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 emphasizes the presence of increased extravascular lung water (the lung 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 PKD1related 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.

fibrosis. • Calcium channel blockers are preferred in patients with bronchial asthma. • Shortening of the refractory period may persist after recovery from AF and predispose one to reoccurrences. • Digoxin is least effective in controlling the rate especially in physically active patients. • Shortening of the effective refractory period (ERP) and APD and an increase in dispersion of refractoriness perpetuates AF. • There was a non-significant trend toward higher total mortality in the rhythm control group. Other conditions. • AF with rapid ventricular response and aberrant ventricular conduction can result in a wide complex tachycardia which may be mistaken for ventricular tachycardia. Amiodarone could be used in this setting because it prolongs the refractory period of accessory pathway. • AFFIRM demonstrated no advantage to a rhythm control strategy for recurrent AF. can cause irregular pulse. • These findings support the recommendation that anticoagulation be continued in patients even if AF is successfully suppressed. • Factors affecting the conduction and refractoriness in the atrium such as inflammation. 3 Fibrosis. An ECG is necessary to confirm the diagnosis. the study’s primary endpoint. 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. which alters conduction velocity. persistent. AF can be classified into the following categories: 1 Paroxysmal AF: starts and stops spontaneously. which results in shortening of the atrial refractory period. and palpitation. PATHOPHYSIOLOGY AND CLASSIFICATION & Rate Control versus Rhythm Control Aspect of Mgt • Atrial fibrillation (AF) is the most common chronic rhythm disorder. AF occurs in 40% of the patients suffering from congestive heart failure (CHF). particularly if they are asymptomatic and elderly. such as sinus rhythm with frequent supraventricular or ventricular ectopic beats.0. • Irregular rhythm is consistent with but not diagnostic of AF. 3 Chronic AF: persists in spite of therapeutic intervention or based on a decision not to restore sinus rhythm. • Chemical and electrical cardioversion for maintenance of sinus rhythm is easier in AF of short duration. 2 Persistent AF: requires electrical or pharmacologic cardioversion to terminate an episode. dyspnea. and suggests a rate control strategy may be superior in patients above the age of 65. Shortening of the atrial refractory period occurs for the following reasons: • A rapid atrial rate induces atrial ischemia. There was no significant difference in the incidence of stroke (roughly 1% per year). 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. • These results do not apply to patients with symptomatic AF. RACE • The RACE (Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation). 1 A rate control strategy is an acceptable approach to management of patients with AF. • There is a decrease in sodium channel density and current. It is defined as AF occurring in patients less than 60 years of age who have no associated cardiovascular diseases. Extremely rapid ventricular response may appear regular. Rate Control • If the patient is hemodynamically unstable immediate cardioversion should be considered. • Rate adaptation of the refractory period is lost. but 83% of all thromboembolic events occurred in patients who had discontinued warfarin or had an INR <2. resulting in loss of myofibrils. . During chronic AF the following structural and electrical changes may occur: 1 Atrial dilatation. • Pre-specified subgroup analysis demonstrated a statistically significant mortality benefit with rate control for patients above the age of 65. affecting 5% of adults over age 65. • ANF may shorten the atrial refractory period. or multifocal atrial tachycardia. although most episodes of AF remain asymptomatic. • Lone AF can either be paroxysmal. Clinical presentation • Most common symptoms are fatigue. • 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. • Mortality in patients with AF is twice as high when compared with patients in sinus rhythm. • 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. Neurohumoral changes during AF: • Atrial natriuretic factor increases due to atrial stretch and dilation. • Increase in the intracellular calcium load shortens the refractory period. • Higher mortality in rhythm control group may be due to proarrhythmic effects of antiarrhythmic drugs rather than due to maintenance of sinus rhythm. • Elevated ANF decreases after cardioversion. 2 Apoptosis. • Tachycardia from AF can exacerbate angina or CHF. • Rate control can be achieved by AV node (AVN) blocking drugs. 2 Rhythm control should be reserved for patients with symptomatic AF. reduced exercise tolerance. or chronic. • The study demonstrated no significant advantage to a rhythm control strategy for the management of persistent AF. This strategy should also be considered in minimally symptomatic young patients with AF. • The aim should be to achieve a ventricular response between 80 and 100 bpm. • Atrial dilatation and stretch may result in a decrease in the refractory period.0. resulting in shortening of the refractory period. • In AF ICaL is reduced. Any benefits derived by rhythm control may have been neutralized by the proarrhythmic effects of the antiarrhythmic drugs. 4 There may be reduction in Connexion 43.ATRIAL FIBRILLATION MECHANISM. Ito and IKur are decreased in AF. • Patients enrolled in this study were minimally symptomatic. Conversion & maintenance of NSR becomes increasingly difficult with chronic AF. • Paroxysmal AF often progresses to chronic AF. the majority (73%) of ischemic strokes occurred in patients who had discontinued warfarin or had an INR < 2. • β-Blockers and/or calcium channel blockers are effective AVN blocking agents. • No significant difference in cardiovascular death or thromboembolic events was noted. and ischemia are conducive to initiation and maintenance of AF. The absence of P waves is characteristic of AF. Inhibitors of Na/H exchanger abolish ischemia-induced shortening of the refractory period. • AVN blocking agents should be avoided in the presence of ventricular preexcitation. • Human atrial repolarization uses IKur. This results in shortening of action potential duration (APD) and refractory period. sinus arrhythmia.

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. producing thermal latency even after termination of energy delivery. • 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. which is proportional to the power density within tissue. Healing by fibrosis is complete by eight weeks. • Maximum heating occurs at the tip of the electrode and it diminishes as the distance from the tip increases. or autonomic facilitators (parasympathetic ganglion). • Esophageal perforation following posteromedial left atrial or right superior pulmonary vein ablation may occur. Elimination of the triggers • It was noted that the AF is initiated by rapidly firing triggers located in pulmonary veins. • These foci arise from the myocardial muscular sleeve that extends few centimetres into the pulmonary veins. the orifice of the coronary sinus (CS). • When RF current passes through the tissue it produces heat. termed as vagally induced AF. • Initial approaches included identification of PACs with earliest activation and elimination of these foci within the pulmonary vein. This results in deeper and larger lesion. • RF energy delivery should be at least for 60 seconds. need for anticoagulation. • Like pulmonary veins. These electrophysiologic changes are conducive to initiation and maintenance of AF. RF ablation seeks to eliminate these abnormalities. Since the temperature is measured at the catheter tip it does not reflect actual tissue temperature. At higher frequency mode of heating changes from resistive to dielectric. • The rationale is that PACs (triggers) could arise from any of the four pulmonary veins. • Defibrillator with atrial therapy features is implanted in patients who are undergoing ICD implant and also have paroxysmal 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. left atrial appendage or interatrial septum. • The best results of this procedure (up to 85% success) have been achieved in patients with lone AF. • During ablation of the vagal neural terminals. • It may also produce compartmentalization and “debulking” of the LA. or up to 2–3 cm within the CS. Increase in the radius (distance) from the tip will decrease the heat by 4-fold. • The epicardial approach. posterior wall and extended to the mitral annulus. which may be very high. creation of the isthmus that may predispose to atrial tachycardia. Lower frequency may produce muscle stimulation. Modification of the autonomic substrate • The posterior wall of the LA is richly innervated by vagal (parasympathetic) fibers. • AVN ablation should rarely be performed in young patients with AF. Elimination of the substrate • Identification and elimination of the fractionated electrograms may result in termination of the AF during the procedure. • Commonly used RF is 300–1000 kHz. and pericardial tamponade. 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. muscular extension into proximal CS may produce rapidly firing automatic foci responsible for initiating AF. crater formation and may produce tissue pop. • Very high tissue temperature results in heat expansion of the tissue.AF . 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. • This procedure can be performed in conjunction with other cardiac surgery such as mitral valve replacement. • AF can be cured with catheter ablation techniques. using minimally invasive thoracotomy and microwave. • 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.2 This results in an increase in power density and heating at the catheter tip. • It may be necessary to tailor these three approaches when using ablation as the therapeutic modality in the management of AF. • The drawback of this approach includes reoccurrences. or junctional rhythm may occur. • Potential complications of this procedure include pulmonary vein stenosis. 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. A success rate of 80% has been reported. • AVN blocking agents may produce negative inotropic effects or bronchospasm in these patients. • Rise in temperature at deeper tissue level may continue if high power or temperature settings are used. Surgical Maze procedure • Incisions are made in the LA around the pulmonary veins. For example. Lower success rates (50–70%) have been reported in other subsets of AF patients. • RF generated heat produces coagulation necrosis of the myocytes. programming to eliminate PACs or abolish post-PAC pauses may decrease the burden of AF. This is a serious and often fatal complication.NONPHARMACOLOGIC OPTIONS OF MANAGEMENT Radiofrequency (RF) ablation • Arrhythmias are produced by abnormality of impulse generation or impulse propagation. • 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 orifices of the vena cava. It reduces the probability of the pulmonary vein stenosis. Electrical therapies for AF • In patients who have or need pacemaker for other indications. In the right atrium (RA) the fractionated electrograms could be recorded from the crista terminalis. • The surface area of catheter electrode is 12 mm2 and the surface area of the patch electrode is 100–250 cm. • Parasympathetic stimulation produces bradycardia and shortening of the atrial refractory period. Success rates are approximately 80–90%. • The drawback of AVN ablation and the pacemaker approach include persistence of AF. Deeper tissue heating is due to heat conduction. LA esophageal fistula. bradycardia. • The approach to AF ablation could be classified as elimination of the triggers. pacemaker dependence and ventricular dys-synchrony from RV pacing. located in the posterior wall of the LA. • Fractionated electrograms may be recorded from the LA around the pulmonary veins. • RF energy is delivered in a unipolar fashion from the catheter tip to the dispersive patch electrode placed on the skin. substrate. . stroke. • 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. • Vagally induced AF occurs during sleep and may be responsible for the atrial arrhythmias that occur during sleep apnea. It is an alternating current. Apossible risk of pulmonary vein stenois shifted the focus to ablation outside the orifice of the pulmonary vein in a quadrantic fashion. For this reason the depth and the volume of the tissue that is affected by heat is small (2 mm). attempts to isolate the pulmonary veins.

• Neuromuscular side effects may occur when given with amnioglycosides. 30% is excreted by the kidneys. • QRS duration should be monitored and it should not be allowed to exceed more than 20% of the baseline interval. • 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. M4 intestinal. VT. Disopyramide • It is metabolized by N-dealkylation to desisopropyldisopyramide. Prophylactic use of lidocaine in post-acute MI showed an increase in the death rate in the treated group. • It is a nonselective β blocker. • Use of β blockers and hypertonic sodium bicarbonate has been successful in the treatment of proarrhythmias. coombs positive HA. • 50% of the drug is excreted unchanged in urine. • Because of rapid distribution plasma levels fall in 8–10 min. • Its clearance is equal to hepatic blood flow. • The usual dosing is 100–150 mg every 6 hours or 200–300 mg every 12 hours of slow release preparation. • Side effects include nausea. and seizures. • It blocks the sodium and potassium channels. • Anticholinergic side effects include dry mouth. which is an active metabolite. • Lidocaine. Propafenone • High first pass metabolism results in low bioavailability. • It produces a significant negative inotropic effect. hyperkalemia. • Oral dose is 300–600 mg every 6 hours. and/or left ventricular dysfunction. and M3 exocrine gland muscarinic receptors. The dose should be reduced in the presence of hepatic and renal insufficiency. confusion. Lupus syndrome occurs in 30%. It is metabolized in the liver to 5-hydroxypropafenone. It may produce prominent U waves. however. It produces greater depression of upstroke velocity in ischemic tissue. Three added boluses of half of the amount of the initial dose can be given every 10 min. This may result in asystole in the presence of complete AV block. In ischemic ventricular muscle cells lidocaine depresses excitability and conduction velocity. dizziness. Because of use dependent block proarrhythmias may occur during exertion. Its use is not recommended in CHF. tinnitus. • It may cause cholestatic jaundice and agranulocytosis. It binds to activated and inactivated state of the sodium channel. An exercise test is recommended after achieving a steady state. It prolongs the atrial refractory period. • Vagolytic effect may enhance atrio-ventricular node (AVN) conduction and may increase ventricular response in atrial fibrillation (AF)/Atrial Flutter. Class 1B Lidocaine • Lidocaine blocks INa by shifting voltage for inactivation to more negative. which may result in correction of long QT interval. In renal failure the propafenone level remains unchanged. and ventricular arrhythmias. blurred vision. This results in suppression of automaticity. Class 1C Flecainide • It is a fluorinated analogue of procainamide. and CHF. • The bolus and the infusion dose should be reduced in the presence of CHF and liver disease. 20% is excreted unchanged in the urine. It also blocks IK and slow inward calcium currents. • The time to recovery from the block is 700 milliseconds to 15 seconds. • Prolongation of QRS duration is directly related to the plasma level of quinidine while QT interval is not. nausea. It is not very effective in controlling ventricular arrhythmias. • In acute MI lidocaine reduces ventricular tachycardia (VT) ventricular fibrillation (VF) but does not alter mortality. respectively. • NAPA is an active metabolite. Renal dysfunction does not affect dosing. • It is metabolized in the liver to glycinexylidide and monoethylglycinxylidide. • QRS duration monitoring and exercise test is recommended. • 5-hydroxy and N-dealkyl propafenone also blocks INa. • It may cause TDP. • It crosses the placenta and is excreted in breast milk. exacerbation of asthma. which are less active than the parent compound. • The bolus dose is 1. • Half life of rapid distribution is 8–10 min after IV bolus. • It has a negative inotropic effect. diplopia. 5-hydroxy compound is as potent as the parent drug. • Its antiarrhythmic effects are the result of sodium channel blocked in its inactivated state. 90% is excreted by the kidney. This effect is enhanced in slow metabolizers. The time constant for recovery from the block is 21 seconds. • It is a potent sodium channel blocker. • Alpha blocking effect may cause orthostatic hypotension. which is elevated in cute MI and CHF. which may respond to sodium lactate or sodium bicarbonate infusion. It may also suppress digitalisinduced arrhythmias. ICa and Ito. Dose adjustment may be necessary in hepatic and renal failure. • It is effective in the treatment of atrial arrhythmias. Procainamide therapeutic level is 4–12μg/ml and for NAPA it is 9–20μg/ml. headache. 5hydroxypropafenone levels double. • In CHF because of a decrease in the volume of distribution and clearance the EHL remains unchanged.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 useful in the treatment of AF in the presence of WPW syndrome.5 mg/kg. • It also blocks IK1 (inward rectifier). • Continuous activation of INa may cause an increase in action potential duration (APD) (LQT3). However. loss of hearing. and Flecainide exert use dependent block with fast intermediate and slow kinetics. • It prolongs the QT interval and may cause TDP. • It causes use dependent block of INa. • It is 50% effective in controlling AF. • It is an effective Na channel blocker in a use dependent manner. Hypoglycemia may occur due to enhanced insulin secretion. steady state sodium current. Blood pressure may decrease. • It does not alter hemodynamics. and acidosis. • It binds to AAG. It may be useful in patients with diastolic dysfunction and arrhythmias. blurred vision. and abnormal liver function test. • Propafenone and its metabolites are excreted in milk. Hypokalemia facilitates quinidine-induced early after depolarization (EAD) and arrhythmias. Its active metabolite is 3-hydroxy-quinidine. IK1. Dose reduction is warranted in hepatic and renal failure. Oral dose is 3–6 gm/day. It produces use dependent block of the Na channel during the activated state. Both are removed by hemodialysis. Sodium lactate can be used to reverse arrhythmogenic effects. and thrombocytopenia. • It is useful in controlling paroxysmal AF. The arrhythmias are treated by IV infusion of Mg & pacing. NAPA has a half life of 6 hours. • 7% of the Caucasians are poor metabolizers. • Pharmacologic effects are similar to quinidine. A decrease in the blood flow due to propranolol or CHF will result in decreased clearance. • The initial dose is 150–300mg every 8 hours. Antinuclear antibodies may develop in 80% of the patients in the first 6 months of therapy. TCP. • It is metabolized in the liver through oxidation by the cytochrome P450 system. It has been effectively used in the treatment of neurocardiogenic syncope and hypertrophic cardiomyopathy. Other side effects include haemolytic anemia. slurred speech. EHL is 1–2 hrs. • It suppresses normal and abnormal automaticity in Purkinje fibers. . and IKach. constipation. This protein binding results in a decreased level of free unbound drug. • Proarrhythmias include TDP. • It has a negative inotropic effect. Hepatic dysfunction decreases clearance. • The usual oral dose is 150–200 mg every 8 hours. dysarthria. • Quinidine blocks alpha 1 and alpha 2 adrenergic receptors. QRS widening. metallic taste. This current is blocked by Lidocaine and Mexiletine. • Proarrhythmias occur in 5% of the patients. Slow acetylators are more likely to develop lupus. and urinary retention. It is metabolized in the liver to meta-Odealkylated-flecainide. ataxia. • Side effects include diarrhea. They have high levels of propafenone and low levels of 5-hydroxypropafenone. IKatp. It is eliminated by the liver utilizing the P450 system. It causes use dependent block. Procainamide • 60% is excreted by the kidney. which is due to prolongation of the QT interval. Antibodies to DNA do not occur commonly. • Flecainide-induced proarrhythmias occur in patients with ischemic heart disease. It does not cause -ve inotropy. Mexiletine • It is an oral congener of lidocaine. • Central nervous system (CNS) side effects include perioral numbness. Continuous IV infusion rate is 1–4 mg/min. blurred vision. • It is a weak IK and ICa channel blocker. • IV bolus administration should not exceed 50 mg/min and infusion rate of 1–6 mg/min. It blocks conduction in accessory pathways. It passes through the placenta and is excreted in breast milk. which is electrophysiologically active. • It crosses the placenta. • Its anticholinergic effects are due to block of M2 cardiac. It demonstrates slow binding unbinding. IK (delayed rectifier). Its vagolytic effect is produced by M2 receptor blocked. ataxia. The plasma level does not predict the occurrence of arrhythmia. thus affecting depolarization and repolarization. It may cause atrial flutter. Quinidine. Protein binding is weak. ICa. It crosses the placenta and is excreted in breast milk. • Plasma half life is 4–8 hours. • Its side effects include blurred vision. Side effects include tremor. It does not cause proarrhythmias. May also block IK. • N-dealkylation produces a weak metabolite N-dealkyl propafenone. • EAD and delayed after depolarization (DAD) are also suppressed. A single dose of 300mg can be used for converting recent onset AF. A single dose of 600mg can be used in patients with PAF. It binds to AAG. paresthesias. • The initial dose is 100mg every 12 hours and it could be increased to 200mg every 12 hours. • It may cause hypotension when given IV. Ito. 40% by the liver.

The choice of anticoagulant is also determined by the patient's underlying risk for bleeding. will be reviewed here.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. 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. range 2.0 to 3. As these drugs are used in conjunction with fibrinolytic therapy. The bivalirudin regimen is associated with a lower rate of bleeding. Fondaparinux is not recommend for use in patients undergoing primary PCI. irrespective of age. low molecular weight (LMW) heparin. fibrinolytic agents lead to thrombin generation directly or indirectly through the activation by plasmin of prothrombin and factors V and X. The duration of anticoagulant therapy depends on the initial management strategy. thrombolytic therapy with either fibrin specific or non-fibrin specific agents. activation. and sustained restoration of infarct vessel patency. The choice of agent depends upon the overall treatment strategy designed for each patient: primary PCI. intravenous heparin or bivalirudin should be given during the procedure to prevent catheter related thrombosis. this change in formulation will not likely affect practice. we recommend initiation of intravenous therapy with either UFH (plus planned GP IIb/IIIa inhibitor) or bivalirudin (and provisional GP IIb/IIIa inhibitor). However. such as patients with prosthetic heart valves. .5 mg subcutaneously once daily. The use of parenteral anticoagulants to maintain infarct vessel patency early in the treatment of patients with STEMI.5. in addition to antiplatelet therapy. Choice of anticoagulant. and activation of factor XIII. anticoagulant therapy is stopped at the end of the procedure in uncomplicated cases. Fondaparinux: — When used in patients with STEMI.For patients receiving fibrinolysis and <75 years and whose serum creatinine is <2. Thrombin is a central mediator of clot formation through its activation of platelets. Our recommendations are largely consistent with the 2004 ACC/AHA guidelines on the management of acute ST elevation MI and its 2007 focused update. For those patients who are managed with only activated PTTs (aPTT).In STEMI patients not treated with reperfusion therapy. 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. the management strategy should be determined at the local institution. as soon as possible after presentation (Grade1A). 3. In addition. heparin will be manufactured in the United States according to a new standard and concerns about potency have arisen. Dosing. Although the optimal treatment length has not been determined for these. as soon as possible after presentation (Grade 1A). 4. For patients with STEMI referred for primary PCI. bleeding complications are common and may be life-threatening. For patients undergoing PCI. . For patients who are managed early in their course with activated clotting times (ACT).5 to 2 times control). Formation of an occlusive thrombus at the site of plaque rupture in a coronary artery is central to the pathogenesis of STEMI. we use no loading dose and administer 1 mg/kg every 12 hours. anticoagulant therapy is continued until hospital discharge. .0). and refractory myocardial ischemia after STEMI. The dosing schedules depend upon the clinical situation: 1. Thrombin molecules are bound to fibrin within the evolving mural coronary thrombus. For those patients in whom PCI is possible or likely after thrombolytic therapy. Bivalirudin: — Initial bolus of 0. aggressive antiplatelet therapy with multiple agents. history of systemic or pulmonary embolus. in addition to antiplatelet therapy. or echocardiographic evidence of mitral or left ventricular thrombus) or a preexistent rational for long term anticoagulation. we recommend initiation of anticoagulant therapy with enoxaparin. bivalirudin and fondaparinux caused less major bleeding than either enoxaparin or heparin. Bivalirudin was associated with a higher rate of major bleeding after streptokinase compared to UFH. In patients with a creatinine clearance <30 mL/min using the Cockroft-Gault formula. In these situations. including the supporting evidence. or fondaparinux. we suggest an intravenous bolus of 50 to 70 units/kg (target activated clotting time > 200 seconds).75 mg/kg subcutaneously every 12 hours (maximum of 75 mg for the first two doses). Rupture of an atheromatous plaque begins the following cascade. The evidence to support anticoagulant therapy in most cases of STEMI is strong. or no reperfusion. Enoxaparin: .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.In STEMI patients undergoing reperfusion with thrombolytic therapy. and fondaparinux (factor Xa inhibitor) has been evaluated for its ability to improve outcomes of death. 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. . and often in the setting of an invasive strategy. 2. There are insufficient data to make a recommendation for or against its use after fibrinolytic agents such as alteplase. we recommend initiation of anticoagulant therapy with enoxaparin. we consider UFH a reasonable alternative. and chronic oral anticoagulation in this setting are discussed separately. conversion of fibrinogen to fibrin. the following represent commonly employed regimens in clinical practice: For patients undergoing PCI. Effective in early October 2009. These guidelines recommend anticoagulant therapy in most patients with STEMI. we suggest an intravenous bolus of 60 to 100 units/kg (target activated clotting time 250 to 350 s). . There is no rationale for subcutaneous LMW heparin at the time of primary PCI. subcutaneous LMWH. who are at average or low risk of bleeding. the role of antiplatelet agents in STEMI.5 mg/dL [220 micromol/L] in men and < 2.75 mg/kg per h that discontinued after PCI. Duration of therapy. the evidence to recommend one agent over another is less robust. 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). For those patients not receiving a glycoprotein IIb/IIIa inhibitor. atrial fibrillation. Its use should be limited to patients who have received fibrinolytic therapy and have a history of heparin induced thrombocytopenia.Anticoagulant Therapy in Acute STEMI Introduction. 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. complete. the first dose is given intravenously (2.0 mg/dL [175 micromol/L] in women . Anticoagulant therapy with unfractionated heparin (UFH).For patients who are not reperfused. severe left ventricular dysfunction. Experimental animal models reveal that concurrent thrombin inhibition enhances coronary fibrinolysis and limits reocclusion. in addition to oral antiplatelet therapy. as well as with the 2008 American College of Chest Physicians guideline on acute ST-segment elevation MI. which were both were published before the results of the HORIZONS AMI trial of bivalirudin became available.For patients undergoing primary PCI who are receiving a glycoprotein IIb/IIIa inhibitor. who have previously been treated with fondaparinux.5 mg) and then followed by 2. becoming exposed during endogenous or exogenous fibrinolysis. the intravenous regimen may be continued or consideration given to subcutaneous administration of UFH (7500 units every 12 hours to maintain aPTT at 1. An overview of the total therapeutic approach to STEMI. UFH. and conversion to oral warfarin (target INR 2. For patients receiving fibrinolytic therapy or no reperfusion therapy. we suggest fondaparinux (Grade 2A). fondaparinux or UFH. recurrent myocardial infarction. UFH: . In multiple trials. It should be avoided in patients with estimated creatinine clearance less than 30 ml/min. heart failure. we suggest enoxaparin as opposed to UFH or fondaparinux (Grade 2A). we suggest 1 mg/kg every 24 hours without a loading dose. There is evidence of high risk for systemic or venous thromboembolism (anterior STEMI. .75 mg/kg followed by an intravenous infusion of 1. as soon as possible after presentation (Grade 1B). Background. For patients at high risk of a bleeding complication. in patients ≥ 75 years we use no loading dose and 0. This issue is discussed in detail separately. We recommend anticoagulant therapy in all patients with STEMI. direct thrombin inhibitors. For all patients with STEMI not treated with primary PCI. which culminates in thrombus formation: -Exposure of thrombogenic lipids and subendothelial components -Platelet adhesion. 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. leading to fibrin cross-linking and clot stabilization.

rate. the patients are asked to point to these places in a specific sequence. questions. fold it in two. and in patients with Wernicke's aphasia. Speech inflection and prosodic matching of sentence structure are mediated by the left hemisphere. Language The six main parts of the language examination can be performed at the patient's bedside. or breathiness. (2) commands—a series of single or multistep commands. may sound empty and devoid of content. Examination of Speech and Language Directed Neurological Examination Nonfluent aphasic output is associated with pathology involving the anterior left hemisphere. declarative. when severe. 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. produced with considerable effort. Reduced volume (hypophonia) is seen in extrapyramidal motor disorders and in peripheral disorders such as vocal cord paresis. Comprehension of Spoken Language Comprehension can be assessed in many ways. In some cases. . comprehension remains difficult to assess.g. The examiner can classify most aphasic syndromes after evaluating spontaneous speech. Each component of speech can be affected differently in various disorders. colors. nonfluent aphasics speak slowly. Normal English output is 100 to 150 words per minute.. poorly articulated. the door. They are seen most often in patients with upper motor neuron lesions and spastic speech. and fluent aphasia results from pathology posterior to the fissure of Rolando. of short phrase length (often only a single word). it occurs with lesions of the angular gyrus. assessment of affective intent.”). articulation. leading to an overestimation of the deficits. Nonfluent aphasic output is sparse (<50 words per minute). syntax. whereas affective intent is mediated by right hemisphere and basal ganglia functions. posterior inferior temporal cortex. fluent aphasic output features many words and is easily produced. Naming is disturbed in most aphasic patients. The rate of speech may be increased in Parkinson's disease. in which patients speak rapidly. often mandatory tendency to repeat (echolalia) suggests an extrasylvian locus of pathology. Apraxia and other motor disorders may cause a failure to perform. body parts. visuospatial layout. who have pressured speech. are two other qualities of speech that aid in localization. and assessment of pragmatic intent (humor. it features a preferential use of substantive meaningful words with a relative absence of functor words (prepositions. in which substituted letters occur in a variable pattern. words. and gutturals (sounds depending on laryngeal control). tone of voice and facial or arm gesture) and may lead the clinician to underestimate the comprehension deficit. and temporal pole on the left but may occur in concert with other lesions. This helps distinguish dysarthric speech from paraphasic speech. repetition. sarcastic. 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 ___. Dysarthric speech often results in stereotyped speech errors—that is. articles.Speech The examination of speech includes the assessment of speech volume.. and more difficult tasks can also be given [e. adverbs). or nasality. Are the lights on in this room?). or buts” poses special difficulty.. and geometrical figures. the two abilities are dissociated. In contrast. and (6) writing. (4) naming. 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. and (4) pointing—requires a limited motor response (patients can be asked to point to the window. and resonance. A phrase such as “no ifs. prosody.g. and defensive). Repetition The examiner tests repetition by requesting that the patient repeat digits. Prosody evaluation includes assessment of the spontaneous inflection. Articulation defect is a sign of motor impairment. linguals (sounds dependent on the tongue). and the ceiling. Timing of speech initiation is related to supplementary motor area function and its outflow. Writing provides a further sample of expressive language and permits evaluation of spelling. In addition. Testing should evaluate the patient's ability to name objects (both high and low frequency). These parts are (1) expressive speech. Speech volume may be increased with auditory perceptual problems. describe your job). Aphasics with impaired repetition have pathology that involves the perisylvian region. In contrast. and initiation. and mechanics. (2) comprehension of spoken language. Naming Disturbances in confrontational naming are the least specific language abnormalities. (3) repetition.g. with normal phrase length and prosodic quality but often omitting semantically significant words. point to the source of illumination in this room]). The examiner assesses writing to dictation and to command (e. dentals (sounds requiring placing the tongue behind the front teeth). Aphasic verbal output is either nonfluent or fluent. Anomia is generally not a reliable localizing abnormality. and comprehension. repeating the same errors when trying to produce certain sounds. and dysprosodic (abnormal rhythm). The examiner should assess speech through spontaneous conversation or by having the patient read a standardized passage to elicit a wide range of sounds. Despite all of these methods. and sentences. Comprehension is compromised by dysfunction of the heteromodal association cortex or Wernicke's area of the left hemisphere. prosodic matching of sentence structure (declarative sentence. including labials (sounds dependent on the lips). Perseverative answers may further complicate comprehension assessment. and boundaries between clauses). In general. Writing Writing is nearly always disturbed in aphasic patients. often involving the vascular borderzone areas. Also. Patients may derive significant meaning from nonverbal cues (e. (5) reading. paraphasic errors (substitution of phrases or words) are often abundant in fluent aphasic output.. Expressive Speech The evaluation of aphasia traditionally begins by observing the spontaneous or conversational speech of the patient. as well as copying. Laryngeal phonation. a strong. Fluent aphasia.g. Reading The examination tests both reading aloud and reading for comprehension. ands. If the patient fails. such as asking the patient to pick up a piece of paper.

