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Total body water (TBW) is approximately 60% of body

weight in young adult males (42L for 70 kg male). Adult
females comprise slightly less water and slightly more
fat per kilogram body weight. TBW is distributed
between two compartments; extracellular fluid (ECF)
and intracellular fluid (ICF). ECF itself comprises two
compartments; interstitial fluid (1SF) (that part of the
ECF which is outside the vascular system bathing the
bodys cells) and plasma (the non-cellular component
of blood).

Body Weight
70 kg


Total body water

(TBW) 42 liters

Intracellular fluid
28 liters

Bone and fat

28 kg

Extracellular fluid
14 liters

Interstitial fluid (ISF)

11 liters

3 liters


ICF is separated from ECF by a cell membrane that

is highly permeable to water but not to most
electrolytes. Intracellular volume is maintained by
the membrane sodiumpotassium pump, which
moves sodium out of the cell (carrying water with
it) in exchange for potassium. Thus, there are
significant differences in the electrolytic
composition of intracellular and extracellular fluid.

The intravascular space and the ISF are separated by the

endothelial cells of the capillary wall (the capillary
membrane). This wall is permeable to water and small
molecules including ions. It is impermeable to larger
molecules such as proteins. The higher hydrostatic pressure
inside capillaries (compared with that in the ISF) tends to
force fluid out of the vessel into the ISF.

The osmotic pressure of a solution is related directly to the

number of osmotically active particles it contains. The total
osmolarity of each of the fluid compartments is
approximately 280 mOsm I-1 Oncotic pressure is that
component of osmotic pressure provided by proteins. The
higher osmotic pressure inside capillaries tends to pull fluid
back in to the vessels.

Electrolyte concentrations differ markedly between the

various fluid compartments. Notably, sodium and
chloride are chiefly extracellular whilst the majority of







compartment. There is also a relatively low content of





intracellular fluid and plasma.





Crystalloids are fluids comprised of water to which

solutes (e.g., sodium chloride) have been added. Their
distribution following intravenous administration is
determined chiefly by their sodium concentration. Since
sodium is confined mainly to the ECF, fluids with high
sodium concentrations (e.g., 0.9% sodium chloride) will
be distributed mainly through the ECF. Solutions with
lower sodium concentrations (e.g., 5% glucose) will be
distributed throughout both ECF and the intracellular


Colloidal solutions are fluids containing large molecules that

exert an oncotic pressure at the capillary membrane. Natural
colloids include blood and albumin. Artificial colloids contain
large molecules such as gelatin, dextran, starch, and haemoglobin
solutions. Intravenous administration of colloids results chiefly
in expansion of the intravascular compartment, at least in the
first instance. The duration of intravascular persistence depends
on molecular size, shape, and ionic charge. Albumin is a
negatively charged substance and as such is repelled by the
negatively charged endothelial glycocalyx, thus extending its
intravascular duration. Colloid solutions that have an oncotic
pressure greater than that of plasma are also able to draw fluid
from the interstitial space back into the circulating compartment.

1. Blood. Blood is an appropriate replacement fluid

following severe haemorrhage. It will increase the






compartment and thus improve oxygen carriage in the

blood. Intravenous administration of blood results in

expansion of the intravascular compartment with little
or no increase in interstitial fluid.

2. Albumin. Human albumin is a single polypeptide with

a molecular weight of around 68 kDa. It has transport
functions, is able to scavenge free radicals, and has
anticoagulant properties. In health, it contributes about
80% of oncotic pressure but in the critically ill serum
albumin correlates poorly with colloid oncotic pressure.
Albumin is prepared in two concentrations (4-5% and
20%) from many thousands of pooled donors. There is
a theoretical risk of transmission of the prion causing
New Variant CreutzfeldJakob disease. The half-life
of exogenous albumin in the circulating compartment is
510 days assuming an intact capillary wall membrane.
It is expensive to prepare but has a long shelf-life.

3. Gelatins. Gelatins are produced by modifying bovine

collagens and suspending them in ionic solutions. They
have long shelf-lives and do not transmit infection.
Gelatin solutions contain molecules of widely varying
size that are excreted by the kidney chiefly unchanged.
Gelatin solutions remain in the circulating compartment for a short period, only 15% being found in the
intravascular space 24 hours after administration.

