Bongard Frederic , Darryl Sue. Diagnosis and Treatment Critical Care

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FLUIDS, ELECTROLYTES, & ACID-BASE

Therapy of these disorders should be aimed at identifying

the source of the aldosterone or other mineralocorticoid.

When the condition follows excessive administration of min-

eralocorticoids, their use should be stopped. If the patient

has excessive aldosterone secretion from an adrenal ade-

noma, medical management with an inhibitor of aldosterone

(eg, spironolactone) may play a role until more definitive

therapy can be planned.

Galla JH: Metabolic alkalosis. J Am Soc Nephrol 2000;11:369–75.

[PMID: 10665945]

Khanna A, Kurtzman NA: Metabolic alkalosis. J Nephrol 2006;19:

S86–96. [PMID: 16736446]



Respiratory Acidosis

ESSENTIALS OF DIAGNOSIS



Acidemia with increased Pa

and near-normal (acute)

or appropriately elevated [HCO

–

] (chronic).



Fatigue, weakness, confusion, and headaches.



If severe, lethargy, stupor, and coma.



Decreased cardiac contractility, pulmonary artery hyper-

tension, and splanchnic vasodilation.

General Considerations

Elevated Pa

(hypercapnia) with resulting acidemia is

termed respiratory acidosis. After going into solution, dis-

solved CO

turns into hydrogen ion and bicarbonate. The

major problem in acute hypercapnia is that dissolved CO

can rapidly produce tissue acidosis because CO

diffuses eas-

ily into tissues and cells. This is particularly important at the

blood-brain barrier, such that the pH of CSF falls rapidly

after an acute increase in Pa

Hypercapnia is usually attributed to lung disease, such as

COPD. However, hypercapnia can be produced either by an

increase in the production of CO

without compensatory

elimination or by constant production with decreased elimi-

nation. The second mechanism is usually seen in patients with

COPD or restrictive pulmonary disease, in those with a

severely deformed chest wall or neuromuscular weakness, after

trauma, and following anesthesia, where either the respiratory

mechanics or the drive for CO

elimination are compromised.

Increased CO

production is not uncommon because

output follows metabolic rate, and patients in the ICU

are frequently hypermetabolic. What is unusual, however, is

failure of the ventilatory control mechanisms to respond to

the increase in CO

production by stimulating ventilation

and maintaining Pa

at a constant value.

Common causes of respiratory acidosis among criti-

cally ill patients are listed in Table 2–19, and there is

additional discussion of hypercapnic respiratory failure in

Chapter 12.

An acute change in Pa

produces a blood pH change

within minutes. There is a small rise in plasma bicarbonate

concentration owing to acute “mass action” shifts. The pre-

dicted response of [HCO

–

] is an increase of approximately

0.25 meq/L for each 1 mm Hg increase in Pa

.More

marked changes in plasma bicarbonate concentration sug-

gest that a mixed acid-base disturbance is present.

Hypercapnia stimulates renal ammonia production and

increases urinary ammonium excretion because of an increase

in local Pa

and because of the fall in pH. Urine pH decreases

appropriately as newly generated bicarbonate is added to the

blood in exchange for acidifying the urine. An increase in bicar-

bonate absorptive capacity also occurs so that increased quanti-

ties of filtered bicarbonate can be reabsorbed completely. Once

equilibrium has been reached after several days, the plasma

bicarbonate concentration should increase by about 0.5 meq/L

for each 1 mm Hg increase in Pa

. Arterial pH actually may

become slightly alkalemic because of the avid retention of bicar-

bonate; this is one situation in which “complete”correction may

occur and may not represent a mixed acid-base disturbance.

Clinical Features

A. Symptoms and Signs—There are no symptoms or signs

specific to mild respiratory acidosis. Findings are usually

Acute Chronic

Airway obstruction

Emesis with aspiration

Bronchospasm

Laryngospasm

Airway obstruction

Chronic obstructive pulmonary

disease

Respiratory center depression

General anesthesia

Sedative or narcotic over-dose

Head injury

Respiratory center depression

Chronic sedative overdose

Obesity (Picwickian syndrome)

Brain tumor

Circulatory collapse

Cardiac arrest

Pulmonary edema

Neurogenic causes

Cervical spine injury

Guillain-Barré syndrome

Myasthenic crisis

Drugs (paralytic agents,

organophosphates)

Neurogenic causes

Multiple sclerosis

Muscular dystrophy

Amyotrophic lateral sclerosis

Myxedema

Posttraumatic diaphragmatic

paralysis

Phrenic nerve injury

Restrictive defects

Hemothorax or pneumothorax

Flail chest

ARDS

Restrictive defects

Hydrothorax or fibrothorax

Ascites

Obesity

Table 2–19. Causes of respiratory acidosis.



CHAPTER 2

related to the underlying cause, such as COPD, obesity-

hypoventilation syndrome, CNS disease, or severe hypothy-

roidism. When airway obstruction is the cause, patients may

present with shortness of breath and labored breathing. If

respiratory center depression is the cause, slow and shallow

or even apneustic breathing may be noted. As discussed in

Chapter 12, patients may have tachypnea or hyperpnea

(increased minute ventilation) despite hypercapnia (alveolar

hypoventilation).

