Saturday, December 29, 2012

Cellulitis and its mimics

This review deals with several non-infectious mimics. Presentations of cellulitis which harbor more serious conditions such as nec fash, abscess or bad fungal infections were not covered.

Friday, December 28, 2012

Cardiac device therapy: ICD and CRT

A comprehensive review in the Texas Heart Institute Journal covers standard indications (ischemic and non-ischemic cardiomyopathy), unusual indications (infiltrative diseases, channelopathies) and controversies (timing of implantation after MI or onset of HF). Free full text available here.

Thursday, November 29, 2012

Yet another CAM promoting article in a mainstream medical journal

The premise of this article seems to be that treatment choices should be based on perception and preference. What ever happened to evidence and scientific plausibility?

Wednesday, November 28, 2012

A review of acute aortic regurgitation

Key points:

Acute severe AR may be difficult to recognize clinically and is often erroneously diagnosed as another acute condition such as sepsis, pneumonia, or nonvalvular heart disease.

Infective endocarditis and aortic dissection are the “big two” causes and their managements are depicted in this figure.

Tuesday, October 30, 2012

Whither the stethoscope?

Due to the pervasive decline in the basic clinical skills of physicians and trainees the stethoscope has been relegated to the status of an instrument to facilitate CPT coding with the unintended consequence of spreading germs.

Well, after all, the thinking goes, why work to maintain auscultatory skills when you can just get an echo? As this article in CCJM points out, that's dangerous thinking. Echocardiography can mislead. If it doesn't correlate with basic clinical data something's wrong.

As the late J.Willis Hurst was fond of saying, master low technology (basic clinical skills) or you're bound to abuse high technology.

Monday, October 29, 2012

Autoinflammatory syndromes as causes of recurrent fever

Familial Mediterranean fever is the prototype but many new variants are emerging as explained in this review.

Sunday, October 28, 2012

Bad science is no respecter of politics

Is it fair to brand the right as anti-science and the left as pro-science? No.

Did you know, for example, that Barack Obama said, concerning vaccines and autism:

"We've seen just a skyrocketing autism rate. Some people are suspicious that it's connected to the vaccines. This person included..."

Well, so did John McCain.

There's much more in this web cast from C-SPAN Book TV including a general discussion of the hazards of opening scientific discussions to the arena of public debate. Discussions of science should inform policy. They should not be mixed with or driven by a policy agenda.

There's plenty of bad science on both sides of the aisle.

Sunday, August 05, 2012

Guidelines at a glance---chest pain

This is part of my ongoing attempt to alleviate guideline chaos for hospitalists, one guideline at a time. Here I will attempt a nuts-and-bolts summary of the ACCF/AHA 2007guidelines with the 2011 focused update incorporated. While the guideline title references NSTEMI/unstable angina it actually covers all patients presenting with chest pain including those who “rule out” and do not have ACS at all. Patients in the latter group are often attended by hospitalists.

This post will only address questions hospitalists are likely to encounter and will therefore encompass those patients who present as “chest pain-rule out” as well as the initial medical management of those with established or suspected ACS. Decisions usually deferred to cardiologists (invasive versus noninvasive strategy, antithrombotic therapies associated with PCI and revascularization strategies) will not be covered here even though they are included in the guideline document.

First a caveat. Before you go down the path of “R/O ACS” don't forget the life threatening alternative diagnoses: aortic dissection and pulmonary embolism. So apply the ADD and Wells scores to these patients early on when clinical judgment dictates.

Again the presentation the hospitalist most often encounters is “chest pain, rule out ACS.” That is, there are no initial objective diagnostic findings of ischemia and the presentation is not classic but “could be cardiac.” The essentials of the approach to this type of patient are conveyed in figure 2. Simply stated, if cardiac biomarkers and ECGs are normal over at least 12 hours (or the ECG is nondiagnostic) and the patient stabilizes (vitals stable and the pain does not recur or is grossly atypical) then stress imaging is the next step. If it is negative the patient may be discharged for outpatient follow up.

As to the choice of noninvasive imaging modalities a stress imaging test carries a class I recommendation while a CT coronary angio carries a class IIa (considered an alternative).

What about those patients who turn out to actually have ACS (that is they have initial positive objective findings, a classic or suspicious clinical presentation or ultimately “rule in”)?

  • IV nitro if persistent ischemia, heart failure or hypertension.
  • PO beta blocker in the first 24 hours absent decompensated heart failure, low output state, increased risk for cardiogenic shock or the usual contraindications.
  • a rate limiting calcium blocker if beta blocker contraindication, lack of evidence of systolic dysfunction or other contraindication.
  • an ACEI within 24 hours if EF .4 or less, systolic over 100, absent other contraindications
  • discontinuation of any non-ASA NSAIDs.

The above points assume ASA was given in the field, the ER or at home and carry a class I recommendation. Morphine, IV beta blockers, rate limiting calcium blockers for persistent/recurrent ischemia after optimal beta blocker, nitrate and ACEI use in patients with normal LV systolic function are considered reasonable and carry a class IIa recommendation.

What about initial antithrombotic therapies for patients with ACS?

  • ASA ASAP (assuming not already given) and indefinitely. Initial dose non-enteric coated.
  • Plavix load followed by maintenance for patients intolerant of ASA.
  • PPI if history of GI bleed with any antiplatelet.

The above recommendations are class I. If an initial noninvasive strategy is chosen a plavix load and maintenance is a class I recommendation, alongside ASA and anticoagulation.  The use of plavix and other antiplatelet drugs for patients who undergo an initial invasive strategy is not covered here.

For anticoagulation enoxaparin, fondaparinux or unfractionated heparin are given class I recommendations. However a class IIa recommendation favors the first two over the latter.

