Ivan K' Crosby, M'B',B'S', FRCS Ed'

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• Ivan K. Crosby, M.B.,B.S., FRCS Ed.

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(No Transcript)
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Fluid Choices in Surgery, Anesthesiology,and
Intensive Care
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Objectives

• The Physiology of Fluid Distribution
• The Colloid/Crystalloid Debate
• Current Uses of Colloids
• Meta-analyses
• Current Fluid Administration Guidelines

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The Physiology ofFluid Distribution

• (Section 1)

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Body Fluid Compartments

• Total body water
• 60 of total body weight1
• 42 L for a 70-kg male

Total Body Water 42 L 1 L water weighs 1 kg
1. Layon, Kirby. In Civetta et al, eds. Critical
Care. 1988451.
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Distribution of Total Body Water

• Intracellular fluid volume (ICV)
• 40 of 70 kg 28 L
• Extracellular fluid volume (ECV)
• 20 of 70 kg 14 L

Total Body Water ICV ECV
60 40 20
Layon, Kirby. In Civetta et al, eds. Critical
Care. 1988451.
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Division of Extracellular Fluid

• Interstitial fluid volume (ISV)
• 16 of 70 kg 11.2 L
• Plasma volume (PV)
• 4 of 70 kg 2.8 L

ECV ISV PV 20 16 4
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Cell Membranes Separate the Intracellular and
Extracellular Compartments
Cell Membrane

• Water moves across cell membranes only along
  tonicity gradients
• Isotonic fluids do not affect ICV1
• Hypotonic and hypertonic fluids do affect ICV1
• Hypotonic solutions distribute throughoutTBW
  (ECV ICV)
• Hypertonic solutions draw fluid from interstitial
  space and intracellular compartment

ICV
ECV
1. Guyton. Textbook of Medical Physiology.
1991280.
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Capillary Membranes Separate the Intravascular
and Interstitial Compartments
Capillary Membrane

• Permeable to water and small solutes but not
  proteins and red blood cells
• Interstitial fluid identical to plasma except
  less protein and few cellular elements
• Isotonic fluids distribute only to extracellular
  space1
• 1. Guyton. Textbook of Medical Physiology.
  1991280.

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Volume of Distribution of Various Fluids

• Hypotonic and hypertonic fluids
• Affect total body water
• D5W, hypertonic saline
• Isotonic fluids
• Distribute to extracellular space
• Normal saline, lactated Ringers solution
• Colloids
• Tend to remain in intravascular space
• Albumin, starches, dextrans, gelatins

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Effect of Infused Fluids on Plasma Volume

• What will be the change in PV after infusion of a
  given volume of fluid?
• Volume PV
  infused Vd

?

Change in PV
Vd Volume of distribution
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Plasma Volume ExpansionDependent Upon Vd

• PV
• Vd
• Volume of PV Fraction left
• Fluid distribution Vd in
  plasma
• D5W TBW 3/42 1/14 (14)
• NS, RL ECV 3/14 1/5 (20)
• Colloids PV 3/3 1 (100)

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The Importance of Colloid Osmotic Pressure

• Starlings law describes forces that determine
  fluid movement across the capillary membrane JV
  KF (PC PT) ?(?C ?T)
• Balance between pressures on each side of
  capillary membrane
• Hydrostatic pressure (pushes fluid out of
  space)
• Osmotic pressure (pulls fluid into space)

Wilson. Critical Care Manual Applied Physiology
and Principles of Therapy. 199257.
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Capillary Fluid Dynamics
Arterial capillary forces move fluid
outward Capillary hydrostatic pressure 30 mm
Hg Interstitial colloid osmotic pressure 8 mm
Hg Plasma colloid osmotic pressure 28 mm Hg
NET OUTWARD FORCE 10 mm Hg
Venous capillary forces draw fluid
inward Capillary hydrostatic pressure 10 mm
Hg Interstitial colloid osmotic pressure 8 mm
Hg Plasma colloid osmotic pressure 28 mm Hg
NET INWARD FORCE 10 mm Hg
Adapted from Guyton. Textbook of Medical
Physiology. 1991179.
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Pathophysiology of Hypovolemia