In cases of marked respiratory acidosis, fatigue, weakness,

and confusion are present. In milder cases, patients may

complain of headache. Physical findings are nonspecific and

include tremor, asterixis, weakness, incoordination, cranial

nerve signs, papilledema, retinal hemorrhages, and pyram-

idal tract findings. The syndrome of pseudotumor cerebri

(increased CSF pressure and papilledema) may be simu-

lated by respiratory acidosis. Coma begins at levels of CO

that vary from 70–100 mm Hg depending on arterial pH

(pH <7.25) and the rate of increase of Pa

. It is critical to

remember that almost all patients with hypercapnia will have

concomitant hypoxemia unless they are receiving supple-

mental oxygen.

B. Laboratory Findings—Respiratory acidosis is manifested

by acidemia and elevated Pa

in the presence of an appro-

priate [HCO

–

] (see Figure 2–5). Because renal ammonia

production and hydrogen ion secretion are stimulated, urine

pH falls. In chronic respiratory acidosis, plasma pH may be

very close to normal as bicarbonate concentration rises in

compensation. A mild increase in potassium secretion

occurs, although hypokalemia is not inevitable.

Treatment

The key to management of respiratory acidosis is correction

of its primary cause (see Chapter 12). For some patients, this

will require endotracheal intubation and mechanical ventila-

tion or noninvasive positive-pressure ventilation.

Restoration of pH and Pa

should take place over sev-

eral hours if the respiratory acidosis is chronic to prevent

alkalemia. The compensatory increase in plasma bicarbonate

in response to hypercapnia may take hours to days to be

eliminated if the Pa

is immediately corrected to normal.

This results in a form of “metabolic alkalosis” that requires

renal elimination of bicarbonate to a normal value. In many

patients, overcorrection of chronic hypercapnia to normal is

not advised because these patients have poor lung or ventila-

tory function. When mechanical ventilation is removed, they

will be unable to maintain sufficient ventilation to keep the

at the lower level, resulting in recurrence of severe

acute respiratory acidosis.

In general, there is no role for respiratory stimulant drugs

except in a few circumstances. Administration of antagonists

to opiates or benzodiazepines may be helpful if respiratory

depression from these agents is suspected.

Current Controversies and Unresolved Issues

Acute hypercapnia and respiratory acidosis almost always

can be reversed effectively by increasing minute ventilation

until the underlying disorder can be treated (eg, COPD, neu-

romuscular weakness, etc.). It is now recognized that exces-

sively high tidal volume may be associated with damage to

the lungs, prolonged hospitalization, and increased mortal-

ity. Therefore, low tidal volume strategies are recommended

(see Chapter 12). The consequence is mild to moderate

hypercapnia in some of these patients. The bulk of the evi-

dence from large studies suggests that such hypercapnia is

well tolerated and rarely associated with complications. In

fact, some studies have suggested that hypercapnia is not

merely a consequence that must be tolerated but that it actu-

ally may be instrumental in improving outcomes of patients

with acute lung injury (eg, ARDS). For example, in ARDS, a

tidal volume of 6 mL/kg was associated with lower mortality

than 12 mL/kg. However, in the patients randomized to

12 mL/kg, the odds ratio for mortality was 0.14 in those who

were hypercapnic compared with those with a normal Pa

While there have been limited studies of the effects of

ameliorating the fall in pH during so-called permissive

hypercapnia, it remains to be seen if preventing the fall in pH

with bicarbonate or other buffers is beneficial, hazardous, or

neither. Nonbicarbonate buffers may be preferred to avoid

generation of additional CO

Kallet RH, Liu K, Tang J: Management of acidosis during lung-

protective ventilation in acute respiratory distress syndrome.

Respir Care Clin North Am 2003;9:437–56. [PMID: 14984065]

Kregenow DA et al: Hypercapnic acidosis and mortality in acute

lung injury. Crit Care Med 2006;34:1–7. [PMID: 16374149]

Laffey JG, Engelberts D, Kavanagh BP: Buffering hypercapnic aci-

dosis worsens acute lung injury. Am J Respir Crit Care Med

2000;161:141–6. [PMID: 10619811]



Respiratory Alkalosis

ESSENTIALS OF DIAGNOSIS



Alkalemia with decreased Pa

and normal or appro-

priately decreased [HCO

–



Anxiety, irritability, vertigo, and syncope.



Flattened ST segments or T waves.



Tetany in severe cases.

General Considerations

A primary decrease in arterial P

(hypocapnia) indicates

respiratory alkalosis. By definition, alveolar hyperventilation

is synonymous with hypocapnia. The most common causes

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FLUIDS, ELECTROLYTES, & ACID-BASE

of hyperventilation include hypoxemia, CNS disorders,

pulmonary disease, and excessive mechanical ventilation.

Patients who are anxious, pregnant, have liver failure, or are

toxic from salicylates often will hyperventilate. A few patients

seem to have primary hyperventilation of unknown mecha-

nism. In the ICU, hyperventilation may be an early feature of

sepsis. Hyperventilation resulting in respiratory alkalosis

must be distinguished from the low Pa

seen as compen-

sation for metabolic acidosis. In both, Pa

is reduced and

plasma HCO

–

is low. The difference is that in respiratory

alkalosis, low Pa

is primary and pH is above normal,

whereas in metabolic acidosis, pH is in the acidic range and

low HCO

–

is the primary disturbance.

