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Monte Minute

A brief blog about interesting cases happening around Monte. Brought to you by the Chiefs, with guest blogging by our RAT residents.

Alcoholic Hepatitis - by Keon Combie

posted Jun 15, 2015, 2:29 PM by Kevin Hauck

Alcoholic hepatitis

Clinical presentation

- Rapid onset jaundice

- Enlarged and tender liver

- Fever

- Ascites

- Proximal muscle loss

- Can have encephalopathy in severe cases


Lab findings

AST: ALT ratio >2. However, this is neither sensitive nor specific

LFTs are rarely higher than 300

Elevated bilis

Elevated INR

Elevated WBCs- neutrophil predominant


Differential Diagnosis

- Nonalcoholic steatohepatitis, acute or chronic viral hepatitis, drug-induced liver injury, fulminant Wilson’s disease, autoimmune liver disease, alpha-1 antitrypsin deficiency, pyogenic hepatic abscess, ascending cholangitis, and decompensation associated with hepatocellular carcinoma.

Diagnosis can be confirmed on liver biopsy to help rule out other causes but lab findings as stated above in clinical context of heavy alcohol use is enough to make the diagnosis.


Assessing severity

There are several scoring systems used which helps decide whether corticosteroids should be initiated.  Lille score is designed to help decide if corticosteroids could be stopped after 1 week.

Maddrey’s discriminant function is calculated as [4.6×(patient’s prothrombin time−control prothrombin time, in seconds)]+serum bilirubin level, in milligrams per deciliter. A value of more than 32 indicates severe alcoholic hepatitis and is the threshold for initiating corticosteroid treatment


One study showed that patients with a Maddrey’s discriminant function of 32 or more and a Glasgow alcoholic hepatitis score of 9 or more who were treated with corticosteroids had an 84-day survival rate of 59%, as compared with a 38% survival rate among untreated patients.

The Lille score can be used to decide whether or not to stop corticosteroid treatment after 7 days. Al lille score greater than 0.45 indicates a lack of response and a 6 month survival rate of <25%

MELD score is useful as some patients may eventually become transplant candidates.



- Management of alcoholic hepatitis includes both general treatment for decompensated liver disease and specific treatment for underlying disease.

- Management should include treatment of ascites with salt restriction and diuretics and encephalopathy with lactulose

- Patients should have workup for bacterial infection such as pneumonia, spontaneous bacterial peritonitis, and urinary tract infection blood and urine cultures, cell count, culture of ascitic fluid if present, and chest radiography.

- Enteric feeding should be initiated with daily protein intake of 1.5 g/kg even in setting of hepatic encephalopathy as these patients tend to be anorectic. Thiamine supplementation should also be given.

- It is also important to be wary of alcohol withdrawal which should promptly be treated with short acting benzodiazepines despite their risk of hepatic encephalopathy.


- The cornerstone of treatment as with all other alcoholic liver disease is abstinence and psychosocial support should be provided for patients. There is no evidence regarding efficacy of craving-reducing medications such as acamprosate and naltrexone in patients with alcoholic hepatitis. However, baclofen has been reported to promote short term abstinence in active drinkers with alcoholic cirrhosis.


- For patients with a Maddrey’s discriminant function of 32 or more in absence of sepsis, hepatorenal syndrome, chronic hepatitis B infection and GI bleeding should be treated with corticosteroids to curb inflammation. The most common corticosteroid therapy for alcoholic hepatitis is prednisolone at a dose of 40 mg per day for 28 days. At the end of the course of treatment, the prednisolone can be stopped all at once, or the dose can be gradually tapered over a period of 3 weeks.


- Pentoxifylline, a phosphodiesterase inhibitor, has been shown to reduce short term mortality in randomized control trials. The exact mechanism of this effect is not clear but it is speculated to be related to the prevention of hepatorenal syndrome.


- There has been conflicting results regarding use of Anti-TNF agents which have also been shown to increase risk of infection and death. As such, these agents are not standardly used.


- Alcoholic hepatitis is an absolute contraindication to liver transplant given the patient’s active alcohol abuse. A period of abstinence (6 months) is required before a patient with alcoholic hepatitis can be eligible for transplantation.


Rhythm Control vs. Rate Control in Atrial Fibrillation - by Philip Aagaard

posted Jun 15, 2015, 2:25 PM by Kevin Hauck

Rhythm Control is not dead. Rate vs. Rhythm Control Revisited



Atrial fibrillation (AF) is the most common clinical arrhythmia and its incidence is predicted to increase due to the ageing population.[1] AF has several important clinical consequences, including an increased risk of stroke, heart failure and mortality, as well as a negative impact on quality of life.

Important risk factors for developing AF include hypertension, diabetes, and age.[2] In fact, age is the most important risk factor and the prevalence of AF increases from 0.7 % to 17.8% between the 6th and 9th decade of life.[3]

The most common triggers in new onset AF are pulmonary vein (PV) ectopy.[4] However, once an individual has developed AF, important structural and electrical remodeling occur in the atria that create a milieu which facilitates further progression and maintenance of AF, a concept known as “AF begets AF”.[5] This concept may help explain why AF commonly starts out as self-terminating episodes, i.e. paroxysmal AF, which can later progress to become persistent, and ultimately become long-standing persistent. When the patient remains in AF despite repeated attempts to maintain sinus rhytm (SR), and/or when such a strategy has been deemed futile, chronic AF is diagnosed.[6]



Atrial fibrillation has several negative hemodynamic consequences. Heart rate (HR) elevation in AF can cause myocardial ischemia, energy depletion and calcium handling abnormalities, eventually leading to tachycardia-induced cardiomyopathy.[7-10] Furthermore, the decreased ventricular filling during short cardiac cycles in AF cannot be fully compensated for during longer cycles, leading to a decrease in total cardiac output.[11] Finally, the loss of atrial contraction and atrio-ventricular synchrony in AF further reduces cardiac output. Importantly, patients with significant co-morbidities such as heart failure (HF), who may be less able to tolerate the loss of coordinated atrial contraction and atrioventricular synchrony during AF, may derive particular benefit from restoration and maintenance of SR.[12] In addition to its effects on cardiac performance, AF also leads to atrial blood stasis, increasing the risk of cardiac thrombus formation with a subsequent increased risk of stroke.[13] However, despite these known adverse consequences of AF, weather to choose a rhythm or rate control strategy in AF remains controversial.


Rate control

When a rate control strategy is chosen, the optimal rate has been considered to fall in the 60-80 BPM range at rest, and in the 90-115 BPM range during moderate exertion.[14] However, findings from the RACE-II trial failed to show a difference between strict (<80 BPM at rest and <110 BPM with moderate exertion) and more lenient rate control (<110 BPM at rest and with moderate exertion).[15] Beta-blockers or non-dihydropyridine calcium channel blockers (e.g. Diltiazem and Verapamil) are the initial drugs of choice for rate control in patients with AF. When these drugs fail to sufficiently reduce HR, digoxin can be added as an adjunctive agent. In patients who fail pharmacologic rate control, atrioventricular node ablation and ventricular pacing is an option of last resort.[16]


Rhythm control

Rhythm controling agents are used to maintain SR. There are several available agents including amiodarone, flecainide, propenafone, dronedarone, and dofetilide. However, their use is limited by pro-arrythmic effects (increased risk of malignant ventricular arrhythmias), significant drug–drug interactions, and adverse effects. For example, long-term use of amiodarone, one of the more commonly used rhythm control agents, is associated with significant pulmonary, hepatic, and thyroid toxicity and increases the risk for symptomatic bradycardia requiring pacemaker implantation.[17, 18] Promising newer AAD are under investigation, however, this is a topic beyond the scope of this review.[19]

Rate vs. rhythm control

Whether rhythm or rate control is the best strategy in HF failure patients with AF is, as stated previously, controversial. The AFFIRM and RACE trials showed no benefit of pharmacological rhythm control over pharmacological rate control in a general AF population.[20, 21] There was no difference, regardless of strategy, with respect to the endpoints of mortality, or hospitalization for HF or stroke. However, definite conclusions should not be drawn from these trials due to substantial crossover between treatment groups. Also, only pharmacological rhythm control therapies were evaluated and the negative results may partly reflect the poor efficacy of antiarrhythmic drugs to maintain SR. [20-22] In fact, an on-treatment analysis of the AFFIRM trial showed that patients that maintained SR had better outcomes. [23] While this may represent selection bias, it is also possible that the benefits of maintaining SR are offset by the adverse effects of the drugs. Therefore, a therapy that restores SR without the adverse effects of AADs could be superior to rate control.  AF ablation may offer such an opportunity.