Bear in mind that this down-and-dirty summary of what hospitalists might need to refer to at the point of care is an oversimplification driven by some of my biases. For something more comprehensive and nuanced read the original document.

Update August 7 2012:

Another caveat. Don't forget that the STEMI/NSTEMI distinction is artificial. The true distinction is whether or not the patient has acute coronary occlusion! ST segment elevation is a surrogate for acute coronary occlusion but, as I have blogged here and here and as Dr. Smith has pointed out many times, not always a reliable one. Consequently a simplistic adherence to traditional “STEMI criteria” risks putting some patients with acute coronary occlusion in the wrong diagnostic category and depriving them of timely reperfusion. The savvy electrocardiographer will identify these patients; the performance driven approach will likely miss them.

Put another way, some patients meeting performance criteria for NSTEMI actually have acute coronary occlusion (with subtle electrocardiographic findings thereof) and should be considered STEMI equivalents.

Thursday, July 12, 2012

Guidelines at a glance: the new ACCP guidelines on antithrombotic therapy (9th edition)

The title to this post is a little deceptive. There's way too much content here to take in at a glance. In fact this post may go on record as the longest one in history of The Notes. Nevertheless it's my best effort to distill the contents of this vast Chest Supplement down to the nuts and bolts of what hospitalists need to know. The first reference point in the document, and the one from which most of the content herein is cited, is the Executive Summary.

The creators of the guideline, purporting to make it more evidence based, cite in their introduction a diminished role of thrombosis experts in the 9th edition:

That solution is to give primary leadership and responsibility for each article not to a thrombosis expert but to a methodologist who, in almost all cases, also is a practicing physician without important conflicts of interest4,5 ..

They correctly point out that not only financial but also academic conflicts of interest are problematic for experts. But favoring methodologists over experts to lead guideline development is disturbing. Here's the definition of EBM from the landmark article by Sackett and others (my italics):
Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.

In order to judiciously apply evidence doctors need more than a recitation and critical appraisal of published literature when they refer to guidelines. This is where expertise is important. Expertise adds depth. (For a thoroughly conflicted and superb review of superficial thrombophlebitis and an article that belongs in every hospitalist's library see here).

The new guidelines place greater emphasis on patient preferences and values than prior editions. It is not uncommon in the guidelines, for example, to find statements such as this:
Remarks: Patients who are more concerned about avoiding the unknown, but potentially large increase in bleeding risk associated with the perioperative continuation of dual antiplatelet therapy than avoiding the risk for coronary stent thrombosis are unlikely to choose continuation of dual antiplatelet therapy.

This reflects one of the founding principles of EBM: the individual patient is a key element in the process. It's by definition. Proponents of more central control of medical decision making, when they cite EBM with all its popular appeal (and misunderstanding) to bolster their arguments, are merely expressing their ignorance of what EBM really is.

But I digress. Following are some comments about changes from the previous edition of the guidelines along with points I think are of special interest to hospitalists:

Use of warfarin
Recommendations for the management of over anticoagulation with warfarin are no longer included in the executive summary of the guidelines, but are found in the body of this paper from the guideline supplement. For asymptomatic INRs up to and including 10 the authors suggest no active reversal. For asymptomatic INRs over 10 the authors suggest oral vitamin K. For major bleeding at any elevated INR, in a change from previous guidelines, the authors suggest reversal with 4 factor prothrombin complex concentrate (PCC) rather than plasma and that, in order to sustain the reversal effect, this be supplemented with IV vitamin K 5-10 mg via slow infusion. Unfortunately, as of the publication of this recent review, 4 factor PCC was not available in the US. The authors of that review discuss alternatives, such as the use of 3 factor PCC supplemented with small doses of recombinant factor VIIa or the use of factor eight inhibitor bypass activity.

The guideline recommends against routine pharmacogenetic testing of patients starting warfarin therapy.

The guideline suggests that reliable patients with stable INRs on warfarin can have their interval of INR testing extended to three months.

Concerning interacting drugs antibiotics have been controversial. The best evidence for adverse effects is concerning quinolones and co-trimoxazole. The authors suggest avoiding these drugs in patients taking warfarin. This may not apply in the inpatient setting where the INR can be monitored daily.

Outpatient use of unfractionated heparin
Patients eligible for outpatient VTE treatment may be treated with weight adjusted UFH without PTT monitoring, with outcomes comparable to LMH, based on evidence from one RCT.

VTE prophylaxis
Concerning VTE prophylaxis for hospitalized medical patients the ACCP is pretty much in line with the recently released ACP guidelines which restrict pharmacologic prophylaxis in medical patients to those at high risk for VTE and decry prophylaxis as a default option for all medical patients, as is now driven by some performance initiatives. The ACCP guidelines consider two groups of medical patients: critical and non critical. Critical patients, which for practical purposes could be defined as those in the ICU, are all considered high risk and deserving of pharmacologic prophylaxis provided there is not a high bleeding risk. Non-critical (ward) patients should be assessed by the Padua prediction score to determine whether they are at high risk for VTE.

Extending the course of VTE prophylaxis to the post discharge period has garnered a great deal of recent discussion. For medical patients the ACCP guidelines recommend against this practice. They also recommend stopping pharmacologic prophylaxis once the patient is mobile---which would seem to mean that prophylaxis can be stopped at discharge or as soon as the patient becomes ambulatory (anything more than bathroom privileges), whichever happens first.

For outpatients with solid tumors the guidelines suggest pharmacologic prophylaxis but only if the patient has additional risk factors (beyond the cancer) for VTE.

For long distance travelers the guidelines do not recommend pharmacologic prophylaxis although for those at high risk certain non-pharmacologic measures are suggested.

