The Intravenous Contrast Debate

Does intravenous contrast exposure increase the likelihood of developing renal insufficiency? The consensus opinion has been, generally, “yes”. However, evaluated under a closer lens, it is apparent some of these data come from high-dose use during angiography, from exposure to high-osmolar contrast material not routinely used in present day, and weak evidence from observational cohort studies.

The modern take is, increasingly, potentially “no”. However, it is virtually impossible to conclusively study the effect of intravenous contrast exposure. A prospective, controlled trial would require patients for whom a contrast study was believed important to their medical care be randomized to not receiving the indicated study, leading to all manner of potential harms. Therefore, we are reduced to looking backwards and comparing patients undergoing a contrasted study with those who do not.

This study is probably the best style of this type of evidence we are going to get. This is a propensity-matched analysis of patients undergoing contrast CT, non-contrast CT, and those not undergoing CT at all. Between 5,000 and 7,000 patients comprised each cohort, and these were stratified by baseline comorbidities, medications administered, illness severity indicators, and baseline renal function. After these various adjustments and weighting, the authors did not observe any effect on subsequent acute kidney injury relating to the administration of intravenous contrast – limited to patients with a creatinine of 4.0 mg/dL or below at baseline.

I think this is basically a reasonable conclusion, given the approach. There has been a fair bit of observational content regarding the risk of AKI after a contrast CT, but it is impossible separate the effect of contrast from the effects of the concurrent medical illness requiring the contrast CT. Every effort, of course, should be taken to minimize the use of advanced imaging – but in many instances, the morbidity of a missed diagnosis almost certainly outweighs the risk from intravenous contrast.

“Risk of Acute Kidney Injury After Intravenous Contrast Media Administration”
http://www.annemergmed.com/article/S0196-0644(16)31388-9/abstract

An Oddly Dire Look at CIN after CTPA

This is an abstract that sucked me in – not because of the concept of the study – but because of its quoted incidence of adverse outcomes.  23.7% incidence of contrast-induced nephropathy following a CT pulmonary angiogram!  12.5% incidence of renal failure!  12.8% in-hospital mortality!

But, no.

The study itself is a comparison between three different prophylaxis methods for the prevention of CIN after CTPA – N-acetylcysteine plus normal saline, bicarbonate plus NS, or NS alone.  The simple summary: no difference between groups.

But, getting back to those dire numbers – roughly double the typically reported incidence of CIN.  They’re a mirage.  In reality, they assigned the primary outcome to all 26 (9.3%) of patients lost to follow-up.  Therefore, the starting point for their outcomes of interest are in a more reasonable range: 15.2% CIN, 2.6% renal failure, and 3.0% in-hospital mortality.

This, again, leads us back to the question: how much renal impairment is attributable to the CTPA, and how much to the underlying disease processes leading patients to require a CTPA in the first place?  Yield for PE on their CTPA cohort was 31.9%, which, in itself, elevates the comorbid burden of the population and could contribute to heart failure and renal injury.  There is no control group not receiving CTPA – for obvious clinical reasons – so it is hard to estimate the additive injury resulting directly from the CTPA.

But, at least, the big numbers displayed in their abstract a little misleading.

“The high risk of contrast induced nephropathy in patients with suspected pulmonary embolism despite three different prophylaxis: A randomized controlled trial”
http://onlinelibrary.wiley.com/doi/10.1111/acem.13051/abstract

Not Much to Say About SPLIT

The Emergency Department is the land of fluid resuscitation.  The most typical resuscitation fluid tends to be 0.9% Normal Saline.  At simple face validity, this makes little sense as a volume expander – a poor mimic of basic physiology, and associated with an iatrogenic acidosis in large volumes.  Questions abound regarding the risks of renal failure associated with excessive saline administration, as compared to a more balanced or buffered solution.

This SPLIT trial, performed in intensive care units across New Zealand and Australia, provides little additional insight.  It is, happily, a lovely randomized, controlled, double-blind trial of fluid administration, comparing 0.9% NS with “buffered crystalloid”, also known as Plasma-Lyte.  Various outcomes measured changes in renal function, need for renal replacement therapy, and in-hospital mortality.

No differences.

But, also, not terribly generalizable.  Over 70% of these patients arrived to the ICU from the operating room, most of which was after elective surgery, most of which was cardiovascular.  Only 15% arrived from the Emergency Department, and only 4% carried a diagnosis of sepsis.  Patients also received only a median of 2 liters of fluid during their median of 1.5 days in the ICU.