4. Dextrans. Dextrans are polysaccharide products of

sucrose. The polysaccharides themselves are of varying
molecular weight and their classification is based upon
this. Dextran 70 (average molecular weight 70 000) has
an intravascular half-life of about 12 hours. Dextrans
cause a mild aheratiori in platelet stickiness and
function and thus have an antithrombotic effect. They
have been shown to reduce the incidence of fatal
pulmonary embolism in susceptible patients.

5. Hydroxyethyl starch. Hydroxyethyl starch (HES) is

manufactured by polymerizing cornstarch. A number of
HES solutions are produced, each with a different average
molecular weight. Most HES solutions have a longer
intravascular half-life than other synthetic colloids. The
higher molecular weight starch solutions will impair factor
VII and von Willebrand factor function, thus altering
haemostatic function. There is a theoretical concern about
accumulation of higher molecular weight HES in the
reticular activating system. Some starch solutions (e.g., Haes
10%) have a higher oncotic pressure than plasma.

6. Haemoglobin solutions. Blood is the only fluid in clinical use that

has significant oxygen carrying capability. While this property makes
it indispensable during resuscitation of haemorrhagic shock, it is
expensive, in short supply, antigenic, requires cross-matching, has a
limited shelf-life, requires a storage facility and carries a risk of
disease transmission. Free haemoglobin causes severe renal injury.
Polymerization of the haemoglobin overcomes this problem and
improves intravascular persistence. Haemoglobin solutions under
development are derived from one of three sources; bovine blood,
out of date human blood (5-13% of blood donated in the United
States is discarded), and recombinant haemoglobin.

Fluid therapy

Fluid therapy is based on an assessment of the water and electrolyte

deficiency and anticipated needs of the physiological fluid compartments.
Resuscitation of the intravascular space is the most important aspect of fluid
therapy in the hypovolaemic patient. The status of the intravascular space can
be assessed clinically using heart rate, blood pressure, urine output, CVP and
PAOP for guidance. The interstitial and intracellular fluid spaces are more
difficult to assess but remain in dynamic equilibrium with the intravascular
space. Serial body weight measurements offer an indicator of total body fluid
balance. Hidden losses (e.g., ileus, pleural effusion) will not be accounted for
by weight measurements.

In patients with continuing blood loss haemorrhage control must be achieved.

Thereafter, the goals of fluid resuscitation are to optimize oxygen delivery and
improve microcirculatory perfusion.

Crystalloids vs. colloids

A lack of quality outcome data to allow evidence-based decisions

over the choice of crystalloid or colloidal solutions tor
resuscitation has allowed a debate to simmer for many years.
Crystalloid containing isotonic concentrations of sodium or
colloids can be used to expand the intravascular space. Crystalloid
solutions are readily available, cheap, and associated with fewer
adverse reactions. However, a greater fluid and sodium load is
required to resuscitate a volume depleted intravascular space using
crystalloids than colloids. Crystalloids offer no oxygen carrying
capacity. Loss of more than 40% of the total blood volume is likely
to require replacement with red cells.

However, acute anaemia is far better tolerated than hypovolaemia.

Thus, initial resuscitation is achieved with non-blood solutions,
and, where appropriate, blood is given at a later stage. Patients with
SIRS are more likely to loose fluid from the intravascular space
through endothelial leakage (e.g., burns, sepsis, and critical illness).
Fluid resuscitation of such patients may be better achieved with
colloids than with crystalloid solutions although this remains
controversial. Crystalloids may worsen tissue oxygenation in such
patients, especially if leakage occurs into the lungs.

Fluid warming

All intravenous fluids given to critically ill patients

should be warmed. Hypothermia has a number of
adverse effects including: shifting the oxygendissociation curve to the left (impairing tissue oxygen
unloading), decreasing haemostatic function, increasing
oxygen demand and lactic acidosis if shivering is
induced, and increasing the chance of an adverse
cardiac event.


Improvements in the safety of the blood supply have

been achieved but cost has increased substantially.
All donors are screened carefully:
HIV 1 and 2 antibodies.
Hepatitis B surface antigen.
Hepatitis C antibody.
Syphilis serology.