The VTE prevention guidelines for abdominal and pelvic surgical patients are complex and based on risk assessment via the Rogers and Caprini scores. Those tools are contained in the body of this paper from the supplement. If the surgery is for cancer, pharmacologic prophylaxis extended through 4 weeks is highly recommended. Recommendations based on the scores: Rogers 10 or less, Caprini 2 or less, no pharm prophylaxis. Pharm prophylaxis is recommended for higher scores.

Pharmacologic prophylaxis is not recommended for cardiac surgery patients without complications. It recommended for those whose course is prolonged by non-hemorrhagic complications.

Pharmacologic prophylaxis is suggested for non-cardiac thoracic surgery patients judged to be at moderate or high risk.

In craniotomy patients the guidelines suggest adding pharmacologic prophylaxis only in patients at very high risk and only after hemostasis is achieved and bleeding risk is decreased. Similar recommendations are applied to spinal surgery and trauma patients.

For orthopedic surgery patients total hip arthroplasty, total knee arthroplasty and hip fracture surgery may, for practical purposes, be considered as one group. Aspirin, strangely enough, is listed among the alternatives for pharmacologic prophylaxis. However low molecular weight heparin is favored over all the alternatives including fondaparinux, unfractionated heparin, warfarin and novel oral anticoagulants. Duration of prophylaxis is for a minimum of 10 days. Extension of prophylaxis for up to 35 days is suggested. It is suggested that mechanical prophylaxis be combined with pharmacologic prophylaxis. Doses for LMWH are not given in the guideline and the product labeling should be consulted. Recommended start time for pharmacologic prophylaxis is 12 or more hours before or after surgery.

No pharmacologic prophylaxis is recommended for distal leg surgery or knee arthroscopy.

A prophylactic IVC filter is NOT recommended in ANY surgical or trauma scenario, even when pharmacologic prophylaxis is contraindicated.

Perioperative management of patients on warfarin, bridging
Patients on warfarin who are scheduled for surgery should have it interrupted approximately 5 days before surgery and resumed 12 to 24 hours after, if hemostasis is achieved.

Bridging indications: whether in patients with mechanical heart valves, atrial fibrillation or VTE as the warfarin indication the decision to bridge or not depends on risk assessment. Yes for high, no for low, and individualized decision making for moderate. How is that risk determined? For mechanical heart valve prostheses mitral position, tilting disc or caged ball, or cerebrovascular event in the past 6 months constitute high; bileaflet aortic position with a fib, prior cerebrovascular event, HT, DM, CHF or age over 75 constitute moderate; aortic bileaflet absent the above constitutes low. For a fib, CHADS 2 of 5 or above, cerebrovascular event within 3 months or rheumatic disease constitute high; CHADS 2 of 3 or 4 constitutes moderate; CHADS 2 of 2 or less with no cerebrovascular history constitutes low. For VTE event within 3 months or severe thrombophilia (meaning protein C, S, or antithrombin deficiency or APLS) constitute high risk; non-severe thrombophilia, history of multiple VTEs, event within 12 months or active cancer constitute moderate; event greater then 12 months out absent the above constitutes low.

For minor procedures (dental, derm, cataract) stopping warfarin is not recommended across the board. For dental procedures, however, administration of a local oral hemostatic agent or interruption of warfarin for 2-3 days prior is suggested. Aspirin interruption is not recommended in any of these scenarios.

Perioperative management of patients on antiplatelet agents
It is suggested that ASA be continued perioperatively in non-cardiac surgery in patients at high cardiovascular risk, but interrupted 7-10 days prior if not.

For CABG, ASA continuation is recommended but stopping clopidogrel or congeners 5 days before.

For patients with coronary stents the guidelines recommend postponing surgery for at least 6 weeks post bare-metal stent placement and at least 6 months (as opposed to a year) following DES placement. If surgery cannot be delayed the guidelines recommend continuing dual antiplatelet therapy through the perioperative period rather than stopping them.

DVT treatments, acute
For isolated distal DVT serial imaging and no anticoagulation is favored if no severe symptoms or risk factors for extension. If the latter exist or extension (even still within the confines of the distal veins) is demonstrated then anticoagulation is recommended.

In the treatment of VTE parenteral anticoagulants are to be continued 5 days or until the INR is therapeutic for at least 24 hours whichever is longer.

For acute DVT all things being equal LMWH or fondaparinux is favored over UFH. The guideline writers recognize the convenience advantage of once over twice daily administration of LMWH when treating acute VTE with full therapeutic anticoagulation. However such once daily administration is recommended only for those LMWH products whose labeling calls for the same total daily dose in the once and twice daily regimens. In other words the labeling doubles the dose per injection for the once daily regimen. Thus enoxaparin, whose labeling for once daily dosing calls for 1.5 time the injection dose for twice daily use, would not be appropriate for once daily administration in the treatment of VTE.

Home over hospital treatment of acute DVT is recommended when circumstances are favorable. (This is not the case for PE---see below).

Anticoagulation alone is suggested over regional or systemic thrombolysis, or surgical clot removal. The writers acknowledge that, particularly in circumstances of high risk for PTS, patient values and preferences might favor one of the alternatives.

In patients with acute DVT the only recommended indication for an IVC filter is those patients with contraindication to anticoagulants.

DVT, anticoagulation duration
The authors do not consider the presence of a permanent IVC filter, by itself, as an indication for indefinite anticoagulation.

In terms of duration of anticoagulation for DVT the authors have defined the terms in a way that differs from prior popular usage:
In this review, the term long-term treatment refers to treatments (eg, VKA therapy, LMWH, dabigatran) that are continued after initial therapy (eg, parenteral anticoagulation, thrombolytic therapy) (Fig 1). In addition, we consider treatment with rivaroxaban, which is used without initial parenteral therapy. Long-term therapy has two goals: (1) to complete treatment of the acute episode of VTE and (2) to prevent new episodes of VTE that are not directly related to the acute event. During the early phase of long-term treatment (ie, first 3 months), treatment of the acute episode of VTE predominates. During the late phase of long-term treatment (ie, after the first 3 months), prevention of new episodes of VTE predominates. We use the term extended anticoagulation to refer to anticoagulation that is continued beyond 3 months without a scheduled stop date.

