Symptoms Over Science

There’s a reason general primary care has evolved to diagnose and treat uncomplicated urinary tract infections over the phone: the patient is the authority, not any test we order.

We’ve tried relying upon some constellation of the urinalysis, the urine microscopic examination, and, finally, the urine culture. Each of these has limitations, although, in many settings, the culture result has been the gold standard. However, this culture result, some quantification of the number of colony-forming units, is also somewhat of an arbitrary diagnostic – an arbitrary numerical cut-off must be used, with its own implications for sensitivity and specificity.

This brief clinical microbiology article evaluates the urine culture as a gold standard for the diagnosis of UTI by comparing it with polymerase chain reaction-based methods for measuring the presence of pathogenic bacteria. Based on 86 asymptomatic women and 220 general practice women complaining of UTI symptoms, these authors compared the number of positive culture results with positive PCR results. Of this sample, 149 had positive cultures for e. coli, while 211 patients had positive PCR for e. coli. Finally, combining the culture results – which identified other pathogens, as well – with the PCR for e. coli, 216 of 220 symptomatic women had pathogenic bacteria identified. In the control cohort, there were similar numbers of positive culture and PCR results – ~10% in each, which these authors feel accurately reflects the general rate of asymptomatic bacteruria in the general population.

These data correlate nicely with similar findings demonstrating a negative urine culture does not exclude clinical improvement while on antibiotics, and thus the reasonable conclusion we ought simply treat appropriate symptomatic patients without specifically relying on testing.

“Women with symptoms of a urinary tract infection but a negative urine culture: PCR-based quantification of Escherichia coli suggests infection in most cases”
http://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(17)30209-4/abstract

The Effects of Dilution on Ureteral Stone Passage

In the distant past, I critiqued the Cochrane Review regarding the use of alpha-blockers for ureteral stone passage. I combed through each individual study cited and found, almost universally, they were small, biased, and probably unreliable. Pooling together these poor data, then, was simply a larger pile of junk.

Following the publication of that Cochrane Review, however, were a handful of well-done clinical trials – and they have shown little reliable beneficial effect on stone passage. There was a small inclination towards benefit for those patients demonstrated to have >5mm distal stone disease, but the magnitude of effect was small enough these trials were underpowered to find a difference.

This systematic review and meta-analysis, then, essentially combines this more recent high-quality evidence with the truckload of older evidence from the Cochrane review. With the larger combined sample size, they are now better able to find stronger associations between treatment with alpha-blockers and successful stone passage in these larger stones. Predictably, however, the quality and reliability of their evidence has diminished by simple diluation.

Alpha-blockers are generally benign therapy in ureteral stones, but, if they’re not going to help, they should be avoided. The authors suggest their empiric use should be encouraged, as stone size is not always part of the initial diagnostic evaluation. Most stones are small, however – and the resulting number needed to treat to successfully pass one additional ureteral stone is probably forbiddingly high in such an empiric strategy.
“Alpha blockers for treatment of ureteric stones: systematic review and meta-analysis”
http://www.bmj.com/content/355/bmj.i6112

Magic Stone Mountain

Roller coasters are fun – and have many health benefits. They’re good for asthma. Now, apparently, they’ll help you pass kidney stones.

See the headlines:
Here’s Why Kidney Stone Sufferers Should Ride Big Thunder Mountain Railroad

Thrilling Cure: A Roller Coaster Ride Can Help Get Rid Of Kidney Stones

Got kidney stones? Ride a roller coaster! Study shows it is the most pain-free cost-efficient way to pass them

Kidney Stones? Science Suggests Heading To Disney World

And so on.

It’s just clickbait, as usual.

Now, I’m not saying the citation here isn’t on to something – but in this study, zero people pass kidney stones. Rather, a rubber ureteroscopic simulator was loaded with calcium oxalate calculi of various sizes and taken on Thunder Mountain. A few stones were shaken loose – particularly at the rear of the coaster train – and, presto! Roller coasters cure kidney stones!

Now, this may yet have some element of truth supporting anecdotal tales of stone passage while on coasters – but it’s clearly a surrogate far removed from reliable in vivo evidence.

“Validation of a Functional Pyelocalyceal Renal Model for the Evaluation of Renal Calculi Passage While Riding a Roller Coaster”
http://jaoa.org/article.aspx?articleid=2557373

NSAIDs Probably Best for Renal Colic

It has long held that non-steroidal anti-inflammatory treatment is specifically ideal for symptomatic ureterolithiasis – leading to the popularity of such treatments as intravenous and intramuscular ketorolac, diclofenac, and the like.

