Thursday, April 30, 2015

Outpatient treatment of PE: what does the evidence tell us?


The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched October 2014) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 9). The TSC also searched clinical trials databases. The review authors searched LILACS (last searched November 2014).


Randomized controlled trials of outpatient versus inpatient treatment in people diagnosed with acute PE...


We included one study, involving 339 participants. We ranked the quality of the evidence as very low due to not blinding the outcome assessors, the small number of events with imprecision in the confidential interval (CI), the small sample size and it was not possible to verify publication bias. For all outcomes, the CIs were wide and included clinically significant treatment effects in both directions: short-term mortality (30 days) (RR 0.33, 95% CI 0.01 to 7.98, P = 0.49), long-term mortality (90 days) (RR 0.98, 95% CI 0.06 to 15.58, P = 0.99), major bleeding at 14 days (RR 4.91, 95% CI 0.24 to 101.57, P = 0.30) and 90 days (RR 6.88, 95% CI 0.36 to 134.14, P = 0.20), recurrent PE within 90 days (RR 2.95, 95% CI 0.12 to 71.85, P = 0.51) and participant satisfaction (RR 0.97, 95% CI 0.92 to 1.03, P = 0.30). PE-related mortality, minor bleeding, and adverse course such as hemodynamic instability and compliance were not assessed by the single included study.


Current very low quality evidence from one published randomized controlled trial did not provide sufficient evidence to assess the efficacy and safety of outpatient versus inpatient treatment for acute PE in overall mortality, bleeding and recurrence of PE adequately. Further well-conducted research is required before informed practice decisions can be made.

Now that target specific oral anticoagulants are approved for PE treatment this becomes an important question. If good quality RTC evidence is unavailable we do have other types of evidence that address the problem, specifically evidence showing that, using biomarkers, echocardiography and clinical criteria we can predict patients whose sort term risk is very low. Is that type of evidence enough? Do we even need RCT evidence?

Wednesday, April 29, 2015

Saddle pulmonary embolism and knee jerk alarm

Here's an interesting paper linked at Hospital Medicine Virtual Journal Club. From the abstract:

Saddle pulmonary embolism (PE) is defined as the presence of a visible thromboembolus that straddles the bifurcation of the main pulmonary artery. It occurs in about 2-5% of all PE cases [1]. Visualization of saddle PE on a Computed Tomography (CT) scan causes alarm among physicians due to the possibility of a large clot burden and impending hemodynamic collapse. However, recent studies have challenged this reflexive assumption, along with the assumption that clot burden predicts outcomes [2].

Not that saddle PE isn't serious, but all too often the appearance of a “saddle” trumps further thinking about parameters that mean more such as the shock index, biomarkers and echocardiographic assessment of RV function.

Tuesday, April 28, 2015

New oral anticoagulants for heparin induced thrombocytopenia (HIT)

Low level evidence suggests they may provide an alternative:

We retrospectively identified 22 patients with HIT who were treated by our group with a combination of NOAC and a short course of argatroban. These patients were evaluated in a prospective fashion for development of outcomes at a mean follow up of 19±3months.


There were a total of 5 deep and 2 superficial vein thromboses diagnosed at index hospitalization. No patient developed arterial thrombosis. All patients tolerated NOAC and their platelet count normalized before discharge. At 19months of follow-up, 6 patients had died of non-thrombotic causes. There was no bleeding, limb loss or recurrent venous thromboembolism in any patient.


In patients with HIT, a short course of parenteral treatment with argatroban followed by administration of a NOAC is highly safe and effective in prevention of thrombosis and normalization of platelet count. Development of HIT however, portends a poor prognosis independent of vascular thrombosis.

Via Hospital Medicine Virtual Journal Club.

Sunday, April 26, 2015


This post from Emergency Medicine Ireland has a link to a full text review which should be read in its entirety. I have posted previously on the subject here and here.

Saturday, April 25, 2015

Update on serious MRSA infections

From Current Opinion in Infectious Diseases:

Recent findings  Elevations in the vancomycin minimum inhibitory concentration within the susceptible range are associated with treatment failure and mortality in the treatment of MRSA infections. Ceftaroline and ceftobiprole are anti-MRSA cephalosporins and are noninferior to comparator agents in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and pneumonia. Tedizolid is more potent than linezolid, has improved pharmacokinetics and reduced toxicity and is active against cfr-containing S. aureus. Telavancin now has approval for treatment of hospital-acquired pneumonia, and recent phase 2 trial data showed similar cure rates in S. aureus bacteremia. Dalbavancin and oritavancin are administered once weekly and are noninferior to comparators for acute bacterial skin and skin structure infections. Resistance has emerged against many new anti-MRSA antimicrobials including ceftaroline. Combination therapy of β-lactams with vancomycin or daptomycin is increasing.