• Loss of fluid from vascular space to external
  environment
• Hemorrhagic shock
• Loss of fluid from vascular space to interstitial
  space
• Decreased plasma proteins
• Burns
• Kidney disease
• Liver disease
• Increased capillary permeability
• Sepsis
• Prolonged ischemia
• Burns

Hypovolemia is the abnormally decreased volume of
circulating fluid in the body
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The Colloid/Crystalloid Debate

• (Section 2)

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Goal of Fluid Therapy

• To ensure adequate oxygen delivery to the tissues
• Oxygen delivery is determined by the product of
  cardiac output and arterial oxygen content
• Volume resuscitation is often the first step
  toward ensuring adequate cardiac output

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Fluid Choices in Hypovolemia Crystalloid vs
Colloid

• Crystalloid Solutions
• Most common
• Normal saline
• Lactated Ringers solution
• Freely cross intact capillary membrane
• Comparatively short duration of action, and large
  volume required for fluid resuscitation
• Inexpensive

• Colloid Solutions
• Most common
• Human serum albumin
• Hetastarch
• Intact capillary membrane relatively impermeable
  to colloids
• Comparatively long duration of action, and
  smaller volumes required for fluid resuscitation
• More expensive than crystalloid

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Fluid Resuscitation with Crystalloid

• Reduces colloid osmotic pressure by dilution of
  plasma proteins1
• After 30 min, only 33 of infused volume remains
  in vascular space after 1 h, only 25 remains1
• Peripheral edema common with infusion of gt10 L in
  24 h2

1. Layon, Kirby. In Civetta et al, eds. Critical
Care. 1988461. 2. Wilson. Critical Care Manual
Applied Physiology and Principles of Therapy.
1992250.
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Fluid Resuscitation with Colloid

• Contains large, osmotically active molecules
• Maintains plasma colloid osmotic pressure
• 100 mL of 25 albumin solution draws 350 mL into
  the intravascular space, increasing plasma volume
  by 450 mL over 30-60 min1

1. Wilson. Critical Care Manual Applied
Physiology and Principles of Therapy. 1992250.
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The Colloid/Crystalloid Debate

• Colloids have theoretical advantage
• Greater plasma volume expansion with given fluid
  volume
• Remain in intravascular space longer
• Cause less interstitial edema
• Crystalloids
• Require greater volume to achieve equal plasma
  volume expansion
• Cheaper

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Acquisition Costs

• Hetastarch 16.02 / 500 ml
• Albumin 5 19 / 500 ml
• Albumin 25 19 / 100 ml

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Current Uses of Colloids

• (Section 3)

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Colloids Common Practice Patterns1. Support of
Blood Pressure

• Hemodynamic rescue
• Acute normovolemic hemodilutionPlasmapheresis
• Support of cerebral perfusion pressure
• Head injury
• Subarachnoid hemorrhage
• Burns
• Volume resuscitation
• Prevention of flash pulmonary edema

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Colloids Common Practice Patterns2. Maintenance
of Colloid Oncotic Pressure

• To minimize edema formation in certain surgical
  procedures
• Plastic surgery
• To mobilize peripheral edema after resolution of
  capillary leak syndrome
• 25 albumin followed by slow IV injection of
  furosemide (Lasix chaser)

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Colloids Common Practice Patterns3. Special
Clinical Situations (Albumin Specific)

• Cardiopulmonary bypass prime
• To coat circuit (to decrease contact activation)
• Meningococcal sepsis
• Liver failure and bacterial peritonitis
• Hemolytic disease of the newborn
• Nutritional support

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Albumin in Patients with Cirrhosis and
Spontaneous Bacterial Peritonitis

• Randomized, multicenter, non-blinded trial
• 126 cirrhotic patients with spontaneous bacterial
  peritonitis treated with either
• Cefotaxime alone
• Cefotaxime albumin 1.5 g/kg during initial 6 h
  and 1 g/kg on day 3

Sort et al. N Engl J Med. 1999341403.
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Albumin in Patients with Cirrhosis and
Spontaneous Bacterial Peritonitis Less
Nephropathy and Mortality

