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

Post cardiac arrest
* 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majority of patients who were receiving oxygen at baseline experienced no change in respiratory comfort when oxygen was withdrawn, 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!)

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.

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

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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.

1. 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.
2. 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).
3. 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).
4. 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.

1. For patients with non-diabetic chronic kidney disease, target blood pressure is < 140/90 mmHg (Grade B).
2. 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).

Weekly blog - DVT prophylaxis in cirrhotics

Two short snappers from our guest blogger EGM:

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:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756631/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033790/

(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."

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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

https://www.healthpartners.com/ucm/groups/public/@hp/@public/@ime/@content/documents/documents/cntrb_010830.pdf

Weekly Blog - IgG4 related diseases

Thanks to EGM for today's blog:

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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)

http://www.nejm.org/doi/full/10.1056/NEJMra1104650

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?

http://ard.bmj.com/content/early/2014/03/20/annrheumdis-2013-204907.long

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!

http://onlinelibrary.wiley.com/doi/10.1111/pim.12001/full

http://www.jstor.org/stable/30123064?__redirected

If you’re really curious about IgG4 you might be interested in this appropriately titled article: Immunoglobulin G4: An Odd Antibody

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2222.2009.03207.x/abstract;jsessionid=B16A13C577CC8421FE8E69B9A0F73EB7.f03t04

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

Weekly Blog - COPD

Today we discussed COPD in rounds.  Some "take home" points:

1) Antibiotics may have value in purulent exacerbations (2 of 3 of increased dyspnea, sputum, or change in sputum color) in patients who are hospitalized.  There is evidence in support of amoxicillin–clavulanic acid, trimethoprim/sulphamethoxazole, doxycycline, and penicillin in the recent meta-analysis.  

http://annals.org/article.aspx?articleid=1676474

Due to the association with C. difficile, we locally suggest to reserve the fluoroquinolones to those who have anaphalactic allergy to all of the above, known or highly suspected to be infected with Pseudomonas, or recent treatment failure with a macrolide (with penicillin severe allergy)

Some narrower agents have been shown to be non-inferior:
http/www.ncbi.nlm.nih.gov/pubmed/20536364

Duration should probably be limited to five days in most cases
http://www.ncbi.nlm.nih.gov/pubmed/18234905

2) Dose/Duration of oral steroids should be limited to 40mg of prednisone for 5 days in most patients.

http://www.ncbi.nlm.nih.gov/pubmed/23695200

3) Inhaled steroids should be more carefully administered to balance the improvement in exacerbations with the risk of bacterial pneumonia.  Number needed to treat for three years to prevent one exacerbation is 44 with number needed to harm to cause pneumonia is 16.  I usually review the indication for the steroid in patients hospitalized with pneumonia and discuss with them the risk:benefit of stopping (which in most cases leads to stopping)

thorax.bmj.com/content/68/6/540.full

FINALLY -- with thanks to KS for bringing up the point --

When admitting a patient with "COPD" the best practice is to properly understand the diagnosis and document it in the admission history
* Is this actually objectively COPD?  Not everything that wheezes is COPD -- does the spriometry suggest it?
* If they have known COPD part of the history is to know that is their FEV1; are they on home oxygen; do they have pulmonary hypertension; how often to they have exacerbations?

Many times patients are admitted with a diagnosis of COPD without documenting these things...  Sometimes they don't even have COPD on previous pulmonary function tests!