BEEM Cases 2 – Renal Colic Imaging, Analgesia, Fluids & Medical Expulsive Therapy

BEEM Cases 2 on EM Cases – Renal Colic optimal imaging modality, the best analgesic strategy, the role of fluids and the value of medical expulsive therapy. BEEM Cases is a collaboration between Andrew Worster of Best Evidence in Emergency Medicine (BEEM) and Emergency Medicine Cases’ Anton Helman, Rory Spiegel and Justin Morgenstern.

Written by Rory Spiegel (@EMNerd_), edited by Anton Helman (@EMCases), May 2016

Clinical Decision Making in Renal Colic

The Case…

A 43 year old previously healthy man on medications presents to your ED with a 2 hour episode of abrupt onset severe left sided flank pain that radiates to the groin, associated with nausea. He tells you that this episode feels identical to a single previous episode he suffered when he was diagnosed with kidney stones one year prior. He reports no urinary, GI or respiratory symptoms. On exam he appears to be in pain, pacing back and forth holding his left flank. His vitals are unremarkable.

Urolithiasis is one of the more frequent diagnoses we are faced with in the Emergency Department. As such we are tasked with its diagnosis, prognosis and treatment. The following is a brief summation of the evidence regarding some of the most frequent questions encountered when diagnosing and managing urolithiasis.

Question #1

What is the optimal initial imaging modality for the diagnostic work-up of urolithiasis?

Jump to Question 1 Discussion

Question #2

Once the diagnosis of renal colic has been made, what is the most efficacious analgesic strategy?

Jump to Question 2 Discussion

Question #3

Is there clinical utility to IV fluid administration in the management of renal colic?

Jump to Question 3 Discussion

Question #4

What is the value of medical expulsion therapy in the management of urolithiasis?

Jump to Question 4 Discussion

Question #1 Discussion: The Optimal Imaging Modality for Renal Colic

What is the optimal initial imaging modality for the diagnostic work-up of urolithiasis?

The Papers

Smith-Bindman R, Aubin C, Bailitz J, et al. Ultrasonography versus computed tomography for suspected nephrolithiasis. N Engl J Med. 2014;371:1100-1110.

Daniels B, Gross CP, Molinaro A, et al. STONE PLUS: Evaluation of Emergency Department Patients With Suspected Renal Colic, Using a Clinical Prediction Tool Combined With Point-of-Care Limited Ultrasonography. Ann Emerg Med. 2016;67(4):439-48.

Background for Optimal Imaging in Renal Colic

The utilization of non-contrast CT has increased exponentially in the past decade without any evidence of a concomitant improvement in clinical outcomes (1). To state that every patient in whom the suspicion for urolithiasis is present requires a CT is certainly unwarranted. But it is equally unwarranted to say this form of diagnostic imaging is never necessary. And so the question becomes, which patients truly require a CT? To answer these questions, we have to examine a number of issues. First, is it important to anatomically diagnose the size and location of the stone in question? Second, when do we require further imaging to rule out alternative dangerous diagnoses that commonly masquerade as renal colic? Finally, how can we use ultrasound to risk stratify patients with an indeterminate physical exam?

It is well known that the majority of patients with nephrolithiasis have an uncomplicated course. Even larger stones will often pass without interference (2), when given the appropriate time to do so. Therefore in the majority of patients presenting to the Emergency Department with signs and symptoms of acute renal colic, anatomically defining the specifics of their disease is for the most part unnecessary. For a large majority of these patients, the CT scan becomes a means of ruling out an alternative serious cause of the patient’s current symptoms. When examined in a large cohort of Emergency Department patients, Wang et al found that when the Emergency Physician was certain of the diagnosis of renal colic, the rate of missed important alternative diagnoses was 2.8%. This miss rate could be further decreased to 1.2% if the STONE score was utilized to risk stratify patients into high, medium and low risk for urolithiasis (3).

CT vs Radiology Ultrasound vs Point of Care Ultrasound for Renal Colic

Smith-Bindman et al published a large RCT of 2759 patients, who were randomized to receive either a CT scan, radiology-based ultrasound, or point-of-care ultrasound performed by the Emergency Department clinician as their initial diagnostic strategy. These authors found no difference in the rate of missed important alternative diagnoses between the groups (4). On first glance this appears to suggest that the diagnostic accuracy of ultrasound is comparable to CT. In reality, this equivalence was based on the negative predictive value of the respective diagnostic strategies. Specifically, this statistical equivalence was due to the extremely low rate of important alternative diagnoses rather than the diagnostic accuracy of ultrasound.

