Today we discussed a case where the treating physician ordered a procalcitonin assay to decide whether or not the patient had a bacterial respiratory infection. The result was (very) negative. Nonetheless they continued antibiotics. Was that the right decision?
This Lancet ID meta-analysis looks at the operating characteristics of the test. There is a lot of heterogeneity of the pooled studies which is a caveat. But to me, I'm not sure that a pooled sensitivity of 77% and specificity of 79% is all that impressive.
This would yield a positive likelihood ratio of 3.6 and a negative likelihood ratio of 0.27
If the patient has a 20% pre-test probability of bacterial sepsis the test would perform as follows:
Positive predictive value = 47%
Negative predictive value = 6%
(FYI the numbers for 10% and 30% are 28%/3% and 60%/12%)
Does that help you in the care of that patient? Maybe if it is negative; however, it depends on the context and how ill the patient is and the consequences of being among the 6%.
FYI as of 2012 an estimate of the per unit cost was $10-15 for the test... Given the volume of tests which would be (maybe unnecessarily) ordered in the emergency department each day it is no wonder that not all hospitals cover the test (ours does not at time of posting). See technology assessment 2012 available online here.
Wednesday, September 3, 2014
Tuesday, August 26, 2014
Weekly blog -- "Ebola"
We discussed Ebola today. Rather than blog I will shamelessly plug local work... See "Five things to know about Ebola"
Tuesday, August 12, 2014
Weekly blog -- "Aggressive lymphoma in an elderly patient"
Some take home reading:
This lancet oncology article discusses the challenges in treating elderly patients with hematological malignancies (link)
It also addresses "pre-chemo" treatment for DLBCL including corticosteroids for 7 days to be helpful in patients with poorer ECOG status to see if there is an improvement (but likely not helpful in ECOG 0-1)
For DLBCL reduced dose CHOP with full dose rituximab seems (on the basis of 2012 article) to be the best therapy for suitable patients. Overall survival quoted in the article ranged from 35-56% at three years.
Standardized geriatric assessment may be helpful in deciding on a treatment strategy (link)
Burkitt's lymphoma may be another animal compared to other DLBCL -- with median survivals measured in months for patients over age 70 (link) ... And with CHOP-R 2 year progression free survival is less than 30%
HyperCVAD isn't tolerated by the majority of elderly patients.
EPOCH has not been tested in the elderly, but has been investigated with some success in the younger populations (link)
Really, a clinical trial is needed.
*****
On to rasburicase -- a pricy little addition to TLS management --
One way to reduce cost is to use less drug -- this meta-analysis suggests one dose may be as good as a full course (link) as does this smaller study (link) and this one where they saved 2 million dollars over 48 patients... (link) There are more articles on this showing the same thing... (here too)
One could consider adding allopurinol after rasburicase (link) -- though it may not differ to single shot rasburicase
What was interesting is that in 2010 a Cochrane review in CHILDREN could not find an effect for the drug on renal failure or mortality (link)
A meta-analysis in ADULTS was performed (but not meta-analyzed due to heterogeneity) in 2013 which showed that uric acid goes down, but couldn't confirm hard outcomes either (link)
For a drug which costs up to $3600 per 7.5-mg vial (and you get 0.2mg/kg x 5 days if you follow the manufacturer's instructions) that is more than $30,000 per person treated (we pay much less if local data is believable)... Amazing there is no better RCT data on this drug which is recommended for anyone with "high TLS risk, being >5%" or intermediate TLS risk (1-5%) with comorbidities.
For those interested in cost-benefit articles -- here is one on rasburicase (link) which makes a number of assumptions and states the drug is cost-effective... I couldn't find the conflict of interest statements from the authors. Also the cost of the drug modelled was only $2200 for adults (total course).
Assuming the drug is only 3 times that price. I'm pretty sure this would yield significantly different conclusions about its cost-effectiveness. The CER for PREVENTION in ADULTS would be $120,000.
For treatment, that would depend on whether or not it works to prevent the downstream costs... and as I eluded to above, that is unclear.
This lancet oncology article discusses the challenges in treating elderly patients with hematological malignancies (link)
It also addresses "pre-chemo" treatment for DLBCL including corticosteroids for 7 days to be helpful in patients with poorer ECOG status to see if there is an improvement (but likely not helpful in ECOG 0-1)
For DLBCL reduced dose CHOP with full dose rituximab seems (on the basis of 2012 article) to be the best therapy for suitable patients. Overall survival quoted in the article ranged from 35-56% at three years.
Standardized geriatric assessment may be helpful in deciding on a treatment strategy (link)
Burkitt's lymphoma may be another animal compared to other DLBCL -- with median survivals measured in months for patients over age 70 (link) ... And with CHOP-R 2 year progression free survival is less than 30%
HyperCVAD isn't tolerated by the majority of elderly patients.
EPOCH has not been tested in the elderly, but has been investigated with some success in the younger populations (link)
Really, a clinical trial is needed.
*****
On to rasburicase -- a pricy little addition to TLS management --
One way to reduce cost is to use less drug -- this meta-analysis suggests one dose may be as good as a full course (link) as does this smaller study (link) and this one where they saved 2 million dollars over 48 patients... (link) There are more articles on this showing the same thing... (here too)
One could consider adding allopurinol after rasburicase (link) -- though it may not differ to single shot rasburicase
What was interesting is that in 2010 a Cochrane review in CHILDREN could not find an effect for the drug on renal failure or mortality (link)
A meta-analysis in ADULTS was performed (but not meta-analyzed due to heterogeneity) in 2013 which showed that uric acid goes down, but couldn't confirm hard outcomes either (link)
For a drug which costs up to $3600 per 7.5-mg vial (and you get 0.2mg/kg x 5 days if you follow the manufacturer's instructions) that is more than $30,000 per person treated (we pay much less if local data is believable)... Amazing there is no better RCT data on this drug which is recommended for anyone with "high TLS risk, being >5%" or intermediate TLS risk (1-5%) with comorbidities.
