NEJM report on ACOs

From the paper:

Using Medicare claims from 2009 through 2013 and a difference-in-differences design, we compared changes in spending and in performance on quality measures from before the start of ACO contracts to after the start of the contracts between beneficiaries served by the 220 ACOs entering the MSSP in mid-2012 (2012 ACO cohort) or January 2013 (2013 ACO cohort) and those served by non-ACO providers (control group), with adjustment for geographic area and beneficiary characteristics...

Results

Adjusted Medicare spending and spending trends were similar in the ACO cohorts and the control group during the precontract period. In 2013, the differential change (i.e., the between-group difference in the change from the precontract period) in total adjusted annual spending was −$144 per beneficiary in the 2012 ACO cohort as compared with the control group (P=0.02), consistent with a 1.4% savings, but only −$3 per beneficiary in the 2013 ACO cohort as compared with the control group (P=0.96). Estimated savings were consistently greater in independent primary care groups than in hospital-integrated groups among 2012 and 2013 MSSP entrants (P=0.005 for interaction). MSSP contracts were associated with improved performance on some quality measures and unchanged performance on others.

Conclusions

The first full year of MSSP contracts was associated with early reductions in Medicare spending among 2012 entrants but not among 2013 entrants. Savings were greater in independent primary care groups than in hospital-integrated groups.

So as far as cost savings go these results were modest and somewhat mixed. I have to wonder if the effects of ACOs on costs will mirror what happened in the mid 90s with the wave of managed care, when there was an initial slash in costs but the “success” was short lived, as the reductions were not sustainable. I put very little stock in the statement that there was partial improvement in quality, since quality really means the weak and unproven surrogate of performance.

Another Zika virus review

Free full text from BMJ.

Zika virus review

Free full text via NEJM.

Higher prevalence of pancreatic cancer in patients newly diagnosed with type 2 diabetes

This is an association that has long been suspected. Additional evidence for the association was found in this study.

The effect of high flow nasal oxygen post-extubation, in patients at low risk

From a recently reported study:

Importance Studies of mechanically ventilated critically ill patients that combine populations that are at high and low risk for reintubation suggest that conditioned high-flow nasal cannula oxygen therapy after extubation improves oxygenation compared with conventional oxygen therapy. However, conclusive data about reintubation are lacking.

Objective To determine whether high-flow nasal cannula oxygen therapy is superior to conventional oxygen therapy for preventing reintubation in mechanically ventilated patients at low risk for reintubation.

Design, Setting, and Participants Multicenter randomized clinical trial conducted between September 2012 and October 2014 in 7 intensive care units (ICUs) in Spain. Participants were 527 adult critical patients at low risk for reintubation who fulfilled criteria for planned extubation. Low risk for reintubation was defined as younger than 65 years; Acute Physiology and Chronic Health Evaluation II score less than 12 on day of extubation; body mass index less than 30; adequate secretions management; simple weaning; 0 or 1 comorbidity; and absence of heart failure, moderate-to-severe chronic obstructive pulmonary disease, airway patency problems, and prolonged mechanical ventilation.

Interventions Patients were randomized to undergo either high-flow or conventional oxygen therapy for 24 hours after extubation.

Main Outcomes and Measures The primary outcome was reintubation within 72 hours, compared with the Cochran-Mantel-Haenszel χ2 test. Secondary outcomes included postextubation respiratory failure, respiratory infection, sepsis and multiorgan failure, ICU and hospital length of stay and mortality, adverse events, and time to reintubation.

Results Of 527 patients (mean age, 51 years [range, 18-64]; 62% men), 264 received high-flow therapy and 263 conventional oxygen therapy. Reintubation within 72 hours was less common in the high-flow group (13 patients [4.9%] vs 32 [12.2%] in the conventional group; absolute difference, 7.2% [95% CI, 2.5% to 12.2%]; P = .004). Postextubation respiratory failure was less common in the high-flow group (22/264 patients [8.3%] vs 38/263 [14.4%] in the conventional group; absolute difference, 6.1% [95% CI, 0.7% to 11.6%]; P = .03). Time to reintubation was not significantly different between groups (19 hours [interquartile range, 12-28] in the high-flow group vs 15 hours [interquartile range, 9-31] in the conventional group; absolute difference, −4 [95% CI, −54 to 46]; P = .66]. No adverse effects were reported.

