Is less more or do we have to do more with less?

Liberal vs Conservative vs Restrictive vs Limited vs Standard vs Normal,… or a bit of everything?

The bottom-line

The bottom-line is that this large randomized controlled clinical trial showed that it is safe to restrict IV fluids. The median between-group difference in the volume of intravenous fluids administered was approximately 2 liters less in the restrictive group compared to the standard of care. In view of the many deleterious side effects of IV fluids that are still not considered drugs coming with indications, contraindications, and potential adverse effects (AKI, electrolyte disturbance, hyperchloremic metabolic acidosis, coagulopathy, fluid accumulation) this is a very strong message! So despite the fact that the study results were not statistically significant, the clinical relevance cannot be mistaken.

I am very proud to have been able to contribute, albeit modest to a recent paper published in the latest issue of the New England Journal of Medicine: “Restriction of Intravenous Fluid in ICU Patients with Septic Shock”. Being a co-author on the first article page of this prestigious journal does not happen every day. Kudos to the fantastic CRIC research team led by Prof Dr Anders Perner: with first authors Tine S. Meyhoff, M.D., Peter B. Hjortrup, M.D., Ph.D., J?rn Wetterslev, M.D., Ph.D., and Praleene Sivapalan, M.D.

Background

Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU).

Methods

In this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before the screening. The primary outcome was death from any cause within 90 days after randomization.

Results

We enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). Patients received a median of 3 liters of intravenous fluid before they underwent randomization and were enrolled within 3 hours after admission to the ICU.

In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], ?4.7 to 4.9; P=0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, ?1.7 percentage points; 99% CI, ?7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups.

Conclusions

Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy.

Funded by the Novo Nordisk Foundation and others; CLASSIC ClinicalTrials.gov number, NCT03668236. opens in new tab.

Article: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2202707 with temporarily available free preview: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2202707

Accompanying editorial: https://www.nejm.org/doi/full/10.1056/NEJMe2206160?query=recirc_curatedRelated_article with temporarily available free preview: https://www.nejm.org/doi/pdf/10.1056/NEJMe2206160

Video with presentation and discussion of the study results during CCR22 in Belfast https://criticalcarereviews.com/meeting/ccr22

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What is next?

The term deresuscitation was coined in 2011 by Manu Malbrain during the first IFAD meeting in Antwerp https://www.fluidacademy.org/memberresources/item/extended-overview.html?(page A30 - the screenshot below) and later on in 2014 defined as active fluid removal in patients with fluid overload using drugs and/or ultrafiltration (UF).

?The term ‘de-escalation’ relates more to reducing the amount and rate of previously started fluid administration.

The big question is when should we de-resuscitate: As soon as salvage resuscitation has been completed, de-escalation should begin, aiming for a zero fluid balance (passively, by decreasing fluid intake). Thus, de-resuscitation should be considered when Fluid accumulation negatively impacts organ function. This implies that fluids are seen as drugs that have indications and contraindications and potential adverse effects. In brief, clinicians should adhere to fluid stewardship in analogy to the use of antibiotics.

The best cure for fluid accumulation is to prevent it. Fluid tolerance and fluid responsiveness are 2 different and distinct topics. A patient may be fluid responsive but giving fluids may cause harm. Vice versa some patients with fluid intolerance may need fluids. It is all about balancing the risks and benefits and considering fluids as any other drug. This brings me to a potential set of diagrams to illustrate the balance between tolerance vs responsiveness, liberal vs restrictive, early vs late management.

If controls are not distinctly different, the absence of a therapeutic signal may suggest that both populations were treated in a broadly similar manner. When the intervention is a drug or device, the use of a placebo or sham allows valid inferences of causality. But when the intervention is a management strategy, the issue becomes more complex. The combination of early (EL) vs late liberal (LL) fluids with early (ER) vs late restrictive (LR) is shown below.

This gives four distinct groups with risk stratification for adverse effects.

ELER: early liberal and early restrictive

ERLL: early restrictive and late liberal

ELLR: early liberal and late restrictive

LLLR: late liberal and late restrictive

It is clear that the ELER and LLLR groups are a bit counterintuitive and difficult to understand, but ELER should be seen as early aggressive fluids that are immediately stopped with a switch to a restrictive strategy when they are no longer needed. LLLR would make no sense as this would lead to fluid accumulation that would then need de-resuscitation. Therefore, a final way to look at all things fluid is shown below with a focus on early vs late liberal or conservative therapy, this gives the following groups:

ELLR: early liberal followed by late restrictive (de-escalation)

ERLR: early restrictive followed by late restrictive

ELLL: early liberal followed by late liberal

ERLL: early restrictive followed by late liberal

Further reading

The 4 fluids of life: https://www.dhirubhai.net/pulse/4-fluids-life-call-action-manu-malbrain

Fluid stewardship: https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-018-0402-x

IFA Executive summary on perioperative fluids: https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-020-00679-3

De-resuscitation: https://www.termedia.pl/Fluid-overload-de-resuscitation-and-outcomes-r-nin-critically-ill-or-injured-patients-a-systematic-review-r-nwith-suggestions-for-clinical-practice,118,38250,1,1.html