Coronary sinus atrial flutter The circuit travels from the coronary sinus to the lateral left atrium down the interatrial septum & back to the cs. 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. pericardial disease. amiodarone). 56% of patients presenting with typical AFL develop AF. AV nodal blockers (e. Fractionated or double potentials can be recorded at the CTI just outside the coronary sinus ostium & the circuit can be entrained. 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. A zone of slowed conduction is required for both initiation & perpetuation. Upper loop re-entry Upper loop re-entry circuits are due to functional obstacles rather than anatomic obstacles. Left septal atrial flutter The circuit rotates in either a CW or CCW manner around the left septum primum. 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. or electrically silent areas serve as a substrate for left atrial flutter. an organized macroreentrant arrhythmia. congestive heart failure. pulmonary embolus. & the subsequent release of atrial natriuretic factor (ANF). The circuit is bound medial CTI & the coronary sinus ostium the lateral CTI is not involved. This band of tissue is able to conduct rapidly in the longitudinal direction but very slowly in the transverse direction. after major cardiac surgery. 2. Patients tend to be more symptomatic when the ventricular response rate is rapid and/or when they present with episodes of both AF & AFL. 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. Of these. aVF. The ventricular rate is generally a 2:1 ratio. cannon ‘a’ waves may be observed. This remarkable difference in conduction is due to the non-homogeneous distribution of gap junctions. DIAGNOSIS OF AFL Generally.ATRIAL FLUTTER There are 200 000 new cases of atrial flutter (AFL) in the United States each year. Intra-isthmus re-entry The intra-isthmus re-entry AFL circuit is localized to the CTI. 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. Initiation of the tachycardia circuit requires unidirectional block in one limb of the circuit. 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. In ‘typical’ flutter the saw-tooth waves are negative in the inferior leads & positive 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.g. 88. Areas that have low voltage provide an anatomic obstacle for macro-re-entry. Atrial fibrillation (AF) has a 10 times greater prevalence than AFL. The atria usually contract at a rate of 250–350 beats per minute (bpm) while in AFL. In order for reentry to initiate. & orifices of the superior vena cava (SVC). & the coronary sinus (cs). Conditions Associated with AFL include thyrotoxicosis. patients often complain of shortness of breath. & posteriorly bound by the vena cava orifices. TOOLS FOR DIAGNOSING ATRIAL FLUTTER A multi-polar reference catheter that covers the septal & anterior walls allows recording of almost the entire circuit. & weakness. which occurs as a result of increased atrial pressure from rapidly contracting atria against a closed AV valve. not as profoundly as when it is coupled with AF. (ii) a rapid negative deflection. The openings of the IVC & the SVC linked by the CT constitute the posterior obstacle. thus providing the first stepping stones which would later give insight into how to successfully ablate atrial flutters. Eustachian ridge. & perpetuate certain criteria must be present: 1. male gender. The conduction ratio is 10:1. It has been reported that over a year’s follow-up. 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. .000 present solely as AFL. Vagal maneuvers (Valsalva or gentle carotid sinus message) can also assist in slowing the heart rate down enough to distinguish flutter waves. 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 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. possible genetic predisposition. AFL can coexist with AF in 25% of patients with AF. chest discomfort. pulmonary veins. cardiac tumors & sodium channel blocking agents to treat AF (5%).On physical examination. alcohol intoxication. This wavefront perpetuates in a circular CCW direction until it is interrupted. CLINICAL PRESENTATION AFL. The acceleration of the tachycardia is due to two successive activation fronts traveling in the same direction in the re-entrant circuit. The number of AFL cases rises exponentially in relationship to advancing age. Atrial flutters circus around an unexcitable anatomic or functional barrier. Recently. Surgical repair of congenital heart defects may cause a right atrial scar. AFL is associated with an increased risk of morbidity. ECG findings of CCW left atrial circuits include low amplitude flutter waves & positive waves in leads V1 & V2. chronic pulmonary disease. However. prior CVA & myocardial infarction. palpitations. inferior vena cava (IVC). & V1. & S1 is of variable intensity. Scar & pulmonary vein related atrial flutter This circuit rotates around one or more of the pulmonary veins or scar in the posterior wall. Clockwise (CW) atrial flutter This represents 10% of clinical AFL cases. Left atrial flutter Left atrial flutter occurs less frequently than right atrial CTI-dependent tachycardias & often co-exists with AF. AFL may also present more subtly in the form of exercise-induced fatigue. One case has been reported in a patient with no structural abnormality. 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. mitral ring. Spach12 suggested that the right atrium is able to support re-entry due to anisotropic conduction. This is especially true if there are multiple circuits as in those cases of scardependent macro-re-entry. the tricuspid orifice (TR) constitutes the anterior obstacle. around the roof down the free lateral wall & bounded anteriorly by the tricuspid orifice. however. it can also present as sustained & persistent. ECG findings include dominant positive waves in V1. block. In 1980. or pulmonary disease. Re-entrant circuits include normal anatomic boundaries such as the tricuspid ring. Patients may also complain of polyuria. Functional barriers are created due to an inability to conduct action potentials as rapidly as that seen in AFL. Acutely. resulting in a unidirectional antidromic block of the paced impulse & acceleration of the CCW–AFL. The wavefront was demonstrated to circulate in a clockwise direction up the septum. Flutter waves resemble the edge of a wood saw. NOMENCLATURE In the past. that (iv) with a slight overshoot leads to the slowly descending segment of the next cycle. will provide information on the remaining circuit. The crista terminalis (CT) is a thick bundle of myocardial fibers that run in a superior/inferior direction. the peripheral pulse is generally rapidand regular (less often irregular). It is hypothesized that atrial conduction slowing is secondary to either atrial dilated cardiomyopathy or anti-arrhythmics (sotalol. hence the name ‘saw-tooth’ wave. it is routine to test local return cycles after a couple of pacing runs to verify isthmus involvement. dizziness. Anatomically. recorded with a mapping/ablation catheter. RE-ENTRANT MECHANISM OF AFL In a primary sense. hypertrophic cardiomyopathy. short episodes ranging from seconds to hours. & in regions of low conduction within the scar located in the free right atrial wall can all create & support reentrant circuits. often presents as paroxysmal. The negative waves can be described in succession: (i) a slowly descending segment. worsening heart failure. there has been some confusion about how to describe the different types of AFL. The circuit rotates around the mitral annulus in either a CW or CCW direction. Maintenance of the conduction gap is vital for the perpetuationof the circuit. However.13 ECG findings include negative sawtooth waves in the inferior leads & positive waves in V1 that transition tonegative in V6. Right atrial cavotriscuspid-isthmus-dependent flutter Counterclockwise (CCW) atrial flutter This represents 90% of clinical AFL cases. The CW–AFL circuit has the same anatomic boundaries as CCW–AFL. The circuit can travel in either a clockwise or counterclockwise direction. extending from the roof of the right atrium adjacent to the SVC opening laterally & inferiorly to the IVC. 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. Scar tissue located within the posteriolateral & inferiolateral right atrium. Areas of slowed conductance. valvular heart disease. DWR flutter is not sustained. An electrogram of the IVC–TR isthmus. 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. III. this creates a ring that is able to support re-entry in either a clockwise or counterclockwise direction. Right atrial non-cavotricuspid-isthmus-dependent flutter Scar-related atrial flutter Macro-re-entrant circuits can occur at sites other than the CTI. congenital cardiac disease. after open heart surgery. The longitudinal spindle-shaped cells have ten times as many gap junctions in an end-toend direction for conduction compared to the transverse ones in a side-to-side direction. the diagnosis of AFL can be made on a 12-lead surface ECG by identifying flutter waves in leads II. ECG findings include positive saw-tooth waves in the inferior leads & negative waves in V1. re-entry occurs as a repetitive excitation of an area of the heart & transmission of that impulse around a conduction or functional barrier. 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. Rosenbleuth further demonstrated that the circulating wavefront could be extinguished by creating a lesion between the IVC & the inferior edge of the tricuspid orifice. diaphoresis. When a characteristic ECG pattern is identified & the endocardial activation map is ‘circular’ a diagnosis can be made without pacing studies. When it is difficult to distinguish flutter waves. Left atrial flutters arise in structurally damaged left atria. adenosine or diltiazem) remove QRS complexes. This wavefront propagates in a circular CW direction until it is interrupted. RISK FACTORS Independent Risk Factors include advanced age. Scheinman & his colleagues have provided a classification system based on the location & mechanism of AFL. the circuit is anteriorly bound by the tricuspid orifice. propagate. Termination of DWR AFL results in complex atrial arrhythmias which include AF. (iii) a sharp upstroke. resulting in regions of low voltage. This property allows for a functional barrier. & the coronary sinus (CS).

and sympathetic activity decreases in the course of the tilting phase. Example: A patient suffering from diabetic autonomic neuropathy showing a very low power spectral density.Expiration 79bpm – 59 bpm -. Therefore the test should always be performed in combination with a beat-tobeat blood pressure measurement. 30:15 ratio = 898/712 = 1. 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.1. Abnormal values are below 1.1. During tilt testing only little modulation of the spectral components can be seen. The physiologic value ranges over 1.2. 12 bpm and more for 51-60. 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. 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. And heart rate increases with cessation of expiration. please open the Data View “Beat-to-Beat”. due to rounding ups the values from the Graphic View may vary marginally.AUTONOMIC FUNCTION TESTS In order to evaluate the reaction of the autonomic reflex system. The change in heart rate within the first 30 seconds after standing up permits an evaluation of the cardiovagal system. please open the Data View “Beat-to-Beat” after the measurement is complete. the combination of heart rate and blood pressure variability increases the specificity of the assessment of sympathetic functions and sympatho-vagal balance. Valsalva Maneuver The patient forcibly exhales for 15 seconds against a fixed resistance (40 mmHg). Analysis from Graphic View (Tool-tip Function) After having completed the measurement or after having reloaded the file (if it is an earlier measurement). Furthermore. this method does not require active participation of the patient. The E/I difference should be >15 beats per minute. The blood pressure changes are accompanied by an increase in heart rate. By means of the power spectral analysis malfunctions of the cardiovascular autonomic function can be detected earlier than by traditional functional tests. E/I-Difference The E/I difference results from the difference of the RR intervals during expiration minus the RR intervals during inspiration. Blood pressure overshoot causes a decrease in heart rate due to baroreflexes. 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”. This so-called POWER SPECTRAL ANALYSIS allows the evaluation of parasympathetic and sympathetic dysfunctions.bpm .04. The relation between the longest RR . values below 1. 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. Analysis In order to analyse the test performed with the Task Force Monitor. Total sum of difference/6 = ---. values below 10 beats per minute are regarded as abnormal.26 For a patient of any age range. Tests for the evaluation of the parasympathetic nervous system are combined with tests for the evaluation of the sympathetic nervous system. In patients with autonomic neuropathy such as those with diabetes. Furthermore. See table for normal values. 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.bpm Difference = 20 = -- 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. Breath 1 2-6 Inspiration . 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. 16 bpm and more for 41-50.21. whereas a response of <10 mmHg is considered abnormal. please open the graphic view “short trend” means of the tool-tip function (keep right mouse click pressed). this would fall into the normal values. In a healthy subject this quotient should be higher than 1.0 are considered abnormal. TIP: The analysis from the Data View is to be preferred. 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. In weak and elderly patients the sustained hand-grip test can be replaced by the cold pressor test (ice water test). abnormal values are under 1. 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. Example Start Beat 15th heart beat (= 783 + 10 beats) 30th heart beat (= 798 + 10 beats) 768 773-793 788-808 From these ranges select the required values for calculating the 30:15 ratio. There is a fall in cardiac output due to impaired venous return. a combination of various tests in the form of a test battery is often used. PHASE 4: Blood pressure increases above baseline values ( overshoot) because of delayed vasoconstriction and restored normal cardiac output. 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.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. PHASE 3: Blood pressure falls for 1-2 seconds. Attention: in patients with isolated sympathetic vasomotoric lesion with intact cardiovagal function the bradycardia is limited after 20-30 seconds. In a healthy subject the 30:15 ratio should be higher than 1. After having completed the measurement or after having reloaded the file (if it is an earlier measurement).-. Normal values are 18 bpm and more for 10-40. Both analyses are specified by means of the following examples. the blood pressure regulation through baroreceptors and/or autonomic nervous system is disturbed. 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. 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. PHASE 2: Early fall in blood pressure with a subsequent recovery of blood pressure later in this phase. 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. the resulting fallin blood pressure causes via the baroreflexes compensatory cardiac acceleration and increased peripheral resistance. 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. PHASE 1: Transient rise in blood pressure and a reflex fall in heart rate due to compression of the aorta. The normal response is a rise of diastolic blood pressure >16 mmHg. 8 bpm and more for 61-70.

contraction. • It is implicated in cell growth.CALCIUM CHANNELS AND CURRENTS • The process of channel opening and closing is called gating. It is called calcium-induced calcium release (CICR). It produces inward current that contributes to depolarization in SAN and AVN. and hydrogen channels. III Sarcoplasmic reticulum (SR) Ca release channel. Mexiletine. produced by L-type Ca channel. • There are four types of calcium channels: I L-type expressed on surface membrane. Propafenone. Calcium and sodium channels open in response to depolarization and enter the nonconducting state during repolarization. IV Inositol triphosphate (IP3) receptor channels are present on internal membrane. • Calcium release from SR is triggered by increase in intracellular calcium. • This results in increased contractility. • Elevated intracellular Na may activate reverse Na/Ca exchange. ii It rapidly inactivates (Transient T). • Calcium channel dependent inward current is responsible for EAD. • T-type Ca channel density is increased in the presence of the growth hormone. • Alpha 1 subunit of the Ca channel contains the binding site for calcium channel blocking drugs. • Failing myocytes also demonstrate increase density of T-type Ca channels. • It is found in high density in SAN and AVN. It is blocked by TTX. This causes CICR from SR. increases the flux of calcium into cytoplasm. • Caffeine releases calcium from SR. thus increasing the Camp level. iii It demonstrates slow deactivation. • These channels mediate the influx of calcium from SR into cytosol. • Verapamil blocks Ca current and decreases calcium activated chloride current. Parasympathetic stimulation • It decreases L-type calcium activity through muscarinic and cholinergic receptors. Sodium and calcium exchange • Opening of voltage operated calcium channel. Reverse mode will increase intracellular calcium. and Azimilide suppress L-type calcium current. Mibefradil • T-type Ca channel is up regulated by norepinephrine. Effect of antiarrhythmic drugs on calcium channel • Most Na and K channel blocking drugs also affect Ca channels. • Magnesium and ATP potentiates channel flux. and pressure overload. 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. Flunarizine. • Amiodarone blocks both L and T-type Ca currents. • Lowering of pH blocks sodium/calcium exchange. • Open channels are active. Cadmium. • Quinidine. T-type calcium channel • These are found in cardiac and vascular smooth muscles. • Sympathetic stimulation may also activate alpha1 receptors. • In ischemia decreased intracellular ATP decreases calcium release and causes ischemic contractile failure. iv Has low conductance (tiny T). SR controls the cytoplasmic Ca level by release or uptake during systole and diastole. • It may contribute to cardiac arrhythmias. • β-Blockers have no direct effect on calcium channel. • Sotalol has no effect on Ca channel. • Stimulation of myocytes angiotensin II receptor by angiotensin increases intracellular IP3. Inositol triphosphate receptors (IP3) • These receptors are found in smooth muscles and in specialized conduction tissue. • During diastole calcium is removed from the cell by sodium/calcium exchange located in the cell membrane. Tetrodotoxin (TTX) sensitive calcium channel • It produces inward current. Verapamil. i It opens at more negative potential. II T-type expressed on surface membrane. Flecainide. sodium. • In AF decrease activity of the ICaL channel shortens APD and perpetuates arrhythmia (electrical remodeling). • Stimulation of receptors activates guanosine triphosphate binding protein Gs. which makes MDP more negative and decreases the slope of diastolic depolarization. heart rate. • Verapamil has no effect on sarcoplasmic Ca release channel (SCRC). • The arrhythmogenic effect of angiotensin II in CHF may be due to elevated IP3. during the plateau phase of APD. a gating process known as inactivation. • SR calcium ATPases. through G protein. . Diphenylhydantoin. which may cause DAD. Moricizine. which may trigger SR calcium release. • 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. • Doxorubicin decreases cardiac contractility by depleting SR calcium. 3. • During calcium removal inwardly directed current is observed. • SR also has potassium. Regulation of pacemaker and Ca currents β-Adrenergic receptor stimulation • It increases L-type calcium channel activity. Sarcoplasmic calcium release channels (also called Ryanodine receptors) • These are intracellular channels that are regulated by calcium. • Acetylcholine. This inhibition results in an increase in intracellular Na. • These receptors have been implicated in apoptosis. and coupling. • It is responsible for excitation in sino atrial node (SAN) and atrioventricular node (AVN). • These are up regulated by angiotensin II and α-adrenergic stimulation. • It provides calcium for cardiac contraction. This results in slowing of the heart rate. • Drugs and compounds that block T-type Ca channels include the following: Amiloride. respectively. • Increased calcium current prolongs depolarization and increases the height of the AP plateau. • It does not contribute to AP upstroke which is dominated by sodium channel. including coronary arteries. which in turn leads to an increase in intracellular Ca through Na/Ca exchange. activates inwardly rectifying IKach. • Magnesium acts as an L-type calcium channel blocker. • The channel that carries this current is permeable to both sodium and calcium. Nickel. thus increasing the levels of intracellular Ca which may trigger SR calcium release. Tetradrine. Blockade of these channels results in negative inotropic effects. Closed channels are inactive. • It produces inward current responsible for plateau of AP. L-type calcium channel (L = Large and lasting) • It is a major source of Ca entry into the cell.4-Dichrobenzamil. It opens when depolarization reaches positive to −40 mV. and LVH. which in turn stimulates adenylyl cyclase activity. and conduction velocity. • Digoxin inhibits sodium/potassium ATPases. alpha agonist (phenylephrine). Disopyramide. • Calcium channels are very selective and allow Ca permeability 1000fold faster. • When a cell is calcium overloaded SR releases calcium spontaneously and asynchronously causing DAD (delayed after depolarization) seen in digitalis toxicity. Lidocaine. Diltiazem. extracellular ATP. • ICaL is responsible for excitation.endothelin-1.

Because of these concerns. drug for three reasons: compared to 45 percent by history in the one month prior to the onset of *multiple daily doses over several days are required. were treated with levofloxacin. In addition. some criteria for appropriate fluoroquinolone therapy. The drugs noted above are as effective. more convenient to median time of return to work was six days even though one-third had at use. therapy should not be stopped until the patient is afebrile for 48 to 72 hours and is clinically stable. occurs after the fifth day of therapy. and/or use of response to treatment. 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 clarithromycin XL 1000 mg once daily) or doxycycline (100 mg twice daily). In one report of 768 ambulatory patients with CAP seen in an emergency department in 2000 and 2001. promote the development of fluoroquinolone-resistance among respiratory pathogens (as well as other colonizing pathogens) and may lead to an Pathogen-directed therapy Once the etiology of CAP has been identified using reliable microbiologic increased incidence of C. least one persistent symptom at 14 days. asplenia. most commonly fatigue. *Combination therapy with a beta-lactam effective against S. fluoroquinolones continue to be given.CAP TREATMENT IN THE OUTPATIENT SETTING TREATMENT REGIMENS Treatment regimens for outpatients with CAP are based upon studies of the effectiveness of antibiotics. 245 (32 percent) Most patients with CAP begin to improve soon after the initiation of appropriate antibiotic therapy as evidenced by resolution of symptoms. Treatment should be continued for a minimum of five days. In another report. but a higher rate (14 percent) in women under 40 years of age who received the drug for seven or more days. Antibiotic antibiotic use described in the next section can be followed. antimicrobial therapy should be directed at that pathogen. At least one symptom (eg. pneumoniae (DRSP). These regimens are also appropriate where there is a high prevalence of "high-level" macrolide-resistant S. 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 . pneumoniae (high-dose amoxicillin. antibiotics within the prior three months. or moxifloxacin 400 mg daily) for a minimum of five days. Despite these recommendations.Support for this recommendation comes from a meta-analysis of 15 level macrolide-resistant S. fatigue. the severity of illness. tuberculosis without an appropriate assessment for tuberculosis infection. the presence of comorbid conditions. Treatment duration and response The administration of a fluoroquinolone in patients with tuberculosis has been associated with a delay in diagnosis. Telithromycin should be reserved as an option for patients at risk for drugresistant pneumococcal infection in whom alternative agents are not appropriate. chronic obstructive pulmonary Persistence of such symptoms is not an indication to extend the course of disease [COPD]. even in the absence of comorbidity or recent antimicrobial use. Gemifloxacin causes a rash in 2. and CAP. we recommend any one of the following oral regimens: *Azithromycin (500 mg on day one followed by four days of 250 mg a day). When such randomized controlled trials of almost 2800 patients with mild to moderate resistance is present.8 percent of patients overall. and where there is not a high prevalence of macrolide-resistant strains. dyspnea) Although erythromycin is the least expensive macrolide. The following approach to empiric antimicrobial therapy is suggested. However. The rash is generally mild. pneumoniae in the local community. and poor With respect to treatment duration. chronic heart antibiotic therapy as long as the patient has demonstrated some clinical disease. which found comparable clinical outcomes with less than seven days compared to more than seven days of antimicrobial therapy. pneumoniae. and the prevalence of risk factors for drug resistant S. Ambulatory patients with CAP should be treated for a outcomes. 76 percent had at least one symptom at 30 days. cancer. This was illustrated in a Telithromycin is NOT recommended as a first-line empiric regimen because study of sequential interviews in 134 ambulatory patients with CAP. and resolves with discontinuation of the agent. often inappropriately. we rarely use this was still present at 28 days in one-third of patients. *compliance is limited by gastrointestinal side effects. the clinical significance of these findings is not yet clear. CAP because population-based studies would be required. diabetes. The rash is not associated with phototoxicity or hypersensitivity and does not preclude the use of other fluoroquinolones in the future. both cough and fatigue. We recommend one of the following oral The nonresponding patient Among patients with CAP. we generally agree with the 2007 IDSA/ATS guidelines. These symptoms are usually not sufficient to interfere with work as particularly when other drugs metabolized by CYP3A4 are taken illustrated in a review of 399 ambulatory patients with CAP in which the concurrently. for CAP. as well as dosing. No comorbidities or recent antibiotic use For uncomplicated pneumonia in patients who do not require hospitalization. or immunosuppression). nonresponse is primarily seen in those who regimens for such patients: *A respiratory fluoroquinolone (gemifloxacin 320 mg daily. liver or renal disease. in vitro studies of moxifloxacin and gemifloxacin show more activity against penicillin-resistant pneumococci strains than levofloxacin. minimum of five days. The median time to resolution ranged from three days for fever to 14 days for of concerns about toxicity. the use of fluoroquinolones is discouraged in ambulatory patients with CAP without comorbid conditions or recent antimicrobial use. occurring in 6 to 15 percent of such patients. However. increase in resistance. symptoms often persist as the patient convalesces. cough. When choosing between fluoroquinolones. levofloxacin 750 require hospitalization. and less toxic. unless it is known that there is a high prevalence of high. empiric use of fluoroquinolones should not be used for patients at risk for Mycobacterium methods. The incidence of treatment failure is not well defined in ambulatory patients with mg daily. the regimen for patients with comorbidities or recent CAP. *there is a risk of sudden cardiac death due to QT interval prolongation. although repeated courses of gemifloxacin should be avoided in such patients. it should NOT be prescribed in patients with known There is concern that widespread use of fluoroquinolones in outpatients will liver disease. one-half of these patients did not meet the physical findings. have no significant comorbidities and/or use of antibiotics within the last three months. and laboratory signs of active infection. Comorbidities or recent antibiotic use The presence of significant comorbidities (ie. because of the prolonged half-life of azithromycin. alcoholism. increases the risk of infection with more resistant pathogens. difficile colitis. a shorter duration of drug administration may be indicated for this agent. 500 mg a day for three days.