So there is no longer a category distinction between 3 months, 6 months and “indefinite.” Here are the recommendations:

Association with transient risk factor (provoked): 3 months.

No transient risk factor (unprovoked): extended. There is no predefined stop time but upon periodic reassessment the clinician and patient may decide to stop at some point. (If the patient is at high bleeding risk the recommendation is for 3 months).

The recommendation is similar for a recurrent unprovoked DVT.

LMWH is recommended over warfarin for long term treatment of patients with DVT and cancer.

Prevention of PTS: compression stockings for all patients with acute symptomatic DVT, worn for at least 2 years.

PE treatment
For treatment of PE the recommendations are similar to those for DVT with the following differences:

Outpatient treatment is not recommended but early discharge is suggested for patients at low risk.

Who gets thrombolytic therapy? Absent a high bleeding risk the authors suggest systemic thrombolysis for those with hypotension and for selected patients without hypotension who are clinically deemed at high risk for developing hypotension. This latter recommendation is vague. The authors advocate for patient selection in non hypotensive patients based on an overall clinical assessment rather than any particular test or battery of tests.

Concerning catheter interventions and surgical embolectomy for PE the guidelines state:

5.7 Catheter-Based Thrombus Removal for the Initial Treatment of Patients With PE

5.7. In patients with acute PE associated with hypotension and who have (i) contraindications to thrombolysis, (ii) failed thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (eg, within hours), if appropriate expertise and resources are available, we suggest catheter-assisted thrombus removal over no such intervention (Grade 2C).

5.8 Surgical Embolectomy for the Initial Treatment of Patients With PE
5.8. In patients with acute PE associated with hypotension, we suggest surgical pulmonary embolectomy over no such intervention if they have (i) contraindications to thrombolysis, (ii) failed thrombolysis or catheter-assisted embolectomy, or (iii) shock that is likely to cause death before thrombolysis can take effect (eg, within hours), provided surgical expertise and resources are available (Grade 2C).

The guidelines recommend insertion of an IVC filter for acute PE when a contraindication to anticoagulation exists. (Note that the Thrombosis Interest Group of Canada recommends against this indication for an IVC filter unless an acute proximal DVT is also demonstrated).

Thromboembolic pulmonary hypertension
For chronic thromboembolic pulmonary hypertension: extended anticoagulation, consider surgical thromboendarterectomy in selected cases such as central disease with appropriate expertise available.

Lower limb superficial vein thrombosis
For lower limb superficial vein thrombosis of at least 5 cm in length the guidelines suggest a prophylactic dose of anticoagulant, preferably fondaparinux (2.5 mg daily) for 45 days. That is based on this study which I blogged here. (Contrast the guideline recommendation with the recommendation for full systemic anticoagulation of SVT found in this recent expert review).

Upper extremity DVT Upper extremity DVT
If it is in the axillary vein or more proximal, 3 months systemic anticoagulation whether or not the DVT is associated with an IV catheter. However if the catheter is not removed (and the authors do not recommend removal of the catheter if it is functional and there is ongoing need for it) then anticoagulation continues for the length of time the catheter is in place if over 3 months. The authors do not recommend regional thrombolysis for UEDVT although they acknowledge that in patients with risk factors for PTS patient preferences and values may dictate thrombolysis as a reasonable alternative.

Clots in unusual places
Clots in veins draining the abdominal viscera:  anticoagulation if symptomatic, not if incidentally discovered.

Alternative form of anticoagulation (e.g lepirudin, argatroban, danaparoid) for HIT with or without thrombosis.

Platelet transfusions for HIT? Only if bleeding or for a procedure with high bleeding risk.

When to transition to warfarin? Only after substantial platelet recovery (150K).

For patients with HIT or a history of same who require PCI:

..we suggest the use of bivalirudin (Grade 2B) or argatroban (Grade 2C) over other nonheparin anticoagulants.

For patients with a remote history of HIT requiring acute anticoagulation: fondaparinux.

Atrial fibrillation
The below recommendations for anticoagulation include patients with paroxysmal AF and patients with atrial flutter, as well as patients being managed on a rhythm control strategy.

Anticoagulation is indicated for patients with a CHADS 2 score of 1 or above, and for those with mitral stenosis. Dabigatran is suggested over warfarin for this purpose for patients who meet the labeling criteria for dabigatran with the exception of patients with coronary artery disease on antiplatelet therapy, in whom warfarin is preferred.

What about cardioversion? In all cases anticoagulate 4 weeks after regardless of CHADS 2 score, and follow the above recommendations re long term. If elective and greater than 48 hrs duration (or unknown duration) anticoagulate 3 weeks prior or do TEE guided CV. If known 48 hours or less, or in cases of emergency cardioversion, then immediately parenterally anticoagulate and cardiovert.

PFO and atrial septal aneurysm
Asymptomatic: no antithrombotic therapy.
Cryptogenic stroke, first episode without DVT: ASA
Cryptogenic stroke, repeat episode on ASA or with DVT: warfarin and consideration for closure therapy.

Intensity of warfarin anticoagulation for patients with mechanical valves
Aortic without additional risks: INR 2-3 All others 2.5-3.5

Low dose aspirin added in all if low bleeding risk.

Tuesday, June 12, 2012

Leapfrog gets a bad report card

---from some of our nation's best hospitals.

