The Latest Myth: Contrast-Induced Nephropathy?

Here’s the simple explanation for why none of our observed treatments to prevent contrast-induced nephropathy – acetylcysteine, hydration, sodium bicarbonate – reliably work:  CIN is a myth.

There’s a lot of observational literature evaluating the incidence of mild acute-kidney injury after iodinated contrast exposure – either CT scans or vascular procedures – and every study shows some increase in serum creatinine in a small, but significant, proportion of patients.  But, as this study suggests, is this just random effects, a confounder from co-occurring medical illness, or true dose-dependent renal injury?

This study, although retrospective, is almost precisely how I would have addressed the question.  This is a single-center review of ten years of patients receiving CT scans.  There were 116,694 contrast-enhanced scans and 40,446 non-contrast scans for whom before-and-after serum creatinine values were available.  These CT scan events were compared by both risk-stratification as well as propensity score-matched subsets, as well as a counterfactual set of patients who had both independent contrast-enhanced and non-contrast CTs in their records.  With every adjusted and unadjusted analysis, regardless of baseline renal insufficiency, there was no evidence of an excess of CIN following the contrast-enhanced events.

This is retrospective, so it’s hard to say whether there are undetected confounders – other comorbid illnesses, diagnosis disparities – that influenced these results despite the large numbers analyzed.  However, it is absolutely reasonable to move forward with a prospective study design based on the hypothesis that intravenous contrast-enhanced CT scans do not increase risk of AKI.  These results are not yet generalizable, however, to other interventional procedures in which higher volumes of contrast might be used.

This article was also covered by James Roberts in Emergency Medical News.

Addendum:  Joel Topf argues this and related work is junk science at Precious Bodily Fluids.

“Intravenous Contrast Material-induced Nephropathy: Casual or Coincident Phenomenon”
http://www.ncbi.nlm.nih.gov/pubmed/23360742

What Santa Claus, the Tooth Fairy and Low-Dose Dopamine Have in Common

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.

We have known for some time that the renal sparring effects of low-dose dopamine is a story we tell to our cardiologists to tuck them in at night. Despite a large meta-analysis published in 2005, finding no evidence of this theoretical renal benefit, the authors of the recent Renal Optimization Strategies Evaluation (ROSE) felt that this question was again worth investigating. Nesiritide, a drug made infamous for causing renal failure, was also examined for its renal sparing attributes.

A total of 360 patients with acute heart failure and renal dysfunction (GFR between 15-60 mL/min) were, in a convoluted fashion (to reduce unnecessary use of central lines), randomized to either low-dose dopamine (2mcg/kg/min), low dose nesiritide (0.005 mcg/kg/min) or placebo infusion for a 72-hour period. The two co-primary end points assessed were urine output and change in cystatin C level over a 72-hour period. There was no benefit of either low dose dopamine or low dose nesiritide when added to standard therapy of acute heart failure in any of the authors’ primary, secondary or tertiary (yes tertiary) endpoints. Though there was no statistical increase in adverse events seen in either the dopamine or nesiritide groups, this is far too small a cohort to truly assess safety.
With the publication of this trial surely it has come time to close the book on low dose dopamine. So next time a consultant requests we start a dopamine infusion for its renal sparring properties, may I suggest we sit him or her down and politely explain that like Santa Claus and the Tooth Fairy, there is no such thing as renal dose dopamine.
“Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction” http://www.ncbi.nlm.nih.gov/pubmed/24247300

What Santa Claus, the Tooth Fairy and Low-Dose Dopamine Have in Common

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.

We have known for some time that the renal sparring effects of low-dose dopamine is a story we tell to our cardiologists to tuck them in at night. Despite a large meta-analysis published in 2005, finding no evidence of this theoretical renal benefit, the authors of the recent Renal Optimization Strategies Evaluation (ROSE) felt that this question was again worth investigating. Nesiritide, a drug made infamous for causing renal failure, was also examined for its renal sparing attributes.

