blockers. • Decrease in extracellular pH slows the rate of dissociation of Lidocaine from the sodium channel. A combination of acidosis and membrane depolarization increases the block produced by Lidocaine. • Class 1C drugs are slow to unbind from the channel site and cause slowing of conduction, which may produce incessant tachycardia. • Marked sinus bradycardia may be proarrhythmic for drugs with fast half time of recovery from the block because the channels are left unprotected for the major part of APD. Slow sodium currents (inward) • Agents that increase the slow component of sodium current (Diphenylmethyl- Piperanzinyl-Indole derivatives) are likely to increase inotropy by increasing the entry of Na during the plateau phase. This leads to an increase in intracellular calcium through sodium/calcium exchange. Increase in intracellular Ca may lead to EAD and PVC. • Methanesulfonalide Ibutilide prolongs APD by increasing the slow sodium channel current. • Lidocaine and other class 1B agents block the slow component of sodium current and decrease QT in patients with LQT3. • Negative inotropy by sodium channel blockers may be due to blockage of the slow sodium channel current. • Slowing of heart rate produced by class 1B agents is due to blocking of background sodium current that contributes to the phase 4 of pacemaker AP. • β-Adrenergic stimulation reverses the effects of class I drugs. • Proarrhythmia from class IC drugs develops during increased heart rate when sympathetic activity is enhanced. Beta blockers may reverse this phenomenon. • Angiotensin II increases the frequency of reopening of the sodium channel and increases the Na current.

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TILT TABLE TEST In comparison to healthy subjects, patients suffering from neurally mediated syncope often show less baro-reflex sensitivity, which is not only restricted to the tilting phase. This generally results in a clear decrease of the sympathetic drive immediately before the onset of syncope. In the case of vasovagal syncope, the onset of the syncopal phase can be identified by an immediate withdrawal of sympathetic tone. In contrast to neurally mediated effects a healthy subject shows a fair amount of vagal activity in supine position during controlled breathing with an immediate increase in sympathetic drive at the onset of tilting. VASOVAGAL SYNCOPE There are three types of vasovagal syncope. Type I: Mixed 1. Heart rate falls but not to 40 or less beats/min or 2. Heart rate falls to less than 40 but only for less than 10 seconds 3. Blood pressure falls before the heart rate falls Type 2A: Cardioinhibition without Asystole 1. Heart rate falls to less than 40 beats/min for more than 10 seconds 2. Asystole for more than 3 seconds does not occur 3. Blood pressure falls before the heart rate falls Type 2B: Cardioinhibition with Asystole 1. Asystole occurs for more than 3 seconds 2. Blood pressure fall coincides with or occurs before the heart rate falls Type 3: Vasodepressor Heart rate does not fall more than 10% from its peak at the time of syncope Exception 1: Chronotropic incompetence No heart rate rise during the tilt testing, i.e, less than 10% from the pre-tilt phase Exception 2: Excessive heart rate rise An excessive heart rate rise both at the onset of the upright position and throughout its duration before syncope (i.e. greater than 130 beats/min) POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME Heart rate increase of more than 30 beats/min from baseline or a maximum heart rate of 120 beats/min during tilting. No profound hypotension. Symptoms can include light-headedness, fatigue, presyncope and dizziness.

CAROTID SINUS HYPERSENSITIVITY Diagnosis by carotid sinus massage 1. CARDIOINHIBITORY SUBTYPE: Asystole of 3 or more seconds. 2. VASODEPRESSOR SUBTYPE: Fall in systolic blood pressure of 50 mmHg or more. 3. MIXED SUBTYPE: Asystole for 3 or more seconds and fall in systolic blood pressure of 50 mmHg or more. HEMODYNAMIC PARAMETERS Parameter Normal Value Heart Rate (HR) 60-90 bpm RR-Interval (RRI) 660-1000 ms Systolic Blood Pressure (sBP) 90-140 mmHg Diastolic Blood Pressure (dBP) 50-90 mmHg Mean Arterial Blood Pressure (mBP)1

<105 mmHg

Stroke Volume (SV) 60-120 ml Stroke Index (SI)2 30-80 ml/m2 Cardiac Output (CO) 4-8 L/min Cardiac Index (CI)2 2.5-4.5 L/min/m2 Total Peripheral Resistance (TPR) 800-1200 dyne*sec/cm5 Total Peripheral Resistance Index (TPRI)2