Conclusions and Relevance Among extubated patients at low risk for reintubation, the use of high-flow nasal cannula oxygen compared with conventional oxygen therapy reduced the risk of reintubation within 72 hours.

Hepatitis B and C associated glomerular diseases

From a recent review:

The most common histopathologic presentation of HBV-GN is HBV-associated membranous nephropathy, which usually manifests clinically with varying grades of proteinuria and microscopic hematuria. The pathogenesis is likely to be immune complex mediated; however, other host and viral factors have been implicated. The treatment of HBV-GN revolves around antiviral therapy. Various histologic types of glomerular diseases are reported in association with HCV infection, the most frequent being Type 1 membranoproliferative glomerulonephritis, usually in the context of Type 2 mixed cryoglobulinemia. The pathogenesis of HCV-GN can be attributed to glomerular deposition of cryoglobulins or noncryoglobulin-immune complexes. Cryoglobulins typically comprised immunoglobulin Mκ with rheumatoid factor activity. Clinically, patients may present with proteinuria, microscopic hematuria, hypertension, and acute nephritic and/or nephrotic syndrome. The treatment of HCV-GN, especially cryoglobulinemic membranoproliferative glomerulonephritis, encompasses various options including contemporary antiviral therapy with or without conventional and novel immunomodulatory agents.

Mentioned in the body of the paper are several other glomerular diseases that have been associated with hep B as well as polyarteritis nodosa which, though not a cause of glomerulonephritis, can cause renal damage as part of the vasculitis.

How to work up hematuria

This topic was recently reviewed in Advances in Chronic Kidney Disease. From the body of the paper:

On finding a urine dipstick positive for blood, the test should be repeated after several days, to account for any transient causes of MH, such as physical activity, sexual intercourse, or menstruation. If the dipstick remains positive, urine microscopy should be performed to identify RBCs and to define their morphology (dysmorphic or isomorphic)..For our purposes, we define MH as 3 or more RBC/hpf. If no RBCs are visualized, patients should be evaluated for alternative causes of a positive dipstick, such as myoglobinuria. We agree with the CUA guidelines ² and Huussen and colleagues, ³⁵ who suggest that urologic imaging and cystoscopy may not be required if dysmorphic cells or RBC casts are seen, suggesting a glomerular etiology. Such findings should, however, prompt assessment of kidney function and urinary protein excretion. If the patient has a reduced GFR or proteinuria, referral to nephrology is warranted and a kidney biopsy should be considered. For those individuals with isolated glomerular MH, a clinician should assess these patients annually for kidney function changes and/or the development of albuminuria or proteinuria. If isomorphic RBCs are seen on urine microscopy, the clinician should confirm with the patient whether possible benign causes of MH such as recent physical activity or trauma, sexual activity, menstrual bleeding, viral symptoms, or urethral instrumentation may account for these findings. If a benign cause is present, a repeat urinalysis should be done in several weeks to ensure resolution. If the earlier mentioned causes are not identified, imaging of the GU tract is indicated. Although CTU has demonstrated the best testing characteristics, we emphasize the importance of limiting cumulative doses of radiation exposure, especially in younger individuals..alternative imaging modalities should be considered, including US or MR...

If no parenchymal lesion is detected on imaging, the clinician should assess the patient's GU cancer risk factor profile. If risk factors are present, they should be promptly referred to urology for cystoscopy. If a patient has no such risk factors, age should be considered before undergoing cystoscopic evaluation. We consider the evidence presented in the 2012 AUA guidelines inadequate to support cystoscopy for anyone with asymptomatic MH younger than 40 years. Patients with asymptomatic MH aged 50 years or older have sufficient cancer risk to warrant cystoscopy, regardless of risk factor profile. 6 For patients aged 40 to 49 years, the data are unclear; if no risk factors are present, clinical judgment for cystoscopy referral is advised.