For those interested in cost-benefit articles -- here is one on rasburicase (link) which makes a number of assumptions and states the drug is cost-effective... I couldn't find the conflict of interest statements from the authors. Also the cost of the drug modelled was only $2200 for adults (total course).
Assuming the drug is only 3 times that price. I'm pretty sure this would yield significantly different conclusions about its cost-effectiveness. The CER for PREVENTION in ADULTS would be $120,000.
For treatment, that would depend on whether or not it works to prevent the downstream costs... and as I eluded to above, that is unclear.
Tuesday, July 29, 2014
Weekly blog - Overwhelming Post Splenectomy Infection (OPSI)
I couldn't do better than to refer you to the great "Care of the Asplenic Patient" NEJM article from July 24... Get that here.
What was discussed was this (?false!) belief that ceftriaxone ought not be used in patients with sickle cell anemia due to a fear of antibiotic associated hemolysis. I do believe that rare drug adverse events do exist -- but I'm uncertain we should en masse change our practices over the fear of rare events.
There certainly is a literature on ceftriaxone induced hemolytic anemia (drug induced hemolytic anemia, DIHA), occuring in sickle cell anemia patients as well as other patients (see here). In this reference lab, of 169 cases of drug induced hemolysis reported there were 15% of them due to CTX -- the proportion due to CTX increasing as the rates of CEFOTETAN use went down. In fact, CTX was the number two reported agent for DIHA!
PIP-TAZO has also been linked to drug induced severe and acute hemolysis... (see here) ... oh, and in the report of ceftriaxone I referenced above -- Guess who was number one cause? PIPERACILLIN.
... also there are case reports for the FLUOROQUINOLONES as well... (see here)
The key is that these are RARE events given the frequency in which these agents are used. The keen clinician is mindful that they exist but does not knee-jerk avoid very useful agents for potential fatal infections out of a fear of rare events.
People can die from adverse reactions to CT contrast (example). This doesn't mean that we shouldn't use CT contrast. Rather it means that CT contrast should be used when the expected benefit of contrast exceeds the risks.
***
As discussed, fluoroquinolones carry they own risks -- particularly in sickle patients who may be receiving QTc prolonging medications (think torsades) like methadone or other narcotics. They may also (in our setting) be associated with an increased risk of C. difficile.
Piperacillin-Tazobactam seemingly would cover most S. pneumoniae but I really cannot say how effective it would be against AMPICILLIN resistant Neiserria species or beta-lactamase negative ampilillin resistant (BLNAR) H. infuenzae, which would likely be resistant. Ceftriaxone has been used in Neiserrial and BLNAR infections.
What was discussed was this (?false!) belief that ceftriaxone ought not be used in patients with sickle cell anemia due to a fear of antibiotic associated hemolysis. I do believe that rare drug adverse events do exist -- but I'm uncertain we should en masse change our practices over the fear of rare events.
There certainly is a literature on ceftriaxone induced hemolytic anemia (drug induced hemolytic anemia, DIHA), occuring in sickle cell anemia patients as well as other patients (see here). In this reference lab, of 169 cases of drug induced hemolysis reported there were 15% of them due to CTX -- the proportion due to CTX increasing as the rates of CEFOTETAN use went down. In fact, CTX was the number two reported agent for DIHA!
PIP-TAZO has also been linked to drug induced severe and acute hemolysis... (see here) ... oh, and in the report of ceftriaxone I referenced above -- Guess who was number one cause? PIPERACILLIN.
... also there are case reports for the FLUOROQUINOLONES as well... (see here)
The key is that these are RARE events given the frequency in which these agents are used. The keen clinician is mindful that they exist but does not knee-jerk avoid very useful agents for potential fatal infections out of a fear of rare events.
People can die from adverse reactions to CT contrast (example). This doesn't mean that we shouldn't use CT contrast. Rather it means that CT contrast should be used when the expected benefit of contrast exceeds the risks.
***
As discussed, fluoroquinolones carry they own risks -- particularly in sickle patients who may be receiving QTc prolonging medications (think torsades) like methadone or other narcotics. They may also (in our setting) be associated with an increased risk of C. difficile.
Piperacillin-Tazobactam seemingly would cover most S. pneumoniae but I really cannot say how effective it would be against AMPICILLIN resistant Neiserria species or beta-lactamase negative ampilillin resistant (BLNAR) H. infuenzae, which would likely be resistant. Ceftriaxone has been used in Neiserrial and BLNAR infections.
So, I would agree with the uptodate article on the issue (link) -- ceftriaxone should proabably be the "go to drug" in asplenic patients with sickle-cell anemia and probable infection in the asplenic host.
With a careful observation for worsening hemolysis and consideration of an early change in the face of the rare, but severe, side effect of intravascular hemolysis. And an attention to proper dosing in the very young or very underweight individuals.
Tuesday, July 22, 2014
Weekly blog -- Harms of benzodiazepines in the elderly...