The principal compensatory response for respiratory

alkalosis is renal elimination of bicarbonate, which takes sev-

eral hours to days to complete. Hypocapnia itself reduces

bicarbonate reabsorption from the proximal tubule, but

hydrogen ion secretion in the distal nephron is also

decreased, resulting in loss of tubular bicarbonate. Increased

delivery of bicarbonate from the proximal tubule stimulates

a marked kaliuresis. In the steady state, plasma bicarbonate

concentration falls by about 0.5 meq/L for each 1 mm Hg

decrease in Pa

during chronic respiratory alkalosis, and

there is a smaller decreased in plasma bicarbonate with acute

respiratory alkalosis. The arterial pH therefore is corrected

toward normal but not to normal.

Clinical Features

A. Symptoms and Signs—Severe hyperventilation may

result in tetany that is clinically indistinguishable from the

hypocalcemic variety except that total plasma calcium and

the ionized fraction of calcium are normal. Hyperventilation

also may decrease blood pressure and cerebral perfusion,

which can cause increased irritability, anxiety, and inability

to concentrate. Occasionally, awake patients will complain of

vertigo and experience syncope. Other features are those of

the underlying disorder leading to respiratory alkalosis.

Patients with severe damage to the midbrain may have cen-

tral neurogenic hyperventilation. Prolonged respiratory alka-

losis may have adverse effects on patients with head injury

despite transient reduction in intracranial pressure acutely

largely because of decreased oxygen delivery and unloading

in the brain. Interestingly, respiratory but not metabolic

alkalosis may impair fluid resorption from lungs with pul-

monary edema.

B. Laboratory Findings—The hallmark of respiratory alka-

losis is the presence of alkalemia (pH >7.44) and decreased

in the presence of normal or decreased HCO

–

.The

extent of plasma bicarbonate reduction depends on the

duration of the respiratory disorder and the effectiveness of

the kidneys. The nomogram in Figure 2–5 may aid in deter-

mining whether the respiratory alkalosis is occurring alone

or is a mixed disorder. Most patients with chronic respira-

tory alkalosis will have a decline in plasma bicarbonate of

0.5 meq/L for each 1 mm Hg decrease in Pa

. Mild

hyponatremia and hypochloremia often are present.

Hypophosphatemia owing to excess renal phosphate wasting

seems to be more marked with respiratory alkalosis than in

metabolic alkalosis.

For patients with central neurogenic hyperventilation,

evaluation may include CT scan or MRI of the head. Drug

ingestions (particularly salicylates) can be investigated with a

toxicology screen or blood salicyate determination.

Because hypoxemia appropriately may stimulate respira-

tory drive and cause respiratory alkalosis, the adequacy of

arterial oxygenation must be assessed.

C. Electrocardiography and Electroencephalography—

Electrocardiographic changes may include ST-segment or T-

wave flattening or inversion. Alterations in the QRS complex

also have been reported. Electroencephalographic studies are

usually normal but may show an increase in the number of

slow high-voltage waves.

Differential Diagnosis

The most important differential is metabolic acidosis with

respiratory compensation. As described earlier, in metabolic

acidosis, the blood pH is less than 7.38, whereas respiratory

alkalosis is associated with alkalemia. Mixed or combined dis-

turbances are often seen with respiratory alkalosis—notably

salicylate overdose, which may cause primary metabolic aci-

dosis and primary respiratory alkalosis simultaneously.

Treatment

A. Correction of Underlying Disorder—The key to treat-

ment is identification and management of underlying disor-

ders. If the patient is hypoxemic, the inspired oxygen

concentration may need to be increased. Anemia also may be

contributory and may be helped by blood transfusion. Other

potentially reversible causes include sepsis and liver failure.

Severe CNS disorders may cause respiratory alkalosis.

B. Mechanical Ventilation—Probably the most common

cause of respiratory alkalosis among critically ill patients is

iatrogenic hyperventilation owing to excessive mechanical

ventilation. Strict attention to blood gases and examination

of trends over several days usually will disclose this problem.

If the ventilator has been set to deliver too much minute ven-

tilation and the patient is not triggering, reducing the respi-

ratory rate and tidal volume will cause a marked and

predictable fall in pH. One reasonable goal is to reduce

minute ventilation just until the patient begins to trigger

spontaneous ventilation. At this point, pH is likely to be near

normal.

On the other hand, if the patient is already triggering the

mechanical ventilator, that is, choosing the respiratory rate,

then he or she is generating the primary drive for hyperventi-

lation. In most of these cases, changing the settings on the



CHAPTER 2

ventilator will not affect the patient’s spontaneous respiratory

rate. Hyperventilation sometimes can be moderated by

increasing paradoxically the inspiratory flow rate or tidal

volume.

Clinicians often opt for intermittent mandatory ventila-

tion to treat respiratory alkalosis; controlled trials have

shown that this is ineffective. Adding dead space to the ven-

tilator circuit tubing should not be done. In rare circum-

stances, severe respiratory alkalosis that cannot be managed

in any other way may require paralyzing the patient and con-

trolling the Pa

and pH.

Laffey JG, Kavanagh BP: Hypocapnia. N Engl J Med

2002;347:43–53. [PMID: 12097540]

Laffey JG, Kavanagh BP: Carbon dioxide and the critically ill: Too

little of a good thing? Lancet 1999;354:1283–6. [PMID:

10520649]

Myrianthefs PM et al: Hypocapnic but not metabolic alkalosis

impairs alveolar fluid reabsorption. Am J Respir Crit Care Med

2005;171:1267–71. [PMID: 15764729]

Wise RA, Polito AJ, Krishnan V: Respiratory physiologic changes in

pregnancy. Immunol Allergy Clin North Am 2006;26:1–12.