Summary  Several new MRSA-active agents are now approved for use, although much of the data is derived from treatment of acute bacterial skin and skin structure infections or pneumonia. Further studies are required for more invasive infections, such as bacteremia and endocarditis.

Friday, April 24, 2015

MRSA pneumonia: what's the best treatment?

Is it vancomycin or linezolid? The evidence is mixed and the controversy continues but according to this review linezolid seems to be gaining the edge.

Via Hospital Medicine Virtual Journal Club.

Thursday, April 23, 2015

Procalcitonin as a prognostic indicator in sepsis


Procalcitonin is useful for the diagnosis of sepsis but its prognostic value regarding mortality is unclear. This prospective observational study was designed to study the prognostic value of procalcitonin in prediction of 28 day mortality in patients of sepsis. Fifty-four consecutive patients of sepsis, severe sepsis and septic shock defined using the 2001 Consensus Conference SCCM/ESICM/ACCP/ATS/SIS criteria from medical Intensive Care Unit (ICU) of a tertiary care center in New Delhi, India were enrolled from July 2011 to June 2013. Procalcitonin (PCT), C-reactive protein (CRP) measurements were recorded on day 1, day 7 and day 28 of follow up.


Procalcitonin value was a better predictor of all-cause short-term mortality than C-reactive protein. Those patients with Procalcitonin levels less than 7 ng/ml showed higher cumulative survival than those with level [greater than or equal to]7 ng/ml (69.1% vs. 39.5%, p = 0.02). No such effect was observed in relation to C-reactive protein. Procalcitonin levels [greater than or equal to]7 ng/ml predicted mortality with a hazard ratio of 2.6(1.1-6.3).


A Procalcitonin value [greater than or equal to]7 ng/ml obtained at the time of admission to the ICU is a predictor of short-term mortality and thus may allow the identification of those septic patients at increased mortality risk, and help improve their treatment.

Median procalcitonin levels for survivors and non survivors are presented here.

Also of note from the study:

Procalcitonin levels were also significantly higher in patients with septic shock as compared to that with severe sepsis (34.6 ± 36.7 vs. 15.0 ± 29.9 ng/mL; p = 0.03) and sepsis (34.6 ± 36.7 vs. 3.8 ± 1.6 ng/mL; p = 0.008) (Figure 3).

Initial arrest rhythm to drive post resuscitation care decisions

Here are the findings from an interesting study published in Resuscitation:

We investigated the impact of intensified postresuscitation treatment in comatose survivors of out-of-hospital cardiac arrest (OHCA) of presumed cardiac etiology according to the initial rhythm at the emergency medical team arrival.

Interventions and survival with Cerebral Performance Category (CPC) 1–2 within each group were retrospectively compared between the periods of conservative (1995–2003) and intensified (2004–2012) postresuscitation treatment.

In shockable group, therapeutic hypothermia (TH) increased from 1 to 93%, immediate invasive coronary strategy from 28 to 78%, intraaortic balloon pump from 4 to 21%, vasopressors/inotropes from 47 to 81% and antimicrobial agents from 65 to 86% during the intensified period as compared to conservative period (p less than 0.001). This was associated with increased survival with CPC 1–2 from 27 to 47% (p less than 0.001). After adjusting for age, sex and prehospital confounders, TH (OR = 2.12, 95% CI 1.25–3.61), percutaneous coronary intervention (OR 1.77, 95% CI 1.15–2.73) and antimicrobial agents (OR = 12.21, 95% CI 5.13–29.08) remained associated with survival with CPC 1–2. In non-shockable patients, TH also significantly increased from 1 to 74%, immediate invasive coronary strategy from 8 to 51%, intraaortic balloon pump from 2 to 9% and vasopressors/inotropes from 56 to 84% during intensified period without concomitant increase in survival with CPC 1–2 (7% vs. 9%; p = 0.27). After adjustment, only antimicrobial agents (OR = 8.43, 95% CI: 1.05–67.72) remained associated with survival with CPC 1–2.

Of particular interest is the frequency with which antibiotics were given and the degree to which their use was associated with better survival.

Karl B. Kern MD, in a related editorial, made the following points:

In contrast to the referenced study, findings form a large database in Arizona showed benefit from a similar intensified post-arrest care bundle regardless of the presenting rhythm. (In the referenced study only antibiotics were associated with better outcomes across all rhythm groups).

Wednesday, April 22, 2015

Overdiagnosis and treatment of pulmonary embolism: the emperor still has no clothes

That fairy tail reference, of course, is to the famous Annals article way back in 1977. Some 38 years later we still may be overdiagnosing and overtreating PEs, but for different reasons. That is the subject of a great post overat EP Monthly. It focuses on 1) the knee jerk overuse of CTA in patients with chest symptoms (failure to apply clinical prediction rules such as the Wells score) and 2) the frequent finding, with the current heavy use of CTA, of questionable isolated small filling defects that may not need to be treated, or may not represent PE at all. It's a great read and well referenced. In reading the post, keep in mind the following:

It is not known whether such low clot burden PEs need to be treated at all. Investigators believe there is clinical equipoise and so a randomized clinical trial is now ongoing to answer the question.