In Choosing Wisely, The Canadian Geriatrics Society advised physicians and patients to refrain from using benzodiazepines as first-line treatment for insomnia in older adults (link).
To quote them:
"The number needed to treat with a sedative-hypnotic for improved sleep is 13, whereas the number needed to harm is only 6"
Adverse events include:
To quote them:
"The number needed to treat with a sedative-hypnotic for improved sleep is 13, whereas the number needed to harm is only 6"
Adverse events include:
- Cognitive impairment (link)
- Hip Fracture
- In this cohort study there was a 10-40% increased rate of hip fracture in users of sedative-hypnotics including benzodiazepines and non-benzo sedative hypnotics (link).
- Shockingly the population attributable risk may be as high as 8.2%! (link)
- Respiratory events in patients with chronic lung illnesses
- In this cohort (Ontario) patients with COPD who received benzos had an increased rate of adverse respiratory events (link)
- Increased risk of death in this population (link)
- All cause mortality:
- In this cohort, sleeping pills were associated with a 3 fold increase of death (link).
- Similar effect size in this cohort (link)... 4 deaths per 100 people over 7.6 years.
- Pneumonia and death in age <60 (link)
- Car accidents
- FDA advisory of sedative/hypnotics and car accident risk (and need to reduce dose) (link)
Below is a must read for those who are interested in reducing benzodiazepine use in the frail elderly...I think it is a real example of success in intervening against potentially (probably) inappropriate prescription drug use.
(And yes, before anyone sends me angry emails, I know that maybe INSOMNIA is associated with all of these adverse events and that the sedatives may be the "innocent bystander"... To you, I can only say, "primun non nocere"... Show me the randomized controlled trial...)
Tuesday, July 15, 2014
Weekly blog - Liver lesions (to aspirate or not to aspirate)
Aspirations
of liver lesions... it’s not just about their hopes and dreams.
Today in
rounds we discussed a case of liver lesion and debated as to whether or not it should
have been drained. In the case of a
cystadenocarcinoma you may want to avoid drainage to prevent disease
dissemination; in contrast, drainage of a pyogenic liver abscess is a common
therapeutic and diagnostic procedure.
Here’s a
review on how to differentiate cystadenocarcinoma from liver abscess: https://webvpn.mcgill.ca/http/www.sciencedirect.com/science/article/pii/S0039610910000393
The
bottom line is that a cystadenocarcinoma that secretes mucin can be difficult
to distinguish from a pyogenic abscess based on imaging.
It can be helpful to identify patient risk factors for
pyogenic abscess. In a susceptible
patient presenting with infectious symptoms, you will likely aspirate the lesion to avoid unnecessary surgical
intervention and the associated morbidity and mortality.
Host factors and susceptibilities for pyogenic liver abscess:
· * delayed treatment of intraabdominal processes (appendicitis,
diverticulitis, cholecystitis)
· * biliary obstruction, stenting, or manipulation
· * diabetes/immunosuppression/congenital immune deficiency (i.e. Chronic Granulomatous Disease)
· * endocarditis or IVDU (leading to hematogenous spread)
The original 1946 NEJM article describing the “five ways in which
pyogenic organisms invade the liver”:
See previous blog on this issue here and my color rendition of the mechanisms
Microbiology
(not an exhaustive list):
·
Polymicrobial, gram negatives and anaerobes
·
S. milleri /S.
anginosus, S. aureus, S.pyogenes (and other gram positive cocci),
·
Klebsiella pneumonia (think of this pathogen in patients with
diabetes, particularly with monomicrobial abscess with metastatic spread to other organs)
·
Other: Candida,
Tuberculous, Burkholderia. Amebiasis.
Some
diagnostic pearls pertaining to liver abscess:
·
Initially, an abscess may be hyperechoic and
indistinct; but with maturation and pus formation, it becomes hyperechoic with
a distinct margin. Thick pus or multiple small lesions might be confused with
solid lesions
·
Peripheral
enhancement on CT is VERY helpful!
·
Don’t forget
to do blood cultures (non invasive, though sensitivity only about 40%)
·
I Infectious
symptoms may only occur late. “Large infections with bacteria of modest
virulence can develop with only subtle symptoms.” To illustrate this point, here is a case of pyogenic liver abscess, caused by
strep mitis:
Any discussion of indolent abscess should also include a nod to S. milleri group organisms.
To learn
about klebsiella pneumonia liver abscess (a 2013 review of the European
literature with some illustrative case reports from the journal Infection):
See the previous blog on this particular entity here.
Finally, a “NEJM
case records of the Massachusetts General Hospital”, looks at a case of liver
abscess (read more to find out what interesting pathogen was involved in this
case!)
- egm and tcl
Tuesday, July 8, 2014
Weekly Blog - Whipple's disease with amyloidosis
Since it was mentioned I thought it would be worth a quick note on Whipple's disease:
See review NEJM here.
It is a disease mostly described in men (>85%)
The majority of patients have:
* Weight loss (>90%)
* Diarrhea (80%)
* Arthritis (70%)
Neurologic symptoms or the classic occular findings are seen in 33% and <10% respectively.
"Roughly 15% of patients with Whipple's disease do not have the classic signs and symptoms of the disease"
Diagnosis is made through:
* PAS staining of GI biopsies -- usually several are required
* PCR on tissue or blood/CSF can also be positive
* Electron microscopy can also be used
Treatment:
CEFTRIAXONE induction, TMP/SMX consolidation
Alternative: DOXYCYCLINE
Note that discussed patient also had evidence of a monoclonal light chain in the urine prompting suspicion of amyloidosis (not seen on biopsy of the gut, nor in the serum).