• Cefotaxime Cefotaxime P value
• albumin
• Renal impairment 33 10 0.002
• In-hospital mortality 29 10 0.01
• Mortality at 3 months 41 22 0.03
• Albumin reduced renal impairment and mortality

Sort et al. N Engl J Med. 1999341403.
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Labeled Indications for Albumin and Hetastarch

• Human Serum Albumin
• Major labeled indications
• Hypovolemia with or without shock
• Burns
• Hypoalbuminemia
• Cardiopulmonary bypass
• ARDS
• Cirrhosis
• Nephrosis
• Hemolytic disease of newborn
• Plasmapheresis

• Hetastarch
• Labeled indications
• Plasma volume expansion for hypovolemia or shock
• Leukapheresis (hetastarch in normal saline only)

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Scientific Support for Colloid UseProspective
Outcome Data

• Albumin Hetastarch
• Ø Ø
• Ø Ø
• Ø Ø
• ? Ø
• Ø Ø
• Ø Ø
• Ø Ø
• Ø Ø
• ? Ø
• ? NA
• Ø Ø
• ? Ø
• ? NA
• ? Ø

• Hemodynamic rescue
• Acute normovolemic hemodilution/plasmapheresis
• Support cerebral perfusion pressure
• Systemic inflammatory response syndrome
• Burns
• Maintain colloid oncotic pressure
• Mobilize edema
• Minimize edema (plastic surgery)
• CPB prime
• Nutritional support
• Refractory ascites
• Ascites and spontaneous bacterial peritonitis
• Hemolytic disease of newborn/preserve platelets
• ARDS/acute lung injury
• ?prospective outcome data Øno prospective
  outcome data
• NAnot applicable

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Meta-analyses

• (Section 4)

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Recent Meta-analyses Comparing Crystalloid and
Colloid

• Schierhout, Roberts (1998)
• Cochrane Review (1998)
• Choi et al (1999)
• Wilkes, Navickis (2001)

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Summary of Meta-analyses

• No clear winner in this episode of the
  colloid/crystalloid debate
• The Cochrane Group meta-analysis reported
  increased risk of death with albumin across
  subgroups1numerous methodologic criticisms
• Suggestion that crystalloid may be superior in
  trauma patients (Schierhout, Roberts2 Choi et
  al3)
• The Wilkes and Navickis meta-analysis found no
  evidence of excess mortality in albumin
  recipients4

1. Cochrane Injuries Group Albumin Reviewers.
BMJ. 1998317235. 2. Schierhout , Roberts. BMJ.
1998316961. 3. Choi et al. Crit Care Med.
199927200. 4. Wilkes, Navickis. Ann Intern Med.
2001 135149.
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Current Fluid Administration Guidelines

• (Section 5)

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Guidelines for Fluid Resuscitation
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UHC Model Guidelines for Volume Expansion

• First published in 1993
• Revised in 1998 when the availability of albumin
  was limited
• Revision published in May 2000

University HealthSystem Consortium. Technology
Assessment Albumin, Nonprotein Colloid, and
Crystalloid Solutions. 20005.
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UHC Model Guidelines for Volume Expansion (Contd)

• Do not represent standards of care
• Developed to help hospitals design their own
  guidelines
• Delphi method i.e., unanimous agreement of
  reviewers not required

University HealthSystem Consortium. Technology
Assessment Albumin, Nonprotein Colloid, and
Crystalloid Solutions. 20005.
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Revised UHC Model GuidelinesHemorrhagic Shock

• Crystalloid and colloid solutions should not be
  considered substitutes for blood or blood
  components
• Crystalloids are considered to be the initial
  resuscitation fluid of choice
• When 4 L of crystalloid fail to produce a
  response within 2 h in adults, consider
  non-protein colloids or 5 albumin (when
  non-protein colloids are contraindicated)

University HealthSystem Consortium. Technology
Assessment Albumin, Nonprotein Colloid, and
Crystalloid Solutions. 20005.
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ACCCM/SCCM Practice Parameters for Hemodynamic
Support in Sepsis

• Isotonic crystalloids and iso-oncotic colloids
  are equally effective in restoring tissue
  perfusion when titrated to the same hemodynamic
  end points
• Crystalloid solutions will require 2 to 4 times
  more volume than colloids to achieve equivalent
  hemodynamic end points
• Large-volume crystalloid resuscitation results in
  significant decreases in plasma colloid oncotic
  pressure