Many such low burden filling defects picked up on CT would be “missed” with perfusion lung scanning. However, perfusion lung scanning is at least as sensitive (with normal perfusion or when very low probability criteria are met) as CT for clinically significant emboli and in terms of outcomes.

Despite the reported incidence of PE going way up over the years since the introduction of CT motality for PE has not changed, indirect evidence that the small lesions picked up on CT are clinically insignificant and should not be treated.

The use of CTA in preference to VQ scanning is popularity based and not evidence based. There is no evidence that CT is superior to nuclear scanning as the initial imaging modality.

Cardiovascular consequences of hypoglycemia in diabetes treatment: an emerging threat

From a recent review:

Hypoglycemia in people with diabetes mellitus (DM) has been potentially linked to cardiovascular morbidity and mortality. Pathophysiologically, hypoglycemia triggers activation of the sympathoadrenal system, leading to an increase in counter-regulatory hormones and, consequently, increased myocardial workload and oxygen demand. Additionally, hypoglycemia triggers proinflammatory and hematologic changes that provide the substrate for possible myocardial ischemia in the already-diseased diabetic cardiovascular system. Hypoglycemia creates electrophysiologic alterations causing P-R–interval shortening, ST-segment depression, T-wave flattening, reduction of T-wave area, and QTc-interval prolongation. Patients who experience hypoglycemia are at an increased risk of silent ischemia as well as QTc prolongation and consequent arrhythmias.

Tuesday, April 21, 2015

FDA approval of ivabradine for heart failure

The FDA on Wednesday approved ivabradine (Corlanor), Amgen’s new heart failure drug. The drug has been available for several years in Europe, where it is sold by Servier under the brand names of Corlentor and Procoralan.

Ivabradine was approved for the reduction of hospitalization from worsening heart failure. It is indicated for use in stable heart failure patients who are in sinus rhythm, have a resting heart rate of at least 70 bpm, and who are also taking the highest tolerable dose of a beta blocker. Ivabradine slows the rate of the heart by inhibiting the so-called “funny” current within the heart’s natural pacemaker, the sinoatrial node.

The funny current is an inward cation flux which helps initiate diastolic depolarization in pacemaker cells. So, if you inhibit the funny current heart rate slows. I have seen the FDA press release for consumers but not the product labeling. From the press release:

Corlanor is approved for use in certain people who have long-lasting (chronic) heart failure caused by the lower-left part of their heart not contracting well. The drug is indicated for patients who have symptoms of heart failure that are stable, a normal heartbeat with a resting heart rate of at least 70 beats per minute and are also taking beta blockers at the highest dose they can tolerate.

Reading between the lines it would appear that the drug is approved for patients with systolic dysfuction. The proviso concerning beta blockers, it would seem to me, will restrict the use of the drug, since many patients at the limits of beta blocker tolerance are there due to low heart rate. The niche for ivabradine may be in those patients at the limits of beta blocker tolerance for blood pressure reasons who still have a heart rate of at least 70.

An often forgotten fact is that heart rate reduction by itself is good for patients with heart failure. That was the premise of the the SHIFT study, the results of which are the basis of the drug's approval. From the Lancet paper:


Raised resting heart rate is a marker of cardiovascular risk. We postulated that heart rate is also a risk factor for cardiovascular events in heart failure. In the SHIFT trial, patients with chronic heart failure were treated with the selective heart-rate-lowering agent ivabradine. We aimed to test our hypothesis by investigating the association between heart rate and events in this patient population...


In the placebo group, patients with the highest heart rates (greater than or equal to 87 beats per min [bpm], n=682, 286 events) were at more than two-fold higher risk for the primary composite endpoint than were patients with the lowest heart rates (70 to less than 72 bpm, n=461, 92 events; hazard ratio [HR] 2·34, 95% CI 1·84–2·98, p less than 0·0001). Risk of primary composite endpoint events increased by 3% with every beat increase from baseline heart rate and 16% for every 5-bpm increase. In the ivabradine group, there was a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes. Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (n=1192; event rate 17·4%, 95% CI 15·3–19·6) than did patients with higher heart rates. The effect of ivabradine is accounted for by heart-rate reduction, as shown by the neutralisation of the treatment effect after adjustment for change of heart rate at 28 days (HR 0·95, 0·85–1·06, p=0·352).


Our analysis confirms that high heart rate is a risk factor in heart failure. Selective lowering of heart rates with ivabradine improves cardiovascular outcomes. Heart rate is an important target for treatment of heart failure.

Detrimental effect of hyperoxia post-arrest

From a recent systematic review and meta-analysis:

Studies have shown the detrimental effect of hyperoxia in animals with return of spontaneous circulation (ROSC) after cardiac arrest. To maximize the value of existing clinical studies, we performed the systemic review and meta-analysis of human observational studies to examine the effect of hyperoxia on outcomes of post-ROSC patients...