[PMID: 16443140]



The discovery of the ABO and Rh blood groups and the

development of nontoxic anticoagulant-preservative solu-

tions for blood storage during the first half of the 20th cen-

tury made it possible for human blood to be widely used as

lifesaving therapy in critically ill patients. Subsequent refine-

ments in cross-matching and the development of sophisti-

cated screening tests for transmissible diseases have made

blood transfusion a safe and often lifesaving form of therapy.

Because of the wide range of potential adverse effects of

transfusion therapy, however, the clinician must have a clear

understanding of the indications, efficacy, and complications

of blood component therapy.

BLOOD COMPONENTS

In modern transfusion practice, blood is separated into vari-

ous components (see Table 3–1), and individual components

are selected for transfusion based on the needs of the patient.

Blood component therapy is superior to whole blood

replacement because it concentrates those portions of blood

a patient needs, thereby increasing efficiency and minimizing

volume and subsequent transfusion requirements—as well

as increasing the efficiency of blood banking by putting

donated blood to maximal and optimal use.



Red Blood Cells

The products available for replacement of red blood cells are

listed in Table 3–1. Homologous packed red blood cells from

volunteer donors are transfused most often. Leukocyte-poor

red blood cells are prepared by a variety of techniques to

remove at least 70% of leukocytes. Washing red blood cells

in saline removes most plasma proteins and some leukocytes

and platelets. Red blood cells frozen in liquid nitrogen with

glycerol as a cryoprotective agent can be stored for up to

10 years. Extensive washing after thawing removes most

plasma proteins and cellular debris. Neocytes (young red blood

cells) can be prepared by differential centrifugation or cell

separators and have a longer circulating life span than stan-

dard red cells, but they are rarely used. Directed donations of

red blood cells from ABO- and Rh-compatible individuals

who are appropriately screened may be substituted for

homologous red blood cells at the patient’s request.

Autologous red blood cells may be collected preoperatively,

by perioperative blood salvage, or by acute normovolemic

hemodilution to decrease homologous red blood cell use.

Indications

Red blood cell transfusions are indicated to promote oxygen

delivery in patients who are actively bleeding, for sympto-

matic anemia unresponsive to conservative management, or

when time does not permit alternative treatment. Red blood

cell transfusions also may be useful for improving the bleed-

ing tendency of a severely anemic patient with platelet dys-

function (eg, uremia) or severe thrombocytopenia.

The decision to transfuse red blood cells should be made

only after consideration of several factors. The age and gen-

eral condition of the patient and the presence of coexisting

cardiac, pulmonary, or vascular conditions will influence the

patient’s ability to tolerate acute blood loss or chronic ane-

mia. The degree and chronicity of the anemia are also impor-

tant determinants of the physiologic responses to anemia.

Finally, the cause of the anemia must be considered because

alternative therapy (eg, iron sulfate, vitamin B

, folate, or

epoetin alfa [erythropoietin]) may eliminate the need for

transfusions altogether.

A. Chronic Hypoproliferative Anemia—Chronic anemia is

accompanied by several physiologic adaptations that enhance

oxygen delivery despite a reduced red blood cell oxygen-

carrying capacity. Increased cardiac output, increased

intravascular volume, and redistribution of blood flow to vital

organs maintain organ function. Tissue extraction of oxygen

occurs over a wide range of hemoglobin concentrations and is

Transfusion Therapy

Elizabeth D. Simmons, MD

Table 3–1. Blood component therapy.

enhanced by a rightward shift in the oxyhemoglobin dissoci-

ation curve (owing to increased erythrocyte 2,3-DPG produc-

tion and the Bohr effect). Additional responses to anemia

include increased erythropoietin production and early release

of young red blood cells into the circulation. These adaptive

responses allow most individuals to tolerate severe decreases

in oxygen-carrying capacity. Therefore, red blood cell transfu-

sions are rarely necessary for patients with chronic anemia

who have hemoglobin concentrations above 7 g/dL unless

significant cardiopulmonary disease is present, and transfu-

sions may result in circulatory overload if given rapidly or in

excessive quantity.



CHAPTER 3

Products Available Indications for Transfusion

Red Blood Cells (RBC)

Homologous packed RBC Promote oxygen delivery for patients with active bleeding or severe anemia; improve bleeding tendency in

severely anemic patients with platelet dysfunction; replace sickle RBC with normal RBC by exchange transfusion.

Leukocyte-poor RBC Reduce febrile reactions; prevent HLA alloimmunization and CMV infection in potential transplant recipients or

those requiring chronic platelet transfusions.

Irradiated RBC Reduce graft-versus-host disease.

Washed RBC Substitute for homologous RBC in patients sensitive to a plasma component; avoid transfusion of anti-A and

anti-B antibodies when O-negative blood is used in patients who are type A, B, or AB.

Frozen RBC Preserve autologous RBC; maintain store of rare blood types.

Neocytes Increase efficacy of individual transfusion for patients with transfusion-dependent anemia.

Directed donor RBC After screening and informed consent, may be substituted for volunteer RBC at patient request.

Autologous RBC Decrease or eliminate need for homologous RBC in patients undergoing elective surgical procedures or obstetric

delivery.

Platelets

Random donor platelets Treat or prevent bleeding associated with severe thrombocytopenia or platelet dysfunction; replace platelets

lost with massive bleeding; treat excessive bleeding associated with cardiopulmonary bypass.

Platelet pheresis Decrease exposure to infectious agents.

