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Title: Update on Fluid Management Intravenous Fluid Therapy Using Colloids: New Data, New Controversies

Update on Fluid ManagementIntravenous Fluid
Therapy Using Colloids New Data, New
  • D John Doyle MD PhD FRCPC
  • Cleveland Clinic Foundation
  • September, 2004

(No Transcript)
This talk can be downloaded from http//colloidt
Goals and Objectives
  • To compare and contrast crystalloids and colloids
    and their use in the perioperative period
  • To compare the various HES preparations
  • To provide an update on the SAFE trial
  • To present information on the drawbacks of using
    crystalloids such as normal saline in large
  • To present information on fluid resuscitation in
    a real clinical case
  • To present information on immediate versus
    delayed fluid resuscitation for hypotensive
    patients with ongoing blood loss.

Boldt J. New light on intravascular volume
replacement regimens what did we learn from the
past three years?. Anesthesia Analgesia.
97(6)1595-604, 2003 Dec. Definition of the
"ideal" intravascular fluid volume replacement
strategy still remains a critical problem. This
article analyzes studies on volume replacement by
using a MEDLINE search of the past 3 years (from
January 1, 2000, to December 12, 2002). Forty
original studies in humans with a total of 2454
subjects were identified. Five studies were
performed in volunteers (n 113) the other 35
studies (n 2341) were performed in a variety of
patients (e.g., cardiac surgery, trauma patients,
children, and intensive care unit patients). The
influence of different volume replacement
regimens on coagulation was one of the major
topics of interest (16 studies with 1183
subjects), and other studies focused on metabolic
state, alterations in macro- and
microcirculation, volume distribution, and organ
function (e.g., kidney function and splanchnic
perfusion). Among all synthetic colloids,
hydroxyethyl starch (HES) was the solution most
often studied. Two new HES preparations have been
approved (Hextend), a balanced hetastarch
solution, and a new third-generation HES
130/0.4). Only two studies used albumin, and no
superiority of albumin was found over less
expensive synthetic colloids. In almost all
studies, the outcome either was no end-point or
was not reported. Volume replacement has often
been hitherto based on dogma and personal
beliefs. Future well performed studies in this
area will hopefully help to shed new light on the
ideal volume replacement strategy. IMPLICATIONS
By using a MEDLINE search covering the last 3 yr,
the present knowledge on volume replacement
regimens was analyzed. Forty studies in humans
were identified. New hydroxyethyl starch
preparations have shed light on this topic,
whereas no additional data supporting the use of
albumin have been presented
no additional data supporting the use of
albumin have been presented. THIS PART IS NO
Joachim Boldt (Germany) Fluid choice for
resuscitation of the trauma patient a review of
the physiological, pharmacological, and clinical
evidence. Can J Anesth 2004 51 500-513. (May
Purpose Volume replacement regimens are
discussed very emotionally. Interpretation of the
literature is difficult due to variations in
study design, patient population, target for
volume replacement, endpoints, and type of
fluids. Meta-analyses may not be very helpful
because all kinds of patients and very old
studies are included. The principles and options
for volume replacement were reviewed exclusively
in trauma patients and studies from the
literature focusing on this problem were
Source Using a MEDLINE search, volume
replacement therapy in adult trauma patients
published in the English language from 1985 to
the end of 2002 were identified and analyzed.
Studies on prehospital volume replacement, volume
replacement in the emergency area or in the
operating room, and volume therapy in trauma
intensive care unit patients were included.
Principle findings The age-old crystalloid
/colloid controversy has still not been resolved
but has been enlarged to a colloid/colloid
debate. It is now widely accepted that human
albumin could easily be replaced by synthetic
colloids for volume replacement in trauma
patients. No superiority of a specific volume
replacement strategy with regard to outcome was
found. However, in several studies outcome was
not the major endpoint. Although showing some
promising results, the importance of hypertonic
solutions for volume replacement in the trauma
patient is not yet defined.
Conclusion The choice of fluid therapy in trauma
patients engenders the most controversy and an
examination of the body of literature on this
subject results in confusion. It is imperative to
continue the search for substances that are
effective in avoiding the development of
post-trauma multi-organ dysfunction syndrome
without detrimental side-effects.
  • Physiological basis of fluid therapy
  • Colloids and crystalloids
  • Sample case
  • What is the controversy?
  • What are the consequences?
  • Massive fluid therapy
  • New developments (SAFE trial)

  • Starling EH. Physiological Factors in the
    Causation of Dropsy
  • Lancet 1896

  •   The American Heritage Dictionary of the
    English Language Fourth Edition.  2000.
  • Edema.
  • No longer in scientific use.

Starlings Law
  • Jv Kf (Pc-Pt) - ?d (?c-?t)
  • Jv fluid flux
  • Kf filtration constant
  • ?d osmotic coefficient
  • P hydrostatic pressure
  • ? oncotic pressure
  • t tissue
  • c capillary

Fluid Compartments
  • ECF Volume Plasma Volume
  • Interstitial Volume

Fluid Compartments
  • Total Body Water (0.6 L/kg)
  • 2/3 Intracellular (ICF) 0.4 L/kg
  • 1/3 Extracellular (ECF) 0.2 L/kg
  • ECF Volume (0.2 L/kg)
  • Plasma Volume (0.05 L/kg)
  • Interstitial Volume (0.15 L/kg)
  • Ratio of plasma volume to interstitial volume
    is 1-to-3 rationale for 3-to-1 replacement of
    blood losses with crystalloid

Where the IV fluid goes
  • Crystalloids
  • NS, RL
  • 75 Extravascular
  • 25 Intravascular/
  • Plasma Volume
  • Colloids
  • Albumin, HES
  • Almost 100 Intravascular/ Plasma Volume