However, I hadn’t quite seen as large and well-designed comparative efficacy trial as this, as recently published in The Lancet.  This trial, a placebo-control, double-blind, randomized trial compared 75mg intramuscular diclofenac, 1g intravenous paracetamol, and 0.1mg/kg intravenous morphine for patients with acute renal colic.  This means, most impressively, every patient received three injections – one active and two placebo.  The primary outcome was 50% reduction in initial pain score by 30 minutes, with relevant secondary outcomes of persistent pain and need for secondary analgesia.

Based on an analysis only of those who ultimately had confirmed diagnosis of stone on imaging (CT or ultrasound), both diclofenac and paracetamol were similar or superior to morphine, with fewer adverse effects.  Pain scores were halved in 68% of diclofenac, 66% of paracetamol, and 61% of morphine.  Most importantly, need for rescue medication in this trial was only 12% with the intramuscular diclofenac, an important consideration when potentially forgoing an IV start.  The authors actually probably understate the advantage of diclofenac here, as time zero is the time of study medication administration, not time of ED arrival, as an intramuscular injection can be provided much more rapidly than one requiring an IV.

Generalizability may be limited, as it is a single-center study from Qatar in which 80+% of patients were male.  At least however, the nationality of patients were quite diverse, representing Indian, Egyptian, Nepalese, Pakistani, Bangladeshi, Sri Lankan, and many others.

“Delivering safe and effective analgesia for management of renal colic in the emergency department: a double-blind, multigroup, randomised controlled trial”
https://www.ncbi.nlm.nih.gov/pubmed/26993881

Ureterolithiasis: There’s a Better Way

Much as been made of a debate over the efficacy of tamsulosin.  Once in favor, espoused by urologists the world ‘round – but now the subject of multiple neutral, high-quality, trials.

But, what if I told you there might be a better way?

This prospective, randomized trial enrolled male patients with distal ureterolithiasis into three arms: symptomatic care-only control, daily tamsulosin, or a prescription for sexual intercourse at least three times a week.  Furthermore, patients in the symptomatic care arm and tamsulosin arms were forbidden from real or simulated sexual relations for the duration of the study.  Stone presence was confirmed by plain x-ray, and passage confirmed by correlating patient report of stone passage with absence of stone on follow-up x-ray.

As you’ve probably already gleaned from the build-up, the sexual intercourse group was the clear winner.  Mean stone size was 4.7 to 5mm across groups, so these were fairly large stones.   83% of the intercourse group had stone passage within 2 weeks, compared with 48% of tamsulosin and 35% of control.  By the end of follow-up, the other two groups had improved – but still hadn’t entirely caught up.

Unfortunately, there were only 90 total patients in this trial – and 15 were lost to follow-up.  There was no mechanism in place to confirm compliance with the treatment protocol.  Finally, of course, patients could not be blinded to treatment allocation, and no placebo for tamsulosin was provided to other groups.

Presumably, this is a low-cost, low-harm treatment intervention – and there’s some reasonable physiologic basis for the observed effect.  It may be a bit of brilliance – or, at the minimum, it might be worth an IgNobel prize?

“Can Sexual Intercourse Be an Alternative Therapy for Distal Ureteral Stones? A Prospective, Randomized, Controlled Study”
https://www.ncbi.nlm.nih.gov/pubmed/26142575

The Value-Add of Ultrasound to STONE Score

There are a few major questions to be addressed in patients with suspected renal colic:

  • Is there an infection?
  • If there is a stone, will it pass spontaneously or require urologic intervention?
  • If I make a clinical diagnosis without CT, will I miss an important alternative diagnosis mimicking stone?

The STONE score addresses the last question – using a weighted decision instrument to classify patients with suspected stone into low-, moderate-, and high-risk cohorts for ureteral stone disease.  There are some issues with face validity for STONE, and likewise the validation has shown its performance to be somewhat inexact.  However, it helps reinforce gestalt and aids in shared decision-making.

This study adds in point-of-care ultrasound to assess the degree of hydronephrosis.  The hope of these authors was the presence of hydronephrosis would improve the performance of the STONE score by identifying the few patients with stones at the low- and moderate- end, while also using moderate or greater hydronephrosis to predict the need for subsequent urologic intervention.

The answer: only marginally.

Generally, the most useful positive likelihood ratios are above 10, and the most useful negative likelihood ratios are below 0.1.  In this study, only one LR potentially met that criteria.  The presence of moderate or greater hydronephrosis in a patient with a low likelihood of stone disease had a +LR of ~20 for both the presence of stone and for stone disease requiring urologic intervention – but this +LR was based on only a handful of patients, and the 95% CIs range from 4 to 110.