Collection and storage

Approximately 430 ml of whole blood is collected into
a closed triple pack containing CPD-A (citrate,
phosphate, dextrose-adenine) anticoagulant. Platelets
and plasma are separated off and the remaining red
cells are resuspended in optimal additive [e.g., SAGM
(saline, adenine, glucose and mannitol)]. The shelf life
of SAGM blood is up to 42 days.

Continuing metabolic activity causes the following

biochemical and cellular changes (referred to as storage

Depletion of 2, 3 DPG, ATP, P042-, platelets and factors V and

Accumulation of CC)2, H+, activated clotting factors, denatured
and activated proteins, microaggregates of platelets, white cells
and fibrin.
The Hb-O2 dissociation curve is shifted to the right by acidosis
which is offset by the left shift due to reduced 2, 3 DPG and
The P50 is less than 18 mmHg after 1 week.
A reduction in red cell membrane integrity causes an increase in
extracellular K+, increased osmotic fragility, and an increase in
free haemoglobin.

Blood components
1. Blood. Fresh blood is less than 5 days old. It is rich in clotting factors
and platelets. It is inefficient to store blood as whole blood. Most
patients will require red cells only and the separation off of platelets and
plasma allows these products to be targeted at the needs of individual
patients. The shelf life of whole blood is shorter than packed cells. There
is more microaggregate formation and a higher risk of haemolysis and
GvHD because of larger amounts of plasma and white cells. Packed cells
have a haematocrit of 0.5-0.6.
Leukocyte depleted red cells are indicated in patients with a history of
non-haemolytic febrile transfusion reactions (NHFTR) which are due
usually to recipient antibody to donor white cells. Following theoretical
concerns about the transmission of prions in white cells, all donated
blood in the UK is now leukocyte depleted.
Frozen red cells are used for rare blood groups or autologous storage in
large amounts.

2. Platelets. One unit of platelet concentrate will increase the

platelet count by approximately 7 X 109 I-1.The shelf life is up to
7 days, but they need to be stored on a horizontal shaker. The
presence of some red cells can result in sensitization if ABO-Rh
incompatible platelets are transfused. This can cause Rhesus
sensitization in Rhesus negative females, low grade haemolysis
and a positive Coombs test.
3. Fresh frozen plasma. The fractionated volume of fresh frozen
plasma (FFP) is approximately 200 ml. It can be spun further
into cryoprecipitate and supernatant. FFP contains all the
clotting factors, and components of the fibrinolytic and complement systems.

Large volumes (4-8 units) are required to produce clinically

important increases in serum levels of clotting factors. It
carries infectious risks, and donor plasma antibodies can
cause haemolysis. There are methods of reducing the
infectious risk:

Photochemical inactivation with methylene blue is effective

against enveloped viruses (hepatitis B, hepatitis C and HIV) and
partially effective against non-enveloped viruses (hepatitis A,
parvoviruses). Approximately 7080% of clotting factor activity
is retained.
Detergent methods require pooling of at least 2000 1 and are not
effective against non-enveloped viruses. The factor retention is
Pasteurization also requires pooling but is more effective against
no enveloped viruses with 75-90% factor retention rate.

4. Cryopredpitate. Cryopreciptate is prepared from FFP.

It contains factor VIII (FVIIPC), fibrinogen, factor
XIII, von Willebrands factor and fibronectin. It is




particularly in DIC and massive transfusion.

Pre-operative autologous donation

In an attempt to avoid the hazards of homologous

transfusion, patients undergoing elective procedures that are
likely to require transfusion can pre-donate their own blood.

Collections can occur weekly for up to 4 weeks pre-surgery.

This autologous blood is subject to the same screening tests as
the homologous supply. The process is relatively expensive
because unused autologous blood cannot be returned to the
homologous blood bank. The risk of administrative errors is

the same as for homologous blood.

