Week 9 – Bicarbonate supplementation in CKD

“Bicarbonate Supplementation Slows Progression of CKD and Improves Nutritional Status”

J Am Soc Nephrol. 2009 Sep;20(9):2075-84. [free full text]

Metabolic acidosis is a common complication of advanced CKD. Some animal models of CKD have suggested that worsening metabolic acidosis is associated with worsening proteinuria, tubulointerstitial fibrosis, and acceleration of decline of renal function. Short-term human studies have demonstrated that bicarbonate administration reduces protein catabolism and that metabolic acidosis is an independent risk factor for acceleration of decline of renal function. However, until the 2009 study by de Brito-Ashurst et al., there were no long-term studies demonstrating the beneficial effects of oral bicarbonate administration on CKD progression and nutritional status.

Population: CKD patients with CrCl 15-30ml/min and plasma bicarbonate 16-20 mEq/L

Intervention: sodium bicarbonate 600mg PO TID with protocolized uptitration to achieve plasma HCO3 ≥ 23 mEq/L, for 2 years

Comparison: routine care

1) decline in CrCl at 2 years
2) “rapid progression of renal failure” (defined as decline of CrCl > 3 ml/min per year)
3) development of ESRD requiring dialysis

1) change in dietary protein intake
2) change in normalized protein nitrogen appearance (nPNA)
3) change in serum albumin
4) change in mid-arm muscle circumference

134 patients were randomized, and baseline characteristics were similar among the two groups. Serum bicarbonate levels increased significantly in the treatment arm (see Figure 2). At two years, CrCl decline was 1.88 ml/min in the treatment group vs. 5.93 ml/min in the control group (p<0.01); rapid progression of renal failure was noted in 9% of intervention group vs. 45% of the control group (RR 0.15, 95% CI 0.06–0.40, p<0.0001, NNT = 2.8); and ESRD developed in 6.5% of the intervention group vs. 33% of the control group (RR 0.13, 95% CI 0.04–0.40, p<0.001; NNT = 3.8). Regarding nutritional status: dietary protein intake increased in the treatment group relative to the control group (p<0.007), normalized protein nitrogen appearance decreased in the treatment group and increased in the control group (p<0.002), serum albumin increased in the treatment group but was unchanged in the control group, and mean mid-arm muscle circumference increased by 1.5 cm in the intervention group vs. no change in the control group (p<0.03).

Oral bicarbonate supplementation in CKD patients with metabolic acidosis reduces the rate of CrCl decline and progression to ESRD and improves nutritional status.

Primarily on the basis of this study, the KDIGO 2012 guidelines for the management of CKD recommend oral bicarbonate supplementation to maintain serum bicarbonate within the normal range (23-29 mEq/L).

This is a remarkably cheap and effective intervention. Importantly, the rates of adverse events, particularly worsening hypertension and increasing edema, were unchanged among the two groups. Of note, sodium bicarbonate induces much less volume expansion than a comparable sodium load of sodium chloride.

In their discussion, the authors suggest that their results support the hypothesis of Nath et al. (1985) that “compensatory changes [in the setting of metabolic acidosis] such as increased ammonia production and the resultant complement cascade activation in remnant tubules in the declining renal mass [are] injurious to the tubulointerstitium.”

The hypercatabolic state of advanced CKD appears to be mitigated by bicarbonate supplementation. The authors note that “an optimum nutritional status has positive implications on the clinical outcomes of dialysis patients, whereas [protein-energy wasting] is associated with increased morbidity and mortality.”

Limitations to this trial include its open label, no placebo design. Also, the applicable population is limited by study exclusion criteria of morbid obesity, overt CHF, and uncontrolled HTN.

Further Reading:
1. Nath et al. “Pathophysiology of chronic tubulo-interstitial disease in rats: Interactions of dietary acid load, ammonia, and complement component-C3” (1985)
2. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (see page 89)
3. UpToDate

Summary by Duncan F. Moore, MD


“Hydrocortisone Therapy for Patients with Septic Shock”

N Engl J Med. 2008 Jan 10;358(2):111-24. [free full text]

Steroid therapy in septic shock has been a hotly debated topic since the 1980s. The Annane trial in 2002 suggested that there was a mortality benefit to early steroid therapy and so for almost a decade this became standard of care. In 2008 the CORTICUS trial was performed suggesting otherwise.

