This document summarizes a clinical trial comparing hydroxyethyl starch (HES) to crystalloids for fluid resuscitation in critically ill patients with sepsis. The trial found that HES increased the risk of death within 90 days compared to Ringer's acetate. Patients receiving HES also had higher rates of renal replacement therapy, fewer days alive without RRT, and fewer days alive outside the hospital. The study demonstrated that HES 130/0.42 should not be used for fluid resuscitation in critically ill septic patients due to worse clinical outcomes compared to crystalloids.

1. Presenter: Dr. Mustahsin
Moderator: Dr. Rahul Anand

2.  Fluid Resuscitation is fundamental component of management of critically
ill patients
 Choice of fluid is longstanding debate
 Not just TYPE of resuscitation fluid that determines outcome, but the
TIMING and DOSE
 No Ideal fluid at present

3.  Produce predictable and sustained increase in IV volume
 Chemical composition as close as possible to ECF
 Metabolized and completely excreted without accumulation in tissues
 Does not produce adverse metabolic or systemic effects
 Cost-effective
 Improves outcomes

5.  Colloid vs Crystalloids
 Albumin vs Crystalloids
 Albumin vs HES
 Normal Saline vs Balanced Crystalloids

6. Favoring Crystalloid Favoring Colloids
 VISEP (2008)
 6S (2012)
 CHEST (2012)
 CRISTMAS (2012)
 CRYSTAL (2013)
Favoring Balanced
Crystalloids
 SMART (2018)
 Yonus NM
 SPILIT (2015)
 SALT (2017)
 SALT-ED ( 2018)
Balanced Crystalloids=
Saline

8.  In patients with severe sepsis and septic shock, does intensive
insulin therapy and hydroxyethyl starch (HES) reduce
morbidity and mortality as compared to conventional insulin
therapy and Ringer's lactate, respectively?

9.  Role of Intensive Insulin therapy in severe sepsis is Uncertain
 Fluid resuscitation improves survival in septic shock patients
 Evidence lacking in support of crystalloid vs colloids
 In Animal model HES improved microcirculation during
endotoxemia and lessened tissue damage
 HES was associated with serious side effects, including
coagulopathy and acute renal failure

10.  Multicenter, two-by-two factorial, randomized, controlled trial
 N=537
 Median follow-up: 28 days (first analysis), 90 days
(discontinued)
 Intention-to-treat
 Primary outcome: all-cause mortality and morbidity at 28
days
 Morbidity was assessed using SOFA score

11.  18 academic tertiary hospital ICUs in Germany
 April 2003 to June 2005
Inclusion Criteria
 Age ≥18 years
 ICU patients with severe sepsis or septic shock
 Onset of sepsis or septic shock <24 hours before
admission to the ICU or <12 hours after admission if the
condition developed in the ICU

12. Exclusion Criteria
 Received HES >1 L within 24 hours prior to study
 Pre-existing kidney disease requiring dialysis or serum creatinine 3.6 mg/dl
 Pregnancy
 Allergy against HES
 Intracerebral hemorrhage
 NYHA IV heart failure
 Requirement of FiO2 of ≥0.7
 Immunosuppression due to chemotherapy
 Receiving high doses of steroids
 AIDS
 Participation in another trial
 Severe comorbidities
 Order to withhold or withdraw therapy

13. Insulin Therapy Fluid Resuscitation
 Intensive-therapy (n=247):
◦ Insulin infusion started when blood glucose
level exceeded 110 mg/dl
◦ Insulin level was adjusted with a target
glucose level of 80-110 mg/dl
 Convention-therapy (n=290):
◦ Continuous insulin infusion started when
blood glucose level exceeded 200 mg/dl
◦ Insulin level was adjusted with a target
glucose level of 180-200 mg/dl
 Patients were randomized to receive
HES (n=262) compared to Ringer's
lactate (n=275)
 During 96 hours after randomization,
fluid resuscitation was commenced with
a target CVP of 8 mm Hg
 HES (10% hydroxyethyl starch) was given
at a maximum limit of 20 ml/kg/day
 HES was not used as a maintenance fluid

14.  The study was designed to detect a reduction in mortality
from 40% to 30% at 28 days expected to reduce the mean
SOFA score by 1.2 points
 To detect a difference of 1.2 in the mean SOFA score with a
power of 80%, 600 patients were enrolled
 Chi-square test and the t-test to assess differences in
mortality at 28 days and the mean SOFA score