What this likely means is that in well appearing patients with signs and symptoms consistent with renal colic, the likelihood of an important alternative diagnosis is low. In these cases, either a CT scan or ultrasound performs equally well. In fact, in a patient population such as this, where neither accuracy nor timeliness of diagnosis confers a substantial downstream benefit, the more important question becomes, do these patients require any diagnostic imaging at all?

In the case of patients who appear unwell, or in whom the treating physician has a high clinical suspicion for an alternative diagnoses, the rate of important alternative diagnoses is high (7.6%)(3). In these patients the increased diagnostic accuracy provided by CT becomes important.

Imaging for patients who appear well but have an indeterminate risk history and physical exam

What about the patients who appear well but have an indeterminate history and physical exam? Can the finding of hydronephrosis on ultrasound help shift the diagnostic certainty into a category where no further imaging is required? Daniels et al examined this question in an a article published in The Annals of Emergency Medicine in April 2016 (5). The authors examined a cohort of 853 prospectively enrolled Emergency Department patients and examined how the use of bedside ultrasound could augment the diagnostic utility of the previously derived and validated STONE score. They found that in patients with a high risk STONE score, there was no added diagnostic benefit to the use of ultrasound; and while in the low and moderate risk groups, the finding of hydronephrosis helped identify additional patients with renal colic. In this cohort, of the 54 patients with an important alternative diagnoses, 12 patients had hydronephrosis on bedside ultrasound. Ten of these patients were in the low and moderate risk groups(5).

STONE score calculation on MDcalc

The Bottom Line for Imaging Renal Colic

In the end what we can conclude is that in the well appearing patient, with stable vitals, and a clear clinical picture, further diagnostic imaging is not often useful. In the patient who is clinically unwell, or there is high clinical suspicion for an important alternative diagnosis, the diagnostic accuracy provided by CT imaging is clinically warranted. In the intermediate patient, with a significant degree of diagnostic uncertainty, there is still a significant equipoise on the proper imaging strategy. The use of bedside ultrasound to further risk stratify these patients is currently not supported by the available evidence.

For EM Cases Journal Jam on ultrasound vs CT imaging for renal colic where we interview Dr. Smith-Bindman go here.

Case continued…

You decide to order a radiology-based ultrasound and some IM diclofenax. This man appears to be in agony…

Question #2 Discussion: Analgesia for Renal Colic

Once the diagnosis of renal colic has been made, what is the most efficacious analgesic strategy?

The Papers

Pathan, SA, Mitra, B, Straney, LD et al. Delivering safe and effective analgesia for management of renal colic in the emergency department: a double-blind, multigroup, randomised controlled trial. Lancet. 2016.

Holdgate A, Pollock T. Nonsteroidal anti-infl ammatory drugs (NSAIDs) versus opioids for acute renal colic. Cochrane Database Syst Rev 2005; 2: CD004137.

NSAIDs vs Acetominophen vs Morphine for Renal Colic

A recent randomized double blind placebo controlled trial published in the Lancet in March 2016 examined this question. Pathan et al randomized 1644 patients presenting to the Emergency Department with renal colic to receive either IM diclofenax, IV acetaminophen, or IV morphine, each with their respective placebos (6).

Patients randomized to both IM diclofenax and IV acetaminophen achieved moderately more pain relief than patients randomized to receive IV morphine. 61% of the patients randomized to receive IV morphine achieved the authors’ primary outcome, a reduction in pain by greater than 50% at 30 minutes. By comparison, 68% and 66% of the respective patients randomized to IM diclofenax and IV acetaminophen experienced the same reduction in pain. This difference became only more apparent when the per-protocol analysis (the patients with radiographically confirmed renal colic) was examined. In this subset, 50% reduction was achieved in 69%, 68% and 60% in the diclofenax, acetaminophen, and morphine groups respectively. Likewise, more patients randomized to either the IM diclofenax or IV acetaminophen groups had a 3-point or greater drop in their pain scores by 30-minutes. In addition, patients in the IV morphine group more frequently required rescue doses of IV morphine.