1200-2400 dyne*sec*m2/cm5

Left Ventricular Work Index (LVWI)

3.0-5.0 kg*m/min/m2

Index of Contractility (IC) 33-65 1000/s Thoracic Fluid Content (TFC) 21-50 1/kOhm Maximum Rise in Pressure (dP/dt)3

500-1000 mmHg/s

1 Depending on sBP and dBP. 2 Depending on body surface area (BSA) 3 Calculated from beat-to-beat finger blood pressure curve; this parameter is only displayed in the software application “pacemaker”. PARAMETERS OF THE AUTONOMIC CARDIOVASCULAR REGULATION4

Parameter Normal Value Baroreflex Sensitivity (BRS) > 9.3 ms/mmHg Heart Rate Variability –LF (LF_RRI; 0.04-0.15 Hz)

1170 + 420 ms2

Heart Rate Variability – HF (HF_RRI; -0.15-0.40 Hz)

975 + 200 ms2

Normalized Units Low Frequency (LFnu_RRI)

55 + 5 %

Normalized Units High Frequency (HFnu_RRI)

30 + 5 %

Power Spectral Density (PSD_RRI) 3500 + 1100 ms2 LF/HF Ratio (LF_RRI/HF_RRI) < 2.0 Sympatho-Vagal Balance (LF_dia/HF_RRI)

< 2.0

TINNITUS - ETIOLOGY/PATHOGENESIS Tinnitus can be triggered anywhere along the auditory pathway. It is believed to be encoded in neurons within the auditory cortex. The majority of patients have "sensorineural" tinnitus, due to hearing loss at the cochlea or cochlear nerve level. Somatic sounds may be perceived as tinnitus, and originate in structures with proximity to the cochlea. These sounds are often generated in vascular structures, but may also be produced by musculoskeletal structures. Somatic sounds are most often associated with pulsatile tinnitus and continuous tonal tinnitus (single pure-tone) is usually not somatic in origin. In a retrospective review of 84 patients with pulsatile tinnitus seen in a neurology department, 42 percent were found to have a significant vascular disorder (most commonly a dural arteriovenous fistula [AVF] or a carotid-cavernous sinus fistula). In 12 patients (14 percent), nonvascular disorders such as paraganglioma or intracranial hypertension (due to a variety of causes) explained the tinnitus. Thus, patients with pulsatile tinnitus should be thoroughly evaluated. Vascular disorders — Pulsatile tinnitus is most commonly, though not exclusively, vascular in etiology. Some vascular tinnitus, such as venous hums and tinnitus due to atherosclerotic plaque narrowing of vessels, can be non-pulsatile. Arterial bruits — Arterial vessels near the temporal bone may transmit sounds associated with turbulent blood flow, especially if the loudness of the sound exceeds the hearing threshold in that ear. The petrous carotid system is the most common source, although other arteries may also be involved. An arterial bruit is not itself a serious condition, although the patient may require an evaluation for underlying atherosclerotic disease. These patients usually do not have other otologic complaints (eg, hearing loss, vertigo, aural fullness). As with many other causes of tinnitus, their tinnitus is greatest in quiet environments (eg at night). Arteriovenous shunts — Congenital arteriovenous malformations (AVMs) are rarely associated with hearing loss or tinnitus. Acquired arteriovenous fistulas (AVFs) are more likely to be symptomatic. Dural AVFs are often associated with dural venous sinus thrombosis, which may occur spontaneously or be associated with infection, tumor, trauma, or surgery. Large dural AVFs can result in intracranial hemorrhage; early detection and treatment (surgery and/or vascular embolization) can be life-saving for high grade lesions. Paraganglioma — This is a vascular neoplasm arising from the paraganglia cells found around the carotid bifurcation, within the jugular bulb, or along the tympanic arteries in the middle ear. Also known as glomus tumors, they commonly cause a loud pulsing tinnitus that may interfere with hearing. The lesion may be visible through the tympanic membrane as a reddish or blue mass, or may be palpable in the neck. As the tumor enlarges, it may cause hearing loss because of impingement on the ossicular chain (conductive loss) or the labyrinth or cochlea (sensorineural loss). Other cranial nerves may also be affected (eg, facial nerve or lower cranial nerve palsies). Venous hums — These may be heard in patients with systemic hypertension, increased intracranial pressure (often due to pseudotumor cerebri), or in patients with a dehiscent or dominant jugular bulb (abnormally high placement of the jugular bulb). The latter may also cause a conductive hearing loss. Tinnitus in patients with a venous hum is often described as a soft, low-pitched hum that may decrease or stop with pressure over the jugular vein, with a change in head position, or with activity. Neurologic disorders — Pulsatile tinnitus of muscular origin can result from spasm of one or both of the muscles within the middle ear (the tensor tympani and the stapedius muscle). These muscles are enervated by cranial nerves V and VII respectively. Such muscle spasms can occur spontaneously, because of local otologic disease, and also in the presence of neurologic disease such as multiple sclerosis. Patients may also complain of hearing loss or aural fullness associated with these muscle spasms. Tympanometry and otoscopy can be particularly useful in diagnosing middle ear spasmodic activity. Clicking noises or irregular or rapid pulsations may also result from myoclonus of the palatal muscles that attach to the Eustachian tube orifice. Myoclonus of the palatal muscles most often is caused by an underlying neurologic abnormality, such as multiple sclerosis, microvascular disease affecting the brainstem, or neuropathy related to metabolic or toxic etiology; the history and physical examination should include a search for other neurologic disease. Eustachian tube dysfunction — A patulous eustachian tube can cause tinnitus with sounds similar to an ocean roar that may be synchronous with respiration. It most commonly occurs after significant weight loss or after external beam radiation to or near the nasopharynx. The symptoms may disappear when the patient lies down. Patients can also complain of an unusual awareness of their own voice (autophony) and of ear discomfort. The cause of these symptoms is a eustachian tube that