Their safety metrics are too subjective, according to some of the experts. I note, too, that, according to the article, Leapfrog looks at at least one measure that has not been proven to enhance safety: CPOE.

Saturday, June 09, 2012

Bleeding and Pradaxa (and other novel anticoagulants)

Bleeding on blood thinners is a common problem. Until recently the drill was straightforward. Not so much anymore. Enter the novel anticoagulants, which require novel treatment strategies.

This ToxTalk podcast (the second half of it) contains a nice discussion of the ins and outs of dabigatran (Pradaxa) associated bleeding. When a patient on dabigatran is bleeding the first decision is whether or not it will suffice to merely temporize by stopping the drug, waiting for its effect to wear off and supporting the patient in the meantime with volume resuscitation and packed red cells. If not (life threatening bleeding such as into the head) you're in a bit of a pickle. Then the issue becomes reversal but nobody seems to really know how to go about it! For all the talk about reversal agents none have been proven to work. As the tox experts pointed out we shouldn't expect any of them to work because they all have their effects upstream from dabigatran's site of action.

The discussants cited this paper which showed that 4 factor PCC had no effect toward reversing any of the coagulation tests altered by dabigatrin (although it did reverse rivaroxaban effects).

While there are no outcome based data hemodialysis accelerates removal of the drug and is, according to the discussants, a “reasonable” option for treatment in life threatening situations.

Since there is so much dispute and uncertainty about how to handle dabigatran associated bleeding (do your heme people know what to do? Are the nephrologists on board?) it is important for institutions to have protocols set up in advance. That was perhaps the most important point made by the tox experts.

Friday, May 11, 2012

Cosmetic treatment of fever not warranted

We practice in an era of outcome based medicine. It’s not enough anymore, at least when it comes to things like blood pressure and blood sugar, just to treat the numbers (cosmetic treatment).  Why, then, in everyday practice, don’t we apply the same rigorous skepticism to the problem of fever?

A recent study in Critical Care looked at the question. Lowering of body temperature was not associated with improved outcomes and in some patients was harmful.

Don’t forget the exceptions, e.g. the better brain outcomes in cardiac arrest and stroke patients, and, of course, treatment of heat stroke and the other hyperthermia syndromes.

Thursday, May 03, 2012

Dabigatran review

From the Journal of Medical Toxicology. Concerning bleeding complications:

However, no therapeutic agent has been accepted to reliably reverse the hemorrhagic complications of dabigatran. As of yet, there is no solid evidence to guide management of bleeding complications; management should start with local control of bleeding when possible and transfusion of pRBCs if needed. Transfusion of FFP would not be expected to help control bleeding. Limited and mixed data exist for transfusion of factor VIIa and prothrombin complex concentrates; these therapies should be considered as well as dialysis..

It's not just the QT interval, stupid!

Traditionally we look to the QT interval to assess the risk of Torsades des pointes ventricular tachycardia when monitoring the effects of certain drugs. Moreover, QT interval prolongation, rather than “twisting about the point” morphology, has been the defining characteristic of Tdp. But as pointed out in a recent post over at Clinical Correlations, that thinking is simplistic. Even correcting the QT interval for rate (QTc) is of limited value. While it's true that prolonged repolarization is at fault that's only part of the story, as reflected in the post and as exemplified by amiodarone, which prolongs the QTc but does not cause Tdp. In actuality the abnormal repolarization that characterizes Tdp has other components and these may better lend themselves to the subjective “eyeball test” than to a single measurement. That said, some of the references cited in the Clinical Correlations post deal with attempts at quantitative treatment of the various components.

None of this is new mind you. I blogged this very concern over two years ago and said this:

Although the traditional assessment for prolongation of repolarization is the measurement of the QT interval, that assessment is simplistic and fraught with error due to controversy about normal limits and rate corrections, poor T wave demarcation, poor distinction between the T wave and the U wave and cycle length dependency. More subjective features including pause dependency, particularly in short-long cycle sequences, splayed T waves (or TU fusion) and macroscopic T wave alternans may be more important.

Among drugs that prolong the QT interval amiodarone has a uniquely low risk of producing TdP because the prolongation of repolarization it induces is homogeneous. Heterogeneous repolarization abnormality is the more likely substrate for TdP.

Monday, April 30, 2012

Physostigmine for anticholinergic delirium?

This piece from the folks at ToxTalk caught my eye. It's another example of medicine's swinging pendulum. It looks like physo has made a comeback for the treatment of anticholinergic poisoning. Why? Because these days the problem is so much less often the result of TCA overdose.

Here's a little of the history. Back in the day TCA OD was the prototypical anticholinergic toxidrome. When I was a med student physo was popular in the treatment of TCA overdose. It readily reversed the anticholinergic delirium. Patients woke up promptly. Then came the reports of adverse cardiac effects and seizures. By the time I finished residency it was a no-no.

Fast forward.  Today anticholinergic toxidromes are more commonly the result of over the counter antihistamines such as diphenhydramine. For many of those patients physo is safe and effective according to the ToxTalk expert. Careful, though, when the antihistamine OD is massive it may resemble the TCA toxidrome, so watch for signs like QRS widening and don't use physostigmine on those folks.

Contraindications are those situations in which cholinomimetic action would be harmful, e.g. asthma.

Thursday, April 19, 2012

I’m back

This blog is not dead. Priorities of life outside the blogosphere came calling. During the hiatus I realized how important a part of my professional life blogging has been. I have also reevaluated the focus, which will more clinical. An effort to improve the quality of clinical posts may result in a decreased frequency. Expect the new and improved Notes to resume apace in the near future.