Peri-operative red cell salvage

Salvage techniques are used widely in trauma, cardiothoracic,

vascular and orthopaedic surgery. Post-operatively, cardiac

surgical patients can receive both retransfused pump blood

and blood from thoracic drains. lntraoperative cell saver blood
consists of washed red cells without platelets or clotting
factors. Problems with these techniques include traumatic
haemolysis, air emboli, microemboli, infusion of irrigants, and


Other plasma products

1. Albumin. Albumin is made by fractionation followed by heating to
600 for 10 hours to inactivate viruses. It is supplied as 45% or 20%
albumin solution, each with varying constituents. Albumin infusion
does not improve outcome in critically ill patients.
2. Factor VIII. The current sterilization processes for factor VIII are
thought to inactivate viruses completely. However, human factor VIII
exposes each recipient to 20000 donors. In the UK, the theoretical risk
of disease transmission has provoked legislation dictating the use of
genetically engineered product only in new haemophilia patients and
those under the age of 16. Recombinant factor VIII is derived from
genetically engineered Chinese hamster ovary cells. It is structurally
similar with the same biological activity to human AHF. It is indicated
for bleeding in patients with haemophilia A, but is not useful in von
Willebrands disease.

Blood transfusion
Causes of anaemia in the critically ill I
Compatibility testing
Complications of blood transfusions

1. Immediate immune reaction

Acute haemolytic transfusion reaction is usually due to an

ABO, Lewis, Kell or Duffy incompatible transfusion. IgM
complement mediated cytotoxicity or IgG mediated lvsis of
red cells results in liberation of anaphylotoxins, histamine,
and coagulation activation. There may be fevers, rigors, chest
pain, back pain, dyspnoea, headache, urticaria, cyanosis,
bronchospasm, pulmonary oedema, and cardiovascular
collapse. Acute renal failure

NHFTR account for 75% of all reactions (15% of all

transfusions) and are to recipient antibody to donor white
cell/platelet HLA antigens. Patients may require washed or
leukocyte depleted red cells subsequently.

Allergy is more common after whole blood or plasma

transfusions. The reaction is usually mild but can be severe
with hypotension, angioedema, bronchospasm, urticaria, and

Transfusion related acute lung injury.

2. Delayed immune reactions. Delayed haemolytic

transfusion reactions (4-14 days after transfusion) are
due to undetected antibody. They can be similar to
acute reactions but are generally more benign.
Alloimmunization to cellular or protein antigens is
common, and rarely affects the patient until the next
time they need a blood transfusion. GvHD is due to
donor lymphocytes in blood products that react
against host tissue. It is more likely in
immunocompromised individuals, or those with some
shared HLA antigens (family member donors).

3. Non-immune immediate reactions

The risk of microbial contamination of blood is related

directly to the length of storage. The most commonly
implicated organism is Yersinia enterocolitica but a
number of other organisms have been described.
There is considerable evidence that homologous
transfusion has an immunosuppressive effect and
increases the risk of infection that is independent of
bacterial contamination. Whether blood transfusion
increases the risk of recurrence of cancer is still

Volume overload is more likely with a normovolaemic

transfusion in the elderly and those with impaired
cardiac function.
Haemolysis due to red cell trauma, osmotic lysis and
senescent red cells can occur but is rarely of great
clinical significance.
Microaggregates of white cells, platelets and fibrin arc
associated with lung sequestration and ALT and the
potential for ARDS.

Massive transfusion (> 10 units or > 1 blood volume) may

cause coagulopathy, hypothermia, DIC, hyperkalaemia,
hypoalbuminaemia, and acidosis. The coagulopathy of
massive transfusion is multifactorial (deficiencies of factors
V and VIII and platelets, DIC, hypothermia). FFP and
platelets should be given empirically after 10 bags if non-

surgical bleeding is a problem and hypothermia has been


Metabolic abnormalities resulting from a storage lesion are

rarely a clinical problem except during rapid administration
or massive transfusion. It is more likely with older blood.

Hyperkalaemia, metabolic acidosis, and metabolic alkalosis

(citrate metabolism) may occur. Citrate toxicity, resulting in
hypocalcaemia, is exceedingly rare.

4. Non-immune delayed reactions

Viral infections. The current estimated infection risks
(per unit transfused) associated with voluntary donor
programmes are approximately: HIV 1:1000000,
hepatitis B 1:100000, hepatitis C 1:100000, CMV 1:2.
The risk of transmitting non-A, non-B, non-C hepatitis
is unknown.
Iron overload is a complication of multiple transfusions
over a long period of time. It results in haemosiderin
deposition with myocardial and hepatic damage.

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