VISEP

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Brunkhorst FM, et al. "Intensive insulin therapy and pentastarch resuscitation in severe sepsis". The New England Journal of Medicine. 2008. 358(2):125-139.
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Clinical Question

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?

Bottom Line

In patients with severe sepsis and septic shock, both intensive insulin therapy and HES are harmful as compared to conventional insulin therapy and Ringer's lactate, respectively.

Major Points

In the Leuven Surgical Trial (2001) of surgical ICU patients, intensive insulin therapy (target glucose 80-110 mg/dL or 4.4-6.1 mmol/L) reduced the in-hospital mortality to 7.2% as compared to 10.9% in patients with conventional treatment (target glucose 180-200 mg/dL or 10-11.1 mmol/L; (P=0.01). This survival benefit was not seen in the follow-up Leuven Surgical Trial of medical ICU patients.[1] The debate between intensive and conventional glycemic control would be better settled in 2009 with the publication of NICE-SUGAR, but prior to its publication, evidence one way or another was limited.

The Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) study assessed the efficacy and safety of intensive insulin therapy compared to conventional insulin therapy and hydroxyethyl starch (HES) compared to Ringer's lactate in 537 medical ICU patients. Adults with severe sepsis or septic shock were included within 24h of ICU admission, and were randomized to intensive glycemic control (target glucose 80-110 mg/mL) or conventional glycemic control (target glucose 180-200 mg/mL). A second randomization was performed, randomizing patients to either 10% hydroxyethyl starch volume resuscitation, or to conventional fluid resuscitation with a solution similar to lactated Ringer's solution. The primary outcome was 28-day mortality and morbidity.

The trial was stopped early due to safety concerns. Intensive insulin therapy was associated with increased rate of severe hypoglycemia (17.0% vs. 4.1% in conventional treatment, P<0.001) and serious adverse events (10.9% vs. 5.2% in conventional treatment, P=0.01) without survival benefits. HES treatment was associated with increased risk of acute kidney injury (34.9% vs. 22.8% in Ringer's lactate group, P=0.002) and requirement for renal replacement therapy (31% vs. 18.8% in Ringer's lactate group, P=0.001).

In 2009, the NICE-SUGAR trial (n=6,104) reported that in medical ICU patients, intensive glycemic control was associated with a higher mortality rate as compared to conventional treatment.[2]

Similarly, the CHEST, CRYSTMAS, and 6S trial did not show a survival benefit of HES for fluid resuscitation in critically-ill patients.[3][4][5] A 2013 Cochrane analysis concluded that the use of HES for resuscitation may increase mortality risk (pooled RR 1.10, 95% CI 1.02-1.19; 25 trials, 9,147 patients).[6] Another Cochrane analysis reported that HES may increase the risk of AKI (RR 1.14, 95% CI 1.01-1.30; 15 trials, 8,402 participants) and renal replacement therapy (RR 1.31, 95% CI 1.16-1.49; 19 trials, 9,857 participants) in all patient populations.[7]

Guidelines

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012[8]

  • In ICU patients with severe sepsis, commence insulin when 2 consecutive blood glucose levels are are >180mg/dL. The treatment target is blood glucose level ≤180mg/dL (grade 1B).
  • In patients with severe sepsis and septic shock, crystalloids are the initial fluid of choice for resuscitation (grade 1B).
  • The use of HES for fluid resuscitation of severe sepsis and septic shock is not recommended (grade 1B).

ADA Standards of Medical Care in diabetes, 2016[9]

  • Insulin should be initiated for treatment of persistent hyperglycemia when glucose levels are ≥180 mg/dL (10.0 mmol/L). Target glucose level is 140-180 mg/dL (7.8–10.0 mmol/L) for critically ill patients (grade A) and non-critically ill patients (grade C).
  • For selected critically ill patients, more stringent goals, such as 110-140 mg/dL (6.1-7.8 mmol/L) may be appropriate, if this can be achieved without significant hypoglycemia (grade C).

Design

  • Multicenter, two-by-two factorial, randomized, controlled trial
  • N=537
    • Intensive insulin therapy (n=247) compared to conventional insulin therapy (n=290)
    • HES therapy (n=262) compared to Ringer's lactate (n=275)
  • Setting: 18 centers in Germany
  • Median follow-up: 28 days (first analysis), 90 days (discontinued)
  • Analysis: intention-to-treat
  • Primary outcome: all-cause mortality and morbidity at 28 days
    • morbidity was assessed using the mean score on the Sequential Organ Failure Assessment (SOFA)
    • the SOFA takes into account of the functioning status of cardiovascular, respiratory, coagulation, renal, hepatic and central nervous system
    • higher SOFA scores indicate more severe organ impairment

Population

Inclusion Criteria

  • age ≥18 years
  • ICU patients with severe sepsis or septic shock[10]
  • 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

Exclusion Criteria

  • received HES >1 L within 24 hours prior to study
  • pre-existing kidney disease requiring dialysis or serum creatinine ≥ 320 µmol/l (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