Lastly, did the presence of hydronephrosis rule out any important alternative diagnoses?  No.  Out of 835 patients, there were 54 with an important alternative diagnosis.  There were 11 patients with hydronephrosis plus an important alternative, including 3 appendicitis, 1 cholecystitis, 2 diverticulitis.  The presence of moderate or severe hydronephrosis was helpful, but would not obviate imaging for an alternative diagnosis if indicated.

“STONE PLUS: Evaluation of Emergency Department Patients With Suspected Renal Colic, Using a Clinical Prediction Tool Combined With Point-of-Care Limited Ultrasonography”
http://www.ncbi.nlm.nih.gov/pubmed/26747219

Again With No Antibiotics, This Time for UTI

Frequent readers of this blog may have noticed a bit of an anti-antibiotic tendency.  Diverticulitis!  Strep throat!  All manner of upper respiratory symptoms!

How about urinary tract infections?

This German study randomized ambulatory women with urinary tract infection symptoms and positive findings on urine dipstick to either fosfomycin plus placebo tablets for three days, or simply ibuprofen for three days.  Patients were then reassessed after three days, and those with treatment failure were provided an additional course of antibiotics.  “Co-primary” endpoints were antibiotics utilization and the AUC of sums of daily symptom scores.

The results are, like last week’s URI trial, a little mixed.  The authors included 484 patients in their intention-to-treat analysis, and 77% of them ultimately had culture-positive UTIs.  A lot – 69% – of patients randomized to ibuprofen had spontaneous resolution of their symptoms and avoided antibiotic use for their UTI.  However, obviously, those who did not improve spontaneously, and ultimately were given antibiotics, did worse than their fosfomycin counterparts – and the symptom scores clearly favored the antibiotic cohort.  Furthermore, 5 of 241 of patients randomized to ibuprofen advanced to pyelonephritis, and one more patient suffered ulcer-related bleeding due to ibuprofen.

I’m not sure how many women would opt for the trial of ibuprofen as part of a shared decision-making conversation, were practice to be based on this specific trial.  That said, it does raise a bit of an interesting question regarding potential strategies to reduce antibiotic use.  Would a 24- or 48-hour “waiting period” help?  If routine urine cultures weren’t already grossly low-value care, could waiting for those results help triage appropriate use of antibiotics?  Could a different symptom adjunct, such as pyridium, help reduce the difference in symptom scores while awaiting spontaneous resolution?

Regardless, it is is yet again an insight into the general effectiveness of the human body’s natural antibacterial defense mechanisms.  How much of modern medicine is critically important – and how much is simply are mildly harmful minor ameliorations of mostly self-limited disease processes?

“Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial”
http://www.bmj.com/content/351/bmj.h6544

STONE Score Close, But Not Quite

The STONE score is a lovely idea for a common problem – ureteral stones are a frequent source of low-value imaging in the Emergency Department.  An adequately sensitive or specific decision-instrument would improve diagnostic accuracy while reducing imaging.  Unicorns would bloom from the frozen tundra.

STONE, however, has a couple issues.  Firstly, it was derived and validated at a single institution in similar cohorts.  Secondly, it has a few variables that probably lack face validity, i.e., three points for non-black ethnicity?

This report is from the large, multi-center trial comparing CT vs. ultrasound for the diagnosis of ureterolithiasis.  Of the 2,759 patients randomized from the original trial, 845 underwent CT as gold standard and had the data available for evaluation of the STONE score.  This constituted their retrospective validation cohort.

So, STONE is OK.  Not great, but OK.  The AUC of STONE was 0.78, which is a step up from 0.68 of physician gestalt.  However, it was only 87% specific at the high end in the validation to rule-in stone, and, then, 96% sensitive at the low end as stone rule-out.  Phrased otherwise, there were about 10 to 20% fewer cases of ureterolithiasis identified in the moderate and high cohorts in this validation, compared with the original.  There were also, unfortunately, a greater number of significant alternative diagnoses in the low and moderate cohorts, as well.

The authors come to very reasonable conclusions.  First, the STONE score isn’t perfect.  It can be a useful adjunct to risk-stratification and shared decision-making, but the positive and negative likelihood ratios are inadequate as a standalone rule.  As a corollary, the score definitely requires refinement or reinvention, based on their analysis of the predictive contribution of different variables in the original score.  It is probably still fair to use this score to supplement gestalt in the context of pursuing judicious use of resources, but it must be considered in the context of other predictive features to determine the appropriate imaging strategy.