more ed These currents are ve responsive t metabolic cha e ery to anges. With he pe u time.4 While there communic cation between cardiac cells. e taneous action potential using If p f They have the ability to generate a spont ‘funny’. and dephosphorylatio d on. hiighly selective. polarized membran due to ne voltage-re egulated inward rectifiers (IK1). The exp pression of are m specific T-type antagonists. When a cell receives depolarizing cu n urrent. there are no AP. There are th kinds of K g d hree concentra ations in differen areas of the at nt trioventricular no (AVN). and d s these cells. a inward rectifier K-channels (Ik1. During patholog longer action potentials (APs these channe gic n s). ventriicular fibrillation or polymorphic ventricular tachy Basic arrhythmia physio ology and mech hanisms SODI IUM CHANNELS S The s sodium (Na) cha annel is a voltage e-gated channell that is responsible for the rapid depolariz e zation of conduc cting myocardiall cells. and Iks). Additionally downregulatio of voltage y. ca y ausing early after depolarization GAP junc ction channels ar the functionall units that allow direct ionic re w (EAD) arrhythmias. . The distrib along with Na/Ca and Na/K exchangers. which in t provides a c turn contraction signa to the al myocyte contractile eleme c ents. In contrast to the delayed rectifier ch hannels. these c channels open a the resting sta and are at ate closed du uring depolarizat tion. and congenital conduction dise ease (CCD D). ventricular AP has a longer d n h duration. ehind cell depola arization and ac ction potential for rmation: Na or C Ca. antag GAP junc ction channels ar not uniformly distributed arou the heart re und ASSIUM CHANN NELS tissues. stable. pH. the conne exins is not unifo They are m concentrate along the orm. This inact tivation will then ELECTRI ICAL COUPLING (GAP JUNCT TION) partly recover as [Ca]I decreases. will be inactivated. in tur initiate onts rn. nnel te Abnormalities in struc cture or function of the Na channel. and w. Compared to atrial action potential (AP). TWIK-2). spont and a alpha-agonists re educe Ito curren velocity. blished the base eline diastolic Em m. These re e-entrantwavefro could. L-type and T-type. In t IkATP Background K currents estab P). HCN1–4. promoting early ated s This gives rise to anisotro propagation of depolarizatio with faster s opic n on (EAD) and delayed (D DAD) after depo olarization. al the regula K channels can lead to AP prolongation. IKr and IKs. low intracellular d ase gonist. result in an intercellular voltage gradient sufficie ent to gen nerate a depolar rizing current tha is capable of initiating re-entr at rant wavefronts. At the same time. myocytes. els modulated by cyclic AMP d P.27) with a and is dependent on intracellular calc memb brane potential ( (Em). Inactivatio is dependent on time. L-type Ca channe are activated generating the slow upstroke els d. Em. e neuro innervating t heart. long QT syndrome (LQTS sick sinus sy S). to ode chann nels: background (TASK-1. a shorterCalciu the and zed These cellls are found in t sinus node a the specializ conduction system. A Activation is initiiated by membra depolarization hyperpola ane arization-activate cyclic nucleot gated chann ed tide nels. form a single-pore. This is impor rtant for mechan synchrony.o phase of the AP is the result of an L-type Ca P Phase 2 or the plateau p current stabilizing Em by counteracting th outward K currents. TWI IK-1. This results in a fast early repolarization that dr rives Em to 0 mV V. thu giving a he es us in me etabolic arrhythm mias. conductio velocities alon the cardiac m on ng muscle fiber orien ntation than across the fiberorientation Abnormalities in connexins ha been found e n. hetics bind to the e by ph open inactivated chan and facilitat closure. v voltage-gated (Ito o. It consists of one alpha and occasionally o one or mu ultiple beta subunits. Na chann are activated nels d result in a net inwa (depolarizing current manifested as phase 0 of ting ard g) the AP. yndrome (SSS). significant expression in t faster condu the ucting atrial and ventricular v Ikslow Ikr. IkAch. W While neurotoxins cause inactivat s tion hysically blocking the channel po local anesth g ore. playing a role ends of th myocytes than along the side of the cell. T-type Ca and K r rectifier currents These currents confer the s. s ave to play a key role in brady k yarrhythmias and tachyarrhythm (mainly mias MEMBRANE ACTION POTENTIAL Cardiac myocytes are divided into tw groups depen e wo nding on the driv ving through re e-entry). i ed ward Abnormallities in either typ of these chan pe nnels can cause long QT e syndrome e. ycardias. an on nd slow kinet mode of activ tic vation and deact tivation. m Activa ation and inactiv vation of these c channels are ver complex ry proce esses governed by phosphorylat tion/dephosphor rylation and glycosylation of the a alpha subunit. and the are ey [Ca]i. dihydropy ype s yridine). he potassium curren nt Phase 1 starts with th opening of a rapid outward p (Ito). however. Mibfradil is the most spe ecific T-type these cha annels is affected by protein kina activity. L-typ Ca channels are inactivated and the plateau subsides. ca e rty ausing these ce to develop ells CALC Cardiac myocytes ha two types of voltage-gated c ave calcium (Ca) rhythmic spontaneous slo diastolic depo s ow olarization.g. ponse to membr rane depolarizat and is tion Ito is activated in resp taneously inactiv vated in a time d dependent mann Angiotensin II ner. Phase 3 is due to ‘delaye rectifier’ outw K currents. causing n ges n/inactivation cha aracteristics. It is fo e ormed of two pro oteins called con nnexin. Phase 4 constitutes a ste c eady. Once Em reaches – chann nels. The first cloned ells T contra action and T-typ channels play a role in autom pe ys maticity and If channell was BCNG1 an further clonin resulted in ide nd ng entifying impulse conduction. the distribution of d muscle as well as His Purkinje fibers. hyper nt rthyroidism increa ases Ito current density. on directiona propensity for propagation of t action potential. It has been map nical pped to chrom mosome 3 (SCN N5A). s cium concentrat ([Ca]i) and tion These cha annels are mixe Na and K cha ed annels (Na/K ratio  0. it still has signif ficant L-type ant tagonistic effect ts. the increa in [Ca]i acts as a trigger for release of more ase r Ca stored in the sarcoplasmic d reticulum (SR). POTA Potas ssium (K) channels are responsible for repolariz zation currents bution varies fro almost absen in the sinus no to low om nt ode. Other ty ypes are found iin autonomic 40 mV. and ald dosterone media a receptorates specific downregulation of these channels. hav been involved in ve d chang in activation many diseases includ Brugada’s s y ding syndrome. facilitating fast pro opagation of the many specific L-ty antagonists (e. L-type channels plays a role in ons the e s of the actiion potential in t these types of ce (phase 0). y s drome) a function ning During loss of activity of Na channels (Brugada synd an riving Em toward its resting sta ds ate Ito ca cause full repolarization by dr (–90 m This may r mV). CIUM CHANNEL LS unstable electrical proper of phase 4. ca e ausing a drop in [Ca]i. ion be Sodiu um-channel-dependent AP ce ells. a higher phase 2 due to the abs sence of IKur in the ventricular um-channel-dep pendent AP cells s. The beta subunits are auxiiliary units and their role in cardiac myocy is not well u n ytes understood. The alpha subunit consists of four charg domains arr ged ranged in a clock kwise manner to o monovalent channel.

7 percent per year overall but 5. repetitive. or permanent. In comparison. Moreover. as opposed to a transmitted cardiac or aortic murmur A highpitched 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. 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. bruits were absent in over one-third of such patients. . for example. Transient ischemic attacks — Transient ischemic attacks may be due to either low flow or embolization. However. Features of ocular ischemia or infarction include partial or complete blindness in one eye and an absent pupillary light response. if they can be heard. 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. however. Regardless of their location. patients with impaired vasoreactivity. In a report from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) of patients with symptoms of cerebrovascular disease. In the Systolic Hypertension in the Elderly Program (SHEP). while right hemisphere ischemia may be manifest by left visuospatial neglect. In addition. symptomatic patients have more impaired cerebrovascular reserve compared to those who are asymptomatic . a phenomenon of delayed stroke. There is. they are brief. These may be transient. one-third had carotid bruits . inability to perform purposeful movements) and dysprosody. carotid bruits alone were not sufficiently predictive of high-grade carotid stenosis to be useful in selecting patients for angiography. 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.5 percent per year in those with more than a 75 percent carotid artery stenosis. Similarly. the risk diminishes after the first year . An hourglass configuration to the stenosis typically develops with time. 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. As an example. The carotid arteries were normal in 32 percent of those with a bruit. the stroke more often than not occurred in a vascular territory different from the carotid bruit. Carotid stenosis may also exist in the absence of any clinical signs or symptoms. representing TIAs. suggesting that a carotid bruit can act as a nonfocal marker of advanced atherosclerosis. The plaque encroaches on the lumen of the internal carotid artery and often extends caudally into the common carotid artery. and hemisensory loss. The prognosis of patients with a stroke due to carotid occlusion may be related to collateral flow . hemiparesis. had a significantly greater incidence of ipsilateral ischemic events (14 versus 4 percent in those with a normal index). thrombus can become superimposed on the atheroma which will further increase the degree of stenosis. In one series of 500 patients. 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. None of the above symptoms and signs is specific to carotid stenosis. Atypical symptoms of internal carotid artery stenosis include unilateral limb shaking and transient loss of monocular vision upon exposure to bright light. ocular bruits and abnormalities or asymmetries of facial pulses are not reliable predictors of carotid stenosis. In addition to a reduction in vessel diameter induced by the enlarging plaque. Amaurosis fugax refers to transient monocular blindness caused by a small embolus to the ophthalmic artery. These generally occur as ischemic symptoms downstream from severe internal carotid artery disease. is very suggestive of underlying carotid disease. presumably due to propagation of thrombus or embolism from the distal portion of the clot . After a median follow-up of 28. Total carotid artery occlusion — When the internal carotid artery occludes completely. 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. These relationships can be illustrated by the following observations: In one series of 331 patients referred to a cerebrovascular clinic. several investigators have observed material passing through small retinal arteries during an attack of monocular ischemia. the presence of a carotid bruit was associated with a nonsignificant relative risk of 1. A history of more than one discrete episode occurring in the same carotid territory. Syncope may be a rare consequence of bilateral carotid occlusive disease. and predominantly involves the posterior wall of the vessel. temporal arteritis may produce ocular symptoms that are similar to those produced by carotid stenosis and should be considered in the differential diagnosis. Using carotid duplex ultrasonography. resulting in cerebral infarction. Most often.2 years. that give an indication of the location and severity of the stenosis: A focal bruit suggests an internal carotid artery stenosis. However. With that degree of stenosis.69. When TIAs are due to low flow with inadequate collateral blood supply. constructional apraxia (ie. 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. only 37 percent of these patients had a moderate or severe carotid stenosis compared to 17 percent without a bruit. embolic TIAs are usually single and more prolonged. and the symptoms are related to the vascular territories involved. The greatest risk of low flow TIA or stroke is at the time of occlusion. They often herald strokes occurring in the territory of the internal carotid artery. especially the combination of ipsilateral ophthalmic and hemispheric events (see "Ischemic symptoms" below). 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 .5 mm. although the anterior cerebral artery can also be involved. Thus. stereotyped spells . 75 percent of patients with a bruit had a moderate to severe stenosis (≥ 60 percent stenosis). Hemispheric signs of cerebral infarction from carotid disease include contralateral homonymous hemianopsia. an embolic ischemic event related to carotid artery stenosis will produce symptoms referable to the middle cerebral artery territory. the mechanism of stroke may be embolism of the thrombotic material or low-flow due to the stenosis with inadequate collateral compensation. Classification of the symptomatic status of the artery is important to the neurologist in making diagnostic and treatment decisions.5 months. occurring many months after carotid occlusion. Fundoscopic examination may demonstrate arterial occlusion or ischemic damage to the retina. defined as a breath-holding index <0. 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. and transcranial Doppler ultrasound has verified the passage of formed element emboli into the intracranial cerebral circulation downstream from severe internal carotid artery stenosis . Specific signs of left hemisphere ischemia include aphasia.CAROTID ATHEROSCLEROSIS SYMPTOM MECHANISMS MECHANISM OF SYMPTOMS — Carotid atherosclerosis is usually most severe within 2 cm of the bifurcation of the common carotid artery. CLINICAL MANIFESTATIONS — The clinical manifestations of carotid artery stenosis are a carotid bruit and symptoms of ischemia. 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. Some experienced clinicians believe that there are several characteristics of a carotid bruit. the incidence of stroke was 1. Carotid bruit — An important sign of carotid stenosis is a carotid bruit heard over the site of the stenosis. The management of total carotid occlusion is also discussed separately.29 for stroke over a mean follow-up of 4. 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. This topic is discussed separately.

A sample of urine from e the first vo oiding after awake ening is preferred but a random specimen is d. it is difficult to use the SCr alo to estimate th level of GFR. How wever. maln meat nutrition. k ast . patient should refrain f e. the are few data r py. P/C ratios greater than 500 to 1000 mg/g s 0 usually ind dicate a glomerullar disease (altho ough such values may also be s present in interstitial and va ascular diseases At this level of proteinuria. a the primary SCr as asses ssment of kidney function in stand clinical pract dard tice. other e uria. han variety of reasons. Values between 17 and 250 n mg/g are considered to be in the microalbuminuria range (i. Alte hin ernatively. s acceptable Ideally. ported to correlate better with GFR e R than t SCr alone.g. as indicate in Chapter 2. and the upp limit usually is extended as hig as 200 to 300 tive on mg/day to avoid false-posit evaluations. The algorith for adults who are at hm o increased risk begins with testing of a rando spot urine sample with an om albumin-sp pecific dipstick. suc as those with a family history of polycystic d ch kidney disease or a history of vesicouretera reflux in childho because y al ood. hyper rtension. all patients should be evalu s uated to determin ne wheth they are at inc her creased risk for d developing CKD b because of the presence of susceptibility or initiation fa actors. o one he cially to detect ea arlier stages of CK Measuremen of creatinine KD. more work is required to und s derstand how to best use cystatin b C as a filtr ration marker in c clinical practice.73 m2. to guid clinical decisio sk de ons t rate GFR about the presence of CKD. For these reasons. many studies now sug y ggest that cystatiin C gener ration.73 m2. o ties y radiologic eviden of damage. s nd fore mmon marker for kidney damage is increased r and theref the most com excretion of protein. The M Modification of Die in Renal Disea (MDRD) Stud equation and t et ase dy the Cockc croft-Gault equation provide usefu estimates of GFR in adults. o e Current guidelines focus on estimated GFR rather than SCr alone. on a spot urine sample is acceptable Clinical feature of the nephrotic syndrome typic arise when e. arly the hom s reflect the age-related decline in GFR b t because of a con ncomitant age-related declin in muscle mas and reduced cr ne ss reatinine product tion. ational Committee on e Preve ention. or assay m differ among populations. the N y NKF. An elevated albumin excretion rate is amage. In have a measured GFR that is actually greater than 60 m nician must turn to alternative infor o rmation. derived fro the lower urin tract.g.. Patie with two or more positive results on quantitative tests temporally spac over 3 month have s ced hs persistent proteinuria and a considered to have CKD irres are o spective of the level of kid dney function. an in many patien s f nd nts GFR m decline by a must approximately 50 before SCr ris above the no 0% ses ormal range This is particula important in t elderly. In addition. there is a wiide range of per s gh 0 normal values. the corr responding range is 25 to 355 mg/g. or out r r may b inaccurate in p geogr raphic groups. there is a wide range of “normal” SCr. GFR estimates be populations witho CKD. which is inc convenient and freque ently inaccurate. GFR estimating ons with tions should be used in conjunctio with the clinica context. ethnic. P Patients with a po ositive result on a dipstick test for albuminuria (≥20 mg/L or 1 should under confirmation by measurement 1+) rgo b t urine sample with 3 months. fever. or hy ypertension. some min/1. Detection. in wh the SCr does not e. measurem of total prote instead of alb ment ein. The Kidn Disease Impr ney roving Global Out tcomes (KDIGO) recom mmended annual testing for CKD in patients with h hepatitis C as welll as testing at the initiation of any cancer diagnosis and with each change in g h therap At resent. given the imprecision in the G estimating e GFR equations. for a y Cr nfluences other th GFR. A positiive result for the urine total protein to creatinine n (P/C) ratio is 200 mg/g or h o higher. ed these and other estima ating equations d not perform as well in populatio do s ons and settings other than those in which they were develo n oped. . 0 D roteinuria and al lbuminuria Table 1: Definitions of pr Proteinuria can be seen int a termittently in peo without kidn disease ople ney secondary to vigorous exercise. and r The most common causes of CKD in adults are diabetes an hypertension. it e Cr. it is reasonable to suggest that those at increased risk be tested at lea every 3 years. iincluding imaging studies. Ove erall. ere regarding the opt timal frequency o of testing for CKD in indiv g viduals who have risk factors othe than diabetes a e er and hyper rtension. ) respectively. Until eviidence is available. CKD is diagno osed when the estimated GFR is found to be less than 60 mL/min/1. Those deemed at high risk k d ent atinine concentrat tion should at minimum have a measureme of serum crea (SCr) to estimate GFR and assessmen of proteinuria. Urine dips or sediment examination sho also be perfo stick ould ormed in all patients who are at high ris for CKD. For on al equat example. Clinical judgm should deter ment rmine the necess of additional sity ods kidney damage. Kidney Da amage Markers of kidney damage include proteinu hematuria. or in y nfection. Howe n ever. nce abnormalit of the urinary sediment. Values e greater tha these upper limits are considered to represent an macroalbu uminuria. Evaluation and T Treatment of Hig Blood Pressure. of the A/C ratio on a spot u uld e ents m testing cou begin with the A/C ratio. T recommende R nt The ed metho for assessmen of proteinuria in most individualls at increased ris is od nt sk measurement of the albumin-to-creatin ratio in an un nine ntimed (“spot”) ur rine sample.e not c e. h arring from the remote injury that increases their they may have chronic sca risk for ong going progressiv kidney disease ve e. Asses ssment of Kidne Function ey The N National Institute o Diabetes. high le evels of dietary m intake. proteins derived fro tubular epithe om elium (e. a cleara ance measureme should be obtained.73 m2 would people with estimated GFR of slightly less than 60 mL/m R mL/min/1. A hydration and is far more c r urine albumin-to-creatinine (A/C) ratio is greater “positive” result for a spot u than 17 mg/g in men or 25 mg/g in women.. or conditio associated w muscle wasting). If an accur estimate of G is required. requir collection of a timed urine sam res mple. spinal co injury. Imag studies should be performed w sk ging in selected individuals. particularly in elderly patients or those with FR m CVD. ord amputation. and sp o pecifically of albu umin. detectable by spot or timed urine collection for the detection of total protein) e d n in men. Dige of estive and Kidney Diseases. The ul e MDRD study equation is more accurate and more preciise than the D e Cockc croft-Gault equation or CrCl for pe ersons with a GFR less than appro oximately 60 mL/m min/1..73 m2 on two occasions more than 3 months apart. wh may g hich would limit its widespre application a a filtration mar d ead as rker. Tamm m-Horsfall protein and proteins n). there is little or no improv vement over GFR R estima ating equations. ts from vigorous ex xercise for 24 hours befo sample collec ore ction. either a 24 ent 4-hour urine collec ction for CrCl or c clearance of an ex xogenous filtratio marker. Cystatin C has been suggested as an alternative e filtratio marker to SCr It has been rep on r. such a on as iothala amate or iohexol. or in individuals in whom creatinine production would be expec to differ from the general pop cted m pulation (e.Diagn nosis of Chronic Kidney Diseas c se Scree ening Procedure es As pa of routine chec art ckups. in women. It is the earliest sign of kidney diseas caused by diabetes. such as the these instances. a specific sign of kidney da o s atinine in a spot The ratio of concentrations of albumin or total protein to crea urine spec cimen has replace 24-hour excre ed etion rates as the preferred e method for measuring albu uminuria and prot teinuria (see Tab 1). Many studie es have s shown that cysta C is a better p atin predictor of adverse events than S SCr or GF estimated from SCr. es cally the spot urine P/C ratio is g greater than 3000 mg/g. which is relate to glomerular th ed s se injury. other u g urine metho of detecting k or ser markers. s). ho the owever. Healthy persons usually excrete only 50 om nary y y 0 to 100 mg/day of protein in the urine. extremes of body size. Urine protein includes albu umin as well as ot LMW protein that are ther ns filtered by the kidney and in ncompletely reab bsorbed by the tu ubules. gy he determ mined from the S with an estimating equation. The most commo type of protein seen in patients wit CKD is albumin. kidney han ndling. and th American Soc he ciety of Nephrolog recommend th use of GFR. nt espec cleara ance (CrCl) can a avoid some of the limitations of SC however. or b rum biopsy of the kidn The Joint Na ney. Use of ble ariations in urinary protein concent y tration due to such a ratio corrects for va convenient than timed urine collec ctions. bumin. glomerular diseases. in other racial. gh the Am merican Diabetes Association. a clin presence of kidney damage or CKD ris factors. SC is affected by in Conse equently. and hum immunodefic man ciency virus (HIV) infection. an the Infectious D s nd Disease Society of Ameriica recommend y yearly testing for CKD in patients with diabetes.

nts risk Becau of the age-re use elated decline in G GFR.Eva aluation and Management of CK KD Evalu uation Startin treatment earlly in CKD is esse ng ential to prevent a adverse outcome es.. Strong se ot s 00 d fficacy of these th herapies to slow progression of evidence documents the ef CKD. Nondiabetic kidney disease in ncludes glomerullar. Prevalence. which may e w include life estyle alterations. adjustment of medication dosage for decreased GFR. and nervous sy ystem disorders (neuropathy. as /90 her a discussed earlier. Its earliest manif festation is microa albuminuria with a normal or elev vated GFR (CKD stage 1). bone disease. Other potential ta argets of interven ntion to slow kidney disease progression are dietary prot restriction. albumin. a measuremen of and nt serum electrolytes. The physical exa amination should pay details such as fu unduscopy.g uncontrolled hy D g. For mos diseases. hyperpara athyroidism. ue 100 mg/dL is recommende in patients with CKD. urine prote should be ons. In the absence o risk factors for CKD. unlike many of its counterparts. ypertension. Avoid exposure to medications that are toxic to the kidneys Treatm of progress factors is the cornerstone of c for patients w ment sion e care with CKD. ce Patient ed ducation is also im mportant with respect to avoidanc of exposure to ce medication that are toxic t the kidneys. and care must be taken L ed h in the use of fibrates becau of the increas risk of myopa in use sed athy combinatio therapy with s on statins. also. urine pH. These indiviiduals are at low risk for progression osis ge to kidn failure but ar at increased ris for CKD comp ney re sk plications and for CVD. treatment of CVD risk fact is critical for n ut tors the preven ntion of initial and subsequent eve d ents. Close attention t returning the e to extracellular fluid volume to norma al. s fic sodium. As in patients withou CKD. potassiu bicarbonate). and c cystic kidney diso orders. Use of ACE with w inhibit or angiotensin receptor block (ARBs) is rec tors kers commended for a all patien with diabetic k nts kidney disease and for those with nondiabetic kidn ney diseas who have spo urine P/C ratios greater than 20 mg/g. Treat uremic c complications. and prepare for kidney replacement t therapy if appr ropriate 5. clinicians may e to defer som parts of the elect me ation for CKD. and me s e etformin should be avoided. Diabetic and ropathy is the larg single cause of kidney failure in the United gest e e nephr States accounting for approximately one third of new c s. Ho owever. ). Evaluation of CKD starts with a thoroug history and ph gh hysical examination tect t to det any signs and symptoms that may be clues to the cause of kidney diseas and. diure are his e st etics preferred as the second ag a gent. D ded blood pres ssure goal of less than 130/80 mm Hg. Additional th herapies may be considered for patients with spot urine P/C ratios greater th 500 to 1000 mg/g. However. inclu uding maintenanc of ce the filt tration barrier for plasma proteins resorption or ex r s. an ACE inhibitor or ARB is the preferred first-line agent in f g The m the setting of proteinuria. in particu any reversib elements or treatable risk facto se ular. T use of oral diabetes agents must often be altered wh the GFR is lo Glipizide is pr hen ow. and non ng s. urine specific gr ment ravity. Treat progress factors sion 4. in patients with n CKD there are several diffe e erences in manag gement of these risk factor conditions Hypertensive patients with CKD are recommend to have a s.73 m2 and fulfill the criteria for a ss r diagno of CKD stag 3. f estima GFR are ap ated ppropriate measures. The usual target blo ood pressure for patients w CKD is below 130/80 mm Hg. markers of kidney damage. includin ACE inhibitors ARBs. The include uld ese electrolyte abnormalities (h e hyperkalemia. Imaging studies sho be performe if indicated bas m ould ed sed on clin clues. Ad n dditional studies m be necessar to may ry evalua symptoms of CVD more fully o to detect asym ate f or mptomatic CVD in n patien with multiple r factors. The g goals of evaluation are to 1.g. he Furthe testing may be indicated if ther is concern abo anatomic er e re out abnor rmalities. Treat other rev decreased GFR 3. e Uremic co omplications shou be monitored and treated. hype erphosphatemia. st glycemic con in diabetes. Detect com mplications of dec creased GFR Diagn nosis of CKD is tr raditionally based on pathology an etiology. g ure. or of f complications of CKD. xcretion of water or specif solutes (e. use of nonsteroidal anti-inflam mmatory drugs). an parathyroid ho evalua ation should also include a search for traditional C risk factors. blood pressure. which is low than the s m wer recommen nded goal of 140/ mm Hg in oth populations. s o h CVD such as a liipid profile. ein quant tified with spot urine examination f the P/C or A/C ratio. monitoring of blood pressu and adherenc to plans for medical follow-up. and p possibly tests for nontraditional ris factors such as sk s insulin resistance and inflammation. referred to other sulfonylureas s because. Patient ed ducation is a cent aspect of the management str tral rategy. Individuals with CKD are co s onsidered to be a high risk for de at evelopment of CVD. agement of chronic dis sease requires be ehavioral change by the patient. Diagnose th type of kidney disease 2 he y 3. lip n tein pid-lowering therapy. Identify risk factors for CVD k 6. malnutrition. Treat specific c causes of kidney disease y versible condition causing kidney damage or ns y 2. Nat tional Kidney Fou undation K/DOQI Clinical Practice Guidelines on I: Hypertens and Antihype sion ertensive Agents in Chronic Kidne Disease ey Table. functio In individualls known to have CKD. a search for reversible ca h auses of decreas sed evalua GFR. Table. appropriat es te attent to CVD risk f tion factor manageme and subsequent monitoring of ent. Ultras nical sonography shou be performed in all cases to de uld etect anatomic abnormalities and to exclude obstruction of th urinary tract. Nat tional Kidney Fou undation K/DOQI Classification. A d nd simpliified classification emphasizes dis n seases in native k kidneys (diabetic or c nondiabetic in origin) a diseases in transplanted kidneys. ndihydropyridine calcium ch hannel blockers. cog gnitive changes). Laborato ory serum calcium. Laboratory tests should be performed to detect disrup ptions of other kid dney functions be esides GFR. and d particular attention to d ular s vascu examination. many elder individuals hav rly ve an est timate GFR of les than 60 ml/min/1. it is not degraded to a metabolite u s that is dep pendent on the kidneys for elimina ation. including w C han a lower blo pressure goa or initiation or iincreased dosage of agents that ood al e reduce pro oteinuria. Identify risk factors for progr 4 k ression of kidney disease y 5. Identify the stage of CKD 2. caref consideration must be given in the use of ful iodinated contrast agents o gadolinium for angiography or magnetic c or m resonance imaging. ble ors for pro ogression of CKD or for CVD (e. phosphate.. achiev vement of the tar blood pressu and blockade of the reninrget ure. particularly in that CKD is a chronic and ofte asymptomatic disease and y en c patients may not understan the importance of multidrug reg m nd e gimens and laboratory testing without e y explicit education Complete mana n. cases. and I: P Action Pla for Stages of C an Chronic Kidney D Disease . Detect reve ersible causes 4. vascular. adherence to m medication regime selfens. Mos patients require more than two a st e antihypertensive agents to achieve th blood pressure target. and smoking ces trict ntrol ssation. In b the treatm of dyslipidem a plasma LDL cholesterol valu of less than ment mia.73 m2) should have measure ements of hemoglobin as well as m nd ormone. Patients must be aware that any ns to a drugs or herbal remedies m be directly ne h may ephrotoxic or ma require a ay dosage ad djustment for the level of kidney fu unction. Treat CVD and its risk factors d 6. e angiot tensin system are key components of therapy. Individu with CKD sta uals ages 3 through 5 (GFR <60 mL/min/1. and endocrine um. tubulo ointerstitial. Mana agement The e essential features of management are as follows: s t 1. Dosages of incretin f enhancers may need to be lowered. Investigat tions for the diagn nosis of CVD must also be altered. me etabolic acidosis) anemia. urine for C sedim examination.

