Renal Artery Stenosis - Ultrasound or MRI?

Motivation: During this year, I have presumed renal artery stenosis in many people, tested some of them, and found none.  Among so many with vascular disease just about everywhere, I have not discovered a single new case of renal artery stenosis.  After the last patient in whom I was very sure of finding renal artery stenosis and found myself fooled once more when reading the radiology report, I wondered whether I am using the right test.  The first-line test used - at least as far as I can tell from my experience - has been renal ultrasound with doppler.  I wondered whether other imaging ways such as MRI might be better.

Paper: Solar, M., Zizka, J., Krajina, A., et. al. "Comparison of Duplex Ultrasonography and Magnetic Resonance Imaging in the Detection of Significant Renal Artery Stenosis." Acta Medica (2011) 54: 9-12.

Methods: In an academic hospital in Prague, 94 patients with high clinical suspicion of renovascular hypertension were examined by duplex ultrasound, MRA with contrast, and angiography.  Angiography was performed last.  The gold standard was angiography.  For ultrasound, significant renal artery stenosis was defined by peak systolic velocity above or equal to 180 cm/sec (usual standard).  For MRA and angiography, a cutoff of 60% stenosis was used.

Results:
Cohort: Of the 94 patients, 41 were women.  Average age was 60 years with patients taking on average 3.8 anti-hypertensives.  The mean systolic pressure was 153 mmHg (standard deviation of 31).  About a third had diabetes.  Based on angiography, renal artery stenosis was found in 61 kidneys among 186 kidneys examined (atherosclerosis in 58 and additional four had fibromuscular dysplasia - unexplained whether one case of fibromuscular dysplasia was overlap with atherosclerosis or did not cause significant stenosis).

Duplex Ultrasonography: Ultrasonography could be performed successfully in 81 patients (86%).  The most common reason for inability was poor imaging quality.  For ultrasound (among imaged kidneys), sensitivity: 85%, specificity: 84%.  Positive predictive value: 70%, negative predictive value: 92%.

MRA: By MRA, adequate images could be obtained in 93 of 94 patients.  Sensitivity: 93%, specificity: 93%.  Positive predictive value: 86%, negative predictive value: 97%.

Discussion:  Based on this direct comparison of ultrasound and MRA, testing for someone with high pre-test probability of renal artery stenosis should probably proceed by MRA given higher sensitivities.  In cases with low to moderate pre-test probability, renal ultrasound may sufficiently decrease the probability.  Neither method is, of course, perfect.  While this study was done in Prague, it is likely that a regular American population might be more obese and have higher BMI - particularly in patients with sustained hypertension.  The adequacy of an ultrasound examination may be further decreased in this group.  A misconception that I had was that if an ultrasound examination could be performed well, it is just as good as MRA.  But, even among kidneys that could be examined well, the sensitivity of ultrasound was lower than MRA.  Some caveats of this study are that this was a single center study and that there is no verification that radiologists examining the MRA were blinded to the results of the ultrasound (although with MRA, more lesions were detected compared to US).  So, from now, if I am really suspicious of renal artery stenosis, I will go ahead with the MRA.  Maybe, I will find someone with renal artery stenosis.

Aspirin After Stenting

Motivation: Reviewing a patient's home medication list yesterday, I found my favorite offender on the list - aspirin at 325 mg dosage.  The man had a drug eluting stent placed two years ago.  I grumbled out loud something about unnecessary risks to patients.  One of the seniors sitting within earshot struck back that in fact every patient is kept on a full dose aspirin plus clopidogrel after drug eluting stent placement.  Turns out that this fact had escaped me nine months into internship.  But, is there data to support the practice?

Paper: Mehta, S.R., Tanguay, J.-F., Eikelbloom, J.W., et. al. "Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS7): a randomized factorial trial." Lancet (2010) 376: 1233-43.

Methods: Multinational randomized factorial trial.  Inclusion criteria were symptoms of acute coronary syndrome and either EKG evidence or raised biomarkers.  All patients underwent coronary angiography with intent to undergo PCI within 72 hours.  Exclusion criteria was increased risk of bleeding or active bleeding.  All patients initially got full dose aspirin.  From day two, patients were randomized to either high dose (300-325 mg) or low dose (75-100 mg) aspirin.  In the clopidogrel arm, patients either received 600 mg loading dose followed by 150 mg from days 2-7 or received 300 mg loading dosed followed by 75 mg on days 2-7.  With the factorial design, there were four groups receiving varying combinations of clopidogrel and aspirin.  Primary outcome was composite of CV death, MI, or stroke within 30 days.