“External Validation of the STONE Score, a Clinical Prediction Rule for Ureteral Stone: An Observational Multi-institutional Study”
http://www.ncbi.nlm.nih.gov/pubmed/26440490

And The Stoning Continues

A couple months ago, the world of ureterolithiasis was upended by The Lancet and its publication of a trial examining medical expulsive therapy.  In direct contrast to the prior (worthless) Cochrane Review, this large, reasonably-designed trial, does away with the notion of universal benefit of alpha- and calcium channel-blockers for MET.

Following on its heels comes the publication of another trial of moderate size, but with even more rigorous follow-up.  Rather than previously mentioned trial’s “urologic intervention” as the patient-oriented outcome, this trial used a disease-oriented outcome.  This trial, enrolling patients with distal ureteral stones, required patients to under go CT at 28 days to definitively assess for stone passage.

The trial randomized 403 patients to either tamsulosin 0.4mg daily for 28 days or identical placebo, but, unfortunately, 87 did not ultimately undergo second CT.  Of the patients that did undergo CT, there was no statistically significant difference in stone passage: 87.0% tamsulosin vs. 81.9% placebo, an absolute difference of 5.0% (95% CI -3.0 to 13.0).  Of the 87, 77 were available for follow-up regarding urologic intervention.  If a combined endpoint of CT passage and lack of urologic intervention is used, the results remain unchanged.

However, the trial was designed specifically to enroll adequate numbers of patients with stones of 5-10mm in size – targeting adequate sample size with which to include at least 49 patients to detect a difference in stone passage of 5 to 25%.  They ultimately randomized 103 large stones and completed imaging or clinical follow-up on 77.  The difference in stone passage rate in the large stones was 83.3% in the tamsulosin group, compared with 61.0% with placebo, for an absolute difference of 22.4% (95% CI 3.1 to 41.6).

So, what’s the takeaway – from decades of poor-quality studies, the recent Lancet publication, and now this?  There’s probably some signal in the noise – and that signal, all along, has probably been these large, distal stones.  Unless there’s a truly diminished risk of stone passage, there’s never been any reasonableness to the use of MET – but if passage rates are ~60%, the likelihood of a clinically meaningful benefit is finally possible.

If I’ve obtained a CT in a patient and diagnosed a large, distal stone – I am offering tamsulosin.  Otherwise, no.

Rory Spiegel also shares his typically excellent similar evaluation of the evidence: EM Nerd

“Distal Ureteric Stones and Tamsulosin: A Double-Blind, Placebo-Controlled, Randomized, Multicenter Trial”

Finally, an End to Tamulosin for Renal Colic?

Most urologic professional societies recommend “medical expulsive therapy” for ureterolithiasis, with an expectation of increased stone expulsion, improved time-to-passage, and reduced need for analgesia.

As I’ve covered before – breaking down a pro-tamulosin Cochrane Review – the evidence in support of this practice is junk.  David Newman, Anand Swaminathan, and Salim Rezaie agree.  The last time I posted, I posited there was probably some small benefit to a subgroup of patient with renal colic, but, alas, we would probably never have high-quality evidence.

I was wrong.

This study in The Lancet tested MET by randomizing patients with CT-confirmed ureterolithiasis to three arms – placebo, nifedipine, or tamulosin.  The randomization algorithm balanced the arms between stone size and stone location.  The primary outcome was need for urologic intervention at 4 weeks, with secondary outcomes of patient-reported time to stone passage and pain medication use.

With 1,167 patients randomized – 31 of which were excluded or lost to follow-up – there was no difference in need for urologic intervention between groups: 20% placebo, 19% tamulosin, 20% nifedipine.  Secondary outcomes – measured by follow-up questionnaire – were likewise similar, with no differences detected in the number of pain medication nor days until stone passage.

Now, urologic intervention is a rather imprecise surrogate outcome for evaluating the efficacy of MET for promoting stone passage.  And, only 62% of patients returned the surveys regarding the secondary outcomes of subjective stone passage and analgesic use.  This is high-quality evidence, but hardly infalliable.  The authors also state no subgroup showed benefit – which is not entirely true.  MET was slightly beneficial (86% vs. 82%) for patients with lower ureteral tract stones, with a p-value of 0.099.  Giving into the tyranny of p-values, yes, there’s no benefit – but using the p-value akin to a likelihood ratio, judged against the larger context of other (albeit, low-quality) trials showing benefit, I would not find it unreasonable to contest the totality of these authors’ conclusion.

Regardless, the empiric use of tamulosin has simply been an urban legend taken one step too far.  Short of large stones in the lower urinary tract, the benefit is fleeting at best – and the magnitude of the benefit may be too low to matter.

“Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60933-3/abstract (oa)