Podcast #32 - Is Prophylactic Hydration with IV Contrast in CT a "Busted" Pseudo-Axiom?

It may feel like we have been talking about a lot on imaging recently, but in emergency medicine, we do a lot of imaging!  More specifically, CTs are a cornerstone in the emergency department and contrast is frequently used.  However, there have been concerns about the use of contrast in higher risk populations which we have also discussed before.  In patients at higher risk, is prophylactic hydration beneficial?  We discuss that on today's podcast with a new randomized control trial.

 Title:
​Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial
 
Case:
A 52 y/o male with a history significant for chronic kidney disease and insulin dependent diabetes mellitus comes to your emergency department complaining of chest pain you suspect is from a new onset pulmonary embolism.  Per hospital protocol, you obtain routine labs including obtaining an estimated glomerular filtration rate (eGFR) prior to ordering a CT with IV contrast.  The eGFR is 48 mL/min/1.73m2 and you remember from previous studies that such as value is not considered to be an independent risk factor for post-contrast acute kidney injury (PC-AKI).  He does not appear to need fluid resuscitation and after ordering the CT, the CT tech calls to ask if you plan to give the patient IV fluid hydration prophylactically to protect renal function.
 
Background:
Recent literature has been dismantling many of the arguments related to the concerns of PC-AKI and even if contrast induced nephropathy (CIN) is a real concern in the modern age of CT imaging.  There are current practice guidelines that support the use of intravenous normal saline to prevent PC-AKI and CIN.  Given the lack of effective treatment for these conditions, prevention is the key.  However, debate has developed on if this is cost-effective or more importantly clinically effective.  Despite being widely recommended in guidelines, no randomized trial has prospectively compared peri-procedural intravenous hydration with normal saline with a group receiving no prophylactic hydration in the high-risk population targeted by the guidelines (including the ESUR, ACR, and NICE). IV fluid hydration is also not without risks.  It can lead to symptomatic heart failure due to volume overload, electrolyte abnormalities such as hyponatremia or hypernatremia, and even arrhythmias (all monitored in the study).  Another risk with this process is that this could lead to hospitalization of the patients to fulfill the IV fluid protocol, which exposes patients to risks such as hospital-acquired infections. 
 
Clinical Question:
Is not giving prophylactic hydration non-inferior to standard care prophylactic hydration in regards to the rate of CIN?
 
Reference:

• Population: Patients aged 18 years and older that were referred for an elective procedure requiring intravascular iodinated contrast material at Maastricht University Medical Centre with known eGFR lower than 60 mL/min/1.73m2 were screened.  They were eligible for inclusion if they had an eGFR between 45 and 59 combined with either diabetes or at least two predefined risk factors (age >75 years; anemia defined as hematocrit values of <0.39 L/L in men, and <0.36 L/L in women; NSAID or diuretic use).  A patient may also be eligible if they had an eGFR between 30 and 45, multiple myeloma, or lymphoplasmacytic lymphoma with small chain proteinuria. These criteria corresponded to the criteria for identifying high-risk patients according to guidelines in Europe and the Netherlands.  The authors calculated eGFR with serum creatinine concentrations and the Modification of Diet in Renal Disease (MDRD) study equation.        
  • Exclusion Criteria: Patients unable to provide informed consent, eGFR lower than 30, renal replacement therapy, emergency procedures, intensive care patients, known inability to plan primary endpoint data collection, no referral for prophylactic hydration, participation in another randomized trial, and isolation (infection control).
• Intervention: No hydration prophylaxis. 
• Comparison: Standard hydration prophylaxis.
• Outcome: Rate of CIN at 2-6 days after contrast exposure.

 
Author’s Conclusions:
No prophylaxis was found to be non-inferior and cost saving in preventing contrast-induced nephropathy (CIN) compared with intravenous hydration according to current clinical practice guidelines.
 
