Nephrology – Emergency Medicine Literature of Note

Potpourri

Just a quick-hit collection of articles I’ve wanted to highlight/catalogue for future reference, but couldn’t find the time for deep dives into each:

Shared Decision Making in Patients With Suspected Uncomplicated Ureterolithiasis: A Decision Aid Development Study.
For this common clinical scenario in the Emergency Department, the authors have developed a patient-facing packet to facilitate shared decision-making. However, more important than the product, is the process these authors have described for its creation. A similar roadmap could be followed to address similar opportunities in your department.

Reduction of Inappropriate Antibiotic Use and Improved Outcomes by Implementation of an Algorithm-Based Clinical Guideline for Nonpurulent Skin and Soft Tissue Infections.
Amazing – using the correct antibiotics reduces treatment failures and, likewise, treatment failures necessitating admission to the hospital. This is an effort-intensive intervention featuring provider education and individual prescribing feedback, but, given the limitations, can be considered a change management success. Whether this can be replicated at your institution will depend on many cultural factors.

Utility of INR For Prediction of Delayed Intracranial Hemorrhage Among Warfarin Users with Head Injury.
Here’s a topic with a ton of practice variation – do you admit patients with closed head injury on anticoagulation for observation? This retrospective review of those patients just on warfarin tries to make the case patients with INR <2 are safe for discharge, whereas those with higher scores are not. Again, however, the yield of observation is somewhere south of 1% in their entire therapeutic cohort, making it truly challenging to find the inflection point of value. Another opportunity for shared decision-making?

Performance of Novel High-Sensitivity Cardiac Troponin I Assays for 0/1-Hour and 0/2- to 3-Hour Evaluations for Acute Myocardial Infarction: Results From the HIGH-US Study.
A detailed look at high-sensitivity Troponin I rule-in/rule-out algorithms suggests a 0/1-hour strategy is similar to a 0/3-hour strategy. Overall, while the disposition of patients is likely to be more rapid from the 0/1 hour strategy, a greater proportion of patients ultimately fall into the “intermediate” zone requiring further observation and diagnostics. Certainly, combinations of hsTnI and other risk-stratification instruments ought to mean the majority of patients with straightforward chest pain presentations may be discharged from the Emergency Department.

Randomized Clinical Trial of IV Acetaminophen as an Adjunct to IV Hydromorphone for Acute Severe Pain in Emergency Department Patients.
In this trial, patients receiving hydromorphone were randomized to receive adjunctive treatment with IV acetaminophen or placebo. With 159 patients, they found advantages to the multi-modal approach favoring the addition of acetaminophen – but the confidence interval for their primary outcome crossed unity by 0.01. The authors conclude this is a negative trial, but it rather seems to me there’s certainly no harm in adding acetaminophen (it need not be IV) – adding it likely has a favorable effect, even if the effect size may not be large.

Effect of No Prehydration vs Sodium Bicarbonate Prehydration Prior to Contrast-Enhanced Computed Tomography in the Prevention of Postcontrast Acute Kidney Injury in Adults With Chronic Kidney Disease: The Kompas Randomized Clinical Trial.
In news surprising no one, another trial fails to show benefit of prehydration in staving off post-contrast exposure acute kidney injury. As seen on Twitter, rather than “contrast-induced nephropathy”, the clinical paradigm is effectively “contrast-adjacent nephropathy.” The impairment in renal function is associated with the underlying medical illness and not the exposure to IV contrast. Thus, no intervention – such as prehydration – can prevent such.

Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.
This interesting observational study evaluated patients with a diagnosis of non-ST elevation acute coronary syndrome using coronary CT angiography prior to invasive coronary angiography. The good news: CT angiography was probably useful at excluding obstructive coronary disease. The bad news: nearly 70% of patients had a coronary stenosis identified on invasive angiography, so patient selection prior to CT angiography will be important to improve the value of using it as a screen to prevent invasive angiography.

Industry Payment to Vascular Neurologists: A 6-Year Analysis of the Open Payments Program From 2013 Through 2018.
As we watch our healthcare delivery system struggle and groan under the various strains and burdens, one of the culprits has always been the influence of pharmaceutical/device manufacturers targeting investments to improve uptake of their products. In this observational analysis of the OpenPayments database, these authors identified the recipients of financial support from the manufacturers of endovascular devices. About 16% of vascular neurologists received funding from industry, but over 75% could be identified as “influencers” – chiefs of staff, department chairs, or similar. Pharma et al should always be remembered they are serving the interests of owners and shareholders, and not patients and our healthcare system.

IV Contrast, Unleashed

“The putative risk of administering modern intravenous iodinated contrast media in patients with reduced kidney function has been overstated.”

What a glorious lead sentence to the summary of this most recent guideline, a product of the American College of Radiology and the National Kidney Foundation. Historically, there has been great concern – including delay or exclusion of imaging – regarding the potential for acute kidney injury from intravenous contrast media in advanced imaging. However, a variety of recent different pieces of evidence have led to changes in perspective. This lovely guideline summarizes the data and issues a panoply of clarifications and recommendations regarding its use.