Task Force of the ACCCM/SCCM. Crit Care Med.
199927639.
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AASLD Practice Guidelines for Refractory Ascites
Caused by Cirrhosis

• DefintionRefractory ascites is ascites that is
  not responsiveto a low-sodium diet and
  diuretics
• Guideline Treat with serial paracentesis
  every 2 weeks
• For large-volume paracentesis (?5 L),consider
  infusion of ?50 g albumin

Runyon. Hepatology. 199827264.
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The History of Human Serum Albumin

• First isolated from plasma 60 years ago
• Plasma fractionation allowed isolation of
  albuminand other components
• First inventory used to treat injured American
  servicemen at Pearl Harbor. Dried plasma was
  used in WWII as a whole blood substitute

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Albumin Derived by Fractionationof Plasma
Recovered plasma
Coagulation factors (FACTOR VIII, factor IX)
IMMUNOGLOBULINS (fraction II and III)
Fibrinogen (fraction I)
Lipoproteins, transferrin (fraction IV)
ALBUMIN (fraction V)
Hyperimmune globulins
IV immuneglobulin
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Fractionation of Plasma
PLASMA
Plasma, 1 Liter
1 Liter
Fibrinogenand other factors
Human serum albumin25 g
Factor VIII 200 IU
IV immune globulin4 g
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Properties of Albumin

• Major osmotically active protein in plasma
• Water soluble
• Consists of 575 amino acids
• MW 69 kd
• Anionic
• Reversibly binds many ligands1,2
• Endogenous steroids, fatty acids, bilirubin
• Exogenous many drugs
• 1. Peters. All About Albumin. 199677,103.
• 2. Vorum. Dan Med Bull. 199946379.

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Properties of Albumin (Contd)

• Half-life in circulation 20 days
• Turnover about 15 g/kg/day
• Normal transcapillary leak 5/h
• Returned to the circulation via lymphatics
• Increased in sepsis and other critical illness

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Proposed Beneficial Effects of Albumin

• Antioxidant/free-radical scavenger1
• AntiTNF?2
• Decreases microvascular permeability3
• Causes less neutrophil activation (vs
  hetastarch)4

1. Soriani et al. Arch Biochem Biophys.
1994312180. 2. Nathan et al. J Cell Biol.
1993122243.3. Holbeck, Grände. Crit Care Med.
2000281089.4. Rhee et al. Crit Care Med.
20002874.
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Reported Adverse Effects of Albumin

• Hypersensitivity reactions1
• Volume overload
• Edema
• Reduction in GFR (with 25 albumin)2
• Aluminum toxicity (renal failure)1
• Hypocalcemia3
• 1. McEvoy. AHFS Drug Information. 20011356.
• 2. Roberts, Bratton. Drugs. 199855621.
• 3. Kovalik et al. J Trauma. 198121275.

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Safety of Albumin Viruses

• Pasteurization inactivates HIV and hepatitis
  viruses1
• No known transmission of HBV, HCV, or HIV in
  almost 60 years of clinical use1
• Pasteurized albumin from a known infected source
  failed to transmit HAV
• Stringent donor selection and screening

1. Tabor. Transfusion. 1999 391160.
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Safety of Albumin Prions

• Donors are screened and deferred for history of
• Receipt of transplanted tissue, dura mater or
  corneas
• Blood transfusions
• Pituitary-derived growth hormone
• Residence in or visits to UK or continental
  Europe between 1980 and 1996
• No known transmission of Creutzfeldt-Jakob
  disease or variant-type CJD to date1,2

1. Dormont. Ann Fr Anesth Réanim. 199615560. 2.
McEvoy. AHFS Drug Information. 20011356.
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Properties of Hetastarch

• Branched polymer of amylopectin
• Metabolized by amylase
• Hydroxyethyl groups added to slow degradation
• Spectrum of MWs 101000 kd
• Mean MW of high-MW hetastarch ?450 kd
• 23 extravasated to the interstitial space in 24
  htrace amounts remain in circulation for up to
  26 wk
• Renal excretion of particles with MW lt72 kd(?
  increased risks in renal failure)