remains abnormally patent, allowing too much and then too little aeration of the middle ear space with respiration. Other somatic disorders — Somatic non-pulsatile tinnitus is commonly caused by temporomandibular joint (TMJ) dysfunction. It has also been associated with whiplash injuries and other cervical-spinal disorders . Tinnitus may improve when patients respond favorably to treatment for symptoms of TMJ dysfunction and craniocervical disease. The exact neurophysiologic mechanism for the generation of tinnitus from either the TMJ or the cervical spine is not known, but may involve disinhibition of the dorsal cochlear nucleus. Tinnitus with a machine-like or pulsing character is sometimes associated with intracranial lesions, such as chondrosarcoma, aberrant carotid artery, and endolymphatic sac tumors. Tinnitus originating from the auditory system — Most tinnitus is due to a sensorineural hearing loss with resulting dysfunction within the auditory system. The auditory system includes the cochlear end-organ, the cochlear nerve (with its projections to and from the cochlea), the brainstem (site of the cochlear nuclei), and the primary and secondary auditory cortical projections. Etiologies of tinnitus generated from within the auditory system are as varied as the types of noises that patients report . The presence of tinnitus often is an early indicator of cochlear hair cell dysfunction or loss, as in the case of prolonged noise exposure, Meniere's syndrome (also characterized by aural fullness and vertigo), or ototoxicity. Ototoxic medications — Tinnitus is commonly caused by ototoxic medications. Ototoxicity affects the various components of the cochleovestibular end-organ. When such structures are damaged, a change in neural firing between the end-organ and the remainder of the auditory system can be exhibited by hearing loss, distortions in hearing, or tinnitus. Presbycusis — Presbycusis (sensorineural hearing loss with aging) or any acquired high frequency hearing loss is commonly associated with tinnitus (often described as a high-pitched ringing sound, crickets, or bells in the ear) along with the hearing loss. Otosclerosis — This is a condition of abnormal bone repair of the stapes footplate bone (third bone in the ossicular chain) and of the otic capsule. Tinnitus can result when otosclerosis damages cochlear structures. Progressive otosclerosis can result in fixation of the stapes footplate and worsening conductive hearing loss. Vestibular schwannoma — Tumors compressing or stretching the cochlear nerve can cause tinnitus; tinnitus can be the presenting sign of a schwannoma of the vestibular nerve within the cerebellar-pontine angle or the internal auditory canal (acoustic neuroma). Chiari malformations — Tinnitus is one of the auditory signs associated with a symptomatic Chiari malformation and occurs when low lying cerebellar tonsils causes tension on the auditory nerve . Other etiologies — Hearing loss due to a variety of causes, including vascular ischemic events, infection, nerve compression, genetic predisposition, congenital hearing loss, endocrine or metabolic damage to the auditory system, can produce tinnitus to a variable degree. Tinnitus may occur with barotrauma to the middle or inner ear (often associated with vertigo and hearing loss) and with fluid in the middle ear (eg, with otitis media). Pathogenesis — Recent pathogenetic theories target the central nervous system as the source or "generator" of all tinnitus that does not have a somatic origin, even in patients whose associated hearing losses are due to cochlear injury. PET scanning and functional MRI studies indicate that the loss of cochlear input to neurons in the central auditory pathways (such as occurs with cochlear hair cell damage due to ototoxicity, noise trauma, or a lesion of the cochlear nerve) can result in abnormal neural activity in the auditory cortex. Such activity has been linked to the perception of tinnitus. A current theory likens tinnitus to phantom pain perception that is thought to arise from a loss of suppression of neural activity. Known neural feedback loops act to help tune and reinforce auditory memory in the central auditory cortex. Disruption of auditory input or the feedback loop may lead to the creation of alternative neural synapses and to loss of inhibition of normal synapses. Tinnitus has also been likened to a type of auditory seizure, and antiseizure medications have had limited success in some patients. Abnormal auditory-evoked magnetic field potentials associated with tinnitus can be suppressed in selected patients with intravenous lidocaine, confirming a central tinnitus phenomenon and potentially indicating a physiologic mechanism for lidocaine sensitive tinnitus.