The most important distinction this guideline makes is between contrast-associated AKI and contrast-induced AKI. CA-AKI, as the authors note, is quite common – but is a rather a product of the underlying medical illness rather than the administration of IV contrast. CI-AKI, the attributable injury associated with IV contrast, is much harder to reliably observe. As noted in this article, summarizing mostly observational data sets, tweezing out the actual risk of harm from IV contrast media is challenging.

This guideline bundles together a whole list of concise questions and answers with regard to which patients may be at risk, the reliability of those estimates of risk, and what – if any – prophylaxis could be considered. Effectively – and the authors use many more words to clarify individual scenarios – the uncertainty regarding the safety of IV contrast begins to creep in around an eGFR of 30mL/Min/1.73m2. It should be noted this is related to a paucity of data, rather than a known observable risk. The authors recommendation, however, is not to exclude these patients from imaging, but rather to prompt a conversation between the referring professional and the radiologist to discuss the risks and benefits of IV contrast. Certainly life-threatening illnesses may require imaging, thus the careful weighing of risks versus benefits, and in these areas of uncertainly, additional cognitive consideration is reasonable.

With regard to prophylaxis against CI-AKI, the authors also make eminently reasonable statements saline volume expansion could be considered if clinically tolerated. The authors note this recommendation is based rather on observations of the utility of volume expansion for treating CA-AKI rather than CI-AKI, specifically, but likely represents a reasonable clinical practice.

In all, these guidelines quite nicely represent the uncertainly regarding harms from IV contrast administration, and, absent known harms from contrast, the potential harms from exclusion of IV contrast. As with most clinical problems, additional prospective research is critical to better inform practice.

“Use of Intravenous Iodinated Contrast Media in Patients with Kidney Disease: Consensus Statements from the American College of Radiology and the National Kidney Foundation”
https://pubs.rsna.org/doi/10.1148/radiol.2019192094

Dialysis Purgatory

This little article is not terribly generalizable and the results are eminently predictable – but this barbaric practice was my daily routine a couple years ago while working in Houston.

To received routinely scheduled dialysis, someone must, of course, pay for it. For those U.S. citizens without the means to pay, various federal mechanisms provide coverage. For non-U.S. citizens in this country without the means to pay, there is no external payor source – unless “necessary for the treatment of an emergency medical condition.” Therefore, many facilities simply restrict dialysis to non-citizen patients in extremis.

As you might expect, this is bad and bad for you. This retrospective cohort study follows 5-year survival and resource utilization, comparing those at hospitals where non-U.S. citizens could be eligible for scheduled dialysis with those at facilities where only emergency dialysis was available. The sample sizes are small – 169 in the “emergency-only” cohort and 42 in “standard” – but at 5 year follow-up, over half the “emergency-only” cohort had died, as compared with about 10% of the standard hemodialysis. Various statistical analyses and propensity matching further quantify the exact excess hazard of emergency dialysis.

Patients receiving emergency dialysis received, obviously, fewer sessions per month – 6.2 instead of 10.3. However, these savings are potentially offset by a ten-fold increase in acute care days, probably associated with those episodes of emergency dialysis. In the most morbid sense, unfortunately, total cost-savings probably favor the emergency dialysis cohort owing to the greatly increased mortality.

There are uncertainties and holes in these sorts of retrospective studies, particularly in a cohort whose deaths are potentially not documented in our national registries. The face validity for the overall findings is strong, however, even if the specific numbers are not reliable.

Regardless, just as a manner of respecting basic human decency, it is simple cruelty to layer this additional suffering onto the already miserable state of being dialysis-dependent. All feasible efforts should be made to provide access to regular dialysis, considering the burden on the health system infrastructure is likely similar.

“Association of Emergency-Only vs Standard Hemodialysis With Mortality and Health Care Use Among Undocumented Immigrants With End-stage Renal Disease”
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2665387

Yet Another Failure to Prevent Contrast-Induced Nephropathy

I’m not the first one to this party, but this is worth a short note to touch upon, regardless, in case you missed it before the holiday break. I’ve written about retrospective propensity-matched analyses and other data suggesting the impact of contrast administration on acute kidney injury is overstated. This is yet another piece of the puzzle supporting these conclusions.

This is a beautifully massive trial, the PRESERVE Trial, with 5,177 patients enrolled in a 2×2 factorial design to test the impact of sodium bicarbonate and acetylcysteine on kidney injury following coronary angiography. This study was conducted in the United States, Australia, Malaysia and New Zealand, and was planned to enroll 7,680 to detect an increase in the primary end point of 8.7% to 6.5% for each trial intervention. As you might now have gathered, they stopped the trial early after an interim analysis when their statistical analysis met criteria for futility. The incidence of the primary end point, a composite between increase in creatinine, dialysis, and death, was effectively identical between each of the various arms, as were non-renal adverse events.

The short takeaway from these data: if contrast-induced nephropathy cannot be prevented by any available treatment, is it a true clinical entity at the doses currently used in clinical practice? Or, rather, do the clinically ill simply suffer kidney injury, regardless?

“Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine”
http://www.nejm.org/doi/full/10.1056/NEJMoa1710933

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