A total of 360 patients with acute heart failure and renal dysfunction (GFR between 15-60 mL/min) were, in a convoluted fashion (to reduce unnecessary use of central lines), randomized to either low-dose dopamine (2mcg/kg/min), low dose nesiritide (0.005 mcg/kg/min) or placebo infusion for a 72-hour period. The two co-primary end points assessed were urine output and change in cystatin C level over a 72-hour period. There was no benefit of either low dose dopamine or low dose nesiritide when added to standard therapy of acute heart failure in any of the authors’ primary, secondary or tertiary (yes tertiary) endpoints. Though there was no statistical increase in adverse events seen in either the dopamine or nesiritide groups, this is far too small a cohort to truly assess safety.
With the publication of this trial surely it has come time to close the book on low dose dopamine. So next time a consultant requests we start a dopamine infusion for its renal sparring properties, may I suggest we sit him or her down and politely explain that like Santa Claus and the Tooth Fairy, there is no such thing as renal dose dopamine.
“Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction” http://www.ncbi.nlm.nih.gov/pubmed/24247300

Chloride-Restriction & More JAMA Inadequacy

“The implementation of a chloride-restrictive strategy in a tertiary ICU was associated with a significant decrease in the incidence of AKI and use of RRT.”

Pretty clear, eh?  This article is one of several in a line of folks working to divorce us from normal saline.  The argument is that this hypernatremic, hyperchloremic solution, when given for large-volume resuscitation in the critically ill, leads to metabolic acidosis and decreased urine output.  This study, sponsored by Baxter, the makers of Plasma-Lyte, is an open-label, before-and-after design.  One year, they gave whatever fluid they wanted – mostly saline.  The next year, saline-containing fluids were restricted, and they used 20% albumin, lactated ringers (Hartmann’s solution), or Plasma-Lyte.

Firstly, the primary outcome doesn’t match their clinicaltrials.gov registration.  They’ve changed it from mean base excess during hospital stay to two primary outcomes that weren’t even both previously defined as secondary outcomes – increase in creatinine from baseline and incidence of acute kidney injury according to the RIFLE classification.

Then, they offer two positive results from their study – a decrease in the incidence of AKI and the use of renal replacement therapy.  The authors use RIFLE as their indicator of AKI – but they don’t pre-define which categories of RIFLE they use, and lump “Injury” and “Failure” together to a composite endpoint to gain statistical significance.  Otherwise, it’s a 7.4% control and 5.4% intervention difference in “Failure” that doesn’t reach statistical significance – and considering the mean baseline creatinine was lower in the intervention period, it ought to be expected to reach the failure definition less frequently.

The difference in rise of creatinine reaches statistical significance – but they’ve hidden the details in their online supplement  The mean serum creatinine in the baseline period rises from 10.4 mmol/L to 11.0 mmol/L, and in the intervention period from 10.3 mmol/L to 10.7 mmol/L.  This might be statistically significant, but hardly clinically significant.  Luckily, the authors use a skewed y-axis to distort and magnify the difference in their graph of these results.

Lastly, the RRT difference reported in their six-month study period is befuddling.  The overall rate of RRT in the entire year of their baseline period is 7.9%, while the rate of RRT in the entire year of their intervention period is 7.4%.  Yet, in the six months reported for this study, they report RRT use of 10% in the baseline period and 6.3% for the intervention period.  This implies the authors retrospectively selected their study period in order to magnify the effect of the RRT difference.  This difference in RRT also doesn’t match the 2% absolute difference in RIFLE classification for “failure” during the study period.  This implies the open-label nature of the study influenced the frequency of RRT use, as the authors may have exerted control over an outcome measure.

As far as patient-oriented outcomes go, after all this splitting of hairs, ICU length of stay was no different, the incidence of long-term dialysis was no different, and mortality was no different.  This is also a “bundle-of-care” study, with multiple different chloride-poor and chloride-rich fluids in use, which confounds the generalizability of the results.

Maybe chloride-sparing therapy is important.  But these authors are guilty of distorting and misleading with their presentation of results – and the JAMA editors, again, have failed us.

“Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults”
www.ncbi.nlm.nih.gov/pubmed/23073953

Credit for much of the insight into this article goes to Greg Press, who prepared this article for last month’s Journal Club at UT-Houston – but he is in no way responsible for this unhinged rant.

Nephropathy Was As Common as PE after CTPA

It’s Jeff Kline Week at EMLitOfNote, with the second Carolinas paper this week – and, as a Patient Safety and Quality Fellow, I just can’t help but cite articles that deal with the consequences of otherwise well-meaning practice.

This small study followed 174 patients undergoing CTPA demonstrated a yield of 7% for PE.  On the other hand, this same cohort demonstrated a yield of 14% for contrast-induced nephropathy – as defined by an increase in serum Cr of 0.5 mg/dL or >25%.  Three of the 24 patients with CIN progressed to severe renal failure, two of whom died.  The proportion of CIN and renal failure were similar to the outcomes observed in the additional 459 patients they followed for CT imaging on other contrast protocols.