INa depolarizes the membrane at 382 V/s. • IKs attains a large magnitude during a plateau. The end of phase 3 occurs when the resting potential is reached. It is not faster than normal. Its diagnosis is made by deductive analysis and exclusion of the other conduction abnormalities such as block of conduction. CX43 is a major conductor of intercellular currents in ventricle. Potassium currents are outward currents. During normal propagation. Its gradual appearance correlates with the appearance of Ito.A 50% reduction in CX43 produces a marked slowing of conduction velocity. Its level of activity is low due to instantaneous inward rectification. • During the plateau phase of AP current flow activity is reduced. • Ito2 is a calcium activated chloride current. • The duration of the preceding cycle length (CL) determines the location of supernormal conduction. • Longitudinal conduction velocity in myocardium is 0. It is found in human atrium and ventricles. hypertrophy. • Impedance of a scar is lower than that of normal myocardium.CONDUCTION AND BLOCK Electrophysiology of action potential (AP) • Normal APD is 180 milliseconds. • In ventricle connective tissue. Exit block • It is commonly seen in sino atrial. • During AV block a sinus impulse may conduct or an electronic pacemaker may capture during the period of supernormal excitability. • The PR interval remains unchanged or is shorter. Ito and J wave • Transmural voltage gradient between epicardium and endocardium due to Ito results in J wave (Osborn wave). sodium (inward) current provides the charge for membrane depolarization except in atrioventricular node (AVN) and sino atrial node (SAN). Outward movement of positive ions repolarizes the cell membrane by making the inner surface more negative than the outer surface. • The period of supernormal excitability correlates with the end of the T wave and the beginning of diastole. • Maximum negative membrane potential is defined as a resting potential. junctional. • Atrial impulse may propagate during a supernormal period and result in displacement of the subsidiary pacemaker due to concealed conduction. It is a major repolarizing current. • Absence of a notch in endocardium correlates with weaker Ito. • Atrial trabeculation may contribute to conduction discontinuities. • Gap junctions in Purkinje tissue facilitate rapid conduction. • 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 scar from myocardial infarction (MI) may add to discontinuities. Longer CL shifts the supernormal period to the right. • The magnitude of Ito and spike and dome in right ventricular epicardium is more prominent than left ventricular epicardium. • Slow conduction in the SA and AV nodes is due to small and sparsely distributed gap junctions. Connexion 43 (CX43) is a major gap junction protein. • ICaL (inward current) supports AP plateau against repolarizing (outward current) Ik. which slows repolarization and prolongs APD. • The end of the plateau phase heralds the beginning of phase 3 of AP. • Capillaries may contribute to anisotropic conduction. • IKr increases during the early phase of AP. As the current flows through the cell membrane it shifts membrane potential to threshold potential by activating sodium and calcium currents. • In a parasystole. Supernormal conduction • During a recovery phase of APD supernormal conduction may exist when a subthreshold stimulus may evoke a response. • CX40 is a major conductor of intercellular currents in atrium. peeling of refractory period and dual AV nodal physiology. Phase 1 of AP is a result of early repolarization produced by Ito. • Prominent J waves may occur in the presence of hypothermia and hypercalcemia. during repolarization. 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. supernormal conduction may manifest as normalization of QRS. Plateau phase is phase 2 of AP.2 m/s. Concealed conduction • It is characterized by unexpected behavior of a subsequent impulse in response to incomplete conduction of a preceding electrical impulse. This produces the substrate for anisotropic conduction. extrudes calcium. • Supernormal conduction may manifest as unexpected normalization of bundle branch block at a shorter RR interval. • Supernormal conduction depends on supernormal excitability and exists only in Purkinje fibers. Cells capable of producing spontaneous depolarization initiate phase 4 of AP. • A repetitive pattern or group beating of type I or II periodicity is suggestive of exit block. • Supernormal conduction is recorded in diseased cardiac tissue. • When the membrane potential reaches the threshold level it results in the onset of AP. Propagation of an impulse through specialized conduction tissue is not recorded on a surface electrocardiogram but can be inferred. • 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. • Type II exit block is characterized by a pause that is multiple of basic CL. • An Impulse arriving during supernormal excitability conducts better than expected or conducts when the block was expected. • In crista terminalis the ratio of longitudinal to transverse conduction is 10:1. • Improved AV conduction (not supernormal conduction) may be due to gap phenomenon. This produces phase 0 of AP. • In the presence of acceleration dependent aberration during atrial fibrillation (AF) or sinus rhythm with premature atrial contractions (PACs). This is typical of Wenckebach periodicity. • Occurrence of elevated J point may be due to transmural gradient and dispersion of early repolarization. During this phase depolarizing Ca and Na currents decline and K currents enhance repolarization.7 m/s and transverse velocity of 0. Calcium inward current is essential for allowing the current to pass through the cell junction. It may be noted in the presence of a complete AV block. • Concealment is commonly encountered at the level of AVN or bundle branches. not in His bundle or myocardium. • Ik repolarizes the membrane to the resting potential. • 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. It takes in three sodium ions for each calcium ion that is removed. thereby excluding equal delay in both bundles as a cause of normalization of the QRS. It separates phase 2 from phase 3 of AP. failure of the impulse to manifest may be due to an exit block or physiologic refractoriness. • ECG reflects conduction and electrophysiologic properties of the myocardium. • These are located at or near the ends of working atrial and ventricular myocytes where intercalated discs connect adjacent cells. and ventricular pacemaker. The same stimulus may fail to produce a response before or after the supernormal conduction period. • Repolarization begins when the net current flow becomes outward either by an increase in outward or by a decrease in inward currents. ICaL triggers calcium release from sarcoplasmic reticulum (SR) through calcium induced calcium release (CICR). • INa/Ca pump. 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. This causes significant inward current. Atypical Wenckebach delay may resemble sinus arrhythmia. Gap junction • Gap junctions are for intercellular transfer of current. When the threshold stimulus excites the cell. IKr is potassium selective. • A concealed impulse may become intermittently manifest in other parts of the same tracing. • Delay in propagation may occur in the gap junction. Electrical heterogeneity • AP of ventricular epicardium and M cells shows a prominent notch due to Ito mediated phase 1. . Continuous and discontinuous conduction • The difference between the electrical potential of excited and nonexcited tissue produces a flow of current. • Spike and dome morphology of AP is absent in the neonate.

etc). • Swallow saliva/sip of water. papillitis • Hemorrhages: • Liner/flame or ecchymoses – hypertensive/diabetic retinopathy • Petechiae – diabetes • Subhyaloid (crescent) – subarrachnoid hemorrhage Oculomotor. ptosis • Direct and consensual reaction • Swinging flashlight – keep on each pupil just long enough to maintain constriction. cardinal directions and corners • Ask about diplopia. or use counting fingers. relative size. these are usually printed on the near card. 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. • Screen with finger wiggle in four quadrants (left. clench and palpate) • Light touch and pinprick in V1. Trochlear and Abducens Pupils • Shape. 20/50. V2. perception of hand movements or perception of light. Efferent motor is VII) Auditory/Vestibulocochlear • Whisper numbers at arm’s length. Near vision may be recorded in 1 of 3 standard notations. For instance.B. conduction loss = bone more than air. • 6 meter = 20 feet • 60 meter = 200 feet N. blow out cheeks (check naso-labial grooves) • Taste in anterior 2/3 of tongue – not usually tasted • Corneal reflex (Afferent is V. rub fingers in other ear • Rinne test (tuning fork on mastoid) – normal = air conduction more than bone conduction.Quick Examination of the Cranial Nerves Olfactory Nerve • This is usually not tested. 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. etc) is a century-old standard in which the lower numerals represent better vision. both) • Define with white pin. horizontally and vertically (red for scotomata) Color vision not routine (red desaturation in optic neuritis) Fundoscopy • Optic atrophy – pallor of the nerve head. sensorineural loss – best in normal. bring closer. J3. symmetry. can be used (20/20. right. • Swelling of the optic head – papilledema. LR6 • Both eyes. and J1+ is 20/20. J3 is equivalent to 20/40. a recalibration for the near test. Glossopharyngeal and Vagus Nerves • Palate/Uvula at rest and when saying “Ah”. 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. abnormal to normal. the distance equivalent. • Finally. Visual Fields • “Look at my nose – are any parts of my face missing?” macular degeneration.SO4. conductive – best in abnormal. • Ask patient to say “Eee” (recurrent laryngeal nerve) • Gag reflex (both sides) Spinal Accessory • Trapezius (also C2-C4) – shrug the shoulders and test power. • Another notation is the point system used commercially to denote print size. sensorineural loss = air bone than bone. with N3 being 20/20 and higher numbers indicating poorer vision. abnormal dilatation (relative afferent pupillary defect) Eye Movements . • 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. • Weber test (tuning fork on forehead) – normal is R=L. • SCM – turn head to side. • The Jaeger system (J1. test power • Coordination – ask to say “la la la” . J2. test power Hypoglossal Nerve • Look at the tongue for wasting and fasciculations • Poke out tongue (deviates to weak side).

serum total or LDL-C did not add independent predictive value to the ratio. and very-low-density lipoprotein. Non-HDL-C includes all cholesterol present in lipoprotein particles that is considered atherogenic. The impact of these changes on the treatmenteligible population was examined by analyzing data from 13. and endothelial dysfunction. Importance of other risk factors A number of other risk factors for CHD have been suggested by epidemiologic data. 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). Data from the Lipid Research Clinics and the Framingham Heart Study demonstrated the following advantages of the ratio: Among men. Other methods of risk assessment Total-to-HDL-cholesterol ratio Given the protective value of serum HDL-C. such as the apolipoprotein B to apolipoprotein A ratio. or time intervals studied. intermediate-density lipoprotein. we consider chronic renal insufficiency (defined by a plasma creatinine concentration that exceeds 1. women ≥ 55 years) -HDL-C ≥ 60 mg/dL (1. which serves as the basis for the treatment guidelines. There are five major steps to determining an individual's risk category. Number of patients affected The ATP III guidelines include absolute risk and lower LDL-C levels to assess eligibility for lipid lowering therapy. their presence does not influence current guidelines for cholesterol lowering. The goal for nonHDL-C in this circumstance is a concentration that is 30 mg/dL (0. Non-HDL-cholesterol Non-HDL-C is defined as the difference between the total cholesterol and HDL-C.03 mmol/L]) *Family history of premature CHD (in male first degree relatives <55 years. and the LDL particle number to HDL particle number. It is not clear in all cases if these differences are real or if they are due to differences in research methods. homocysteine. when to initiate therapeutic lifestyle changes. It has been suggested that the nonHDL-C fraction may be a better tool for risk assessment than LDL-C. In addition to the conditions identified by ATP III as CHD equivalents. the 10-year risk of CHD is assessed using the ATP III modification of the Framingham risk tables. lipoprotein(a). but it overestimated risk among Japanese American and Hispanic men and Native American women.73 m2) to be a CHD equivalent. Overall eligibility for treatment increased by 157 and 122 percent for men and women. respectively. ATP III identifies the non-HDL-C concentration as a secondary target of therapy in people who have high triglycerides (≥ 200 mg/dL [2. adjudication procedures.6 or more identified a group at 25 to 45 percent greater risk than predicted from serum total or LDL-C In contrast.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. 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. that is.78 mmol/L) higher than that for LDL-C (show table 4).5 mg/dL [133 µmol/L] or an estimated glomerular filtration rate that is less than 60 mL/min per 1. Step 2 CHD equivalents. and when to consider drug therapy. the results are classified as shown in Table 1 (show table 1). such as obesity. there has been no evidence from controlled trials that targeting these risk factors improves outcomes.26 mmol/L]). 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. physical inactivity. in female first degree relative <65 years) *Age (men ≥ 45 years. Step 5 The last step in risk assessment is to determine the risk category that establishes the LDL goal. abnormalities of thrombosis. 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). However. which measures the major proteins in LDL-C and HDL-C respectively. Thus. a ratio of 5.589 subjects in the NHANES III survey. Other ratios Other lipoprotein ratios have also been proposed. it has been suggested that the serum total-to-HDL-C is of greater predictive value than the serum total or LDL-C. impaired fasting glucose. respectively.4 or more identified a group at 2 to 14 percent greater risk than predicted from serum total or LDL-C Among women. although ATP III suggests that these factors can be used to modify clinical judgment in some circumstances. markers for inflammation. and 131 and 201 percent for those ≥ 65 or <45 years of age. including LDL.55 mmol/L) counts as a "negative" risk factor. 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. . Step 1 The first step in determining patient risk is to obtain a fasting lipid profile. 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. Several studies have suggested that the Framingham criteria also overestimate the risk in European and Asian populations. its presence removes one risk factor from the total count. a ratio of 6. risk factors that place the patient at similar risk for CHD events as a history of CHD itself.

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). For this reason. Chronic decompensated MR. In normal individuals. If the blood pressure at the time of the study is low. Furthermore. PISA. 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. in the absence of heart failure. The velocity at which the blue-red color shift occurs identifies the PISA shell. momentum. vena contracta. to denote increasing grades of MR severity is also popular. does not cause LA dilatation. and so on. CW jet density.7 cm indicates severe regurgitation. i. and spatial relationships and has excellent sensitivity and specificity. with severe MR jets more than 40% of total LA area (or a maximal jet area > 10 cm2). This results from the rapid surge in LA pressures in severe MR—the atrial V-wave. pulmonary vein flow pattern.0 cm2). The CW Doppler envelope may show blunting or notching of the CW envelope. unlike the flow convergence zone and the distal turbulent jet profile. LA Size The LA will dilate in response to chronic volume and pressure overload. The signal intensity (jet density) of the CW envelope of the MR jet can be a guide to MR severity. VENA CONTRACTA WIDTH The vena contracta is the narrow neck of the MR jet as it traverses the regurgitant orifice. Blunting of pulmonary forward flow may lack specificity. but with moderate or severe MR. LV contractility can decrease silently and irreversibly in chronic MR. A dominant Ewave more than 1. There are 3 major phases of MR and they produce various impact on LV performance. and direction. are not reliable measures of MR severity. 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. 2+. Acute MR phase. blunting or reversal of this pattern may be seen.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. 1. The vena contracta measured from the parasternal long-axis view is best optimized by using a narrow sector scan. Atrial fibrillation and elevated LA pressures from any cause can blunt forward systolic pulmonary vein flow. Increased LA pressures and systolic flow into reversal pulmonary veins may be the only echocardiographic findings that document the severity of acute-onset MR. wall thickness. prolapse or perforation. Measurements should be adjusted for age and body surface area. The PISA method makes several assumptions—many of which are violated in the clinical setting. Larger color jet areas indicate more severe MR when the jet is centrally directed. or when water from a lake flows into a narrowed estuary. A thorough evaluation of eccentrically directed jets should include evaluation for etiologies. 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. A VCW less than 0. and fractional shortening—are the most important echocardiographic barometers of the hemodynamic effects of MR on global cardiac function. The apical four-chamber view is recommended for optimal visualization of the MR jet PISA measurement. but this should be assessed relative to the density of antegrade flow signal (mitral inflow). Mild MR jets cover less than 20% of total LA area (or a maximal jet area < 4. Its dimensions may help to assess MR severity and chronicity. Qualitative estimates of MR jets are categorized on a scale of 0–4: grade 0 = none or trace MR. but can be misleading with eccentrically directed jets. as occurs with papillary muscle rupture. The MR index is a composite score comprising six echocardiographic parameters—jet length. Each of the 3 components of the MR jet—flow convergence zone. a VCW more than 0. Hugging or entrainment (Coanda effect) of the eccentric jet to the LA wall results in smaller jet areas even when MR is severe. As regurgitant blood converges toward the regurgitant orifice at the proximal convergence zone. Color jet areas are influenced by jet velocity. Chronic compensated MR. and outcomes following mitral valve surgery. In patients with preserved systolic function. cardiac output is maintained via an increase in the LVEF. optimal color gain. VCW measurements are not valid for assessing MR severity with multiple MR jets. 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. Peak MR jet velocities alone. providing there is no concomitant mitral stenosis. but is nonetheless a useful parameter that provides information independent from color Doppler methods used to assess MR severity. and Nyquist limit between 40–70 cm/s. 3D echocardiography may ultimately assist in overcoming some of these limitations. 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). especially when supported by other indicators of severity. LV contractility and LVEF increase in response to an increase in preload. the aliasing velocity (Nyquist limit)—VALIAS —to give the regurgitant flow rate. ejection fraction. but is otherwise of little prognostic value in MR itself. 3. The notation 1+. and therefore influence the frequency of clinical follow-up. The PISA method can also be assessed by transesophageal echocardiography when indicated. grade 1 = mild MR through to grade 4 = severe MR. Reguritant flow rate = 2πr2 × VALIAS (mL/s). It is. Visualization of flow reversal into one or more pulmonary veins on color flow Doppler. 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. Systolic flow reversal may be indicative of severe MR even if the color jet area suggests milder disease. is a 2D snapshot across an elongate regurgitant orifice area that extends to a variable degree along the crescenticleaflet coaptation line. Severe MR with eccentrically directed jets sometimes exhibit a “wrap around” effect in the LA. PROXIMAL FLOW CONVERGENCE AND PROXIMAL ISOVELOCITY SURFACE AREA According to fluid dynamics. a more reliable marker of MR severity with significant advantages over other methods provided that the recommended technique is used. 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. The same principle applies when blood in the LV stream converges toward a narrowed (stenosed or regurgitant) orifice. it should be corrected to 180°. Integrating Indices of Severity Integrated scores have been devised to improve the diagnostic validity of parameters of MR severity. and such patients typically have LVEFs greater than 65%. However. COLOR JET AREA The same color jet profiles can be measured within the LA. functional. Such considerations are better appreciated and measured on 3D echocardiography.2 m/s may indicate more severe MR. In chronic compensated MR. pulmonary artery systolic pressure. therefore. the EROA can be quantified using the continuity principle equation for flow rate: Area1 × Velocity1 = Area2 × Velocity2. and 3D. direction. At least two orthogonal views should be used with the Nyquist limit set at 50–60 cm/s. A small nondilated atrium in the setting of acute regurgitation constrains the regurgitant jet momentum and hence the visible color jet area. increasingly earlier surgical interventions for less severe degrees of MR are being recommended. even centrally directed jets may be misleadingly small. 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. DOPPLER METHODS FOR GRADING MR SEVERITY Color Flow Doppler Parameters Color flow Doppler imaging is perhaps the most intuitive of all measures. The PISA radius (r) is then measured and multiplied by the PISA velocity.3 cm indicates mild MR. the peak velocities and gradients will also be low. therefore. however. Even in the acute setting. most closely mirrors that of the actual regurgitant orifice. 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. fluids within an enclosure stream symmetrically toward a narrowed outlet or orifice in near concentric isovelocity zones. timing of surgical intervention. This portion of the regurgitant jet. If the base of the PISA hemisphere is not horizontal. according to the continuity principle. LV end-systolic dimensions and LV ejection fraction (LVEF) reflect the heart’s ability to adapt. 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. The vena contracta appears as the well-defined light blue or light yellow high-velocity core on the red-blue color Doppler scale. the MR jet velocity shows a rapidly early in systole. or more reliably—pulsed Doppler evidence of flow reversal into the pulmonary veins are measures of MR severity. MR jets are best assessed using multiple windows to obtain a three-dimensional (3D) perspective. A lower dP/dT can unmask patients with declining systolic function. . 2. Such scores should be integrated with global cardiac function and the patient’s clinical status. 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. the size and velocity of the innermost shell or hemisphere can be measured. and jet profile—can provide a semiquantitative or quantitative measure of MR severity. LA size may predict the onset of atrial fibrillation. and therefore serve as a guide to more aggressive intervention. and LA size. is useful for detecting the jet origin. A single vena contracta width (VCW) measurement. total flow at the proximal isovelocity surface area (PISA) will equal total flow in the distal MR jet. Therefore. In acute MR. From this. This is akin to water being drained from a kitchen sink. a positive systolic (S) wave followed by a smaller positive diastolic (D) wave is seen. A closer approximation of the actual regurgitant orifice area is best obtained by scanning through multiple planes and selecting the greatest VCW. Averaging VCW measurements over at least three beats and using two orthogonal planes is recommended. This may reflect an LA that has not yet dilated and show discordance with color Doppler severity. Acute-onset severe MR.. such as a flail leaflet. pulsed wave Doppler.e.

with a score of 8 or less indicating a higher probability of success than higher m/sec. M-mode echocardiography M-mode confirmation of the altered pattern of mitral motion in mitral stenosis remains a useful tool. Mitral regurgitation is not included in any of these indices. 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 the parasternal short axis plane. with a score of 1 representing normal. Anatomically. . the opening of the valve can be imaged just above the tips of the papillary muscles. the latter are rarely seen in echocardiograms taken from the precordial windows. and its qualitative estimation by a number of indirect observations. The opening snap (OS) of the mitral valve coincides with the initial peak opening (E) of the valve. The elevated gradient initiates the opening motion in an abrupt manner. The most frequently used measurement for the determination of the transmitral gradient during diastole is the pressure half-time. Compared with two dimensional echocardiography. 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. Empirically. dobutamine has been used to increase heart rate. Among the methods for estimating mitral stenosis severity. 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. taking the square of the peak velocity of fluid flowing between them (in this case. generating the opening snap and a characteristic "knee bend" appearance on the precordial long axis view. 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. 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. a pressure half-time of 220 msec is equivalent to a mitral valve area (MVA) of 1 cm2. Echocardiography in balloon valvuloplasty The role of echocardiography in mitral stenosis has become even more demanding with the development of catheter-based palliative interventions. which is derived from hemodynamic data. 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. 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. 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 four elements are the mobility of the anterior leaflet. noting the presence of right ventricular and atrial dilatation. In mitral stenosis. Severe mitral stenosis is defined by a mean transmitral gradient greater than 10 mmHg. When successful. 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. noting the degree of left ventricular underloading (ie. a peak velocity of 1 m/sec indicates a peak gradient of 4 mmHg. Thus. These variables include the gradient across the valve at rest and with exercise. occurring as a complication of the procedure. often Peak gradient. the increase is heart rate reduces diastolic filling. biphasic motion of the valve is altered because the valve can open only partly and as a single unit. Although this method is the least reliable means of quantitating the severity of obstruction. The algorithm to convert Doppler velocity into pressure gradient is the modified Bernoulli equation. The peak gradient between two reservoirs connected by scores. and the thickness of the anterior leaflet. 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.41 (square root of 2). These changes cause a limiting orifice that obstructs diastolic transit of blood from atrium to ventricle. but a degree of regurgitation multiplying by four. 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. as determined by Doppler of tricuspid regurgitant jet. and a mitral valve area <1 cm2. blood) and by the location and distribution of calcium around the stenotic orifice. the continuity equation or the proximal flow convergence method. Quantitation of mitral stenosis severity can be accomplished by direct methods. these techniques offer dramatic relief of symptoms and may avoid surgery. In order to convert Doppler velocity into a pressure gradient. An example of such a change is additional ventricular filling from aortic regurgitation. severe mitral regurgitation. The Doppler methods can measure the velocity of mitral inflow. 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. Doppler echocardiography Doppler methods provide a constellation of measurements by which the severity of mitral stenosis can be gauged. In patients who cannot exercise. estimating the extent of leaflet calcification. and the pulmonary pressure at rest and during exercise from the tricuspid regurgitant jet velocity. a valve orifice area of <1 cm2 is considered severe.Echocardiography in Mitral Stenosis In mitral stenosis. However. Other features of mitral stenosis on the two dimensional echocardiogram include chordal foreshortening and atrial thrombi. in a clinical setting. The 2006 ACC/AHA guidelines on valvular heart disease defined severe mitral stenosis as typically having a mean transmitral gradient >10 mmHg. the severity of subvalvular disease. direct planimetry of the orifice is probably the most accurate when performed correctly. This method is a reliable means of judging the severity of obstruction. Three dimensional echocardiography Three-dimensional echocardiography (3-D echo) has been evaluated for its utility in assessing mitral stenosis. to which planimetry can be applied to determine the valve area. 3 m/sec indicates a peak gradient of 36 mmHg. pulmonary artery systolic pressure >50 mmHg. These interventions require a transseptal puncture to deliver a dilating balloon across the obstructed mitral orifice. From this orientation.5 value for each of these four scores is added together for a total "splitability index" of 4 to 16. noting the degree of left atrial enlargement. it is the universal practice to achieve cross validation by applying the full array of methods. a narrow orifice or pipe (in this case the left ventricle and the left atrium connected by Other studies have proposed an alternate means of judging suitability for valvotomy the stenotic mitral valve) can be calculated by the modified Bernoulli formula. 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. One hemodynamic consequence of this alteration is a holodiastolic pressure gradient between the left atrium and ventricle. its maximum diastolic opening area can be measured by direct planimetry of the two dimensional image. a peak velocity of 2 m/sec indicates a peak gradient of 16 mmHg. The early diastolic closure slope. more than mild is considered a relative contraindication to the procedure. because velocity bears a second order relationship to pressure. Indeed. this velocity increases at rest from a normal value of less than 1 m/sec to greater than 1. Doming of the anterior leaflet corresponds temporally to the opening snap on auscultation. the normal. in mmHg = 4 x peak velocity(2) requires urgent valve replacement. volume decrease). the E-F slope. regardless of the method used to calculate its size. the initial flow velocity is divided by 1. the calcification of the anterior leaflet. the inferred area by the pressure half-time method. 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. rapid. Exercise and stress echocardiography During exercise. This technique can provide an en-face cross sectional view of the mitral orifice. it performs better when cardiac catheterization derived mitral valve area is used as the gold standard. Typically. 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. and noting the degree of tricuspid regurgitation and pulmonary hypertension. Indirect methods to identify the severity of mitral stenosis include observing the degree of foreshortening of the chordae tendineae.