Results:
When the trial was first released, the clopidogrel trial results attracted much attention and controversy.  Multiple editorials comment on the analysis of the clopidogrel piece of the trial.  I will just describe the aspirin portion of the trial.

Cohort: There were 8624 patients randomized to high dose aspirin and 8639 randomized to low dose aspirin. The two treatment arms were very similar in baseline characteristics.  Average age was about 61 years with 25% female.  About 63% of the patients had NSTEMI/UA while the remaining patients presented with STEMI.  About 37% of patients took regular aspirin, and another 20% took regular clopidogrel prior to randomization.

Angiography: After initial angiography, 8160 of the 8624 (94.6%) in the high dose ASA group received a stent (58% BMS and 42% DES).    In the low dose ASA group, 8163 of the 8639 (94.5%) received a stent (58% BMS and 42% DES).  Patient did not undergo PCI because of (1) no coronary disease - most common, (2) no suitable area for revascularization, or (3) CABG was better alternative.

Follow-up: Primary outcome of cardiovascular death, stroke, or MI did not differ between the high dose and low dose group (HR: 0.98, 95% CI 0.84-1.13, p = 0.76).  Between high and low dose aspirin, there was no difference in definite or probable stent thrombosis (0.9% vs 1.0%, CI: 0.68-1.26).  In secondary analysis, recurrent ischemia was slightly higher in low dose aspirin (0.4%) compared to high dose aspirin (0.2%) though event numbers were small to make meaningful post-hoc secondary comparisons.  In the overall trial analysis (including those who got PCI and those who did not), high dose aspirin resulted in significant increase in minor bleeding (5.0% vs 4.2%, p = 0.04).

Discussion: This trial shows that even in the acute post-PCI setting, use of a lower dose aspirin does not increase likelihood of stent thrombosis.  Some of the strengths of this trial are the randomized trial design with very large number of subjects (over 8,000 in both groups).  While this trial looks only at initial 30 day events, low dose aspirin is expected to be adequate in long-term setting as well given its equivalence to high dose aspirin in the high-risk post-procedure period.  There are no randomized trials in the long-term setting, but there have been retrospective observational studies which show that there is no increased risk of stent thrombosis with low dose aspirin.  On the other hand, there is more definite evidence showing increased risk of bleeding with high dose aspirin compared to low dose aspirin.  Current practice guidelines, however, continue to recommend prolonged administration of high dose aspirin after stenting!

Diuresis on steroids

Motivation: Ever been stuck with diuresis?  Every morning you are drawing even with fluid balance, and metolazone plus bumex is making no progress on the crackly lungs.  Short of sending the patient to the ICU for ionotropes, is there anything else?  Recently one of my fellow interns pointed out that prednisone may actually help with diuresis.  I was at first skeptical.  After all, with the mineralocorticoid activity of prednisone, I would expect prednisone to worsen diuresis.  But, turns out that there is more to steroids.  Prednisone also has renal vasodilatory effects and increases renal plasma flow and GFR.  So, some data?

Paper: Zhang, H., Liu, C., Ji, Z. et. al.  Prednisone Adding to Usual Care Treatment for Refractory Decompensated Congestive Heart Failure.  Int. Heart J. (2008) 49: 587-95

Methods: The authors conducted an observational study in which patients were recruited who had been been hospitalized for at least one week for decompensated heart failure and had failed to respond to IV diuretics.  Exclusion criteria included infection, cardiogenic shock, SBP<80 or >140, HFpEF, or myocarditis.  Patients could receive IV ionotropes so long as they were maintaining blood pressure.  Prednisone (1 mg/kg/day with max dose of 60 mg) was added to therapy for nine days.  Primary end-points were urine volume, patient assessed dyspnea, changes in renal function, and physician assessed clinical status.