These finding are consistent with the previously published Cochrane analysis regarding NSAIDs vs opiates for the treatment of renal colic (7). And while these results are consistent, so are the methodologic flaws influencing these results in the majority of the studies included. Patients in the Pathan trial randomized to receive IV morphine, were given a 0.1 mg/kg bolus. And while this dose is commonly used in clinical trials, it does not consistently provide clinically adequate analgesia. A large portion of patients administered 0.1 mg/kg will require additional doses of IV morphine to reach blood levels required to achieve analgesia. In fact, in most cohorts examining the adequate dose of IV morphine, when administered a dose of 0.1 mg/kg, more than 50% of patients will require further dosing to attain analgesic effects. Bijur et al found when using a dose of 0.1 mg/kg of IV morphine in a cohort of patients presenting to the Emergency Department in severe pain, only 35% would have a reduction in their pain scores by 50% by 30 minutes (8). Birbaum et al found that only 44% of patients receiving a dose of 0.1m/kg achieved a 50% reduction in pain at 30 minutes (9).  As such, the 39% of patients requiring additional pain medication observed in the Pathan et al cohort is far from unexpected.

In most cohorts examining the adequate dose of IV morphine, when administered a dose of 0.1 mg/kg, more than 50% of patients will require further dosing to attain analgesic effects.

IV Opiate Dosing Requires Rapid Escalation of Appropriate Doses to Relieve the Pain of Renal Colic

Despite the 0.1 mg/kg dose being commonly utilized, it is an unfair and unrealistic comparison. It is what amounts to a straw man comparator. Allowing for the appearance of sport without truly posing a challenge. To truly obtain fast and adequate analgesia from IV morphine, the dose should be rapidly titrated to effect. In a trial performed by Aubrun et al on post-surgical patients, a protocol of 2-3mg of IV morphine every 5-minutes achieved analgesia in 100% of patients, but the number of doses varied wildly from patient to patient (10). Multiple Emergency Department cohorts have demonstrated that appropriate analgesia is safely and quickly achieved in close to 100% of patients when rapid escalation of opiate pain medication is utilized (11,12). And so what is noted as need for rescue medications in clinical trials, is in reality the appropriate method of achieving adequate analgesia when using IV opiates.

Bottom Line for Analgesics in Renal Colic

While IM diclofenax and IV acetaminophen may provide superior relief to inadequate doses of IV morphine, this does not translate to appropriate or adequate pain relief for the patient. Although 68% and 66% percent of patients in the diclofenax and acetaminophen groups experienced a 50% reduction in pain at 30 minutes, 32% and 34% did not. 12% and 20% required rescue analgesia. These reductions in pain were achieved at 30-minutes following medication administration. With the appropriately titrated dose of morphine, adequate pain relief can be achieved far earlier. And while this data certainly demonstrates that NSAIDs are reasonable options over the course of a patient’s Emergency Department stay, it should not dissuade us from the early and appropriate use of IV opiate analgesics when clinically necessary.

Case Continued…

You have managed to get this patient’s pain under control with rapid escalation of repeated doses of IV morphine in addition to diclofenax and the nurse asks you whether she should administer a bolus of normal saline. The patient has not been vomiting and does not show any signs of volume depletion.

Question #3 Discussion: IV Fluids for Renal Colic

Is there clinical utility to IV fluid administration in the management of renal colic?

The Paper

Worster AS, Bhanich supapol W. Fluids and diuretics for acute ureteric colic. Cochrane Database Syst Rev. 2012;2:CD004926.

Though the evidence is limited, in a 2012 Cochrane analysis Worster et al identified two studies with a total of 118 patients, and concluded that the use of fluid boluses in renal colic added no clinical benefits in the form of time to stone passage, decreased need for surgical intervention or hourly pain score (13). Although the data is underpowered to definitively exclude a benefit, it is safe to say that patients should be given fluid as per the judgment of the treating physician, and in line with their current fluid status.

Case Continued…

The ultrasound report comes back showing a 4mm stone in the distal ureter. The patient is pain free and you decide to discharge him home. You’ve heard various opinions about medical expulsive therapy such as tamsulosin and nifedipine for outpatient management of urolithiasis.

Question #4 Discussion: Medical Expulsive Therapy for Renal Colic

What is the value of medical expulsive therapy in the management of urolithiasis?

The Papers

Pickard R, Starr K, Maclennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015.

