FLUID RESUSCITATION IN

SEPSIS; DOSE, TYPE AND THE

TOXICITY

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OPTIMIZING FLUID RESUSCITATION
THE SPONTANEOUSLY BREATHING PATIENT:

1. In euvolaemia: CVP close to zero / slightly negative = optimal CO for

venous return
2. CVP can detect fluid overload or CCF but not hypovolaemia during
spontaneous breathing
3. Greater filling pressures are not necessarily associated with greater SV or
CO
4. Greater filling pressure indicates RV diastolic dysfunction
5. CVP & PCWP do not reflect RVEDV

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OPTIMIZING FLUID RESUSCITATION
THE MECHANICALLY VENTILATED PATIENT

1. Neither absolute CVP values nor “trend tracking” the response to

bolus or challenge fluid therapy is valid or reproducible
2. The higher CVP & PCWP values here, indicate intrathoracic
pressures rather than cardiac filling or IV fluid status
3. Low pressures indicate good cardiac Function - very high pressures
indicate overload

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OPTIMIZING FLUID RESUSCITATION

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‘CRYSTALLOIDS VS
COLLOIDS’

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 Meta-Analysis: Colloid vs Crystalloid
• Meta analysis of 8 RCTs1
– Trauma patients: crystalloids favored
– Non-trauma patients: colloids comparable
– Non-septic/elective Sx (BM intact): colloids also efficacious
• A systematic review of 37 RCTs2 does not support the
continued use of colloids for volume replacement in critically ill
patients
• A systematic review of 17 studies3: no overall difference in
mortality, pulmonary edema, or length of stay between
crystalloids and colloids in fluid resuscitation

1. Velanovich V. Surgery .1989;105(1):65-71.

2. Schierhout G, et al. BMJ. 1998;316(7136):961-964.
3. Choi PT, et al. Crit Care Med. 1999;27(1):200-210.
 Meta-Analysis: Colloid vs Crystalloid
Cochrane review of IV fluids for abdominal aortic surgery

• 38 trials involving 1589 patients included

• No single fluid affected any outcome measure significantly
more than another fluid across a range of outcomes
• No studies examining the effects of combination fluid therapy;
limited data on mortality
• The review concluded that although the beneficial effects of
colloids were confirmed, further studies still required

Toomtong P, et al. Cochrane Database Syst Rev. 2010;1:2-CD000991.

Colloids vs Crystalloids in the ICU
•Meta-analysis of 65 trials
•Pooled mortality RR vs. crystalloids:
–All colloids combined: 1.01 (95% CI 0.92-1.10)
–HES: 1.18 (95% CI 0.96-1.44)
–Modified gelatin: 0.91 (95% CI 0.49-1.72)
–Dextran: 1.24 (95% CI 0.94-1.65)
–Dextran in hypertonic crystalloid: 0.88 (95% CI 0.74-1.05)
•Results unchanged after exclusion of Boldt et al
•Conclusion
–No evidence that colloids are more effective than
crystalloids in reducing mortality in people who are critically
ill or injured
Perel P, et al. Cochrane Database Syst Rev. 2011;3:CD000567.
 CRYSTALLOID VS COLLOID:
TIME TO END AN ERRONEOUS DISCUSSION
INFUSION SOLUTION ARE GENERALLY NOT CONSIDERED FOR
WHAT THEY ARE: DRUGS WITH INDICATION,
CONTRAINDICATIONS AND SIDE EFFECT

CRYSTALLOID – replacement of fluid losses:

1. Insensible perspiration
2. Urinary losses
COLLOIDS – replace plasma deficits:
1. Acute blood loss
2. Protein fluid shifts to the interstitial space

Use the right kind of fluid in appropriate amounts of the right time
It is erroneous to compare 2 classes of drugs with different indications
regarding their impact on patient outcome
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QUANTITAIVE TOXICITY
(FLUID OVERLOAD)

