A paper regarding to acute pancreatitis was published in the New England Journal of Medicine on 15 September of 2022. It is titled “aggressive or moderate fluid resuscitation and acute pancreatitis”. Hat tips to the authors. I would tell you to read this article for yourself but, unfortunately, it is hidden behind the pay wall and all the limitations that come with that. I’m glad that this article was published and the findings were reflective of the way that I was transitioning my practice. You see, the historical thinking of acute pancreatitis is to bombard the patient with IV fluids as they are “dry”. As an aside, to learn about fluid responsiveness, CLICK HERE.

Why is it important to define fluids in acute pancreatitis?

When you read the article, they state that moderately Severe or severe disease develops in “approximately 35% of patients with acute pancreatitis”. The data has been all over the place and the studies have been small and conflicting. Clinical gestalt has stated to just go ahead and give the fluids and worry about the consequences later. We have learned more about the consequences and challenges of patients with food overload over the past several years which is why these authors decided to tackle the experiment of assessing how much fluid resuscitation would be beneficial to patients.

I’m going to dig a little bit deeper into the study than I normally do for others simply because I find it to be quite important and also you cannot get your hands on it unless you have access to New England Journal of Medicine. That’s nice keep my recommendation that you should really try to read the article for yourself as this is the medical advice and you should not trust me.

This trial took place in four different countries. India, Italy, Mexico, and Spain. It is a multi center, open label, parallel group, randomized, controlled, superiority trial.

How did they diagnose acute pancreatitis?

The way that they diagnose the acute pancreatitis included typical abdominal pain, serum lipase or amylase level higher than three times the upper limit of normal, or acute pancreatitis on imaging. It’s important for me to Mention how Acute pancreatitis is defined because sometimes it is diagnosed with a lipase or amylase level that is slightly above reference range.

Breaking down the two groups

There was a one-to-one ratio between the patients who were in the aggressive fluid resuscitation group and the moderate fluid resuscitation group. One of the limitations of the study is that both “patients and investigators were aware of the assigned trial groups”. This is a limitation because it introduces bias.

To defined the two groups more specifically, let’s start with the aggressive resuscitation group. These patients received lactated ringers at 20 cc per kilogram of body weight over two hours. Then patient received an infusion of 3 cc per kilogram per hour of lactated ringers. To put this into perspective, a patient who is 70 kg would receive 1.4 L of fluid over the First two hours. Then, they would receive a drip lactated ringers at 210 cc per hour. Again, this is just a patient who is 70 kg. If a patient weighs, say, 200 pounds then we would be looking at higher numbers. Let’s use 90 kilograms for the sake of simplicity. that would mean that they received an infusion of 270 cc per hour. That seems like quite a lot to me for any type of aggressive resuscitation. To be frank, even the most aggressive fluid resuscitator’s. I’ve seen in my day would consider this to be quite extreme. thankfully, and both groups they had a safety check point where they would decrease or stop infusion if there was a concern for fluid overload. amongst the other goodies presented in the fluid resuscitation protocol, they state that checkpoints were performed at three, 12, 24, 48, and 72 hours. If the patient was either hypotensive, or had decreased urine output, the patient would receive additional boluses of 20 cc per kilogram.

The moderate fluid resuscitation group was far more “moderate”. Upon presentation, they would receive an infusion of 1.5 cc per kilogram per hour. They would only get a bolus of 10 cc per kilogram if the patient was deemed to have hypovolemia. doing the same mass as the aggressive fluid resuscitation group that means that a 70 kg patient would receive an infusion of 105 cc per hour of LR compared to the same 210 cc per hour in a 70 kg patient that one would find in the aggressive resuscitation group. Similar to the aggressive resuscitation group, the moderate fluid resuscitation group received additional boluses. If the patient had decreased urine output, or was hypotensive defined as a systolic blood pressure of less than 90. Same check points for safety applied here as well.

Starting Enteral Nutrition in Patients with Acute Pancreatitis

One of the more recent evolutions of our management of acute pancreatitis, includes starting oral feeding earlier in the course of the illness. Here, they started oral feeding at 12 hours if the patient reported pain of less than five on a 0 to 10 scale. Fluids were stopped if the patient was able to tolerate PO for eight hours. From what I’m seeing, this could be at 48 hours for the aggressive resuscitation group versus as early as 20 hours after randomization for the moderate resuscitation group.

The Primary Outcome

And as their primary outcome, they were trying to see if there was a difference in the development of moderately, severe or severe acute pancreatitis, while the patient was hospitalized. It’s important to define what moderately severe or severe acute pancreatitis actually means. It would need to include at least one of the criteria from the revised Atlanta classification. These include “local complications, exacerbation of pre-existing co-existing condition, a creatinine of at least 1.9, hypotension with a systolic of less than 90 despite fluid resuscitation, and a PF ratio of less than 300. They had a number of secondary outcomes, which I will get into later.

They were able to recruit 122 patients into the aggressive fluid resuscitation group and 127 into the moderate food resuscitation room. When looking at the baseline characteristics, it’s always important to think about what your preconceived notion‘s are with regards to the patient population being studied. What caught my eye here was that Approximately 50% of the patients recruited were female. I must say that in my practice the vast majority of cases of acute pancreatitis, take place in males. In addition, the majority of the causes of pancreatitis or secondary to gallstones. You and I have probably seen more commonly cases of pancreatitis secondary to alcoholism or hypertriglyceridemia more so than gallstone pancreatitis. I ran a search in the article to see if there is a reason why gallstone pancreatitis was more common than alcohol related pancreatitis in this patient population, but I was unable to find an answer. there wasn’t much else in the baseline characteristics of the patients that caught my eye.