It’s of mild interest to see no difference, but it does very little to further inform the sort of large-volume, rapid resuscitation routinely performed in the Emergency Department.

“Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit The SPLIT Randomized Clinical Trial”
http://jama.jamanetwork.com/article.aspx?articleid=2454911

Also: for an excellent review of the “buffered crystalloid” solutions, visit PulmCrit.org.

Irresponsible Use of NOACs in End-Stage Renal Disease

Frequent readers may have noted this blog is somewhat skeptical regarding the novel oral anticoagulants, with particular criticism reserved for dabigatran.*  The bleeding risks, particularly for dabigatran, are profoundly increased in renal impairment – while the Factor Xa inhibitors simply do not have sufficient safety data to describe their risks in this population.

So, in dialysis patients with zero renal function – wouldn’t it perhaps be safest to continue using our present, time-tested, warfarin anticoagulation strategy?

This review of the Fresenius Medical Care database of end-stage renal patients on dialysis captured 8,064 patients with non-valvular atrial fibrillation who were initiated on anticoagulation between 2010 and 2014.  During this time, 5.9% of patients receiving new anticoagulation were initiated on dabigatran or rivaroxaban, with the remainder started on warfarin or aspirin.  And, dabigatran or rivaroxaban use increased the incidence of minor bleeding, major bleeding, and bleeding-associated mortality – with relative risk increases ranging from ~1.3 for minor bleeding to ~1.7 for hemorrhagic death.  Even rates for ischemic stroke were low in all groups, and no meaningful protective difference for thromboembolic events was observed.  Small baseline differences between the various anticoagulant cohorts are present, but they are probably clinically unimportant.

More bleeding?  More death?  It seems clear it is not responsible medicine to initiate the NOACs in a dialysis population.

“Dabigatran and Rivaroxaban Use in Atrial Fibrillation Patients on Hemodialysis”
http://www.ncbi.nlm.nih.gov/pubmed/25595139

*Disclosure: I provided legal consultation pertaining to dabigatran, with funds paid to my institution.

A Brave New Kayexalate Free World

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

There may soon come a time when we witness the death of the much maligned cation-exchange resin, Kayexalate  Unfortunately not for the reasons we hoped. We will not see the use of sodium polystyrene sulfonate fade from use in the modern Emergency Department because of our tireless efforts to remind our Internal Medicine colleagues of its lack of efficacy. Rather its clinically irrelevant place in the management of acute hyperkalemia will now be replaced by a brand new shiny cation-exchange resin that our Nephrologist consultants can use to delay the 3 am dialysis treatment our patient with a potassium of 9 mmol/L desperately requires.

Enter sodium zirconium cyclosilicate (ZS-9), a highly selective cation-exchanger that entraps potassium in the intestinal tract in exchange for sodium and hydrogen. Makers of this medication, ZS Pharma, claim it entraps 10 times as much potassium as the tried and (not-so-)true Kayexalate  A recent article published in the NEJM examines its efficacy in patients presenting with hyperkalemia. Authors, Packham et al, randomized 753 patients presenting with mild hyperkalemia (5.0 to 6.5 mmol/L) to either 1.25g, 2.5g, 5g, 10g, or placebo every 8 hours for 48 hours. Only the patients who responded to ZS-9 during the initial phase and were normokalemic after 48 hours were then randomized to either once daily ZS-9 at the original dose they were randomized to or placebo.  Unfortunately none of the patients who truly concern us were included in this trial. Authors excluded patients if they were receiving dialysis, had diabetic ketoacidosis, had a potassium level of more than 6.5 mmol/L, or a cardiac arrhythmia that required immediate treatment. These are often the patients in which we are asked to perform a trial of Kayexalate therapy in place of definitive dialysis.

For the initial phase of the trial, the authors found a statistically significant difference in their primary endpoint, the between-group difference in the exponential rate of change in the mean serum potassium level during the first 48 hours of treatment, between patients receiving the 2.5g, 5g, and 10g dose when compared to placebo.  At 48 hours, the absolute mean reductions in the 2.5g, 5g, and 10g group were 0.46 mmol/L, 0.54 mmol/L, and 0.73 mmol/L respectively. These differences were statistically significant when compared with a mean reduction of 0.25 mmol/L that was seen in the placebo group. The overall reduction in potassium seemed to be mildly correlated with the extent of hyperkalemia at presentation, but authors only presented the results of this analysis in the group who was administered the 10g dose of ZS-9 (1.1 mmol/L > 5.5 mmol/L, 1.0 mmol/L 5.4 to 5.5 mmol/L, and 0.6 mmol/L < 5.3 mmol/L or less). Additionally patients who received the 5g and 10g doses of ZS-9 during the 15-day maintenance phase, had significantly fewer repeat episodes of hyperkalemia. A second study just published in JAMA by Kosiborod et al also examining the utility of ZS-9 in the acute management of mild hyperkalemia (5.0 to 6.5 mmol/L) confirms these findings. Though in this trial, patients in the first 48 hours were not randomized, but rather all were given a 10g dose every 8 hours, the mean absolute change in serum potassium was comparable to the change observed in the 10g group in the Packham et al trial( −0.7 mmol/L at 24 hours and −1.1 mmol/L at 48 hours). Likewise the severity dependent response was also observed in this second trial.