15.  After the first safety analysis, involving 488 patients, intensive insulin
therapy was terminated early by the data and safety monitoring board
due to hypoglycemic events (12.1% vs 2.1%; P<0.001)
 Comparison b/w HES and RL was continued
 The planned interim analysis after the enrollment of 600 patients showed
a significantly greater incidence of renal failure and a trend toward higher
90-day mortality among patients who received HES, so the study was
suspended

21. P=0.36
P=0.14
P<0.001

23.  In 537 patients with septic shock- no benefit of intensive insulin therapy
 Study stopped early after first planned safety analysis because of severe
hypoglysemia
 After the first planned interim analysis, this trial was suspended because
of increased rates of renal failure and death at 90 days in the group
receiving HES
 Schortgen et al. in 2001 reported adverse renal effects associated with a
starch solution that had a higher degree of molar substitution (0.6) than
that used in this study (0.5).

24.  Fluid resuscitation volume in the trial exceeded the manufacturer's
recommendation
 More patients who received HES had heart failure or emergency surgery
 The study was underpowered
 The definition of AKI consists of doubling of baseline serum creatinine and
requirement for renal-replacement therapy
 The serum creatinine level of 3.6 mg/dL used as an exclusion criteria is
higher than the recommended specification for HES

26. In critically ill adults with severe sepsis, does 6%
hydroxyethyl starch (HES) compared to Ringer’s
acetate reduce the incidence of death or end stage
kidney failure?

27.  Septic shock is a complex heterogeneous state with a combination of fluid
deficiency and vasoplegia
 Intravenous fluid therapy is currently a key treatment--30 ml/kg as boluses for the
initial treatment of sepsis
 Colloids and crystalloids are available and numerous trials have attempted to
identify the best fluid for restoring intravascular volume
 Starch-based colloids with high molecular weight and high substitution ratios were
shown to be associated with acute kidney injury
 This 6S trial attempted to investigate a starch-based colloid with relatively lower
molecular weight and substitution ratio

28.  Investigator initiated, blinded, stratified, parallel-group clinical trial
 Computer generated allocation sequence
 Treatment assignments were concealed from patients, clinicians, research
staff, data monitoring and safety committee, the statistician, and the
writing committee
 Randomization stratified according to the presence or absence of shock,
presence or absence of hematological cancer, and admission to a
university or non-university hospital

29.  26 intensive care units (13 university and 13 non
university)
 Denmark, Finland, Norway and Iceland.
 Data collected between December 2009 and
November 2011

30. Inclusion Criteria: Adult patients who needed fluid resuscitation in the ICU, as
judged by ICU clinicians, who fulfilled the criteria for severe sepsis within the
previous 24 hours
Exclusion Criteria:
-Burn patients
-IC Bleeding
-RRT
->1L colloid in previous 24 hrs
-Enrolled in another ICU study
-Refusal to give consent

32. Intervention Control
 6% HES 130/0.42 in Ringer’s acetate
(Tetraspan 6%) was given if volume
expansion was required
 Prepared by staff not involved in trial
or patient care
 Hidden by custom-made opaque bag
 Max. Daily dose 33ml/kg
 Ringer’s acetate if volume expansion
was required
 Prepared by staff not involved in trial
or patient care
 Hidden by custom-made opaque bag

33.  Routine management of patient was maintained apart from which resuscitation
fluid was used
 Fluids given for a maximum of 90 days
 Maximum daily dose of 33 ml/kg of ideal body weight to nearest 500 ml
◦ Further fluid, if required, was unmasked (open label) Ringer’s acetate
 In case of bleeding, Alergic reaction or renal replacement therapy (RRT), trial fluid
was permanently stopped and replaced by NS or Ringer’s lactate
 Other crystalloid and albumin solutions were allowed except for the indication of
volume expansion

34.  Primary Outcome: Death or dependence on dialysis 90 days after
randomization
 Secondary outcomes:
-Use of RRT
-Severe bleeding
-Death at 28 days

35.  800 patients required for study to have 80% power to show an absolute
difference of 10% between groups in the primary outcome measured at a
two-sided alpha significance level of 0.05, assuming a 45% mortality rate
and a 5% rate of dependence on dialysis at 90 days
 Data were analyzed with the use of unadjusted chi-square tests for binary
outcome measures and Wilcoxon signed-rank tests for rate and ordinal data
 Modified intention to treat principle was used
 Two sided P<0.05 significant

39.  Patients with severe sepsis who received fluid resuscitation with
hydroxyethyl starch compared with Ringer’s acetate had:
- Higher risk of death within 90 days
- More likely to receive RRT
- Fewer days alive without RRT
- Fewer days alive out of hospital
 HES 130/0.42 increased the absolute risk of death at 90 days by 8
percentage points, corresponding to a number needed to harm of 13