Quality Checklist for Randomized Clinical Trials:

1. The study population included or focused on those in the ED. Unsure, not specifically mentioned in the study
2. The patients were adequately randomized. Yes
3. The randomization process was concealed. No (essentially impossible by design of the study)
4. The patients were analyzed in the groups to which they were randomized. Yes
5. The study patients were recruited consecutively (i.e. no selection bias). Yes
6. The patients in both groups were similar with respect to prognostic factors. Yes
7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No (again impossible by design)
8. All groups were treated equally except for the intervention. Yes
9. Follow-up was complete (i.e. at least 80% for both groups). Yes for the primary endpoint (see below)
10. All patient-important outcomes were considered. Yes
11. The treatment effect was large enough and precise enough to be clinically significant. Yes, but there are some finer details (see below)

 
Key Results:
The mean 2-6 day change in serum creatinine was 0.31 μmol/L in the prophylactic hydration group (SD 13.79), and 1.30 μmol/L in the group without prophylactic hydration (SD 15.09; p=0.4049). An increase of more than 25% or 44 μmol/L increase in serum creatinine from baseline (which was the definition for CIN) was recorded for eight (2.7%) of the 296 patients in the prophylactic hydration group and for eight (2.6%) of 307 patients in the group without prophylactic hydration. The absolute difference in proportions with contrast-induced nephropathy (no hydration vs hydration) was -0.10% (one-sided 95% confidence interval of -2.26 to 2.06 and a one-tailed p=0.4710). The upper limit was below 2.1%, which excludes a difference in favor for the hydration group of more than 2.1%.
 
Key Points of Debate:

• Not all PC-AKI is CIN
  • This is an important first point, as the wording may be confusing when you read PC-AKI and CIN.
  • We have discussed this in detail before, but to summarize, the rates of CIN listed here are not necessarily accurate and are reflecting PC-AKI.
  • This is an important technical difference by definition but not necessarily for what the study was trying to demonstrate which was a decrease in acute kidney injury (AKI). 
  • Also, keep in mind that their definition is slightly different in regards to their lab values compared to the commonly accepted numbers.  They used an increase in serum creatinine by more than 25% or 44 μmol/L in 2-6 days versus the more widely accepted 48-72 hours.
  • Keep in mind this is for more reasonable outpatient follow-up and that although serum creatinine rises within 48 hours it peaks in 4-5 days post-contrast on average.
• While this study did not focus on patients in the ED, it is still very important for us to know this study
  • Think about how this effects department flow.  Patients may have to wait to have their fluid hydration both before and after they receive their CT scan with contrast leading to more congestion in the department.
  • Keep in mind we fluid resuscitate many patients but that is not the same as the extensive protocols that can require 3-4 mL/kg/hr of normal saline for 4 hours before and after or in the “long protocol” can be 1 mL/kg/hr for 12 hours both before and after the CT with contrast is performed.
• Although the process could not conceal randomization, it does not necessarily make this a flawed study
  • Researchers masked whatever areas they could and randomly assigned patients by stratifying them by diabetes (yes or no), eGFR (over or under 45), contrast route (IV or intra-arterial), and procedure type (diagnostic or interventional).
  • Treating physicians were not masked but were not specifically informed on the treatment allocation.
  • It would be essentially impossible to blind patients or nursing staff due to the obvious differences in treatment.
  • Oddly, research staff does not appear to be blind in this study.  It is not fully determined if this is only for the staff who were at the bedside or if this extends to those recording and analyzing the data (potentially could be masked in the process).
• There was great follow-up at 2-6 days, but it was under the desired 80% at the 26-35 day timeframe
  • This has some potential limitations to the study, especially if talking about longer-term adverse events.
  • Of the 328 patients allocated to the prophylactic hydration group there were 32 lost to follow-up (296/328=90.2%) at 2-6 days and 68 (260/328=79.3%) at 26-35 days post-contrast exposure.
  • The 332 patients allocated to the no prophylaxis group had 25 lost to excluded (307/332=92.5%) at 2-6 days and 72 (260/332=78.3%) at 26-35 days post-contrast exposure.
  • Having less than 80% follow-up at 26-35 days post-contrast exposure is less than ideal for longer-term studies and measurements.
• The initial numbers that were the goal for the study could not be achieved which led to a change during the trial
  • This does have some concerns regarding power for the study.
  • The authors report their sample size was based on what their literature search reported to be the expected proportion of patients with CIN after prophylactic hydration (which was a rate of 2.4%).
  • Their plan was to include 1300 patients in a two-year period to detect an absolute difference of more than 2.1% as their non-inferiority margin with 80% power and a one-sided alpha of 5%.
  • However, they revised their calculation due to feasibility of the study in consultation with their research ethics committee and considered 600 patients more feasible.  Assuming 10% of patients would not have a baseline serum creatinine it was decided to recruit 660 patients for randomization (their actual number obtained).
  • It is worth noting this decision was made in December 2015 (trial started June 17, 2014 and concluded July 17, 2016).
• This study is a reminder as to the risks of fluid hydration when it is not necessary
  • In this study, there were 18 clinically significant adverse events for the prophylaxis group and none in the group without prophylactic hydration.
  • The largest group was 13 patients (4.0%) who experienced complications leading to hydration being stopped prematurely, forced diuresis, or extended hospitalization.
  • One patient (0.3%) in the prophylaxis group developed hyponatremia (none had experienced hypernatremia).
  • Four (1.2%) more patients had developed an arrhythmia during hydration treatment.