Results:
Cohort: The authors recruited 35 patients with median age of 52.3 years and gender distribution of 48.6% male.  All patients were in class IV heart failure with all patients having LVEF less than 30%.  Besides IV diuretics, 74% of patients (26/35) were also receiving IV ionotropes with the majority also getting IV nitroglycerine (91.4%, 32/35) and digoxin (82.9%, 29/35).

Outcomes: After nine days of prednisone therapy, mean urine output increased from 1400 mL/day to 2400 mL/day (statistically significant).  Interestingly, the main jump in urine output occurred at day 3 when urine output jumped to about 2100 ml/day.  Patient assessed dyspnea improved in 80% of patients (p<0.01).  All but one patient were transitioned entirely to PO medications (off IV diuretics, ionotropes, or nitroglycerin) by day nine.  GFR increased from baseline of 63.4 mL/min to 74.1 mL/min (p<0.05).  Average weight loss was 3.17 kg. 

Safety: There were no deaths.  Prednisone therapy increased fasting glucose levels in diabetic patients but did not affect fasting levels in non-diabetic patients.  There were no new infections noted in the cohort.

Discussion:  This study could really benefit from a control group!  The patients improved remarkably with prednisone administration, but one could also argue that if you stick with diuresis long enough, you will eventually make some headway.  The argument made by the authors is that the patients had received conventional therapy for the week prior without improvement in clinical status.  A concurrent control group or even a historical control group in the second week of therapy for CHF would make the case more convincing.  On the flip side, 34 out of 35 patients progressed from decompensated CHF dependant on IV therapy to PO therapy.  The progress was quite dramatic and may suggest benefit from prednisone.  So, how does this change therapy?  I would still not add prednisone to usual therapy for CHF, but if a patient presents with dyspnea along with the usual CHF/COPD combination, I would be less hesitant to add on the steroids.  Also, this topic is a great mini research project for a retrospective outcomes analysis for CHF patients who got steroids (likely for COPD) compared to CHF patients who did not get steroids.

Drinking Stool

Motivation: Pouring mashed up liquid stool down NG tube? Sounds disgusting.  Imagine the smell from the next burp.  I heard about his idea from a friend last night post-dinner, and I almost could not believe that it works.  But, "fecal transplant" or fecal bacteriotherapy exists and, in some niche corners of the country, is considered the salvage therapy of choice for severe C. diff infections.  What about the data?  There have not been RCTs but plenty of convincing case series. Reviewed is one of the larger case series.

Paper: Aas, J., Gessert, C.E., and Bakken, J.S.  Recurrent Clostridium difficile Colitis: Case Series Involving 18 Patients Treated with Donor Stool Administered via a Nasogastric Tube. CID (2003) 36: 580-585.

Methods: Study was conducted in a single centre in Minnesota.  Inclusion criteria for stool receipients were documented C. difficile infections and two or more relapses despite adequate treatment.  Stool donors were usually spouses or other close family members or donors if family members were not present.  Collected stool was screened by culture and O+P screen to rule out pathogenic infection.  Collected stool was mixed with 50-70 mL of normal saline and then homogenized using a household blender.  The blended mixture was filtered through a paper coffee filter.  For four days prior to transfer, receipients were treated with oral vancomycin and then treated with omeprazole on the day of transplantation.  An NG tube was placed with instillation of 25 mL of liquid stool followed by 25 mLof NS through the tube.  Then, the NG tube was removed, and patients were discharged or returned to their wards.

Results:
Cohort: The study recruited 18 participants.  Mean age was 73 years (range, 51-88) with 72% female (13/18 patients).  Five were inpatients while 13 were treated at GI clinic.  Patients in general had received a mean of 3.6 courses of anti-microbial therapy (metronidazole/vancomycin) prior to consideration for stool transplant.

Follow-up Results:  Of the 18 patients treated, 15 experienced complete resolution defined as cessation of diarrhea and negative C. diff stool testing at ninety day follow-up! Two inpatients treated with stool transplant died (one had ESRD undergoing peritoneal dialysis who developed peritonitis and died, other patient had COPD complicated by pneumonia 14 days after stool transplant).  There was one treatment failure in the protocol who developed recurrent C. diff that was successfully treated after one additional course of oral vancomycin.