Plasma Volume Expansion
  • Fluid Loss
  • Burns
  • Sepsis
  • Blood Loss
  • Hemorrhage
  • Surgery
  • Trauma

Plasma Volume Expansion
  • 1.0 L NS (0.9) ? 0.33 L ? Plasma Volume
  • 1.0 L Hypertonic Saline (3, 5, 7.5) ?draws
    water out from ICF to ECF leading to ? ECF
  • 1.0 L of Colloid ? 1.0 L ? of Plasma Volume

Advantage of Crystalloids
  • Inexpensive
  • Promote urine output
  • Chemically simple

Disadvantages of Crystalloids
  • Potential to impair blood supply (e.g. replanted
    digit or flap)
  • Facial edema (especially patient in the prone
  • Airway edema
  • Scleral edema
  • GI edema
  • Acid base disturbances

Hypertonic Saline
  • Hypertonic Saline
  • Currently, only 3 solutions are available
    "off-the-shelf" in the United States.
  • In Sweden, a commercially prepared 7.5 solution
    in combination with 6 dextran 70 (RescueFlow,
    BioPhausia, Knivsta, Sweden), is available.

  • Hypertonic solutions are beneficial in
    resuscitation from shock and trauma. Compared
    with isotonic solutions, the lesser volumes are
    associated with equivalent or improved systemic
    blood pressure, cardiac output, and survival in
    experimental animals. A positive cardiac
    inotropic effect is documented, as is a decrease
    in systemic vascular resistance.
  • Invited CommentaryHypertonic Saline
    Resuscitation in Anesthesia and SurgeryRobert R
    Kirby MD and Emilio B Lobato MDCurrent
    Anesthesiology Reports 2000 2257-258 (published
    1 July 2000) http//www.biomedcentral.com/1523-385

  • Human serum albumin (5 and 25)
  • Fresh frozen and stored plasma
  • HMW hydroxyethyl starch
  • LMW hydroxyethyl starch
  • Dextrans
  • Gelatins

Artificial Colloid Solutions
  • Hydroxyethyl Starches (HESs)
  • LMW (Pentaspan, PentaLyte)
  • HMW (Hespan, Hextend)
  • Dextrans
  • Gelatins
  • Artificial colloids, unlike crystalloids, are
    complex entities that undergo a regulatory
    approval process similar to that for a drug.

Properties of an Ideal Colloid
  • Non toxic
  • Non infective (sterile)
  • Non allergenic
  • Not teratogenic or mutagenic
  • No effect on diagnostic tests
  • Compatible with medications
  • No influence on hemostasis
  • Complete elimination
  • No storage in tissues
  • Good shelf life
  • No special storage requirements
  • Few very small or very large molecules

Properties of an Ideal Hydroxyethyl Starch (HES)
  • Long shelf life and easy storage
  • Few very small or very large molecules
  • No adverse effects on coagulation
  • Can be repeatedly administered

HES Properties
  • HES are a mixture of differently sized and
    differently substituted molecules
  • A higher degree of molar substation results in
    poorer degradation of the HES molecule by alpha
  • Volume effect exceeds drug concentration
    decreased HES concentration by renal elimination
    of molecules is compensated by the supply of new
    molecules (still oncotically active) from the
    degradation of the larger fragments

Characterizing HES Colloids
  • Degree of substitution (molar substitution)
  • C2/C6 ratio
  • Molecular weight distribution
  • Concentration
  • Maximum daily dose
  • Degradation by amylase

Advantages of Colloids
  • Less edema
  • Less volume administered
  • Less thermal load effect for given level of
    plasma volume expansion
  • Volume administer stays in intravascular space

  • Volume replacement with HES products is
    associated with decreased release of cytokines
    (proinflammatory molecules), and other effects
    that may improve the microcirculation.
  • Cytokines are the neurotransmitters of the
    immune system