Triggered Activity • Triggered activity is initiated by after-depolarization. There are two types of after-depolarizations, early and delayed. • EAD occurs before and DAD occurs after completion of AP repolarization. Delayed after-depolarization • DAD occurs after repolarization of AP. It is caused by inward currents produced by an increase in the intracellular Ca load. • DADs are associated with fast heart rate and Ca overload. • Increase in the level of catecholamines and cAMP enhances Ca uptake and causes DAD in atrial and ventricular myocytes. • Catecholamines increase sarcolemmal calcium by stimulating sodium/calcium exchange. • The most common cause of DAD is Digoxin. It inhibits the Na/K pump and leads to an increase in intracellular calcium. • Increase in the extracellular ATP levels potentiates the DAD effect of catecholamines. • Withdrawal of cholinergic stimulation increases calcium in atrial myocytes and may cause DAD. • Longer APD favors DAD. Longer CL allows for more calcium entry into cells. The amplitude of the DAD depends on CL. • Quinidine may increase DAD by prolonging APD. Lidocaine shortens APD and thus decreases DAD. Sodium and calcium exchange and DAD • Opening of voltage-operated Ca channels, during the plateau phase of APD, increases the flux of Ca into cytoplasm. This causes CICR from SR. • During diastole calcium is removed from the cell by the sodium/calcium exchange pump, located in the cell membrane. • Lowering of pH blocks sodium/calcium exchange. • SR calcium ATPase, Sarcolemmal calcium ATPase, and sodium/calcium exchange decrease cytoplasmic calcium from the elevated systolic level to the baseline diastolic level by pumping Ca back into SR or by extruding Ca out of the cell. • During calcium removal, inwardly directed current INa/Ca is observed, which may cause DAD. • DAD occurs when there is a pathologically high calcium load either due to digitalis toxicity or following reperfusion. • Na/Ca exchange is able to transport calcium bi-directionally. Reverse mode will increase intracellular calcium, which may trigger SR calcium release. • DAD is induced by a spontaneous release of calcium from the overloaded SR, which in turn activates the Na/Ca exchanger to extrude Ca from the cell. This generates, because of the 3 : 1 ratio of Na/Ca exchange, a large inward current that causes depolarization and DAD. ICaL does not participate in DAD. Early after-depolarizations Phase 2 EAD • EAD occurs when a large inward current during the plateau phase occurs, resulting in prolongation of plateau. This provides time for reactivation of ICaL. It is this second phase of reactivation of inward ICaL that produces EAD by depolarizing the membrane. • EAD does not require a spontaneous release of calcium from SR and does not require inward activation of INa/Ca. • ICaL is a primary depolarizing factor responsible for EAD. • The delicate balance between depolarizing and repolarizing currents controls the plateau phase of the AP. An increase in the inward current and/or a decrease in the outward current may induce EADs. Examples include persistent inward INa in LQT3 and reduced IKr and IKs in LQT2 and LQT1, respectively.