Discussion: I am amazed that the procedure works.  The cure rate was 83% in patients with refractory C. difficile infection.  I think that this therapy points out the important fact that C. diff flourishes because of the lack of normal bowel flora, and continuous rounds of metronidazole/vancomycin do little to fix that problem.  The authors chose close family members for donors because presumably their bowel flora is similar to the patient's bowel flora.  A cautionary note for the article are the two deaths.  While both patients were sick prior to the transplantation, it is possible that introducing stool to a very sick patient at risk for aspiration could be dangerous (one patient died of PNA after stool transplantation).  This procedure is probably best suited to the outpatient setting.  On the other hand, there have been reports of C. diff induced ICU level colitis being treated with stool transplantation introduced by colonoscopy, which bypasses the risk of aspiration and ileus in sick patients.  While this theory needs confirmation with a RCT, the stool transplant is cheap and probably effective!

PS: Sorry for the far between posts.  I will write more regularly.

PCP and Steroids

Motivation: For prevention of PCP in patients taking steroids, I have heard a variety of rumors on the needs of Pneumocystis pneumonia prophylaxis.  After what dose of steroid and what duration do patients need prophylaxis?  Some doctors prescribe Bactrim for more than 20 mg of prednisone use for more than a month to some GI doctors who do not prescribe prophylaxis even on higher doses of prednisone.  Recently, our medicine team wondered where the data came from.  One of the major studies addressing this question came from Mayo Clinic in 1996.

Paper: Yale, S.H. and Limper, A.H. "Pneumocystis carinii Pneumonia in Patients Without Acquired Immunodeficiency Syndrome: Associated Illnesses and Prior Corticosteroid Therapy." Mayo Clinical Proc.(1996) 71: 5-13.

Methods: Between 1985-1991, data on patients presenting to Mayo Clinic with Pneumocystis pneumonia but without HIV were retrospectively analyzed.  PCP was proven by bronchoalveolar lavage, lung biopsy, or autopsy.  Patients were excluded from analyses if clinical syndrome was suggestive of AIDS.

Results:
Cohort: Between 1985-1991, there were 116 patients with PCP pneumonia without AIDS.  These patients commonly had associated conditions of hematologic malignancy (30.2%), organ transplantation (25%), inflammatory diseases (22.4%), solid tumors (12.9%), and other diseases.

Steroid Use: Of the 116 patients, 105 (90.5%) had used steroid therapy within one month of diagnosis of PCP.  98 (84.5%) were using steroids at time of diagnosis.  Prednisone use dose and duration are depicted as below:

• Median dose: 30 mg of prednisone (25th percentile was 16 mg meaning 25% were using less than 16 mg)
• Median duration: 12 weeks (25th percentile was at 8 weeks)

Concurrent Infections: In 57.8% of patients, additional infectious agents were detected.  No significant differences in incidence of concurrent infections were noted among different underlying illnesses (such as malignancy vs inflammatory diseases).  The most common concurrent infection was CML (35.3%) followed by Candida infection (18.1%).

Outcome: Overall, in-hospital mortality was 34%.  Respiratory failure occurred in 43% of patients and was associated with 66% mortality.  Of note, PCP infection was associated with a 100% mortality in patients with solid malignancies.  Finally, survival to discharge from hospital was linked to lower dose of corticosteroid at the time of diagnosis.

Discussion: Overall, this paper provides a rough guide to the dose of steroid (median 30 mg) and duration (median 12 weeks) associated with PCP.  However, I think that this paper also shows that there is no absolute threshold effect beyond which the risk clearly skyrockets.  The 25th and 75th percentiles were very  wide.  Another interesting and cautionary outcome is that in the immunosuppressed, there is often co-infection of multiple pathogens, and the process of diagnosis should not stop after detecting PCP.  Also, 11 patients got PCP without using steroids.  PCP should remain on the differential for any immunosuppressed individual.

This paper also has some significant limitations.  First, patients who were selected in this analyses had received at least BAL or lung biopsy.  Currently, many patients are diagnosed by stains of sputum and may be less sick than those getting BAL.  Also, the paper does not address properly the more interesting question of what is a safe dose of prednisone to use without prophylaxis.  Perhaps if the authors picked a population with medium to low dose prednisone use, then a "safe" dose could be described.