Ablation strategies

The observation that ectopic beats originating near the pulmonary veins are responsible for the majority of paroxysmal AF episodes sparked interest in ablation as a curative therapy for AF.[24] Today, AF ablation by pulmonary vein isolation successfully restores SR in 60 to 80% of AF patients. A landmark study in 2004 showed that AF ablation resulted in significant improvements of left ventricular function, exercise tolerance, symptoms and quality of life.[12] This improvement occurred independent of the level of pre-procedural rate control, suggesting that factors other than rate (e.g. loss of atrial contraction, atrioventricular dyssynchrony, etc) also drives the deterioration of cardiac function in AF patients. Large clinical trials, including the CABANA trial, powered to also detect differences in mortality between AF ablation and rate control are currently ongoing, with Montefiore as one of the participating centers.  


1.         Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129:837-47.

2.         Kirchhof P, Lip GY, Van Gelder IC, et al. Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options--a report from the 3rd Atrial Fibrillation Competence NETwork/European Heart Rhythm Association consensus conference. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2012;14:8-27.

3.         Heeringa J, van der Kuip DA, Hofman A, et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. European heart journal. 2006;27:949-53.

4.         Kalifa J, Jalife J, Zaitsev AV, et al. Intra-atrial pressure increases rate and organization of waves emanating from the superior pulmonary veins during atrial fibrillation. Circulation. 2003;108:668-71.

5.         Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995;92:1954-68.

6.         January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130:2071-104.

7.         Shinbane JS, Wood MA, Jensen DN, et al. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. Journal of the American College of Cardiology. 1997;29:709-15.

8.         Van Gelder IC, Crijns HJ, Blanksma PK, et al. Time course of hemodynamic changes and improvement of exercise tolerance after cardioversion of chronic atrial fibrillation unassociated with cardiac valve disease. The American journal of cardiology. 1993;72:560-6.

9.         Wilson JR, Douglas P, Hickey WF, et al. Experimental congestive heart failure produced by rapid ventricular pacing in the dog: cardiac effects. Circulation. 1987;75:857-67.

10.       Zipes DP. Atrial fibrillation. A tachycardia-induced atrial cardiomyopathy. Circulation. 1997;95:562-4.

11.       Gosselink AT, Blanksma PK, Crijns HJ, et al. Left ventricular beat-to-beat performance in atrial fibrillation: contribution of Frank-Starling mechanism after short rather than long RR intervals. Journal of the American College of Cardiology. 1995;26:1516-21.

12.       Hsu LF, Jais P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. The New England journal of medicine. 2004;351:2373-83.

13.       Shively BK, Gelgand EA,Crawford MH. Regional left atrial stasis during atrial fibrillation and flutter: determinants and relation to stroke. Journal of the American College of Cardiology. 1996;27:1722-9.

14.       Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-354.

15.       Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. The New England journal of medicine. 2010;362:1363-73.

16.       Doshi RN, Daoud EG, Fellows C, et al. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). Journal of cardiovascular electrophysiology. 2005;16:1160-5.

17.       Singla S, Karam P, Deshmukh AJ, et al. Review of contemporary antiarrhythmic drug therapy for maintenance of sinus rhythm in atrial fibrillation. Journal of cardiovascular pharmacology and therapeutics. 2012;17:12-20.

18.       Weinfeld MS, Drazner MH, Stevenson WG, et al. Early outcome of initiating amiodarone for atrial fibrillation in advanced heart failure. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2000;19:638-43.

19.       Trulock KM, Narayan SM,Piccini JP. Rhythm Control in Heart Failure Patients With Atrial Fibrillation: Contemporary Challenges Including the Role of Ablation. Journal of the American College of Cardiology. 2014;64:710-21.

20.       Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. The New England journal of medicine. 2002;347:1825-33.

21.       Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. The New England journal of medicine. 2002;347:1834-40.

22.       Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. The New England journal of medicine. 2008;358:2667-77.

23.       Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109:1509-13.

24.       Haissaguerre M, Shah DC, Jais P, et al. Electrophysiological breakthroughs from the left atrium to the pulmonary veins. Circulation. 2000;102:2463-5.

Steroids and Sepsis

posted Mar 5, 2015, 5:36 PM by Kevin Hauck

A wonderful Monte Minute brought to you by our rising Firm 1 chief resident, Rebecca Braunstein!

Steroids and Sepsis

By Rebecca Braunstein



So, pressors and shock. This is a topic we encounter often over residency, probably most in the MICU but not infrequently on the floors as well. The question is, when should we initiate steroids in sepsis?

So the first question is, why would we do that? The theoretical answer is to help an  altered or insufficient HPA axis during a time of extreme stress, leading to insufficient cortisol and mineralocorticoid. Annane et al (same as group who subsequently conducted a large RCT described below) demonstrated in an observational study JAMA 2000 that ACTH stim test had prognostic value—specifically, that higher initial cortisol level (>34) and an INADEQUATE response to ACTH stim test (change in cortisol of <9) were associated with increased mortality.

But does treating with steroids work? The earliest trials in the 1980s-1990s had varying results, ranging from no mortality benefit to as beneficial as more rapid reversal of shock and earlier ability to withdraw pressors. A concern in treating with steroids includes side effects, especially immunosuppression and superinfection.

Two larger RCT’s were subsequently done, which are the papers we most frequently reference.

 A word on types of steroids: hydrocortisone is a pharmacologic form of cortisol. It has both glucocorticoid and mineralocorticoid activity (about 50/50). Fludrocortisone (used in trial #1 below only) is a pure mineralocorticoid.

1) French trial JAMA 2002 – Annane et al.

- Design: 300 patients in shock on pressors, randomized/double blinded, randomized to receive: treatment with hydrocortisone 50 Q6hr and fludrocortisone 50mcg qday (mineralocorticoid activity only) for 7 days versus placebo. All patients underwent an ACTH stim test to assess adrenal response, and classified into responder (ie adequate adrenal response) and non-responder categories.


For primary end point of 28 day mortality:

Main finding: non-responders ie inadequate adrenal response group: decrease in 28 day mortality (hazard ratio 0.67, confidence interval 0.47-0.95)

No statistically significant difference in the following groups:

All patients: no change in 28 day mortality (hazard ratio 0.65 with confidence interval 0.39-1.07)

Adequate adrenal response group: no change in 28 day mortality (HR 0.97, CI 0.32-2.99)

 This sort of makes sense, right? The patients who were unable to mount a robust stress response benefited from the hydrocortisone/fludrocortisone replacement therapy. Of note, there was no increase in adverse effects secondary to steroids in the treatment group.

2) CORTICUS trial- NEJM 2008

- Design: 499 patients with septic shock (not necessarily on pressors), multicenter, randomized/double blinded, randomized to receive: hydrocortisone 50 Q6hr vs placebo for 5 days. ACTH stim test was done to determine adrenal response and divided into similar groups as above, responders and non-responders.


In summary, there was no mortality benefit in any group or in all patients. The treatment group had faster reversal of shock and increased incidence of superinfection, although not statistically significant.

Here are a few numbers to chew on—

For 28 day mortality, RR 1.09 (0.84-1.41) in all patients. For non-responders, RR 1.09 (0.77-1.52) and for responders, RR 1.00 (0.68-1.49).

Risk of superinfection in treatment arm vs placebo was 1.27 (0.96-1.68)— not quite significant. 