There are several case reports of Whipple's disease being associated with amyloidosis (particularly with renal involvement -- i.e. nephrotic syndrome; also presenting with wasting illness without diarrhea like that discussed)
This case has the full report if you are a McGillian -- here.
Also see here, here, here and here . (many not available online)
Yes, the patient may not have Whipple's disease -- but it is curable and compatible with the illness (which primary amyloidosis, the alternative, is not in the specific patient's condition).
See review NEJM here.
It is a disease mostly described in men (>85%)
The majority of patients have:
* Weight loss (>90%)
* Diarrhea (80%)
* Arthritis (70%)
Neurologic symptoms or the classic occular findings are seen in 33% and <10% respectively.
"Roughly 15% of patients with Whipple's disease do not have the classic signs and symptoms of the disease"
Diagnosis is made through:
* PAS staining of GI biopsies -- usually several are required
* PCR on tissue or blood/CSF can also be positive
* Electron microscopy can also be used
Treatment:
CEFTRIAXONE induction, TMP/SMX consolidation
Alternative: DOXYCYCLINE
Note that discussed patient also had evidence of a monoclonal light chain in the urine prompting suspicion of amyloidosis (not seen on biopsy of the gut, nor in the serum).
There are several case reports of Whipple's disease being associated with amyloidosis (particularly with renal involvement -- i.e. nephrotic syndrome; also presenting with wasting illness without diarrhea like that discussed)
This case has the full report if you are a McGillian -- here.
Also see here, here, here and here . (many not available online)
Yes, the patient may not have Whipple's disease -- but it is curable and compatible with the illness (which primary amyloidosis, the alternative, is not in the specific patient's condition).
Wednesday, June 4, 2014
Weekly Blog: The new 2014 ACC Valvular Heart Disease Guidelines
Some of the updates were reviewed at the rounds this week.
You can find the guidelines here.
The figures are particularly helpful in determining when to consider valve surgery.
AS
AR
MS
MR
Here are a few things in terms of surgery for aortic stenosis:
1) They actually point out the harm in a pet peeve of mine -- premature antibiotics in suspected endocarditis:
"The leading cause of “culture-negative IE,” which can be a significant clinical conundrum, is the use of antibiotics before blood cultures are obtained. Negative blood cultures in the setting of IE can delay diagnosis by slowing other serological and polymerase chain reaction assessments; therefore, it can delay definitive treatment of the patient as well as impair determination of antimicrobial treatment duration"
2) The RCT data for surgery in IE with a vegetation and valve dysfunction made it into the guidelines:
"Class IIb
Early surgery (during initial hospitalization before completion of a full therapeutic course of antibiotics) may be considered in patients with NVE who exhibit mobile vegetations greater than 10 mm in length (with or without clinical evidence of embolic phenomenon)(655,788,789). (Level of Evidence: B)"
3) They abdicate the decision on antibiotics to previous guidelines. Alas, there will be no AMP/CTX for enterococcus in a guideline yet. It is coming!
You can find the guidelines here.
The figures are particularly helpful in determining when to consider valve surgery.
AS
AR
MS
MR
Here are a few things in terms of surgery for aortic stenosis:
- The use of directly supervised exercise testing is recommended for asymptomatic patients with severe disease without symptoms to identify if they have symptoms, hypotension, or markedly increased gradients with exercise.
- Surgery is best considered in a "center of excellence" with a low rate of complications
- "TAVR is not recommended in patients with 1) a life expectancy of <1 year, even with a successful procedure, and 2) those with a chance of “survival with benefit” of <25% at 2 years."
1) They actually point out the harm in a pet peeve of mine -- premature antibiotics in suspected endocarditis:
"The leading cause of “culture-negative IE,” which can be a significant clinical conundrum, is the use of antibiotics before blood cultures are obtained. Negative blood cultures in the setting of IE can delay diagnosis by slowing other serological and polymerase chain reaction assessments; therefore, it can delay definitive treatment of the patient as well as impair determination of antimicrobial treatment duration"
2) The RCT data for surgery in IE with a vegetation and valve dysfunction made it into the guidelines:
"Class IIb
Early surgery (during initial hospitalization before completion of a full therapeutic course of antibiotics) may be considered in patients with NVE who exhibit mobile vegetations greater than 10 mm in length (with or without clinical evidence of embolic phenomenon)(655,788,789). (Level of Evidence: B)"
3) They abdicate the decision on antibiotics to previous guidelines. Alas, there will be no AMP/CTX for enterococcus in a guideline yet. It is coming!
