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.

Improving the CHADS2 Score

Motivation: Recently, I met a man with CHADS2 score of one.  We shook hands, and he had atrial fibrillation.  Slowing his heart down was relatively easy, but what about anti-coagulation, aspirin or warfarin?  A CHADS2 score of one is a grey "intermediate risk" zone without clear indications for using warfarin or aspirin.  About two years ago, a group from England and Netherland proposed a further refinement to the CHADS2 score (called CHA2DS2-VASc) to help decide on anti-coagulation in these intermediate risk cases.

Paper: Lip, G.Y.H., Nieuwlaat, R., Pisters, R., et. al. "Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in Atrial Fibrillation Using a Novel Risk Factor-Based Approach: The Euro Heart Survey on Atrial Fibrillation." Chest (2010); 137: 263-272.

Methods: The authors proposed a revised point scoring system with the following components:

Congestive Heart Failure or LV dysfunction: 1
Hypertension: 1
Age 75 or over: 2
Age 65 or over: 1
Diabetes: 1
Stroke, TIA, or other embolic disease: 2
Vascular disease (MI, PAD, or known aortic plaque): 1
Female gender: 1


To validate the predictive value of this scoring system, the authors analyzed data from 1,084 patients without mitral stenosis or heart valve surgery who did not use warfarin.  The authors tracked survival status and risk of thromboembolic disease.  The patients were derived from Euro Heart Survey cohort, which tracked patients among 182 hospitals in 35 countries.

Results:
Cohort Characteristics: The patients in the tracked cohort were on average 66 years of age and 40.8% were women.  The most common risk factor was hypertension (67.3%) followed by CAD (38.4%).  Overall, 34.9% of the cohort had CHADS2 score of one, 20.4% with score of zero, and rest with higher scores.  74% took anti-platelet agents.

Thromboembolic Risk: The annual risk of thromboembolic events by risk factor is shown below (only the low risk rates are shown).  Adjusted rate for aspirin use assumes a 22% risk reduction by aspirin use.

Score: 0 (103 patients, no risk factors) - Event rate: 0, annual rate adjusted for ASA use: 0
Score: 1 (162 patients) - Event rate: 0.6%, annual rate adjusted for ASA use: 0.7%
Score: 2 (184 patients) - Event rate: 1.6%, annual rate adjusted for ASA use: 1.9%
Score: 3 (203 patients) - Event rate: 3.9%, annual rate adjusted for ASA use: 4.7%

One of the novel risk factors that this scoring system adds is female gender.  In univariate analysis, female gender is associated with event rate odds ratio of 2.53 (1.08-5.92).

Discussion: This paper provides help in further distinguishing patients really at low risk not requiring further treatment.  I was pretty impressed with the zero annual event rate in patients with no risk factors.  On the other hand, for patients with score of 2, treatment with warfarin is likely indicated since the risk of symptomatic embolic complication  (1.9%) balances the risk of major bleeding (about the same risk).  Especially in an older population, aspirin carries a major bleeding risk (estimated to be about the same in elderly population) but provides substantially decreased protection against embolic disease.

The study, while helpful, has some limitations.  First, the analysis was done retrospectively in a cohort.  It is unclear why these patients were not anti-coagulated.  It is possible that factors which led to decision not to anti-coagulate also substantially modified the subsequent risk of embolic events (high risk behaviors such as IV drug use).  Nonetheless, I think that this study adds to the identification of the truly low risk group.    

Dizzy is dizzy

Motivation: During patient presentations, saying that a patient is "dizzy" without further qualifiers is sure to trigger further questions.  Did dizziness actually mean vertigo or fainting ("presyncope") or unsteadiness?  This approach to dissecting dizziness into further subdivisions stems from a 1972 paper which divided dizziness into vertigo, presyncope, disequilibrium, and "vague lightheadedness," with the implication that vertigo stems from vestibular causes, presyncope from cardiovascular causes, disequilibrium from neurological causes, and other dizziness from other causes.  This approach, while never rigorously validated, has permeated medicine and has almost become the standard framework for evaluating dizziness.  Recently, this approach has been questioned with growing evidence that the various subtypes of dizziness have many overlapping etiologies.

Results:  Unlike other posts, I will summarize three articles here that show that the approach of subdividing dizziness may not be valid because many dangerous causes of dizziness have variable presentations.

1. Culic, V., Miric, D. and Eterovic, D. "Correlation between symptomatology and site of acute myocardial infarction." Int. J. Cardiol. (2001) 77: 163-8:

In this paper, the authors attempted to correlate sites of myocardial infarction and symptoms of presentation among 1546 patients.  Among the many symptoms, the authors separated feeling of "vertigo" from "faintness."  Here are the findings:

SITE OF INFARCTION                   % WITH VERTIGO             % WITH FAINTING
      Anterior                                               11.1                                   6.2
      Inferior                                                  4.7                                    4.9
      Lateral                                                  8.3                                    4.2

 
2. Newman-Toker, D.E. and Camargo, C.A. "Cardiogenic Vertigo - true vertigo as the presenting manifestation of primary cardiac disease." Nature Clin. Prac. Neurol. (2006) 2: 167-172.

This is a case report of a 90 year old woman who presented to the ED after saying that "Everything's going around in a circle" followed by a brief period of decreased consciousness without prodromal feelings of palpitations or presyncope.  In the ED, presence of vertigo was used to rule out cardiac causes, and patient was admitted to Neurology.  Monitoring there revealed periods of transient asystole (14 second pauses) during which the woman had similar feelings of vertigo.  Placement of a pacemaker resolved these episodes.  This case-report also referred to another study summarized next.

3. Low, PA, Opfer-Gehrking, TL, McPhee, BR, et. al. "Prospective evaluation of clinical characteristics of orthostatic hypotension."  Mayo Clin. Proc. (1995) 70: 617-22.

This article examined 90 patients with documented orthostatic-hypotension undergoing tilt-table testing.  When patients were put in an upright position, 88% complained of lightheadedness while 37% complained of vertigo with some patients complaining of both symptoms.

Discussion: I thnk that these studies (along with many others) make the point that using the type of dizziness to exclude causes of dizziness is dangerous and can lead to mistakes.  Other more validated algorithms have been created (such as using "timing and trigger" by Dr. Newman-Toker), which use the onset of symptoms and factors provoking the symptoms to generate a differential.  Also, people experience dizziness in many ways, and the same cause could trigger many symptoms both in the same person and in different people.  As far I could tell, there have been no large scale studies which have particularly looked at errors generated by relying on dizziness symptoms.  At some level, dizzy is just, well, dizzy.