ENVOL study – is there a marker for positive fluid balance? #FOAMed





The maintenance of optimal blood volume without the development of a positive fluid balance is something we are all striving to achieve for our critically ill patients. Sick patients become ‘leaky’ and we continue to fill them with fluids, chasing a worsening situation as they seem hypovolaemic.

They get:

  • Large volumes of fluid
  • Worsening oedema
  • Impairment of microcirculation architecture and oxygen diffusion
  • Excess sodium loads

Subsequently, we see worsening organ dysfunction and higher mortality.  4kg weight gain corresponds to an accumulation of 4 L of water and 36 g of sodium chloride – this is the limit beyond which morbidity and mortality increase.

Accurate monitoring is essential, yet is still done poorly. We could do with accurate and reproducible methods to improve the monitoring of fluid balance in the ideal world.

Loads of funky biomarkers have been investigated:

  • Stress hormones, such as cortisol and catecholaminesH
  • Hormones involved in volume regulation by sodium chloride or water retention, such as the renin-angiotensin II-aldosterone system
  • Vasopressin, expressed by (CT)-pro-arginine vasopressin, known as copeptin
  • Endothelin expressed by pro-endothelin and atrial natriuretic peptide (ANP), measured by pro-ANP
  • Factors involved in the production of red blood cells, such as erythropoietin (EPO)
  • Factors that repair the endothelium after injury, such as mid-regional pro-adrenomedullin (MR-proADM)

This study [Etude des marqueurs iNnovants de la VOLémie (ENVOL study)] aimed to:

  1. Identify a reliable surrogate biomarker capable of predicting blood volumes and/or cumulative sodium and water balance (∆Na+ and ∆H2O)
  2. Evaluate any relationship between extracellular volume and blood volume measurements.

They thus plotted changes in extracellular and blood volumes and changes in several plasmatic biomarkers involved in volume regulation during the first 7 days of ICU stay.


Prospective, 7-day observational study, conducted the Intensive Care at Bicêtre University Hospital, in Le Kremlin-Bicêtre, France.

4 patient groups looked at:

  1. Severe brain trauma (SBT) – GCS<9
  2. Aneurysmal subarachnoid hemorrhage (SAH) – WFNS score >eq 4
  3. Severe non-cerebral trauma (NCT) – ISS >eq 25
  4. Postoperative peritonitis with septic shock (PPS) – hypotension, Low CO state, lactate >4

Patients were included if they required continuous mechanical ventilation on day 2.


Extensive osmolality, U&E, full blood screening was performed throughout and weight was carefully measured using weighing beds and recorded on D2 and D7. The baseline weight was that recorded by the patient or a relative.

The daily intravenous fluid administration was based on the monitoring of heart rate, arterial pressure, blood lactate concentration, serial echocardiograms, cardiac filling pressures and output and signs of fluid responsiveness in ventilated patients.

Evaluation of extracellular volume

  • Sodium and fluid balances were calculated daily
  • The previous day’s inputs and outputs of sodium and water were calculated each morning
  • All other losses were measured
  • Sodium losses were measured from all liquids and deducted from sodium intake.
  • The difference between water administration from enteral nutrition and daily crystalloids or colloid infusion and water loss was calculated.
  • Insensitive losses were adjusted for body temperature.
  • The sodium and water gains or losses were calculated daily and added to the previous day’s measurements as cumulative fluid balance (∆Na+ and ∆H2O).
  • The creatinine clearance was calculated daily. All calculations were made by one caregiver and verified by another

>36 g ∆Na+ or >4 L ∆H2O was defined as fluid overload

Blood volume

The red blood cell volume (RBCV) was measured on D2 and D7 (±1 day), using 10 mL of the patient’s red blood cells (RBC) labeled with radioactive chromium. The normal values are:

  • 32 ± 6 mL/kg for RBCV
  • 72 ± 14 mL/kg for TBV
  • 40 ± 8 mL/kg for PV

Hypovolemia was noted when TBV was <20 % of normal values.

On D7, they also measured PV by intravenously injecting a small amount of albumin labeled with radioactive iodine.

Normal is 45 ± 10 mL/kg, slightly larger than that measured with 51Cr-RBC.

Biomarker analysis
Plasma biomarkers were analyzed on D2, D5 and D7.

  • MR-proADM, Pro-ANP, renin, angiotensin II, aldosterone, cortisol, norepinephrine and epinephrine, copeptin, pro-endothelin and EPO



Sodium and hydric balance
Fluid overload (i.e. more than 36 g of Na+ or 4 L of H2O) on:

D2 in:

  • 43 patients (64 %) for ∆Na+
  • 36 patients for ∆H2O (54 %)

D7 in:

  • 18 (27 %) for ∆Na+
  • 33 (49 %) for ∆H2O

This sodium and water positive balances on D2 and D7 were observed in all groups, with a higher increase in sodium and water in the NCT and PPS than in the SBT and SAH groups. Interestingly, the ∆Na+ was related to ∆H2O, confirming that retained water is related to retained sodium. As a known indicator of extracellular space, plasma concentration of proteins and variation in weight were related to ∆Na+ and ∆H2O, though these relationships were weak. Like plasma proteins, haemoglobin was weakly related to ∆Na+ or ∆H20.

