In well-selected patients and within the labeled dose/indication, HES 6% returns as a viable tool for intraoperative volume replacement, not an "absolute villain."
Key takeaways#
Why the topic became "sensitive"
- Hydroxyethyl starch (HES) 6% fell out of favor in fluid therapy after studies in sepsis/ICU with high volumes over several days (often with older formulations), associated with AKI, more RRT, and signs of worse outcomes.
What the EMA identified as a gap
- The EMA restricted use in critically ill and septic patients and identified a gap: robust, long-term data in surgical patients were lacking.
What PHOENICS was designed to answer
- PHOENICS was designed with the EMA to answer: in elective major abdominal surgery, ASA II–III, without sepsis and without relevant renal disease, is HES 6% (130/0.4) in balanced solution as safe as crystalloid?
What the study found and what it means
- In PHOENICS, HES was non-inferior to crystalloid for renal function, major complications + mortality up to 90 days, and mortality up to 1 year.
- HES was associated with less fluid overload and, in post-hoc analysis, less need for vasopressor/inotropes, with no robust signal of renal worsening when used as per label (up to 30 mL/kg/24h).
- Practical takeaway: in well-selected patients and within the labeled dose/indication, HES 6% returns as a viable tool for intraoperative volume replacement, not an "absolute villain."
Insights from the PHOENICS study#
Why did HES 6% become a "sensitive" topic in anesthesia?#
For many years, hydroxyethyl starch (HES) 6% was an option for intraoperative volume replacement: rapid volume expansion, lower total infused volume, and good hemodynamic stability.
This changed when large studies emerged in septic patients, using high volumes of HES over several days, often with older formulations, HES 10% (200/0.5) in saline.
These studies showed:
- Higher incidence of acute kidney injury (AKI)
- Increased need for renal replacement therapy
- Signs of worse ICU outcomes
Based on this, the EMA (European Medicines Agency) strongly restricted HES use in critically ill and septic patients, and identified an important gap: robust, long-term data in surgical patients were lacking.
More recent meta-analyses in surgical settings suggested that HES 6% (130/0.4), used intraoperatively, did not increase AKI or mortality compared to crystalloids, but most studies were small and underpowered. A clinical trial that could definitively resolve the question was needed. This is exactly where PHOENICS comes in.
What was PHOENICS?#
The PHOENICS study ("Prospective, randomised, controlled, double-blind, multicenter, multinational study on the safety and efficacy of 6% HES solution versus an electrolyte solution in elective abdominal surgery") was a phase IV clinical trial, designed together with the EMA, to answer the question:
Is using HES 6% (130/0.4) perioperatively in major abdominal surgery, in patients without sepsis or renal disease, as safe as using only crystalloid?
PHOENICS: study design#
| Item | Description |
|---|---|
| Type | Randomized, double-blind, controlled, multicenter |
| Centers | 53 hospitals in 10 European countries |
| Randomized | 2289 patients |
| Treated patients | 1958 patients (977 HES, 981 crystalloid) |
| Age range | 40–85 years, ASA II–III |
| Surgery | Elective abdominal with expected blood loss ≥ 500 mL |
| Key exclusions | Sepsis, burns, prior AKI or relevant chronic kidney disease, severe heart failure, significant coagulopathy, TBI, critically ill patients. |
Intervention and comparator#
HES group
- HES 6% (130/0.4) in balanced solution (Volulyte), up to 30 mL/kg in the first 24 hours (mainly intraoperative).
Control group
- Same balanced electrolyte solution, but without starch (pure crystalloid).
What was allowed in both groups
- All could receive "maintenance" crystalloids per local routine.
How volume resuscitation was guided
- Volume resuscitation was guided by mean arterial pressure (MAP) and in some cases, advanced hemodynamic parameters (PPV, SV, SVV, etc.).
Methodological robustness#
PHOENICS was described as:
- The largest study ever conducted, randomized and double-blind, comparing HES vs crystalloid in major surgery.
- Renal outcomes assessed with cystatin C (eGFR CKD-EPI), measured at a central laboratory.
- Follow-up to 90 days for major complications and 1 year for mortality and renal function (RRT).
- Pre-specified statistical analysis, without interim analyses that changed sample size.
- Monitoring by an independent Data Safety Monitoring Board.
In terms of design and size, it's a "heavyweight" study to answer the question of HES renal safety in the surgical context.
Key results: what did PHOENICS find?#
1) Early postoperative renal function#
Primary outcome
Change in eGFR (cystatin C-based) from preoperative to lowest value in the first 3 postoperative days.
- HES: mean drop of –3.4 ± 17.7 mL/min/1.73m²
- Crystalloid: mean drop of –1.0 ± 17.1 mL/min/1.73m²
The study was designed to test non-inferiority with a margin of 8.1 mL/min/1.73m² and HES was non-inferior to crystalloid (p < 0.001 for non-inferiority).
Other renal findings in the study
-
Creatinine and eGFR (cystatin C) curves were virtually overlapping between groups up to day 90.
-
AKI classification by RIFLE/AKIN criteria was similar between groups.
-
Need for renal replacement therapy (RRT) was very low and no different:
- Early postoperative: 0.9% (HES) vs 1.0% (crystalloid)
- Up to 1 year: 1.0% vs 1.3%
In summary, the text concludes: no signal of renal toxicity attributable to HES within on-label use.
2) Major complications and mortality#
Key secondary outcome
Composite of mortality + major postoperative complications up to day 90.
- Occurred in 35% of patients in both groups.
- Risk difference: 0.63% (95% CI –3.83 to 5.09) and non-inferiority confirmed.
Mortality
-
Up to 90 days: 3% in each group.
-
Up to 1 year:
- 8.6% in HES group
- 10.1% in crystalloid group
- No statistically significant difference.
