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Update on Fluid Management
Intravenous Fluid Therapy
Using Colloids:
New Data, New Controversies
D John Doyle MD PhD FRCPC
Cleveland Clinic Foundation
September, 2004
This talk can be downloaded from
http://colloidtalk.homestead.com
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 volumes
• 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 LONGER TRUE ! (SAFE Trial)
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 2004)
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. Metaanalyses 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 analyzed.
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 multiorgan dysfunction syndrome without
detrimental side-effects.
Overview
• 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)
History
Starling EH. Physiological Factors in the
Causation of Dropsy
Lancet 1896
Dropsy
The American Heritage® Dictionary of the
English Language: Fourth Edition. 2000.
Edema.
No longer in scientific use.
Starling’s Law
Jv = Kf (Pc-Pt) - d (c-t)
Jv
Kf
d
P

t
c
fluid flux
filtration constant
osmotic coefficient
hydrostatic pressure
oncotic pressure
tissue
capillary
Fluid Compartments
• ICF Volume is INTRACELLULAR
• ECF Volume is EXTRACELLULAR
• 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
Colloids
NS, RL
Albumin, HES
75 % Extravascular
25 % Intravascular/
Plasma Volume
Almost 100 %
Intravascular/
Plasma Volume
Plasma Volume Expansion
Blood Loss
• Hemorrhage
• Surgery
• Trauma
Fluid Loss
• Burns
• Sepsis
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 position)
• Airway edema
• Scleral edema
• GI edema
• Acid base disturbances
Hypertonic Saline
Hypertonic Saline
Currently, only 3% solutions are available "offthe-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 Commentary
Hypertonic Saline Resuscitation in Anesthesia and Surgery
Robert R Kirby MD and Emilio B Lobato MD
Current Anesthesiology Reports 2000 2:257-258 (published 1 July 2000)
http://www.biomedcentral.com/1523-3855/2/257/abstract
Colloids
• 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
amylase
• 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 longer
Cytokines
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 (RLgroup; 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
pg*dL(-1) of IL-6 and 35.8 +/- 11.2 pg*mL(-1) of IL-8 (HES-group) vs 61.2 +/- 11.2 pg*dL(-1) of IL-6
and 57.9 +/- 9.7 pg*mL(-1) of IL-8 (RL-group); P < 0.05]. Serum concentrations of sICAM-1 were
significantly higher in the RL-group [(peak values) 1007 +/- 152 ng*mL(-1) (RL-group) vs 687 +/122 ng*mL(-1), (HES group); P < 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 crystalloidbased 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 >65 years undergoing major abdominal surgery.
INTERVENTIONS: Ringer's lactate (RL; n=22), normal saline solution (NS; n=22) or a lowmolecular HES (mean molecular weight 130 kD) with a low degree of substitution (0.4; HES
130/0.4; n=22) 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 regimens.
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 missing.
Concerns with Colloids
• Decreased hemoglobin
• Dilution of plasma proteins
• Dilution of coagulation factors (PT, PTT)
• Pulmonary edema / Tissue
• Allergic reaction
• Renal Issues
Oxygenation
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 < 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], highsubstituted [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) (n=21), lactated Ringer's solution (RL, n=21) or 6% HES with a low MW (130 kDa) and a
low DS (0.4) (n=21). 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 (CT=reaction time, r)], the
kinetics of clot formation [clot formation time (CFT=coagulation time, k)] and maximum clot firmness
(MCF=maximal 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 highmolecular 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 saline
• 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 20ml/kg/hr
• 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 2002.538-544
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 Study
Fluid 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 allergies.
Diagnosis
A diagnosis of squamous cell carcinoma of
the maxillary sinus was made by
magnetic resonance imaging and confirmed
by biopsy following a workup.
Surgical Plan
SURGERY
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 freeflap 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 mmol/L
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 mL.
ABL=2(5300) x (130-100)/(130+100)
=1400 mL (approx.)
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
reached.