Blood volumes
A decrease in TBV was observed in most patients.

  • Only 28 patients on D2 (45 %) and 31 on D7 (49 %) were in the normal range.
  • Hypovolemia (TBV <20 %) was present in 34 patients (55 %) on D2 and 32 patients (51 %) on D7
  • Low RBCV was observed in all but three transfused patients. Decrease in RBCV was sometimes notably low with a RBCV <50 % in 34 patients (55 %) on D2 and 21 patients (33 %) on D7.
  • Plasma volumes remained in normal ranges in the main with barely no relationship between PV and sodium / water flux. There was a weak relationship between PV and plasma proteins as well.
  • Hemoglobin concentration was weakly related to RBCV and was not related to PV.


  • Most biomarkers increased on D2 and decreased significantly on D5 and D7 (copeptin, angiotensin II and renin).
  • MR-proADM and EPO decreased significantly on D7.
  • Cortisol, aldosterone, pro-ANP and pro-endothelin remained unchanged.
  • Plasma norepinephrine concentration was not reliable because it was infused as a treatment.
  • It is noteworthy that among all biomarkers, only EPO was related to RBCV.

Of all biomarkers tested, only MR-proADM and angiotensin II were significantly related to ∆Na + (P = 0.01 and P = 0.03) and MR-proADM to ∆H2O (P < 10-5).

SOFA >9 was related to ∆Na+, MR-proADM, and EPO. No difference was found associated to the type of pathological characteristics.

MR-proADM has good discriminative properties for ∆H2O and for ∆Na+. They determined a threshold of MR-proADM predicting a positive balance greater than 36 g Na+ or 4 L H2O.

These thresholds were:

  • 0.865 nmol/L for ∆Na+

  • 1.125 nmol/L for ∆H2O


This study revealed that MR-proADM, a biomarker of endothelial endothelial permeability, may be used as a surrogate for the increase in sodium and water balance in the extracellular space within the first week after admission of critically ill patients to the ICU. They found no relationship between the increase in sodium or water balance and direct measurement of blood volumes on D2 and D7. So…MR-proADM thresholds of 0.865 nmol/L for ∆Na+ and 1.125 nmol/L for ∆H20 were predictive of fluid and of salt overloads, respectively. Moreover, MR-proADM was related to the concurrent SOFA score.

The study indicated a weak relationship between weight and fluid balance. This goes entirely against the mantra!! Measurement of patient’s weight in inflammatory disorders may be biased by practical issues but also by loss of muscle mass, interfering with the estimate of fluid overload. They also assumed that plasma proteins and haemoglobin gave some indication of volaemic status, but this study showed that relationship was weak.

No marker accurately estimated the TBV, PV or RBCV. Moreover, ∆Na+ or ∆H2O are not predictors of blood volume. They found no relationship between fluid balance and plasma volume. This was particularly unexpected, because plasma volume expansion is the main justification for fluid infusion. Yet, plasma was the only volume that was in the normal range on D2 and D7. The absence of correlation between PV and fluid balance supports the hypothesis of possible trapping of Na+ and water in the interstitial volume. Tighter control of PV would be useful in daily practice, though they did not find relationships with biomarkers, proteins or hemoglobin.

The distribution of albumin was interesting; depleted on day 2 but back to normal by day 7 suggesting capillary leak had improved.

We need to be careful in assuming Hb concentration relates to RBCV, it doesn’t in ICU as there’s too many other things at play!

There are so many other physiological processes at play here, so finding one golden bullet biomarker from this study would have been grandiose! This does permit better monitoring  cumulative salt and water balance, which could be an interesting tool for fluid management in the ICU. They also looked at days AFTER the primary admission, where the patient had most likely already undergone the vital resuscitation. This interesting period of severe physiological flux was thus missed for the more stable periods. Bare in mind, their patients were not standardised and reflected the daily practice of their clinicians’ discretion.

So…reality is MR-proADM may offer a measure of sodium balance and extracellular volume changes in the first week after critical inflammatory illnesses? It will need to be done with basal weight or plasma protein concentration as well. A positive sodium balance is an important negative prognostic factor…so, if it’s not too expensive to monitor (which undoubtedly it ill be!!), we could perhaps use this to guide vasopressor, fluid and diuretic therapy for the benefit of our sick patients.


One thought on “ENVOL study – is there a marker for positive fluid balance? #FOAMed

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  1. bare in mind? Great new phrase!
    More seriously, what is the evidence that sick patients have ‘leakier’ capillaries than not-sick patients? Are you thinking of raised Js, raised Jv, or both?
    And is it not possible for a euvolaemic patient to have a TBV that is 20% lower than ‘normal’? In other words, should a patient be diagnosed hypovolaemic just because his TBV is below the normal range?

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