Lang K. Suttner S. Boldt J. Kumle B. Nagel D.
Volume replacement with HES 130/0.4 may reduce
the inflammatory response in patients undergoing
major abdominal surgery. Canadian Journal of
Anaesthesia. 50(10)1009-16, 2003 Dec. PURPOSE
To investigate the effects of intravascular
volume replacement therapy on the inflammatory
response during major surgery. METHODS
Thirty-six patients scheduled for elective
abdominal surgery were randomized to receive
either 6 hydroxyethylstarch (130,000 Dalton mean
molecular weight, degree of substitution 0.4 n
18, HES-group) or lactated Ringer's solution
(RL-group n 18) for intravascular volume
replacement. Fluid therapy was given
perioperatively and continued for 48 hr in the
intensive care unit. Volume replacement was
guided by physiological parameters. Serum
concentrations of interleukin (IL)-6, IL-8 and
IL-10 and soluble adhesion molecules (sELAM-1 and
sICAM-1) were measured after induction of
anesthesia, four hours after the end of surgery,
as well as 24 hr and 48 hr postoperatively.
RESULTS Biometric and perioperative data,
hemodynamics and oxygenation were similar between
groups. On average, 4470 /- 340 mL of HES
130/0.4 per patient were administered in the
HES-group compared to 14310 /- 750 mL of RL in
the RL-group during the study period. Release of
pro-inflammatory cytokines IL-6 and IL-8 was
significantly lower in the HES-group (peak
values) 47.8 /- 12.1 pgdL(-1) of IL-6 and 35.8
/- 11.2 pgmL(-1) of IL-8 (HES-group) vs 61.2
/- 11.2 pgdL(-1) of IL-6 and 57.9 /- 9.7
pgmL(-1) of IL-8 (RL-group) P lt 0.05. Serum
concentrations of sICAM-1 were significantly
higher in the RL-group (peak values) 1007 /-
152 ngmL(-1) (RL-group) vs 687 /- 122
ngmL(-1), (HES group) P lt 0.05). Values of
sELAM-1 were similar in both groups. CONCLUSION
Intravascular volume replacement with HES 130/0.4
may reduce the inflammatory response in patients
undergoing major surgery compared to a
crystalloid-based volume therapy. We hypothesize
that this is most likely due to an improved
microcirculation with reduced endothelial
activation and less endothelial damage.
Boldt J. Ducke M. Kumle B. Papsdorf M. Zurmeyer
EL. Influence of different volume replacement
strategies on inflammation and endothelial
activation in the elderly undergoing major
abdominal surgery. Intensive Care Medicine.
30(3)416-22, 2004 Mar. OBJECTIVE Adequate
restoration of intravascular volume remains an
important maneuver in the management of the
surgical patient. Influence of different volume
replacement regimens on inflammation/endothelial
activation in elderly surgical patients was
assessed. DESIGN Prospective, randomized study.
SETTING Surgical intensive care unit of a
university-affiliated hospital. PATIENTS
Sixty-six patients gt65 years undergoing major
abdominal surgery. INTERVENTIONS Ringer's
lactate (RL n22), normal saline solution (NS
n22) or a low-molecular HES (mean molecular
weight 130 kD) with a low degree of substitution
(0.4 HES 130/0.4 n22) were administered after
induction of anesthesia until the 1st
postoperative day (POD) to keep central venous
pressure between 8-12 mmHg. MEASUREMENTS AND
RESULTS C-reactive protein, interleukins (IL-6,
IL-8), adhesion molecules endothelial leukocyte
adhesion molecule-1 (ELAM-1) and intercellular
adhesion molecule-1 (ICAM-1) were measured prior
to volume therapy at the end of surgery, 5 h
after surgery and at the morning of the 1st POD.
RL patients received 10,150/-1,660 ml of RL, NS
patients 10,220/-1,770 ml of NS and the
HES-treated group 2,850/-300 ml of HES 130/0.4
and 2,810/-350 ml of RL. Hemodynamics were
similar in all groups. CRP, IL-6 and IL-8 plasma
levels increased significantly higher in both
crystalloid groups (IL-6 in the NS group
increase to 407/-33 pg/ml RL increase to
377/-35 pg/dl) than in the HES-130 treated group
(IL-6 increase to 197/-20 pg/dl). Plasma levels
of ELAM-1 and ICAM remained almost unchanged in
the HES 130-, but significantly increased in the
RL- and NS-treated patients. CONCLUSIONS In
elderly patients, markers of inflammation and
endothelial injury and activation were
significantly higher after crystalloid- than
after HES 130/0.4-based volume replacement
Concerns with Colloids
  • Decreased hemoglobin
  • Dilution of plasma proteins
  • Dilution of coagulation factors (PT, PTT)
  • Pulmonary edema / Tissue Oxygenation
  • Allergic reaction
  • Renal Issues

Concerns with Colloids
  • Decreased hemoglobin
  • Dilution of plasma proteins
  • Dilution of coagulation factors (PT, PTT)
  • Pulmonary edema / Tissue Oxygenation
  • Allergic reaction
  • Renal Issues

Boldt J. Priebe HJ. Intravascular volume
replacement therapy with synthetic colloids is
there an influence on renal function?. Anesthesia
Analgesia. 96(2)376-82, 2003 Feb. FINAL
PARAGRAPH In reviewing the literature on HES and
kidney function, the general recommendation that
HES should be avoided in ICUs and during the
perioperative period cannot be supported. All
HES preparations are not created equally. There
are large differences in physicochemical
properties between the first-generation HES (Mw,
450 kd DS, 0.7 Hetastarch) and the newest,
third-generation HES solution (Mw, 130 kd DS,
0.4). Although promising results with this
rapidly degradable HES preparation have been
published regarding patients with moderate to
severe kidney dysfunction showing no
deterioration in kidney function, large, well
controlled, prospective studies demonstrating no
adverse effects of this HES preparations on
kidney function in the critically ill are
Concerns with Colloids
  • Decreased hemoglobin
  • Dilution of plasma proteins
  • Dilution of coagulation factors (PT, PTT)
  • Pulmonary edema / Tissue Oxygenation
  • Allergic reaction
  • Renal Issues

Lang K. Boldt J. Suttner S. Haisch G. Colloids
versus crystalloids and tissue oxygen tension in
patients undergoing major abdominal surgery.
Anesthesia Analgesia. 93(2)405-9, 2001
Aug. The effects of intravascular volume
replacement regimens on tissue oxygen tension
(ptiO(2)) are not definitely known. Forty-two
consecutive patients scheduled for elective major
abdominal surgery were prospectively randomized
to receive either 6 hydroxyethyl starch (HES)
(mean molecular weight 130 kd, degree of
substitution 0.4, n 21) or lactated Ringer's
solution (RL, n 21) for intravascular volume
replacement. Fluids were administered
perioperatively and continued for 24 h on the
intensive care unit to keep central venous
pressure between 8 and 12 mm Hg. The ptiO(2) was
measured continuously in the left deltoid muscle
by using microsensoric implantable partial
pressure of oxygen catheters after the induction
of anesthesia (baseline, T0), 60 min (T1) and 120
min thereafter (T2), at the end of surgery (T3),
and on the morning of the first postoperative day
on the intensive care unit (T4). HES 130/0.4 2920
/- 360 mL and 11,740 /- 2,630 mL of RL were
given to the patients within the study period.
Systemic hemodynamics and oxygenation (PaO(2),
PaCO(2)) did not differ significantly between the
two volume groups throughout the study. From
similar baseline values, ptiO(2) increased
significantly in the HES-treated patients (a
maximum of 59 at T4), whereas it decreased in
the RL group (a maximum of -23 at T4, P lt 0.05).
The largest differences of ptiO(2) were measured
on the morning of the first postoperative day. We
conclude that intravascular volume replacement
with 6 HES 130/0.4 improved tissue oxygenation
during and after major surgical procedures
compared with a crystalloid-based volume
replacement strategy. Improved microperfusion and
less endothelial swelling may be responsible for
the increase in ptiO(2) in the HES
130/0.4-treated patients. IMPLICATIONS In
patients undergoing major abdominal surgery, a
colloid-based (with hydroxyethyl starch HES
130/0.4) and a crystalloid-based (with lactated
Ringer's solution RL) volume replacement
regimen was compared regarding tissue oxygen
tension (ptiO(2)) measured continuously by
microsensoric implantable catheters. The ptiO(2)
increased in the HES-treated (59) but decreased
in the RL-treated (-23) patients. Improved
microcirculation may be the mechanism for the
better ptiO(2) in the HES group.
Factor VIII
  • The presence of large, highly substituted
    molecules are believed to contribute to decreases
    in Factor VIII after HES administration