What should we make of these conflicting data?

Differences in studies:

1) Annane study had sicker patients based on clinical prediction scores, and the fact that they were all steroid dependent – this is reflected in total mortality in both placebo groups (61% in Annane vs 32% in CORTICUS).

2) Time to onset of enrollement into trial Annane et al trial within 8 hrs versus 72 hours in CORTICUS.



A number of meta-analyses have been performed. With all of this data together, the main conclusions have been:

1) Steroids are most likely to benefit patients with more severe or refractory septic shock (where fluids and pressors fail to restore hemodynamic stability).  Steroids may be harmful in septic shock of lesser severity.

2) Based on doses used in trials, “stress” steroids is recommended to be hydrocortisone 50mg Q6hr for 5-7 days with some degree of taper. Fludrocortisone is not included based on the idea that hydrocortisone has mineralocorticoid activity and a different trial (COIITSS) which did not show a difference in outcomes with addition of fludrocortisones to hydrocortisone.

3) ACTH stim test is not routinely recommended. has failed to reliably identify patients with septic shock that benefit from corticosteroid use.

Constrictive Pericarditis

posted Mar 5, 2015, 5:34 PM by Kevin Hauck   [ updated Mar 5, 2015, 5:46 PM ]

A Fantastic Monte Minute brought to you by Jian Shan from Firm 2!  It was based on a November CRS. 

56M with PMH of hypothyroidism, CKD, ‘cryptogenic cirrhosis’ with chief complain of dyspnea for 2 weeks with worsening LE swelling and abdominal distension.



Constrictive pericarditis is the end stage of an inflammatory process involving the pericardium. In the developed world, the etiology is most commonly idiopathic, postsurgical, or radiation injury (Table 1). Tuberculosis is the most common cause in the developing world. It usually takes months to years to develop constriction after initial injury. The end result is dense fibrosis, often calcification, and adhe­sions of the parietal and visceral pericardium. Scarring is usually more or less symmetric and impedes filling of all heart chambers.


TABLE 1 Causes of Constrictive Pericarditis






Autoimmune (connective tissue) disorders




Methysergide therapy

Implantable defibrillator patches



Pericardial scarring is markedly restricted filling of the heart which results in elevation and equilibra­tion of filling pressures in all chambers and the systemic and pulmo­nary veins. In early diastole, the ventricles fill abnormally rapidly because of markedly elevated atrial pressures and accentuated early diastolic ventricular suction, the latter related to small end-systolic volumes. During early to mid diastole, ventricular filling abruptly ceases when intracardiac volume reaches the limit set by the stiff pericardium. As a result, almost all ventricular filling occurs early in diastole.


Systemic venous congestion results in hepatic congestion, peripheral edema, ascites and sometimes anasarca, and cardiac cir­rhosis. Reduced cardiac output is a consequence of impaired ventricu­lar filling and causes fatigue, muscle wasting, and weight loss. In “pure” constriction, contractile function is preserved, although ejection frac­tion can be reduced because of reduced preload. The myocardium is occasionally involved in the chronic inflammation and fibrosis, leading to true contractile dysfunction that can at times be quite severe and predicts a poor response to pericardiectomy.


High systemic venous pressure and reduced cardiac output result in compensatory retention of sodium and water by the kidneys. Inhibition of natriuretic peptides also may contribute to renal sodium retention, further exacerbating increased filling pressures.

Clinical Presentation

·          Signs and symptoms of right-sided heart failure: LE edema, vague abdominal complaints, and passive hepatic congestion happen at a relative early stage.

·          As the disease progresses, hepatic congestion worsens and can prog­ress to ascites, anasarca, and jaundice due to cardiac cirrhosis.

·          Signs and symptoms ascribable to elevated pulmonary venous pressures: exertional dyspnea, cough, and orthopnea, Atrial fibrillation and tricuspid regurgitation.

·          In end-stage constrictive pericarditis, the effects of a chron­ically low cardiac output are prominent: severe fatigue, muscle wasting, and cachexia.

·          Other findings: recurrent pleural effusions and syncope.

·          Constrictive pericarditis can be mistaken for any cause of right-sided heart failure as well as end-stage primary hepatic disease.

Physical Examination

·          markedly elevated jugular venous pressure with a prominent, rapidly collapsing y descent, combined with a normal x descent, results in an M- or W-shaped venous pressure contour

·          Kussmaul sign, an inspiratory increase in systemic venous pressure, is usually present,or the venous pressure may simply fail to decrease on inspi­ration. These characteristic abnormalities of the venous waveform contrast with tamponade.

·          A paradoxical pulse occurs in perhaps one third of patients with constriction, especially when there is an effusive-constrictive picture.  Table 75-3 is a comparison of hemodynamic findings in tamponade and constrictive pericarditis.

·          pericardial knock, an early diastolic sound best heard at the left sternal border or the cardiac apex. It occurs slightly earlier and has a higher frequency content than a typical third heart sound. Widen­ing of second heart sound splitting may also be present.

·          Abdominal examination reveals hepatomegaly, often with palpable venous pulsations, with or without ascites.

·          Jaundice, spider angiomas, and palmar erythema may exist.

·          Lower extremity edema is the rule.

·          With end-stage constriction, muscle wasting, cachexia, and massive ascites and anasarca may appear.

Table 2: Hemodynamics in Cardiac Tamponade and Constrictive Pericarditis





Paradoxical pulse

Usually present

Present in 1/3

Equal left- and right-sided filling pressures



Systemic venous wave morphology

Absent y descent

Prominent y descent (M or W shape)

Inspiratory change in systemic venous pressure

Decrease (normal)

Increase or no change (Kussmaul sign)

“Square root” sign in ventricular pressure







Laboratory Testing

ECG. There are no specific electrocardio­graphic findings. Nonspecific T wave abnormalities, reduced voltage, and left atrial abnormality may be present. Atrial fibrillation is also common.

CHEST RADIOGRAPHY. The cardiac silhouette can be enlarged secondary to a coexisting pericardial effusion. Pericardial calcification is seen in a minority of patients and suggests tuberculosis.  but calcification per se is not diagnostic of constrictive physiology. Pleural effusions are occasionally noted and can be a presenting sign of constrictive pericarditis.


ECHOCARDIOGRAPHY.  Pericardial thickening, abrupt displacement of the interventricular septum during early diastole (septal “bounce”), and signs of systemic venous congestion such as dilation of hepatic veins and distention of the inferior vena cava with blunted respiratory fluctuation. Premature pulmonic valve opening as a result of elevated right ventricular early diastolic pressure may also be observed. Exaggerated septal shifting during respiration is often present.

Tissue Doppler examination reveals increased E′ velocity of the mitral annulus as well as septal abnormalities corresponding to the bounce. Tissue Doppler appears to be at least as sensitive as mitral-tricuspid inflow Doppler for diagnosis of constriction. Superior vena caval flow velocities are helpful in distinguishing constrictive pericarditis from chronic obstructive pulmonary disease. Patients with pulmonary disease display a marked increase in inspiratory superior vena caval systolic forward flow velocity, which is not seen in constriction. TEE is superior to TTE for measuring pericardial thickness and has an excellent correlation with CT. When mitral inflow velocities by TTE are technically inadequate or equivocal, measurement of TEE pulmonary venous Doppler velocity demonstrates pronounced respiratory variation, larger than that observed across the mitral valve.

CARDIAC CATHETERIZATION AND ANGIOGRAPHY. Cardiac catheterization provides documentation of the hemodynamics of constrictive physiology and assists in discriminating between constrictive pericarditis and restrictive cardiomyopathy. Whereas there is limited need for contrast ventriculography, coronary angiography should ordinarily be performed in patients being considered for pericardiectomy. On rare occasions, external pinching or compression of the coronary arteries by the constricting pericardium is detected.

Both right and left ventricular pressures reveal an early, marked diastolic dip followed by a plateau (“dip and plateau” or “square root” sign; Fig. 3). Stroke volume is almost always reduced, but resting cardiac output can be preserved because of tachycardia. Depression of stroke volume is primarily caused by reduced diastolic filling.

