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.

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.