Boldt J. Haisch G. Suttner S. Kumle B.
Schellhaass A. Effects of a new modified,
balanced hydroxyethyl starch preparation
(Hextend) on measures of coagulation. British
Journal of Anaesthesia. 89(5)722-8, 2002
Nov. BACKGROUND Hydroxyethyl starch (HES) may
affect blood coagulation. We studied the effects
of a modified, balanced, high-molecular weight
mean molecular weight (MW) 550 kDa,
high-substituted degree of substitution (DS)
0.7 HES preparation (Hextend) on coagulation in
patients undergoing major abdominal surgery.
METHODS Patients were allocated randomly to
receive Hextend) (n21), lactated Ringer's
solution (RL, n21) or 6 HES with a low MW (130
kDa) and a low DS (0.4) (n21). The infusion was
started after induction of anaesthesia and
continued until the second postoperative day to
maintain central venous pressure between 8 and 12
mm Hg. Activated thrombelastography (TEG) was
used to assess coagulation. Different activators
were used (extrinsic and intrinsic activation of
TEG) and aprotinin was added to assess
hyperfibrinolytic activity (ApTEG). We measured
onset of coagulation coagulation time
(CTreaction time, r), the kinetics of clot
formation clot formation time (CFTcoagulation
time, k) and maximum clot firmness (MCFmaximal
amplitude, MA). Measurements were performed after
induction of anaesthesia, at the end of surgery,
5 h after surgery and on the mornings of the
first and second days after surgery. RESULTS
Significantly more HES 130/0.4 2590 (SD 260) ml
than Hextend) 1970 (310) ml was given. Blood
loss was greatest in the Hextend) group and did
not differ between RL- and HES 130/0.4-treated
patients. Baseline TEG data were similar and
within the normal range. CT and CFT were greater
in the Hextend) group immediately after surgery,
5 h after surgery and on the first day than in
the two other groups. ApTEG MCF also changed
significantly in the Hextend) patients,
indicating more pronounced fibrinolysis. Volume
replacement using RL caused moderate
hypercoagulability, shown by a decrease in CT.
CONCLUSION A modified, balanced high-molecular
weight HES with a high degree of substitution
(Hextend) adversely affected measures of
coagulation in patients undergoing major
abdominal surgery, whereas a preparation with a
low MW and low DS affected these measures of
haemostasis less. Large amounts of RL decreased
the coagulation time.
Human Serum Albumin
  • Most abundant protein in the plasma
  • MW 69,000 daltons
  • Prepared from human donor plasma in isotonic
  • Source of unending controversy
  • SAFE study

Hespan (6 Hydroxyethyl Starch)
  • Available as 6 solution in normal saline w/
    osmolarity of 310 mOsm/l
  • Plasma volume expansion for more than 24 hrs
  • Like Dextran, can be associated w/ urticarial
    anaphylactoid reactions
  • Half life for 90 of particles is 17 days,
    whereas that of remaining 10 is 48 days
  • Dosage - usually 500-1000ml (do not usually
    exceed 1500ml/day) IV at a rate not to exceed
  • Precautions - Not a substitute for blood or
    plasma Contraindicated in patients with severe
    bleeding disorders, severe CHF, or renal failure
    with oliguria or anuria

Hespan and Heparin Mix-ups
  • Problem A fatal error occurred when a nurse
    mistakenly selected and administered two heparin
    25,000 unit per 500 mL premixed bags instead of
    HESPAN (hetastarch) for a patient who was
    actively bleeding. Such mix-ups have been
    reported on several occasions to USP, ISMP and
    FDA. Although this is primarily a nomenclature
    issue (both names include the characters h-e-p-a
    and n in the same sequence), the drugs are also
    found in similar IV bags with blue and red
    labeling. Since Hespan may be used in patients
    who are actively bleeding, the danger of
    inadvertent heparin administration is obvious.
  • Recommendation Since hetastarch is now
    manufactured generically by other companies,
    consider using an alternate to Hespan and refer
    to hetastarch products by generic name. If Hespan
    remains in stock, do not store alphabetically
    next to premixed heparin products. Label
    products, storage bins, and automated dispensing
    machine pockets with a reminder about error
    potential. ISMP has communicated with FDA and the
    manufacturer about this serious problem.
  • http//www.ismp.org/MSAarticles/A4Q99Action.html

Hextend (6 Hydroxyethyl Starch)
From Wilkes Anesth Analg, Volume 94(3).March
HES - Pentaspan
  • Synthetic plasma volume expander
  • Average MW 200,000 300,000 daltons
  • Plasma volume expansion exceeds volume of
    Pentaspan infused lasting 18-24 h
  • 12-24 h improvement in hemodynamic status
  • 70 excreted in the urine in 24 hr
  • Metabolized by serum amylases