 COMPUTED TOMOGRAPHY AND CARDIAC MAGNETIC RESONANCE. CT provides detailed pericardial images and is helpful in detecting even minute amounts of pericardial calcification. Its major disadvantage is the frequent need for iodinated contrast medium to best display pericardial disease. The thickness of the normal pericardium measured by CT is <2 mm. CMR provides a detailed and comprehensive examination of the pericardium without the need for contrast material or ionizing radiation. It is somewhat less sensitive than CT for detection of calcification. The “normal’’ pericardium visualized by CMR is up to 3 to 4 mm in thickness. This measurement most likely reflects the entire pericardial “complex,” with physiologic fluid representing a component of the measured thickness.

Additional findings include distorted ventricular contours, hepatic venous congestion, ascites, pleural effusions, and occasionally pericardial effusion. Cine acquisition (CMR or CT) shows abnormal motion of the interventricular septum (septal bounce) in early diastole.  Enhanced uptake of gadolinium appears useful for detection of pericardial inflammation. There is a cohort of patients with well-documented constriction who have no pericardial thickening on the basis of measurements in pathologic specimens despite histologic evidence of inflammation and calcification. These patients constituted 18% of those with constrictive pericarditis in a Mayo Clinic series. Almost all had normal pericardial thickness by CT. Calcification and distorted ventricular contours occurred in a majority, providing clues to the diagnosis despite normal thickness.

Differentiation of Constrictive Pericarditis from Restrictive Cardiomyopathy

Because their treatment is radically different, distinguishing constrictive pericarditis from restrictive cardiomyopathy is extremely important (Table 3).

ECHO: TEE measurements of pericardial thickness correlate well with CT. With use of two-dimensional speckle tracking, differences in contraction mechanics that are useful in distinguishing constriction from restriction have been described. In constriction, deformation of the left ventricle and early diastolic recoil velocity were attenuated in the circumferential direction, whereas in restriction, they were attenuated in the longitudinal direction. Doppler measurements are also useful in differentiating constrictive from restrictive physiology. Enhanced respiratory variation in mitral inflow velocity (>25%) is seen in constriction; in restriction, velocity varies by <10%. In restriction, pulmonary venous systolic flow is markedly blunted and diastolic flow is increased. This is not observed in constriction. Hepatic veins demonstrate enhanced expiratory flow reversal with constriction, in contrast to increased inspiratory flow reversal in restriction. Tissue Doppler echocardiography and color M-mode flow propagation are complementary to mitral Doppler respiratory variation in distinguishing constriction from restrictive cardiomyopathy. Higher tissue Doppler mitral annulus E′ values in constriction versus restrictive cardiomyopathy are reported to have a higher sensitivity than mitral inflow parameters for making the distinction.

Cath: In both conditions, right and left ventricular diastolic pressures are markedly elevated. In restrictive cardiomyopathy, diastolic pressure in the left ventricle is usually higher than in the right ventricle by at least 3 to 5 mm Hg; in constrictive pericarditis, left- and right-sided diastolic pressures typically track closely and rarely differ by more than 3 to 5 mm Hg. Pulmonary hypertension is common with restrictive cardiomyopathy but rare in constriction. The absolute level of atrial or ventricular diastolic pressure elevation is also sometimes useful in distinguishing the two conditions, with extremely high pressures (>25 mm Hg) much more common in restrictive cardiomyopathy. Finally, the ratio of right ventricular to left ventricular systolic pressure-time area during inspiration versus expiration is greater in constriction versus restriction (reflecting exaggerated ventricular interaction) and is reported to have a high sensitivity and specificity for distinguishing between them.

CT and CMR:  Pericardial calcification or distorted ventricular contour is helpful in making the correct diagnosis in these patients.

Endomyocardial or abdominal fat pad biopsy: This establishes the diagnosis of restrictive cardiomyopathy due to amyloidosis.

Brain natriuretic peptide (BNP) levels: May be useful in distinguishing constriction from restriction. BNP is reported to be elevated in restrictive cardiomyopathy and normal in constriction. More recent data indicate that this difference is more useful in secondary constriction (e.g., postoperative, irradiation) than in idiopathic cases.


Table 3. Hemodynamic and Echocardiographic Features of Constrictive Pericarditis Compared with Restrictive Cardiomyopathy




Prominent y descent in venous pressure



Paradoxical pulse

1/3 of cases


Pericardial knock



Equal right- and left-sided filling pressures


Left at least 3-5 mm Hg > right

Filling pressures >25 mm Hg



Pulmonary artery systolic pressure >60 mm Hg



“Square root” sign



Respiratory variation in left- and right-sided pressures or flows



Ventricular wall thickness


Usually increased

Atrial size

Possible left atrial enlargement

Biatrial enlargement

Septal bounce



Tissue Doppler E′ velocity



Pericardial thickness







Surgical pericardiectomy is the definitive treatment. surgery should not be delayed once the diagnosis is made.


·         Transient constriction should be suspected in patients presenting relatively earlier after cardiac surgery or with relatively rapid development of symptoms. Such patients can be monitored for several months to look for spontaneous improvement. They may respond to a course of corticosteroids.

·         High risk patients: Patients with major comorbidities or severe debilitation are often at too high risk to undergo pericardiectomy. Radiation-induced disease is also considered a relative contraindication to pericardiectomy. Healthy older patients with very mild constriction may also be managed nonsurgically, with pericardiectomy held in reserve until there is disease progression. 


Medical management with diuretics and salt restriction is useful for relief of fluid overload and edema, but patients ultimately become refractory.

treatment of sinus tachycardia:  it is a compensatory mechanism, beta-adrenergic blockers and calcium antagonists should be avoided. In patients with atrial fibrillation and a rapid ventricular response, digoxin is recommended first. In general, the rate should not be allowed to drop below 80 to 90 beats/min.


Prognosis of pericardiectomy:

Hemodynamic and symptomatic improvement is achieved in some patients immediately after operation. In others, improvement may be delayed for weeks to month. After pericardiectomy, 70% to 80% of patients remain free from adverse cardiovascular outcomes at 5 years and 40% to 50% at 10 years. Long-term results are worse in patients with radiation-induced disease, impaired renal function, relatively high pulmonary artery systolic pressure, reduced left ventricular ejection fraction, moderate or severe tricuspid regurgitation, low serum sodium, and advanced age.

Pericardiectomy has a 5% to 15% perioperative mortality in patients with constriction. The highest mortality occurs in patients with Class III or IV symptoms, supporting the recommendation of early pericardiectomy.


2014 ATPIV Guidelines

posted Mar 5, 2015, 5:16 PM by Kevin Hauck   [ updated Mar 5, 2015, 5:18 PM ]

Here's a fantastic Monte Minute brought to you by one of our rising chief residents, Mayce Mansour! 

2014 ATP-IV Evidence-Based Guidelines for the Management of Hyperlipidemia


Whether in the CCU or in primary care clinic, lipid management is a recurrent, bread-and-butter theme in medical management.  In recognition of myocardial infarction and stroke being leading causes of mortality, the National Cholesterol Education Program was created in 1985 to address hyperlipidemia as a public health concern.  The goal of this program was to raise awareness of hyperlipidemia as a risk factor for coronary heart disease.  Most recent guidelines have broadened this focus to include risk assessment of atherosclerotic cardiovascular disease (ASCVD)—i.e., non-fatal and fatal MI, non-fatal and fatal CVA.  A panel of experts, the Adult Treatment Panel (ATP), was subsequently created to provide data-driven practice guidelines.   The ATP-IV guidelines released in November 2013 have fundamentally changed the way we approach lipid management—moving from LDL goals to atherosclerotic cardiovascular disease risk stratification. 


-Who do we screen?

-Why have current guidelines moved away from LDL goals?

-What are suggested lifestyle modification guidelines?

-How are “statin benefit” groups defined?