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FLUID BALANCE AND CLINICAL
OUTCOME IN ICU
FOUR PHASES IN THE TREATMENT OF SHOCK

Salvage Optimization Stabilization De-escalation

Obtain a minimal Provide adequate Provide organ support Wean from vasoactive
acceptable blood oxygen availability agents
pressure

PERFORM LIFESAVING Optimize cardiac Minimize complications ACHIEVE A NEGATIVE

MEASURES output, ScvO2, lactate FLUID BALANCE

Vincent JL. De Baker. NEJM 2013

 Fluid overload, de-resuscitation, and outcomes in critically ill or
injured patients: a systematic review with suggestion for clinical
practice. Anesthesiology Intensive Therapy 2014
 THE “ROSE” CONCEPT
RESUSCITATION OPTIMIZATION STABILIZATION EVACUATION
HIT 1ST HIT: WHEN DO I 2ND HIT: WHEN DO I 3RD HIT: WHEN DO I 4TH HIT: WHEN DO I
START TO GIVE STOP TO GIVE START UNLOADING STOP UNLOADING
FLUIDS? FLUIDS? FLUIDS? FLUIDS?

TIME FRAME MINUTES HOURS DAYS DAYS-WEEKS

GOALS Correct shock Maintaining tissue Aim for zero or Mobilise fluid
perfusion negative Fluid accumulation
Balance (LGFR) = emptying or
DE-resuscitation

FLUID Rapid bolus (4 mL kg- Titrate maintenance Minimal maintenance Oral intake if possible
1 10−15 min) fluids, conservative if oral intake Avoid unnecessary IV
THERAPY use of fluid bolus inadequate, provide fluids
replacement fluids

MONITORIN A-line, CV-line, PPV Calibrated CO (TPTD, Calibrated CO (TPTD, Calibrated CO (TPTD);
or SVV (manual or via PAC) PAC) Balance; BIA; DE-
G TOOLS monitor), escalation
uncalibrated CO, TTE,
TEE

MALBRAIN 2014
 PHASE OF FLUID THERAPY
PHASE I
RESUSCITATION

Dilemma
PHASE II - III
MAINTENANCE /HOMEOSTASIS
FLUID BALANCE

• Early/Aggressive Initial
Resuscitation
• Hemodynamic • Fluid Restriction PHASE III
stabilization • Loop diuretic REMOVAL/DE-RESUSCITATION
• Shock reversal • Early initiation of IHD/CRRT to
maintain fluid balance
0
HOURS HOURS - DAYS • Active elimination TIME
• Forced Diuresis
• Extracorporeal fluid removal
(IHD/CRRT)

DAYS

Fluid is a Drug. It has a toxic cumulative effects and need guide for
optimal dosing
Fluid accumulation is harmful, need an ideal strategies to remove
excess extravascular fluid post-resuscitation
George 2016
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WHAT ABOUT STARCH

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10% HES 200/0.5
vs
Ringer’s Lactate

VISEP Study
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 Guidet et al (2012)
 RCT, double-blind, prospective, multicenter
 196 subjects, ICU setting
 Intervention:
○ Control : 0.9% NaCl
○ HES: 6% HES 130/0.4 in 09% NaCl (Voluven ®)
 Outcome:
○ Primary: volume needed to achieve initial hemodynamic stabilization
○ Secondary: time to target, mortality rate, LOS, AKI incidence
 Results:
○ Volume needed is lower in HES (HES 1,379 ±886 ml, NaCl 1,709 ±1,164 ml,
mean difference = -331± 1,033, 95% CI -640 to -21, P = 0.0185)
○ No difference in mortality (HES 40.0% vs 33.0%, p=0.33),
○ No difference in AKI (p=0.81) or ARF (p=0.454)