Source BioTime, Inc.
Case StudyFluid Management for Craniofacial
Resection with Rectus Free-Flap
Case Craniofacial Resection with Rectus Free-Flap
  • A 76 year-old male, weighing 81 kg who was 185
    cm tall, presented with complaints of facial pain
    and swelling. The patient had smoked a pack of
    cigarettes a day for almost 50 years. About 10
    years ago, he developed angina while playing
    tennis. The angina was treated with the
    beta-blocker atenolol and the patient quit his
    smoking habit. At the time of diagnosis, the
    patient reported that his infrequent angina
    attacks responded quickly to sublingual
    nitroglycerine tablets. He described his exercise
    tolerance as good, being able to climb three
    flights of stairs before "getting pooped". The
    patient took no other medications and had no

  • A diagnosis of squamous cell carcinoma of the
    maxillary sinus was made bymagnetic resonance
    imaging and confirmed by biopsy following a

Surgical Plan
  • The surgical plan was to undertake a 10-hour
    craniofacial resection of the right maxilla and
    orbit and to replace the defect with a rectus
    muscle free-flap using microvascular techniques.
    A three litre blood loss is expected.
  • 10-hour craniofacial resection
  • 3 L expected blood loss

Preoperative Tests
  • Laboratory results included a hemoglobin
    concentration of 130 g/L, a creatinine of 99
    mmol/L. Vital signs, serum electrolytes,
    electrocardiogram and chest X-ray were all
    unremarkable. Hb 130 g/L Creatinine 99

Coronary Artery Disease
  • Although this patient appeared to be in fairly
    good shape, with good exercise tolerance, he had
    known coronary artery disease.
  • Because of his coronary artery disease, most
    anesthesiologists would not allow his hemoglobin
    to drop significantly below 100 g/L.

Blood Volume Estimate
  • Using 65 mL/kg as a blood volume estimate, his
    blood volume (BV) was calculated to be about 5300

ABL2(5300) x (130-100)/(130100)1400 mL
  • This suggests that with appropriate fluid
    replacement using crystalloid or colloid, the
    patient could lose up to about 1400 mL of blood,
    before a transfusion of packed red blood cells
    would likely become necessary. If serial blood
    samples were taken from an arterial line, it
    would be possible to know exactly when a minimum
    acceptable hemoglobin or hematocrit had been

ABL Formula
  • The allowable blood loss (ABL) was estimated
    using the following formulaABL2BV x (Starting
    Hb-Allowable Hb)/(Starting HbAllowable
    Hb)ABL2(5300) x (130-100)/(130100)1400 mL

Two options to replace ongoing blood losses
  • 41 with a crystalloid such assaline or Ringers
    lactate solutionor
  • 11 with a colloid such as Pentaspan(10
    pentastarch in 0.9 sodium chloride injection)
    This is given in order to keep the patient

Rule of Thumb
  • One often used "rule of thumb" is to replace
    initial blood losses with crystalloid such as
    saline on a 41 basis until blood losses reach
    15-20 of blood volume. Replace subsequent losses
    11 with a colloid such asPentaspan (to keep
    patient isovolemic) until the hemoglobin or
    hematocrit falls below the "transfusion trigger".

Rule of thumb Start Colloids at 15 - 20 Blood
Volume Loss
  • Example (20 blood loss rule of thumb)
  • 77 kg man
  • Blood volume estimated at 65 ml/kg x 77 kg 5
  • 20 blood volume 1 liter of blood
  • Crystalloid replacement for 1 liter blood is 3-4
  • Thus, consider starting a colloid after 3-4
    liters of crystalloid given to replace lost blood

Transfusion Trigger
  • In this case, a transfusion trigger of 100 g/L
    would be used because of thepatient's
    cardiopulmonary disease. In a much younger
    patient without anyknown cardiopulmonary
    disease, the trigger level might be set at 80 or
    even 70 g/L, depending on clinical judgement.

Preoperative Fluid Deficits
  • Preoperative fluid deficits are often
    estimated using the 4-2-1 rule. For an 81 kg
    patient this amounts to about 130 mL/hr. Assuming
    that the patient has been NPO for about 10 hours
    preoperatively and has had no IV prior togoing
    to the OR, the preoperative fluid deficit would
    be about 130 mL/hr x 10 hrs 1300 mL. Many
    anesthesiologists attempt to replace this deficit
    over about a two hour span at the beginning of
    the case.

4-2-1 Rule
  • 4 ml/kg/hr for first 10 kg
  • 2 ml/kg/hr for next 10 kg
  • 1 ml/kg/hr thereafter
  • 10 kg 40 ml/hr
  • 20 kg 60 ml/hr
  • 30 kg 70 ml/hr
  • 40 kg 80 ml/hr
  • 70 kg 120 ml/hr

Maintenance Fluid Requirements
  • Maintenance fluid requirements would amount to
    about 130 mL/hr

Third Space Losses
  • Third space losses include both evaporative
    losses from surgical area and fluid that enters
    the interstitium as a result of tissue trauma.
    For a case such as this one, a reasonable
    estimate of the third space losses would be about
    4 mL/kg/hr or about 320 mL/hr.

  • Preoperative fluid deficit anticipated at 1300 mL
  • Third space losses of 320 mL/hr expected
  • Maintenance fluid requirements of 130mL/hr

Desired Fluid Therapy 1
  • Run the IV at 450 mL/hour (130 mL/hr
    maintenance 320 mL/hr third space loss
    replacement) throughout course of treatment.In
    addition, for the first two hours add 650 mL/hr
    to the above amount to replace the 1300 mL
    deficit over 2 hours. The infusion rate will then
    be 1100 mL/hr (450 mL/hr 650 mL/hr) for the
    first two hours.