• Once the plateau is prolonged, reactivation of ICaL induces EAD. This mechanism applies to phase 2 (plateau) EAD. • EAD occurs in Purkinje fibers and M cells of the myocardium. • Other conditions that can cause EAD are bradycardia, which reduces the outward current caused by delayed rectifier IK, hypokalemia, and increase in Ca current induced by sympathetic stimulation in the presence of ischemia or injury. • Pharmacological agents such as potassium channel blockers (Quinidine, Sotalol), in the presence of hypokalemia and bradycardia prolong repolarization and induce EAD. • IKr blockers such as Erythromycin, Piperidine derivatives that block histamine H1 receptors such as Astemizole and Terfenadine, and Cisapride increase APD and cause EAD. • Magnesium, Flunarizine, and Ryanodine can abolish EAD by decreasing the intracellular calcium load. • EAD caused by inward sodium current are abolished by sodium channel blocker Mexiletine. Phase 3 EAD • These occur during fast repolarization and share the mechanism of DAD (spontaneous Ca release from SR and activation of the INa/Ca). They are called EAD because they occur before the completion of AP repolarization (Fig. 3.1). • EAD may occur during the plateau phase and are caused by L-type Ca current. EAD that occur during phase 3 of APD are due to the Na/Ca exchange current. Torsades De Pointes (TDP) • TDP is a polymorphic ventricular tachycardia (VT) associated with long QT syndrome (LQTS). • Quinidine and hypokalemia produce EAD and triggered activity resulting in TDP. Initial event in TDP is EAD-induced triggered activity. • TDP often follows short long short CL. Excitability and conduction • Excitability is dependent on the availability of sodium channels; thus reduced Na channel activity will reduce excitability and conduction velocity. • Reduced membrane excitability and reduced gap junction coupling slows conduction, which may predispose to reentrant arrhythmias. • Reduced gap junction coupling also slows conduction velocity, which may allow ICaL to induce inward depolarizing currents. • ICaL plays a dominant role in maintaining conduction in the setting of reduced coupling. While INa controls excitability, ICaL influences conduction during reduced coupling. Phase 2 EAD Phase 3 EAD DAD CIRCA in SR Reactivation of ICaL Fig 3.1 Mechanisms of EAD and DAD. Summary • DADs occur during calcium overload due to Ca release from SR. This activates INa/Ca. • EAD is generated by recovery and reactivation of ICaL. • Phase 3 EAD shares the mechanism of DAD. • Slow conduction could be due to decreased membrane excitability or reduced gap junction coupling. • INa causes slow conduction, due to decreased excitability. • Slow conduction due to decreased gap junction coupling requires contribution of ICaL.

POTASSIUM CHANNELS AND CURRENTS Voltage Gated Currents

• There are more than eight types of potassium currents. • The plateau phase of the action potential (AP) depends on the balance between inward (depolarizing) and outward (repolarizing) currents. • Potassium currents (outward movement of the K through the potassium channels) are the main contributors to repolarization. Classification of potassium currents

1. Voltage gated currents = Ito ; IKur ; IKr ; IKs 2. Inwardly rectifying currents = IK1; IKach; IKatp 3. Background currents = IKp

• AP duration (APD) determines the amount of calcium influx and tissue refractoriness. It is inversely related to heart rate. Prolongation of AP plateau increases the strength and duration of contraction. It also increases refractoriness. • In congestive heart failure (CHF) and in left ventricular hypertrophy (LVH), repolarizing outward currents are reduced by 50%. This increases APD and results in early after depolarization (EAD) and arrhythmias. Use of class III drugs in patients with CHF needs reevaluation as the intended target (K channels) is down regulated or absent. • In atrial fibrillation (AF) repolarizing outward currents (IK, Ito) are reduced. Reduction of these currents may exacerbate the arrhythmic effect of hypokalemia and hypomagnesemia. • Potassium channel expression is decreased in hypothyroid and hypoadrenal states. Delayed and inwardly rectifying voltage sensitive potassium channels • Rectification is a diode-like property of unidirectional current flow, which could be inwards or outwards. It limits the outward flow of potassium through IKr and IKs during a plateau. Delayed rectifier potassium channels have slow onset of action. • Voltage gated potassium channels are activated during AP upstroke. • Rapidly activating and inactivating voltage-sensitive transient outward current produces phase 1 of repolarization. • Slowly activating delayed rectifier potassium current, and inward rectifier IK1, which includes fast inactivating rapid component IKr and slow component IKs,contributes to plateau and phase 3 of AP. Fig 1.1 Outward currents. • K channels carry a positive charge, which acts as a voltage sensor. • Potassium channels are closed at resting potential and open after depolarization. • Two types of voltage-gated channels play a major role in repolarization. i Transient outward current (Ito), which is characterized by rapid activation and inactivation. ii Delayed rectifier IK, which has several components (Fig. 1.1): • IKr is a rapidly activating current with inward rectification. • IKs is a slowly activating current. • IKp is a time independent background plateau current. • IKur is an ultra rapid current. Transient outward potassium current (Ito)5 • There are two types of Ito currents: Ito1 and Ito2. • Ito is present in ventricular epicardium but not in endocardium. It is responsible for spike and dome morphology of AP in epicardium. • In human atrium it recovers rapidly from inactivation, thus allowing rapid repolarization at a fast heart rate. • Flecainide, Quinidine, and Ambasilide inhibit Ito. Flecainide binds to inactivated Ito1. It also demonstrates fast unbinding. Quinidine binds to open channel; its slow recovery from block causes a rate dependent effect. • Inhibition of Ito prolongs repolarization in diseased human ventricle. • Ito2 is calcium activated.