Furyk, Jeremy S. et al. Distal Ureteric Stones and Tamsulosin: A Double-Blind, Placebo-Controlled, Randomized, Multicenter Trial. Annals of Emergency Medicine. Published online: July 17 2015.

Background on Medical Expulsive Therapy for Renal Colic

In 2014 a Cochrane analysis was published citing the benefits of alpha blockers in the management renal colic (14). However, the interpretation of this analysis was limited by the fact that it was made up of small studies with a significantly heterogeneous population. Since then, two high quality randomized control trials performed on Emergency Department patients have been published contradicting its findings.

Tamsulosin vs Nifedipine vs Placebo for CT confirmed uterolithiasis

The first of these trials published in May 2015 by Pickard et al in The Lancet examined both alpha blocker (tamsulosin 0.4 mg) and calcium channel blocker (nifedipine 30 mg) therapy in patients with CT confirmed ureterolithiasis (15). The authors randomized 1137 patients with stones 10 mm or less to receive either 0.4 mg of tamsulosin, 30 mg of nifedipine or placebo. Patients were excluded if they presented with obvious signs of sepsis, had significant renal failure (GFR<30) or required immediate invasive therapy as prescribed by the treating physician.

The authors found there to be no significant difference in their primary outcome, the rate of spontaneous passage at 4 weeks, between those randomized to the tamsolusin, nifedipine or placebo arms. Spontaneous stone passage, defined by the absence of need for intervention to assist stone passage during the 4 week follow up, was 307 (81%), 304 (80%), and 303 (80%) respectively. Additionally there was no significant differences noted in the need for pain medication, the number of days pain medication was required, or the visual analog scale (VAS) of patients pain at 4 weeks (15). By all accounts this was an impressively negative trial.

Tamsulosin vs Placebo for Distal Ureteric Stones

A second study was recently published online in July 2015 in Annals of Emergency Medicine. Like the Pickard et al trial, Furyk et al examined the effects of medical expulsive therapy in patients with CT confirmed ureterolithiasis (16). The authors randomized patients with stones 10 mm or less located in the distal ureter to either medical expulsive therapy with 0.4 mg of tamsulosin or placebo. Patients were excluded if they demonstrated signs of infection or presented with a compromised GFR. Like the previous study, the authors found no statistical difference in the number of patients who experienced stone passage at 28 days (87.0% and 81.9% in the tamsulosin and placebo groups respectively (16). We now have two high quality RCTs demonstrating that the use of medical expulsive therapy is not beneficial in the management of acute ureteral colic.

Despite these findings, these trials failed to address the pressing question regarding medical expulsive therapy. The majority of patients in both these trials had stones less than 5 mm in diameter. Most small stones will pass without difficulty (17,18). As these trials demonstrate it is impossibly hard to show a statistically significant difference in an undifferentiated cohort of renal colic patients. The real question is, does medical expulsive therapy work in patients with stones greater than 5 mm in diameter? Can these trials definitively demonstrate a lack of utility of medical expulsive therapy in these patients?

In the subset of patients with stones greater than 5 mm in width, Pickard et al observed an absolute difference of 10% in the rate of stone passage at 4 weeks in favour of those randomized to receive tamsulosin(15). This difference did not reach statistical significance, but clearly this trial was not designed to answer the question of whether medical expulsive therapy is beneficial in patients with large diameter ureteral stones.

The results of the Furyk trial are even more compelling. Though the primary endpoint was the overall proportion of patients with stone passage at 28 days, the authors powered their study for an entirely different question. The study was powered to detect a difference in the rate of stone passage in patients with larger stone diameters (5-10 mm). The authors calculated that they would require 98 patients with stones greater than 5 mm to detect a 20% difference in stone passage with an 80% power (16). While their primary outcome was negative, in the subgroup of patients this study was powered to examine, the authors found a 22.4% absolute difference in the rate of stone passage at 28 days.

Update 2018:  A double-blind, placebo randomized controlled trial of 512 patients demonstrated tamsulosin (0.4mg) did not significantly increase the stone passage rate compared to placebo in stones smaller than 9mm, at 28 days post ED visit. Abstract

Bottom Line for Medical Expulsive Therapy in Renal Colic

Although these trials demonstrate that for the majority of patients presenting to the Emergency Department with renal colic, medical expulsive therapy provides little additional benefit above symptomatic treatment, there is certainly a convincing trend towards improved outcomes in the subset of patients with large stones (>5mm).