Further testing and interventions are unlikely to be beneficial. multiple reversible defects. current In addition. and recommendations are often made on the The Fleisher-Eagle algorithm is easier to use. A subsequent algorithm from Auerbach and Goldman is virtually identical to the Fleisher-Eagle algorithm.8-7. It does not include patients with high-risk conditions additional risk stratification (eg. 1. *Preoperative serum creatinine >2. pulmonary edema. Rate of cardiac death. risk indices derived from elective surgery cohorts are not accurate. the first five of which are also in the revised Goldman cardiac risk index. The initial risk estimate derived from one of the above indices is often adequate to guide decisions regarding perioperative management. concurrent imaging is essential if the ECG has abnormalities complaint of chest pain considered to be secondary to myocardial ischemia.and value (between 6 and 67 percent. intrathoracic. and nonfatal cardiac arrest according to the number of predictors patients with a murmur. When stress testing is performed.0. additional testing and treatment may be warranted.8 percent) in dyspnea of uncertain cause. and complete heart block that used the approach in the ACC/AHA guidelines.2 to 6. orthopedic degenerative joint disease.9 percent) C. Initial risk assessment The initial risk assessment consists of three steps: preoperative stress testing in the following circumstances: Patients with at least one *Does the patient have a high risk condition that is considered a major predictor of clinical risk factor and poor functional capacity (<4 METS) who are scheduled for risk in the ACC/AHA guidelines on perioperative cardiovascular evaluation and care intermediate-risk surgery when such testing will change management Patients with at for noncardiac surgery? Such patients require intensive management and often a least one clinical risk factor and good functional capacity (≥ 4 METS) who are delay in or cancellation of surgery. and suprainguinal vascular Urgent surgery procedures) For urgent surgery (eg. revascularization procedures. Despite the elevated risk. Refinement of initial risk assessment with noninvasive testing in selected patients. with indications for noninvasive testing and cardiac catheterization. Initial risk assessment. The evidence was considered less well established for the benefit of 2.6 % with beta blockers revascularization.5-1. the Renal insufficiency value of additional testing and treatment is often limited except for identifying and Poor functional status (defined as the inability to walk four blocks or climb two flights stabilizing patients with unstable cardiac disease . helpful in some cases to refine this estimate with noninvasive stress testing.0 mg/dL (177 mol/L) Resting echocardiography We suggest resting echocardiography to quantify valvular dysfunction in B.0 % (95% CI 0.1.3-3. *History of ischemic heart disease (history of MI or a positive exercise test. patients who are able to exercise sufficiently to reach the target heart rate (eg. initial risk estimates should be made. it is . or suprainguinal wall defect. If preoperative PCI is considered.2. In these cases. However.2. Refinement of initial risk estimate patients who are candidates for preoperative revascularization. 4. because the predictors used largely overlap with the revised Goldman cardiac risk index. revascularization). 3. blockers The rate of intervention may be even lower in asymptomatic patients. We and others studies of thallium perfusion imaging). functional capacity. do not count prior coronary echocardiography. required during the same admission but a delay Diabetes mellitus (especially insulin-requiring) of days may be acceptable). transient ischemic dilatation). surgery would be delayed. *Three or more risk factors . The algorithmic approaches cited above provide strategies to determine which patients require additional risk stratification prior to surgery. 2. Defining the urgency of surgery. Fleisher-Eagle criteria A subsequent review by Fleisher and Eagle emphasized six factors.ESTIMATION OF CARDIAC RISK PRIOR TO NONCARDIAC SURGERY SUMMARY AND RECOMMENDATIONS The process of estimating and reducing the risk of perioperative cardiac events (eg. dual antiplatelet therapy).8 to 1. patients are usually best served by proceeding directly to surgery. exercise perfusion imaging or nitrate therapy.0. or severe deconditioning) can undergo exercise ECG testing often with concurrent imaging to better identify highA. the results of noninvasive testing will affect both the timing of surgery and the need for preoperative revascularization.4 % (95% CI 2. if necessary. reversible large anterior *High-risk type of surgery (includes any intraperitoneal. Urgency of Surgery Emergent surgery Emergent surgery carries unique. beta blockers. surgery when such testing will change management. associated with increased cardiac risk in patients undergoing noncardiac surgery. In this setting there is adequate time to complete recommended risk factors. it may underestimate a patient's true risk. nonfatal myocardial infarction. All combine surgery. *Two risk factors .4 % (95% CI 0. is estimated risk if negative (or normal) than for identifying patients at very high risk simple to use. or ECG with pathological Q waves. or to evaluate for possible pulmonary hypertension. often substantial risks. and the surgery-specific risk. scheduled for vascular surgery *What is the surgery-specific risk of the planned operation? Stress testing has a very high negative predictive value for postoperative *What is the patient-specific risk? cardiovascular events (between 90 and 100 percent) but a low positive predictive Various indices are used to help define the risk. cardiac arrest or cardiac catheterization and revascularization appears to be very low.0 % versus <1 % with beta blockers studies included symptomatic patients who may have been more likely to undergo *One to two risk factors . The main option patients with one or more of these risk factors. The 2007 ACC/AHA tests and. canceled. or performed on that are considered major predictors of risk. The following approach to cardiac risk stratification primarily applies to Stress testing Recommendations for preoperative stress testing are based upon clinical elective surgery. vascular procedures) extensive stress-induced wall motion abnormalities. It is the best validated risk index. which may supersede risk stratification. since these *No risk factors . those who are not limited by Revised Goldman cardiac risk index (RCRI) claudication. stress testing is more useful for reducing suggest the revised Goldman cardiac risk index. We prefer either the ACC/AHA guidelines or the Fleisher-Eagle algorithm. including vascular surgery: Ischemic heart disease (angina or prior MI) Heart failure High-risk surgery (including intraperitoneal.4 percent) Routine echocardiography is not recommended. revascularization procedure unless one of the other criteria for ischemic heart Patients who are unable to ambulate sufficiently to increase their cardiovascular disease is present) workload should undergo pharmacologic stress with either dipyridamole-thallium rMPI *History of HF or dobutamine stress echocardiography. In three studies ventricular fibrillation. but refers only to patients basis of initial risk indices. Rate of cardiac death and nonfatal myocardial infarction.4 % (95% CI 1.6 % versus 0. intrathoracic. ischemia occurring at a low heart rate. Premature criteria) and with poor functional capacity (<4 METS) who are scheduled for vascular discontinuation of antiplatelet therapy carries a substantial risk of stent thrombosis. However. for risk reduction is a beta blocker. However. In selected patients. Beta blockers may be helpful in patients who are hemodynamically stable and in whom benefit has been shown.>9 % versus >3 % with beta blockers These findings indicate that there are few asymptomatic intermediate-risk 3.5 percent) Preoperative revascularization The proportion of noncardiac surgery patients who undergo preoperative *Three or more risk factors . use of that interfere with interpretation of exercise stress.5. Six independent predictors of major cardiac complications risk features that would warrant referral for angiography (eg. *One risk factor . 2 to 11 % of patients underwent according to the number of predictors and the nonuse or use of beta coronary angiography and only 0 to 2 % underwent preoperative revascularization. Goldman and Detsky risk indices. and appears to have greater predictive value than the original when positive. with a value of 18 % in a review of five large patient-specific risks to provide an initial estimate of operative risk. of stairs) Such patients are usually not candidates for CABG and the need for The authors recommended that further evaluation was required in prolonged dual antiplatelet therapy markedly limits the use of PCI. to evaluate ventricular dysfunction in poorly controlled HF or *No risk factors . The choice of test should be based upon *History of cerebrovascular disease local experience and availability and the relative safety of the different procedures in *Diabetes mellitus requiring treatment with insulin the individual patient. cardiac death and nonfatal MI). If the surgical approach would be altered on the basis of who are candidates for surgery. any potential benefit must be balanced against the requirements for a full 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 course of aggressive antiplatelet therapy with aspirin and clopidogrel. Thus. includes the following four components: 1. Efforts to reduce risk in high-risk patients (eg.1-0.4 to 1.

When suspected clinically the diagnosis can be confirmed using ultracentrifugation of plasma. The approach to treatment is the same. Table. The two disorders can be distinguished clearly only by genetic tests. typically over the knees and elbows.g. 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. but because of clustering within families the prevalence is lower in some lists and much higher in others. the aorta and the skin. These include xanthomatous thickening of the Achilles tendons and xanthomas over the extensor tendons of the fingers. They have a hugely elevated LDL cholesterol concentration. Patients may have no physical signs. CLINICAL FEATURES AND INVESTIGATION OF PRIMARY HYPERLIPIDAEMIAS As the genetic basis of lipid disorders becomes clearer.hypercholesterolaemia alone -. 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. which may need treatment in their own right. Over 150 different mutations in the LDL receptor have been described to date. The most common patient group is a polygenic combined hyperlipidaemia. The average primary care physician would therefore be expected to have four such patients on his or her list. It is due to accumulation of LDL remnant particles and is associated with an extremely high risk of cardiovascular disease. Combined hyperlipidaemia (hypercholesterolaemia and hypertriglyceridaemia).Disorders of LDL . 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. Homozygous familial hypercholesterolaemia is very rare indeed. lipaemia retinalis and retinal vein thrombosis. Liver transplantation offers the possibility of cure. An abnormality of apoprotein C can be deduced if the hypertriglyceridaemia improves temporarily after infusing fresh frozen plasma.Disorders of HDL -. Disorders of LDL . Disorders of HDL . but the numbers of patients having undergone this procedure is small. or phenotyping apoprotein E. it can present in adults with gross hypertriglyceridaemia resistant to simple measures. 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. Xanthelasma may be present. if untreated. The genetic defect is the underproduction or malproduction of the LDL cholesterol uptake receptor in the liver. affecting1 in 200 of thegeneral population. For clarity we have used the functional/genetic classification and not the Fredrickson classification. Surprisingly. . The main clinical feature is a history of attacks of pancreatitis or retinal vein thrombosis in some individuals. Polygenic hypercholesterolaemia is a term used to lump together patients with raised serum cholesterol concentrations. Patients present in childhood with eruptive xanthomas. The presence of chylomicrons floating like cream on top of fasting plasma suggests this diagnosis. 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. pancreatitis). Cardiovascular disease. Such cases are often classified as familial hypertriglyceridaemia. South Africans). this defect also results in high LDL concentrations in the blood. 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.hypercholesterolaemia alone Heterozygous familial hypercholesterolaemia is an autosomal dominant monogenic disorder present in 1 in 500 of the normal population. or because the triglycerides cannot gain access to the normal enzyme owing to deficiency of the apoprotein C-II on their surface. They exist in the right-hand tail of the normal distribution of cholesterol concentration. If not identified in childhood. It is as yet unknown whether abnormalities of this gene contribute to the low HDL cholesterol concentrations commonly seen in cardiovascular disease patients. Secondary hyperlipidaemia If a lipid disorder has been detected it is vital to carry out a clinical history. but without one of the monogenic disorders above. Fifty per cent of men with the disease will die by the age of 60. most from coronary artery disease. The lack of direct correspondence between these two systems of classification can be confusing. corneal opacities and a polyneuropathy also occur. 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). thiazide diuretics. The defect underlying the vast majority of such cases is not understood.HYPERLIPIDAEMIA Hyperlipidaemia results from genetic predisposition interacting with an individual's diet . It is confirmed by plasma electrophoresis or ultracentrifugation. Repeated plasmapheresis has been used to remove LDL cholesterol with some success in these patients. The possibility of gene therapy offers a glimmer of hope on the horizon for affected individuals. This has the advantage that the genetic disorders may be grouped by the results of simple lipid biochemistry into causes of: -. 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. and lipoprotein lipase deficiency is likely if it does not. Patients have an increased cardiovascular risk due to both high LDL concentrations and suppression of HDLby the hypertriglyceridaemia. Cholesterol accumulates in RES tissue and arteries causing enlarged orange-coloured tonsils and HSM. sirolimus (and other immunosuppressive agents) CLASSIFICATION. Other mutations in this gene have been found in a few families with autosomal dominant HDL deficiency. Affected children have no LDL receptors in the liver. corticosteroids. This has been shown to be due to a mutation in the ATP-binding cassette transporter 1 gene (ABC1 gene .Combined hyperlipidaemia. There are no typical physical signs. It is diagnosed by finding raised cholesterol and triglyceride concentrations in association with a typical family history. Since LDL particles bind to their clearance receptor in the liver through apoprotein B-100.g. There is an increased prevalence in some racial groups (e.see HDL physiology above) which normally promotes cholesterol uptake from cells by HDL particles. and massive deposition of lipid in arterial walls. In a proportion of cases there will be a family history of a lipid disorder or its effects (e. examination and simple special investigations to detect causes of secondary hyperlipidaemia. The genetic basis for the disorder has not yet been characterized. most individuals with this disorder remain undetected. op'DDD (used in the treatment of Cushing's syndrome). Mutations in the apoprotein B-100 gene cause another relatively common single gene disorder. such cases being termed polygenic hypertriglyceridaemia. pancreatitis and hepatosplenomegaly.Disorders of VLDL and chylomicrons – hypertriglyceridaemia alone -. The chylomicrons persist because the triglyceride within cannot be metabolized if the enzyme lipoprotein lipase is defective. The natural history is for death from ischaemic heart disease in late childhood or adolescence. Familialcombined hyperlipidaemia This is relativelycommon. but is not diagnostic of familial hypercholesterolaemia. Diagnosis can more easily be made if typical clinical features are present. Remnant hyperlipidaemia This is a rare (1 in 5000) cause of combined hyperlipidaemia.normal total cholesterol and triglycerides Tangier disease Tangier disease is an autosomal recessive disorder characterized by a low HDL cholesterol concentration. Finns. and a clinical picture which closely resembles classical heterozygous familial hypercholesterolaemia. French Canadians.

We suggest insulin treatment for elevated serum glucose >185 mg/dL (>10. and 100 percent. Severe elevations in blood pressure may worsen ICH by representing a continued force for bleeding. Lowering ICP helps to maintain CPP in an adequate range. . We suggest continuous monitoring of ICP and arterial blood pressure when using these aggressive therapies. Intravenous mannitol is the treatment of choice to lower ICP.SPONTANEOUS ICH – PROGNOSIS AND TREATMENT The 30-day mortality from intracerebral hemorrhage ICH ranges from 35 to 52 percent. Treating hypertension is the most important step to reduce the risk of ICH. the prognosis for functional recovery depends upon the location of hemorrhage. heavy alcohol use. Suggested intravenous agents for sedation are propofol. and nitroglycerin are useful intravenous agents for controlling blood pressure. It is administered as an initial bolus of 1 g/kg. we reserve hyperventilation until the above therapies have been maximized. Among survivors. mannitol). Drawbacks of neuromuscular blockade include an increased risk of pneumonia and sepsis. We suggest use of antipyretic medications to lower body temperature to normothermia in febrile patients. etomidate. enalapril. and of cerebellar hemorrhage with fourth ventricle compression. and anticoagulant effect should be reversed immediately with appropriate agents. The prevention of venous thromboembolism and deep venous thrombosis in patients with ICH is discussed separately. <80 (= 0 points) Thirty-day mortality rates increased steadily with ICH score. Surgery for supratentorial ICH is controversial. Barbiturate coma acts by reducing cerebral metabolism. level of consciousness. Stopping smoking.25 to 0. the ability to evaluate the neurologic status is lost once the patient is paralyzed. hydralazine. This scale incorporates several clinical components that may be independent predictors of outcome. 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 . as muscle activity can contribute to increased ICP by raising intrathoracic pressure. we suggest aggressive reduction of blood pressure with continuous intravenous infusion of medication accompanied by blood pressure monitoring every five minutes . absent (= 0 points) Infratentorial origin yes (= 1 point). 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. 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. mortality rates for ICH scores of 1.3 mmol/L). For patients with cerebellar hemorrhages >3 cm in diameter who are deteriorating or who have brainstem compression and/or hydrocephalus due to ventricular obstruction. 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. with the dose titrated to a burstsuppression pattern of electrical activity. In addition. 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. and none had a score of 6 in the cohort. major side effects include hypovolemia and a hyperosmotic state. More aggressive therapies for reducing elevated ICP include osmotic diuretics (eg. Some patients will develop communicating hydrocephalus and require a ventriculoperitoneal shunt. Suggested agents for analgesia and antitussive effect are morphine or alfentanil. especially arterial hypotension. The ICP lowering effect of hyperventilation to a PaCO2 of 25 to 30 mmHg is dramatic and rapid. 72. Barbiturate anesthesia can be used if mannitol fails to lower ICP to an acceptable range. However. Ventriculostomy allows a means of both monitoring ICP and relieving hydrocephalus. 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. Patients with acute ICH should be managed in an intensive care unit. Prognostication for individual patients with acute ICH remains an uncertain science at best. nicardipine. 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. and hyperventilation. esmolol. with the goal of maintaining cerebral perfusion pressure above 70 mmHg. The goal of therapy is to achieve plasma hyperosmolality (300 to 310 mosmol/kg) while maintaining an adequate plasma volume. which is a common complication of thalamic hemorrhage with third ventricle compression. Thus. we recommend surgical removal of hemorrhage. respectively. The ICH score is determined by adding the score from each component as follows: Glasgow Coma Scale (GCS) score 3 to 4 (= 2 points). Continuous electroencephalogram monitoring is suggested during high-dose barbiturate treatment. hypotonic fluids are contraindicated. 97. Infectious complications include bacterial colonization in 0 to 19 percent of patients and bacterial meningitis in 6 to 22 percent. and current guidelines suggest consideration of standard craniotomy only for those who have lobar clots within 1 cm of the surface. The ICH score has been validated by retrospective and prospective analysis. Mild hypernatremia should be tolerated. size of the hematoma. Ventriculostomy is often used in the setting of obstructive hydrocephalus.5 g/kg every six hours. or midazolam. Cerebrospinal fluid drainage by intraventricular catheter placement (ventriculostomy) is an effective means of lowering ICP. patient age. Reducing ICP CPP equals mean arterial pressure (MAP) minus ICP. and 5 were 13. there are no prospective studies. Sources of fever should be treated. 2. ventricular catheter drainage of cerebrospinal fluid. which results in a lowering of cerebral blood flow and thus decreases ICP. No patient with an ICH score of 0 died. Available evidence suggests its use is associated with high rates of morbidity and mortality. Normal saline initially should be used for maintenance and replacement fluids.For patients with SBP >180 mmHg or MAP >130 mmHg and evidence or suspicion of elevated ICP. neuromuscular blockade.For patients with SBP >200 mmHg or MAP >150 mmHg. ICH volume <30 cm3 (= 0 points) Intraventricular extension of hemorrhage present (= 1 point). followed by infusions of 0. However. but marked hyperosmolality should be avoided to prevent precipitation of acute renal failure. and probably recurrent ICH. All anticoagulant and antiplatelet drugs should be discontinued acutely. no (= 0 points) Age ≥ 80 (= 1 point). Initial management of elevated intracranial pressure (ICP) includes elevating the head of the bed to 30 degrees and use of analgesia and sedation. 3. 26. GCS 5 to 12 (= 1 point) and GCS 13 to 15 (= 0 points) ICH volume ≥ 30 cm3 (= 1 point). 4. . and overall medical health and condition.For patients with SBP >180 mmHg or MAP >130 mmHg and no evidence or suspicion of elevated ICP. thereby reducing cerebral venous outflow. Appropriate intravenous antiepileptic treatment should be used to quickly control seizures for patients with ICH and clinical seizures. the effect only lasts for minutes to a few hours. Neuromuscular blockade is sometimes employed to reduce ICP in patients who are not responsive to analgesia and sedation alone. The routine evacuation of supratentorial ICH in the first 96 hours is not recommended. nitroprusside.

They stabilize the resting membrane potential by high resting potassium conductance. Ii Blocking of potassium channels (outward currents) may be counterbalanced by inward currents ICa. iii Nonspecific effects of potassium channel blockers. • IKatp decreases APD and calcium influx. ii Do not occur when Ito is blocked. . • Ito block may establish electrical homogeneity and abolish arrhythmias due to dispersion of repolarization caused by drugs and ischemia. Antihistamine. 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. adenosine. • IKatp causes coronary vasodilatation. oxygen free radicals. • Parasympathetic stimulation slows heart rate by activating muscarinic receptors. slow conduction. but cannot bind it during the resting state. Inability of IKs to deactivate rapidly and fully will produce less of an increase in APD. • Trapping block occurs when the channel closes around the drug without need for the drug to unbind. IKur is found in the atria but not in the ventricles. and ICl. INa. • Resting potassium conductance is produced by voltage independent inwardly rectifying potassium channels. either by direct blocking of the channel (Quinidine) or by muscarinic receptor antagonism (Ambasilide. In addition to IK1. • Potassium channel blockers prolong APD. This may be the mechanism of increase in QT interval and QT dispersion seen in nonQ wave myocardial infarction (MI). Characteristics of potassium channel block • Voltage gated potassium channels are activated during upstroke of AP. v Caused by inhibition of ICa or activation of IKach. ATP sensitive potassium channel (Katp) • Katp channel opens when the intracellular ATP level falls and closes when the ATP levels rise. Voltage gated currents = Ito . Katp counteracts these effects by shortening APD. Increased potassium conductance is a result of an increased level of intracellular sodium that occurs during ischemia. • Sodium and potassium pump and other ATPases degrade ATP. and protein kinase C open the Katp channel and mimic preconditioning. this may prevent transmural dispersion of refractoriness. M cells. Long depolarization permits longer efficient contraction. IKatp current decreases. • Open channel block occurs when the drug is present during activated or open state. • M cells play an important role in the inscription of T waves by producing a gradient between epicardium. This suggests that there may be other pathways involved in preconditioning. • During ischemia there is loss of intracellular potassium and increase in extracellular potassium resulting in membrane depolarization. IK. • Potassium channels contribute to repolarization. These differences could be aggravated by drugs that prolong QT interval or in patients with LQTS. It preserves high-energy phosphates. IKs 2. • Antiarrhythmics. It influences Ito. vi IKr block could shift repolarization to IKs at rapid rates. Background K currents IKp • These currents contribute to repolarization and resting membrane potential. and increasing potassium conductance during ischemia and hypoxia. • M cells show disproportional AP prolongation in response to slow heart rate. Classification of potassium currents 1. and altered refractoriness resulting in reentrant arrhythmias. and outflow tract. vii Many antiarrhythmics are capable of causing potassium channel block and other ion channel blocks simultaneously. IKatp and IKach are also inward rectifiers. • Amiodarone prolongs APD in epicardium and endocardium and to a lesser extent in M cells. Activation is required to remove the drug from the binding site. v Potassium channel distribution may be variable. resulting in decrease of APD and loss of dome in epicardium and not in endocardium. ATP produced by the glycolytic pathway is preferentially sensed by the Katp channel. IKur . IKr . It is mediated by acetylcholine. • IKatp is a weak inward rectifier but produces a large outward current during depolarization and its activation decreases APD. • Epicardium and endocardium electrically stabilize and abbreviate APD of M cells. IKach (Acetylcholine-dependent K current) • Stimulation of muscarinic receptors activates this current. and inward rectifier IK1. promoting inexcitability. This is xic of Class III action. Aprikalim. lateral wall. IKach. • Diazoxide does not activate IKatp in sarcolemma but mimics preconditioning. These currents contribute to phase 1 and phase 3 of AP. • These channels permit inward potassium flux on membrane hyperpolarization but resist outward potassium flux on depolarization. • Amiloride. Bimakalim. prolongs APD and refractoriness. Inwardly rectifying currents = IK1. contributes to plateau and phase 3 of AP. Potassium channel expression varies within different layers of myocardium. GI prokinetic. and M cells. Psychotropic. • Arachidonic acid and polyunsaturated fatty acids modulate these channels. • Rapidly activating and inactivating voltage sensitive transient outward current produces phase 1 of repolarization. endocardium. Thus no one current dominates repolarization. f stands for funny) in pacemaker cells. Increase in extracellular potassium depolarizes the resting membrane. iv Persist in the presence of Propranolol. Increase in intracellular pH inactivates IK1. These effects are as follows: i Reversed by atropine. IKatp 3. and extracellular potassium increases. • Potassium currents (outward movement of the K through the potassium channels) are the main contributors to repolarization. reverse use dependent block will manifest itself during repolarization at the channel level. ICa. Effect of pharmacologic agents on action potential • Acetylcholine in low concentration prolongs and in high concentration produces abbreviation of epicardial AP. and a host of other pharmacologic agents may alter repolarization. • Protons. • Inwardly rectifying potassium channels (K1) produce less outward currents than inward currents. • Quinidine inhibits Ito. viii Drugs that need a long plateau phase to work will be more effective in the ventricle than the atrium. • Isoproterenol causes epicardial AP abbreviation more than endocardial. • Cromakalim. but during depolarization produce little outward current. • Blocking of K channel may not consistently affect repolarization because: i Many potassium channels are involved in repolarization.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. thus. • These currents are inhibited by decreasing intracellular pH. • M cells may enforce pump efficiency at slow rates. • Loss of either layer by infarction will lead to prolongation of APD. potassium currents. • Organic calcium channel blockers (Verapamil) and inorganic calcium channel blocker MnCl2 decreases the ICa (inward current) and leaves the outward currents unopposed. Sulfonylureas such as Glipizide and Tolbutamide block Katp and abolish preconditioning. Nicorandil. • During ischemia. a potassium sparing diuretic. Disopyramide). • U waves are due to repolarization of His Purkinje cells. and polyamines block IK1. iii Accentuated by isoproterenol. • The drug may bind the channel during the inactive state. This phenomenon is called reverse use dependence. which reduces If (hyperpolarizing cation current. and muscarinic receptor stimulation desensitize the Katp channel to the effects of the ATP level. IKach is inwardly rectifying potassium current. • It is responsible for ischemia preconditioning where brief episodes of ischemia protect the myocardium from prolonged episodes of ischemia. which includes fast inactivating rapid component IKr and slow component IKs. • Some potassium channel blockers produce less block at a fast heart rate and more blocks at a slower heart rate. • Electrophysiologically they resemble Purkinje cells. Iv Extracellular potassium level may affect K currents. decreasing workload. This may be due to weaker IKs and stronger late INa. It prevents potassium ion leak during prolonged depolarization. • The effect of potassium channel blockers on atrial repolarization depends on their ability to counteract cholinergic activation of IKach. and INa/Ca. intracellular magnesium and sodium levels increase. Antimicrobial. • Intracellular magnesium. calcium. Adenosine. lactates. and APD • M cells are found in the mid-myocardium of anterior. • Slowly activating delayed rectifier potassium current.