-How are “statin intensity” categories defined?  Which statins fall into these categories?

-What are the new guidelines?


Who do we screen?

Per the ATP-IV guidelines, we should be screening everyone >21yrs every 4-6 years.

Per the USPTF, we should be routinely screening men>35yrs (grade A), women>45yrs (grade A), OR men 20-35yrs and women 20-45yrs “at increased risk for coronary heart disease” (grade B).  We should be screening every 5 years.

Why have current guidelines moved away from LDL goals?

Prior to the newest ATP-IV guidelines, you may all remember our previously LDL goal targets (LDL<130 “desirable,” <100 “optimal,” <70 for highest-risk groups).  The most recent report moved away from these guidelines because most clinical trials did not treat to a goal, but instead used different intensities of statins in their treatment arms.  Therefore, insufficient evidence was found for LDL/HDL treatment goals in the prevention of primary and secondary ASCVD, and we have moved away from this management strategy.  Interestingly, since most trials with non-statin cholesterol medications focused solely on LDL-lowering (and NOT on clinical outcome reduction), you will notice non-statins are conspicuously missing from the newest ATP-IV guidelines.  Current guidelines suggest using non-statins only if statins are not tolerated or if goal LDL percent-reduction is not reached despite maximal statin therapy.


What are suggested lifestyle modification guidelines?

Remember, this is always the FIRST approach to lipid management—both on tests and in real life.

ACC/AHA lifestyle management guidelines:

·         Diet—

o   Increase intake of vegetables, fruits, whole grains

o   Include nuts, low-fat dairy products, poultry, fish and vegetable oils

o   Limit red meat

o   Fats:

§  <5-6% total calories from saturate fat

§  reduce % calories from transfats

o   Limit sodium intake to help with blood pressure reduction

·         Physical activity: aerobic exercise moderate to vigorous intensity, 3-4x/week, 40 mins/session

How are different “statin benefit” groups defined?


Group 1

Clinical ASCVD: acute coronary syndrome, primary MI, stable/unstable angina, prior coronary artery revascularization, stroke, TIA and peripheral artery disease

Group 2

LDL>190 mg/dl (ages 21 and older)

Group 3

Diabetes- Type 1 or 2 (ages 40-75)

Group 4

10-year ASCVD risk >7.5%


Conspicuously missing is guidance on folks in groups 3 and 4 who are <40yrs or >75yrs.  Additionally, our old friend Framingham is no longer in the picture, though in completing the ASCVD risk calculator, you’ll see a resemblance.  In order to broaden included patient populations, the ASCVD risk calculator is based on a combination Framingham, CARDIA, ARIC, and Cardiovascular Health studies.


How are “statin intensity” categories defined?  Which statins fall into these categories? 


Goal: LDL reduction by…




Simvastatin 10mg

Pravastatin 10-20mg

Lovastatin 20mg

Fluvastatin 20-40mg



Atorvastatin 10-20mg

Rosuvastatin 5-10mg

Simvastatin 20-40mg

Pravastatin 40-80mg

Lovastatin 40mg

Fluvastatin 40mg BID



Atorvastatin 40-80mg

Rosuvastatin 20-40mg


Finally…what are the new guidelines? 

****see Mayce's wonderful ATP4 diagram below****

*Don’t forget, this is simply a risk-estimator— at the end of the day, clinical judgment and patient-centered goals are crucial to starting any new intervention.

**Consider treating with statin (or increasing to high-intensity statin) in this category if:

·         Family history of premature CVD (1st degree M<55yrs, F<65yrs)

·         CRP>2mg/L

·         Coronary artery calcium score >300 Agatston units or >75th percentile for age, gender, ethnicity

·         Ankle-brachial index <0.9


For those of us strongly rooted in the race-as-social-construct camp, the heavy reliance on race in determination of risk calculation is tricky—particularly the markedly increased risk for patients classified as African American; per ATP-IV guidelines, in order to determine risk of patients with Asian or Hispanic descent (not specific categories in risk calculator), you should estimate risk for same-gender white individuals and assume lower-risk.  Additionally, the cut-off of ASCVD 10-year risk >7.5% is viewed as overly-aggressive by some groups.  In one subsequent analysis, the 10-year risk of having MI/stroke was overestimated by 75-150% by the risk calculator; subsequently, other expert panels have suggested that cut-offs of 10-15% may be more appropriate. 


ACC/AHA Expert Panel. 2013 ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Am Coll Cardiol, 2013.

ACC/AHA Expert Panel. 2013 ACC/AHA Guideline on the assessment of cardiovascular risk: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation, 2013.

ACC/AHA Risk Calculator: Calculator:

Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 201310.1016/S0140-6736(13)62388-0. 

Thyroid Storm

posted Mar 5, 2015, 5:02 PM by Kevin Hauck

Another Monte Minute, this time brought to you by PGY3 Janine Lebofsky, on Thyroid Storm! Based on one of our CRS from way back in October (the lateness is on my part!). 

Definition: life-threatening, rare, severe exacerbation of hyperthyroidism

Etiology: Usually precipitated by acute illness: surgery (especially thyroid surgery), stroke, radio iodine load in patient with partially treated or untreated hyperthyroidism, acute infection, trauma, childbirth.


-     Clinical manifestations are the same as those of untreated hyperthyroidism but tend to be more severe:

-    tachycardia to 140s (most commonly sinus tachycardia, but atrial fibrillation can occur and is more likely in patients over 50 years old)

-    hypotension

-    anxiety, tremors, psychosis, seizure, delirium

-    coma

-    fever

-    vomiting, diarrhea, jaundice

-    Physical exam findings can include moist and warm skin, goiter, ophthalmoplegia (only if Graves’ Disease present), lid lag, tremors, altered mental status.

Laboratory Values:

-    TSH, T3 and T4 reveal suppressed TSH and elevated T3 and free T4

-    Other lab abnormalities may include hypercalcemia (due to hemoconcentration and increased bone resorption), hyperglycemia (due to increased catecholamine activity inhibiting insulin release), abnormal liver function tests, leukocytosis or leukopenia


-    Diagnosis is a clinical diagnosis based on symptomatology, physical exam findings, thyroid function studies.

-    There are no validated clinical tools, but one known scoring system is called the “Burch Criteria” which assigns numerical value to different clinical manifestations of disease to help determine suspicion level of disease.


-    Same as for hyperthyroid but with higher doses of medication and more frequent administration

-    ICU care is indicated due to high mortality rate, as high as 30% even with treatment

-    Beta blocker: for symptom management (often propanolol is used, can be given intravenously when vital signs can be closely monitored, need to watch closely for hypotension/negative inotropic effects)

-    Thionamide (propylthiouracil/PTU or methimazole) used to block hormone synthesis. PTU is preferred for initial treatment over methimazole, because it blocks T4 to T3 conversion (methimazole does not). However, methimazole should be used for long-term treatment as it has a longer duration of action than PTU and is less hepatotoxic. Neither PTU nor methimazole acts to prevent release of already formed thyroid hormone.

-    Iodine solution given to block release of T3 and T4. Give iodine at least 1 hour after thionamide so that iodine cannot be used as substrate to make more thyroid hormone.

-    Iodinated radiocontrast agent given to block conversion of T4 to T3 and to block thyroid hormone release.

-    Glucocorticoids used to reduce T4 to T3 conversion, for vasomotor stability, and to treat potential associated adrenal insufficiency

 Long-term Treatment: Once patient recovers from thyroid storm, iodine can be discontinued and glucocorticoids tapered. Beta blockers can be decreased as tolerated. As discussed above, if PTU was used, treatment should be transitioned to methimazole.  Definitive treatment depends on underlying etiology of thyroid storm. 

Myelodysplastic Syndrome

posted Mar 5, 2015, 4:56 PM by Kevin Hauck

Better late than never!  A Monte Minute brought to you by Shubha Bhar from Firm 3!