Progress in the understanding and treatment of hairy cell leukemia

From a recent review:

Initially a uniformly fatal disease, new therapies in rapid succession transformed HCL into a chronic disease with a normal life expectancy in many cases. More recently, the identification of BRAFV600E mutations in the majority of patients with classic HCL have enabled targeted therapies as a therapeutic option. Additional discoveries into the biology of the disease have identified new subtypes of HCL. Modern approaches to the evaluation and treatment of HCL include detailed molecular analysis which informs therapeutic options, which may consist of traditional therapies such as purine nucleoside analogs, or targeted therapies with antibodies, BTK inhibitors, or BRAF inhibitors, or combination therapy.

Genetics of eosiniphilic esophagitis

This is reviewed in a recent paper. Though not inherited in a simple Mendelian fashion it is a disease of genetic predisposition. This results in considerable overlap with atopic conditions. Some key points:

EoE is a complex genetic disease. Five susceptibility loci have been identified to date.

Three of the EoE predisposition loci are shared across other atopic phenotypes; the remaining two appear to be specific to EoE

The effect sizes of the shared loci are more significant in EoE which may facilitate the characterization of the loci and development of novel therapy.

Fresh fruit consumption and cardiovascular disease

From a recent study:

In Western populations, a higher level of fruit consumption has been associated with a lower risk of cardiovascular disease, but little is known about such associations in China, where the consumption level is low and rates of stroke are high.

Methods

Between 2004 and 2008, we recruited 512,891 adults, 30 to 79 years of age, from 10 diverse localities in China. During 3.2 million person-years of follow-up, 5173 deaths from cardiovascular disease, 2551 incident major coronary events (fatal or nonfatal), 14,579 ischemic strokes, and 3523 intracerebral hemorrhages were recorded among the 451,665 participants who did not have a history of cardiovascular disease or antihypertensive treatments at baseline. Cox regression yielded adjusted hazard ratios relating fresh fruit consumption to disease rates.

Results

Overall, 18.0% of participants reported consuming fresh fruit daily. As compared with participants who never or rarely consumed fresh fruit (the “nonconsumption” category), those who ate fresh fruit daily had lower systolic blood pressure (by 4.0 mm Hg) and blood glucose levels (by 0.5 mmol per liter [9.0 mg per deciliter]) (P<0 .001="" 0.54="" 0.56="" 0.58="" 0.60="" 0.64="" 0.66="" 0.67="" 0.72="" 0.74="" 0.75="" 0.79="" 10="" a="" across="" adjusted="" amount="" and="" associations="" baseline="" between="" both="" by="" cardiovascular="" characteristics.="" ci="" comparisons="" confidence="" consumed.="" consumption="" coronary="" daily="" death="" defined="" dose="" each="" events="" for="" fresh="" fruit="" hazard="" hemorrhagic="" in="" incidence="" incident="" interval="" ischemic="" log-linear="" major="" nonconsumption="" of="" outcome="" p="" participants="" ratios="" regions="" relationship="" respectively="" response="" similar="" stroke.="" stroke="" strong="" study="" subgroups="" the="" there="" these="" to="" trend="" versus="" was="" were="">

Conclusions

Among Chinese adults, a higher level of fruit consumption was associated with lower blood pressure and blood glucose levels and, largely independent of these and other dietary and nondietary factors, with significantly lower risks of major cardiovascular diseases.

This was a study from China. Note that fresh fruit consumption is a component of the Mediterranean diet.

Hyponatremia in cirrhosis

This was the subject of a recent review in Advances in Chronic Kidney Disease. From the article:

Cirrhosis is characterized by systemic and splanchnic vasodilation that leads to excessive nonosmotic secretion of vasopressin (antidiuretic hormone). Hyponatremia is a common electrolyte abnormality in advanced liver disease that results from the impaired ability of the kidney to excrete solute-free water that leads to “dilutional” hyponatremia—water retention disproportionate to the retention of sodium.

The excessive vasodilation is mediated by nitric oxide (NO). NO synthesis in endothelial cells of cirrhotic patients is induced by high levels of circulating endotoxins translocated from the gut having bypassed the portal circulation.

Besides non osmotic vasopressin release the paper also mentions impaired water delivery to the thick ascending limb of the Loop of Henle as a contributing mechanism.

More from the paper:

Hyponatremia in liver diseases carries the prognostic burden, correlates with the severity of cirrhosis, and, in recent studies, has also been implicated in the pathogenesis of hepatic encephalopathy.