Pulmonary Embolism and Atrial Fibrillation

Motivation: Last November, I admitted a patient with dyspnea.  He had new onset atrial fibrillation, and discussion in the morning predictably revolved around causes of atrial fibrillation.  One of the causes mentioned was pulmonary embolism (the "green book" lists it under pulmonary triggers).  I find PE to be a strange trigger though.  I associate atrial fibrillation with processes that chronically stretch the atria resulting in a dilated atrium, but PE is an acute process.  Searching the literature at that time did not reveal any evidence for or against assoication of atrial fibrillation with PE.  Recently, when revisiting the question, I found an article by a European group published in December of 2011 addressing this issue.

Paper: Gex, G., Righini, M., Gal, G.L., et. al. "Is atrial fibrillation associated with pulmonary embolism?" J. of Thrombosis and Haemostasis (2011) [e-pub ahead of print]

Methods: To analyze association, the authors pooled together data from two large trials (CT-EP3 and CT-EP4) investigating PE diagnostic strategies.  In both studies, patients were included if they presented with clinical suspicion of PE defined largely as acute dyspnea or chest pain without obvious cause.  All patients had EKG at baseline with confirmation of PE diagnosis by CT.

Results:
Cohort: Total of 2,449 patients were analyzed.  The mean age was 59.9 years and 43.7% were males.  Of this group with clinical suspicion of PE, 22.6% had PE confirmed by CT.

Association with AF: Atrial fibrillation was detected at baseline in 133 patients.  Prevalence of PE was 22.8% (n=519) in patients without atrial fibrillation but 18.8% (n=25) in patients with atrial fibrillation (p = 0.28).  To adjust for differences in comorbidities between patients with AF and those without AF, the authors next created an adjusted model accounting for age, sex, CHF, COPD, stroke, renal clearance, and neoplasm.  After adjustment, there was no increased association with AF and PE (OR of 0.68, 0.42-1.11, p = 0.122).   AF failed to be associated with PE even in patient less than age 65 (OR 0.86, 0.35-2.12) or with no heart failure (OR 0.63, 0.37-1.06).  Authors attempted to separate association of AF with presenting symptoms (dyspnea or chest pain), but the numbers were too small to make meaningful conclusions.

Discussion: This paper establishes that in patients presenting with acute dyspnea or chest pain, finding atrial fibrillation on EKG does not meaningfully change the likelihood of PE.  If anything, finding atrial fibrillation had a trend towards reducing the likelihood of PE (adjusted OR of 0.68, 0.42-1.11).  This effect is likely from similar presenting symptoms of atrial fibrillations and PE.  While this paper in part answers my initial question of the utility of using atrial fibrillation to suspect PE, there are some important limitations.  First, the paper only examined patients presenting with acute dyspnea or chest pain.  The paper did not examine patients with new onset AF and ask how many had PE.  Therefore, the results cannot be extended to patients with atrial fibrillation without obvious symptoms though presumably the incidence of PE would be even lower.  Also, given the structure of the paper in which PE had to be a likely diagnosis, patients with AF with RVR and dyspnea were likely excluded.  Incidence of PE in this population is also unclear.  Depsite these limitations, I think that this paper provides important insights into the limited utility of considering AF in the diagnosis of PE.

Does venipuncture cause lymphedema for woman after breast cancer surgery?

Does venipuncture cause lymphedema for

woman after breast cancer surgery?

Motivation: An 85 year old woman is admitted from the ED for IV
antibiotic treatment of community acquired pneumonia. During the
night, the RN pages me because the peripheral IV in the patient’s
right hand infiltrated and attempts to place another IV in that arm
were unsuccessful. A simple solution would be to try on the left hand
but both the RN and the patient are adamantly against this idea
because the patient had “breast cancer surgery” on the left side 20
years ago. They state that inserting a peripheral IV in the left hand
would cause lymphedema which would become debilitating. However, it
seems peculiar to me that having a distant surgery would preclude the
use of an entire extremity therefore I set out to find the evidence.