Leukocyte-poor platelets Reduce febrile reactions; reduce HLA alloimmunization for patients requiring chronic platelet transfusions.

Irradiated platelets Reduce graft-versus-host disease.

HLA-matched platelets Treat bleeding associated with thrombocytopenia in patients who are refractory to platelet transfusions due to

HLA sensitization.

Plasma and Derivatives

Fresh frozen plasma (FFP) Correct coagulation factor deficiencies in bleeding patients or those who require invasive procedures if

concentrated or recombinant product not available; treat TTP/HUS, protein-losing enteropathy in infants;

antithrombin III deficiency; C-1 esterase inhibitor deficiency.

Fresh plasma (liquid plasma) Same as FFP, except does not contain factors V and VIII.

Cryoprecipitate-poor plasma Correct coagulation factor deficiencies other than VIII, XIII, fibrinogen, vWF; may be indicated for treatment of

refractory TTP.

Cryoprecipitate Correct severe hypofibrinogenemia; may be useful for treatment of bleeding associated with uremia; provides

factors VIII and XIII, fibrinogen, and vWF.

Granulocytes

Stimulated leukapheresis Treat severe bacterial infections unresponsive to antibiotics in patients with prolonged, severe neutropenia or

congenital neutrophil dysfunction; may be indicated in the management of neonatal sepsis.



TRANSFUSION THERAPY

B. Acute Blood Loss—In contrast, physiologic responses

may be inadequate to maintain organ function and hemody-

namic stability following acute blood loss, even with appar-

ently normal hemoglobin concentration, because it takes time

for mobilization of extracellular fluid into the intravascular

space and for increased production of erythrocyte 2,3-DPG.

However, a healthy young person generally tolerates

500–1000 mL of acute blood loss without red blood cell

transfusion, and intravascular volume can be repleted with

crystalloid solutions. Acute blood loss of 1000–2000 mL usu-

ally can be managed with volume replacement alone, but red

blood cell transfusions are necessary occasionally. More than

2 L of acute blood loss usually will require red blood cell

transfusion. Other clinical factors are important. For exam-

ple, because of the vasodilatory effects of anesthesia, intraop-

erative blood loss of more than 500 mL may require red blood

cell transfusion to maintain hemodynamic stability, and burn

patients often require vigorous blood product support

because of volume depletion through denuded body surfaces.

C. High-Risk Patients—Any condition that impairs the

patient’s ability to increase intravascular volume, heart rate,

stroke volume, or blood flow can result in poor tolerance of

chronic anemia or acute blood loss (eg, patients with cardio-

vascular disease, volume depletion from diuretics or gas-

trointestinal losses, vascular fluid redistribution, and elderly

patients). In these circumstances, transfusion may be neces-

sary in patients with physiologic signs of inadequate oxy-

genation despite higher hemoglobin concentrations than in

normal individuals with adequate physiologic reserves. The

use of objective scoring systems (such as the APACHE II

[Acute Physiology and Chronic Health Evaluation II] and the

multiorgan dysfunction scores) to stratify patients according

to severity of illness may be useful for determining which

critically ill patients may benefit from a restrictive transfu-

sion approach.

Studies have demonstrated that patients younger than

55 years of age with less severe illness may have improved

outcomes using a lower hemoglobin threshold (<7 g/dL) for

transfusion compared with more liberal use of transfusion

(<10 g/dL). This lower threshold for transfusion appears to

be at least as safe in older patients and those with more severe

disease as well.

Exceptions include those with acute bleeding (discussed

earlier) or myocardial ischemia. Although baseline anemia in

patients with acute myocardial infarction is associated with

adverse outcomes, including increased mortality, there is no

clear evidence that a liberal blood transfusion strategy (ie,

hemoglobin <10 g/dL as a trigger for transfusion) improves

outcomes. Available clinical data are inadequate to make a

firm recommendation regarding the hemoglobin threshold

for transfusion for these patients; therefore, decisions about

red blood cell transfusions must be individualized.

D. Hemolytic Anemia—Red blood cell transfusions are

indicated in the management of some patients with a variety

of severe and symptomatic hemolytic anemias. Patients with

markedly symptomatic antibody-mediated hemolytic ane-

mias may require red blood cell transfusion until definitive

therapy is effective. Autoantibodies are often reactive with all

donor red blood cells in vitro such that cross-matching is

impossible. Transfusion of ABO- and Rh-compatible red

blood cells is usually safe in these patients; the blood bank

can perform an extended cross-match to identify units with

the least degree of in vitro hemolysis. Patients with cold-

reacting antibodies (usually IgM) should receive blood

through a blood warmer if transfusion is necessary.

E. Sickle Cell Anemia—Patients with sickle cell anemia may

require red blood cell transfusion (and, in selected cases, par-

tial or complete exchange transfusion) for management of

specific complications, including splenic sequestration and

aplastic crises (with rapidly falling hemoglobin concentra-

tion), recurrent priapism, chronic unremitting osteomyelitis,

severe leg ulcers, pneumonia, or pulmonary sequestration

crises. Red blood cell transfusion is also indicated for such

patients undergoing major surgery, particularly those under-

going orthopedic procedures. Simple preoperative transfu-

sion to achieve hematocrit levels of about 30% appears to be

as effective as regimens aimed at reducing the fraction of

hemoglobin S to 30% of total hemoglobin (by exchange

transfusion or multiple transfusions over time) and is associ-

ated with fewer transfusion-related complications. Patients

with sickle cell anemia are not candidates for autologous

donation and transfusion.