Hyponatremia's contribution to hepatic encephalopathy is complex. Not only do the manifestations of hyponatremic encephalopathy overlap considerably with those of hepatic encephalopathy but hyponatremia is contributory to the pathogenesis of hepatic encephalopathy itself by multiple mechanisms. One of these involves the exhaustion of certain astrocyte functions as a result of the extrusion of ions and organic molecules as an adaptive response to hyponatremia.

As a prognostic indicator, hyponatremia is associated with hepatorenal syndrome and spontaneous bacterial peritonitis.

Although hyponatremia is associated with adverse outcomes in cirrhosis, at what level one should attempt to raise the sodium and by what means are unclear. The article recommends against the use of demeclocycline to treat hyponatremia in cirrhosis despite its popularity in the treatment of hyponatremia of a variety of causes.

Proton pump inhibitors and eosinophilic esophagitis

The question is addressed in this paper. Although EO is in general unresponsive to PPIs there is a subset that is:

Gastro-oesophageal reflux disease (GORD) is the most common oesophageal disorder, whereas eosinophilic oesophagitis (EoE) is an emerging disease unresponsive to PPI therapy. Updated guidelines in 2011 described proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE), a novel phenotype in EoE patients who were responsive to PPIs.

Treatment of eosinophilic esophagitis

From a recent review:

If left untreated, eosinophilic inflammation induces fibrosis, angiogenesis and stricture formation, resulting finally in a so called remodelling with structural and functional damage of the organ. In addition, patients with untreated EoE are permanently at risk of experiencing food impactions...Avoidance of food allergens by elimination diets as well as anti-inflammatory drugs have both the ability to achieve these goals. Among the pharmacological options, only corticosteroids have documented efficacy, whereas alternatives have shown rather disappointing results or are still under evaluation. Of note, swallowed topical corticosteroids are at least as efficient as systemically administered corticosteroids but have fewer side effects. As such topical corticosteroids are widely used as first-line drug in the treatment of EoE, even though this compound is currently not approved for this indication by regulatory authorities.

Unfortunately, complete resolution of symptoms can be achieved with swallowed topical corticosteroids only in approximately 70% of patients despite appropriate dosing and despite correct administration of these compounds. Control of inflammation is even harder to achieve, as only in approximately 50% of patients tissue eosinophilia disappears completely under this anti-inflammatory medication. For this group of “difficult to treat” patients, therapeutic alternatives are urgently needed.

Painful LBBB syndrome

A paper here describes this rarely encountered entity.

Lifestyle intervention, weight loss and atrial fibrillation incidence in type 2 diabetes

From the Look AHEAD trial:

A total of 5,067 overweight or obese individuals 45 to 76 years old with type 2 diabetes without prevalent AF were randomized to either an intensive lifestyle intervention (ILI) designed to achieve and maintain weight loss through caloric reduction and increased physical activity or a diabetes support and education usual care group. Atrial fibrillation was ascertained from electrocardiograms at study examinations and hospitalization discharge summaries. Multivariable Cox models were used to estimate the intention-to-treat effect of the intervention adjusting for baseline covariates. During a mean follow-up of 9.0 years, 294 incident AF cases were identified. Rates of AF were comparable in the ILI and diabetes support and education groups (6.1 and 6.7 cases per 1,000 person-years, respectively, P = .42). The intervention did not affect AF incidence (multivariable hazard ratio [HR] 0.99, 95% CI 0.77-1.28). Similarly, neither weight loss nor improvement in physical fitness during the first year of the intervention was significantly associated with AF incidence: multivariable hazard ratio (95% CI) comparing top versus bottom quartile was 0.70 (0.41-1.18) for weight loss and 0.88 (0.55-1.43) for physical fitness improvement.

Conclusion

In a large randomized trial of overweight and obese individuals with type 2 diabetes, an ILI that induced modest weight loss did not reduce the risk of developing AF.

This is a little disappointing. There is evidence that obesity is a risk factor for atrial fibrillation and it is appealing to believe that lifestyle modification is an effective treatment. In light of this study the best we can say at this point is that the evidence is mixed.

Fluid overload after fluid resuscitation

It happens and may be unavoidable. Strategies to deal with it in the post resuscitation period are needed. Review here.