Penetrating artery occlusions usually cause symptoms that develop over a short period of time. loss of consciousness. although some clinical syndromes are more predictive than others . agnosia. and symptoms sometimes evolve over several days. Global metabolism was impaired proportionally to cognitive decline. and leg on one side of the body in the absence of motor deficit or "cortical" signs. and dementia. in a prospective MRI study of 1015 patients without baseline dementia. Occlusion of a single penetrating artery involving both arterial territories is difficult to implicate. silent subcortical infarcts were associated with later development of dementia over four years of follow-up." which was found to be predictive of an acute internal capsule infarct on head CT. choosing among treatment modalities. Patients characteristically develop ipsilateral weakness and limb ataxia that is out of proportion to the motor deficit. Preceding TIAs and nonsudden onset may increase the positive predictive value for these lacunar syndromes. A series of the latter cases has been described as the "capsular warning syndrome. 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. incontinence. The motor deficit may develop as a single event or. and questions have been raised about whether the patients in the original description had unrecognized normal-pressure hydrocephalus. Other syndromes that have not been studied in large clinical series but that may be related to lacunar infarcts are shown in Table 2. Patients developing dementia more often had thalamic strokes at baseline and accumulated new subcortical lesions on a second MRI scan. or hemianopsia (so-called "cortical" signs). However. . and leg on one side of the body in the absence of the aforementioned "cortical" signs. Dysarthria-clumsy hand syndrome Dysarthria-clumsy hand syndrome is the least common of all lacunar syndromes in most case series. while regional rightsided frontal lobe metabolism was impaired in relationship to the presence of subcortical infarcts. Sensorimotor stroke Sensorimotor stroke is characterized by weakness and numbness of the face. and gait deviation towards the affected side. dysarthria. arm. neglect. More than 20 lacunar syndromes have been described. typically minutes to hours. be preceded by hemiplegic TIAs. dysphagia. patients with subcortical strokes and normal cognitive function. lacunar syndromes lack findings such as aphasia. Some patients may exhibit dysarthria. the above-mentioned "cortical" signs are absent. apraxia. Pure motor hemiparesis Pure motor hemiparesis is the most frequent syndrome in most clinical series. No relationship was found between the number or location of the subcortical infarcts and the presence of cognitive impairment. or hemianopsia) or sensory deficit. Taken together. It is characterized by weakness involving the face. and leg on one side of the body in the absence of "cortical" signs (aphasia. neglect. as with large artery thrombosis. Ataxic hemiparesis Ataxic hemiparesis is responsible for 3 to 18 percent of lacunar syndromes in case series. In fact. penetrating arteries from the posterior cerebral artery (PCA) supply the thalamus and the internal capsule is supplied from the lenticulostriate branches of the MCA. coma. less frequently. Monoplegia. even in patients with multiple subcortical infarcts. Theoretically. the presence of these syndromes has a positive predictive value of 87 to 90 percent for detecting a radiological lacune. pseudobulbar signs. and seizures also are typically absent. apraxia. stupor.CLINICAL FEATURES OF LACUNAR INFARCTS. Acute identification of lacunar syndromes is important in triaging medical resources. the first description of a lacunar syndrome in 1901 included a chronic neurologic course with episodes of mild hemiparesis progressing to abnormal gait. There are no sensory deficits or "cortical" signs. It is responsible for 15 to 20 percent of lacunar syndromes. Cases such as these have become rare. 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. arm. 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." This hypothesis is supported by case series of CT-demonstrated subcortical infarcts presenting with transcortical aphasia or neglect. lacunar infarction is the main ischemic stroke subtype associated with worsening motor deficits after hospital admission. the site of vascular occlusion was not identified in the original case description. It is found in 7 to 18 percent of lacunar syndromes in case series. One study using PET compared cortical glucose metabolism in patients with dementia and subcortical infarcts. nystagmus. and controls without cognitive impairment or stroke. Predicted infarct locations in relation to clinical manifestations are shown in Table 1. Sensorimotor strokes arise from infarcts involving the posterolateral thalamus and posterior limb of the internal capsule. and predicting clinical outcome. Syndrome recognition may be more difficult in the hyperacute setting. accounting for 45 to 57 percent of all lacunar syndromes. socalled "diaschisis. but its prevalence is probably underestimated because many cases present as TIA and were not included in the series. a stuttering course may ensue. The exact vascular anatomy is debated. However. Multiple subcortical infarcts and dementia As previously mentioned. A study of patients admitted within 6 hours of symptom onset reported only a 30 percent positive predictive value. as well as by functional studies using SPECT or positron emission tomography (PET). 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. As with other lacunar syndromes. As a general rule. Facial weakness. and slight weakness and clumsiness of one hand are characteristic. accounting for 2 to 6 percent of lacunar syndromes. 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. arm. Pure sensory stroke Pure sensory stroke is defined as numbness of the face. agnosia. dysarthria.

6 x 7. 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. Unilateral disease of prefrontal cortex often has surprisingly few clinical consequences. date.. alexia. . and maintain attention on the task so that the current result can be taken as the basis for generating the next one. but not in a patient who is unable to answer any questions because of impaired language function or a depressed level of consciousness. and it is usually futile to try to determine if one function is more severely affected than another. a river and a lake?". some are defined in Table 2 (show table 2). or when there is reduction in the level of alertness. ". Calculation — Ask some straightforward computation problems (eg. purple). ".. 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). baseball. and by asking questions about events of the past few days or weeks. draw a cube and ask them to copy it. and instead rely upon the interpretation of similarities and differences as an assay of abstract thought. appropriately placed structural lesions (especially expanding ones) may produce the same result. sleepy. horse. then ask the patient to recall the list. The remainder of the mental status examination can be presented in any order. a basketball and a grapefruit?". including all the numbers. season. Thus. The patient can also be asked about details of personal life such as birth date. and writing.. determine which ones are difficult for the patient. Give clues if an item is missed (eg. assuming an independent source is available for verification. The left hemisphere is also language-dominant in most lefthanded subjects. Mental status changes in alert patients can result from either focal or generalized processes. observe whether the patient is alert. This ambiguity is avoided by reporting the level of alertness first.. but they do not necessarily reflect the way in which the brain functions. Nondominant parietal lesions may also produce anosognosia (the inability to recognize the existence or severity of one's own impairment). difficulty with simple calculations may have some localizing significance in a patient who is otherwise cognitively intact. "How many nickels are there in $1.. The most common examples of selective mental status abnormality involve language function. comprehend language well enough to understand a fairly abstract command. it is very unlikely that any region or circuit in the brain is devoted specifically to calculation. Abstraction — Ask the patient to explain similarities ("What do an apple and an orange have in common?". place (eg. The latter usually affect all cognitive functions equally.18) and some word problems (eg. Lengthen or shorten the string until you find the longest string the patient can repeat correctly. ". Construction — Ask the patient to draw a clock. state. 31 . then language function. Neglect of one side of the environment is seen with a focal lesion in either hemisphere. "What did you have for supper last night?"). day... repetition. Less often. especially the parietal lobe. Decreased level of alertness occurs only with dysfunction of both cerebral hemispheres or of the brainstem reticular activating system. comprehension. for example. The ability to copy a sequence of repetitive hand movements is relatively independent of education. assuming independent verification is available. reading. content. attentive. When patients are asked to subtract serial sevens.35?". or a horse"). naming. None of these focal findings has any localizing significance unless it occurs out of proportion to other cognitive deficits. The assessment of language function and the categorization of aphasias are discussed separately. and work history." this is really more appropriately considered "attention." A confusing array of terminology is often used to report the findings on mental status testing. Assess recent memory by testing orientation to time (eg. interpretation of proverbs is so dependent upon cultural and educational background that I consider it useless. Long-term — Long-term memory includes both recent and remote memory. year). and apraxia.MENTAL STATUS EXAMINATION Level of alertness — No special testing is required to determine the level of alertness. The left hemisphere is dominant for language in almost all right-handed individuals. there is no reliable way to correct for this. In fact. it is often impossible to assess language function or other "focal" functions when significant dementia is present. Each can occur as part of a general dementing illness. Some tests are affected more than others.. person. "Who are the current candidates for president?" or. 5 + 8. "One was an animal"). Other cognitive abnormalities that may be seen in relative isolation include acalculia. As an example. possess the necessary calculation skills. or by asking about important historical events and dates. building). (See "Approach to the patient with aphasia"). (eg. Despite its categorization as "immediate memory. agraphia. and try to determine the kinds of cognitive processing common to those tasks. month. Interpreting mental status — Patient background will influence performance on mental status testing. While taking the history and examining the patient. and to place the hands at 4:10. rather than interpretations such as "mildly abnormal" or "slightly concrete. offer a multiple choice if this isn't enough (eg. the pattern of cognitive deficits can have some localizing significance. This complicates interpretation of the mental status examination. "How many quarters in $3. ". The examiner must observe the response to a variety of tasks. names and ages of children and grandchildren. a bicycle and an airplane?") and differences ("What's the difference between a radio and a television?". be able to verbalize the response. ". a tent and a cabin?". or unresponsive." Short-term — Ask the patient to memorize three unrelated words (eg. but the relationship is less predictable.. "It was either a cat. city. but it is much more common and tends to be more severe when the lesion is in the nondominant hemisphere. they must be alert. Ask the patient to draw a cube. The usual cause is a generalized metabolic abnormality such as hypoxia or hyperglycemia.. As an example. Each of these deficits is associated with focal lesions in the dominant hemisphere. Remote memory can be tested by asking for the names of the presidents in reverse order as far back as the patient can remember. Focal lesions typically affect some cognitive functions more than others. a bear. distract him or her for five minutes (usually by performing other parts of the examination). it is most informative to convey patients' actual responses. In contrast. Certain findings on the mental status examination can only be interpreted by knowing a patient's ability to perform other more fundamental tasks. Memory Immediate — Ask the patient to repeat a string of seven digits immediately after you complete it. All of the categories used to describe mental status are convenient simplifications.75?"). When reporting the results of mental status testing. and then memory.a baby and a midget?"). Language — Language function is assessed by testing and noting deficits in fluency. retain the command in memory long enough to process it. 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. although early on the main manifestations may just be inattention or word finding difficulty. Patients with generalized cognitive impairment perform poorly on all aspects of the mental status examination. but bilateral prefrontal disease is associated with difficulty maintaining and shifting attention. for patients who have trouble doing so.

extension (C7-C8) • Finger flexion (C7-C8). 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). extension (C7-C8) • Pronation and supination (C5-C6) • Wrist flexion (C6-C7). deltoid.Motor Examination – Upper Limb Inspection: • Wasting • Fasciculations • Abnormal movements (tremor. other small muscles of the hand. radial heel of hand (palmar) Ulnar Nerve (C8-T1. anterior thigh muscles) • Test knee extension (reflex lost). test extension (wrist/elbow) • Test sensation at anatomical snuff box Median Nerve (C6-T1. all muscles below knee. ulnar). 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. and flexor pollicis brevis) • Test APB if lesion at wrist. heel walking (L4-L5) • Romberg test – stand feet together. 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. proprioception any Tone: • Elbow flexion and extension • Pronation and supination • Wrist flexion and extension Power: • Sholder abduction (C5-C6). none below) • Test sensation at posterior thigh. lateral two lumbricals. some hamstrings) • Look for foot drop • Test knee flexion (reflex intact. tics. extension (L3-L4. myoclonic jerks. radial) • Finger abduction (C8-T1. femoral) • Ankle plantar flexion (S1-S2. lift from below • Rapidly dorsiflex foot and maintain (clonus) Power: • Hip flexion (L1-L3). foot Common Peroneal Nerve (L4-S1. triceps. 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. athetosis. extension (C7-C8. extension (L5) • Hip abduction (L4-S1). dorsiflexion (L4-L5. toe walking (L5-S1). slows down if EPS) Motor Examination – Lower Limb Inspection: • Wasting • Fasciculations • Abnormal movements • Posture • Gait including turning and heel-toe. common peroneal) • Ankle inversion (L4-L5). flexor digitorum if at cubital fossa (Ochsner’s clasping test) • Test sensation at pup of index figner (digital). opponens pollicis. sciatic). cerebellar up. 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. palmar forearm muscles except FCU and ulnar half of FDP. brachioradialis and hand extensors) • Look for wrist drop. hip flexion • Test sensation at medial thigh Sciatic Nerve (L4-S2. adduction (L2-L4) • Knee flexion (L5-S1. other involuntary activity) • Check outstretched arm for drift – UMN down. teres minor) • Test should abduction • Test sensation at regiment badge area Radial Nerve (c5-c8. anterior/lateral compartument muscles of the leg) • Look for foot drop • Test dorsiflexion/eversion (reflexes intact) • Test sensation at lateral aspect of dorsal foot . abductor pollicis brevis. sciatic). dystonia. lateral/posterior calf. adduction (C6-C8) • Elbow flexion (C5-C6). eyes closed (proprioception) Tone: • Roll legs side to side • Knee flexion and extension. ballismus. chorea.

similar to myoclonus but more random in location and more likely to blend into one another Athetosis — slow. and ankle plantar flexion. Also look for festination. then the tip of his or her nose. place the limb near the middle of its range. Rigidity is usually accentuated by distracting the patient. so that in most clinical situations the scale does not allow precise differentiation of the severity of weakness from one muscle to the next. In particular. 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. A unilateral pronator drift in one arm suggests an upper motor neuron lesion affecting that arm. producing a ratchet-like effect. Repeat with the left hand. forming a letter T with the body. writhing movements of the limbs Ballismus — large amplitude flinging limb movements Tics — abrupt. then your finger again. grade 4 covers a wide range. As an example. and regularity of rhythm. Finally. an involuntary tendency for steps to accelerate and become smaller. and quadriplegia are analogous terms that refer to complete or nearly complete paralysis of the involved limbs. a table. Involuntary movements — Observe the patient throughout the history and physical examination for the following: Tremor Myoclonus — rapid. hip extension. test hip flexion. place the right heel on the left knee. without such distraction. Rigidity — Rigidity. Many clinicians try to compensate for this by using intermediate grades. This is harder for most patients than you might imagine. Fasciculations (random. When it is prominent. classically resulting in a "clasp-knife phenomenon" when the limb is moved rapidly. Have the patient walk toward you while walking on the heels. place one hand above the joint being examined to stabilize the joint. Terminology of weakness — Monoparesis refers to weakness of a single limb. wrist extension. Lead-pipe rigidity applies to resistance that is uniform throughout the movement. then walk away from you on tiptoes. Rapid alternating movements — Have the patient alternately pronate and supinate the right hand against a stable surface (eg. In the lower extremities. Paratonia — Paratonia (also called gegenhalten) is increased resistance that becomes less prominent when the patient is distracted. Repeat using the left heel on the right shin. Hemiparesis is weakness of one side of the body. and rhythm. but this is a misnomer. A major limitation of the scale is that it is insensitive to subtle differences in strength. 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. is characterized by increased resistance throughout the movement. hemiplegia. Paraparesis is weakness of both lower extremities. Observe speed. test shoulder abduction. placing one foot directly in front of the other as if walking on a tightrope. Again. and move it to several different positions during the testing. Cogwheel rigidity is characterized by rhythmic interruption of the resistance. including spasticity.MOTOR EXAMINATION Gait — Observe the patient's casual gait. rigidity. but this results in less reproducibility because there is no consensus on how these intermediate grades should be defined. in testing shoulder abduction. ankle dorsiflexion. preferably with the patient unaware of being observed. or ask them to let their limbs go limp. an examiner is unlikely to assign a score of 1 to a muscle that another examiner graded 3 or stronger. Impaired ability to perform this task is referred to as dysdiadochokinesis. and then ask the patient to resist you as you try to move the limb from that position. severe arm weakness will prevent a patient from performing finger-to-nose testing even though the cerebellum and its pathways may be intact. Repeat the test using the patient's left arm. Finger tapping — Ask the patient to make a fist with the right hand. such as 3+ or 5-. other systems also play critical roles. 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. "like a wet noodle. elbow flexion. Observe for speed. Heel-to-shin testing — Have the patient lie supine. Although the cerebellum is very important in the production of coordinated movements and particular abnormal findings on coordination testing may suggest cerebellar disease. other abnormalities of tone are difficult to assess. Quadriparesis is weakness of all four limbs. This is particularly common in patients who are anxious or demented. and you may need to try to distract them by engaging them in unrelated conversation. Watch for 5 to 10 seconds to see if either arm tends to pronate (so that the palm turns inward) and drift downward." Several forms of increased tone (hypertonia) are distinguished. When possible. repeat for the left hand. to isolate the specific movement you are trying to test. knee flexion. Muscle tone — Muscle tone is the slight residual tension present in voluntarily relaxed muscle. Similarly. Spasticity is generally greatest in the flexors of the upper extremity and the extensors of the lower extremity. shock-like muscle jerks Chorea — rapid. Note if the patient is unsteady with any of these maneuvers or if there is any asymmetry of movement. in contrast to spasticity. and finger abduction. 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. have the patient walk in tandem. Observe for accuracy and tremor. the patient's own thigh or left hand) as rapidly as possible. finger flexion. As an example. Diplegia is a term that is best avoided because it is used differently by different authors. and paratonia. Spasticity — Spasticity depends upon the limb position and on how quickly the limb is moved. and then close the eyes. Monoplegia. 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. elbow extension. accuracy. accuracy. and then move the heel smoothly down the shin to the ankle. and exert pressure with your other hand just below the joint. For each movement. Tone is qualitatively assessed by asking the patient to relax and let you manipulate the limbs passively. 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. finger extension. Strength testing — In the upper extremities. the patient's arms should be horizontal. Hold your finger so that it is near the extreme of the patient's reach. involuntary muscle twitches) should also be noted. knee extension. Coordination — Coordination testing is often referred to as cerebellar testing. it is not a sensitive tool for documenting moderate changes in strength over time. wrist flexion. able to overcome full resistance The most compelling feature of this scale is its reproducibility. observe for accuracy and tremor. 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. Muscle bulk — The muscles active in each movement should be inspected and palpated for evidence of atrophy while testing strength. The limb moves freely for a short distance. paraplegia. and so forth. jerky twitches. Decreased tone (hypotonia) also occurs. stereotyped. . the patient seems unable to relax the muscle.

transesophageal echocardiography. may be seen. diagnostic accuracy was pressure recordings from the left atrium (or pulmonary capillary wedge higher for transesophageal echocardiography compared to transthoracic position) may demonstrate a significant "cv" wave from the regurgitant blood echocardiography. vegetations are present. and pulmonary artery pressure. systole. Ischemic mitral function. particularly of the posterior leaflet. Left ventricular size and systolic function are normal early in the leaflet motion. ST-T wave abnormalities (ST segment is depressed and the T wave is inverted) are also common in this setting. is characterized by restricted increased. on color flow imaging. there is significant thickening of the leaflets and some evidence of commissural fusion or Echocardiogram chordal shortening Echocardiography is essential for establishing the etiology and • Secondary (functional) MR due to left ventricular dilation and systolic hemodynamic consequences of mitral regurgitation. the diagnosis of severe chronic MR should be seriously questioned. there is no specific formula for making this adjustment. regurgitation nor does left atrial size correlate with the elevation of left atrial pressure. which is heard at variable times during cardiomegaly. and prolapsed or flail In patients in the ICU with a right heart catheter in place. This generally The most common finding on the chest radiograph is correlates with the click. severe chronic MR does not exist (with rare exceptions) without clear evidence of left atrial or left ventricular enlargement. the next step is ventricular hypertrophy. the QRS amplitude increases. more sensitive than transthoracic imaging for detection of vegetations Enlargement of the left atrium results in a straightening of the left heart and should be considered when endocarditis is suspected. passing through the leaflet. and • A regurgitant orifice area ≥ 0. has a notching and has a significant negative component in V1 (called "P-mitrale"). or vena contracta. • With mitral regurgitation due to rheumatic fever. resulting from enlargement of the left ventricle and left atrium. the movement pulmonary hypertension. . Calcification of the mitral valve annulus papillary muscle is seen in the left atrium in systole. especially in the precordial leads and lead aVL. and ventricular function. Either one or both leaflets may prolapse to variable degrees. a form of secondary MR. The P wave broadens (>0. The diagnostic finding is opacification of the left atrium severity of MR. left ventricular size does not correlate with the degree of mitral In addition.40 cm2 management of acute mitral regurgitation". clinical features. the lung fields are usually clear unless of the leaflets is markedly exaggerated and the ruptured chord or congestive heart failure is present. (See "Pathophysiology. which can lead to left atrial enlargement. In contrast to its occasional utility in chronic MR. • With endocarditis. border with the appearance of a double density and elevation of the left • When a perforated mitral valve leaflet is present. • When pulmonary hypertension is present. left ventricular angiography may establish the presence and Doppler and color flow Doppler can be used to measure the severity of MR. when clinically can also provide a measure left atrial and ventricular dimensions and left indicated. One study evaluation of chronic MR. • A regurgitant fraction ≥ 50 percent Coronary angiography prior to mitral valve surgery is recommended in patients with chronic MR who have or are suspected to • A jet area >40 percent of left atrial area. The rapidity and density of opacification of the left atrium segment of the jet. The right ventricle is usually normal in size. regurgitant fraction. The simplest approach is measurement of the narrowest during systole. and 88 percent for ruptured chordae. assessment of the overall severity of MR should take into account the cause and acuteness of the lesion. often called "tenting" or fraction occur with chronic severe regurgitation. a jet can be seen main stem bronchus. when compared to surgical diagnosis. which includes a tall R wave in V1 or V2 with R/S ratio >1. unless there is • When a chordal or papillary muscle rupture is present. Left atrial size is usually regurgitation. typically on the atrial side Left ventricular enlargement causes the cardiac silhouette to be of the mitral valve leaflets. The angiogram regurgitant severity can be measured more precisely. flow into the left atrium. there may be evidence of right ventricular hypertrophy. the are when echocardiography does not provide diagnostic information or the accuracy of transesophageal echocardiography was high: 99 percent for findings are discrepant from the clinical features. The diagnosis of severe regurgitation is most secure when more than one of these findings is present. presence of vegetations. Other important dysfunction is characterized by failure of the mitral leaflets to close echocardiographic features are left atrial size. Transesophageal echocardiography is displaced towards the left chest wall and the chamber becomes globular.MITRAL REGURGITATION-EKG AND ECHO Electrocardiogram The electrocardiogram in chronic MR most often reflects the hemodynamic burden placed on the left atrium. However. segment. left ventricular size and systolic function. there is posterior movement of the leaflets Chest radiograph (hammocking) into the left atrium during systole. etiology and mechanism. the leaflets are thickened and redundant. Left atrial size may reflect the "history" (severity and duration) of chronic MR.12 sec in lead II). similar to that seen in mitral stenosis. If transthoracic echocardiography is nondiagnostic. Mitral provides a semiquantitative index of regurgitant severity. left ventricle size and systolic completely and a dilated mitral valve annulus. Similarly. but if image pressures and/or left ventricular angiography is rarely needed for the quality is suboptimal. If the left ventricular end-diastolic dimension (by echocardiography) is less than 60 mm (approximately 35 mm/m2). transesophageal imaging is recommended. The major indications for cardiac catheterization of 248 patients found that. Serial studies permit "tethering" of the leaflets. Other changes are less specific: • When there is left ventricular hypertrophy. becomes increased in amplitude. • With mitral valve prolapse. Regardless of echo-Doppler grading. the following findings are consistent with severe MR: catheterization in patients with acute MR because of the contrast load in an • A vena contracta width ≥ 7 mm already compromised patient. contrast Based upon the 2003 American Society of Echocardiography angiography of the left ventricle is generally avoided at the time of guidelines. In patients undergoing cardiac catheterization for other Severity of MR indications. left atrial size. but this is not so have coronary disease (and who may have ischemic MR) and those at risk reproducible and less often used for coronary disease. by calculation of the regurgitant volume. section on Cardiac • A regurgitant volume ≥ 60 mL catheterization). regurgitant orifice area using standard Doppler approaches. In addition. measurement of changes in ventricular dimensions or left ventricular ejection fraction. Pulmonary pressures also can be noninvasively estimated Cardiac catheterization and angiography using Doppler echocardiography. however. this may not occur in patients who also have left 2D imaging allows accurate determination of the cause of MR. These values are based on an average adult size and may need to be adjusted for body size in small or large patients. Cardiac catheterization for measurement of intracardiac Transthoracic imaging is diagnostic in most cases. Although right ventricular hypertrophy tends to shift Cause of MR the axis to the right. resulting in disease course but progressive ventricular dilation and a decline in ejection inadequate apposition of the leaflets. and pulmonary artery pressures.