Monday, January 23, 2012

Anti-vaxxers challenge younger docs' clinical skills

It's not often I see a good article in the lay press on health and medicine. This one from the Chicago Tribune is an exception. It goes like this: Many childhood diseases, thanks to vaccines, disappeared from the scene. A generation of doctors went through training without seeing a single case. They “learned” about these diseases once in med school from lectures and textbooks but never encountered a patient. They enter practice not thinking about these diseases and have no real sense of what they look like. Enter the anti-vaccine movement. Now these diseases, until recently of mainly historical interest to today's doctors, are re-emerging. And today's doctors are unprepared.

Not only that, according to the article, survey data presented at IDSA recently suggested that younger docs are not as attuned to the importance of vaccines as their older colleagues.

According to one expert quoted in the article:

"During medical training, you can learn as much as you want about these diseases from textbooks, but unless you see a child struggling to breathe from whooping cough or brain damaged from bacterial meningitis, the feeling of how bad these diseases can be is not visceral," he said.

Aside from the lack of a visceral appreciation of these diseases a rising influence of quackery in medical education (quackademic medicine) along with a growing cynical distrust among medical students toward the pharmaceutical industry may have contributed to the shift.

As an aside, one form of the meningitis referenced above is Haemophilus influenzae type b (Hib). For a somewhat visceral view of that story see this article.

Measles is prominent among the re-emerging childhood diseases that are challenging today's doctors. Few docs in practice today have ever seen a case. I have never seen a case in my career. My defense against missing the diagnosis is to know when to think of it: in any patient with a rash, fever and a really bad cold. Background here.

More about the missed diagnosis of measles from the article:

Last summer, one of the largest outbreaks occurred in Indiana when 14 people came down with measles after an unvaccinated person returned from a yearlong trip to Indonesia. It was initially misdiagnosed as the mosquito-borne tropical disease dengue fever, and it took 17 days to figure out it was the measles, said Angela Cierzniewski, the Indiana state epidemiologist. By then, more than 800 people had been exposed.

And this concerning whooping cough:

Studies show that 20 percent of adults with a cough that lasts more than two weeks actually are suffering from whooping cough, which is often misdiagnosed as bronchitis or asthma.

It's a combination of nasty anti-vaccine quackery and ignorance of the seriousness of childhood diseases that has led to reduced vaccination rates and their re-emergence.

Saturday, January 21, 2012

A bad report card for Medicare's pilot projects

---according to a CBO study as reported in this Medscape piece:

Most Medicare demonstration projects aiming to reduce costs and improve the quality of care — prime goals of healthcare reform — miss their mark, according to a new study from the Congressional Budget Office (CBO) published online Wednesday.

The projects consisted of numerous P4P schemes, disease management programs and bundled payments. The whole thing was a bust with the exception of one bundled payment project for CABG patients which saved money. (Well, after all if you pay less it'll cost less, won't it?).

It brings to mind some of the lessons we learned from managed care a decade ago. Managed care was a smashing financial success simply because they refused to pay for stuff. It was short lived. After a public backlash managed care “matured” and focused on integration of services and “quality.” The cost benefits waned and there was no demonstrable gain in real quality that could be directly attributed to managed care.

I could go on but take a look at what DB had to say about the report:

Boys and girls, this stuff is much more complex than these demonstration projects can address. Physicians really do their best out there.

One of his commenters said it better that I could:

Pretty much destroys a lot of the assumptions used to promote ACOs and PCMHs. I doubt if the true believers will pay any attention to this report.

Imipenem outdoes doripenem in ventilator associated pneumonia

---according to a recent announcement.

Before getting into the report this might be a good time to compare some attributes of the four “penem” antibiotics approved in the U.S.

Imipenem (Primaxin)---from rxlist:

Approved for:
Lower respiratory tract infections. Staphylococcus aureus (penicillinase-producing strains), Acinetobacter species, Enterobacter species, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae*, Klebsiella species, Serratia marcescens

Urinary tract infections (complicated and uncomplicated). Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)*, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii*, Proteus vulgaris*, Providencia rettgeri*, Pseudomonas aeruginosa

Intra-abdominal infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)*, Staphylococcus epidermidis, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii*, Proteus species, Pseudomonas aeruginosa, Bifidobacterium species,Clostridiumspecies, Eubacterium species, Peptococcus species, Peptostreptococcus species, Propionibacterium species*, Bacteroides species including B. fragilis, Fusobacterium species

Gynecologic infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains)*, Staphylococcus epidermidis, Streptococcus agalactiae (Group B streptococci), Enterobacter species*, Escherichia coli, Gardnerella vaginalis, Klebsiella species*, Proteus species, Bifidobacterium species*, Peptococcus species*, Peptostreptococcus species, Propionibacterium species*, Bacteroides species including B. fragilis*

Bacterial septicemia. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Enterobacter species, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Serratia species*, Bacteroides species including B. fragilis*

Bone and joint infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Enterobacter species, Pseudomonas aeruginosa

Skin and skin structure infections. Enterococcus faecalis, Staphylococcus aureus (penicillinase-producing strains), Staphylococcus epidermidis, Acinetobacter species, Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Morganella morganii, Proteus vulgaris, Providencia rettgeri*, Pseudomonas aeruginosa, Serratia species, Peptococcus species, Peptostreptococcus species, Bacteroides species including B. fragilis, Fusobacterium species*

Endocarditis. Staphylococcus aureus (penicillinase-producing strains)

Polymicrobic infections. PRIMAXIN I.V. (imipenem and cilastatin for injection) is indicated for polymicrobic infections including those in which S. pneumoniae (pneumonia, septicemia), S. pyogenes (skin and skin structure), or nonpenicillinase-producing S. aureus is one of the causative organisms. However, monobacterial infections due to these organisms are usually treated with narrower spectrum antibiotics, such as penicillinG.