I to and J wave • J wave (Osborn wave), elevated J point and T wave alternans may be due to a transmural gradient between epicardium and endocardium as a result of uneven distribution of Ito. • Prominent J waves are often seen in hypothermia and hypercalcemia. Rapidly activating delayed rectifier IKr • It is blocked by methane sulfonamide, class III agents (D-Sotalol). • Inward rectification of IKr results in a small outward current. • It plays an important role in atrial pacemaker cells. It rapidly recovers from inactivation and it peaks at −40 mV. • KCNH2 (HERG, Human Ether Related-a-go-go gene protein) encodes IKr channel. • IKr is increased in the presence of elevated extracellular potassium. Normally, increased extracellular potassium will decrease the outward potassium current by decreasing the chemical gradient, but the activity of IKr is increased. • Increase in serum potassium by 1.4 mEq/L decreases QTc by 24% and decreases QT dispersion. • The efficacy of IKr blockers is limited by inverse rate dependency. The drug is more effective at a slower heart rate. A high heart rate increases the prevalence of IKs, which is insensitive to IKr blocker. This offsets the k blocking effects of the IKr blockers. • The effect of IKs but not of IKr is enhanced by β-adrenergic stimulation. Thus, the effects of pure IKr blockers will be antagonized by sympathetic stimulation. • Selective IKr blockers (D-Sotalol) lose efficiency at high rates and during sympathetic stimulation. • IKr and IKs are present in the human atrium and ventricle. Slowly activating delayed rectifier IKs • IKs is controlled by the gene KvLQT1 (voltage-dependent potassium controlling protein) and MinK (minimal potassium current controlling protein). MinK combined with protein of KvLQT1 induces IKs. Expression of both these proteins is necessary for normal function of I1 Ks. • MinK, a protein, acts as a function altering β subunit of KvLQT1. MinK modifies KvLQT1 gating and pharmacology. • Mutation in MinK and KvLQT1 causes congenital long QT syndrome (LQTS). • MinK suppression leads to inner ear abnormalities and deafness, seen in the Jarvell Lange-Nielson syndrome. • Reduced activity of IKs in M cells prolongs APD. • Bradycardia and class III drugs, which reduce IKs in M cells, prolong APD and predispose to arrhythmias. • Slow deactivation of IKs is important for rate dependent shortening of AP. As the heart rate increases, IKs has less time to deactivate during shortened diastole, it accumulates in an open state, and contributes to faster repolarization. • Increase in intracellular magnesium decreases and increase in intracellular calcium increases IKs. • Indapamide (Diuretic), Thiopental, Propafol (Anesthetics) Benzodiazepine, and chromanol block IKs. • Increasing cAMP either by β-adrenergic stimulation or by phosphodiesterase inhibitors increases IKs. • Activation of protein kinase C increases IKs. IKur current • It is responsible for atrial repolarization. It is a potassium selective outwardly rectifying current. Short APD of the atria is due to IKur. • IKur is also found in intercalated disks. • IKur is absent from the human ventricular myocardium. • It is enhanced by β-adrenergic agonists and is inhibited by α-adrenergic agonists. • Drugs inhibiting IKs (Amiodarone, Ambasilide) or IKur (Ambasilide) will be therapeutically superior. • The presence of IKur in the human atrium makes atrial repolarization relatively insensitive to agents that fail to inhibit this current (D-Sotalol and Flecainide). Quinidine and Ambasilide block IKur in a rate independent fashion. • IKur decreases with increasing heart rate.