Environmental etiologic factors for eosinophilic esophagitis

Like many chronic conditions EO represents an interaction between genetics and environment. From a recent review:

Few studies have been conducted, however a consistent inverse association between EoE and H. pylori has been described. Several studies suggest a weak association between season and EoE diagnosis, but the evidence is inconclusive. EoE has also been associated with early life factors, including Cesarean delivery and antibiotic use. Larger studies are needed to evaluate these associations more thoroughly. Several papers have speculated the potential for anti-secretory agents to contribute to EoE.

Mineralocorticoid excess and related syndromes

This was the topic of a recent review in Advances in Chronic Kidney Disease. Below are some take home points.

Hyperaldosteronism has deleterious effects beyond hypertension and hypokalemia such as hypertension independent LVH, myocardial fibrosis and an increase in other organ manifestations (eg hemorrhagic stroke) compared to the general population of hypertensive patients.

Sporadic primary aldosteronism

About a third are due to an adrenal adenoma for which unilateral adrenalectomy is the treatment of choice. About two thirds have bilateral adrenal hyperplasia in which the biochemical disturbances tend to be milder and for which medical management with aldosterone receptor antagonists is the treatment of choice.

Familial hyperaldosteronism type I

AKA glucocorticoid responsive hyperaldosteronism.

Reported in 1966.

Autosomal dominant.

Rare among causes of hyperaldosteronism but the most common form of monogenic hypertension.

As a result of the mutation aldosterone secretion is under the control of ACTH, thus treatment is with a glucocorticoid, preferably dexamethasone due to its long duration of action and minimal mineralocorticoid effect. Treatment may also include standard antihypertensive therapy including mineralocorticoid antagonists.

Familial hyperaldosteronism type II

Described in 1992.

Autosomal dominant.

Not suppressible by glucocorticoid.

Like sporadic hyperaldosteronism, it can be associated with adenoma or hyperplasia and the treatment is the same as in the sporadic form.

Familial hyperaldosteronism type III

Described 2008.

Not suppressible by glucocorticoid.

Massive hyperplasia.

Severe presentation with treatment resistance.

Liddle syndrome

Described 1963.

Though rare, second most common cause of monogenic hypertension.

Numerous mutations discovered, all of which cause increased activity of the epithelial sodium channel (ENaC).

Aldosterone levels low.

Treatment is with ENaC antagonists (triamterene, amiloride) but not mineralocorticoid antagonists such as spironolactone.

Apparent mineralocorticoid excess

Described 1977.

Autosomal recessive.

Third most common form of monogenic hypertension.

Local (renal tubular) deficiency of 11 beta hydroxysteroid dehydrogenase type 2 resulting in defective local conversion of cortisol to cortisone. The result is a local excess of cortisol, which has mineralocorticoid activity.

Treatment is with potassium sparing diuretics and possibly dexamethasone.

Licorice ingestion mimics this syndrome by causing inhibition of the intracellular enzyme.

Congenital adrenal hyperplasia

This is a group of diseases associated with numerous enzyme deficiencies. Only 17 alpha hydroxylase and 11 beta hydroxylase deficiencies cause mineralocorticoid excess syndromes. These result from an accumulation of precursors in the steroid biosynthetic pathway which possess mineralocorticoid activity. Glucocorticoid administration is the treatment.

Premature ventricular contractions: everything you wanted to know and more

A detailed review was recently published, which should be read in the original. Below are a few key issues covered.

Mechanisms:

Known or purported mechanisms include automaticity, triggered activity and re-entry. Automaticity causes ventricular ectopy (VE) by premature depolarization of pacemaker cells. This results from a shortening of the time it takes for phase 4 diastolic depolarization to reach threshold, due to an increased slope of diastolic depolarization or other mechanisms.

So called triggered activity is the result of afterdepolarizations, which could take the form of delayed (DAD) or early afterdepolarizations (EAD). DAD occur in phase 4 and are believed to be related to increased intracellular calcium concentrations due to a variety of mechanisms (eg catecholamine effects) with increased cAMP levels as a final common pathway. This in turn leads to a transient inward depolarizing sodium current generated by the Na/Ca exchanger. DAD is believed to be the mechanism of adenosine sensitive RVOT ectopy.