Guidet et al. Critical Care 2012, 16:R94

 6S TRIAL (2012)
 Perner et al (2012)
 RCT, double-blind, multicenter
 804 subjects, ICU setting
 Intervention:
○ Control : Ringer’s acetat (RA)
○ HES: 6% HES 130/0.4 in RA (Tetraspan®)
 Outcome:
○ Primary: death and dependence on dialysis 90 days after randomization
○ Secondary: death at 28 days, severe bleeding, SOFA score
 Results:
○ Higher death in HES group (51% vs 43%,RR:1.17; 95% CI: 1.01-1.36; p=0.03)
○ Higher pts on RRT in HES group (22% vs 16%; RR: 1.35; 95%CI: 1.01-1.80;
p=0.04)
○ No difference in severe bleeding incidence (p=0.09)

N Engl J Med 2012;367:124-34.

 Myburgh et al (2012) CHEST TRIAL 2012
 RCT, double-blind, multicenter, prospective
 7000 subjects, ICU setting
 Intervention:
○ Control : 0.9% NaCl
○ HES: 6% HES 130/0.4 in 0.9% NaCl (Voluven®)
 Outcome:
○ Primary: all-cause death 90 days after randomization
○ Secondary: AKI, use of RRT
 Results:
○ No difference in death rate (HES 18.0% vs 17.0%, RR 1.06; 95% CI: 0.96-
1.18; p=0.26)
○ Higher incidence of AKI in HES group (22% vs 16%; RR: 1.35; 95%CI: 1.01-
1.80; p=0.04)
○ Higher use of RRT in HES group (7.0% vs 5.8%; RR: 1.21; 95%CI: 1.00-1.45;
p=0.04)

N Engl J Med 2012; 367:1901–1911

 CHEST TRIAL 2012

N Engl J Med 2012; 367:1901–1911

 CHEST TRIAL 2012

N Engl J Med 2012; 367:1901–1911

SSC 2008

SSC 2012
WHAT ABOUT ALBUMIN?

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 THE STORY OF ALBUMIN RESUSCITATION IN SEPSIS

1941
First clinical use of human albumin in trauma and circulatory shock
1943
First published reports of human albumin use in 200 pts.
(Woodruff LM, Gibson ST: The clinical evaluation of human albumin. US Naval Med Bull 1943, 40:791–796)

1975
First RCT of human albumin in pts undergoing abdominal aortic surgery. Result: albumin
infusion led to less extracellular fluid expansion.
(Skillman JJ. Randomized trial of albumin vs. Electrolyte solutions during abdominal aortic operations. Surgery 1975, 78:291–303)

1998
Cochrane Metaanalysis. Results; Albumin is harmful, may increased mortality.
(Cochrane Injuries Group Albumin Reviewers: Human albumin administration in critically ill patients: systematic review
of randomised controlled trials. BMJ 1998, 317:235–240)

1998
US FDA issued a “dear doctor” letter, urging physicians to exercise discretion in albumin use
2001
Wilkes and Navickis mata-analysis, Results; no overall effect of albumin on mortality.
Wilkes MM, Navickis RJ: Patient survival after human albumin administration. A meta-analysis of randomized, controlled trials. Ann
Intern Med 2001, 135:149–164

2003
Vincent JL Metanalysis. Results; albumin >3.0 gr/L associated with reduced complication.
Vincent JL, et al. Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled
trials. Ann Surg 2003, 237:319–334.

2004
SAFE Study, comparing albumin and saline. Results; no difference in mortality – Albumin is safe.
Subgroup analysis showed benefit albumin in pt with severe sepsis.
Finfer S. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004, 350:2247–2256
 THE STORY OF ALBUMIN RESUSCITATION IN SEPSIS

2005
US FDA , SAFE study had resolved the prior safety concern raised by the Cochrane 1998

2006
Results of SOAP Observational Study, albumin use was associated with decreased mortality in
critically ill patients.
Vincent JL, et al. Is albumin administration in the acutely ill associated with increased mortality? Results of the SOAP study. Crit Care 2005,
9:R745–R754.