40.  Low risk of bias as all groups and procedures blinded
 Web-based randomisation process with stratification
 Broad inclusion criteria –University & non University hospitals
 Pragmatic approach with routine practice maintained except
fluid resuscitation

41.  A significant proportion of patients received fluid volumes in excess of the
protocol, although this was balanced fairly evenly between the two
groups so it is unlikely to have led to a bias
 Seventy-seven patients were given open label synthetic colloids during the
trial period
 AKI patients included at the time of randomization
 Sixty-nine patients were given trial fluid at doses higher than the
maximum daily dose

43. In critically ill patients requiring fluid resuscitation, does 6%
hydroxyethyl starch (6% HES) compared to 0.9% sodium
chloride (Saline) reduce mortality at 90 days?

44.  Multicenter, Prospective, Randomized controlled, double-blinded clinical trial
 Computer generated randomization via website providing complete concealment
 A priori publication of trial protocol and statistical analysis plan
 Intention-to-treat analysis
 Powered at 90% to detect absolute difference of 3.5% difference in mortality at 90
days from baseline of 26%, with alpha significance of 0.05

45.  32 adult ICUs
 Mixed medical and surgical
 Australia and New Zealand
 December 2009 to January 2012

46. Inclusion Criteria: Attending physician judged fluid resuscitation to be needed; age
over 18 years
Exclusion Criteria:
-1000ml or more 6% HES prior to ICU admission
-Impending or current renal replacement therapy
-Intracranial haemorrhage
-Women of child-bearing age unless known negative pregnancy state
-Cardiac surgery, burn injury or liver transplant.

47.  Intervention: 6% HES (Voluven, Fresenius Kabi as 500ml bags)
 Control: 0.9% Saline (identical 500ml bags)
 Fluid administered at clinician’s discretion for all fluid resuscitation
◦ To correct hypovolaemia
◦ Supported by at least one objective physiological parameter
 Continued until death, discharge or day-90
 HES Limited at 50 ml/kg/day as per product license
◦ Open-label saline as required after this limit
 Change to open-label saline if renal replacement therapy required
 Maintenance and replacement fluid not controlled; fluid outside of ICU not controlled

49. Primary Outcome: All cause mortality at 90 days
Secondary Outcomes:
-Incidence of AKI (Defined by RIFLE)
-Use of RRT
-New Organ Failure (SOFA>3)
-Duration of MV
-Duration of RRT
-Cause specific mortality

52. Survival Curve

56.  This study does not provide evidence that resuscitation with 6% HES (130/0.4) as
compared with saline, in the ICU provides any clinical benefit to the patient
 HES resulted in an increased rate of renal replacement therapy
 No effect on mortality in 6 predefined subgroups

57.  Well designed, large, multi-centre randomized, controlled trial
 Biases minimized with double-blinding, predefining
subgroups
 Pragmatic design – administration at clinician’s discretion
 A priori statistical plan and intention-to-treat analysis

58.  Patients recruited after admission to ICU: less fluid
requirement
 6% HES had been administered to 15% of patients in Saline
group prior to randomization. This small cross-over may bias
towards a conclusion of ‘no difference’
 The lower baseline mortality rate may have contributed to a
false negative conclusion
 The clinician-judged need for renal replacement therapy

60.  In critically ill patients does the administration of balanced crystalloids
compared with saline, reduce a 30 day composite outcome of death, new
renal replacement therapy or persistent renal dysfunction?

61.  Randomized Controlled Pragmatic, cluster-randomized, multiple-
crossover, Unblinded
 For each month of the trial, ICUs were randomized to use saline during
even number month or balanced crystalloids during odd number month
 Intention to treat analysis
 15802 patients, provide a 90% power to detect an absolute difference of
1.9% points between groups with a P-value of 0.05

62.  5 ICUs in a single US academic centre; Vanderbilt Medical Centre, Nashville,
Tennessee
 Medical (34 beds), Neurological (22 beds), Cardiac (27 beds), Trauma (31 beds),
Surgical (22 beds)
 Date of study: June 1st 2015 – April 30th 2017

63.  Inclusion Criteria: Adult patients admitted to the ICU
 Exclusion Criteria: Age <18
 15802 adults randomized
 Patients were well matched at baseline

64. Balanced Crystalloid
 All adult patients admitted to certain ICUs were
allocated to receive balanced crystalloid
(plasmalyte-A or lactated Ringer’s solution)
 If the patient had the relative contraindication
of hyperkalaemia or traumatic brain injury, then
0.9% sodium chloride could be used in
preference to balanced crystalloid, at the
discretion of the treating physician
 7942 patients were allocated to the balanced
crystalloid group
Normal Saline
 All adult patients admitted to
the alternate ICUs were
allocated to receive normal
saline
 7860 patients were allocated
to saline