– inclusion criteria: ICU patients with septic shock onset with past 72 hrs (defined as SBP < 90 despite fluids or need for vasopressors, and hypoperfusion or organ dysfunction from sepsis)
– exclusion criteria: “underlying disease with a poor prognosis,” life expectancy < 24hrs, immunosuppression, recent corticosteroid use

Intervention: hydrocortisone 50mg IV q6h x5 days with taper

Comparison: placebo injections q6h x5 days plus taper


Primary: 28 day mortality among patients who did not have a response to ACTH stim test (cortisol rise < 9mcg/dL)

– 28 day mortality in patients who had a positive response to ACTH stim test
– 28 day mortality in all patients
– reversal of shock (defined as SBP ≥ 90 for at least 24hrs without vasopressors) in all patients
– time to reversal of shock in all patients

In ACTH non-responders (N=233): intervention vs. control 28 day mortality was 39.2% vs. 36.1% (p=0.69)

In ACTH responders (N=254): intervention vs. control 28 day mortality was 28.8% vs. 28.7% (p=1.00); reversal of shock 84.7%% vs. 76.5% (p=0.13)

Among all patients:
– intervention vs. control 28 day mortality was 34.3% vs. 31.5% (p=0.51)
– reversal of shock 79.7% vs. 74.2% (p=0.18)
– duration of time to reversal of shock was significantly shorter among patients receiving hydrocortisone (per Kaplan-Meier analysis, p<0.001; see Figure 2), median time to reversal 3.3 days vs. 5.8 days (95% CI 5.2 – 6.9)

The CORTICUS trial demonstrated no mortality benefit of steroid therapy in septic shock, regardless of a patient’s response to ACTH. Despite the lack of mortality benefit, it demonstrated an earlier resolution of shock with steroids. This lack of mortality benefit sharply contrasted with the previous Annane study. Several reasons have been posited for this including poor powering of the CORTICUS study (it did not reach the desired N=800), CORTICUS inclusion starting within 72 hrs of septic shock vs. Annane starting within 8 hrs, and Annane patients generally being sicker (including their inclusion criterion of mechanical ventilation). Subsequent meta-analyses disagree about the mortality benefit of steroids, but meta-regression analyses suggest benefit among the sickest patients. All studies agree about the improvement in shock reversal. The 2016 Surviving Sepsis Campaign guidelines recommend IV hydrocortisone in septic shock in patients who continue to be hemodynamically unstable despite adequate fluid resuscitation and vasopressor therapy.

Per Drs. Sonti and Vinayak of the GUH MICU (excerpted from their excellent Georgetown Critical Care Top 40): “Practically, we use steroids when reaching for a second pressor or if there is multiorgan system dysfunction. Our liver patients may have deficient cortisol production due to inadequate precursor lipid production; use of corticosteroids in these patients represents physiologic replacement rather than adjunct supplement.”

References / Further Reading
1. Wiki Journal Club
2. 2 Minute Medicine
3. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock (2016), section “Corticosteroids”
4. Annane trial (2002) [free full text]
5. Georgetown Critical Care Top 40 [iTunes / iBooks link]
6. UpToDate,“Glucocorticoid therapy in septic shock”

Summary by Gordon Pelegrin, MD

Week 7 – FUO

“Fever of Unexplained Origin: Report on 100 Cases”

Medicine (Baltimore). 1961 Feb;40:1-30. [free full text]

In our modern usage, fever of unknown origin (FUO) refers to a persistent unexplained fever despite an adequate medical workup. The most commonly used criteria for this diagnosis stem from the 1961 series by Petersdorf and Beeson.

This study analyzed a prospective cohort of patients evaluated at Yale’s hospital for FUO between 1952 and 1957. Their FUO criteria: 1) illness of more than three week’s duration, 2) fever higher than 101º F on several occasions, 3) diagnosis uncertain after one week of study in hospital. After 126 cases had been noted, retrospective investigation was undertaken to determine the ultimate etiologies of the fevers. The authors winnowed this group to 100 cases based on availability of follow up data and the exclusion of cases that “represented combinations of such common entities as urinary tract infection and thrombophlebitis.”

126 cases were reviewed as noted above, and ultimately 100 were selected for analysis. In 93 cases “a reasonably certain diagnosis was eventually possible.” 6 of the 7 undiagnosed patients ultimately made a full recovery. Underlying etiology (see table 1 on page 3): infectious 36% (including TB in 11%), neoplastic diseases 19%, collagen disease (e.g. SLE) 13%, pulmonary embolism 3%, benign non-specific pericarditis 2%, sarcoidosis 2%, hypersensitivity reaction 4%, cranial arteritis 2%, periodic disease 5%, miscellaneous disease 4%, factitious fever 3%, no diagnosis made 7%.