and other DPP-IV inhibitors (saxagliptin. repaglinide could be considered as initial Metformin — In the absence of contraindications. Before Sitagliptin can be considered as monotherapy in patients who are intolerant beginning a sulfonylurea. Sulfonylureas — Sulfonylureas are the oldest class of oral hypoglycemic because of modest glucose lowering effectiveness. Dose adjustments TYPE 2 DIABETES MELLITUS NON-INSULIN MEDICATIONS FOR INITIAL THERAPY . with less than 10 percent renally excreted. and rosiglitazone for monotherapy. sulfonylurea. Furthermore. Exenatide requires two daily glipizide. expense. Meglitinides are monotherapy. sitagliptin is more commonly used as a second agent in concentrations by 20 percent and A1C by 1 to 2 percent. if at all. or insulin therapy. especially in older patients. If a thiazolidinedione is used. 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 Meglitinides — Repaglinide and nateglinide are short-acting glucoselowering drugs that act similarly to the sulfonylureas and have similar or agents.5 mg/dL in men). which may limit their acceptance. It is approved in the is similar. rosiglitazone and pioglitazone. or as a third agent when dual therapy with metformin and a sulfonylurea does not provide adequate glycemic control. such as glipizide and gliclazide. Furthermore. pioglitazone is recommended held until renal function and circulation can be established (normal urine because of the greater concern about atherogenic lipid profiles and a output. pharmacologically distinct from sulfonylureas and may be used in patients who have allergy to sulfonylurea medications. The major adverse effect of sulfonylureas is hypoglycemia. This class of drugs is less potent than the have no therapeutic advantage over these other drugs that warrant the sulfonylureas or metformin. It generally reduces A1C by 1. metformin often leads to modest weight reduction or weight stabilization. They have a similar risk for Alpha-glucosidase inhibitors — Because they act by a different mechanism. Thus. clinical trials. The cardiovascular benefits of metformin in the UKPDS need to be confirmed before metformin can be recommended to reduce cardiovascular The United States Food and Drug Administration has approved pioglitazone disease. Factors analyses have questioned the safety of rosiglitazone with regard to the risk predisposing to lactic acidosis are discussed in detail elsewhere. There are inadequate data to support the use of exenatide as slightly less efficacy in decreasing glycemia. However. and no physical exam evidence of fluid overload or circulatory compromise). two to three days after contrast administration. the patient should be instructed about the symptoms and treatment of hypoglycemia. Heart Association class III or IV heart failure. Thiazolidinediones — The thiazolidinediones. sulfonylureas. we do not consider them to be usual first-line therapy because of reduced efficacy. As monotherapy. some metaconcurrent liver disease or alcohol abuse. was removed from the market in the United Kingdom and the United States because of relatively of the aggregate diabetes-related endpoint and all-cause mortality. but severe idiosyncratic hepatic injury that was either fatal or necessitated liver transplantation. In contrast with most other antidiabetic drugs. group. decreased tissue symptomatic heart failure and are contraindicated in patients with New York perfusion or hemodynamic instability due to infection or other causes. acarbose and miglitol. have weight gain as sulfonylureas but possibly less risk of hypoglycemia. given the unknown consequences of long-term age. metformin should not be administered when conditions predisposing to lactic acidosis more expensive than generic sulfonylureas and metformin. the accumulation of active diarrhea. Although these drugs have been studied as monotherapy for initial metabolites and hypoglycemia has occurred. the alpha-glucosidase inhibitors. Drugs in this class are not recommended in patients with above 1. since the efficacy of the available drugs Glucagon-like peptide 1 agonists — Exenatide is a glucagon-like peptide 1 (GLP-1) analog that is administered subcutaneously. reductions in the rare. percentage points. Such conditions include impaired renal function (creatinine entirely clear. The choice of sulfonylurea is primarily dependent upon cost. their those who do not respond to a single agent. The first drug in this class. sitagliptin might be a good choice as acting sulfonylureas may be severe and is often prolonged in the absence initial therapy in a patient with chronic kidney disease at risk for of appropriate therapy. long-acting sulfonylureas. lower blood glucose concentrations by increasing insulin obese patients in the UKPDS who were assigned initially to receive metformin rather than sulfonylurea or insulin therapy had a decreased risk sensitivity. sulfonylureas. In a patient who is not a candidate for metformin or who cannot United States by the FDA for the treatment of type 2 diabetes in patients not tolerate metformin. or thiazolidinediones. points. and poor tolerance. poor nutrition. Risk factors for hypoglycemia include increasing hypoglycemia. Hepatotoxicity does not appear to occur risk of macrovascular complications were maintained in the metformin with rosiglitazone and pioglitazone. Initiation of several countries. and local availability. but metformin monotherapy does probably somewhat less effective in lowering glycemia than metformin.5 to 0. Serum creatinine is typically assessed potential increased risk for cardiovascular events with rosiglitazone. we do not generally choose thiazolidinediones for initial therapy Patients who are about to receive intravenous iodinated contrast material and reserve their use for second-line treatment in combination with other (with potential for contrast-induced renal failure) or undergo a surgical procedure (with potential compromise of circulation) should have metformin anti-diabetic medications where synergistic effects can lower A1C substantially. such as a sulfonylurea. by the liver. and renal insufficiency.8 percentage added cost. Shorter acting DPP-IV inhibition. vildagliptin is available in the preferred sulfonylureas. and heart failure. not usually cause hypoglycemia. and therefore are treatment of type 2 diabetes in the United States.5 to 1. lowering A1C by only 0. In addition. such as sufficiently controlled with oral agents. and limited agents. During the post-interventional observation period of the UKPDS. we prefer to use repaglinide in this situation. additive hypoglycemic effects in patients receiving diet. However. alcohol abuse. normal serum creatinine. and metformin. lowering A1C by 0. DPP-IV inhibitors — Sitagliptin is a DPP-IV inhibitor that is approved as initial pharmacologic therapy for the treatment of type 2 diabetes. Metformin can rarely cause lactic acidosis. troglitazone.4 percentage points. and are considerably and because of the potentially fatal outcome of this side effect. expense. we suggest a shorter-duration sulfonylurea. are less likely to cause Although sitagliptin is currently the only DPP-IV inhibitor available for the hypoglycemia than the older. As an example. As a result.of or have contraindications to metformin. lowering blood glucose clinical experience. With decreased renal function. This drug must therefore be used cautiously in this setting. repaglinide is somewhat more effective in lowering A1C than nateglinide. However. risk of hypoglycemia. Hypoglycemia induced by long. with renal excretion of active The main side effects. They are moderately effective.4 mg/dL in women and 1. the cardiovascular benefit-risk ratio of individual thiazolidinediones is not are present. are flatulence and metabolites.with this agent do not appear to be necessary in patients with renal insufficiency. Nateglinide is hepatically metabolized. In addition. of myocardial infarction. However. Repaglinide is principally metabolized treatment of diabetes. They are also associated with more weight gain and fluid retention than metformin. alogliptin) are in sulfonylurea therapy is also associated with weight gain.5 sulfonylureas. metformin or a thiazolidinedione. effectiveness decreases over time. they are considerably more expensive than sulfonylureas. thiazolidinediones are Gastrointestinal side effects are common. metformin is the first therapy in a patient with chronic kidney disease who is intolerant of choice for oral treatment of type 2 diabetes.

(a) During a forced expiration.75% may be normal or increased because of increased traction on the intrathoracic airway walls. Lung volume relationships are as follows: a. Compliance is reduced because lung elastic recoil is increased. expressed as a percentage (normal.e. TLC = VC + RV b. The FRC reflects the resting position of the lungs and chest wall. and RV/TLC.. causing an increase in the FRC. and is less reproducible than FEV1. small peripheral airway resistance. b. Forced vital capacity (FVC) is the same as VC. between 25% and 75%). D. (3) Chest wall stiffness (e. FEV1/FVC is particularly useful in evaluating obstructive disorders but is also helpful in the evaluation of restrictive disorders. Definition. The FRC has two components: a. However. d. 2. and it is more sensitive than the FEV1 for identifying early airway obstruction. the FEV1/FVC may be normal even with considerable peripheral airway obstruction.. Lung volumes. the range of normal FEF25% . The FEF25% .75% values is wide.75% is the forced expiratory flow rate over the middle half of the FVC (i. The expiratory flow rate is the maximum rate of airflow during forced expiration. because lung elastic recoil is reduced. A reduced FEV1/FVC (<70%) is the time-honored indicator of obstructive airway disease. Raw is decreased because the elastic forces maintain wider airways at any lung volume. restriction is suggested. Lung volumes (1) A reduction in VC and TLC is the most useful indicator of a restrictive ventilatory defect. The FEV1 primarily reflects the status of large airways. RV = FRC + ERV Patterns of pulmonary function impairment 1.e. Lung volumes are the volumes of the various intrapulmonary compartments. age. The portion of the VT that participates in gas exchange is the alveolar volume (VA). 4. (2) In emphysema. b. 6. a. Flow rates.) The FEV1/FVC is effort dependent (i. . Tidal volume (VT) is the volume of air in one breath during normal quiet breathing. (Note: In this case. 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. a. in kyphoscoliosis) lowers lung volumes because it restricts lung expansion. Total lung capacity (TLC) is the volume of air in the lungs after a maximal inspiratory effort. FEF25% . 1.30% of TLC). hyperinflation results. The range of normal is 80% . 7. Airflow increases with increasing effort. Obstructive lung disorders a. 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.120% of the predicted value. The rate of airflow is influenced by lung volume and by effort (i. is or wasted dead space. Forced expiration causes the airways to narrow. 2. it increases with increasing expiratory effort). (b) In small airway disorders. Raw is increased in obstructive lung disease. 3. 2. Other factors influencing flow rate include the elastic recoil of the lung. Static lung volumes reflect the elastic properties of the lungs and chest wall. 500 – 800 mL) varies according to effort and level of ventilation. Forced expiratory volume in 1 second (FEV1) is the volume of air forcefully expired during the first second after a deep breath. The VT (normal. C. FEV1/FVC is the ratio of the FEV1 to FVC. >70%). or the portion of the FVC exhaled in 1 second. functional residual capacity (FRC). (2) Lung stiffness in restrictive diseases increases the lung elastic recoil. Uses. approximately 30% of the VT. b. the alveolar wall destruction and loss of lung elastic recoil cause an increase in the TLC. 2. b. d..g. Introduction Tests of pulmonary function provide three basic kinds of information: 1. Because VC decreases progressively with restrictive lung disease. Compliance is increased in emphysema.75% is effort independent. (1) Lung volume measurements are useful in identifying hyperinflation caused by premature airway closure. if the terminal airways close before all the air is expelled. it can not measure any lung volume containing RV [e.. B.g. it is the lung volume at which the inward recoil of the lungs is balanced by the outward recoil of the chest wall. it is useful. Spirometry is a simple test of pulmonary function. c. Because spirometry cannot measure residual volume (RV). total lung capacity (TLC)]. Functional residual capacity (FRC) is the volume of air remaining in the lungs at the end of a normal expiration. It is useful both as a diagnostic aid and as a monitoring tool. If only the FEV1 is low (FEV1/FVC <70%). Restrictive lung disorders a.. c.e. if both the FEV1 and FVC are low (FEV1/FVC > 70%).75% has a wide range of normality. However. A reduced FEF25% . the RV may increase while the FRC and FEV1 remain normal. The FEF25% . Other lung volumes 1. RV. and the cross-sectional area of larger central airways. Flow rates. 25% . Dynamic lung volumes reflect the patency of the airways. except that the inhalation is performed as rapidly and forcefully as possible. 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. Spirometry 1. in conjunction with DLCO (see I E 1). 3.75% primarily reflects the status of the small airways.Pulmonary Function Studies A. especially at high lung volumes [>75% of the vital capacity (VC)].75% (60% or less of predicted value) may detect airway obstruction when the FEV1/FVC is normal. Changes in lung volume may be seen in moderate-to-severe obstructive airway disease. 5. Diffusing capacity of the lung for carbon monoxide (DLCO) is the efficiency of gas transfer from the alveoli to pulmonary capillary blood. The expiratory reserve volume (ERV) is the amount of the FRC that can be expelled by a maximal expiratory effort. for monitoring the course and response to therapy in a patient with a restrictive lung disorder. RV. thereby slowing the rate of expiration. Vital capacity (VC) is the maximum volume of air that can be expelled from the lungs after a maximal inspiration. obstruction is suggested. thus lowering the FRC. and height. 3. force of expiration). FEV1/FVC and FEF25% . because of air trapping. 2. it is also called the maximal midexpiratory flow rate (MMEFR or MMFR). b. percentage is not a percentage of predicted normal. The RV is the volume of air remaining in the lungs after a maximal expiratory effort (normal. The FEF25% . the remainder.

Spatial excitable gap (EG): pathlength – wavelength. • Crista. • When Ito. It is 4. but only a slight abbreviation of AP in endocardium. 6. found in mid-myocardium of anterior. conduction or shortening of the refractory period or both facilitate the • U waves are due to repolarization of His Purkinje cells. drugs prolong APD in M cells and predispose to arrhythmias. • Half of all cell-to-cell connections are side to side and the other half are end to end. and outflow tract terminates it. After 60 minutes of ischemia irreversible damage occurs to the gap junction membrane and CX43. and Backman bundle propagate sinus impulses rapidly. it • M cells. This mechanism is transmural gradients from cell-to-cell uncoupling (drugs. membrane) and the tissue near the anode (positive electrode) is • Loss of either layer by infarction will lead to prolongation of APD. Unidirectional block: This block can be physiologic: caused by a premature complex. (anisotropic re-entry). • Crista terminalis and pectinate muscle produce anisotropic conduction and act as facilitators of reentry. slow conduction across the crista terminalis (upper loop tachycardia). an outward current. exhibit marked AP prolongation in response to bradycardia and on exposure • Functional reentry is not terminated by entry of the stimulus inside the to class III agents. • At slower rates M cells may contribute to pump efficiency because • Decrease in tissue excitability. • This may occur during ischemia and may result in a decrease of the plateau phase of AP.5). • Ito blockers restore homogeneity and abolish reentrant activity. whether anatomic or functional. which may result in shortening of APD. 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). Quinidine obstacle. • Ectopic beat may alter normal conduction and produce changes in refractoriness which promotes reentry. Slow conduction to prevent collision of the head and the tail of the depolarizing wave: physiologic: caused by AV nodal slow pathway (AVNRT). • Discordant activation of atrial epicardium and endocardium at a faster rate promotes reentry. is dominant it results in APD shortening and The former can be caused by repolarization gradients due to spatial heterogenicity of repolarization (ischemia. • Isoproterenol causes epicardial AP abbreviation more than it does in the • Decrease in conduction velocity. the tissue near the • Epicardium and endocardium electrically stabilize and abbreviate APD of cathode (negative electrode) is depolarized (positive charge on the M cells. endocardium. There are three prerequisites for re-entry: 1. and M cells. or increased heart rate. • If a stimulus enters a vulnerable window of an anatomical reentry. At least two pathways: slow and fast AV nodal pathways. Wavelength (WL): spatial length of the active tissue that is refractory to • Reduced activity of IKs in M cells prolongs APD. and repolarization. pathologic: incisional scars. This may hyperpolarized (negative charge on the membrane). The gap junction membrane provides resistance to current flow Re-entry 1 Re-entry is a depolarizing wave traveling through a closed path. excitable gap. activating IKAch. myocardial infarction.  2. Cycle length (CL)/period: time required for the depolarizing impulse to Pinacidil. discordant repolarization loss of plateau of AP in some epicardial sites producing dispersion of alternans (T-wave alternans during ischemia. vulnerable window. These differences could be aggravated by drugs that prolong • For initiation and maintenance of reentry. On the other hand. responsible for spike and dome morphology of AP in epicardium. Phase 2 reentries • Prominent outward current due to Ito results in shortening of the APD.that results in slower conduction transversely than longitudinally. the exact cellular path might be different in a higher dimension re-entrant circuit where an impulse can travel transversely through myocytes. pectinate muscles. Path length: spatial length of the physical re-entrant circuit. sodium channel blockers Flecainide. autonomic abnormalities). prolonged depolarization permits longer and more efficient contraction. period. This results in anisotropic conduction through the myocardium. Q wave MI. • Multiple reentries may result in fibrillation. This terminates the be the mechanism by which QT prolongation and dispersion occurs in nonarrhythmia. • Organic calcium channel blockers (Verapamil) and inorganic calcium • Decreasing wavelength will increase the tendency to cause reentry channel blocker MnCl2 can cause loss of AP plateau phase in epicardium arrhythmias. • This may be due to weaker IKs activity and stronger late INa activity. decrease in the circuit length will make reentry less likely. • Pacing induces a drift in the reentry circuit. prolongs APD and refractoriness. the re-entrant circuit. termed as phase 2 reentry. Pharmacological differences in epicardium and endocardium • Ach may alter the epicardial repolarization pattern by blocking ICa or Reentry 2 • The size of reentry circuit depends on tissue excitability. Temporal excitable gap (diastolic interval): CL–RP. • Ito is present in ventricular epicardium but not in endocardium. • Amiloride. AV node (AVRT). unidirectional conduction block and the presence of excitable tissue ahead • M cells play an important role in the inscription of T waves by producing a of propagating wave front (excitable gap) are essential. pathologic: ischemic or remodeled cells in atrium and ventricle (ventricular tachycardia. the QT interval or in patients with LQTS. These changes may occur nonuniformly throughout In functional re-entry. A re-entrant circuit can be defined with the following: • Phase 2 reentry may occur in the presence of potassium channel opener 1. unidirectional block can be due to dispersion of the myocardium and cause dispersion of repolarization and phase 2 refractoriness (repolarization) or dispersion of conduction velocity reentries. It has no effect on Ito. • Restitution is described as the recovery of excitability after the refractory • Sodium current block decreases APD in epicardium. heart failure). Bradycardia and class III excitation which is RP x CV (conduction velocity). Reduction in myocardial CX43 results in slowing of conduction velocity. Refractory period (RP): the shortest coupling interval that could capture calcium. This results in local reexcitation and premature beats. This results in slowing and non-uniform conduction. • Ito block may establish electrical homogeneity and abolish arrhythmias • The spiral of reentry wave may drift or it could be fixed (pin) around the due to dispersion of repolarization caused by drugs and ischemia. 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 reentrant activation. . Slowing of gradient between epicardium. by slowing conduction. or pathologic: caused by changes in repolarization gradients. • Reentry can be classic (anatomical) or functional. • Repolarization is sensitive to changes in the heart rate. atrial flutter). accessory pathway or the presence of barrier (anatomic: tricuspid valve. increase in extracellular return to its spatial origin. lateral wall. and functional scar) (Figure 1. 3. 5. and ischemia. 2. • When an electrical shock is applied to the heart. a potassium sparing diuretic. inhibits Ito. • During myocardial ischemia slowing of the conduction occurs due to changes in ion channel function and increased resistance at gap junctions. • It overdrive suppresses normal pacemaker cells. increase in the refractory period and/or endocardium. eliminates reentry. 3. • Block or decrease in calcium current leaves outward currents unopposed. drugs). cavotricuspid isthmus (AFL). • The reentry wave dies when it reaches the border of the tissue.

intermediate. • 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. Carrier Mediated Ion Transport Pumps require ATP to transport. • Negative inotropy by sodium channel blockers may be due to blockage of the slow sodium channel current. The other type of channel block is voltage dependent. Na ion conduction through the channel occurs when the channel is in the open state and not during the resting state. Fewer channels are available in the open state. • Chronic exposure to Na channel blocking antiarrhythmic drugs increases the sodium channel messenger RNA which counteracts the effects of channel blockade. Disopyramide. 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. • 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. Channels display selectivity and gating properties. Ca Pump Pumps Ca out of the cell. Increase in intracellular Ca may lead to EAD and PVC. This leads to an increase in intracellular calcium through sodium/calcium exchange. For example. • β-Adrenergic stimulation reverses the effects of class I drugs.2 Inward currents. • 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. this may result in slowing of conduction and widening of QRS at the normal heart rate. Fig 1. • The process of channel opening is called activation and the process of closing is called inactivation. • During phase 0 Na channels open (open state) for less than 1 millisecond and then become inactive. 1. thus decreasing the effectiveness of the drugs that are open state blockers. 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. • Proarrhythmia from class IC drugs develops during increased heart rate when sympathetic activity is enhanced. The fraction of channels available in the open state is reduced during ischemia. 1 Ca out 3. • Methanesulfonalide Ibutilide prolongs APD by increasing the slow sodium channel current. • Decrease in extracellular pH slows the rate of dissociation of Lidocaine from the sodium channel. • Movement of the sodium occurs through channels and pumps (Fig. In LQT3 SCN5A. drugs with fast kinetic may displace drugs with slower kinetic. thus increasing the time sodium channels spend in the inactivated state. On completion of repolarization the Na channel returns from the inactive to the closed state. • Lidocaine may reverse the Quinidine. It is also called use dependent or frequency dependent block. ii Phasic block occurs when there is a sequential decline in the peak current from beat to beat. Lidocaine produces inactivated state block. thus. dextropropoxylene can be treated with Lidocaine. block accumulates. • Class 1C drugs have the slowest dissociation of 12 seconds. and Flecainide exert use dependent block with fast. This will enhance the effectiveness of the drugs that bind to the inactivated state (Class 1B drug such as lidocaine). Na-Ca Exchange 3Na in. • Angiotensin II increases the frequency of reopening of the sodium channel and increases the Na current. respectively. • Drugs can produce Na channel block during the resting. This causes prolongation of the QT interval. 1. and stretch reduce the resting membrane potential. • Lidocaine and other class 1B agents block the slow component of sodium current and decrease QT in patients with LQT3. Both β1 and β2 subunits are expressed in the Na channels of the brain neurons. Quinidine. which increases during tachycardia. These are called state dependent blocks. • Class 1C drugs are slow to unbind from the channel site and cause slowing of conduction. • The gating process measures current movement rather than ion movement. an Na channel remains open during repolarization resulting in continued inward current. It binds to the activated and inactivated states of the sodium channel. This results in slowing of conduction and widening of QRS.SODIUM CHANNELS AND CURRENTS • Inward movement of the Na or Ca across the cell membrane through the specific channels produces inward current. 2. thus reducing the overall block. or inactivated state. • During phase 2 and phase 3 (plateau phase) less than 1% of sodium channels remain open (inactivated state). • Repolarization occurs due to outward K currents. • During the early part of repolarization Na channels become inactive. • Lidocaine inhibits the inactivated state of the sodium channel. • Class 1A drugs have intermediate kinetics of more than 1 second but less than 12 seconds. • Class 1B drugs have dissociation constant of less than one second. 3 Na out. which may produce incessant tachycardia. It decreases AP upstroke and slows conduction velocity. Na current depolarizes the cell membrane and is voltage dependent.3). • Na and Ca L during entire AP period. Propafenone Flecainide induced block. and slow kinetics. • Lidocaine. open. This increases the fraction of inactivated channels and potentiates the effects of the drugs that act on the inactivated state. • Lidocaine blocks INa by shifting voltage for inactivation to more negative. This type of block increases with repetitive stimulation. . Drug kinetics and channel state • Membrane depressants such as increased extracellular potassium. During resting potential the sodium channel is closed. Passive & Electrochemical gradient dependent ion movement. Fig 1. • Drugs with different binding kinetics may interact. • Voltage-dependent opening of Na channel occurs as voltage decreases and conformational change in channel protein occurs (activation). • Ventricular tachycardia due to Flecainide. • Channels flip between conducting and non-conducting states. hydrogen. It is seen in drug-induced reduction of current during infrequent stimulation. it is effective in ischemic zones.3 Ion pumps and channels. • Ca T during early period. A combination of acidosis and membrane depolarization increases the block produced by Lidocaine. Slow sodium currents (inward) • Agents that increase the slow component of sodium current (Diphenylmethyl. Na and Ca inward transport. Beta blockers may reverse this phenomenon.Piperanzinyl-Indole derivatives) are likely to increase inotropy by increasing the entry of Na during the plateau phase. During inactivation phase channel enters a nonconducting state while depolarization is maintained. Yew needle toxin. • When all the gates (active or inactive) are open would a channel allow the passage of the ions. • There are no β2 subunits of sodium channel in cardiac myocytes. If the interval between AP is less than four times the recovery constant of the channel. • During the resting state dissipation of block occurs (drugs dissociate from the site). Ion Channels for K. 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. • Quinidine. • Class 1A drugs increase APD. and Propafenone produce open channel block. • Two different sodium channel blocking drugs may act synergistically. Na-K Pump 2 K in.