Fourteen studies were identified from 2982 references. Odds ratio (OR) was used as effect estimate. OR was reconstructed if not provided in original articles. Hyperoxia was defined as a PaO2 greater than 300 mmHg. Meta-analysis indicated that hyperoxia appeared to be correlated with increased in-hospital mortality (OR, 1.40; 95% CI, 1.02–1.93; I2, 69.27%; 8 studies) but not worsened neurological outcome (OR, 1.62; 95% CI, 0.87–3.02; I2, 55.61%; 2 studies). However, the results were inconsistent in subgroup and sensitivity analyses.

Hyperoxia appears to be correlated with increased in-hospital mortality of post-ROSC patients.

Monday, April 20, 2015

Emerging evidence for mineralocorticoid receptor antagonists in heart failure with preserved ejection fraction

Form a review:

Recent findings: Three randomized trials were reviewed: the Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial; the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial; and its echocardiography substudy. The Aldo-DHF trial showed improvements in echocardiographic measures of diastolic function. In the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist trial, hospitalization for heart failure was significantly reduced with MRA therapy with no difference in the primary outcome of cardiovascular death or hospitalization. In patients with high risk, however, there may be a reduction in cardiovascular mortality. We will also briefly discuss finerenone, a new generation MRA associated with a lower incidence of hyperkalemia.

Summary: New evidence shows that MRA therapy decreases left ventricular mass and left atrial size, reduces hospitalization, and may reduce cardiovascular mortality in patients with high risk.

Sunday, April 19, 2015

Which newly diagnosed heart failure patients should be evaluated for ischemia and how?

From the 2013 ACCF/AHA guidelines (executive summary here):

No class I recommendations.

Assuming the patient is a potential revascularization candidate---

If ischemia “may be contributing” to heart failure: coronary angiography reasonable (class IIa).

Known CAD but no angina: non invasive imaging reasonable (class IIa).

Other indications for imaging may be present.

Saturday, April 18, 2015

Atrial fibrillation guidelines 2014

These are the latest from the American Heart Association, the American College of Cardiology and the Heart Rhythm Society.

Colon cleanse for hepatic encephalopathy?

From JAMA Internal Medicine:

We hypothesized that rapid catharsis of the gut using PEG may resolve HE more effectively than lactulose...

Design, Setting, and Participants The HELP (Hepatic Encephalopathy: Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution) study is a randomized clinical trial in an academic tertiary hospital of 50 patients with cirrhosis (of 186 screened) admitted for HE.

Interventions Participants were block randomized to receive treatment with PEG, 4-L dose (n = 25), or standard-of-care lactulose (n = 25) during hospitalization.

Main Outcomes and Measures The primary end point was an improvement of 1 or more in HE grade at 24 hours, determined using the hepatic encephalopathy scoring algorithm (HESA), ranging from 0 (normal clinical and neuropsychological assessments) to 4 (coma). Secondary outcomes included time to HE resolution and overall length of stay.

Results A total of 25 patients were randomized to each treatment arm. Baseline clinical features at admission were similar in the groups. Thirteen of 25 patients in the standard therapy arm (52%) had an improvement of 1 or more in HESA score, thus meeting the primary outcome measure, compared with 21 of 23 evaluated patients receiving PEG (91%) (P less than .01); 1 patient was discharged before final analysis and 1 refused participation. The mean (SD) HESA score at 24 hours for patients receiving standard therapy changed from 2.3 (0.9) to 1.6 (0.9) compared with a change from 2.3 (0.9) to 0.9 (1.0) for the PEG-treated groups (P = .002). The median time for HE resolution was 2 days for standard therapy and 1 day for PEG (P = .01). Adverse events were uncommon, and none was definitely study related.

Conclusions and Relevance PEG led to more rapid HE resolution than standard therapy, suggesting that PEG may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute HE.

Friday, April 17, 2015

Anticoagulation decisions for patients with atrial fibrillation

This review recently appeared in the Cleveland Clinic Journal of Medicine. It centers around the updated guidelines promulgated last year by the American Heart Association, American College of Cardiology, and Heart Rhythm Society.

Although it's pretty much the usual rundown, a few points of particular interest are noteworthy:

The new guidelines favor risk assessment using the CHA2DS2-VASc score instead of CHADS2.

HAS-BLED should not be used to exclude patients from anticoagulation therapy.

This is because in all patients except for those at the very lowest risk for thromboembolism the risk of stroke exceeds the risk of intracranial bleeding. Low risk patients will be excluded by the CHA2DS2-VASc score. That being said, HAS-BLED can be useful in identifying patients in need of closer monitoring.