Saturday, May 31, 2014
Weekly blog: The Harms of Oxygen Therapy
From my slides presented at this week's adverse events and deaths rounds:
* Too much oxygen can be dangerous
* This danger is preventable
* Shortness of breath DOES NOT equal need for oxygen
* Hypoxia (Sa02 below 90-92% in normal lungs and 88% in COPD/hypercapnic lungs) means that oxygen is likely required
Examples: Cornet et al, 2012 Jama Internal Medicine
http://archinte.jamanetwork.com/article.aspx?articleid=1108704
Acute MI (DOI: 10.1002/14651858.CD007160.pub3)
* RR mortality 2
CHF
* No RCT; increases afterload, increases LVEDP and decreases cardiac output
* Too much oxygen can be dangerous
* This danger is preventable
* Shortness of breath DOES NOT equal need for oxygen
* Hypoxia (Sa02 below 90-92% in normal lungs and 88% in COPD/hypercapnic lungs) means that oxygen is likely required
Examples: Cornet et al, 2012 Jama Internal Medicine
http://archinte.jamanetwork.com/article.aspx?articleid=1108704
Acute MI (DOI: 10.1002/14651858.CD007160.pub3)
* RR mortality 2
CHF
* No RCT; increases afterload, increases LVEDP and decreases cardiac output
Post cardiac arrest
* OR 1.8 death
Ischemic stroke
* In RCT 40% death in O2 group vs 17% no O2 (p<0.01)
* OR 1.8 death
Ischemic stroke
* In RCT 40% death in O2 group vs 17% no O2 (p<0.01)
COPD* Mortality with TITRATED O2 (88-92) vs. usual care RR 0.2
What about in palliative care? (Campbell ML J symptom pain management 2013)
* The majority of patients who were receiving oxygen at baseline experienced no change in respiratory comfort when oxygen was withdrawn,
* Oxygen provides little benefit in non-hypoxemic patients.
* Oxygen may be an unnecessary intervention near death
* Potential to add to discomfort through nasal dryness and decreased mobility
Other harms:
* Length of stay likely increased with failure to wean
* Decreased mobility as patient attached to tank
* Financial harm -- costs of oxygen (it isnt free!)
Tuesday, May 13, 2014
Weekly blog - Coumadin in Dialysis Patients with Atrial Fibrillation
Great discussion today -- very nuanced and the blog may not do it justice:
The CCS guidelines 2012 focused update:
We suggest that such patients not routinely receive either OAC (Conditional Recommendation, Low-Quality Evidence) or ASA for stroke prevention in AF (Conditional Recommendation, Low-Quality Evidence). Values and preferences. This recommendation places a relatively higher weight on observational data linking warfarin and ASA use with mortality in patients on dialysis, and relatively lower weight on the potential for these agents to prevent ischemic stroke. Therapy with OACs or antiplatelet drugs may be appropriate for some patients with eGFR < 15 mL per minute (on dialysis) in whom there is a stronger preference for avoiding ischemic stroke."
A recent observational study (well done, large study, and one of many to show this association) done here @ McGill shows that there is no decrease in the rate of stroke with a significant increase in bleeding in patients on dialysis with or without coumadin
The associated editorial (here) calls for a randomized controlled trial. I like this quote from that editorial which is also worth reading:
"It is ironic that we are routinely treating many patients with renal disease and atrial fibrillation every day with great uncertainty as to benefit or harm without their consent, and at the same time, major regulatory and ethical barriers exist that prevent efficient enrollment of patients into clinical trials that are needed to answer this (and other) important questions."
I searched CLINICALTRIALS.GOV and as of now there are no studies looking at coumadin in the dialysis population. So experimental evidence is long from publication.
Clearly we need to think before getting out the pen (or throwing away the prescription pad) and have discussions with our patients that are transparent and evidence based.
The CCS guidelines 2012 focused update:
We suggest that such patients not routinely receive either OAC (Conditional Recommendation, Low-Quality Evidence) or ASA for stroke prevention in AF (Conditional Recommendation, Low-Quality Evidence). Values and preferences. This recommendation places a relatively higher weight on observational data linking warfarin and ASA use with mortality in patients on dialysis, and relatively lower weight on the potential for these agents to prevent ischemic stroke. Therapy with OACs or antiplatelet drugs may be appropriate for some patients with eGFR < 15 mL per minute (on dialysis) in whom there is a stronger preference for avoiding ischemic stroke."
A recent observational study (well done, large study, and one of many to show this association) done here @ McGill shows that there is no decrease in the rate of stroke with a significant increase in bleeding in patients on dialysis with or without coumadin
The associated editorial (here) calls for a randomized controlled trial. I like this quote from that editorial which is also worth reading:
"It is ironic that we are routinely treating many patients with renal disease and atrial fibrillation every day with great uncertainty as to benefit or harm without their consent, and at the same time, major regulatory and ethical barriers exist that prevent efficient enrollment of patients into clinical trials that are needed to answer this (and other) important questions."
I searched CLINICALTRIALS.GOV and as of now there are no studies looking at coumadin in the dialysis population. So experimental evidence is long from publication.
Clearly we need to think before getting out the pen (or throwing away the prescription pad) and have discussions with our patients that are transparent and evidence based.
Tuesday, May 6, 2014
Weekly blog - Goal setting in hypertension
There was a fun argument about goal setting in hypertension targets:
I am a believer that you must always balance expected benefits (reductions in stroke, myocardial infarction, renal failure, CHF) against the potential harms (serious adverse drug effects). Strict enforcement of arbitrary targets can lead to patient harm. There is some evidence that the lower you treat the blood pressure, the lower certain events (i.e. stroke) with an increased risk of certain harms (i.e. renal failure, falls in the elderly).
Data on potential harm of over-treatment:
Hip fractures in the elderly:
http://www.ncbi.nlm.nih.gov/pubmed/23165923
"Hypertensive elderly persons who began receiving an antihypertensive drug had a 43% increased risk of having a hip fracture during the first 45 days following treatment initiation relative to the control periods (incidence rate ratio, 1.43; 95% CI, 1.19-1.72)."
Outcomes may be dependent on the diastolic blood pressure:
http://www.ncbi.nlm.nih.gov/pubmed/24026256
"The optimal BP in patients with CKD seems to be 130 to 159/70 to 89 mm Hg. It may not be advantageous to achieve ideal SBP at the expense of lower-than-ideal DBP in adults with CKD."