Again, the text highlights: no signal of increased mortality with HES.
3) Hemodynamics, fluid balance, and vasopressors#
Between anesthetic induction and the morning of the first postoperative day:
Total fluid volume
- HES: 4.8 ± 2.6 L
- Crystalloid: 5.1 ± 2.7 L
Urine output
- Similar in both groups (~2.6 L).
Net fluid balance
- HES: +0.6 ± 2.9 L
- Crystalloid: +1.2 ± 2.7 L
- Text interpretation: HES associated with less fluid overload.
Hemodynamic stability
- MAP drop was smaller with HES (–14 ± 18 mmHg) than with crystalloid (–16 ± 19 mmHg).
In post-hoc analysis, fewer patients needed vasopressors/inotropes in the HES group:
- 26% vs 35% (p < 0.0001).
The text summarizes this section as: HES 6% (130/0.4) delivered better hemodynamic support with less volume and fewer vasopressors, without paying the price of renal worsening.
4) Overall safety and coagulation#
- Adverse event rate was similar (≈71–72% in both, as expected in major surgery).
- Serious adverse events: ~30% in each group.
- Drug-related adverse reactions: 5% in both; the most frequent event was AKI, 4% in each group.
- There was no robust signal of increased bleeding or clinically relevant coagulopathy with HES 130/0.4 6% at the doses studied.
Results table: HES vs crystalloid (PHOENICS values)#
| Domain | HES | Crystalloid | Study interpretation |
|---|---|---|---|
| Primary renal outcome (mean eGFR drop by cystatin C) | –3.4 ± 17.7 mL/min/1.73m² | –1.0 ± 17.1 mL/min/1.73m² | Non-inferiority with margin 8.1 mL/min/1.73m²; p < 0.001 for non-inferiority |
| Early postoperative RRT | 0.9% | 1.0% | No difference |
| RRT up to 1 year | 1.0% | 1.3% | No difference |
| Composite mortality + major complications up to 90 days | 35% | 35% | Risk difference 0.63% (95% CI –3.83 to 5.09); non-inferiority confirmed |
| Mortality up to 90 days | 3% | 3% | No increased mortality with HES |
| Mortality up to 1 year | 8.6% | 10.1% | No statistically significant difference |
| Total fluid volume (induction to morning D1 post-op) | 4.8 ± 2.6 L | 5.1 ± 2.7 L | Lower volume with HES |
| Urine output | ~2.6 L | ~2.6 L | Similar |
| Net fluid balance | +0.6 ± 2.9 L | +1.2 ± 2.7 L | Less fluid overload with HES |
| MAP drop | –14 ± 18 mmHg | –16 ± 19 mmHg | Smaller drop with HES |
| Vasopressors/inotropes (post hoc) | 26% | 35% | Less need in HES group; p < 0.0001 |
| Adverse events | ≈71–72% | ≈71–72% | Similar |
| Serious adverse events | ~30% | ~30% | Similar |
| Drug-related adverse reactions | 5% | 5% | Similar; AKI 4% in each group |
What does this change for the anesthesiologist in practice?#
In which patients does HES 6% appear to be a safe option?#
Based on PHOENICS, the patient profile in which HES 6% (130/0.4) can be considered, when used according to the label, is:
- Elective major abdominal surgery
- ASA II–III
- No sepsis, septic shock, or prior ICU need
- No prior AKI or advanced renal disease
- No formal contraindications to HES (extensive burns, TBI, severe coagulopathy, etc.)
- Moderate/high blood loss, with need for rapid volume resuscitation.
For this group, the text highlights:
- Renal function: HES 6% (130/0.4) is non-inferior to crystalloid in short and long-term renal outcomes.
- Major clinical outcomes (complications + mortality): also non-inferior.
- Hemodynamics: potentially more stable, with less need for vasopressors and lower positive fluid balance.
How to use in real life?#
Practical points
-
Follow the label:
- Maximum dose 30 mL/kg in the first 24 h
- Preferably concentrated intraoperatively.
-
Integrate HES into an individualized fluid therapy strategy, ideally guided by dynamic parameters (PPV, SVV, SV, and CO) when available.
-
Using HES for rapid volume resuscitation in hypotensive episodes associated with hypovolemia, not as maintenance.
Where not to use HES
- Sepsis or septic shock
- Critically ill patients in ICU
- Moderate/severe renal disease or patients on RRT
- Burns, TBI, intracranial hemorrhage.
Quick checklist: when to consider and when to avoid HES 6%#
| Situation | What the text describes |
|---|---|
| When to consider | Elective major abdominal surgery; ASA II–III; no sepsis/septic shock; no prior AKI or advanced renal disease; no formal contraindications (extensive burns, TBI, severe coagulopathy, etc.); moderate/high blood loss, with need for rapid volume resuscitation. |
| How to limit use | Follow 30 mL/kg in the first 24 h, preferably concentrated intraoperatively. |
| How to integrate into strategy | Individualized fluid therapy strategy, ideally guided by dynamic parameters (PPV, SVV, SV, and CO) when available. |
| What to avoid | Sepsis/septic shock; critically ill patient in ICU; moderate/severe renal disease or RRT; burns, TBI, intracranial hemorrhage. |
| What not to do | Use HES as maintenance. |
Conclusion#
In conclusion, for the anesthesiologist, HES 6% (130/0.4) returns, in well-selected patients and within the labeled dose/indication, as a valid tool for intraoperative volume resuscitation, not an absolute villain.
Want to turn this type of evidence into practical decisions in seconds?#
When the question "HES vs crystalloid" arises in your context, you can use Deep Evidence – Scientific Research Engine within AnestCopilot to objectively review the topic, with focus on the perioperative setting.
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