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Chemical Structure of Hetastarch
CH2OH
CH2O
CH2CH2OH
6
O
O
Hydroxyethyl starch Amylopectin with
hydroxyethyl groups added at the 2 and/or 6
carbon atoms
1
O
OH
OH
OH
OH
O
CH2OH
CH2
CH2OH
6
O
O
O
1
4
O
O
O
O
O
O
OH
OH
OH
2
CH2CH2OH
OH
OH
O
53
Revised UHC Model GuidelinesContraindications
to Hetastarch

• Previous hypersensitivity
• Underlying bleeding disorder
• Risk of intracranial hemorrhage
• Renal failure with oliguria or anuria

Guidelines require consideration of individual
patient factors
University HealthSystem Consortium. Technology
Assessment Albumin, Nonprotein Colloid, and
Crystalloid Solutions. 20005.
54
Reported Adverse Effects of Hetastarch

• Allergic or sensitivity reactions to hetastarch
  have been reported
• May cause vomiting, mild temperature elevations,
  chills, itching, enlarged submaxillary and
  parotid glands, mild flu-like symptoms, headache,
  myalgia, peripheral edema of lower extremities,
  and anaphylactoid reactions
• May interfere with platelet function and increase
  PT, PTT, and clotting time
• Large doses may prolong bleeding time
• Large volumes may decrease hematocrit and dilute
  plasma proteins
• Hemodilution by hetastarch and sodium chloride
  may cause 24-h reductions in serum total protein,
  albumin, calcium, and fibrinogen
• McEvoy. AHFS Drug Information. 20012512.

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Common Colloid Choicesin the USA

• Human Serum Albumin
• Hetastarch

• Very similar colloid oncotic properties,
  including
• Dwell times in the intravascular space
• Expansion of plasma volume
• Resultant hemodynamic responses

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Background

• Issues in Colloidal Fluid Therapy Albumin vs.
  Hetastarch
• Cost
• Availability
• Bleeding Risk

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Acquisition Costs

• Hetastarch 16.02 / 500 ml
• Albumin 5 19 / 500 ml
• Albumin 25 19 / 100 ml

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Hetastarch and Coagulation Dysfunction

• Inhibition of factor VIII complex1
• Effect proportional to2
• Average MW
• Hydroxyethyl substitution ratio
• C2/C6 hydroxyethyl group location ratio

1. Conroy et al. Anesth Analg. 199683804. 2.
Treib et al. J Neurosurg. 199685367.
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Hetastarch and Coagulation DysfunctionReports
in Specific Circumstances

• Recommended dose limit exceeded
• Cully et al. Anesthesiology. 198766706.
• At/near dose limit on consecutive days
• Trumble et al. J Neurosurg. 19958244.
• Cardiopulmonary bypass
• Cope et al. Ann Thorac Surg. 19976378.
• Villarino et al. Infect Control Hosp Epidemiol.
  199213282.
• Herwaldt et al. Infect Control Hosp Epidemiol.
  1998199.
• Knutson et al. Anesth Analg. 200090801.
• Canver et al. Chest. 20001181616.

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Cope JT, Banks D, Mauney MC, Lucktong T,
Shockey KS,Kron IL, Tribble CGAnn Thorac Surg
19976378-83

• Intraoperative Hetastarch Infusion Impairs
• Hemostasis After Cardiac Operations

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Patient Groups

• (189 CABG Patients)
• NH no heastarch (n62)
• HIO intraoperative hetastarch (n68)
• HPO postoperative hetastarch (n59)
• (Cope JT et al. Ann Thoracic Surg 1997)

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Demographic Data
(Cope JT et al. Ann Thoracic Surg 1997)
63
Preoperative Hematologic Profile
(Cope JT et al. Ann Thoracic Surg 1997)
64
Operative Variables
(Cope JT et al. Ann Thoracic Surg 1997)
65
Postoperative Hematologic Profile
(Cope JT et al. Ann Thoracic Surg 1997)
66
Conclusions

• Hetastarch infusion just after weaning from CPB
  causes a clinically important impairment in
  postop hemostasis
• Intraoperative hetastarch use during cardiac
  surgery should be avoided