ABL Formula
The allowable blood loss (ABL) was
estimated using the following formula:
ABL=2BV x (Starting Hb-Allowable
Hb)/(Starting Hb+Allowable Hb)
ABL=2(5300) x (130-100)/(130+100)
=1400 mL (approx.)
Two options to replace
ongoing blood losses
• 4:1 with a crystalloid such as
saline or Ringer’s lactate solution
or
• 1:1 with a colloid such as Pentaspan
(10% pentastarch in 0.9% sodium chloride
injection)
This is given in order to keep the patient
isovolemic.
Rule of Thumb
One often used "rule of thumb" is to replace
initial blood losses with crystalloid such as
saline on a 4:1 basis until blood losses reach
15-20% of blood volume. Replace
subsequent losses 1:1 with a colloid such as
Pentaspan (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
liters
 20% blood volume = 1 liter of blood
 Crystalloid replacement for 1 liter blood is 3-4 liters
 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 the
patient's cardiopulmonary disease. In a
much younger patient without any
known 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 to
going 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
EXAMPLES
10 kg
20 kg
30 kg
40 kg
70 kg
40 ml/hr
60 ml/hr
70 ml/hr
80 ml/hr
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.
Remember
• Preoperative fluid deficit anticipated at
1300 mL
• Third space losses of 320 mL/hr expected
• Maintenance fluid requirements of
130mL/hr expected
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 1:1 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.
Remember
• 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 preop 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 ?
ALBUMIN OR SALINE?
FINDINGS FROM THE
SAFE STUDY
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.
ALBUMIN OR SALINE?
FINDINGS FROM THE
SAFE STUDY
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. 1998;317:235-240.
ALBUMIN OR SALINE?
FINDINGS FROM THE
SAFE STUDY
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 albumin’s
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. 2001;135:149-164.
ALBUMIN OR SALINE?
FINDINGS FROM THE
SAFE STUDY
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.
ALBUMIN OR SALINE?
FINDINGS FROM THE
SAFE STUDY
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 randomization.
ALBUMIN OR SALINE?
FINDINGS FROM THE
SAFE STUDY
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.
ALBUMIN OR SALINE?
FINDINGS FROM THE
SAFE STUDY
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 1:1.38 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.
ALBUMIN OR SALINE?
FINDINGS FROM THE
SAFE STUDY
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.
ALBUMIN OR SALINE?
FINDINGS FROM THE
SAFE STUDY
NOW PUBLISHED
NEJM 2004 350:2247-2246
May 27, 2004
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
Car Accidents
from www.trauma.org
(trauma image bank)
Earthquakes
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
management)
• Not enough help
• Not enough lines
• Not enough fluid warmers
• Not monitoring coagulation
Massive Fluid Resuscitation:
Things to Look Out For
•
•
•
•
•
•
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 May;42(5):857-61
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 Transfusions?
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 1998;74 Suppl 2:399-407
Characteristics of Coagulopathy with
Massive Transfusions
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
impaired.
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 tests.
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/Massive.html]
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 1998;74 Suppl 2:399-407
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/Massive.html]
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 situations.”
“
“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 counts.”
Massive blood transfusion, blood volume expansion and hemostasis
Hématologie. Vol. 6, Issue 3, May - June 2000: 191-7, Reviews
http://www.john-libbey-eurotext.fr/articles/hma/6/3/191-7/en-resum.htm
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 trauma.
(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 Injuries
 Bickell, W.H., et al, N Engl J Med 331:1105, 1994
 Prospective trial of 598 patients with penetrating torso
trauma and systolic BP < 90 mm Hg
 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 (p=0.04)
 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.
Pentastarch:
How 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 hemostasis
Hématologie. Vol. 6, Issue 3, May - June 2000: 191-7, Reviews
http://www.john-libbey-eurotext.fr/articles/hma/6/3/191-7/en-resum.htm
World J Surg 1998 Jan;22(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) < 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 > 100 mmHg. Blood
pressure, infused volumes necessary to maintain SBP, and overall survival rates
were determined and compared between groups.
World J Surg 1998 Jan;22(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 < 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 resuscitation.
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.
Hypotheses
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