Desired Fluid Therapy 2
  • Switch predominately to Pentaspan 11 to
    replace the ABL of 1400 mL, with use of
    crystalloids as judged clinically appropriate by
    anesthesiologist.Transfuse packed cells when
    hemoglobin falls below the "transfusion trigger"
    of 100 g/L.

  • Run IV at 450 mL/hr. throughout treatment course
    to replace intra-op fluid losses
  • Add 650 mL/hr over first two hours to replace
    pre-op deficit
  • Add Pentaspan to replace ABL of 1400 mL
  • Transfuse with packed cells when transfusion
    trigger of 100 g/L of hemoglobin is reached

Final Note
  • Note These are starting points only. Most
    anesthesiologists would insert a CVP line, an
    arterial line and a Foley catheter in this
    patient to further guide fluid therapy. Fluid
    delivery may have to be increased should oliguria
    or hypotension occur.

The Colloid Controversy
The Colloid Controversy
  • As colloids are not associated with improved
    survival and are considerably more expensive than
    crystalloids, it is hard to see how their
    continued use outside the randomized controlled
    trial in subsets of patients of particular
    concern can be justified.
  • Schierhout and Roberts BMJ 316 961-964, 1998
  • Cochrane Review

Misuse of Evidence-Based Medicine
  • This paper exhibits all the worst abuses of
    evidence based medicine. It is written without
    insight into the subject being considered, and
    the results have been used to produce a sweeping
    generalisation which is scientifically inept.
  • Wyncoll, DJA, Beale, J and McLuckie, A. BMJ 317
    278-279, 1998.

Key Clinical Questions
  • Is there any benefit to the use of Pentaspan over
    Hespan / Hextend?
  • Are there any differences in outcome between
    albumin and HES ?
  • What are the consequences of prolonged use of HES

Key Clinical Questions
  • What should be the appropriate resuscitation
    protocol for various situations ?
  • What is the role of hypertonic solution in acute
    fluid resuscitation ?
  • What are the advantages/disadvantages of
    commercially available HES ?


Key Point
A large, randomized, double-blind clinical trial has shown that albumin and saline have the same safety and efficacy for fluid resuscitation in most critically ill patients. Only those with traumatic brain injury fared worse with albumin.

In 1998, a Cochrane analysis compared albumin
with other fluid resuscitation methods. After
analyzing 24 randomized controlled trials, the
authors concluded that albumin does not reduce
mortality and, in some cases, may increase it.
They therefore recommended that albumin not be
used outside of clinical trials. Cochrane
Injuries Group Albumin Reviewers. Human albumin
administration in critically ill patients
systematic review of randomised controlled
trials. BMJ. 1998317235-240.

In response to these findings, Wilkes and
Navickis performed a meta-analysis of 55 trials.
Although their data set included many of the same
trials that the Cochrane group used, Wilkes and
Navickis found that albumin had no significant
effect on mortality. They stated that their
findings supported albumins safety but added the
caveat that well-designed clinical trials were
needed. Wilkes MM, Navickis RJ. Patient survival
after human albumin administration a
meta-analysis of randomized, controlled trials.
Ann Intern Med. 2001135149-164.

Recently, Australian and New Zealand researchers
took on the colloid/crystalloid debate by
conducting a randomized, controlled, double-blind
trial comparing albumin and saline in almost
7,000 critically ill patients. Saline versus
Albumin Fluid Evaluation (SAFE) Study. The SAFE
study found that Albumin and saline are
clinically equivalent. The only increase in
mortality with albumin occurred in patients with
traumatic brain injury. Finfer S. Does albumin
kill? Results of a randomized control of 7,000
patients. Presented at 33rd Critical Care
Congress February 22, 2004 Orlando, Fla.

The patients were randomized to receive fluid
resuscitation with 4 albumin or 0.9 saline
solution. The amount and rate of fluid
administration was left to the discretion of the
treating clinician however, the study equipment
was carefully designed so that the ICU staff
could not tell which fluid was being given. Study
treatments were continued until patient discharge
or death, or until 28 days after initial

The primary end point was 28-day all-cause
mortality. Secondary outcomes included survival
time, proportion of new organ failures, duration
of mechanical ventilation or renal replacement
therapy, and length of hospital and ICU stay.
There were 3,473 evaluable patients in the
albumin group and 3,460 in the saline group. Both
groups were well matched for baseline
characteristics and APACHE II scores.

During the first four days of treatment, patients
in the albumin group received less fluid than did
patients in the saline group however, the
difference was not as great as had been expected
The ratio of albumin to saline was 11.38 liters.
Also during the first four days, patients in
the albumin group received more packed red blood
cells (a mean of 79 mL more per patient) than did
those in the saline group. The net daily
positive fluid balance for this period was
greater in the saline group than in the albumin
group by about 1 liter.

There were 726 deaths in the albumin group and
729 deaths in the saline group. Thus, the 28-day
mortality rate was almost identical 20.9 versus
21.1. No significant differences in outcome
were noted when the three subgroups of patients
were analyzed separately. However, when patients
with traumatic brain injury were separated from
the rest of the trauma group, there were 21 more
deaths in patients given albumin than in those
given saline. There was no treatment difference
in trauma patients without brain injury.

NOW PUBLISHED NEJM 2004 3502247-2246 May 27,

Large Volume Fluid Resuscitation
What is Massive Fluid Resuscitation?
  • No strict definition
  • Over 10 liters of crystalloid / colloid (?)
  • Usually involves an unstable patient
  • May involve massive transfusion

What is a Massive Transfusion?
  • Massive transfusion is the replacement of more
    than one blood volume (about 65 ml/kg) with blood
    components within several hours. (Some authors
    say 10 units of blood in under 24 hours).