67
Herwaldt LA, Swartzendruber SK, Edmond MB,
Embrey RP, Wilkerson KR, Wenzel RP, Perl
TMInfect Control Hosp Epidemiol 1998199-16

• The Epidemiology of Hemorrhage Related to Cardiac
  Operations

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Bleeding After Cardiac Surgery

• Observation
• Hemorrhage rate increased from 18 (93/511) to
  27 (78/288) coincident with CPB prime change
  from albumin to hetastarch
• Studied by retrospective case-control review

Herwaldt et al. Infect Control Hosp Epidemiol.
1998199.
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Bleeding After Cardiac Surgery (Contd)

• Hemorrhage defined as
• Reoperation for bleeding
• Postoperative blood loss gt800 mL over 4 h
• Surgeon-diagnosed excessive intraoperative
  bleeding
• Significant risk factors for hemorrhage
  identified as
• Patient age (P0.02)
• Use of gt5 mL/kg of hetastarch (P0.05)

Herwaldt et al. Infect Control Hosp Epidemiol.
1998199.
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Study Design

• 2 Case-control Studies to Evaluate Risk of
  Hemorrhage after Cardiothoracic Surgery
• Definition of Hemorrhage
• Reoperation for bleeding
• Postop blood loss gt 800 ml/4 hrs.
• Surgeon-diagnosed excessive intraop bleeding
• (Herwaldt LA et al. Infect Control Hosp Epidemiol
  1998)

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Comparison of Cases and ControlsIntraoperative
Factors
(Herwaldt LA et al. Infect Control Hosp Epidemiol
1998)
72
Comparison of Cases and ControlsPostoperative
Factors
(Herwaldt LA et al. Infect Control Hosp Epidemiol
1998)
73
Association of Hetastarch With Hemorrhage
P lt0.05 for distribution of hetastarch doses,
cases vs controls
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Unadjusted Hospital Costs
(Herwaldt LA et al. Infect Control Hosp Epidemiol
1998)
75
Cost Saving IssuesAlbumin vs. Hetastarch

• Potential savings with Hetastarch use
• 14 - 107 per patient
• 7,000 - 53,000 per year
• Hetastarch in priming solution doubles risk of
  hemorrhage
• Cost of hemorrhage 3,458 per patient
• Result cost of hemorrhages more than offset
  predicted savings

(Herwaldt LA et al. Infect Control Hosp Epidemiol
1998)
76
Conclusions

• Definition of hemorrhage identified patients
  who
• required increased volumes of blood products
• had an increased crude mortality
• had a higher cost of hospitalization

(Herwaldt LA et al. Infect Control Hosp Epidemiol
1998)
77
Conclusions

• Patient age and hetastarch use were risk factors
  for hemorrhage

(Herwaldt LA et al. Infect Control Hosp Epidemiol
1998)
78
Conclusions

• Efforts to save money by substituting less
  expensive products (e.g. hetastarch) may actually
  increase costs by increasing the probability of
  perioperative adverse events

(Herwaldt LA et al. Infect Control Hosp Epidemiol
1998)
79
Knutson JE, Deering JA, Hall FW, Nuttall GA,
Schroeder DR, White RD, Mullany CJMayo Clinic,
Rochester MN

• Does Intraoperative Hetastarch Administration
  Increase Blood Loss and Transfusion Requirement
  After Cardiac Surgery

(Anesth Analg 200090801-7)
80
Does Intraoperative Hetastarch Increase Blood
Loss and Transfusion Requirement?

• Retrospective chart review of 444 patients
  undergoing cardiac surgery requiring CPB
• Two non-concurrent groups
• 234 received intraoperative hetastarch
• 210 received no intraoperative hetastarch
• Blood loss and transfusion requirements
  significantly greater among hetastarch recipients

Knutson et al. Anesth Analg. 200090801.
81
Increased Blood Loss

1400
1283
1200

979
1000
923
800
Mean blood loss (mL)
681

600
515
377
400
200
0
0-4 h
0-24 h
0-12 h
Plt0.001
Knutson et al. Anesth Analg. 200090801.
82
Meta-analysis of Postoperative Bleeding in CPB
Surgery