Diminishing importance of aspirin in the guidelines

From the review:

Aspirin has been compared with placebo in seven randomized controlled trials. Only the original SPAF study, in which aspirin 325 mg/day was used, found that it was beneficial. This result alone accounted for the 19% reduction in relative risk (95% CI 1%–35%, P less than .05) in a meta-analysis performed by Hart et al.29 Even when combined with clopidogrel 75 mg/day, aspirin 75 to 100 mg/day is still inferior to warfarin.5 While dual antiplatelet therapy resulted in a 28% relative reduction in thromboembolism (95% CI 17%–38%, P less than .01) compared with aspirin alone, major bleeding significantly increased by 57% (95% CI 29%–92%, P less than .01)...

The 2014 guidelines downgraded the recommendation for aspirin therapy. For patients at low risk and for some at intermediate risk, it is permissible to forgo therapy altogether, including aspirin.1

Patients with hypertrophic cardiomyopathy warrant special consideration.

Patients with AF who also have HCM should receive systemic anticoagulation regardless of the CHA2DS2-VASc score, as a class I recommendation in the new guidelines. This can be done with either TSOACs or warfarin.

Heart block complicating acute MI: does it impact long term outcomes in the PCI era?

From a nationwide database:

This study was conducted to investigate the prognostic value of heart block among patients with acute myocardial infarction (AMI) treated with drug-eluting stents. A total of 13,862 patients with AMI, registered in the nation-wide AMI database from January 2005 to June 2013, were analyzed. Second- (Mobitz type I or II) and third-degree atrioventricular block were considered as heart block in this study. Thirty-day major adverse cardiac events (MACE) including all causes of death, recurrent myocardial infarction, and revascularization were evaluated. Percutaneous coronary intervention with implantation of drug-eluting stent was performed in 89.8% of the patients. Heart block occurred in 378 patients (2.7%). Thirty-day MACE occurred in 1,144 patients (8.2%). Patients with heart block showed worse clinical parameters at initial admission, and the presence of heart block was associated with 30-day MACE in univariate analyses. However, the prognostic impact of heart block was not significant after adjustment of potential confounders (p = 0.489). Among patients with heart block, patients with a culprit in the left anterior descending (LAD) coronary artery had worse clinical outcomes than those of patients with a culprit in the left circumflex or right coronary artery. LAD culprit was a significant risk factor for 30-day MACE even after controlling for confounders (odds ratio 5.28, 95% confidence interval 1.22 to 22.81, p = 0.026). In conclusion, despite differences in clinical parameters at the initial admission, heart block was not an independent risk factor for 30-day MACE in adjusted analyses. However, a LAD culprit was an independent risk factor for 30-day MACE among patients with heart block.

Thursday, April 16, 2015

Pulmonary embolism overview

Great post at S.O.A.P. along with links to other resources in the FOAM community.

Using hemoglobin and hematocrit to guide diuresis in heart failure

From a review:

Hemoconcentration was consistently associated with markers of aggressive fluid removal, including higher diuretic dosing and reduced body weight, but increased risk of in-hospital worsening renal function. Despite this, hemoconcentration was associated with improved short-term mortality and rehospitalization. Hemoconcentration is a practical, readily available, noninvasive, economically feasible strategy to help guide diuresis and monitor congestion relief in patients hospitalized for worsening heart failure. Clinicians should strongly consider using changes in hemoglobin and hematocrit as an adjunct..

Wednesday, April 15, 2015

Therapeutic hypothermia (targeted temperature management) post cardiac arrest implemented as a systems improvement at Kaiser Permanente

Here are the surprising findings of the retrospective cohort study carried out at 21 centers in their integrated delivery system:


Retrospective cohort study of patients with OHCA admitted to 21 medical centers between January 2007 and December 2012. A standardized TTM protocol and educational program were introduced throughout the system in early 2009. Comatose patients eligible for treatment with TTM were included. Adjusted odds of good neurologic outcome at hospital discharge and survival to hospital discharge were assessed using multivariate logistic regression.


A total of 1119 patients were admitted post-OHCA with coma, 59.1% (661 of 1119) of which were eligible for TTM. The percentage of patients treated with TTM markedly increased during the study period: 10.5% in the years preceding (2007–2008) vs. 85.1% in the years following (2011–2012) implementation of the practice improvement initiative. However, unadjusted in-hospital survival (37.3% vs. 39.0%, p = 0.77) and good neurologic outcome at hospital discharge (26.3% vs. 26.6%, p = 1.0) did not change. The adjusted odds of survival to hospital discharge (AOR 1.0, 95% CI 0.85–1.17) or a good neurologic outcome (AOR 0.94, 95% CI 0.79–1.11) were likewise non-significant.


Despite a marked increase in TTM rates across hospitals in an integrated delivery system, there was no appreciable change in the crude or adjusted odds of in-hospital survival or good neurologic outcomes at hospital discharge among eligible post-arrest patients.