65.  Volumes and rates were prescribed by the treating physicians
 All other management was at the discretion of the treating physicians
 The ICUs swapped their fluid allocation at the beginning of each calendar
month
 The unassigned crystalloid was also available for when clinicians believed
required for safe treatment of any patient
 Median Volume of Fluid received b/w ICU admission to Hospital Discharge
or at 30 days:
 Balanced Crystalloid Group: 1000ml
 NS group: 1020ml

66. Primary Outcome: Make 30
 The patient met one or more criteria for a Major Adverse Kidney Event at 30 days:
mortality, new receipt of renal-replacement therapy (RRT) or persistent renal
dysfunction (defined as a final inpatient creatinine value of >200% baseline). C
Secondary Outcomes:
-Death before discharge or day 30
-Receipt of New RRT
-Persistant Renal Dysfn
-ICU/Ventilator/Vassopressor free days

70.  This study favours administering intravenous balanced crystalloids over
saline:
-to decrease a composite outcome of death,
-new renal replacement therapy or
-persistent renal dysfunction at 30 days

71.  Large sample size provides power to detect small differences in clinical outcomes
 The use of the composite outcome means that if clinically significant components
are rare it is easier to detect an overall treatment effect
 Pragmatic design, randomized, complete follow-up, intention to treat analysis
 A mixed cohort of medical and surgical patients making the result suitable for
extrapolation to any critically ill patient
 Separation between groups of fluids received indicating that the allocation was
largely successful

72.  Patients remaining in the ICU at the end of a calendar month may have
been exposed to both types of crystalloids. The between group difference
in outcome may therefore be reduced
 Single centre trial may limit the external validity of the results
 The treating clinicians were not blinded. This may introduce an element of
conscious or unconscious bias
 Clinicians decision to initiate RRT may lead to treatment bias
 The trial does not tell us if Plasmalyte-A or Lactated Ringer’s is better, only
that they are likely to be superior to saline in this study

73. 6S trial: HES vs LR
Increased 90 day mortality
Increased need for RRT
Fewer Days Alive without RRT
Fever days Alive out of Hospital
Increased rate of blood product transfusion
CHEST Trial: HES Vs NS
No difference in mortality
Increased AKI and need for RRT
VISEP Trial: HES vs LR
Increased Mortality at 90 days
Increased Rates of Renal Failure

74. CRISTAL Trial: Colloids vs Crystalloids
 No difference in 28 day mortality/Need of RRT
 Trend towards lower 90 day mortality
CRYSTMAS Trial: HES vs NS
 No Difference in Mortality/AKI
 No Difference in other Adverse Effects
 Less volume required to achieve HDS

78. HYPERCHLOREMIA:
 Metabolic acidosis
 Increased Inflammatory Cytokines
 Renal Vasoconstriction
 Increased intrestitial edema
 Possibly Coagulopathy

79. SMART Trial: Balanced Crystalloids vs NS
 Decrease a composite outcome of death
 Decrease RRT
 Decrease persistent renal dysfunction at 30 days
Yunus NM: JAMA 2012;308(15):1566-72 Chlorive liberal vs Chloride-Restrictive
 Chloride Restrictive Stretegy decreases incidence of AKI and need for RRT

81. SPILIT Trial: NS vs Buffered Crystalloid
 No difference in AKI within 90 days(Primary outcome)
 No difference in use of RRT/Inhospital Mortality
SALT Trial: NS vs Balanced Crystalloids
 No Difference in MAKE 30
SALT-ED Trial: NS vs Balanced Crystalloids
 No difference in Hospital free Days (Primary outcome)
 No difference in MAKE30

83.  Use resuscitation fluids like any other intravenous drug: carefully and only in the
doses necessary in appropriate clinical situations
 Consider Balanced Crystalloids (RL, Plasmalyte) in patients who need Large volume
resuscitation
 Saline is well-suited for patients with hypovolemia and alkalosis.
 Albumin seems reasonable as resuscitation during early severe sepsis (but so does
crystalloid)
 Don’t give albumin to patients with traumatic brain injury
 TBI or other risks of ICP should be treated with NS

84. Thank You

85.  VISEP study : Efficacy of Volume Substitution
and Insulin Therapy in Severe Sepsis
 6S:Scandinavian Starch for Severe
Sepsis/Septic Shock (6S) trial
 CHEST: Crystalloids vs HES Trial
 SMART: Isotonic Solutions and Major Adverse
Renal Events Trial