Exchange transfusion is also indicated in the manage-

ment of acute central nervous system infarction or hemor-

rhage (followed by chronic transfusion therapy to prevent

recurrent strokes). Chronic prophylactic transfusion reduces

the risk of initial stroke in children with sickle cell disease

who have abnormal cerebrovascular blood flow on Doppler

ultrasonography; however, alloimmunization (even with

phenotypically matched, leukocyte-depleted red blood cells),

iron overload, and infections complicating chronic transfu-

sion programs have limited the acceptance of this approach.

Furthermore, the duration of transfusion required to prevent

stroke is unclear. Recent studies demonstrate that the risk of

stroke increases once chronic transfusions are stopped.

Routine transfusion during pregnancy should be avoided.

Patients with severe, symptomatic sickle cell anemia or those

suffering recurrent painful crises may require periodic trans-

fusion during pregnancy. Likewise, routine transfusion is not

indicated in the management of painful vaso-occlusive sickle

cell crises and should be reserved for patients with sympto-

matic anemia. Patients with sickle cell anemia appear to be

unusually susceptible to the development of alloantibodies

(see “Complications of Transfusion”), which limits the utility

of chronic transfusion programs. The use of blood from

racially matched donors that has been screened for selected

minor blood group antigens may prevent alloimmunization

in patients requiring chronic transfusion therapy, but this

approach awaits confirmation.



CHAPTER 3

F. Perioperative Transfusion—Transfusion is rarely indi-

cated for patients undergoing noncardiac surgery who have

hemoglobin values greater than 7–8 g/dL and no risk factors

for myocardial ischemia. However, elderly patients with hema-

tocrits less than 28% (hemoglobin of approximately 9 g/dL)

may be at risk for myocardial ischemia during surgery, espe-

cially if tachycardia is present. In these patients—and others at

risk for myocardial ischemia—a hemoglobin value of less than

10 g/dL probably warrants transfusion. The threshold for

intraoperative transfusion depends on many factors, such as

the presence of hemorrhage or coagulopathy, hemodynamic

instability, and ischemic electrocardiographic changes.

G. Unacceptable Indications—Red blood cell transfusions

should not be used to enhance a patient’s general sense of

well-being, to promote wound healing, or to expand vascular

volume when oxygen-carrying capacity is adequate.



Red Blood Cell Transfusion Requirements

There is no single hemoglobin threshold that is universally

appropriate for determining transfusion requirements. The

amount of red blood cells to be transfused should be deter-

mined by the clinical status of the patient rather than by the

hemoglobin concentration. In patients who are actively

bleeding, crystalloid volume repletion is essential.

Hemodynamic instability, symptoms and signs of impaired

organ function, rate of blood loss, and response to transfu-

sion should be used to determine how much blood should be

transfused. Patients with chronic anemia should receive only

the amount of red blood cells necessary to reverse symptoms

and signs. Patients with self-limited anemia (eg, transient

blood loss, hemolysis, or marrow suppression) or those for

whom alternative therapy is available (eg, nutritional defi-

ciencies, anemia of renal failure) should receive red blood

cells only when an immediate need for increased oxygen-

carrying capacity is present, such as during myocardial

ischemia, heart failure, impaired central nervous system oxy-

genation, hypotension, or other evidence of tissue hypoxia.

The patient should be reevaluated after each unit of red

blood cells is transfused rather than giving an arbitrary or

predetermined number of units. Volume overload following

red blood cell transfusion in patients with chronic severe

anemia may eliminate any benefit of increasing the oxygen-

carrying capacity and must be monitored carefully.

When untreatable chronic anemia is present (eg, bone

marrow failure or chronic severe hemolytic anemia), red

blood cell transfusions must be given conservatively to delay

long-term treatment complications such as alloimmuniza-

tion, infections, and iron overload. Red blood cell transfu-

sions may be administered more liberally in the treatment of

anemia associated with severe thrombocytopenia or platelet

dysfunction (eg, acute leukemia or uremic bleeding

episodes) because the salutary effect of increased hematocrit

on platelet function may decrease platelet transfusion

requirements and lessen clinical bleeding.



Platelets

Platelet products available are listed in Table 3–1. The choice

of platelet product depends on the underlying condition of

the patient (eg, acute reversible thrombocytopenia versus

chronic thrombocytopenia) as well as the local availability of

supplies. Pooled random-donor platelets or single-donor

platelets obtained by apheresis are the usual products trans-

fused for correction of severe thrombocytopenia. Filtration

or irradiation with ultraviolet B depletes donor platelets of

leukocytes, and these are equally effective strategies for pre-

venting alloantibody-mediated refractoriness to platelet

transfusions. Such leukodepletion is appropriate for patients

likely to require repeated platelet transfusions (eg, acute

leukemia, aplastic anemia, and other bone marrow failure

states). Leukocyte depletion performed shortly after collec-

tion of platelets also may decrease the risk of febrile reactions

by preventing in vitro accumulation of cytokines, which are

released during storage. Single-donor platelets decrease the

total number of donor exposures and may reduce the risk of

transfusion-transmitted infections but do not appear to offer

additional benefit over filtration or irradiation for preven-

tion of alloimmunization.