Although statistically a success, ZS-9 adds very little to the acute management of clinically relevant hyperkalemia. Even the high doses of ZS-9 reduced the potassium level on average by 0.73 mmol/L at 48-hours, nowhere near the efficacy that would allow us to comfortably hold dialysis overnight in the acutely hyperkalemic patient. Interestingly these results are not dissimilar to what Scherr et al discovered in their 1961 investigation into the effects of Kayexalate on serum potassium. In this non-randomized, non-blinded trial the cation-exchange resin lowered patients potassium by a mean of 1.0 mmol/L over the first 24-hours.  Furthermore unlike the Scherr cohort neither of these studies examined oliguric patients or those with a history of ESRD on dialysis. The very patients which most frequently require emergent dialysis for acutely elevated levels of serum potassium.

Neither of these trials possessed the statistical power to definitively assess safety. Though no obvious concerns were demonstrated in this cohort, the rates of intestinal necrosis observed in patients given Kayexalate are far too infrequent to detect if ZS-9 causes similar effects with such a small sample size. While none of the patients in either of these trial experienced a fatal arrhythmia related to their hyperkalemia, the authors’ inclusion and exclusion criteria insured these types of events would be highly unlikely. On a side note, ED nurses will be happy to see that rate of diarrhea following the administration of ZS-9 at 1.9% is far less than what is commonly seen in patients given Kayexalate.

The editorial published alongside the Packham et al paper in the NEJM is entitled, “A New Era in the Management of Hypoerkalemia”. Though ZS-9 may play a role in the long-term management of patients at risk for hyperkalemia, for the acute management of hyperkalemia it seems we will still be arguing with our consultants over the administration of an ineffective exchange resin as a replacement for the definitive dialysis they require. A new era indeed…

“Sodium Zirconium Cyclosilicate in Hyperkalemia” http://www.nejm.org/doi/full/10.1056/NEJMoa1411487

“Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients With Hyperkalemia The HARMONIZE Randomized Clinical Trial” http://jama.jamanetwork.com/article.aspx?articleid=1936753

VUR, Renal Scarring and other Fictitious Maladies

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

As Emergency Physicians, one of the more vexing tasks asked of us is to identify the otherwise well appearing patient who has an occult illness that, if not identified, will lead to poor outcomes. With this in mind, we now turn our attention to the well appearing febrile infant and our unfounded obsession with urine. The fear that these children are quietly infarcting their nephrons is one of the more far fetched tales in emergency medicine.



In a recent NEJM article published by the RIVUR Trial Investigators, the authors examined whether prophylactic antibiotics for children with voiding cystourethrogram (VCUG) confirmed vesicoureteral reflux(VUR) were effective in preventing recurrent infections and more importantly, decreasing the extent of renal scarring (as per DMSA scan). Patients were randomized to either daily trimethoprim-sulfamethoxazole (TMP-SMX) suspension or placebo for one year. Authors found that children treated with prophylactic antibiotics had an absolute decrease in the recurrence of urinary tract infections by 12%. Meaning, you would have to treat 8 children for 12 months to prevent one case of recurrent UTI. More importantly the rate of renal scaring at follow up was identical.

  Among the children who experienced their first recurrent UTI, the rates of E. coli resistance to to TMP-SMX was 63% in the active group vs 19% in the controls.

Though this trial fails to address the futility of our quixotic attempts to diagnose and treat every UTI, clearly the utility of searching for and diagnosing VUR in febrile children in the hopes of preventing future renal scarring is a flawed concept. Furthermore it is unclear whether the surrogate endpoint of renal scarring, as seen on DMSA, is clinically relevant.  Not only are we most likely treating a fictitious disease process, but as the RIVUR authors demonstrated we are doing so ineffectively.

“Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux.” http://www.ncbi.nlm.nih.gov/pubmed/24795142

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.