 
Comparing Conclusions:
This study has many implications and may further shed light on how we could be managing patients with the more modern contrast media we have today.  While many patients in the emergency department may still need IV fluid hydration for other reasons, such as the severity of their illness and needing fluid resuscitation, this study still is important because of how it can improve department flow and avoid admissions that may not otherwise be necessary.
 
Our Bottom Line:
We agree that this study demonstrates that no hydration prophylaxis is non-inferior to hydration prophylaxis in regards to the rate of CIN (or more accurately PC-AKI).
 
Case Resolution:
You discuss with the CT tech that you do not believe the patient requires prophylactic IV fluid hydration.  You briefly mention this new paper and the CT tech suggests that this could also be discussed in the future with the staff radiologist since there is no such protocol currently regarding this evidence.  Your patient receives his CT without incident and is found to have a sub-segmental PE.  After addressing the patient’s concerns and the PE, he is discharged.  On follow-up, his PCP reports no PC-AKI or CIN.
 
Clinical Application:
The landscape is constantly evolving in the world of radiology especially in regards to PC-AKI and CIN.  It is difficult to say if this myth (or more appropriately a pseudo-axiom) is truly "busted" but it does bring about some important points.  In hospitals where there is currently a protocol for IV fluid hydration, this may be one of the pieces or evidence to bring forward regarding how this protocol could potentially change. For those centers without a protocol, this could further establish practice for the future.  Ultimately, this will need to be a team-based decision across multiple specialties (such as nephrology and radiology when applicable) to further investigate and agree upon this plan.
 
What do I tell my patient?
Due to some of your risk factors such as chronic kidney disease and diabetes, you are traditionally considered to be at a higher risk of complications with regards to contrast being given while receiving a CT.  However, recent studies have demonstrated otherwise.  One such study is that you may not need to receive IV fluids both before and after you receive your CT.  IV fluids are not without risk and can lead to serious complications that could lead to an admission.  Based on the most recent evidence, we can consider withholding this prophylaxis as it does not appear to compromise your safety.
 
Conclusion:
Thank you for listening to the podcast and reading the blog.  Please let us know what you think by giving us feedback here in the comments section or contacting us on Twitter or Facebook.  Remember to look us up on Libsyn and on iTunes.  If you have any questions you can also comment below, email at thetotalem@gmail.com, or send a message from the page.  We hope to talk to everyone again soon.  ​Until then, continue to provide total care everywhere.

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