The authors were unable to explain the negative findings, which go against the strength of prior high level evidence, and correctly point out that this study should not be taken as evidence against the use of therapeutic hypothermia.

Eosinophilic esophagitis review

This emerging disease first described in 1993 is the topic of a review in CCJM.

Tuesday, April 14, 2015

Treatment options for severely ill patients with influenza

From a recent review:

Purpose of review: Cases of severe influenza may occur during seasonal epidemics, following sporadic zoonotic influenza A transmission from animal reservoirs or on a massive scale with the unpredictable emergence of a new pandemic influenza strain. Clinical experience identifies unmet medical need for additional therapies for influenza, in particular to treat severely unwell adults and children. During and following the pandemic of 2009, a wealth of data from hospitalized cases of influenza from many different countries accumulated and are now starting to emerge. Observational clinical data provide information about the efficacy of existing antiviral drugs in severely ill patients. The development pipeline for new therapies contains several promising agents which are focussed on a range of viral targets, and opens the possibility of combination antiviral therapy for the first time, which may be especially useful in clinically challenging cases. Advances in immunological methods and recombinant protein engineering support the potential for use of immunomodulating therapies as adjuncts in treatment of severe influenza.

Recent findings: The main themes are the importance of treating severe influenza early, considering multiple therapy options and the relevance of observational clinical data to treatment of severely ill and risk groups.

Summary: Clinicians, who may have only seen the media headlines following discussion of reviews which deal with randomized controlled trials of neuraminidase inhibitor drug use in mild uncomplicated influenza in the community, may be hesitant to prescribe these drugs. Observational data arising from treatment of severely ill individuals support use of these drugs early in illness and show improvement in outcomes associated with drug use.

Early tube feeding for acute pancreatitis?

From a recent study in NEJM:


We enrolled patients with acute pancreatitis who were at high risk for complications on the basis of an Acute Physiology and Chronic Health Evaluation II score of 8 or higher (on a scale of 0 to 71, with higher scores indicating more severe disease), an Imrie or modified Glasgow score of 3 or higher (on a scale of 0 to 8, with higher scores indicating more severe disease), or a serum C-reactive protein level of more than 150 mg per liter. Patients were randomly assigned to nasoenteric tube feeding within 24 hours after randomization (early group) or to an oral diet initiated 72 hours after presentation (on-demand group), with tube feeding provided if the oral diet was not tolerated. The primary end point was a composite of major infection (infected pancreatic necrosis, bacteremia, or pneumonia) or death during 6 months of follow-up.


A total of 208 patients were enrolled at 19 Dutch hospitals. The primary end point occurred in 30 of 101 patients (30%) in the early group and in 28 of 104 (27%) in the on-demand group (risk ratio, 1.07; 95% confidence interval, 0.79 to 1.44; P=0.76). There were no significant differences between the early group and the on-demand group in the rate of major infection (25% and 26%, respectively; P=0.87) or death (11% and 7%, respectively; P=0.33). In the on-demand group, 72 patients (69%) tolerated an oral diet and did not require tube feeding.


This trial did not show the superiority of early nasoenteric tube feeding, as compared with an oral diet after 72 hours, in reducing the rate of infection or death in patients with acute pancreatitis at high risk for complications.

Note that only higher risk patients were included in this trial.

Recent Annals of Internal Medicine paper on the microbiology of sore throats

The lead author of the paper was Robert M. Centor, MD, the blogger at DB's Medical Rants. I found some of the findings in the study surprising. Form the paper:

Patients: 312 students aged 15 to 30 years presenting to a student health clinic with an acute sore throat and 180 asymptomatic students.

Measurements: Polymerase chain reaction testing from throat swabs to detect 4 species of bacteria and signs and symptoms used to calculate the Centor score.

Results: Fusobacterium necrophorum was detected in 20.5% of patients and 9.4% of asymptomatic students. Group A β-hemolytic streptococcus was detected in 10.3% of patients and 1.1% of asymptomatic students. Group C/G β-hemolytic streptococcus was detected in 9.0% of patients and 3.9% of asymptomatic students. Mycoplasma pneumoniae was detected in 1.9% of patients and 0 asymptomatic students. Infection rates with F. necrophorum, group A streptococcus, and group C/G streptococcus increased with higher Centor scores (P less than 0.001).

What I get from these findings is that the Centor score predicts “sick” patients with bacterial sore throats who need to be treated, but not necessarily just group A strep infections.

Why treat such patients in the first place? Thinking has shifted in the last few decades. In the days of my training it was mainly to prevent rheumatic fever. The effect of treatment on resolution of symptoms was felt to be modest at best. Over time, as rheumatic fever all but disappeared from the developed world, a more minimalist view began to emerge as illustrated in this talk from a few years ago. But in recent years we have seen the re-emergence of suppurative complications, particularly Lemierre’ssyndrome. This may be due to more restrictive antibiotic use over time or the increasing use of macrolides, which have no activity against the most likely pathogen, Fusobacterium necrophorum.