Why dual ACE/ARB combination really should not continue (there are several similar studies):
http://www.ncbi.nlm.nih.gov/pubmed/24206457
" There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001)."
Editorial here
*********
The JNC8 guidelines have abandoned the distinction between diabetics/renal failure patients and others with complicated hypertension:
"There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. "
The CHEP guidelines (2013) continue to make a distinction but use an even higher threshold for treatment in the general population.
I am a believer that you must always balance expected benefits (reductions in stroke, myocardial infarction, renal failure, CHF) against the potential harms (serious adverse drug effects). Strict enforcement of arbitrary targets can lead to patient harm. There is some evidence that the lower you treat the blood pressure, the lower certain events (i.e. stroke) with an increased risk of certain harms (i.e. renal failure, falls in the elderly).
Data on potential harm of over-treatment:
Hip fractures in the elderly:
http://www.ncbi.nlm.nih.gov/pubmed/23165923
"Hypertensive elderly persons who began receiving an antihypertensive drug had a 43% increased risk of having a hip fracture during the first 45 days following treatment initiation relative to the control periods (incidence rate ratio, 1.43; 95% CI, 1.19-1.72)."
Outcomes may be dependent on the diastolic blood pressure:
http://www.ncbi.nlm.nih.gov/pubmed/24026256
"The optimal BP in patients with CKD seems to be 130 to 159/70 to 89 mm Hg. It may not be advantageous to achieve ideal SBP at the expense of lower-than-ideal DBP in adults with CKD."
Why dual ACE/ARB combination really should not continue (there are several similar studies):
http://www.ncbi.nlm.nih.gov/pubmed/24206457
" There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001)."
Editorial here
*********
The JNC8 guidelines have abandoned the distinction between diabetics/renal failure patients and others with complicated hypertension:
"There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. "
The CHEP guidelines (2013) continue to make a distinction but use an even higher threshold for treatment in the general population.
- Antihypertensive therapy should be prescribed for average diastolic blood pressures of 100 mmHg or higher (Grade A), or average systolic blood pressures of 160 mmHg or higher (Grade A) in patients without macrovascular target organ damage or other cardiovascular risk factors.
- Antihypertensive therapy should be strongly considered if diastolic blood pressure readings average 90 mmHg or higher in the presence of macrovascular target organ damage or other independent cardiovascular risk factors (Grade A).
- Antihypertensive therapy should be strongly considered if systolic blood pressure readings average 140 mmHg or higher in the presence of macrovascular target organ damage (Grade C for 140 mmHg to 160 mmHg; Grade A for higher than 160 mmHg).
- Antihypertensive therapy should be considered in all patients meeting the above indications regardless of age (Grade B). Caution should be exercised in elderly patients who are frail.
- For patients with non-diabetic chronic kidney disease, target blood pressure is < 140/90 mmHg (Grade B).
- Persons with diabetes mellitus should be treated to attain systolic blood pressures of less than 130 mmHg (Grade C) and diastolic blood pressures of less than 80 mmHg (Grade A). (These target blood pressure levels are the same as the blood pressure treatment thresholds.)
Caution should be exercised in patients in whom a substantial fall in blood pressure is more likely or poorly tolerated (e.g. elderly patients and patients with autonomic neuropathy).
Tuesday, April 29, 2014
Weekly blog - DVT prophylaxis in cirrhotics
Two short snappers from our guest blogger EGM:
Also:
On DVT prophylaxis in
liver cirrhosis:
this topic has never been WELL studied.
There are about 7 retrospective studies that have looked at this topic
and all of them had MAJOR limitations.
What do we know?
Patients with cirrhosis and an increased INR
CANNOT be considered to be autoanticoagulated.
Thrombotic complications can be observed in patients with cirrhosis, despite
standard coagulation laboratory tests revealing a prolonged PT/INR. They can
have a prolonged PT but normal thrombin generation, as anticoagulant factors are also deficient in these patients.
The bottom line from the available literature:
-the INR is not predictive of the risk for DVT/PE in liver disease
-Decreased albumin may be associated with increased risk of DVT/PE in liver
disease
-Patients with liver disease have at
least the same degree of risk as patients with other chronic diseases and possibly more risk for DVT/PE.
-The perceived coagulopathy in patients with liver disease, as reflected in
prolonged INR values, does not protect liver disease patients
against venous thrombosis.
-It is better established that patients with liver resection, hepatocellular carcinoma or cholestatic liver
disease appear to have increased risks
for PE/DVT compared to other patients with chronic diseases.
References:
(TCL's notes)
Any choice for DVT prophylaxis must take into account the perceived benefits (DVT/PE prevention) vs. risks (bleeding) and needs to be individualized to the clinical context; though in general, is recommended for most acutely ill medical patients in the first 14 days of illness
The 2012 ACP guidelines on DVT prevention are here
What is the risk of DVT -- can I predict it?
Score more than 4 = High risk = Consider prophylaxis based on risk
"VTE occurred in 11.0% of high-risk patients who did not receive prophylaxis vs 0.3% of low-risk patients"
Score below 4; low risk
For acutely ill hospitalized medical patients at low risk of thrombosis (Table 2), we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B).