Product availability often will determine whether pooled

platelets or single-donor platelets are transfused. Whenever

possible, ABO type–specific platelets should be used; how-

ever, because platelets have a limited storage period, they are

not always available. A decreased response to platelet trans-

fusion may result from the use of ABO-incompatible

platelets, but the most significant risk occurs when ABO-

incompatible plasma is infused (ie, type O donor, type A or

B recipient), resulting in hemolysis (estimated risk

1:9000–1:6600). Apheresis units may increase this risk by

increasing the dose of incompatible plasma. If type-specific

platelets are not available, pooled platelets are preferable to

single-donor platelets. Washing the platelets to remove

plasma may help to minimize exposure to incompatible

plasma. Although platelets do not carry Rh antigens, platelets

from Rh-negative donors should be used for transfusion in

Rh-negative women of childbearing years to prevent sensiti-

zation from contaminating red blood cells.

Indications

Platelet transfusions are indicated for treatment of bleeding

associated with thrombocytopenia or intrinsic platelet dys-

function. Platelet transfusions are also indicated in the man-

agement of massive bleeding if severe thrombocytopenia

develops. Patients undergoing cardiopulmonary bypass may

require platelet transfusions if excessive bleeding occurs

because of thrombocytopenia and decreased platelet function

induced by the bypass procedure. Other surgical procedures

in thrombocytopenic patients generally require prophylactic

platelet transfusions to maintain adequate perioperative

platelet counts for at least 3 days (>50,000/μL for major pro-

cedures; >30,000/μL for minor procedures). Prophylactic



TRANSFUSION THERAPY

platelet transfusions are also indicated for severely thrombo-

cytopenic (eg, <10,000/μL platelets) patients undergoing

intensive chemotherapy for acute leukemia; the threshold for

transfusion may be higher in the presence of fever, infection,

or drugs that cause platelet dysfunction.

Factors that determine the risk of serious bleeding owing

to thrombocytopenia include the cause and severity of

thrombocytopenia, the presence of vascular defects, the

functional status of the patient’s platelets, and the presence of

other hemostatic defects. Severe anemia also may contribute

to bleeding in patients with thrombocytopenia or platelet

dysfunction. Because of the increased functional capacity of

younger platelets in patients with decreased platelet survival,

decreased production of platelets carries a higher risk of seri-

ous bleeding at any given platelet count than thrombocy-

topenia owing to destruction, consumption, or hypersplenism.

Typical bleeding manifestations related to the level of throm-

bocytopenia are shown in Table 17–8. If bleeding is out of

proportion to a given platelet count, other contributing factors

to bleeding should be investigated.

The risk of bleeding in patients with disorders of platelet

function likewise depends on the cause and severity of the dis-

order and whether vascular defects, other hemostatic abnor-

malities, or severe anemia is present. Bleeding time is the most

widely used test of platelet function, and although it is useful in

the diagnosis of certain disorders (eg, von Willebrand’s disease,

hereditary platelet disorders), prolonged bleeding time in the

absence of a history of bleeding is not a reliable predictor of

subsequent bleeding. A prolonged bleeding time in the absence

of thrombocytopenia or severe anemia in a bleeding patient,

however, may indicate the presence of platelet dysfunction.

The efficacy of platelet transfusions can be assessed by

observing a sustained rise in platelet count in a patient who

has stopped bleeding. Patients with thrombocytopenia

owing to decreased production of platelets are most likely to

experience a significant, sustained increase in platelet count

following platelet transfusion. Patients with increased

destruction of platelets and those who have hypersplenism

usually do not achieve a significant increase in platelet count

after transfusion, and any increase that occurs is usually tran-

sient. Similarly, patients with massive platelet consumption

owing to bleeding will have a suboptimal increase in platelet

count following transfusion. Hemorrhage owing to platelet

dysfunction can be controlled with platelet transfusions only

if the defect is intrinsic to the platelet (eg, aspirin ingestion,

cardiopulmonary bypass, inherited platelet disorders) rather

than extrinsic (eg, von Willebrand’s disease or uremia).

Platelet transfusions are minimally useful in the treatment

of thrombocytopenia owing to decreased platelet survival and

should not be given unless severe life-threatening bleeding

occurs. Platelet transfusions may be harmful in patients with

thrombotic thrombocytopenic purpura–hemolytic uremic

syndrome (TTP-HUS) despite the presence of thrombocy-

topenia, presumably owing to accelerated thrombosis in vital

organs. Because platelet survival is short in this disorder,

platelet transfusions usually are ineffective in controlling

hemorrhage. The diagnosis of TTP-HUS should be suspected

in a patient with severe thrombocytopenia and hemolysis with

schistocytes on peripheral blood smear (microangiopathic

hemolytic anemia) with or without associated central nervous

system dysfunction, renal dysfunction, or fever. Patients with

heparin-associated thrombocytopenia also may suffer

increased thrombotic complications if platelets are transfused.

Platelet transfusions should be administered to these patients

only when the risk of death from bleeding outweighs the

potential risk of clinical deterioration from transfusion.

Platelet Transfusion Requirements

The quantity of platelets to be transfused depends on the

source of the platelets, the cause and degree of thrombocytope-

nia, and the observed response to transfusions. The usual ini-

tial amount transfused is 6–8 units of random-donor platelets

or 1 unit of single-donor apheresis product. Platelet packs

should contain a minimum of 5.5 × 10

platelets per unit.