I believe the article makes a good case to treat “sick” (and presumably bacterial) sore throats in adolescents and adults based on clinical criteria (and not with a macrolide). It is becoming apparent, however, as minimalist thinking weighs in, that this view is not without controversy.

For some insightful discussions on the article see postings here and here.

Delirium in critically ill patients: attributable mortality

The association of delirium with mortality is widely accepted but does delirium actually cause mortality? In this BMJ study the association largely disappeared after severity adjustment. If there is an independent association any impact of delirium prevention on mortality would be small.

Via Hospital Medicine Virtual Journal Club.

Monday, April 13, 2015

PE update

An organized agenda against evidence based medicine

Who, you might ask, could possibly be against evidence based medicine? Certain policy experts are, it turns out. Their anti-EBM agenda is largely hidden due to pervasive ignorance of what EMB is. Those among them who understand EBM (and not all do) might prefer to keep it that way.

And who are these policy experts? They make up that large and influential group referred to in a recent post by Retired Doc as the Medical Progressive Elite. Before going on it is important to point out what many fail to understand about EBM which is that merely citing population based evidence is not enough. Rather, EBM by definition requires the expertise of the individual clinician to apply the best available evidence to the unique attributes, preferences and values of the individual patient. The progressives referred to in Retired Docs post oppose EBM because they downplay the importance of the individual clinician acting on behalf of the individual patient. From the post:

The Medical Progressive Elite's haunting fear is that someone,somewhere is making their own medical decision with input from their private physician...

The last thing that the third party payers and the medical progressive elite want is that medical decisions be made a physician- patient "dyad".This situation is ripe for a classic Baptists and Bootleggers scenario,the medical elite sincerely believing that medicine is too complex and expensive to be left to the judgment of patients with advice from their physicians...

The “dyad” referenced above consists of two of the three key elements of EBM: the clinician and the patient. Remove those two elements and you are left with evidence, but without the “dyad” how can the evidence be effectively applied? Through core measures, care pathways and central authority according to the elite. Again from the post:

This medicine-is-too important-to-be left-patients-and-their- physicians view is made crystal clear in the following quote from the book,"New Rules" written by Drs. Don Berwick and Troyen Brennan:

"Today, this isolated relationship[ they are speaking of the physician patient relationship] is no longer tenable or possible… Traditional medical ethics, based on the doctor-patient dyad must be reformulated to fit the new mold of the delivery of health care...Regulation must evolve. Regulating for improved medical care involves designing appropriate rules with authority...Health care is being rationalized through critical pathways and guidelines. The primary function of regulation in health care, especially as it affects the quality of medical care, is to constrain decentralized individualized decision making."

But those methods for applying evidence, rules, pathways and authority, have demonstrated failure time and time again.

How can the credibility of the American Board of Internal Medicine be restored?

With some answers, maybe. Walter Bond asked some important questions here and here. Docs need explicit, specific answers if confidence is to be restored. Talking around things will not help.

Update on chronic thromboembolic pulmonary hypertension

From Current Opinion in Pulmonary Medicine:

Recent findings The pathobiology of CTEPH development remains incompletely understood; however, evidence supports both large and small vessel disorder in patients with the disease. Surgical thromboendarterectomy is an increasingly well tolerated and often curative procedure and is the management strategy of choice for most patients. Although excellent outcomes in surgical management have been noted, the role of medical management in selected patients with inoperable or recurrent or persistent disease after surgery is increasing. A recent large, randomized controlled clinical trial of riociguat in CTEPH demonstrated improvements in exercise capacity, functional class, and hemodynamics. A safe, effective angioplasty approach to CTEPH is being pursued in addition.

Summary The approach to CTEPH management in the operable patient remains surgical, without clear benefit to preoperative pulmonary arterial hypertension-specific therapy at this time. Patients with inoperable disease or pulmonary hypertension following thromboendarterectomy, however, should be considered for medical management, with riociguat currently having the strongest evidence specific to CTEPH.

Sunday, April 12, 2015

Antibiotic and steroid regimens for COPD

From a recently published update:

Recent findings: Macrolides should be considered the antibiotic of choice for prevention of AECOPD in patients who qualify for therapy. Macrolides, fluoroquinolones, and beta-lactams are all reasonable treatment options for severe AECOPD and the decision to use one over the other should be based upon patient characteristics and institutional or regional antimicrobial susceptibility patterns. The best available evidence now suggests that higher-dose corticosteroids are not superior to treatment with lower-dose corticosteroids in patients with severe AECOPD. Additionally, longer durations of systemic corticosteroid therapy do not improve clinical outcomes.

Summary: Several antibiotic options are efficacious in the management of severe AECOPD and drug selection should be patient-specific. Recent studies suggest that lower dosages and shorter durations of corticosteroid treatment may be prudent.