Clearly, diagnostic modalities have improved markedly since this 1961 study. However, the core etiologies of infection, malignancy, and connective tissue disease / non-infectious inflammatory disease remain most prominent, while the percentage of patients with no ultimate diagnosis has been increasing (for example, see PMIDs 9413425, 12742800, and 17220753). Modifications to the 1961 criteria have been proposed (e.g. 1 week duration of hospital stay not required if certain diagnostic measures have been performed) and implemented in recent FUO trials. One modern definition of FUO: fever ≥ 38.3º C, lasting at least 2-3 weeks, with no identified cause after three days of hospital evaluation or three outpatient visits.

Per UpToDate, the following minimum diagnostic workup is recommended in suspected FUO: blood cultures, ESR or CRP, LDH, HIV, RF, heterophile antibody test, CK, ANA, TB testing, SPEP, CT of abdomen and chest.

Further Reading:
1. “Fever of unknown origin (FUO). I A. prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. The Netherlands FUO Study Group.” Medicine (Baltimore). 1997 Nov;76(6):392-400.
2. “From prolonged febrile illness to fever of unknown origin: the challenge continues.” Arch Intern Med. 2003 May 12;163(9):1033-41.
3. “A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol.” Medicine (Baltimore). 2007 Jan;86(1):26-38.
4. UpToDate, “Approach to the Adult with Fever of Unknown Origin”
5. “Robert Petersdorf, 80, Major Force in U.S. Medicine, Dies” The New York Times, 2006

Summary by Duncan F. Moore, MD

Week 6 – COURAGE

“Optimal Medical Therapy with or without PCI for Stable Coronary Disease”

by the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial Research Group

N Engl J Med. 2007 Apr 12;356(15):1503-16 [free full text]

The optimal medical management of stable coronary artery disease has been well-described. However, prior to the 2007 COURAGE trial, the role of percutaneous coronary intervention (PCI) in the initial management of stable coronary artery disease was unclear. It was known that PCI improved angina symptoms and short-term exercise performance in stable disease, but its mortality benefit and reduction of future myocardial infarction and ACS were unknown.

Population: US and Canadian patients with stable coronary artery disease
(See paper for inclusion/exclusion criteria. Disease had to be sufficiently and objectively severe, but not too severe, and symptoms could not be sustained at the highest CCS grade.)
Intervention: optimal medical management and PCI
(Optimal medical management included antiplatelet, anti-anginal, ACEi/ARB, and cholesterol-lowering therapy.)
Comparison: optimal medical management alone
1º: composite of all-cause mortality and non-fatal MI
2º: composite of all-cause mortality, non-fatal MI, and stroke, and hospitalization for unstable angina

2287 patients were randomized. Both groups had similar baseline characteristics with the exception of a higher prevalence of proximal LAD disease in the medical-therapy group. Median duration of follow-up was 4.6 years in both groups. Death or non-fatal MI occurred in 18.4% of the PCI group and in 17.8% of the medical-therapy group (p=0.62). Death, non-fatal MI, or stroke occurred in 20.0% of the PCI group and 19.5% of the medical-therapy group (p=0.62). Hospitalization for ACS occurred in 12.4% of the PCI group and 11.8% of the medical-therapy group (p=0.56). Revascularization during follow-up was performed in 21.1% of the PCI group but in 32.6% of the medical-therapy group (HR 0.60, 95% CI 0.51–0.71, p<0.001). Finally, 66% of PCI patients were free of angina at 1 year follow-up compared with 58% of medical-therapy patients (p<0.001); rates were 72% and 67% at 3 years (p=0.02) and 72% and 74% at five years (not significant).

In the initial management of stable coronary artery disease, PCI in addition to optimal medical management provided no mortality benefit over optimal medical management alone.

However, initial management with PCI did provide a time-limited improvement in angina symptoms.

As the authors of COURAGE nicely summarize on page 1512, the atherosclerotic plaques of ACS and stable CAD are different. Vulnerable, ACS-prone plaques have thin caps and spread outward along the wall of the coronary artery, as opposed to the plaques of stable CAD which have thick fibrous caps and are associated with inward-directed remodeling that narrows the artery lumen (and thus cause reliable angina symptoms and luminal narrowing on coronary angiography).

Notable limitations in this study: 1) the population was largely male, white, and 42% came from VA hospitals, thus limiting generalizability of the study; 2) drug-eluting stents were not clinically available until the last 6 months of the study, so most stents placed were bare metal.