So, the rate of CIN is not insignificant – particularly compared to the rate of diagnosis of PE at this institution.  It seems to be suggested by this study, although not shown, that the relative risk of death conferred by receiving contrast and developing CIN might even exceed the number of adverse events that might have occurred from PE if left undiagnosed or untreated.

“Prospective Study of the Incidence of Contrast-induced Nephropathy Among Patients Evaluated for Pulmonary Embolism by Contrast-enhanced Computed Tomography”
http://www.ncbi.nlm.nih.gov/pubmed/22687176

The Risks of Missing Dialysis

Hemodialysis patients have an elevated risk of death – and it’s even higher for patients on scheduled dialysis during their “weekend.”

Most scheduled plans are every other day Mon-Wed-Fri or Tue-Thu-Sat, which leads to a two-day interval between dialysis – resulting in an extra day of fluid retention and electrolyte abnormalities.  Bad hearts + extra fluid results in a much higher incidence of essentially any kind of mortality or morbidity associated with cardiovascular causes – significantly more myocardial infarction, congestive heart failure, stroke, and dysrhythmia.  Overall, there were 22.1 vs. 18.0 deaths per 100 person-years on the long-interval days than the others.  Retrospective registry data-mining, but it probably illuminates a logical truth.

This particular article caught my eye because we have a significant population at our county facility that comes for “compassionate dialysis”.  Non-U.S. citizens that do not qualify for scheduled dialysis, they “live” a tortured existence in which they can only receive “emergency dialysis”, as in, we routinely wait until they’re at the precipice of death – with strict criteria of pulmonary edema, K+ > 6.0, bicarbonate less than 10, etc. – before pulling them back a small increment and sending them home to repeat the cycle in another week.  Barbaric.  I can’t even imagine what their outcomes are like….

“Long Interdialytic Interval and Mortality among Patients Receiving Hemodialysis”
http://www.ncbi.nlm.nih.gov/pubmed/21992122

Putting Acetylcysteine To Rest

Essentially, another study to nail the coffin shut for using n-acetylcysteine to prevent contrast-induced acute kidney injury.

Over 1000 patients each in the acetylcysteine and placebo groups, this study showed exactly equal 12.7% chance of acute kidney injury resulting from contrast exposure during cardiac catheterization.  In addition, the 30-day mortality was nearly identical at 2.2% for acetylcysteine and 2.3% for placebo, and only 3 patients in each group required dialysis within 30 days.
Perplexingly enough, the only advantage acetylcysteine had was a lower incidence in adverse effects versus placebo, 2.2% vs. 1.3%.  They do not mention what formulation their placebo formulation was, but apparently it caused more nausea & vomiting.
The authors also do a mini meta-analysis to evaluate why previous studies showed a benefit, and they additionally find that studies that had appropriately blinded allocation showed identical outcomes while patients with inadequate blinding demonstrated an acetylcysteine advantage.
“Acetylcysteine for Prevention of Renal Outcomes in Patients Undergoing Coronary and Peripheral Vascular Angiography.”

Forced Diuresis Prevents CIN

I admit, I was shocked when I got to the end of the paper and found the authors had no disclosures – it seems nearly every study concerning a commercial product has someone on the payroll.  Heck, the study is even registered with clinicaltrials.gov, and they didn’t change their protocol at all.

Anyway, this paper is in regards to the RenalGuard system, which is basically a closed-loop system that replaces a furosemide forced diuresis with normal saline.  They compare this to “usual therapy”, which, for them, is sodium bicarbonate and n-acetylcysteine (NAC) for the prevention of contrast-induced nephropathy as a result of some iodixanol contrast load.  Basically, they ran this system through a few patients who were at high-risk for CIN for ~5 hours around the time of their contrast procedure and tried to get their urine flow rate >300 mL/hr.  When successful, those patients had significantly less CIN than the “usual therapy” group (10% vs. 20%).

So, seems like it works.  There was more pulmonary edema (3 vs. 1) in the RenalGuard system, and more electrolyte abnormalities to replace, but this is a therapy that might yet have some utility.  It may even be practical in an ED setting, to a limited extent.

“Renal Insufficiency After Contrast Media Administration Trial II (REMEDIAL II)”
www.ncbi.nlm.nih.gov/pubmed/21518686