Saturday, April 11, 2015

Cognitive function three months post cardiac arrest

From a recent study:

To describe cognitive functioning with neuropsychological tests and examine predictors of cognitive outcome in adult survivors of out-of-hospital cardiac arrest (OHCA) of cardiac cause...

45 survivors (4 women) completed the assessment. Neuropsychological tests of fine motor functioning, memory, attention and executive functions were significantly below normative means. Depending on the test, impairment ranged from 9 to 31%. For twenty-five survivors (56%), all cognitive tests were within the normal range. Shorter coma duration and induced hypothermia treatment were associated with favourable cognitive outcomes and explained 45% of the variability in the cognitive composite score. Coma duration was predictive across all cognitive tests, hypothermia treatment of specific tests of memory, attention and executive functioning.

Cognitive outcome was normal in more than half of the survivors. Shorter coma duration and induced hypothermia were associated with favourable cognitive outcomes in the participating survivors three months after OHCA.

Friday, April 10, 2015

Chronic kidney disease is a cause of acquired long QT

From a recent study:

This was a retrospective, chart-review study of admissions or clinic visits to a university hospital between 2005 and 2010 by patients with a diagnosis of CKD. Inclusion criteria selected patients who had 12-lead surface electrocardiography (ECG), renal function tests within 24 hours, and transthoracic echocardiography within 6 months. Cases with a documented etiology for the corrected Qt (Qtc) interval prolongation including structural heart disease, QT prolonging drugs, or relevant disease conditions, were excluded.

Our sample size was 154 ECGs. Two-thirds of patients with CKD had QTc interval prolongation, and about 20% had a QTc interval greater than 500 ms. QTc interval was significantly different and increased with each successive stage of CKD using the Bazett (P less than 0.006) or Fridericia (P = 0.03) formula. QTc interval correlated significantly with serum creatinine (P = 0.01). These finding were independent of age, gender, potassium, and calcium concentrations.

The progression of CKD resulted in a significant delay of cardiac repolarization, independent of other risk factors. This effect may potentially increase the risk of sudden cardiac death, and may also increase the susceptibility of drug-induced arrhythmia.

Thursday, April 09, 2015

The Choosing Wisely recommendations: tools or rules?

This post by Retired Doc is from a few months ago but it it is important and especially timely now in light of all the questions swirling around what the ABIM Foundation is up to. 

The Choosing Wisely (hereafter CW) recommendations were compiled from submissions by leaders of various specialties and are, hence, suggestion based as opposed to evidence based. They were initially promulgated as tools to help clinicians deliver high value care.   But, as Retired Doc pointed out, another agenda is at play:

However in the two years since the launching of CW ( at the time of this writing) several policy experts and wonks have envisioned a much more full bodied, authoritative and coercive role  for the pronouncements announced under the CW brand.  It is this expanded role for CW that I refer to as the medical law of the land...

So based on some of these experts' recommendations, what would the medical landscape look in the era in which the decisions of Choosing Wisely would be much more than the suggestions or recommendations,which is how they are sometimes presented  and  instead be  determinative in regard to the reimbursements of third party payers, private and public as well being used in decisions regarding medical specialty certification  and maintenance of certification and other mechanisms to decrease medical costs.

He quoted these proposed uses of CW from the ABIMF blog:

ABIM could require candidates to achieve a perfect score on questions related to costs and redundant care as a requirement for admission to secure exams for initial certification or MOC.

ACP could grade use of resources through MKSAP questions.

CMS, which has the ultimate negotiating position in the form of reimbursement for Medicare services, could only accept negotiated bundled charges. It could also refuse payment for non-compliance with the Choosing Wisely recommendations.

He quoted other policy leaders proposing a similar agenda and then went on:

Physicians would have to follow the CW guidance or risk loosing certification let alone payment for services. As bound as physicians would be to the  dictates of the CW authority how much trust could a patient have that his physician is acting in his ( the patient's) best interests .Making CW the medical law of the land would be a giant step toward the collectivization of medicine and destruction of the traditional physician patient relationship.

As such it would also mean the destruction of evidence based medicine as I once noted in a post in which I outlined EBM's history, intended purpose and definition:

Two of the interviews are with David Sackett, widely known as one of EBM's main apologists. He talked about the beginnings of the movement and emphasized that it is not merely a collection and critical appraisal (a term the EBM founders coined) of evidence. Rather, it goes beyond that to encompass the judgment of the individual clinician and the preferences and values of the individual patient. Those two elements often get left out of the discussion. Because the individual patient is a key element of EBM, proponents of medicine done by central planning can never claim to advocate for evidence based medicine. Along the same lines Dr. Gordon Guyatt remarked that there is no clinical decision that doesn't have the individual patient's preferences and values attached to it. As a corollary, evidence alone cannot inform a clinical decision.

Clearly those who would leverage central authority to impose CW dogma on medical care are opposed to EBM whether they admit it or not.