Case resolution…

Your patient passed his stone spontaneously 10 days after discharge from the ED and followed up with their primary care physician.

Dr. Spiegel and Dr. Helman have no conflicts of interest to declare.

References

1. Westphalen AC,Hsia RY, Maselli JH, Wang R, Gonzales R. Radiological imaging of patients with suspected urinary tract stones: national trends, diagnoses, and predictors.Acad Emerg Med 2011;18:699-707
2. Miller OF, Kane CJ. Time to stone passage for observed ureteral calculi: a guide for patient education. J Urol. 1999;162(3 pt 1):688-690; discussion 690-691.
3. Wang RC, Rodriguez RM, Moghadassi M, et al. External Validation of the STONE Score, a Clinical Prediction Rule for Ureteral Stone: An Observational Multi-institutional Study. Ann Emerg Med. 2016;67(4):423-432.e2.
4. Smith-Bindman R, Aubin C, Bailitz J, et al. Ultrasonography versus computed tomography for suspected nephrolithiasis. N Engl J Med. 2014;371:1100-1110.
5. Daniels B, Gross CP, Molinaro A, et al. STONE PLUS: Evaluation of Emergency Department Patients With Suspected Renal Colic, Using a Clinical Prediction Tool Combined With Point-of-Care Limited Ultrasonography. Ann Emerg Med. 2016;67(4):439-48.
6. Pathan, SA, Mitra, B, Straney, LD et al.Delivering safe and effective analgesia for management of renal colic in the emergency department: a double-blind, multigroup, randomised controlled trial.Lancet. 2016
7. Holdgate A, Pollock T. Nonsteroidal anti-infl ammatory drugs (NSAIDs) versus opioids for acute renal colic. Cochrane Database Syst Rev 2005; 2: CD004137.
8. Bijur PE, Kenny MK, Gallagher EJ. Intravenous morphine at 0.1 mg/kg is not effective for controlling severe acute pain in the majority of patients. Ann Emerg Med. 2005;46(4):362-7.
9. Birnbaum A, Esses D, Bijur PE, Holden L, Gallagher EJ. Randomized double-blind placebo-controlled trial of two intravenous morphine dosages (0.10 mg/kg and 0.15 mg/kg) in emergency department patients with moderate to severe acute pain. Ann Emerg Med. 2007;49(4):445-53, 453.e1-2.
10. Coghill RC, Eisenach J. Individual differences in pain sensitivity: implications for treatment decisions. Anesthesiology. 2003;98(6):1312-4.
11. Chang AK, Bijur PE, Campbell CM, et al. Safety and efficacy of rapid titration using 1mg doses of intravenous hydromorphone in emergency department patients with acute severe pain: the “1þ1” protocol. Ann Emerg Med. 2009;54:221-225.
12. Chang AK, Bijur PE, Holden L, Gallagher EJ. Efficacy of an Acute Pain Titration Protocol Driven by Patient Response to a Simple Query: Do You Want More Pain Medication?. Ann Emerg Med. 2015.
13. Worster AS, Bhanich supapol W. Fluids and diuretics for acute ureteric colic. Cochrane Database Syst Rev. 2012;2:CD004926.
14. Campschroer T, Zhu Y, Duijvesz D, Grobbee DE, Lock MT. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014;4:CD008509.
15. Pickard R, Starr K, Maclennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015.
16. Furyk, Jeremy S. et al. Distal Ureteric Stones and Tamsulosin: A Double-Blind, Placebo-Controlled, Randomized, Multicenter Trial. Annals of Emergency Medicine. Published online: July 17 2015.
17. Coll, D.M., Varanelli, M.J., and Smith, R.C. Relationship of spontaneous passage of ureteral calculi to stone size and location as revealed by unenhanced helical CT. AJR Am J Roentgenol. 2002; 178: 101–103.
18. Miller, O.F., Kane, C.J. Time to stone passage for observed ureteral calculi: a guide for patient education. J Urol. 1999;162:688–690 (discussion 690-691).

Other FOAMed Resources on Renal Colic Imaging, Analgesia, Fluids and Medical Expulsive Therpay

Journal Jam 3 – Ultrasound vs CT for Renal Colic

Ryan Radecki’s take on Tamsulosin for urolithiasis

Peter Rosen on EM Decision Making in Renal Colic on EMDocs

Ultrasound vs CT for Renal Colic on CoreEM