With respect to risk of bleeding:
"the panel considered patients to have an excessive risk of bleeding if they had multiple risk factors or had one of the three risk factors with the strongest association with bleeding (OR > 3.0): active gastroduodenal ulcer, bleeding in 3 months before admission, and platelet count < 50 × 109/L"
With respect to continuing prophylaxis beyond 14 days:
" In terms of absolute effects, extended-duration enoxaparin prevented six fewer symptomatic proximal DVT per 1,000 (95% CI, from three fewer to seven fewer) at a cost of five more major bleeding events per 1,000 (95% CI, from one more to 14 more) (Table 9, Tables S10, S11). In addition to the bleeding risk, extended prophylaxis also entails the burden and cost of daily injection."
The 2012 ACP guidelines on DVT prevention are here
What is the risk of DVT -- can I predict it?
Score more than 4 = High risk = Consider prophylaxis based on risk
"VTE occurred in 11.0% of high-risk patients who did not receive prophylaxis vs 0.3% of low-risk patients"
Score below 4; low risk
For acutely ill hospitalized medical patients at low risk of thrombosis (Table 2), we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B).
With respect to risk of bleeding:
"the panel considered patients to have an excessive risk of bleeding if they had multiple risk factors or had one of the three risk factors with the strongest association with bleeding (OR > 3.0): active gastroduodenal ulcer, bleeding in 3 months before admission, and platelet count < 50 × 109/L"
With respect to continuing prophylaxis beyond 14 days:
" In terms of absolute effects, extended-duration enoxaparin prevented six fewer symptomatic proximal DVT per 1,000 (95% CI, from three fewer to seven fewer) at a cost of five more major bleeding events per 1,000 (95% CI, from one more to 14 more) (Table 9, Tables S10, S11). In addition to the bleeding risk, extended prophylaxis also entails the burden and cost of daily injection."
Also:
How to convert between Dabigatran and Warfarin (should you wish to do so...)
When converting patients from warfarin therapy to Dabigatran, discontinue warfarin and start Dabigatran when the INR is below 2.0.
When converting from Dabigatran to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows:
• For CrCl >50 mL/min, start warfarin 3 days before discontinuing Dabigatran.
• For CrCl 31-50 mL/min, start warfarin 2 days before discontinuing Dabigatran.
• For CrCl 15-30 mL/min, start warfarin 1 day before discontinuing Dabigatran.
• For CrCl <15 mL/min: you shouldn’t be using Dabigatran.
Dabigatran can contribute to an elevated INR so the INR will better reflect warfarin’s effect after Dabigatran has been stopped for at least 2 days.
Reference: Dabigatran guidelines
Tuesday, April 22, 2014
Weekly Blog - IgG4 related diseases
Thanks to EGM for today's blog:
Today in CTU rounds we discussed
the case of a 72-year-old woman, originally born in Egypt, with idiopathic
cholangitis. Lot’s of interesting
questions and stimulating discussion took place! IM gave a great
presentation on IgG4-related disease (IgG4RD). Here is a brief overview of IgG4
and an attempt to answer a few of the tough questions that came up in our
discussions:
New England Journal of Medicine review
article on IgG4-related disease (2012)
Highlights:
1.
IgG4-related disease has been described in the biliary
tree, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes,
meninges, aorta, breast, prostate, thyroid, pericardium, and skin.
2.
For pathological findings, diagnostic criteria and
treatment- please see the review article above.
3.
IgG4 has negligible binding to C1q and Fcγ receptors. In theory, IgG4 does not activate the classical complement
pathway effectively and has been traditionally considered to play only a limited role in immune activation.
IgG4 does not have the ability to form immune complexes. It’s production is
controlled mostly by Th2 cells. REPEATED antigen stimulation activates IgG4.
4.
“…the excess of IgG4 may simply be an overexpression of
these antibodies in response to an unknown primary inflammatory stimulus…”
5.
IgG4 plays a
major role in other diseases:
pemphigous vulgaris, idiopathic membranous glomerulonephritis and thrombotic
thrombocytopenic purpura (it is the autoantibody against ADAMTS13).
6.
Fevers and elevations of C-reactive protein levels are
unusual in IgG4RD. The disorder is often identified incidentally through radiologic findings or unexpectedly in
pathological specimens.
7.
Two common findings in IgG4-related disease can cause
tumour-like swellings in many organ systems and is often associated with allergic
disease.
a.
Many patients with IgG4-related disease have allergic
features such as atopy, eczema, asthma, and modest peripheral-blood
eosinophilia.
b.
Up to 40% of patients with IgG4-related disease have
allergic diseases such as bronchial asthma or chronic sinusitis.
8.
30% of
patients with IgG4-related disease on pathological biopsy have normal serum
IgG4 levels. IgG4 doesn’t always decrease
with steroid treatment even when the patient improves clinically.
How good is the positive predictive value of
an elevated IgG4 level? Can the test characteristics be improved by examining
the IgG4 to IgG ratio?
According to
an article in the Annals of the Rheumatic diseases the PPV is only 34% and the test characteristics are not improved when
you examine the IgG4 to IgG ratio. Doubling the cut-off improved the
specificity of the test from 60 to 91% but at a great cost to the sensitivity.
That being said- some investigators have previously reported that an elevated
ratio can be helpful in distinguishing IgG4RD from other diseases with
associated elevations of IgG4.
Today we also learned that elevated IgG4 levels
(along with IgE) are associated with parasitic infections such as filariasis,
schistosomiasis and stongyloides!