2006
Pilot Study of 100 patients with .serum albumin < 3 g/L, organ function was improved in patients
treated with albumin.
Dubois MJ, et al. Albumin administration improves organ function in critically ill hypo-albuminemic patients: a prospective, randomized,
controlled, pilot study. Crit Care Med 2006, 34:2536–2540

2011
Delaney Meta-analysis, 17 studies of patients with sepsis, survival benefit for patients
received albumin.
Delaney AP, et al. The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis.
Crit Care Med 2011, 39:386–391.

2012
ESICM Task Force Consensus Statement, suggesting that albumin maybe included in the
resuscitation of severe sepsis patient
2013
Surviving Sepsis Campaign Guideline, for the first time specifically suggest use of albumin in the
fluid resuscitation of severe sepsis and septic shock.
Dellinger RP, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care
Med 2013, 41:580–637.
SSC 2008

SSC 2012
37
Baseline Characteristic Albumin Saline
Age in years - mean ± SD 58.6 ± 19.1 58.5 ± 18.7

Female gender– N (%) 1424 (40.7) 1376 (39.3)

Reason for admission to ICU – N (%)

Surgical 1,473 (42.9) 1,465 (42.7)

Medical 1,955 (57.1) 1,958 (57.3)

Pre-defined sub-groups – N (%)

Trauma 597 (17.4) 590 (17.2)

Severe sepsis 603 (18.1) 615 (18.4)

ARDS 61 (1.8) 66 (1.9)

APACHE II score - mean ± SD 18.7 ± 7.9 19.0 ± 8.0

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Mortality in patients with and without
severe sepsis.

p = 0.09

Mortality %

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 BALANCE VERSUS
UNBALANCED FLUID
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 Hyperchloremic
Acidosis
SID <<

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 Decreased renal
cortical perfusion

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 RECOMMENDATION FOR FLUID
RESUSCITATION
1. Fluids should be administered with the same caution that is
used with any intravenous drug.
1. Consider the type, dose, indications, contraindications, potential for toxicity,
and cost.
2. Fluid resuscitation is a component of a complex
physiological process.
1. Identify the fluid that is most likely to be lost and replace the fluid lost in
equivalent volumes.
2. Consider serum sodium, osmolarity, and acid–base status when selecting a
resuscitation fluid.
3. Consider cumulative fluid balance and actual body weight when selecting the
dose of resuscitation fluid.
4. Consider the early use of vasopressor as concomitant treatment of shock.

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 RECOMMENDATION FOR FLUID
RESUSCITATION
1. Fluid requirements change over time in critically ill
patients.
1. The cumulative dose of resuscitation and maintenance fluids is
associated with interstitial edema.
2. Pathological edema is associated with an adverse outcome.
2. Oliguria is a normal response to hypovolemia and should not
be used solely as a trigger or end point for fluid
resuscitation, particularly in the post-resuscitation period.
3. The use of a fluid challenge in the post-resuscitation period
(≥24 hours) is questionable.

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 RECOMMENDATION FOR FLUID
RESUSCITATION
1. Specific considerations apply to different categories of patients.
2. Bleeding patients require control of hemorrhage and transfusion with red
cells and blood components as indicated.
3. Isotonic, balanced salt solutions are a pragmatic initial resuscitation fluid for the
majority of acutely ill patients.
4. Consider saline in patients with hypovolemia and alkalosis.
5. Consider albumin during the early resuscitation of patients with severe sepsis.
6. Saline or isotonic crystalloids are indicated in patients with traumatic brain injury.
7. Albumin is not indicated in patients with traumatic brain injury.
8. Hydroxyethyl starch is not indicated in patients with sepsis or those at risk for
acute kidney injury.
9. The safety of other semisynthetic colloids has not been established, so the use of
these solutions is not recommended.
10. The safety of hypertonic saline has not been established. The appropriate type
and dose of resuscitation fluid in patients with burns has not been determined.
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Terima kasih

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