Some Sources of Massive Blood Loss from
www.trauma.org (trauma image bank)
Car Accidents
Penetrating Trauma
Penetrating Trauma
from www.trauma.org (trauma image bank)
28 yr old male, motorcycle collision, fall over
pieces of wood. The patient was haemodynamically
normal, conscious, just demanding the removal of
the stick. Nevertheless, he was submitted to an
emergent left thoracotomy, and left laparotomy.
The piece of wood was just located behind the
sternum and in front of the heart with no major
vascular or cardiac injury found, only a
perforation of the diaphragm. Intraabdominally,
the piece passed between the left lobe of the
liver and the spleen with no further injury. We
found this almost unbelievable! Source Luis
Filipe Pinheiro, Viseu, Portugal
from www.trauma.org (trauma image bank)
Widened Mediastinum from Aortic Tear
Massive Fluid Resuscitation Sources of Trouble
  • Not enough experience (lack of proactive
  • Not enough help
  • Not enough lines
  • Not enough fluid warmers
  • Not monitoring coagulation

Massive Fluid Resuscitation Things to Look Out
  • Hypothermia
  • Hypocalcemia and hypomagnesemia
  • Coagulopathy
  • Acidosis
  • Severe anemia
  • Airway edema

Predicting Life-Threatening Coagulopathy in the
Massively Transfused Trauma Patient
  • Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan
    M, Burch JM, Galloway B Predicting
    life-threatening coagulopathy in the massively
    transfused trauma patient hypothermia and
    acidoses revisited. J Trauma 1997
  • CONCLUSION Postinjury life-threatening
    coagulopathy in the seriously injured requiring
    massive transfusion is predicted by persistent
    hypothermia and progressive metabolic acidosis.

What Mechanisms Lead to Coagulopathy in Massive
  • Coagulation defects develop primarily from
    dilution of protein coagulation factors and
    platelets when crystalloid, colloid and red blood
    cells are used to replace lost volume.
  • Hypothermia frequently also plays a role.

Massive Fluid Resuscitation Using Plasma-Poor
Red Cells
  • Hypofibrinogenemia develops first followed by
    other coagulation factor deficits and later by
    thrombocytopenia. Therefore the use of fresh
    frozen plasma (FFP) is the primary intervention
    to treat abnormal bleeding encountered in the
    replacement of massive blood loss with
    plasma-poor red cells.
  • Replacement of massive blood loss. Hiippala S.
    Vox Sang 199874 Suppl 2399-407 

Characteristics of Coagulopathy with Massive
  • Coagulopathy associated with massive transfusion
    is characterized clinically by microvascular
    bleeding or oozing from the mucosa, wound and
    puncture sites.
  • Surgeons will complain that clot formation ins

How Should Coagulopathy From Massive Transfusions
Ideally be Treated?
  • Empirical formulas using ratios of various
    components to volume administered are often
    inadequate to appropriately treat or prevent
    coagulopathy of massive transfusion.
  • Treatment should include restoration of systemic
    perfusion, maintenance of normal temperature and
    blood component therapy supported by laboratory

Consequences of Using Plasma-Poor Red Cells
  • Plasma-poor red cells are now commonly used
    instead of whole blood or packed red blood cells
    to supply hemoglobin during blood loss.
  • Since the plasma content of plasma-poor red cells
    is rather small, a deficit of plasma and
    coagulation factors develops earlier than during
    transfusion of whole blood or packed red blood
    cells .

Are Prophylactic Platelets and FFP Indicated in
Massive Transfusion?
  • Platelets should not be routinely
    administered during massive transfusion. While
    thrombocytopenia may develop in massively
    transfused patients, administration of platelets
    should be reserved for the patient exhibiting
    microvascular bleeding and a platelet count less
    than 50 x 109/L. Platelet transfusion may be
    necessary for patients with intermediate platelet
    counts (50-100 x 109/L) if it is determined the
    risk for more bleeding is significant.
  • http//www.asahq.org/ProfInfo/Transfusion/Massiv

Are Prophylactic Platelets and FFP Indicated in
Massive Transfusion?
  • As the development of thrombocytopenia is a
    highly individual phenomenon, the transfusion of
    platelets should be guided by repeatedly
    determined platelet counts.
  • Replacement of massive blood loss. Hiippala S.
    Vox Sang 199874 Suppl 2399-407 

Are Prophylactic Platelets and FFP Indicated in
Massive Transfusion?
  • FFP also should not be administered
    prophylactically for massive transfusion. In the
    massively transfused patient, clinical bleeding
    associated with coagulation factor deficiencies
    is unlikely until factor levels fall below 20
    percent of normal. In the clinical setting, this
    usually does not occur until greater than one
    blood volume has been replaced and the PT and PTT
    are less than 1.5 times control values. In the
    event the PT and PTT cannot be obtained in a
    timely fashion, FFP may be administered for
    correction of microvascular bleeding in patients
    transfused with more than one blood volume.
  • http//www.asahq.org/ProfInfo/Transfusion/Massiv

Another Viewpoint on Massive Blood Transfusions
  • In the past, prophylactic fresh-frozen plasma
    (FFP) and platelets transfusion has been said to
    have no place. However, relying on a specific
    biological diagnosis of the hemostatic defect is
    an unrealistic view in high bleeding rate
  • Considering the time scale for laboratory
    screening and blood components availability, the
    use of FFP is advocated as soon as one blood
    volume has been replaced.
  • If platelet counts and units may be more
    easily obtained, platelets transfusion may be
    guided by repeatedly determined platelet
  • Massive blood transfusion, blood volume
    expansion and hemostasisHématologie. Vol. 6,
    Issue 3, May - June 2000 191-7,