Review of Myelodysplastic Syndrome

During our last crs case, we discussed a 72 yo M(pmh of multiple skin abscesses and folate deficiency) who presented with 5 weeks of persistent violaceous lesions of bilateral hands after recent L hand dog bite.  On routine labs he was found to have anemia and thrombocytopenia.  The patient was ultimately diagnosed with atypical pyoderma gangrenosum with association with myelodysplastic syndrome which was initiated by a pathergic stimulus (dog bite). 

In this monte minute, I will review myelodysplastic syndrome including its pathogenesis, clinical presentation, diagnosis, and treatment.    

Myelodysplastic Syndrome: 

Definition:  Myelodysplastic syndrome is an ineffective maturation of the myeloid blood cells.  It can affect red blood cells, neutrophils, and platelets, thus putting patients at risk for anemia, infection, and bleeding.  There is variable risk for progression to acute myeloid leukemia. 

Population:  The median age at diagnosis is greater than 65 yo, it rarely affects individuals younger than 50.  Incidence rates are 1.8 higher in men than women. Median age of diagnosis is 71 years, 72% of patients are 70 or older.

Risk factors:  male age, prior treatment with chemotherapy or radiation, tobacco use, occupational exposure to chemicals (benzene).  The risk is also higher in certain genetic syndromes including Diamond-Blackfan syndrome, ataxia telengiectasia, Fanconi’s anemia, Down’s Syndrome, and certain blood disorders including paroxysmal nocturnal hemoglobinuria and congenital neutropenia.  There is also a rare autosomal dominant familial MDS.

Pathogenesis:  The majority of cases are de novo, about 10% of cases are secondary to radiation or chemotherapy.  Secondary MDS has a worse prognosis than primary MDS, typically MDS develops 5 years after tx with chemotherapy or radiation.  MDS develops from a series of mutations in the hematopoietic stem cell, affecting growth and differentiation, and leading to abnormal, immature myeloid cells in the bone marrow.  Multiple mutations in MDS have been found including chromosomal abnormalities and those affecting DNA methylation, histone modification, RNA splicing, transcription factors, and cytokine signaling pathways.  Many of these mutations have also been found in patients with AML.  The inciting cause is often unknown for most cases.  Detection of certain chromosomal and genetic abnormalities aids in MDS classification and prognostication. 

Clinical Presentation: Many patients diagnosed with MDS are asymptomatic and are diagnosed with routine blood screening.  Other patients will be diagnosed with non-specific symptoms.  As anemia is the most common cytopenia in MDS (present in approximately 80-85% of patients), patients can present with fatigue, weakness, palpitations, sob/cp on exertion.  Patients may present with recurrent infection due to neutropenia and impaired granulocyte dysfunction.  Bacterial infections are most common, and the skin is most commonly affected.  Fungal, viral, and mycobacterial infections are less common. Additionally patients presenting with thrombocytopenia may present with petechial/purpura, bleeding of mucosal services, and easy bleeding. 

Physical exam rarely shows splenomegaly and lymphadenopathy, and should raise suspicion for a myeloproliferative or lymphoproliferative neoplasm.  Skin lesions in MDS are uncommon but can occur. Sweet’s syndrome (aka acute febrile neutrophilic dermatosis) is an inflammatory disorder characterized by painful, edematous, and erythematous papules, plaques, or nodules of the skin, often accompanied by fever and leukocytosis.  Biopsy shows neutrophilic infiltration.  Myeloid sarcoma is an extramedullary collection of immature myeloblasts, it can occur in any organ or tissue, and may be a sign of transformation into aml.  The most common area for involvement is the skin ad the gingiva.  Lesions are typically violaceous, raised, nontender plaques or nodules.  Biopsy shows myeloblast infiltration. 

Autoimmune abnormalities may be associated with mds.  This includes cutaneous vasculitis, psoriasis, rheumatoid arthritis, polymyalgia rheumatica, and pernicious anemia.  Additionally patients can develop acquired Hb H disease.

Classification:  There are two major classification systems for MDS, the FAB classification and the WHO classification systems.  While aiding in diagnosis, they are not as helpful in prognostication.

Below is the WHO classification for myelodysplastic syndromes:

1. Refactory cytopenia with unilineage dysplasia (refractory anemia, neutropenia, or thrombocytopenia

2. Refractory anemia with ring sideroblasts (ring  sideroblast >= 15% bone marrow)

3. Refractory cytopenia with multilineage dysplasia

4. Refractory anemia with excess blasts (RAEB.  RAEB 1: 2-4% circulating blasts, or 5-9% marrow blasts; RAEB 2: 5-19% circulating blasts or 10-19% marrow blasts or Auer rods)

5. Myelodysplastic syndrome with isolated del(5q)

6. Myelodysplastic syndrome (unclassifiable

There are three prognostic systems which include the international prognostic scoring system (IPSS), WHO prognostic scoring system, and MD Anderson Cancer Center MDS model.  The IPSS is the simplest and most commonly used.  The IPSS takes into account the percentage of blast cells, the karyotype, and number of blood cell lineages involved. Prognosis worsens with percentage of blast cells and number of cell lines affected.

Diagnosis:  Diagnosis is based on peripheral blood smear, bone marrow bx, and certain genetic abnormalities

- in evaluating a patient for cytopenias/dysplastia, should obtain the following for further workup:  iron studies, b12, folate, copper, hiv, tsh, lfts, hiv, hepatitis panel.  Medications should be reviewed.

- CBC: isolated or multilineage cytopenia.  Consider MDS in elderly patients with persistent macrocytic anemia, multiple cytopenia, or dysplastic peripheral blood cells after exclusion of other conditions. 

a.       Anemia: typically macro or normocytic.  RDW is generally increased

b.      Leukopenia: present in ½ of pts, fewer than 20% blasts

c.       Thrombocytopenia:  present in ¼ pts

-          Peripheral smear/BM bx:  erythroid, granulocyte, or megakaryocytes are > 10% dysplastic on visual inspection.  Generally bm bx reveals hypercellular bone marrow, but about 5-10% of patients can have hypocellular bone marrow.  Less than 20% blasts should be present, cases with >20% are considered to have AML.  Patients with certain genetic abnormalities are diagnostic of AML regardless of the blast cell count.

Treatment:  Low risk disease, especially for anemia is tx with growth factors, lenalidomide, and transfusions.  Higher risk patients are tx with hypomethylating agents and if possible allogenic stem cell transplant.

a.       supportive care:  with rbc transfusions as needed for anemia

b.      erythropoiesis stimulating agents for anemia at Hb of <10

c.       hypocellular or immune mediated MDS:  tx with immunosuppressive therapy with thymoglobulin

d.       MDS with isolated chromosome 5q deletion: tx with lenalidomide

e.       advanced MDS (excess blasts) or pancytopenia unresponsive to other therapy: azacitidine or dacogen

f.       Stem cell transplant


“Myelodysplastic Syndromes” N Engl J Med 2009;361:1872-85.

“Myelodysplastic Syndromes: A practical guide to diagnosis and treatment.” Cleveland Clinic Journal of Medicine January 2010 vol. 77 1 37-44

“Myelodysplastic Syndrome” The Lancet, Volume 383, Issue 9936, Pages 2239 - 2252, 28 June 2014

up to date 

Untitled Post

posted Feb 9, 2015, 11:28 AM by Kevin Hauck

Today we have a post on the Milk-Alkali Syndrome from Firm 3's very own Julie Lorton:

Milk- Alkali Syndrome

In this week's Chief of Service noon conference, Dr. Fleischer from the Endocrinology Department precepted the case of a 67 year old woman presenting with altered mental status who was discovered to have an elevated calcium of 16.3, in the setting of taking up to 20 Tums tablets daily for reflux symptoms.

What is it?

The classic findings in Milk-Alkali syndrome are hypercalcemia, metabolic alkalosis, and AKI. The name is derived from the historic etiology of the disease, an antiacid regimen from the early 1900s involving hourly doses of milk plus sodium bicarbonate. Current cases usually involve large doses of calcium carbonate (or other calcium derivatives) rather than milk – often for bone health rather than ulcer disease these days. Following hyperparathyroidism and malignancy, it is the third most common cause of hypercalcemia.