Off label antimicrobial susceptibility:
Gram-positive aerobes

Bacillus spp.
Listeria monocytogenes
Nocardia spp.
Staphylococcus saprophyticus
Group C streptococci
Group G streptococci
Viridans group streptococci
Gram-negative aerobes

Aeromonas hydrophila
Alcaligenes spp.
Capnocytophaga spp.
Haemophilus ducreyi
Neisseria gonorrhoeae including penicillinase-producing strains
Pasteurella spp.
Providencia stuartii
Gram-negative anaerobes

Prevotella bivia
Prevotella disiens
Prevotella melaninogenica
Veillonella spp.

Though not mentioned in the labeling imipenem has activity against Listeria.

Advantages, disadvantages, comments:
Much broader range of approved indications compared to the other penems.
Experience with a wider range of antibiotic susceptibility.
Dosing information in product labeling extremely difficult to use.
May have higher seizure risk.

Meropenem (Merrem)---from Rx list:

Approved for:
Skin and Skin Structure Infections. Complicated skin and skin structure infections due to Staphylococcus aureus (β-lactamase and non-β- lactamase producing, methicillin susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis (excluding vancomycin-resistant isolates), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis, and Peptostreptococcus species.
Intra-abdominal Infections

Complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species.

Bacterial Meningitis (Pediatric patients ≥ 3 months only)

Bacterial meningitis caused by Streptococcus pneumoniae‡, Haemophilus influenzae (β-lactamase and non-β-lactamase-producing isolates), and Neisseria meningitidis.

Off label antimicrobial susceptibility:
Aerobic and facultative Gram-positive microorganisms

Staphylococcus epidermidis (β-lactamase and non-β-lactamase-producing, methicillin-susceptible isolates only).

Aerobic and facultative Gram-negative microorganisms
Acinetobacter species
Aeromonas hydrophila
Campylobacter jejuni
Citrobacter diversus
Citrobacter freundii
Enterobacter cloacae
Haemophilus influenzae (ampicillin-resistant, non-β-lactamase-producing isolates[BLNAR isolates])
Hafnia alvei
Klebsiella oxytoca
Moraxella catarrhalis (β-lactamase andnon-β-lactamase-producingisolates)
Morganella morganii
Pasteurella multocida
Proteus vulgaris
Salmonella species
Serratia marcescens
Shigella species
Yersinia enterocolitica

Anaerobic microorganisms
Bacteroides distasonis
Bacteroides ovatus
Bacteroides uniformis
Bacteroides ureolyticus
Bacteroides vulgatus
Clostridium difficile
Clostridium perfringens
Eubacterium lentum
Fusobacterium species
Prevotella bivia
Prevotella intermedia
Prevotella melaninogenica
Porphyromonas asaccharolytic
Propionibacterium acnes
Although not mentioned in the product labeling meropenem has activity against Listeria.

Advantages, disadvantages, comments:
May have lower seizure risk than imipenem.
Labeling is user friendly.
Narrow range of approved indications compared to imipenem.

Doripenem (Doribax)---from Rx list:

Approved for:
Complicated Intra-Abdominal Infections

DORIBAX™ (doripenem for injection) is indicated as a single agent for the treatment of complicated intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides caccae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus and Peptostreptococcus micros.

Complicated Urinary Tract Infections, Including Pyelonephritis

DORIBAX™ (doripenem for injection) is indicated as a single agent for the treatment of complicated urinary tract infections, including pyelonephritis caused by Escherichia coli including cases with concurrent bacteremia, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Acinetobacter baumannii.

Off label antimicrobial susceptibility:
Facultative Gram-positive microorganisms

Staphylococcus aureus (methicillin-susceptible isolates only)
Streptococcus agalactiae
Streptococcus pyogenes
Facultative Gram-negative microorganisms

Citrobacter freundii
Enterobacter cloacae
Enterobacter aerogenes
Klebsiella oxytoca
Morganella morganii
Serratia marcescens

Advantages, disadvantages, comments:
Labeling is user friendly.
Narrow range of approved uses compared to imipenem.

Ertapenem (Invanz)---from Rx list:

Approved for:
Complicated Intra-Abdominal Infections

INVANZ is indicated for the treatment of complicated intra-abdominal infections due to Escherichia coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacteroides uniformis.

Complicated Skin and Skin Structure Infections, Including Diabetic Foot Infections without Osteomyelitis

INVANZ is indicated for the treatment of complicated skin and skin structure infections, including diabetic foot infections without osteomyelitis due to Staphylococcus aureus (methicillin susceptible isolates only), Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis, Peptostreptococcus species, Porphyromonas asaccharolytica, or Prevotella bivia. INVANZ has not been studied in diabetic foot infections with concomitant osteomyelitis [see Clinical Studies].

Community Acquired Pneumonia

INVANZ is indicated for the treatment of community acquired pneumonia due to Streptococcus pneumoniae (penicillin susceptible isolates only) including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates only), or Moraxella catarrhalis.
Complicated Urinary Tract Infections Including Pyelonephritis

INVANZ is indicated for the treatment of complicated urinary tract infections including pyelonephritis due to Escherichia coli, including cases with concurrent bacteremia, or Klebsiella pneumoniae.

Acute Pelvic Infections Including Postpartum Endomyometritis, Septic Abortion and Post Surgical Gynecologic Infections

INVANZ is indicated for the treatment of acute pelvic infections including postpartum endomyometritis, septic abortion and post surgical gynecological infections due to Streptococcus agalactiae, Escherichia coli, Bacteroides fragilis, Porphyromonas asaccharolytica, Peptostreptococcus species, or Prevotella bivia.


INVANZ is indicated in adults for:
Prophylaxis of Surgical Site Infection Following Elective Colorectal Surgery

INVANZ is indicated for the prevention of surgical site infection following elective colorectal surgery.

