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.

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.

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.

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.

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.

Handwritten (white board) video tutorials on topics in medicine

I haven't examined the actual content but the topic list looks great. It's definitely worth a look.

HT to Clinical Cases and Images.

Moderation and clean living: the legacy of Dr. Lester Breslow

Profiled in NYT. Via Clinical Cases and Images.

Quick reference: anaphylaxis

From the Paucis Verbis series at Academic Life in Emergency Medicine.

Quick reference: interpreting intraosseous blood

From the Paucis Verbis series at Academic Life in Emergency Medicine.

Woo comes to the mall

Brought to you by Mayo Clinic.

PET scan for Alzheimer disease

The tracer has affinity for brain amyloid. 

HT to Clinical Cases and Images.

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.

Update on parasomnias

Here's an interesting slide show from Medscape.

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.

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.

May have less cross sensitivity in PCN allergic patients.

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.

Prevention

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?

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.

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.

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.