If you’re really
curious about IgG4 you might be interested in this appropriately titled
article: Immunoglobulin G4: An Odd Antibody
Tuesday, April 15, 2014
Weekly blog - PCP (I guess it is PJP now)
Today we discussed a case of a heart transplant patient who developed late onset PCP (PJP)
Classically PCP presents with progressive dyspnea, usually initially with exertion then at rest, with dry hacking cough and fever. Classically the respiratory exam is relatively normal (sometimes there is a pleural rub) despite often remarkably abnormal chest x-ray. The classic x-ray, shown here, is of bilateral perihilar infiltrates.
LDH is usually elevated but can be normal in up to 10%.
LDH can also be elevated in a number of other infections and malignancies.
The degree of LDH elevation is associated with worse prognosis.
Exercise induced desaturation is "an old school classic finding" and one can do exercise oximetry on their patients to see this effect.
http://www.ncbi.nlm.nih.gov/pubmed/2658699
http://www.ncbi.nlm.nih.gov/pubmed/8128398
At our centre the diagnosis is confirmed by direct calciflor stain or silver stain for organisms in the BAL fluid or demonstration of the organism on transbronchial biopsy. The yield of BAL is approximately 70% in solid organ transplant patients (see solid organ transplant below) which is increased with the biopsy. Adding a test like beta-d-glucan (not currently available here) can increase sensitivity to 95% with some loss of specificity.
Monoclonal antibody staining (not available here) for the organism can also increase yield
http://jcm.asm.org/content/42/7/3333.full
Regarding prophylaxis and treatment of patients.
1) The guidelines for the prevention and management of PCP in solid organ transplant are available here.
http://onlinelibrary.wiley.com/doi/10.1111/ajt.12119/full
2) TMP/SMX is the standard of care for the majority of patients. Corticosteroids are commonly used based on the HIV literature (NNT 9 without HAART and 23 with HAART) though the benefit is not as clear in transplant or other non-HIV therapies.
3) There is a significant delay to diagnosis in the transplant patient who presents late.
http://www.ncbi.nlm.nih.gov/pubmed/22548840
As KS suggested today -- when the patient is suspected of having PCP it is important to involve the pneumologists early to obtain a diagnostic sample while the patient is still well enough to undergo diagnostic testing
Sputum induction -- which is currently not done here for this -- has some literature in favor of its negative predictive value if done correctly (and in this case paired with DFA)
http://cid.oxfordjournals.org/content/37/10/1380.full
4) Regarding prophylaxis outside of transplant and hematologic cancers:
Not sure this link will work for all you mcgillians -- check this link!
From the reference -- estimated NNT to prevent one infection varies from:
11 in transplant and some hematologic malignancies
32 in granulomatious polyangiitis (on steroids and cyclophosphomide/other)
73 (or so) with brain tumors on therapy
110 in collagen vascular disease (other than polyangiitis), prolonged prednisone (definition varies -- some say greater than 40mg/day for 3 months, others more restrictive 20mg/day >2 months)
1100 in rheumatoid arthritis
Classically PCP presents with progressive dyspnea, usually initially with exertion then at rest, with dry hacking cough and fever. Classically the respiratory exam is relatively normal (sometimes there is a pleural rub) despite often remarkably abnormal chest x-ray. The classic x-ray, shown here, is of bilateral perihilar infiltrates.
LDH is usually elevated but can be normal in up to 10%.
LDH can also be elevated in a number of other infections and malignancies.
The degree of LDH elevation is associated with worse prognosis.
Exercise induced desaturation is "an old school classic finding" and one can do exercise oximetry on their patients to see this effect.
http://www.ncbi.nlm.nih.gov/pubmed/2658699
http://www.ncbi.nlm.nih.gov/pubmed/8128398
At our centre the diagnosis is confirmed by direct calciflor stain or silver stain for organisms in the BAL fluid or demonstration of the organism on transbronchial biopsy. The yield of BAL is approximately 70% in solid organ transplant patients (see solid organ transplant below) which is increased with the biopsy. Adding a test like beta-d-glucan (not currently available here) can increase sensitivity to 95% with some loss of specificity.
Monoclonal antibody staining (not available here) for the organism can also increase yield
http://jcm.asm.org/content/42/7/3333.full
Regarding prophylaxis and treatment of patients.
1) The guidelines for the prevention and management of PCP in solid organ transplant are available here.
http://onlinelibrary.wiley.com/doi/10.1111/ajt.12119/full
2) TMP/SMX is the standard of care for the majority of patients. Corticosteroids are commonly used based on the HIV literature (NNT 9 without HAART and 23 with HAART) though the benefit is not as clear in transplant or other non-HIV therapies.
3) There is a significant delay to diagnosis in the transplant patient who presents late.
http://www.ncbi.nlm.nih.gov/pubmed/22548840
As KS suggested today -- when the patient is suspected of having PCP it is important to involve the pneumologists early to obtain a diagnostic sample while the patient is still well enough to undergo diagnostic testing
Sputum induction -- which is currently not done here for this -- has some literature in favor of its negative predictive value if done correctly (and in this case paired with DFA)
http://cid.oxfordjournals.org/content/37/10/1380.full
4) Regarding prophylaxis outside of transplant and hematologic cancers:
Not sure this link will work for all you mcgillians -- check this link!
From the reference -- estimated NNT to prevent one infection varies from:
11 in transplant and some hematologic malignancies
32 in granulomatious polyangiitis (on steroids and cyclophosphomide/other)
73 (or so) with brain tumors on therapy
110 in collagen vascular disease (other than polyangiitis), prolonged prednisone (definition varies -- some say greater than 40mg/day for 3 months, others more restrictive 20mg/day >2 months)
1100 in rheumatoid arthritis
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