• 16 randomized controlled trials of 653 patients
  exposed to albumin or hetastarch during CPB
• Results In 88 of trials, post-op blood loss was
  lower in albumin recipients
• Blood loss gt1000 mL 19 of albumin
  recipientsand 33 of hetastarch recipients
• Cumulative blood loss following CPB surgery was
  significantly lower in patients exposed to
  albumin than in those exposed to hetastarch

Wilkes et al. Ann Thorac Surg. 2001 72527.
83
Background

• Bleeding Risk of Hetastarch
• Coagulation abnormalities
• Increased postoperative blood loss
• Bleeding risk increased at doses gt20 ml/kg
  (-1,500ml)
• Possibly due to dilution of blood components

84
Bleeding Drugs

• ASA
• Plavix, Ticlid
• Reopro, Integrillin, Tirofiban
• TPA
• Retavase
• Streptokinase

85
Aprotinin in Cardiac Operations

• Prospective, randomized study
• Patients undergoing cardiopulmonary bypass
• Three groups
• Group 1 prophylactic high-dose aprotinin
• Group 2 postoperative aprotinin
• Group 3 nonmedicated control group

(Cicek et al. Ann Thorac Surg 1996611372-6)
86
Aprotinin in Cardiac Operations

• Significantly decreased chest tube outputs and
  homologous blood products use in both aprotinin
  groups
• Postoperative aprotinin reduces blood loss and
  transfusion requirements comparable with
  prophylactic high dose aprotinin
• Thus its use can be restricted to patients with
  high excess postoperative bleeding

(Cicek et al. Ann Thorac Surg 1996611372-6)
87
Cost ComparisonAprotinin vs Blood Products

• Aprotinin
• 1038.33 - 1869

• Blood Products
• 4x FFP 156
• 10x PLTS 650
• Total 806

88
Patient 1

• 400 lb male aged 60 years
• 8 cm JUXTA-Renal Aortic Aneurysm
• Inflammatory Adhesions
• Cell-Saver (No Bank Blood Products)
• 14 Liters I.V. Infusion Intraoperatively
• Good Renal Function
• Transitory Severe Oliguria Postoperatively
• Normal Renal Function

89
Patient 1 continued)

• Postoperative Fluids Based on
• Hematocrit
• Third Space Loss and Blood Pressure
• Renal Function

90
Patient 2

• 84 year old male with renal failure on dialysis
• 120 lbs
• In community hospital for evaluation of 7 cm
  thoraco-abdominal aneurysm assessing
  therapeutic options
• Aneurysm Ruptured !
• Shock (BP 50/30) - Transfer
  - O.R.
• Fluid resuscitation (crystalloid) until blood
  available

91
Patient 2(continued)

• Graft completed 60 mins from arrival in O.R.
• Additional 60 mins to close
• Early dialysis postoperatively
• Next day patient weighed 45 lbs above preop weight

92
Patient 2 Ruptured Aneurysm In Slow
Motion

• No blood available
• Obligatory crystalloid resuscitation
• Emergency Transfer
• Albumin/Hetastarch if readily available in room

93
Patient 2 In O.R. In Slow Motion

• Initial resuscitation with crystalloids
• Un-cross-matched blood
• Colloids (preferably not hetastarch) as soon as
  lines in and available
• Transfuse with whole blood
• Stop all catch-up infusions when graft in place
  and patient stable

94
Patient 2 Post-Op In Slow
Motion

• Weight up 45 lbs
• Leaky capillary membranes
• Huge third space loss
• Hemodilution Hemorrhage pre and
  intraoperatively
• Hyperalimentation
• Dialysis
• Low Hematocrit
• Albumin/Packed Cells only

95
Patient 3 Pre-OpJehovahs
Witness

• No Pre-op Banking of Own Blood
• Off All Anti-Platelet Meds for 3 Weeks
• Build up Hemoglobin Pre-op (Epogen)
• Delay Surgery if Necessary

96
Patient 3 In O.R.Jehovahs
Witness

• No Albumin in Pump Prime
• Auto Transfusion (500-1000 ml)
• Heart Lung Machine
• Cell-Saver
• Meticulous Hemostasis
• Aprotinin
• Obtain Permission for Each Modality Pre-op !