The mechanisms of EAD are less clear. Because EAD occur in phase 3 they increase repolarization time and appear to be instrumental in causing arrhythmias in the setting of a long QT interval.

Re-entry, once thought to be the primary mechanism of VE, is now in doubt as an important cause of PVCs.

The PVC coupling interval may provide a clue as to the mechanism but this is not entirely clear. A fixed coupling interval implies re-entry (if such exists in man) or triggered activity. Variable coupling intervals imply automaticity. Variable coupling intervals with equal or mathematically related inter-ectopic intervals are designated as parasystole which is usually associated with structural heart disease.

Are PVCs associated with harm?

It is useful to approach this question with respect to the presence or absence of structural heart disease. In both acute ischemia and chronic structural heart disease we know that they are associated with negative outcomes though it is less clear whether as a marker or a cause.

What about patients with no structural heart disease? In such patients VE was traditionally thought to be almost universally benign, based primarily on this paper from 1985 by Harold Kennedy and others. Drawing from a larger database that has accumulated since that time, this notion has been challenged, and there may be risk in some patients. This risk is poorly characterized with the exception of two categories: certain purely electrical heart diseases (channelopathies) and the potential for chronic frequent PVCs to cause a dilated cardiomyopathy (DCM). In purely electrical diseases a single PVC may trigger a life threatening event. From the article:

PVCs can trigger VF or polymorphic VT in patients with or without structural heart disease. 6 30 Some features of PVCs can help to identify “malignant PVCs” that have the potential of triggering VF in some patients. Most often PVCs are not tightly coupled to prior sinus beats; however, in certain conditions, tightly coupled PVCs have been described to trigger VF. This has been described for patients with Brugada syndrome, 31 early repolarization syndromes, 32 idiopathic VF, 33 or in the setting of acute myocardial infarction. 7 In the absence of these conditions, malignant ventricular arrhythmias are rare but have been reported and often have been triggered by tightly coupled PVCs. 6 34 No absolute cutoff value for a tight coupling interval has been defined, although most often the PVC coupling interval was less than 400 ms in these circumstances. 6 Other parameters that need to be assessed include the QT interval and the presence of nonsustained VT, including rate and morphology. More malignant arrhythmias have shorter cycle lengths, 35 and in 1 report, the coupling interval of the second beat of the nonsustained VT was found to be shorter in patients with VF compared with patients without VF. 36

It must be kept in mind that in some conditions (eg LQTS, hereditary and acquired) not all triggering PVCs are short coupled.

Concerning PVC induced DCM recent findings challenge the notion that this is caused chiefly by RVOT ectopy. Though RVOT ectopy is a known cause, DCM can result from VE originating from other foci. Also recently challenged is the idea that 15% of heartbeats is necessarily the ectopic frequency threshold for the development of DCM. The critical frequency is actually quite variable and is likely influenced by other risk factors, one of which is PVC QRS width, which is roughly directly proportional to the risk of DCM. A cutoff of 150 ms has been suggested. Epicardial origin of PVCs is associated with a wider QRS and greater DCM risk. Finally, interpolation of PVCs is also associated with a greater DCM risk. PVC induced DCM was once thought to be a variant of tachycardia mediated DCM but is now believed due to different mechanisms. It should be noted that in patients who already have structural disease for other reasons, frequent PVCs can lead to further deterioration of ventricular function.

Treatment:

Beta blockers are first line despite low efficacy due to their favorable safety profile. I-C antiarrhythmic drugs have stronger efficacy and are considered the next line of treatment provided the patient has no structural heart disease. The concern that these drugs increase the risk of SCD when used to treat PVCs is restricted to patients with structural heart disease. Careful assessment and appropriate expertise are required. Amiodarone is an option for patients who do have structural heart disease. Once DCM ensues due to frequent PVCs therapeutic options become limited for the above stated reasons. Suppression of VE with amiodarone has been reported to reverse DCM in that situation.

Catheter ablation is a preferred option in selected patients and is discussed in detail in the article.

Vagal atrial fibrillation

This entity has long been known. It represents one group of mechanisms accounting for the increased risk of atrial fib with athletic conditioning. Review here.