Development of Milk-Alkali syndrome require intake of a large amount of calcium and absorbable alkali which overwhelms the normal calcium homeostasis system. Only a small percentage of those who consume a large amount of calcium/alkali will develop the syndrome however; in the majority, normal renal function and calcitriol suppression (leading to decreased intestinal calcium absorption) will maintain homeostasis.

The role of calcitriol in development of the syndrome remains unclear (some patients with the syndrome have appropriately suppressed calcitriol while others do not), however  with calcium intake >10 grams daily, large amounts of calcium can be absorbed despite calcitriol suppression.

The majority of mechanisms underlying the development of AKI and alkalosis occur in the kidney. Hypercalcemia leads to volume depletion in a variety of ways including renal vasoconstriction, blockade of ADH-dependent water reabsorption, and inactivation of the Na-K-2Cl channel in the thick ascending limb via a calcium-sensing receptor. Volume depletion subsequently contributes to metabolic alkalosis (in addition to the consumption of alkali via calcium carbonate, sodium bicarbonate, etc) by increasing bicarbonate absorption in the renal tubules. Metabolic alkalosis then actually contributes to ongoing hypercalcemia via activation of the TRPV5 renal calcium channel which increases calcium reabsorption at alkaline pH levels.

Volume depletion is the primary etiology of the AKI associated with Milk-Alkali syndrome, although chronic hypercalcemia/metabolic acidosis from the syndrome have also been associated with more chronic renal changes due to calcium preceiptation/deposition in the renal tubules/interstium.



Presentation depends on acuity/severity of hypercalcemia.

In acute hypercalcemia, patients may present with the classic “bones, stones, groans and psychiatric overtones” we all learned in medical school. More chronic cases may present with findings like polyuria/polydipsia, muscle aches and pruritus.

Milk-Alkali syndrome is often discovered incidentally on routine lab work in asymptomatic patients however. Common clinical scenarios include postmenopausal women on calcium supplements for osteoporosis prevention/treatment, patients taking OTC antiacids with calcium for gastritis/dyspepsia, and dialysis patients on calcium carbonate for secondary hyperparathyroidism. Patients at higher risk to develop Milk-Alkali include those with risk factors for renal insufficiency (elderly, on ACE-i/ARB/NSAIDs, CKD) or volume depletion (on diuretics, particularly thiazides which independently increase renal calcium reabsorption, pregnant women with hyperemesis, bulimic patients).



Clinical/medication history is key in making the diagnosis of Milk-Alkali syndrome; however there are also some findings on labs that can help differentiate the etiology of hypercalcemia.

PTH should be suppressed, differentiating Milk-Alkali from primary (or tertiary) hyperparathyroidism. Hypophosphatemia is a common finding since calcium carbonate binds phosphate (although not in the historic syndrome, since milk itself is high in phosphate and may cause hyperphosphatemia), whereas in Vitamin D intoxication (or granulomatous diseases which cause hypercalcemia via Vitamin D metabolism), hyperphosphatemia is common. Urine calcium, which can be evaluated with a spot Urine calcium:creatinine ration, will be low in Milk-Alkali syndrome unlike all other causes of hypercalcemia with the expception of Familial Hypocalciuric Hypercalcemia (in which degree of hypercalcemia would be expected to be mild and chronic). PTHrp obviously should not be elevated in Milk-Alkali unlike hypercalcemia  of malignancy.



Stopping/reducing the calcium intake is the most important step in management!

For more acute management of hypercalcemia, IV fluids are the most important treatment and will also improve AKI and alkalosis. Diuretics such as furosemide can also speed up calciuresis, however should be given only after adequate volume IV fluid administration as most patients wtih Milk-Alkali syndrome are already volume depleted.

Hypocalcemia can actually result transiently following treatment for Milk-Alkali because once the impetus for hypercalcemia (i.e. oral calcium) has been removed, serum calcium normalizes very quickly while PTH suppression is slower to recover. Bisphosphonate therapy is therefore not recommended for Milk-Alkali since it can contribute to more prolonged hypocalcemia once the initial hypercalcemia has resolved.


The patient in question had in fact received pamidronate in the ED prior to admission in addition to IV fluid and furosemide; her hypercalcemia resolved within 24 hours and currently, 4 days after admission, she is mildly hypocalcemic possibly due in part to bisphosphonate administation.




Morishita Y, Yoshizawa H, Kusano E. Renal injury in calcium-alkali syndrome. J Nephrol Therapeutics, S3:006 (2012), doi:10.4172/2161-0959.S3-006.

Patel AM, Goldfarb S. Got calcium? Welcome to the calcium–alkali syndrome. J Am Soc Nephrol, 21 (2010), pp. 1440–1443.

Cryptococcus Meningoencephalitis - Ronak Shah PGY-3

posted Dec 16, 2014, 8:45 AM by Kevin Hauck

Last week, we had another interesting case for COS with Dr. Nosanchuk. This was a 54-year-old gentleman with 2 weeks of cough and fever, recently treated unsuccessfully with Augmentin in the outpatient setting. On presentation, the patient had severe sepsis with concomitant hypoxia, found to have multiple b/l pulmonary emboli, required to be intubated, and needed a brief stay in the ICU. Post ICU, the patient’s blood cultures came back positive, surprisingly, growing Cryptococcus neoformans.

I encourage all of you to read the beautifully written, thorough Monte Minute article by Dr. Rohit Das back from Feb. 2013 regarding cryptococcus infections. Here, I will focus more on the CNS complications, particularly meningoencephalitis of cryptococcus.

Cryptococcus meningnoencephalitis:

What is it?

This entity is an invasive fungal infection of the CNS caused by the encapsulated yeast, Crytococcus neoformans mostly in immunocompromised patients [particularly HIV]. Fortunately, here in the US, we do not see many cases of this disease. But worldwide, it remains a significant burden as there are up to a million cases annually, with mortality reaching >50% in some areas of sub-Saharan Africa.


  • the presentation of the CNS disease is usually a slow, progressive onset: 1-2 weeks.
  • non-specific symptoms of fever, malaise and a headache.
  • stiff neck, photophobia and vomiting seen in only ¼ of the patients.
  • but disseminated cryptococcemia, like our patient, is more likely to present with cough, dyspnea or even cutaneous lesions. The sepsis and pneumonia studies indicate that cryptococcus is usually an unexpected, incidental finding.
  • physical exam: signs of CNS disease are usually lacking, but meningismus, papilledema and CN palsies [particularly CN VI] indicate advanced disease and a much poorer prognosis.
  • labs: non-specific; look for immunosuppressive hints [leukopenia, protein gap]


Cryptococcal infection is inhaled by aerolized particles. Most people convert serologically during childhood [especially in the Bronx!]. Given the fact that the infection is common and the disease is rare, our body likely has defense mechanisms in immunologic intact hosts. There is some evidence that certain cryptococcal infections lead to state of latency, with viable organisms harbored in possible granulomas. The mechanism of how the fungus disseminates into the extrapulmonary system and into the CNS is not clear. But once in the CNS, the infection proliferates in the subarachnoid space, clogging the arachnoid villi, eventually leading to increased intracranial pressure.


  • prior to LP, obtain imaging! especially in patients suspecting increase ICP and/or HIV.
  • made by LP / analyzing the CSF:
    • elevated opening pressure: >20 cm H20 in 50-60% patients in the US.
    • classically have low WBC count, mild elevation of protein and low glucose.
    • CSF should be sent for cryptococcal culture.
    • perform an India Ink stain [80-85% sensitive in HIV patients]
    • check for cryptococcal antigen: strongly supports the diagnosis and enough to initiate treatment. very sensitive and specific, both >93%.
  • serum cryptococcal antigen: useful diagnostic test in patients that cannot undergo a LP. titers generally correlate to organism burden.
  • routine blood cx: cryptococcus positive in ⅔ patients of meningoencephalitis; but should check fungal blood cx to improve sensitivity.
  • bottom line: diagnosis is conclusive by isolating the organism with culture, but now the antigen testing [given how accurate it is] has surpassed the culture in guiding initial therapy.