The Results: Fluids in Pancreatitis

Now, let’s get into the results. When we look at cumulative fluids during the first 48 hours, the authors reported that the aggressive resuscitation group received a meeting at 7.8 L. The moderate resuscitation group received 5.5 L of fluid. Right here, there’s a difference of over 2 L already. Given that we usually get fluids earlier in the course of resuscitation, the authors noted that “the greatest between group difference in volume administration occurred during the first 12 hours”.

When it comes to the primary, I’ll come which was defined as moderately, severe or severe pancreatitis. It was found at 22.1% of the patients in the aggressive fluid resuscitation group met this endpoint versus 17.3% in the moderate fluid resuscitation group. to the untrained eye, 22.1% seems like for more than 17.3%, but it turns out that this was not statistically significant with a confidence interval that crossed the number one. This was both on the relative risk scale as well as the adjusted relative risk scale.

I always tell people to not read the conclusions as the first take away to any journal article. Here is a great example why you shouldn’t do that. If you were to just read the conclusions, you would know that they do not mention the primary outcome. Instead, they mention , the incidence of fluid overload. Fluid overload, again, is not a primary outcome. It is a safety outcome and very important, though. After all, we do not want to drown our patients.

In fact, if you look at all the primary and secondary outcomes, listed on table 2, which include severe pancreatitis, local complications, incidence of invasive treatment, ICU admission, shock, respiratory failure, etc. you would see that there’s pretty much no difference in any of these primary and secondary outcomes. Also noticed the very wide confidence intervals.

Safety Outcomes: Finding Harm in too much fluids in pancreatitis

Let’s return to analyzing the safety outcomes. This is where the meat and potatoes live in this paper. Here, the incidence of fluid overload and the aggressive fluid resuscitation group was 20.5% versus 6.3% in the moderate fluid resuscitation group. I often recommend that these numbers be plugged into a number needed to treat calculator. Once we do that, we would find that the number needed to treat to cause fluid overload is just seven. Interpret that number as you may. But I also do have to say, that the confidence, interval, for this finding is much wider than I would like. In addition, there were more findings of fluid overload, including prefer, edema and pulmonary rales in the aggressive fluid resuscitation group. This should not come as a surprise. Things that were not statistically significant, but potentially due to the fact that these were under powered, include the incidence of moderate to severe fluid overload, and dyspnea due to fluid overload.

Given that the authors noted that they were causing harm to the patients, the trial was terminated early. I’m glad that they did. Perhaps should they had completed the targeted enrollment, they would have found differences in the primary outcome, as well as more of the secondary outcomes with a tighter confidence interval.

The discussion starts off by saying “this trial showed that aggressive fluid resuscitation increased the risk of volume overload”. I’m really glad that the authors took on the endeavor of proving this. The rationale of recommending aggressive resuscitation in acute pancreatitis, which is in the current management guidelines, is now debunked. We do not need to bombard our patients with fluids, utilizing a protocol similar to the one used in the moderate resuscitation group seems appropriate for our management of acute pancreatitis. Now, every patient is different, so therefore, this is not medical advice. We should always use our best clinical judgment when caring for this and any patient.

Let me know your thoughts, and as always try your best to read the article for yourself. Also, let me know if you would like for me to continue doing deep dives into article such as this one. Hope this helps us all manage the fluids in acute pancreatitis. If your patient is going through alcohol withdrawal as well, here’s a study on using phenobarbital rather than benzodiazepines.

Reel Script for Fluids in Pancreatitis

How much fluids should we give patients with acute pancreatitis?
The guidelines could not make a recommendation regarding the initial rate, volume, and duration of fluid resuscitation because of a lack of data.
Thankfully, a new RCT was published in the New England Journal of medicine trying to answer this question.
Hat tip to the authors.
This is not medical advice. Read the article for yourself.
They recruited 249 patients.
They intended to recruit more but they stopped because of safety concerns.
An example for the aggressive fluid resuscitation group would be a 70kg patient receiving 1.4 L of fluid over the First two hours. Then, they would receive a drip lactated ringers at 210 cc per hour. If they were 200lbs, that rate would jump to 270cc/hr
The moderate group got an upfront bolus only if deemed hypovolemic. Then a 70kg would get fluids at a rate of 105cc/hr.
Check out the protocol for more detail
As mentioned, they stopped the trial early due to safety concerns.
Over 20% developed fluid overload in the aggressive group versus just 6% in the moderate group.
Check out my podcast episode for the full breakdown but we do not need to be so aggressive with these patients after all.

Citations for Fluids in Pancreatitis

Crockett SD, Wani S, Gardner TB, Falck-Ytter Y, Barkun AN; American Gastroenterological Association Institute Clinical Guidelines Committee. American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis. Gastroenterology. 2018 Mar;154(4):1096-1101. doi: 10.1053/j.gastro.2018.01.032. Epub 2018 Feb 3. PMID: 29409760.
Link to Article
Link to FULL FREE PDF

de-Madaria E, Buxbaum JL, Maisonneuve P, García García de Paredes A, Zapater P, Guilabert L, Vaillo-Rocamora A, Rodríguez-Gandía MÁ, Donate-Ortega J, Lozada-Hernández EE, Collazo Moreno AJR, Lira-Aguilar A, Llovet LP, Mehta R, Tandel R, Navarro P, Sánchez-Pardo AM, Sánchez-Marin C, Cobreros M, Fernández-Cabrera I, Casals-Seoane F, Casas Deza D, Lauret-Braña E, Martí-Marqués E, Camacho-Montaño LM, Ubieto V, Ganuza M, Bolado F; ERICA Consortium. Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis. N Engl J Med. 2022 Sep 15;387(11):989-1000. doi: 10.1056/NEJMoa2202884. PMID: 36103415.
Link to (NOT FREE) Article

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