Off label antimicrobial susceptibility:
Gram-positive bacteria:

Staphylococcus epidermidis (methicillin susceptible isolates only)
Streptococcus pneumoniae (penicillin-intermediate isolates)

Note: Methicillin-resistant Staphylococcus epidermidis are resistant to ertapenem.

Gram-negative bacteria:

Citrobacter freundii
Citrobacter koseri
Enterobacter aerogenes
Enterobacter cloacae
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella oxytoca (excluding ESBL producing isolates)
Morganella morganii
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Serratia marcescens

Anaerobic bacteria:

Bacteroides vulgatus
Clostridium perfringens
Fusobacterium spp.

Advantages, disadvantages, comments:
Broader range of approved uses than meropenem and doripenem but the narrowest spectrum of all available penems in the U.S. (Not appropriate as your initial big gun if the patient has risk factors for highly resistant pathogens such as Pseudomonas).

So that brings us back to the FDA report on ventilator associated pneumonia. From Medscape Medical News:

Johnson and Johnson has halted its clinical trial of the antibiotic drug doripenem (Doribax) for patients with ventilator-associated pneumonia after interim results showed a higher death rate among patients receiving the drug compared with those receiving other antibiotics...

The trial, conducted at sites in several countries as part of a postmarketing commitment to the European Medicines Agency, involved 274 participants. It was designed to compare a fixed, 7-day course of doripenem with a fixed, 10-day course of imipenem-cilastatin...

Interim results showed patients receiving doripenem had an all-cause mortality rate of 21.5% at 28 days compared with 14.8% in the control group. In addition, patients in the doripenem group had a 11.2% lower rate of being cured compared with patients in the alternative drug group.

"(The trial) demonstrated excess mortality and a numerically poorer clinical cure rate among subjects treated with Doribax compared to those treated with imipenem-cilastatin," the FDA said in a press statement.

Imipenem seems to come out on top. From what I read about this trial and from the labeling comparisons above I don't know the reason why.

This is an example of comparative effectiveness research but is it also an example of the type of flawed design that is unique to and often creeps into CER? Specifically, why 10 days of imipenem and only 7 days of doripenem? There are other details I'd like to see if this study ever gets published. But for now these are the results and we must make what we can of them.

So for VAP should we be saying “gimme good ole imi”? However you slice it it seems to have the best track record among the penems. (If there've been any direct comparative studies involving meropenem I'm not aware of them).

Can we extrapolate these findings to non-VAP HCAP? Is it worth the down side of possible increased seizure risk and more difficult dosing? Who knows?

Monday, January 16, 2012

Narcolepsy peak seen after 2009 pandemic flu

---with a phase delay of several months. It appears to be related to the pandemic itself, not the vaccination. The mechanism of narcolepsy is believed to be autoimmune destruction of certain hypothalamic neurons. Via Medscape Neurology Minute.

Thursday, January 12, 2012

More evidence demonstrating overuse of PPIs in hospitalized patients

In this study much of the inappropriate use was driven by “prophylaxis” and it was associated with an increased rate of C diff. The authors conclude:

Proton pump inhibitors are frequently inappropriately prescribed to Medicine inpatients who do not have a valid indication and this practice is associated with an increase in C. difficile infection. Interventions are needed to curtail this inappropriate prescribing practice.

Well, had it not been for some misguided performance initiatives we might not have seen this problem in the first place.

So which hospitalized patients should get pharmacologic GI prophylaxis? I haven't searched this literature but my thoughts would be COPD exacerbations and other acute respiratory illnesses when corticosteroids are given; critical patients in the ICU and MI patients who underwent urgent PCI.

Background here.

Wednesday, January 11, 2012

Whither pharmacologic VTE prophylaxis in medical patients?

We've known for a while that it reduces VTE but there's never been a basis for a claim that it saves lives. According to this first ever high level study it doesn't. And these were sick patients, the type we consider high risk. Once again the “quality” movement jumped the gun.

I guess even if there isn't a mortality benefit preventing the occasional VTE means something to the patient. For now I'm with the ACP guidelines which say VTE prophylaxis for medical patients should not be knee jerk but based on the level of risk.

This is for medical patients, mind you, not surgical.

Tuesday, January 10, 2012

Initial antibiotic selection for severe sepsis and septic shock: getting it right in the ER

This study in the Journal of Emergency Medicine retrospectively reviewed patients with severe sepsis and septic shock who had positive blood cultures, and compared the antimicrobial sensitivities of the isolates with the initial ER therapy:

Effective antibiotic coverage was prescribed by emergency physicians in 82% (95% confidence interval [CI] .74–.88) of cases. Of the 25 patients who received ineffective antibiotics, the majority had infections caused by resistant Gram-negative organisms.

So the ER physicians missed the boat in 18% of the cases. This was an academic ER. One might expect a higher miss rate in community hospitals. The investigators then looked at what effect a commonly used readily available guideline would have had on the miss rate:

Health care-associated pneumonia guidelines were applied to all patients, regardless of the source of infection, and were 100% sensitive (95% CI .93–1) for selecting patients who had infections caused by highly resistant organisms.

Using HCAP guidelines may offer an advantage in antibiotic selection over the Surviving Sepsis guidelines because the latter make only general statements about administering sufficiently broad spectrum antibiotics. The HCAP guidelines, on the other hand, list specific regimens.

What's also unique about this method is that the antibiotic selection is based on the general level of microbiologic risk rather than the likely organ source of the infection which is the basis for more traditional recommendations. The presentation of many septic patients is undifferentiated and it has long been my feeling that basing selection on the likely organ source risks too narrow a spectrum in the very ill patients (severe sepsis and septic shock) who so often present to the ER.

Full text at Medscape.