  • Abnormal mental status, CSF titers >1:1024 and CSF WBC <20 are all signs of poor prognosis.


  • The IDSA divides the treatment for cryptococcal meningoencephalitis into three phases:
    • two week induction - preferred regimen: amphotericin B [0.7 - 1.0 mg / kg per d] and flucytosine [100 mg / kg per d]. at the end of the induction phase, repeat LP to ensure clearance of the infection.
    • followed by eight week consolidation - fluconazole 400-800 mg per d
    • extended maintenance phase - for secondary prophylaxis - fluconazole 200 mg per d
  • general principles: there are fungicidal [amphotericin B and flucytosine] and fungistatic drugs [fluconazole]. The fungicidal regimen in the induction phase yields better clinical outcomes.
  • toxicities: amphotericin B - watch for IV related phlebitis, need to administer IVF [1-2 L saline / d], watch for electrolyte abnormalities. lipid formulations are better tolerated.
  • regardless of the antifungal medications, the elevated opening pressure needs to be managed aggressively! Need serial LPs, even on a daily basis until the OP <20 cm. May need therapeutic drains if persistent elevated OP. If symptomatic elevated pressures, then can consider removing up to 30 mL.
  • When to restart ARV? There is not great evidence to support the exact time point for ARV. There is a concern for IRIS if starting too soon, particularly in the induction phase. But on the other side, waiting too long increases the risks for other complications from immunosuppression. Typically ok to restart ARV after 10 weeks.

Back to the patient:

The patient was found to have disseminated cryptococcemia. He received an LP, which showed WBC of 15, glucose 47, total protein 63. +fungal csf cx of cryptococus neoformans. Initial csf cryptococcal antigen titer of 1:2048! He finished a course of induction tx, now only on fluconazole. Patient has started ARV. Unfortunately, currently still in the hospital with headaches and changes in his mental status. Unclear the exact relation of his b/l pulmonary emboli with current disease. But suspect possible hypercoagulable process with HIV. Awaiting to undergo other age appropriate cancer screening.

Attaching some of the review articles:

Prognosis and management of cryptococcal meningitis in patients with HIV. Neurobehavioral HIV Medicine. 2012.

HIV-associated cryptococcal meningitis. AIDS 2007.

IDSA 2010 Cryptococcus Guidelines

Other sources:  Harrison’sUTD  

Cystic Echinococcus - Tania Kupferman PGY-3

posted Dec 16, 2014, 8:08 AM by Kevin Hauck

This week on CRS we solved the case of a 35 year-old man from Peru, who presented to the hospital with stabbing, unremitting right-upper quadrant pain that had started acutely a few hours earlier after he received a blow to the area while playing soccer (i.e., real football).On ROS, he did not have fever or chills, no weight loss and endorsed some nausea and vomiting which occurred after the accident on the field. He had no pleuritic pain and no dyspnea.He had no known past medical history, no prior surgeries, and took no medications. He did not use tobacco or illicit drugs, he consumed occasional alcohol; he was in a monogamous relationship with his wife.

Our initial differential diagnosis took into account the on location and onset of pain and was actually quite broad. We considered injury to the liver/gallbladder as very likely, followed by pancreatitis (from trauma), rib fracture, splenic rupture, and the future cardiologists in the room suggested we considered a possible MI.We also began to think that in this young man, the injury most likely unmasked an underlying problem which had previously gone undetected. We thought of hepatic angiomas, AV malformations, or abscesses that may have ruptured.

On further history, we learned that he had immigrated to the US about 10 years prior to his current presentation. He had no known medical problems in his family. And that he had been a farmed in his native Peru.

At this point we expanded on the possibility of abscess from some infectious etiology that still not clear to us. Some pathogens were thrown around the table but we were not ready to commit, especially since most of there were hard to pronounce.

His physical exam was remarkable for tachycardia with normotension. He was afebrile. There was no erythema at the site of injury and no visible ecchymoses. He had normal heart and lung exams. There was tenderness to deep palpation over the RUQ but there was no rebound or guarding. There was no jaundice and no other stigmata of chronic liver disease.

The exam has helpful in narrowing our differential by focusing our attention to deep structures of the right-upper quadrant. At this point, we thought musculoskeletal injury was unlikely, and there was no reason to continue to suspect a pneumothorax or other lung pathology.

His blood work was significant for hemoglobin ~12g/dL, platelets near 450K/uL, and WBC ~7.6K/uL with about 36% neutrophils and 24% eosinophils. His BNP was unremarkable, as were coagulation tests, and cardiac markers. Liver tests showed a AST/ALT in the 60’s range and an alk phos of 150U/L. Total protein, albumin, and bilirubin levels were all normal.

The high eosinophil count immediately caught our attention and we started to seriously think about the “worms” that our patient was at risk for given his country of origin and past exposures. Some of the pathogens that were brought up included amoeba, ascaris, echinococcus,

We were instead presented with the results of a CT scan with contrast which revealed a very large, heterogenous hypodensity inside the liver. There were no solid masses and no evidence of an intrahepatic bleed.

Although not so obvious to us initially, the finding of a cyst-like mass in a person with a history of exposure to sheepdogs in an area where E. granulosus is endemic, suggests a diagnosis of cystic echinococcosis. While we did eventually come up with the correct diagnosis—a ruptured echinococcus cyst, secondary to trauma—it was not before we ourselves were diagnosed with ‘knowledgeopenia’ by Dr Lefrancois.

To remedy that, here’s a brief review:

Cystic echinococcosis (aka hydatidosis) is a zoonotic disease that results from infection with the larval stage of Echinococcus granulosus, a cestode found in dogs (definitive host), sheep, cattle, goats, foxes, and pigs (intermediate hosts). People become infected by swallowing tapeworm eggs which can be found in the feces and fur of infected animals.

Echinococcus is endemic to Africa, Europe, Central Asia, the Middle East, and Central and South America, with the highest prevalence in populations that raise sheep. In North America, E. granulosus has been reported in Canada and Alaska, whereas in the United States most infections are diagnosed in immigrants from countries where the disease is endemic. In endemic regions, incidence rates for cystic echinococcosis can reach <50 per 100 000 person-years, with a prevalence as high as 5–10% in parts of Argentina, Peru, east Africa, central Asia, and China.

Most infections in humans are asymptomatic for a number of years, but can present with slowly enlarging masses, most commonly in the liver and the lungs. Pain or discomfort in the upper abdomen, nausea, vomiting, or cough as a result of the growing cysts. Cases can also present after rupture of a cyst which can lead to a severe allergic reaction. Larval metastases may spread to organs adjacent to the liver or to distant locations (lungs, brain) through dissemination of the parasite via the blood and lymphatic system. Diagnosis is often suspected by history and imaging as described above. Specific antibodies can be detected by serological tests and can support diagnosis. Biopsies and ultrasound-guided punctures may also be performed.

Echinococcosis infection can be complicated to treat, frequently requiring surgery in addition to prolonged antimicrobial therapy. Drug therapy alone with albendazole is appropriate for single-compartment cysts, that are <5cm in diameter. Praziquantel is sometimes used in addition to albendazole, although there is no clear evidence regarding its efficacy.

Surgery is the treatment of choice for management of complicated, multi-loculated or very large cysts; it must be extensive and usually followed by anti-infective prophylaxis to minimize the risk of secondary infection through seeding. Some countries favor the use of percutaneous aspiration, injection of chemicals and re-aspiration techniques in place of surgery. A small clinical trial suggested that outcomes among patients undergoing percutaneous drainage with albendazole were comparable to those undergoing surgery alone.

Bear in mind that echinococcosis can relapse years after treatment and monitoring is recommended although the exact modality and duration for this are not specified.

Tania Kupferman

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