fo its perpetuation. chest pressure. Since the b bypass tract does not have generallly s the same decrementall conducting prope s erties as the AV node. LFF–PARKINSON N–WHITE SYNDR ROME WOL Pre-e excitation. near to t His bundle pot ght the tential re ecording that cond ducts rapidly but w a long refracto period. It could be located on th left side or the right side of the A he AV junct tion. olff–Parkinson–Wh syndrome is applied to patients with hite a both pre-excitation on the ECG and paro oxysmal tachycard Ebstein’s dias. the PR interval is longer than st R r the RP interval. A i o Another way to initiate the tachycard is dia with a premature ventr ricular contraction (PVC) early enou to be blocked ugh nje retrogradely in the AV node–His. Atrioventricular nod re-entrant tach A dal hycardia (AVNRT) is by far the most t co ommon regular re e-entrant SVT. and is referred to as antidromic tac .SUPRAVENTRICU S ULAR TACHYCAR RDIA IN NTRODUCTION Supraventricular ta S achycardia (SVT) c be defined as any tachycardia can re equiring the atrium or the atrioventriicular (AV) node. This may last fro a few seconds or om minutes to several hours. . SVT is a very co or ommon group of arrhythmias (90%) seen in cllinical practice.8 He s ence the RP interv is longer than the PR interval. PSVT is m commonly se in patients wit most een thout st tructural heart dise ease. hea females and do not have structural heart disease. Rarelly (10%). Supraventricular tachycardias rarely cause sud s dden ca ardiac death. AVRT occurs in th presence of an accessory pathw ents he n way or by ypass tract. It is twice as comm in males as o mon fema The term Wo ales. which reach the AV node w hes when the fast path hway is at contraction (P re efractory from the previous sinus im mpulse. w s which is the most co ommon sustained arrhythmia encou d untered in clinical practice. re eflecting conductio over the AV no and His-Purkin system. which conducts w anter rograde through th normal AV nod he de–His-Purkinje sy ystem and retrogra ade throu an accessory pathway located a ugh along the AV junc ction. S zy. A slow pat thway is located at the lo posteroseptal r ow region of the right atria inside the triangle of Koch. the ventricula ar respo onses during atria flutter or fibrillation may be quite rapid and. Atrial flut tter and atrial fibrillation (A also may occur more commonly in patients with W a AF) y WPW syndrome. Syncope or sudden cardia death may occu by e ac ur this mechanism. anom is the most co maly ommon congenita anomaly associa with WPW al ated syndrome and often co onsists of multiple bypass tracts. Surfa ECG may prov clues to the lo m ace vide ocalization of acce essory pathways a direct mapping The approach described by Arrud et and g. Th QRS complex duration is typicallly narrow (<120 m he ms). and aVF d ually ads F. wh hich co onducts impulses slowly with a short refractory period A fast pathway is d. y opal SVT lig with w uncontrolled ventricular rates ca cause tachycar an rdia-related ca ardiomyopathy an present with fea nd atures of congestiv heart failure.1 P ECG 1–0. cents are more like to have SVT m ely mediated by an accessory pa y athway. CLINICAL PRESENTATION C Symptoms are variable and depend on the presence o underlying hear S of rt disease. or the W Wolff–Parkinson–W White (WPW) syndrome ECG patte ern. (iv short RP/long P interval vs long RP/short PR inte v) PR g erval tachycardias s. A population-based study in Wiscons reported an inc d sin cidence of 35/100 000 0 person-years and a prevalence of pa aroxysmal SVT (P PSVT) of 2. The pre with ory esence of these anatomic/f f functional pathway is the requirem for AVNRT to exist. e m either in whole or in part. the cond duction may exhib a reverse patter bit rn with anterograde cond duction through the bypass tract and retrograde e d cond duction through the normal AV syste This produces a tachycardia w a e em. is more co ommon in males a presents at a younger age than and n patie with AVNRT. o chycardia. the fast pathway is fully re ecovered and is re eady to co onduct it in a retro ograde manner an initiates the tach nd hycardia cycle. AVNRT is more common in patients w are who of middle age or old while adolesc f der. the right ones are commonly associated with Eb s bstein’s anomaly. is characterized by han g (i) a PR interval less th 120 ms during sinus rhythm. Occasiona patients may h m ally. slowly rising onse of the QRS in so leads (delta w et ome wave) and usually a normal termina y al QRS portion. d da al ap ppears to be more precise. The preva ncreases with age. F From an an natomopathology point of view. This cha apter briefly discusses th ECG diagnosis. Ventricular p premature beats ty ypically initiate this s type of arrhythmia and P-waves are usu inverted in lea II. III. thes accessory path se hways are extra bund of conducting tissue that bridge the atria and the ventricles. it is not seen on the surface electrogra way y s am and is therefore said to be concealed. have shortness of breath f or ‘air hunger’. III. t RT althy patients with AVNR are young. with wide QRS complex. e impu arrives at the atria the AV node has recovered an is able to condu ulse e nd uct anteg grade the impulse and initiate the ta e achycardia circuit. At times atrial tion and activity may be see to distort the terminal part of the QRS complex.3% in the gen neral population. lo ocated in the anter roseptum of the rig atria. the AV nodal tissue may have function multiple path P e nally hways with w different electr rophysiologic prop perties. but on ode nje so ometimes can hav a wide QRS co ve omplex due to pre-existent or ratedependent bundle branch blocks or o other aberrant inte erventricular conduction disturbances. Irregular SVT includes atrial fibrillation. also known as orthodromic tachy ycardia. This pattern results fro a fusion of activation of the ventricles over both th om he bypa tract and the A node–His-Purk ass AV kinje system. Mechanism of AV M VNRT Physiologically. clinical presentat he tion. also val t know as atypical AVN wn NRT. In 10% of patients the re R % e-entry circuit is re eversed. The reported prevalence is r 0. AVRT.Purkin system. in which the ventric are totally actiivated by the bypa n cles ass tract. The incidence of ventricular pre-ex f xcitation (Wolff– in Parkinson–White E pattern) is 0. or pa Sometimes pa ain.3% in the general population. e The most common ma anifestation of WPW syndrome is PS with conduction SVT similar to AVRT. By the time the PAC comple its e etes co ourse in the slow pathway. atients will feel ghtheaded or dizz and rarely they will feel presynco or syncopal. and a and pseudo R-waves in V1. rate of ven ntricular response and the overall c e. but able to be retroconducted to the atria through the a accessory pathwa By the time the ay. condition of the pa atient. Usua P-waves are n seen and are b m ally not buried in the QRS S co omplex due to sim multaneous activat of ventricles a atria. Typical presentatio includes palpita T on ations or a sensatio that the heart is on beating rapidly or flluttering or racing. Most of the ent ular. The dles e arrhy ythmia could be in nitiated by a prema ature atrial beat. pseudo S-waves in leads II. AV RE-ENTRANT TA R ACHYCARDIA AV re e-entrant tachycar (AVRT) is the next most common cause of PSVT rdia e T. with the anter rograde conductio over the fast pa on athway and retrograde conduction o over the slow pathway. ve AV A NODAL RE-EN NTRANT TACHYC CARDIA AVNRT is by far the most common c A cause of PSVT and accounts for 50– –60% of patients who prese with rapid.25/1000 0 alence is twice as high in women as compared to men and it s persons. ex EPIDEMIOLOGY E The T frequency of th group of rhythm disorders is abo 1–3 per 1000 p his m out persons. pro en oducing n aVF. Elec ctrocardiographica AVNRT is characterized by regu ally ular narrow QRS tachyc cardia with heart r rates in the range of 150–250 beats per s minute (bpm). and S (iii) secondary ST-T wa changes that are generally dire s ave ected in an opposite direc ction to the major d delta wave and QRS vectors. in rare al r circumstances. Usually AVNRT is triggered by a prematu ure trial PAC). and management xcluding atrial flutter and atrial fibrillation. Antidro tachycardia is omic s more common among patients with multiple accessory pa e athways. The development of A in these patients is thought to be most commonly d d AF due to de egeneration of an A AVRT. If the access sory pathw conducts only retrogradely. CLASSIFICATION C N Supraventricular ta S achycardias can be classified into tw types based on the e wo n siite of origin or re-e entry: (i) atrial tachycardia and as tachycardias.1 to 0. ys ment An A electrophysiolog study usually s gic shows evidence of dual AV nodal pa athway physiology in 40% of patients. acco ounting for 30% of the cases. (ii) atrioventricular t Other classification based on ECG criteria include the following: O ns e (i) regular vs irregu tachycardia. (ii) a QRS complex duration exceeding 120 ms with a slurred. Since the co onduction of the p premature atrial be is anterograde through the slow eat e pathway and retrog grade over the fas pathway. may ca ause VF. (iii) AV node depen ndent vs AV node independent. regu narrow QRS tachycardia. ular (ii) narrow vs wide QRS complex.

No profound hypotension.TILT TABLE TEST In comparison to healthy subjects.3 ms/mmHg 1170 + 420 ms2 975 + 200 ms2 55 + 5 % 30 + 5 % 3500 + 1100 ms2 < 2.e. 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. Symptoms can include light-headedness. on body surface area (BSA) 3 Calculated from beat-to-beat finger blood pressure curve.0-5. the onset of the syncopal phase can be identified by an immediate withdrawal of sympathetic tone. fatigue. 3. MIXED SUBTYPE: Asystole for 3 or more seconds and fall in systolic blood pressure of 50 mmHg or more. CAROTID SINUS HYPERSENSITIVITY Diagnosis by carotid sinus massage 1. i. 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. Type I: Mixed 1. patients suffering from neurally mediated syncope often show less baro-reflex sensitivity. CARDIOINHIBITORY SUBTYPE: Asystole of 3 or more seconds. VASODEPRESSOR SUBTYPE: Fall in systolic blood pressure of 50 mmHg or more. Asystole for more than 3 seconds does not occur 3. Blood pressure falls before the heart rate falls Type 2A: Cardioinhibition without Asystole 1.15-0. Heart rate falls to less than 40 but only for less than 10 seconds 3. -0.0 < 2. 2. 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.04-0.e. In the case of vasovagal syncope. Blood pressure falls before the heart rate falls Type 2B: Cardioinhibition with Asystole 1. 0.0 .40 Hz) Normalized Units Low Frequency (LFnu_RRI) Normalized Units High Frequency (HFnu_RRI) Power Spectral Density (PSD_RRI) LF/HF Ratio (LF_RRI/HF_RRI) Sympatho-Vagal Balance (LF_dia/HF_RRI) Normal Value > 9. presyncope and dizziness.5 L/min/m2 800-1200 dyne*sec/cm5 1200-2400 dyne*sec*m2/cm5 3. VASOVAGAL SYNCOPE There are three types of vasovagal syncope.5-4. 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.0 kg*m/min/m2 33-65 1000/s 21-50 1/kOhm 500-1000 mmHg/s on sBP and dBP. Heart rate falls but not to 40 or less beats/min or 2. PARAMETERS OF THE AUTONOMIC CARDIOVASCULAR REGULATION4 Parameter Baroreflex Sensitivity (BRS) Heart Rate Variability –LF (LF_RRI. HEMODYNAMIC PARAMETERS Parameter Heart Rate (HR) RR-Interval (RRI) Systolic Blood Pressure (sBP) Diastolic Blood Pressure (dBP) Mean Arterial Blood Pressure (mBP)1 Stroke Volume (SV) Stroke Index (SI)2 Cardiac Output (CO) Cardiac Index (CI)2 Total Peripheral Resistance (TPR) Total Peripheral Resistance Index (TPRI)2 Left Ventricular Work Index (LVWI) Index of Contractility (IC) Thoracic Fluid Content (TFC) Maximum Rise in Pressure (dP/dt)3 1 Depending 2 Depending Normal Value 60-90 bpm 660-1000 ms 90-140 mmHg 50-90 mmHg <105 mmHg 60-120 ml 30-80 ml/m2 4-8 L/min 2. Asystole occurs for more than 3 seconds 2. Heart rate falls to less than 40 beats/min for more than 10 seconds 2. this parameter is only displayed in the software application “pacemaker”. 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.15 Hz) Heart Rate Variability – HF (HF_RRI.

Patients can also complain of an unusual awareness of their own voice (autophony) and of ear discomfort. Tinnitus may improve when patients Somatic sounds may be perceived as tinnitus. the cochlear nerve (with its projections to and from the cochlea). with a change in head position. Dural AVFs are often associated with dural venous sinus thrombosis. These muscles are enervated by cranial nerves V and VII respectively. Vestibular schwannoma — Tumors compressing or stretching the cochlear nerve can cause tinnitus. Tinnitus can result when otosclerosis damages cochlear structures. The presence of tinnitus often is an early associated with turbulent blood flow. and originate in structures with respond favorably to treatment for symptoms of TMJ dysfunction and craniocervical proximity to the cochlea. hearing loss. Abnormal auditory-evoked magnetic field potentials associated with tinnitus can be suppressed in selected patients with intravenous lidocaine. Eustachian tube dysfunction — A patulous eustachian tube can cause tinnitus with sounds similar to an ocean roar that may be synchronous with respiration. 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. remains abnormally patent. within the jugular bulb. 42 percent were found to have a significant vascular disorder (most commonly a dural arteriovenous fistula [AVF] or a carotid-cavernous sinus fistula). endocrine or metabolic damage to the auditory system. congenital hearing loss. early detection and treatment (surgery and/or vascular embolization) can be lifesaving for high grade lesions. Tinnitus originating from the auditory system — Most tinnitus is due to a sensorineural hearing loss with resulting dysfunction within the auditory system. or neuropathy related to metabolic or toxic etiology. Known neural feedback loops act to help tune and reinforce auditory memory in the central auditory cortex. 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). As with many other causes of tinnitus. and also in the presence of neurologic disease such as multiple sclerosis. Other etiologies — Hearing loss due to a variety of causes. but may involve disinhibition of the dorsal cochlear nucleus. although the patient may require an evaluation for underlying atherosclerotic disease. a change in neural firing between the end-organ and These patients usually do not have other otologic complaints (eg. Some vascular tinnitus. Venous hums — These may be heard in patients with systemic hypertension. 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. or with activity. Large dural AVFs can result in intracranial hemorrhage. vascular in etiology. Pathogenesis — Recent pathogenetic theories target the central nervous system as the source or "generator" of all tinnitus that does not have a somatic origin. or a lesion of the cochlear nerve) can result in abnormal neural activity in the auditory cortex. confirming a central tinnitus phenomenon and potentially indicating a physiologic mechanism for lidocaine sensitive tinnitus.Other somatic disorders — Somatic non-pulsatile tinnitus is commonly caused by temporomandibular joint (TMJ) dysfunction. It is believed to be encoded in neurons within the auditory cortex. aberrant carotid artery. disease. It has also been associated with whiplash injuries and other cervical-spinal disorders . the brainstem (site of the cochlear nuclei). Tinnitus has also been likened to a type of auditory seizure. Patients may also complain of hearing loss or aural fullness associated with these muscle spasms. facial nerve or lower cranial nerve palsies). Acquired arteriovenous fistulas (AVFs) are more likely to be symptomatic. is usually not somatic in origin. nonvascular disorders such as paraganglioma or intracranial hypertension (due to a variety of causes) explained the tinnitus. or tinnitus. genetic predisposition. Paraganglioma — This is a vascular neoplasm arising from the paraganglia cells found around the carotid bifurcation. aural fullness). though not exclusively. Arteriovenous shunts — Congenital arteriovenous malformations (AVMs) are rarely associated with hearing loss or tinnitus. noise trauma. crickets. even in patients whose associated hearing losses are due to cochlear injury. atherosclerotic plaque narrowing of vessels. Other cranial nerves may also be affected (eg. as in the case of prolonged noise the hearing threshold in that ear. can be non-pulsatile. The majority of patients have "sensorineural" tinnitus. serious condition. they commonly cause a loud pulsing tinnitus that may interfere with hearing. Ototoxicity affects the various components of the cochleovestibular end-organ. with otitis media). It most commonly occurs after significant weight loss or after external beam radiation to or near the nasopharynx. tumor. because of local otologic disease. the history and physical examination should include a search for other neurologic disease. nerve compression. their tinnitus is greatest the remainder of the auditory system can be exhibited by hearing loss. can produce tinnitus to a variable degree. A current theory likens tinnitus to phantom pain perception that is thought to arise from a loss of suppression of neural activity. Tinnitus with a machine-like or pulsing character is sometimes associated with intracranial lesions. due to hearing loss at the cochlea or cochlear nerve level. including vascular ischemic events. or surgery.ETIOLOGY/PATHOGENESIS Tinnitus can be triggered anywhere along the auditory pathway. 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). When such structures are damaged. or source. or in patients with a dehiscent or dominant jugular bulb (abnormally high placement of the jugular bulb). Progressive otosclerosis can result in fixation of the stapes footplate and worsening conductive hearing loss. in quiet environments (eg at night). Tinnitus in patients with a venous hum is often described as a soft. Clicking noises or irregular or rapid pulsations may also result from myoclonus of the palatal muscles that attach to the Eustachian tube orifice. The cause of these symptoms is a eustachian tube that 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. or bells in the ear) along with the hearing loss. Myoclonus of the palatal muscles most often is caused by an underlying neurologic abnormality. These sounds are often generated in vascular structures. increased intracranial pressure (often due to pseudotumor cerebri). Such activity has been linked to the perception of tinnitus. TINNITUS . Etiologies of tinnitus generated from within the auditory system are as varied as the Arterial bruits — Arterial vessels near the temporal bone may transmit sounds types of noises that patients report . The petrous carotid system is the most common exposure. As the tumor enlarges. especially if the loudness of the sound exceeds indicator of cochlear hair cell dysfunction or loss. such as multiple sclerosis. An arterial bruit is not itself a ototoxicity. or may be palpable in the neck. such as venous hums and tinnitus due to the primary and secondary auditory cortical projections. Somatic sounds are most often associated with pulsatile tinnitus and continuous tonal tinnitus (single pure-tone) either the TMJ or the cervical spine is not known. Ototoxic medications — Tinnitus is commonly caused by ototoxic medications. low-pitched hum that may decrease or stop with pressure over the jugular vein. Tympanometry and otoscopy can be particularly useful in diagnosing middle ear spasmodic activity. Such muscle spasms can occur spontaneously. 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. although other arteries may also be involved. such as chondrosarcoma. The latter may also cause a conductive hearing loss. patients with pulsatile tinnitus should be thoroughly evaluated. Also known as glomus tumors. and endolymphatic sac tumors. 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 . trauma. which may occur spontaneously or be associated with infection. vertigo. distortions in hearing. microvascular disease affecting the brainstem. In 12 patients (14 percent). 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. and Vascular disorders — Pulsatile tinnitus is most commonly. allowing too much and then too little aeration of the middle ear space with respiration. infection. The symptoms may disappear when the patient lies down. In a retrospective review of 84 patients with pulsatile tinnitus seen in a neurology department. it may cause hearing loss because of impingement on the ossicular chain (conductive loss) or the labyrinth or cochlea (sensorineural loss). The lesion may be visible through the tympanic membrane as a reddish or blue mass. or along the tympanic arteries in the middle ear. Thus. Meniere's syndrome (also characterized by aural fullness and vertigo). . The exact neurophysiologic mechanism for the generation of tinnitus from but may also be produced by musculoskeletal structures. The auditory system includes the cochlear end-organ. and antiseizure medications have had limited success in some patients.

which in turn activates the Na/Ca exchanger to extrude Ca from the cell. which may trigger SR calcium release. Sodium and calcium exchange and DAD • Opening of voltage-operated Ca channels. They are called EAD because they occur before the completion of AP repolarization (Fig. • EAD occurs in Purkinje fibers and M cells of the myocardium. • ICaL is a primary depolarizing factor responsible for EAD. • Lowering of pH blocks sodium/calcium exchange. Flunarizine. • Other conditions that can cause EAD are bradycardia. • TDP often follows short long short CL. There are two types of after-depolarizations. • Catecholamines increase sarcolemmal calcium by stimulating sodium/calcium exchange. Phase 2 EAD Phase 3 EAD DAD CIRCA in SR Reactivation of ICaL Fig 3. • DAD occurs when there is a pathologically high calcium load either due to digitalis toxicity or following reperfusion. EAD that occur during phase 3 of APD are due to the Na/Ca exchange current. Sotalol). • Reduced gap junction coupling also slows conduction velocity. Reverse mode will increase intracellular calcium. Excitability and conduction • Excitability is dependent on the availability of sodium channels. during the plateau phase of APD. in the presence of hypokalemia and bradycardia prolong repolarization and induce EAD. . • Slow conduction due to decreased gap junction coupling requires contribution of ICaL. • Quinidine and hypokalemia produce EAD and triggered activity resulting in TDP. • Increase in the level of catecholamines and cAMP enhances Ca uptake and causes DAD in atrial and ventricular myocytes. An increase in the inward current and/or a decrease in the outward current may induce EADs. • EAD is generated by recovery and reactivation of ICaL. because of the 3 : 1 ratio of Na/Ca exchange. • DADs are associated with fast heart rate and Ca overload. which may predispose to reentrant arrhythmias.1). due to decreased excitability. • EAD caused by inward sodium current are abolished by sodium channel blocker Mexiletine.1 Mechanisms of EAD and DAD. • Withdrawal of cholinergic stimulation increases calcium in atrial myocytes and may cause DAD. • Pharmacological agents such as potassium channel blockers (Quinidine. and Cisapride increase APD and cause EAD. This mechanism applies to phase 2 (plateau) EAD. This generates. Lidocaine shortens APD and thus decreases DAD. This provides time for reactivation of ICaL. ICaL does not participate in DAD. This activates INa/Ca. inwardly directed current INa/Ca is observed. • DAD is induced by a spontaneous release of calcium from the overloaded SR. • Phase 3 EAD shares the mechanism of DAD. • The delicate balance between depolarizing and repolarizing currents controls the plateau phase of the AP. ICaL influences conduction during reduced coupling. hypokalemia. It is this second phase of reactivation of inward ICaL that produces EAD by depolarizing the membrane. increases the flux of Ca into cytoplasm. It inhibits the Na/K pump and leads to an increase in intracellular calcium. • During diastole calcium is removed from the cell by the sodium/calcium exchange pump. which may cause DAD. which may allow ICaL to induce inward depolarizing currents. • Increase in the extracellular ATP levels potentiates the DAD effect of catecholamines. • SR calcium ATPase. resulting in prolongation of plateau. • INa causes slow conduction. 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. This causes CICR from SR. a large inward current that causes depolarization and DAD. The amplitude of the DAD depends on CL. reactivation of ICaL induces EAD. • Na/Ca exchange is able to transport calcium bi-directionally. It is caused by inward currents produced by an increase in the intracellular Ca load. and increase in Ca current induced by sympathetic stimulation in the presence of ischemia or injury. Early after-depolarizations Phase 2 EAD • EAD occurs when a large inward current during the plateau phase occurs. Delayed after-depolarization • DAD occurs after repolarization of AP. • Slow conduction could be due to decreased membrane excitability or reduced gap junction coupling. Longer CL allows for more calcium entry into cells. • Once the plateau is prolonged. thus reduced Na channel activity will reduce excitability and conduction velocity. Summary • DADs occur during calcium overload due to Ca release from SR. • The most common cause of DAD is Digoxin. 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). • During calcium removal. early and delayed. respectively. Examples include persistent inward INa in LQT3 and reduced IKr and IKs in LQT2 and LQT1. Torsades De Pointes (TDP) • TDP is a polymorphic ventricular tachycardia (VT) associated with long QT syndrome (LQTS). • EAD does not require a spontaneous release of calcium from SR and does not require inward activation of INa/Ca. Sarcolemmal calcium ATPase. 3. While INa controls excitability. • ICaL plays a dominant role in maintaining conduction in the setting of reduced coupling. located in the cell membrane. • Quinidine may increase DAD by prolonging APD. • Magnesium. and Ryanodine can abolish EAD by decreasing the intracellular calcium load. • Longer APD favors DAD. • IKr blockers such as Erythromycin. • EAD may occur during the plateau phase and are caused by Ltype Ca current. Piperidine derivatives that block histamine H1 receptors such as Astemizole and Terfenadine. • EAD occurs before and DAD occurs after completion of AP repolarization.Triggered Activity • Triggered activity is initiated by after-depolarization. • Reduced membrane excitability and reduced gap junction coupling slows conduction. Initial event in TDP is EAD-induced triggered activity. which reduces the outward current caused by delayed rectifier IK.

• MinK. which could be inwards or outwards. Ambasilide) or IKur (Ambasilide) will be therapeutically superior. Short APD of the atria is due to IKur. . acts as a function altering β subunit of KvLQT1. class III agents (D-Sotalol). The drug is more effective at a slower heart rate. • Reduced activity of IKs in M cells prolongs APD. • Rapidly activating and inactivating voltage-sensitive transient outward current produces phase 1 of repolarization. • The effect of IKs but not of IKr is enhanced by β-adrenergic stimulation. • In human atrium it recovers rapidly from inactivation. Slowly activating delayed rectifier IKs • IKs is controlled by the gene KvLQT1 (voltage-dependent potassium controlling protein) and MinK (minimal potassium current controlling protein). which is characterized by rapid activation and inactivation. 1. and contributes to faster repolarization. • IKr and IKs are present in the human atrium and ventricle. • Slow deactivation of IKs is important for rate dependent shortening of AP. Quinidine binds to open channel. IKur . A high heart rate increases the prevalence of IKs. a protein. • In atrial fibrillation (AF) repolarizing outward currents (IK. Reduction of these currents may exacerbate the arrhythmic effect of hypokalemia and hypomagnesemia.4 mEq/L decreases QTc by 24% and decreases QT dispersion. its slow recovery from block causes a rate dependent effect. • Potassium channels are closed at resting potential and open after depolarization. MinK combined with protein of KvLQT1 induces IKs. Flecainide binds to inactivated Ito1. Normally. • IKur is an ultra rapid current. Propafol (Anesthetics) Benzodiazepine. and chromanol block IKs. i Transient outward current (Ito). • Inhibition of Ito prolongs repolarization in diseased human ventricle. which has several components (Fig. Thus. • IKur decreases with increasing heart rate. • Increase in serum potassium by 1. • Activation of protein kinase C increases IKs. • Ito2 is calcium activated. • It is enhanced by β-adrenergic agonists and is inhibited by αadrenergic agonists. • Bradycardia and class III drugs. I to and J wave • J wave (Osborn wave). Prolongation of AP plateau increases the strength and duration of contraction. IKs has less time to deactivate during shortened diastole. • KCNH2 (HERG. It is a potassium selective outwardly rectifying current. prolong APD and predispose to arrhythmias. • Two types of voltage-gated channels play a major role in repolarization. • Inward rectification of IKr results in a small outward current. • Increasing cAMP either by β-adrenergic stimulation or by phosphodiesterase inhibitors increases IKs. but the activity of IKr is increased. IKatp 3. it accumulates in an open state. Delayed rectifier potassium channels have slow onset of action. Rapidly activating delayed rectifier IKr • It is blocked by methane sulfonamide. which reduce IKs in M cells. Classification of potassium currents 1. It limits the outward flow of potassium through IKr and IKs during a plateau. • MinK suppression leads to inner ear abnormalities and deafness.POTASSIUM CHANNELS AND CURRENTS Voltage Gated Currents • There are more than eight types of potassium currents. 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. Use of class III drugs in patients with CHF needs reevaluation as the intended target (K channels) is down regulated or absent. IKach. and Ambasilide inhibit Ito. • The plateau phase of the action potential (AP) depends on the balance between inward (depolarizing) and outward (repolarizing) currents.1 Outward currents. • K channels carry a positive charge. which includes fast inactivating rapid component IKr and slow component IKs. repolarizing outward currents are reduced by 50%. thus allowing rapid repolarization at a fast heart rate. Delayed and inwardly rectifying voltage sensitive potassium channels • Rectification is a diode-like property of unidirectional current flow. Background currents = IKp • AP duration (APD) determines the amount of calcium influx and tissue refractoriness. • Mutation in MinK and KvLQT1 causes congenital long QT syndrome (LQTS). • IKur is also found in intercalated disks. • The efficacy of IKr blockers is limited by inverse rate dependency. the effects of pure IKr blockers will be antagonized by sympathetic stimulation. • It plays an important role in atrial pacemaker cells. Quinidine. It is inversely related to heart rate. MinK modifies KvLQT1 gating and pharmacology. • Increase in intracellular magnesium decreases and increase in intracellular calcium increases IKs. and inward rectifier IK1. • Slowly activating delayed rectifier potassium current. • Drugs inhibiting IKs (Amiodarone.1): • IKr is a rapidly activating current with inward rectification. • Potassium currents (outward movement of the K through the potassium channels) are the main contributors to repolarization. which acts as a voltage sensor. • IKr is increased in the presence of elevated extracellular potassium. • Indapamide (Diuretic). This offsets the k blocking effects of the IKr blockers. • IKp is a time independent background plateau current. Fig 1. • Ito is present in ventricular epicardium but not in endocardium. IKur current • It is responsible for atrial repolarization. Transient outward potassium current (Ito)5 • There are two types of Ito currents: Ito1 and Ito2. It also increases refractoriness. increased extracellular potassium will decrease the outward potassium current by decreasing the chemical gradient. IKr . • IKs is a slowly activating current. As the heart rate increases. ii Delayed rectifier IK. which is insensitive to IKr blocker.contributes to plateau and phase 3 of AP. Voltage gated currents = Ito . • Flecainide. Quinidine and Ambasilide block IKur in a rate independent fashion. It also demonstrates fast unbinding. Expression of both these proteins is necessary for normal function of I1 Ks. It rapidly recovers from inactivation and it peaks at −40 mV. This increases APD and results in early after depolarization (EAD) and arrhythmias. • Potassium channel expression is decreased in hypothyroid and hypoadrenal states. Thiopental. Ito) are reduced. • Selective IKr blockers (D-Sotalol) lose efficiency at high rates and during sympathetic stimulation. • Voltage gated potassium channels are activated during AP upstroke. • In congestive heart failure (CHF) and in left ventricular hypertrophy (LVH). Inwardly rectifying currents = IK1. • 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). IKs 2. Human Ether Related-a-go-go gene protein) encodes IKr channel. It is responsible for spike and dome morphology of AP in epicardium. • IKur is absent from the human ventricular myocardium. • Prominent J waves are often seen in hypothermia and hypercalcemia. seen in the Jarvell Lange-Nielson syndrome.

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