97
Patient 3 Post-OpJehovahs
Witness

• Hetastarch (500-1000 ml)
• Auto-Transfusion System (In the Circuit)
• Crystalloids (Fewer Diuretics)
• In-Frequent Blood Tests (Pediatric Tubes)
• Oxygen Sats vs Blood Gases

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Summary

• Colloid/crystalloid debate remains unresolved
• Many empiric clinical uses of colloids
• Most uses of colloids not supported by RCT data
• Two most common colloid choices in USA
• Albumin
• Good safety record
• More expensive
• Hetastarch
• Coagulation dysfunction at high doses
• Greater risk in CPB?

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Conclusions

• Clinicians perceive advantages of colloid
  administration that are not yet supported by
  prospective, randomized, controlled trials
• Viral safety of albumin is well documented
• Choice between albumin and hetastarch should
  factor in safety considerations and risk of
  adverse outcomes that may increase total cost of
  care
• Large-scale RCTs will help to determine the
  optimal fluid management of patients in various
  clinical settings

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Schierhout and RobertsMeta-analysis

• 19 resuscitation studies
• End point mortality

RR Relative risk
Schierhout, Roberts. BMJ. 1998316961.
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Schierhout and Roberts Meta-analysis Limitations

• Heterogeneous fluid regimens
• Hypertonic crystalloid in five studies
• Dextrans in nine studies
• Gelatins in three studies
• More than one colloid in some studies

McAnulty, Grounds. BMJ. 1998317278. Wyncoll et
al. BMJ. 1998317278. Schierhout, Roberts. BMJ.
1998316961.
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Schierhout and Roberts Meta-analysis
Limitations (Contd)

• 47 of the 50 excess colloid deaths were accounted
  for by just three of the 19 studies
• Two involved prehospital use of hypertonic saline
  ? dextran 70 in hypotensive trauma patients
• One involved massive administration of albumin to
  burn patients without PCWP monitoring

McAnulty, Grounds. BMJ. 1998317278.
Schierhout, Roberts. BMJ. 1998316961.
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Cochrane Group Meta-analysis

• 24 studies of plasma protein fraction or albumin
  vs crystalloid or no albumin
• At least 1 death

Cochrane Injuries Group Albumin Reviewers. BMJ.
1998317235.
RR Relative risk
109
Cochrane Group Meta-analysis Limitations

• Heterogeneous study designs and various control
  fluids1
• Small numbers of heterogeneous patients1
• Unusually large volumes of albumin in some
  trials1
• Mortality not the original study end point1
• Incomplete data on time from resuscitation to
  death
• Deaths concentrated in a limited number of
  trials, including
• Burn patients who received very large volumes
• Premature infants
• One unpublished trial

1. Bell. Adverse Drug React Toxicol Rev.
199918149.
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Choi et al Meta-analysis

• 17 studies comparing isotonic crystalloid vs
  colloid/ 15 had mortality data

Mortality data RR Relative risk Overall No
difference in mortality, pulmonary edema, or
length of staySubgroup Decreased mortality in
trauma victims with crystalloid use
Choi et al. Crit Care Med. 199927200.
111
Choi et al Meta-analysis Conclusions

• Overall, our review does not show a clear
  difference between crystalloids and colloids
  with respect to all-cause mortality.
• We do not believe that colloid use should be
  universally curtailed based on these data.

Choi et al. Crit Care Med. 199927200.
112
Wilkes and Navickis Meta-analysisNo Evidence of
Excess Mortalityin Albumin Recipients

• 55 trials of 3504 randomized patients
• Included four trials (727 patients) excluded by
  Cochrane Group
• Pooled relative risk of mortality for these four
  trials 0.94

Wilkes, Navickis. Ann Intern Med. 2001 135149.
113
Wilkes and Navickis Meta-analysisNo Evidence of
Excess Mortalityin Albumin Recipients (Contd)

• Mortality RR for albumin recipients higher among
• Non-blinded trials
• Trials that did not include mortality as end
  point
• Trials with crossover design
• Smaller trials (lt100 patients)
• No evidence of excess mortality among albumin
  recipients

Wilkes, Navickis. Ann Intern Med. 2001 135149.