Baseline Characteristics

From the intensive-therapy group

  • Demographics: age 64±14.3 years, 61.1% male
  • BMI: 26.9±5.9 kg/m2
  • Other medical conditions: Hypertension 42.5%, T1DM 13%, T2DM 16.2%, heart failure 14.6%, renal impairment 8.5%, COPD 15.4%, cirrhosis 2%, active malignancy 4.5%, immunosuppression 1.2%
  • Source of infection: pulmonary 39.7%, abdominal 38.5%, bone or soft tissue 10.9%, surgical wound 8.5%, urogenital 7.3%, primary bacteremia 4.9%, other 5.3%
  • Organism: gram-positive 42.5%, gram-negative 37.3%, fungus 19%
  • Lab values (median and interquartile range): blood glucose 130 (108–167) mg/dl, HbA1c 5.9 (5.2-6.2)%; CRP 198 (131–290) mg/l, lactate 2.1 (1.4–3.8) mmol/l; creatinine 1.4 (0.96–2.07) mg/dl, creatinine clearance 51.9 (35.3–81.0) ml/min
  • Hemodynamics: heart rate 104 (90-118) bpm, CVP 12 (8-15) mm Hg, MAP 77 (67-85) mm Hg, central venous O2 saturation 75 (68-81)%

Interventions

  • Patients were randomized to receive intensive insulin therapy compared to conventional insulin therapy and HES therapy compared to Ringer's lactate in a two-by-two factorial design

Insulin therapy

  • Intensive-therapy (n=247):
    • insulin infusion started when blood glucose level exceeded 110 mg/dl (6.1 mmol/l)
    • insulin level was adjusted with a target glucose level of 80-110 mg/dl (4.4-6.1 mmol/l)
  • Convention-therapy (n=290):
    • continuous insulin infusion (50 IU of Actrapid HM, Novo Nordisk) started when blood glucose level exceeded 200 mg/dl (11.1 mmol/l)
    • insulin level was adjusted with a target glucose level of 180-200 mg/dl (10.0-11.1 mmol/l)

Fluid resuscitation

  • 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 however ≥10% of patients exceeded this limit
  • HES was not used as a maintenance fluid

Outcomes

Comparisons are intensive vs. conventional therapy and HES vs Ringer's lactate

Primary Outcomes

all-cause mortality at 28 days
Intensive vs. conventional-insulin therapy: 24.7% vs. 26.0% (P=0.74)
HES vs Ringer's lactate: 26.7% vs. 24.1% (P=0.48)
Morbidity assessed by the mean SOFA score
higher SOFA scores indicate more severe organ impairment
Intensive vs. conventional-insulin therapy: 7.8 vs. 7.7 (P=0.88)
HES vs Ringer's lactate: 8 vs. 7.5 (P=0.16)

Secondary Outcomes

All-cause mortality and morbidity at 28 days
Intensive vs. conventional-insulin therapy: 39.7% vs. 35.4% (P=0.31)
HES vs Ringer's lactate: 41.7% vs. 33.9% (P=0.09)
mean cardiovascular SOFA subscore
higher SOFA scores indicate more severe organ impairment
Intensive vs. conventional-insulin therapy: 1.82 vs. 1.75 (P=0.96)
HES vs Ringer's lactate: 1.8 vs. 1.76 (P=0.51)
mean respiratory SOFA subscore
Intensive vs. conventional-insulin therapy: 2.5 vs. 2.57 (P=0.24)
HES vs Ringer's lactate: 2.5 vs. 2.57 (P=0.58)
mean coagulation SOFA subscore
Intensive vs. conventional-insulin therapy: 0.21 vs. 0.21 (P=0.90)
HES vs Ringer's lactate: 0.46 vs. 0.11 (P<0.001)
mean renal SOFA subscore
Intensive vs. conventional-insulin therapy: 0.53 vs. 0.5 (P=0.90)
HES vs Ringer's lactate: 0.67 vs. 0.42 (P=0.02)
mean hepatic SOFA subscore
Intensive vs. conventional-insulin therapy: 0.11 vs. 0.08 (P=0.74)
HES vs Ringer's lactate: 0.09 vs. 0.11 (P=1.00)
mean CNS SOFA subscore
Intensive vs. conventional-insulin therapy: 1 vs. 1 (P=0.82)
HES vs Ringer's lactate: 1 vs. 1 (P=0.5)
Acute kidney injury
defined as doubling of baseline creatinine or requirement for renal-replacement therapy
Intensive vs. conventional-insulin therapy: 31.1% vs. 26.6% (P=0.25)
HES vs Ringer's lactate: 34.9% vs. 22.8% (P=0.002)
Renal-replacement therapy
Intensive vs. conventional-insulin therapy: 27.5% vs. 22.5% (P=0.19)
HES vs Ringer's lactate: 31% vs. 18.8% (P=0.001)
Requirement for red-cell transfusion
Intensive vs. conventional-insulin therapy: 77.3% vs. 67.9% (P=0.02)
HES vs Ringer's lactate: 76% vs. 68.7% (P=0.06)
Number of transfused units
Intensive vs. conventional-insulin therapy: 5 (2-10) vs. 5 (3-10) (P=0.95)
HES vs Ringer's lactate: 6 (4-12) vs. 4 (2-8) (P<0.001)
Length of stay in ICU
Intensive vs. conventional-insulin therapy: 16 (8-30) vs. 14 (7-25) days (P=0.06)
HES vs Ringer's lactate: 16 (8-28) vs. 14 (7-28) days (P=0.32)
Nasopressor-free (days)umber of transfused units
Intensive vs. conventional-insulin therapy: 16 (6-20) vs. 18 (8-20) days (P=0.24)
HES vs Ringer's lactate: 17 (6-20) vs. 17 (8-20) days (P=0.52)
Ventilator-free (days)
Intensive vs. conventional-insulin therapy: 3 (1-7) vs. 3 (1-6) days (P=0.83)
HES vs Ringer's lactate: 2 (1-6) vs. 3 (1-7) days (P=0.06)