The response to platelet transfusions should be deter-

mined by obtaining a platelet count 1 hour after transfusion

and daily thereafter and by observing the effect on control of

bleeding. The 1-hour count should increase by about

5000–10,000 per unit of random-donor platelets or

30,000–50,000 per unit of single-donor platelets. Stored

homologous platelets survive about 3 days in thrombocy-

topenic patients. The 1-hour count and subsequent platelet

survival will be reduced in patients with increased destruc-

tion or hypersplenism. These measurements will help to

determine the magnitude of the benefit to be expected from

subsequent transfusions. If only a minimal response occurs,

or if the platelet rise is short-lived, subsequent prophylactic

transfusions should be withheld. However, in patients with

severe thrombocytopenia owing to destruction or hyper-

splenism who have serious bleeding, platelet transfusions

may be warranted. In any patient, if clinical bleeding does

not improve despite platelet transfusion, other causes of

bleeding should be evaluated and the utility of subsequent

platelet transfusions in such patients reassessed.

The underlying cause of thrombocytopenia or platelet

dysfunction should be determined so that specific therapy

to reverse the process can be given if available. Alternatives

to platelet transfusions in bleeding patients with thrombo-

cytopenia or platelet dysfunction are set forth in Table 3–2.



Plasma

Plasma products available are listed in Table 3–1. Fresh

frozen plasma (FFP) is prepared by separating plasma from

red blood cells (after collection of whole blood or during

plasmapheresis) and freezing it within 6 hours after collec-

tion at –18°C or colder. It can be stored for up to 1 year and

is thawed over 20–30 minutes prior to administration.

Activities of coagulation factors are adequate for 24 hours

after thawing. Fresh plasma and plasma recovered from out-

dated blood products are used for preparation of plasma

derivatives (eg, immunoglobulin, cryoprecipitate, albumin,

coagulation factor concentrates). Fresh plasma may be used

as an alternative to FFP for replacement of coagulation fac-

tors other than factors VIII and V.

Cryoprecipitate-poor plasma is the supernatant plasma

remaining after preparation of cryoprecipitate and contains

adequate quantities of all coagulation factors except fibrino-

gen, factors VIII and XIII, and von Willebrand factor.

Solvent-detergent treatment of plasma (S/D plasma) inac-

tivates lipid-enveloped viruses and has been licensed

recently by the Food and Drug Administration (FDA) to

minimize the risk of transfusion-transmitted infections

and allergic reactions in the management of coagulopathies

and thrombotic thrombocytopenic purpura (TTP). The

highest-molecular-weight von Willebrand factor multimers

are reduced in S/D plasma, enhancing its efficacy in the

treatment of TTP, but protein S and plasmin inhibitor levels

are also variably reduced, potentially causing venous throm-

boembolism (low protein S) or excessive bleeding (low plas-

min inhibitor). Numerous other derivatives of plasma are

now available; Table 3–3 outlines some of these products and

their therapeutic uses.

Alternative Possible Indications

High-dose IgG Life-threatening bleeding in immune-

mediated thrombocytopenia (ITP).

Anti-D immune

globulin

Treatment of bleeding in ITP in Rh-positive

patients.

Desmopressin

(DDAVP)

Bleeding associated with platelet dysfunction,

uremia, von Willebrand’s disease.

Antifibrinolytic agents

(eg, aminocaproic

acid)

Excessive bleeding without evidence of throm-

botic diathesis or hematuria.

Estrogens Bleeding associated with uremic platelet

dysfunction.

Red cell transfusions Severe anemia associated with thrombocy-

topenia or platelet dysfunction.

Erythropoietin Bleeding in anemic, uremic patients.

Corticosteroids ITP, possibly thrombotic thrombocytopenic

purpura-hemolytic uremic syndrome (TTP-HUS).

Splenectomy Refractory ITP, severe hypersplenism,

possibly TTP.

Immunosuppressives,

chemotherapy,

danazol, vinca

alkaloids, interferon

alpha, protein-A

immunoadsorption,

rituximab

Refractory ITP.

Plasma infusion or

exchange

TTP-HUS.

Table 3–2. Alternatives to platelet transfusions.

Table 3–3. Therapeutic products derived from plasma.

Plasma Derivative Therapeutic Use

Fibrin glue (human fibrinogen

combined with bovine

thrombin)

Prevent surgical oozing with

topical use

Albumin (heat-treated) Hypoalbuminemia in nephrotic

syndrome

Plasma-derived factor VIII

concentrate

Hemophilia A*

Humate-P von Willebrand’s disease

Prothrombin complex concentrate Coagulation inhibitors, factor X

and prothrombin deficiencies

Activated factor IX concentrates

(Autoplex, FEIBA)

Factor VIII inhibitors

Plasma-derived factor IX

concentrate

Hemophilia B*

Fibrinogen concentrate Hypofibrinogenemia

Factor VII concentrate Factor VII deficiency

Factor XI concentrate Factor XI deficiency

Factor XIII concentrate Factor XIII deficiency

Antithrombin III concentrate Thrombosis in antithrombin III

deficiency

C1 esterase inhibitor concentrate Angioedema

-Antitrypsin concentrate Prevent lung damage in

-antitrypsin deficiency

Protein C and S concentrate Severe protein C or S deficiency

Intravenous immunoglobulin Immunodeficiency states; immune

cytopenias, Kawasaki syndrome,

Guillain-Barré syndrome,

dermatomyositis

Immune serum globulin Passive immunization against hep-

atitis A, measles, poliomyelitis,

varicella, rubella

*Recombinant products are available as an alternative to plasma-

derived product; see Chapter 17.



CHAPTER 3