  • Minimal Volume Resuscitation
  • Recent studies have shown possible adverse
    outcomes with aggressive fluid resuscitation and
    restoration of blood pressure prior to control of
    bleeding source, esp. in penetrating torso
  • (Minimal volume fluid resuscitation Aim for
    MAP of 40 mm Hg or a SBP of 60 to 80 mm Hg)

Immediate Versus Delayed Fluid Resuscitation for
Hypotensive Patients With Penetrating Torso
  • Bickell, W.H., et al, N Engl J Med 3311105,
  • Prospective trial of 598 patients with
    penetrating torso trauma and systolic BP lt 90 mm
  • Standard resuscitation vs limited resuscitation
    (until time of surgical intervention)

Limited resuscitation
  • 375 mls IV fluid
  • Initial BP 72 mm Hg systolic
  • 30 mortality
  • 23 complication rate

Standard Resuscitation
  • 2,480 mls IV fluid
  • Initial BP 78mm Hg systolic
  • 38 mortality (p0.04)
  • 30 complication rate

Comment by Dr. Edward Crosby
  • Two solitudes are evolving regarding the optimum
    timing and scale of fluid administration after
    penetrating trauma. One view is that immediate
    fluid resuscitation should be avoided in victims
    of penetrating trauma, since restoration of the
    blood pressure may promote further hemorrhage.
    This may result in the need for massive blood
    transfusion with resultant dilutional
    coagulopathy, and technical surgical
    difficulties. The opposing (and more
    conventional) view is that fluid resuscitation
    should be started immediately since the longer
    the period of shock the greater the risk of
    developing multiple system organ failure. An
    argument against fluid restriction is that the
    blood pressure at presentation is an important
    factor influencing survival following trauma with
    the incidence of multisystem complications
    correlating with the duration and intensity of
    shock. An additional concern is that, should
    there be barriers to rapid surgical intervention,
    non-resuscitated patients may exsanguinate while
    awaiting operation. The majority of patients
    assessed by Bickell were in hospital within 30
    min of reported injury and entered the operating
    room in less than one hour of hospital time.
    Finally, it must be recognized that the reviewed
    studies (animal and human) address models and
    clinical situations relating to penetrating
    injury and are not generalizable to the patient
    population with blunt traumatic injury.

PentastarchHow much? How long?
  • WARNING General Administration of large
    volumes of PENTASPAN will decrease haemoglobin
    concentration and dilute plasma proteins
    excessively. Administration should be kept below
    the recommended ceiling of 2000 mL in 24 hours
    (see Dosage and Administration)

HES and Massive Blood Transfusions
  • Hydroxyethyl starch (HES) solutions are
    frequently used and differ in their
    pharmacological properties.
  • An acquired von Willebrand syndrome may result
    from the infusion of high molecular weight (MW)
    or of large volumes of medium MW HES solutions.
  • HES solutions infusions should be restricted
    according to recommended dose limits.
  • Massive blood transfusion, blood volume
    expansion and hemostasisHématologie. Vol. 6,
    Issue 3, May - June 2000 191-7,

World J Surg 1998 Jan22(1)2-5 Use of
pentastarch solution in the treatment of patients
with hemorrhagic hypovolemia randomized phase II
study in the emergency room. Younes RN, Yin KC,
Amino CJ, Itinoshe M, Rocha e Silva M, Birolini
D This study evaluates the hemodynamic effects
of the administration of 10 pentastarch solution
(PS) during the initial treatment of hypovolemia
in trauma patients. This prospective randomized
phase II study included trauma patients admitted
to the emergency room with hemorrhagic
hypovolemia systolic blood pressure (SBP) lt 90
mmHg. Upon admission, the patients were
randomized to receive 10 PS (n 12) or isotonic
0.9 NaCl solution (IS) (n 11), infused
intravenously in 250-ml boluses, repeated until
SBP gt 100 mmHg. Blood pressure, infused volumes
necessary to maintain SBP, and overall survival
rates were determined and compared between
World J Surg 1998 Jan22(1)2-5 Use of
pentastarch solution in the treatment of patients
with hemorrhagic hypovolemia randomized phase II
study in the emergency room. Younes RN, Yin KC,
Amino CJ, Itinoshe M, Rocha e Silva M, Birolini
D SBP increased significantly following either
IS (from 64.4 /- 9.2 mmHg to 111.1 /- 6.3
mmHg), or PS (from 63.7 /- 10.6 mmHg to 108.1
/- 9.8 mmHg) when compared to admission values
(p lt 0.05). Endovenous volumes infused were
greater (p 0.001) in IS patients (1420 /- 298
ml) than in PS patients (356 /- 64 ml). No blood
was transfused into PS patients, compared to 370
/- 140 ml of red blood cells transfused into IS
patients (p 0.015). Mortality rates were
similar in the two groups (p 0.725). We
concluded that PS is a safe, efficient method for
inducing hemodynamic recovery of hypovolemic
trauma patients, with a clear reduction in the
intravenous volumes required for acute
Arellano Pentaspan Study (currently in the
review process)
  • Primary Objective
  • To compare the effect of Pentaspan vs 5
    albumin in doses up to 45 ml/kg on laboratory
    indices of coagulation among patients undergoing
    major plastic surgical procedures.
  • Secondary Objective
  • To compare the efficacy of Pentaspan to 5
    human albumin as a plasma volume expander using
    clinical indices of intravascular volume status.

  • Patients receiving Pentaspan will not have
    clinically significant differences in laboratory
    indices of coagulation compared to patients
    receiving 5 human albumin.
  • Patients receiving Pentaspan will require less
    colloid volume administration than patients
    receiving 5 human albumin to maintain similar
    levels of intravascular volume.

The End
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