Studies:
1. Clark B, Sitzia J, Harlow W. Incidence and risk of arm oedema
following treatment for breast cancer: a three-year follow-up study.
QJM. 2005
2. Winge C, Mattiasson AC, Schultz I. After axillary surgery for
breast cancer–is it safe to take blood samples or give intravenous
infusions? J Clin Nurs 2010;19:1270–1274.
3. May;98(5):343-8.Hayes SC, Janda M, Cornish B, Battistutta D, Newman
B. Lymphedema after breast cancer: incidence, risk factors, and effect
on upper body function. J Clin Oncol. 2008 Jul 20;26(21):3536-42.

Methods:
1. Prospective 3 year observational study of 188 woman who had
undergone surgery for breast cancer that involved sanpling, excision
or biopsy of their axillary nodes.
2. Questionnaires were mailed to all 311 patients who had undergone
removal of axilliary nodes in a major Swedish hospitals in 2000-2001.
Study published in 2010 so I assumed 7-8 years of follow up.
3. Observational study of 287 Australian women with invasive breast
cancer were evaluated 6-18 month after treatment.

Results:
1. At follow-up, 39 (20.7%) had developed lymphoedema. Hospital skin
puncture (vs. none) (RR 2.44, 95%CI 1.33-4.47), mastectomy (vs. wide
local excision or lumpectomy) (RR 2.04, 95%CI 1.18-3.54), and BMI > or
= 26 (vs. BMI 19-26) (RR 2.02, 95%CI 1.11-3.68) were the only
significant risk factors.
2. 88 of 311 women reported venipuncture on the affected arm. Only 4
patients developed lymphedema.
3. 33% (n = 62) of the sample were classified as having lymphedema; of
these, 40% had long-term lymphedema. Older age >50, more extensive
surgery (ie, mastectomy), and having a sedentary lifestyle
significantly increased odds (three- to six-fold) of lymphedema.
Removal of 20 or more lymph nodes, experiencing one or more
treatment-related complication or symptom, and being single each
increased odds 2.6- to 5.0-fold, but CIs were wide and included 1.0.
Conversely, having a lower yearly income significantly decreased odds
of lymphedema over the following 12 months five-fold.

Discussion: Lymphedema results when lymphatic drainage systems are
damaged leading to accumulation of interstitial fluid. More than 2
million American women are diagnosed with breast cancer each year with
more than 200,000 developing lymphedema secondary to cancer or its
treatment. Patients with lymphedema suffer chronic pain and swelling
that causes significant physical and mental anguish and leads to
decreased productivity. Treatment for this condition remains
suboptimal therefore attention has focused on prevention.

The above referenced studies all seem to agree that there are certain
risk factors for developing lymphedema including more extensive
surgery and obesity/sedentary life style. Two studies which
specifically looked at venipuncture in the affected arm had
conflicting results. Clark et al. 2005 was a prospective
observational study which provides level 2 evidence linking
venipuncture with increased risk of lymphedema while Winge 2010 was a
retrospective questionnaire study providing only level 3 evidence
against such a linkage. Clearly, the evidence is far from perfect.
Given the importance of the problem, a randomized clinical trial to
study preventive measures for lymphedema should be undertaken.

In the mean time, the results of these studies should motivate us to
attempt to clarify the nature of the patient’s cancer and surgery
before declaring an extremity off limits. Common sense seems to
suggest that we should avoid the affected arm in patients who are
older, obese and have had aggressive disease requiring more extensive
surgery and lymph node dissection. A patient who had DCIS and was
treated with breast conserving therapy without axillary dissection is
less likely to develop lymphedema. In addition, we need to take into
account the clinical context in which this dilemma takes place. For my
patient, a simple external jugular would have probably solved the
issue. On the other hand, in a patient who is having a massive upper
GI bleed and needs every single access that we can provide, the
uncertain risk of future lymphedema is clearly secondary to the
immediate risk of death from hypovolemia.

Lastly, a quick search of the internet will reveal that breast cancer
survivor’s networks and patient advocacy websites regarding lymphedema
are extremely prevalent and vocal about the need to avoid the affect
extremity. Therefore, communication with our patients is essential.
As with any medical procedures, the risks and benefits should be
clearly delineated and the patient included in the decision making
process. In this way, we avoid the anger and frustration that develops
when patients feel their concerns are not addressed, even in the
absence of lymphedema itself.