Later meta-analyses were weakly suggestive of an association of PCI with improved all-cause mortality. It is thought that there may be a subset of patients with stable CAD who achieve a mortality benefit from PCI. Per UpToDate, there are ongoing RCTs investigating this possibility.

It is important to note that all of the above discussions assume that the patient does not have specific coronary artery anatomy in which initial CABG would provide a mortality benefit (e.g. left main disease, multi-vessel disease with decreased LVEF). Finally, PCI should be considered in patients whose physical activity is limited by angina symptoms despite optimal medical therapy.

Further Reading:
1. Wiki Journal Club
2. 2 Minute Medicine
3. Canadian Cardiovascular Society grading of angina pectoris
4. https://www.uptodate.com/contents/stable-ischemic-heart-disease-indications-for-revascularization

Summary by Duncan F. Moore, MD

Week 5 – Albumin in SBP

“Effect of Intravenous Albumin on Renal Impairment and Mortality in Patients with Cirrhosis and Spontaneous Bacterial Peritonitis”

N Engl J Med. 1999 Aug 5;341(6):403-9. [free full text]

Renal failure commonly develops in the setting of SBP, and its development is a sensitive predictor of in-hospital mortality. The renal impairment is thought to stem from decreased effective arterial blood volume secondary to the systemic inflammatory response to the infection. In our current practice, there are certain circumstances in which we administer albumin early in the SBP disease course in order to reduce the risk of renal failure and mortality. Ultimately, our current protocol originated from the 1999 study of albumin in SBP by Sort et al.

Population: adults with SBP (see paper for extensive list of exclusion criteria)
Intervention: cefotaxime and albumin infusion 1.5gm/kg within 6hrs of enrollment, followed by 1gm/kg on day 3
Comparison: cefotaxime alone
1º: development of “renal impairment” (a “nonreversible” increase in BUN or Cr by more than 50% to a value greater than 30 mg/dL or 1.5 mg/dL, respectively) during hospitalization
2º: mortality during hospitalization

126 patients were randomized. Both groups had similar baseline characteristics, and both had similar rates of resolution of infection. Renal impairment occurred in 10% of the albumin group and 33% of the cefotaxime-alone group (p=0.02). In-hospital mortality was 10% in the albumin group and 29% in the cefotaxime-alone group (p=0.01). 78% of patients that developed renal impairment died in-hospital, while only 3% of patients who did not develop renal impairment died. Plasma renin activity was significantly higher on days 3, 6, and 9 in the cefotaxime-alone group than in the albumin group, while there were no significant differences in MAP among the two groups at those time intervals. Multivariate analysis of all trial participants revealed that baseline serum bilirubin and creatinine were independent predictors of the development of renal impairment.

Albumin administration reduces renal impairment and improves mortality in patients with SBP.

The findings of this landmark trial were refined by a brief 2007 report by Sigal et al. “Restricted use of albumin for spontaneous bacterial peritonitis.” “High-risk” patients, identified by baseline serum bilirubin of ≥ 4.0 mg/dL or Cr ≥ 1.0 mg/dL were given the intervention of albumin 1.5gm/kg on day 1 and 1gm/kg on day 3, and low-risk patients were not given albumin. None of the 15 low-risk patients developed renal impairment or died, whereas 12 of 21 (57%) of the high-risk group developed renal impairment, and 5 of the 21 (24%) died. The authors concluded that patients with bilirubin < 4.0 and Cr < 1.0 do not need scheduled albumin in the treatment of SBP.

The current (2012) American Association for the Study of Liver Diseases guidelines for the management of adult patients with ascites due to cirrhosis do not definitively recommend criteria for albumin administration in SBP – they instead summarize the above two studies.

A 2013 meta-analysis of four reports/trials (including the two above) concluded that albumin infusion reduced renal impairment and improved mortality with pooled odds ratios approximately commensurate with those of the 1999 study by Sort et al.

Ultimately, the current recommended practice per expert opinion is to perform albumin administration per the protocol outlined by Sigal et al. (2007).

Further Reading:
1. AASLD Guidelines for Management of Adult Patients with Ascites Due to Cirrhosis (skip to page 77)
2. Sigal et al. “Restricted use of albumin for spontaneous bacterial peritonitis”
3. Meta-analysis: “Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials
4. Wiki Journal Club
5. 2 Minute Medicine

Summary by Duncan F. Moore, MD