Other Outcomes

Mean morning blood glucose level
Intensive vs. conventional-insulin therapy: 112 mg/dl (6.2 mmol/l) vs. 151 mg/dl (8.4 mmol/l) (P<0.001)
Median insulin dose administered
Intensive vs. conventional-insulin therapy: 32 (20-50) vs. 5 (0-22) units per patient per day (P<0.001)

Subgroup Analysis

No differences in the effect of insulin therapy in subgroup analyses evaluating pre-randomization APACHE II score, reason for ICU admission, diabetes, empirical or appropriate antimicrobial therapy.

Adverse Events

Hypoglycemia (≤40 mg/dl [2.2 mmol/l])

Intensive vs. conventional-insulin therapy: 17% vs. 4.1% (P<0.001)
HES vs Ringer's lactate: 10.3% vs. 9.8% (P=0.85)
  • Considered to be a serious adverse event
    • Intensive vs. conventional-insulin therapy: 7.7% vs. 2.4% (P=0.005)
    • HES vs Ringer's lactate: 5% vs. 4.7% (P=0.90)
  • Considered to be life-threatening
    • Intensive vs. conventional-insulin therapy: 5.3% vs. 2.1% (P=0.05)
    • HES vs Ringer's lactate: 5.4% vs. 3.6% (P=0.90)

Serious adverse events (≥1 episodes)

Intensive vs. conventional-insulin therapy: 10.9% vs. 5.2% (P=0.01)
HES vs Ringer's lactate: 8.4% vs. 7.3% (P=0.63)
  • Resulting in prolonged hospitalization
    • Intensive vs. conventional-insulin therapy: 2.4% vs. 0.3% (P=0.05)
    • HES vs Ringer's lactate: 1.5% vs. 1.1% (P=0.72)
  • Bleeding
    • Intensive vs. conventional-insulin therapy: 2.4% vs. 2.4% (P=0.99)
    • HES vs Ringer's lactate: 3.4% vs. 1.5% (P=0.14)
Other
  • Intensive vs. conventional-insulin therapy: 1.6% vs. 0.3% (P=0.19)
  • HES vs Ringer's lactate: 0.4% vs. 1.5% (P=0.37)

Criticisms

  • Fluid resuscitation volume in the trial exceeded the manufacturer's recommendation.[11]
  • More patients who received HES had heart failure or emergency surgery. These factors may increase their risk to renal impairment. However, the authors do not think that the small differences can account for the adverse effect of HES on renal function.[11]
  • The study was underpowered.[11]
  • The definition of AKI consists of doubling of baseline serum creatinine and requirement for renal-replacement therapy. These endpoints should be analyzed separately.[12]
  • The serum creatinine level of 3.6 mg/dL used as an exclusion criterion is higher than the recommended specification for HES.[12]

Funding

  • German Federal Ministry of Education and Research
  • B. Braun, HemoCue, and Novo Nordisk

Further Reading

  1. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-461
  2. Finfer S, et al. Intensive versus conventional glucose control in critically ill patients. N Eng J Med 2009. 360(13):1283-1297.
  3. Myburgh JA, Finfer S, Bellomo R, et al; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group: Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012; 367:1901–1911
  4. Guidet B, Martinet O, Boulain T, et al: Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Crit Care 2012; 16:R9
  5. Perner A, Haase N, Guttormsen AB, et al; 6S Trial Group; Scan dinavian Critical Care Trials Group: Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med 2012; 367:124–134
  6. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD000567. DOI: 10.1002/14651858.CD000567.pub6
  7. Mutter TC, Ruth CA, Dart AB. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD007594. DOI: 10.1002/14651858.CD007594.pub3.
  8. Dellinger RP, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637
  9. American Diabetes Association. 13. Diabetes Care in the Hospital. Diabetes Care 2016 39:S99-S104; doi:10.2337/dc16-S016
  10. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864-874
  11. 11.0 11.1 11.2 Insulin and pentastarch for severe sepsis. N Engl J Med. 2008;358(19):2073
  12. 12.0 12.1 Thomas G, Balk EM, Jaber BL. Effect of intensive insulin therapy and pentastarch resuscitation on acute kidney injury in severe sepsis. Am J Kidney Dis. 2008;52(1):13-7